Patent Publication Number: US-2003228675-A1

Title: ATM related kinase ATX, nucleic acids encoding same and methods of use

Description:
[0001] This invention was made with government support under grant number CA76193 awarded by the National Institutes of Health. The United States Government has certain rights in this invention. 
    
    
     
       BACKGROUND OF THE INVENTION  
       [0002] This invention relates generally to the fields of molecular biology and molecular medicine and more specifically to the identification of phosphoinositide 3-kinase related kinases (PIKKS) involved in cell cycle control and mRNA surveillance pathways.  
       [0003] The mitotic cell cycle is the process by which a cell creates an exact copy of its chromosomes and then segregates each copy into two cells. The sequence of events of the cell cycle is regulated such that cell division does not occur until the cell has completed accurate DNA replication. To ensure that cells pass accurate copies of their genomes on to the next generation, evolution has overlaid the core cell cycle machinery with a series of surveillance pathways termed cell cycle checkpoints. The overall function of these checkpoints is to detect damaged or abnormally structured DNA, and to coordinate cell cycle progression with DNA repair.  
       [0004] Members of the phosphoinositide 3-kinase related kinases (PIKK) family of kinases are involved in cell cycle checkpoints and DNA damage repair. The PIKK family members identified to date express a carboxylterminal domain that displays significant sequence homology to the catalytic domains of phosphoinositide (PI) 3-kinases. Indeed, many, but not all of the PIKKs have been shown to possess protein serine-threonine kinase activities (McMahon et al.,  Cell  94:363-374 (1998); Vassilev et al.,  Cell  2:869-875 (1998); Grant et al.,  Cell  2:863-867 (1998); Hunter,  Cell  83:1-4 (1995); Tibbetts and Abraham,  Signaling Networks and Cell Cycle: Themolecular Basis of Cancer and Other Diseases  pp. 267-301 (2000)). In mammalian cells, three PIKK family members, ATM, ATR, and DNA-dependent protein kinase (DNA-PK), serve as proximal signal transducers in cell-cycle checkpoint and DNA repair pathways (Abraham,  Genes  &amp;  Dev.  15:2177-2196 (2001); Durocher and Jackson,  Curr. Opin. Cell Biol.  13:2225-231 (2001)). The critical roles of ATM in orchestrating cellular responses to various forms of stress are underscored by the diverse pathologies associated with the hereditary disorder, ataxiatelangiectasia (A-T) (Crawford,  Seminarsin Ped. Neuro.  5:287-294 (1998); Rotman and Shiloh,  Human Mol. Gen.  7:1555-1563 (1998); Rotman and Shiloh,  Oncogene  18:6135-6144 (1999)). A-T patients lack functional ATM and develop symptoms including extreme sensitivity to irradiation, cerebellar degeneration, oculocutaneous telangiectasias, gonadal deficiencies, immunodeficiencies, and increased risk of cancer (Lehman and Carr,  Trends in Genet.  11:375-377 (1995)). Fibroblasts derived from these patients show defects in cell cycle checkpoints and are defective in their response to irradiation (Painter and Young,  Proc. Natl. Acad. Sci.  (USA) 77:7315-7317 (1980)).  
       [0005] In general, the proteins in the PIKK family of kinases play important roles in mRNA surveillance and cell cycle progression in order to insure genetic integrity from generation to generation. Compounds that modulate PIKK polypeptides can result in altered progression through the cell cycle leading to increased or decreased cell survival. For example, a PIKK-modulatory compound can make a cell more or less susceptible to cell death in the presence of radiation or a cytotoxic agent.  
       [0006] All cancer cells have a dysfunctional cell cycle and continue through the cell cycle in an inappropriate manner, either by failing to respond to negative growth signals or by failing to die in response to the appropriate signal. In addition, most cancer cells lack genomic integrity and often have an increased chromosome count compared to normal cells. Therefore, compounds that inhibit cell cycle checkpoints or DNA damage repair, in combination with the cytotoxic agents, can cause cancer cell death by forcing cancer cells to progress through the cell cycle in the presence of DNA damaging agents such that they undergo events that lead to cell death.  
       [0007] Thus, there exists a need to identify additional members of the PIKK family of kinases and compounds that modulate these kinases. The present invention satisfies this need and provides related advantages as well.  
       SUMMARY OF THE INVENTION  
       [0008] The invention provides an isolated nucleic acid molecule having substantially the same nucleotide sequence as SEQ ID NO:1. Also provided is an isolated oligonucleotide having at least 15 contiguous nucleotides of a nucleotide sequence referenced as SEQ ID NO:11. An isolated polypeptide having substantially the same amino acid sequence as SEQ ID NO:2 is further provided as well as an antibody, or antigen binding fragment thereof, which specifically binds to an ATX polypeptide and has an amino acid sequence as referenced in SEQ ID NO:2. A method for identifying an ATX-modulatory compound is additionally provided. The method consists of measuring the level of an ATX polypeptide in the presence of a test compound, wherein a difference in the level of said ATX polypeptide in the presence of said test compound compared to in the absence of said test compound indicating that said test compound is an ATX-modulatory compound, and wherein said ATX-modulatory compound is not caffeine or wortmannin. 
     
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
     [0009]FIG. 1A shows the genomic structure of the ATX locus along with clones isolated to date. The black diamonds denote the locations of translational stop codons and black bars indicate open reading frames that give rise to various ATX polypeptides. The lines and symbols below exon 15 indicate an allelic variant that contains a 27 bp insertion having two in-frame stop codons. FIG. 1B shows the location of N-terminal homology 1 (NH1), NH2, PI3-K catalytic (PI3-Kc), PKC-λ/L-interacting protein (LIP), and FAT-C (C) domains. The numbers shown indicate identity/similarity and shading highlights amino acid identity with ATX. A sequence alignment of the PI 3-Kc domains of ATX, CeSMG-1, mTOR, and ATM is shown. FIG. 1C shows immune complex kinase assays with GST-p53 1-70 , GST-p53 1-70  (S15A), or with GSThUpf11019-1118 as substrates. The reaction products were immunoblotted with α-HA (lower panel). FIG. 1D shows immune complex assays with cells or α-HA-ATX immunoprecipitates treated with wortmannin.  
     [0010]FIG. 2A shows clonogenic survival assays after UV exposure. FIG. 2B shows clonogenic survival assays after IR exposure. The upper panel displays colony outgrowth results from cells transfected with the indicated plasmids, and not exposed to IR. FIG. 2C shows clonogenic survival assays of cells treated with ATX-directed antisense oligonucleotides (AS). The right panel displays colony survival results from non-irradiated cells treated with the indicated oligonucleotides.  
     [0011]FIG. 3A shows whole cell extracts resolved by SDS-PAGE and sequentially immunblotted with the indicated antibodies. FIG. 3B shows extracts of transfected cells separated by SDS-PAGE and sequentially immunoblotted with the indicated antibodies. The p53 phosphoserine-15 specific antibody is designated α-pSer15. FIG. 3C shows extracts of cells treated with S or AS oligonucleotides and analyzed as described in panel A. FIG. 3D shows cell cycle progression in AS-transfected cells examined by flow cytometry. The table shows the percentages of cells in each cell cycle phase. The right panel shows immunoblot analyses from the same cell population. FIG. 3E shows an effect of caffeine on AS-induced cell cycle defects. The table shows percentages of cells in each cell-cycle phase, plus the ratio of G2/M to G1 cells for each sample. The right panel shows immunoblotting results from the same cell populations.  
     [0012]FIG. 4A shows an effect of ATX overexpression on basal viability. Cell densities of the scanned images from each sample were obtained with the ImagePro Plus software program. FIG. 4B shows an effect of ATX overexpression on radiosensitivity. Surviving cells were quantitated as described in panel except that arbitrary unit values for each group were normalized to the corresponding nonirradiated control.  
     [0013]FIG. 5A shows cells transfected with GAL4 or GAL4-hUpf11019-1118 expression constructs with the indicated samples treated with wortmannin. The right panel shows phosphatase treatment. The soluble proteins were separated by SDS-PAGE and immunoblotted with α-GAL4 mAb. The arrow indicates the uppermost band of the phosphorylated GAL4-hUpf11019-1118 reporter protein. FIG. 5B shows an effect of ATMKI or ATXKI expression on UV stimulation of GAL4-hUpf1 phosphorylation.  
     [0014]FIG. 6A shows an effect of HA-ATXKI or HAATMKI expression on NMD. Nuclear RNA was isolated from transfected cells and β-globin and MUP mRNAs were quantitated by RT-PCR and PhosphorImaging. For each pair of transfections, the level of Globin mRNA was normalized to the level of MUP mRNA and expressed below each lane as a percentage of the normalized level of Globin Norm mRNA, which was defined as 100. FIG. 6B shows an effect of ATX AS oligonucleotide on NMD.  
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
     [0015] This invention is directed to isolated ATX nucleic acids and polypeptides. ATX is a novel PIKK kinase family member that participates in stress-induced p53 and cell cycle checkpoint activation in cells exposed to DNA damaging agents. In addition, ATX can activate the intrinsic non-sense mediated mRNA decay (NMD) pathway in these cells. The invention is also directed to methods of identifying ATX-modulatory compounds and using these compounds to modulate cell survival. Compounds that modulate cellular survival can be useful in the treatment of diseases characterized by excessive cell growth or excessive cell death.  
     [0016] In one embodiment, an expressed sequence tag (EST) with homology to a conserved region in the catalytic domains of PIKK family members was used to isolate a full-length cDNA encoding a novel member of the PIKK family, termed ATX. The ATX polypeptide was detected in both the nucleus and cytoplasm of human cells, and formed nuclear foci upon exposure to UV light. In addition, the cell cycle regulatory proteins p53 and hUpf1 were found to be phosphorylated by ATX. Furthermore, the reduction of endogenous ATX in a cell using anti-sense oligonucleotides resulted in decreased survival of cells, and decreased phosphorylation and stabilization of p53 in cells exposed to UV light. Similar to other PIKK family members, ATX activity was inhibited by wortmannin and caffeine.  
     [0017] As used herein, the term “ATX polypeptide” refers to a polypeptide with substantially the same amino acid sequence as that shown in SEQ ID NO:2 (human ATX). “Substantially the same amino acid sequence” is intended to mean an amino acid sequence contains a considerable degree of sequence identity or similarity, such as at least 70%, 80%, 90%, 95%, 98%, or 100% sequence identity or similarity, to a reference amino acid sequence. Substantially the same amino acid sequence includes conservative and non-conservative amino acid changes, gaps, and insertions to an amino acid sequence. Conservative and non-conservative amino acid changes, gaps, and insertions to an amino acid sequence can be compared to a reference sequence using available algorithms and programs such as the Smith-Waterman algorithm and the BLAST homology search program (Altschul et al.,  J. Mol. Biol.  215:403-410 (1990)).  
     [0018] It is understood that a fragment of ATX can be sufficient in order to produce an ATX activity. Activities associated with ATX include, for example, kinase activity, cell cycle checkpoint activity, and NMD activity. For example, fragments of ATX which retain substantially an activity of the entire polypeptide are included within the definition. Fragments can include, for example, amino terminal, carboxyl terminal, or internal deletions of a full length ATX polypeptide. In addition, fragments can include domains of a full length ATX polypeptide, such as for example, a kinase domain, NH1 domain, NH2 domain, or LIP domain. A fragment can contain, for example, at least about 10, 100, 500, 1,000, 1,500, 2,000, 2,500, 3,000, 3,500 or more contiguous or non-contiguous amino acid residues of a full-length ATX polypeptide. ATX polypeptide fragments include the fragments described above, but excludes fragments KIAA0421 (Accession number AB007881), KIAA0220 (Accession number D86974), and LIP (Accession number U32581), which are present in databases. Polypeptide fragments can be generated using a variety of methods. For example, polypeptide fragments can be generated using recombinant DNA methods, enzymatic cleavage, or chemical cleavage of larger polypeptides.  
     [0019] It is understood that limited modifications to the ATX polypeptide can be made without destroying an activity of ATX. For example, ATX is intended to include other ATX family members such as those polypeptides that are found to exhibit the above sequence homologies. Such members include, for example, homologs of ATX that can be cloned from other organisms such as monkeys, cows, rats, mice, chickens, frogs, flies or worms. The sequence of possible homologs of human ATX are available in nucleotide databases.  
     [0020] Various modifications of the ATX primary amino acid sequence can result in polypeptides having substantially equivalent, decreased, or enhanced function as compared to the sequence set forth as SEQ ID NO:2. Those skilled in the art recognize that such modifications can be desirable at times in order to enhance the bioactivity, bioavailability or stability of ATX, or to facilitate its synthesis or purification. Contemplated amino acid substitutions to the native sequence of ATX can include, for example, conservative changes, wherein a substituted amino acid has similar structural or chemical properties such as replacement of a polar amino acid with another polar amino acid or replacement of a charged amino acid with a similarly charged amino acid. Those skilled in the art also recognize that nonconservative changes such as replacement of an uncharged polar amino acid with an non-polar amino acid or replacement of a charged amino acid with an uncharged polar amino acid, can also be made without affecting a function of ATX. In addition, a variety of polypeptide modifications are known in the art for constraining the structure of polypeptides to enhance stability or binding (Cabezas and Satterthwait,  J. Am. Chem. Soc.  121:3862-3875 (1999); Stanfield et al.,  Structure  7:131-142 (1999)).  
     [0021] A polypeptide can be modified by naturally occurring modifications such as post-translational modifications, including phosphorylation, lipidation, prenylation, sulfation, hydroxylation, acetylation, addition of carbohydrate, addition of prosthetic groups or cofactors, formation of disulfide bonds, proteolysis, assembly into macromolecular complexes, and the like. Chemical modifications of the polypeptide such as, for example, alkylation, acylation, carbamylation, and iodination can also be used to modify an ATX polypeptide. In addition, various molecules, such as other polypeptides, carbohydrates, or lipids, or small molecules can be attached to ATX including fragments of ATX. For example, ATX can contain a label moiety, a sequence such as a FLAG epitope, or be fused to another polypeptide such as a DNA binding domain.  
     [0022] Those skilled in the art can determine which residues and which regions of a ATX sequence are likely to be tolerant of modification and still retain an activity associated with ATX. For example, amino acid substitutions or chemical or enzymatic modifications at residues that are less well conserved between species are more likely to be tolerated than substitutions at highly conserved residues. Accordingly, an alignment can be performed among ATX sequences of various species to determine residues and regions in which modifications are likely to be tolerated (FIG. 1B). Additional guidance for determining residues and regions of ATX likely to be tolerant of modification is provided by studies of ATX fragments and variants. In addition, it can be useful to modify ATX in a way that destroys an activity associated with ATX. For example, as disclosed herein, the mutation of an aspartic acid to an alanine at conserved residue Asp-2195 in the ATX kinase domain generates a kinase-inactive version of ATX.  
     [0023] As used herein, the term “level” in reference to a level of an ATX nucleic acid or polypeptide refers to the amount, accumulation, or rate of synthesis of a molecule or to the amount or rate of an activity associated with the molecule. A level can be represented, for example, by the amount or synthesis rate of messenger RNA (mRNA) encoded by a gene, the amount or synthesis rate of polypeptide corresponding to a given amino acid sequence encoded by a gene, or the amount or synthesis rate of a biochemical form of a molecule accumulated in a cell, including, for example, the amount of particular post-synthetic modifications of a molecule such as a polypeptide or nucleic acid. In addition, a level can be represented, for example, by the extent of phosphorylation of a substrate molecule or by the amount of an activity such as cell cycle checkpoint activity, NMD activity or ability to induce cell death or cell survival. The term can be used to refer to an absolute amount of a molecule or activity in a sample or to a relative amount of the molecule or activity, including amounts and activities determined under steady-state or non-steady-state conditions. For example, the expression level of a molecule can be determined relative to a control component molecule in a sample.  
     [0024] As used herein, the term “p53” is intended to mean a polypeptide with substantially the same amino acid sequence as that shown in SEQ ID NO:4 (human p53). As described above for ATX, it is understood that p53 includes fragments of the full length p53 polypeptide. For example, the amino terminal 70 amino acids of p53 (p53 1-70) can be used in the methods of the invention as a substrate for ATX kinase activity. Also, for example, a fragment of p53 that includes the LSQE sequence located at amino acids 14 to 17 of p53 can be used as a substrate for ATX kinase activity. In addition, as described above for ATX, a p53 polypeptide includes p53 from species other than humans, and includes modifications to the p53 polypeptide including conservative and non-conservative amino acid changes, post-translational modifications and chemical modification. Also, as described for ATX, a p53 polypeptide can contain additional sequences such as a known epitope or a label moiety.  
     [0025] The term “specifically binds” is intended to mean the molecule will have an affinity for the target molecule that is measurably higher than its affinity for a non-specific interaction. For example, a nucleic acid can specifically bind to another nucleic acid by complementary base pairing between the nucleotides. In addition, a polypeptide such as an antibody that specifically binds another polypeptide will have an affinity for the target polypeptide or antigen that is measurably higher than its affinity for a non-specific interaction. Furthermore, a compound such as a small organic molecule can specifically bind to a target molecule with an affinity that is measurably higher than its affinity for a non-specific interaction. Binding affinity can be low or high affinity so long as the binding is sufficient to be detectable. For example, a compound can bind ATX with a binding affinity (Kd) of about 10 −4  M or less, 10 −5  M or less, 10 −6  M or less, about 10 −7  M or less, including about 10 −8  M or less, such as 10 −9  M or less. Several methods for detecting or measuring nucleotide, polypeptide, and other compound binding are well known in the art and disclosed herein.  
     [0026] As used herein, the term “compound” is intended to mean an isolated macromolecule of natural or synthetic origin that can be assayed using the methods of the invention. A compound includes, for example, a polypeptide, peptidomimetic, non-peptidyl compound, carbohydrate, lipid, an antibody or antibody fragment, a small organic or inorganic molecule, or a nucleotide sequence including an aptamer, antisense oligonucleotide, interfering RNA or ribozyme. For example, a compound can be an isolated cDNA sequence. A compound can have a known or unknown structure. A compound can be isolated or be part of a population of compounds such as a library. For example, a compound can be a small organic compound obtained from a combinatorial chemical library. A library of compounds can be a random collection of compounds or can be rationally designed based on a physical characteristic. A compound which is assayed in the methods of the invention can be called a “test compound” and if the test compound has the ability to modulate the level of ATX it can be called an “ATX-modulatory compound.” One compound or more than one compound can be used in the methods of the invention.  
     [0027] As used herein, a “stressor agent” is any agent that can induce a stress response pathway within a cell. Several stressor agents are known in the art such as UV light, ionizing radiation, reactive oxygen intermediates, cytotoxic agents, and replicational stress imposed by DNA replication inhibitors including, for example, hydroxyurea and aphidicolin. In addition, environmental conditions such as excessive heat can induce a stress response pathway within a cell resulting in, for example, the induction of heat shock proteins. Stress response pathways include DNA repair pathways, non-sense mediated mRNA decay (NMD), heat shock pathways, the induction of apoptosis, activation of the NFkB transcription factor, activation of the stress-activated MAP kinase pathways including, for example, JNK and p38 pathways, and activation of ubiquitin-dependent proteolysis.  
     [0028] As used herein, the term “non-sense mediated messenger RNA (mRNA) decay (NMD)” is intended to mean the surveillance mechanism within cells whereby imperfect mRNAs that contain premature translation termination codons are preferentially degraded. These imperfect mRNAs can result in polypeptides that are nonfunctional or have altered function such as gain-of function or dominant negative mutations.  
     [0029] As used herein, the term an “amount effective” or “effective amount” when used in reference to a compound that modulates cell survival or growth is intended to mean an amount of the compound or molecule sufficient to increase or decrease cell survival or growth. Modulation also includes induction of cell survival or growth or complete blockage of cell survival or growth. In addition, an effective amount of a compound is intended to mean an amount of the compound that is sufficient to treat or reduce the severity of a condition in an affected subject.  
     [0030] The invention provides an isolated nucleic acid molecule having substantially the same nucleotide sequence as SEQ ID NO:1. In addition, the invention provides an isolated nucleic acid molecule having substantially the same nucleotide sequence as SEQ ID NO:1 where the nucleic acid molecule encodes an ATX polypeptide containing an amino acid sequence shown in SEQ ID NO:2. For example, the invention provides an isolated nucleic acid molecule containing the sequence shown in SEQ ID NO:1.  
     [0031] Substantially the same nucleic acid sequence is intended to mean a nucleic acid sequence contains a considerable degree of sequence identity or similarity, such as at least 70%, 80%, 90%, 95%, 98%, or 100% sequence identity or similarity, to a reference nucleic acid sequence. Substantially the same nucleic acid sequence includes nucleic acid changes, gaps, and insertions to an nucleic sequence. Nucleic acid changes, gaps, and insertions to a nucleic acid sequence can be compared to a reference sequence using available algorithms and programs such as the Smith-Waterman algorithm and the BLAST homology search program (Altschul et al.,  J. Mol. Biol.  215:403-410 (1990)).  
     [0032] Isolated nucleic acid molecules include DNA sequences and RNA transcripts, both sense and complementary anti-sense strands, including splice variants thereof encoding ATX polypeptides. An isolated nucleic acid molecule can contain a double stranded molecules or single stranded molecules, including RNA as well as coding and noncoding DNA. DNA sequences of the invention include genomic and cDNA sequences as well as wholly or partially chemically synthesized DNA sequences. Genomic DNA of the invention comprises the protein coding region for a polypeptide of the invention and includes allelic variants of the preferred nucleic acid of the invention. Genomic DNA of the invention is distinguishable from genomic DNAs encoding polypeptides other than ATX in that it includes an ATX protein coding region found in ATX-encoding cDNA of the invention. Genomic DNA of the invention can be transcribed into RNA, and the resulting RNA transcript can undergo one or more splicing events wherein one or more introns of the transcript are removed, or “spliced out.” Peptide nucleic acids (PNAS) encoding a polypeptide of the invention are also contemplated (Corey, TIBTech 15:224-229 (1997)). PNAs are DNA analogs containing neutral amide backbone linkages that are resistant to DNA degradation enzymes and which bind to complementary sequences at higher affinity than analogous DNA sequences as a result of the neutral charge on the backbone of the molecule.  
     [0033] RNA transcripts that can be spliced by alternative mechanisms, and therefore be subject to removal of different RNA sequences but still encode an ATX polypeptide, are referred to in the art as splice variants which are embraced by the invention. Splice variants comprehended by the invention therefore are encoded by the same DNA sequences but arise from distinct mRNA transcripts. Allelic variants are known in the art to be modified forms of a wild type gene sequence, the modification resulting from recombination during chromosomal segregation or exposure to conditions which give rise to genetic mutation. Allelic variants, like wild type genes, are inherently naturally occurring sequences (as opposed to non-naturally occurring variants which arise from in vitro manipulation).  
     [0034] An allelic variant of ATX is disclosed herein as SEQ ID NO:5. This form of ATX is produced as the result of allelic variation in exon 15 which leads to the insertion of 27 nucleotides beginning at nucleotide 1427 (FIG. 1A). This sequence alteration causes the insertion of two in-frame stop codons and the use of the next available ATG codon in exon 16 as the translational stat site, resulting in an amino-terminally truncated or short form of ATX. A form of ATX that is similar to the long form of ATX disclosed herein (SEQ ID NO:1) is referenced as SEQ ID NO:7. This form of ATX has exon 5 spliced to exon 6 which results in a different N-terminus and 8 additional amino acids in the resulting polypeptide (FIG. 1A). In the experiments disclosed herein clones that were isolated with exon 5 frequently contained exon 3 which place an in-frame stop codon at the 3′ end of this DNA (Example 1). The longest form of ATX (SEQ ID NO:9) was isolated, however the exon 3 associated stop codon was present in this transcript as well.  
     [0035] In addition to genomic DNA, isolated nucleic acids include cDNA. cDNA can be obtained through reverse transcription of an RNA nucleic acid encoding ATX, followed by second strand synthesis of a complementary strand to provide a double stranded DNA. In addition, nucleic acid molecules can be chemically synthesized meaning produced by purely chemical, as opposed to enzymatic, methods. Wholly chemically synthesized DNA sequences are produced entirely by chemical means, and partially synthesized DNAs are those where only portions of the resulting DNA were produced by chemical means.  
     [0036] ATX nucleic acid molecules include homologs of the human ATX sequence. Species homologs in general share at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99% homology with a human DNA of the invention. ATX nucleic acids include species homologs of the human ATX sequence, but exclude a mouse EST that contains a sequence homologous to the 3′ part of ATX is (GenBank Accession Number BC024431) and a  Macaca fascicularis  brain cDNA clone Qf1A-15747 (accession number AB056380).  
     [0037] The invention also provides anti-sense oligonucleotides based on SEQ ID NO:1. For example, the invention provides an isolated oligonucleotide having at least 15 contiguous nucleotides of the nucleotide sequence 5′-AGCAAGCTCCCTCCTGTCTC-3′ (SEQ ID NO:11). The oligonucleotide shown in SEQ ID NO:11 is an ATX anti-sense oligonucleotide that has been shown herein to decrease the level of ATX in a cell (Example 5).  
     [0038] Nucleic acids of the invention also permit identification and isolation of nucleic acid encoding related ATX polypeptides by well known techniques including Southern hybridization, Northern hybridization, and polymerase chain reaction (PCR). Examples of related nucleic acids include human and non-human nucleic acid sequences, including allelic variants, as well as nucleic acids encoding polypeptides homologous to ATX and structurally related polypeptides sharing one or more biological, immunological, or physical properties of ATX.  
     [0039] The invention provides a method for detecting an ATX nucleic acid molecule in a sample, by contacting the sample with an ATX nucleic acid molecule under conditions that allow specific hybridization to ATX nucleic acid, and detecting the specific hybridization. In addition, the invention provides a method for detecting an ATX nucleic acid molecule in a sample, by contacting a nucleic acid fraction derived from the sample with a PCR primer pair set under conditions that allow amplification of an ATX nucleic acid, and detecting amplified ATX nucleic acid. Kits for detecting ATX nucleic acids based on these methods are provided as well.  
     [0040] Fragments of ATX nucleic acid molecules are useful in the invention, for example, as probes for detection of full length or other fragment ATX nucleic acids. A nucleic acid fragment can include for example 5′, 3′, or internal deletions of a full length ATX nucleic acid sequence. For example, the invention provides an isolated ATX nucleic acid molecule as referenced in SEQ ID NO:5. Alternatively, the invention provides ATX nucleic acid fragments other than the fragment as referenced in SEQ ID NO:5. For example, the invention provides ATX nucleic acid fragments that contain carboxyl terminal deletions of a full length ATX polypeptide. In addition, fragments can include domains of a full length ATX nucleic acid sequence, for example, a kinase domain, NH1 domain, NH2 domain, or LIP domain. A fragment can contain, for example, at least about 10, 100, 1,000, 2,500, 5,000, 7,500, 10,000, 12,500 or more contiguous or non-contiguous nucleic acid residues of a full-length ATX nucleic acid sequence. ATX nucleic acid fragments include the fragments described above, but excludes fragments KIAA0421 (Accession number AB007881), KIAA0220 (Accession number D86974), and LIP (Accession number U32581), which are present in databases. One or more fragment nucleic acids can be included in kits that are used to detect the presence of a nucleic acids encoding ATX, or used to detect variations in a nucleic acid sequence encoding ATX, including polymorphisms, for example, single nucleotide polymorphisms.  
     [0041] The nucleic acids of the invention can contain heterologous sequences that are not part of the ATX-encoding sequences in nature. The heterologous nucleic acid sequence can be separated from the ATX-coding sequence by an encoded cleavage site that will permit removal of non-ATX polypeptide sequences from the expressed fusion protein. Heterologous nucleic acids sequences can include sequences encoding epitopes, such as poly-histidine sequences, FLAG tags, glutathione-S-transferase, thioredoxin, and maltose binding protein domains, that facilitate purification of the fusion protein. In addition heterologous nucleic acids can encode domains, such as leucine zipper motifs, that promote multimer formation between the fusion protein and itself or other proteins or immunoglobulins or fragments thereof that can enhance circulatory half-life of the encoded protein.  
     [0042] The nucleic acid molecules of the invention also include DNA sequences encoding ATX species that hybridize under highly or moderately stringent conditions to the non-coding strand, or complement, of the nucleic acid in SEQ ID NO: 1. ATX-encoding nucleic acids of the invention include a) the nucleic acid sequence set out in SEQ ID NO: 1; b) nucleic acids encoding a polypeptide encoded by the nucleic acid of (a), and c) nucleic acids that hybridize to the complement of the nucleic acids of (a) or (b) under moderately or highly stringent conditions. Exemplary high stringency conditions include a final wash in 0.2×SSC/0.1% SDS at 65° C. to 75° C., and exemplary moderate stringency conditions include a final wash at 2× to 3×SSC/0.1% SDS at 65° C. to 75° C. It is understood in the art that conditions of equivalent stringency can be achieved through variation of temperature and buffer, or salt concentration as described in Ausubel, et al. (Eds.), Protocols in Molecular Biology, John Wiley &amp; Sons (1994). Modifications in hybridization conditions can be empirically determined or precisely calculated based on the length and the percentage of guanosine/cytosine (GC) base pairing of the probe.  
     [0043] The invention also provides a vector containing the isolated ATX nucleic acid molecules described above. For example, the invention provides a vector containing an isolated nucleic acid molecule having substantially the same nucleotide sequence as SEQ ID NO:1.  
     [0044] Vectors include autonomously replicating recombinant expression constructs such as plasmid and viral DNA vectors. The invention includes vectors where ATX-encoding nucleic acids are operatively linked to an endogenous or exogenous promoter, enhancer, or operator sequence and a transcription terminator sequence. Promoter and enhancer sequences are generally selected for the ability to increase gene expression, while operator sequences are generally selected for the ability to regulate gene expression. It is understood in the art that the choice of host cell is relevant to selection of an appropriate regulatory sequence. Vectors used in the invention can also include sequences encoding one or more selectable markers that permit identification of host cells bearing the construct. Vectors can also include sequences that facilitate homologous recombination in a host cell.  
     [0045] Suitable vectors for expression in prokaryotic or eukaryotic cells are well known to those skilled in the art (see, for example, Ausubel et al., supra, 1999). Vectors useful for expression in eukaryotic cells can include, for example, regulatory elements including the SV40 early promoter, the cytomegalovirus (CMV) promoter, the mouse mammary tumor virus (MMTV) steroid-inducible promoter, Moloney murine leukemia virus (MMLV) promoter, and the like. A vector can include, for example, viral vectors such as a bacteriophage, a baculovirus or a retrovirus; cosmids or plasmids; and, particularly for cloning large nucleic acid molecules, bacterial artificial chromosome vectors (BACs) and yeast artificial chromosome vectors (YACs). Such vectors are commercially available, and their uses are well known in the art. One skilled in the art will know or can readily determine an appropriate promoter for expression in a particular host cell. For example, as disclosed herein, the long form of ATX can be sub-cloned into pcDNA 3.1 with an HA tag and transfected using Fugene 6 into human embryonic kidney 293T cells (Example 2 and Example 5).  
     [0046] Vectors useful for expression of an ATX polypeptide can contain a regulatory element that provides tissue specific or inducible expression of an operatively linked nucleic acid. Such inducible systems, include, for example, tetracycline inducible system (Gossen &amp; Bizard,  Proc. Natl. Acad. Sci. USA,  89:5547-5551 (1992); Gossen et al.,  Science,  268:1766-1769 (1995); Clontech, Palo Alto, Calif.)); metallothionein promoter induced by heavy metals; insect steroid hormone responsive to ecdysone or related steroids such as muristerone (No et al.,  Proc. Natl. Acad. Sci. USA,  93:3346-3351 (1996); Yao et al.,  Nature,  366:476-479 (1993); Invitrogen, Carlsbad, Calif.); mouse mammory tumor virus (MMTV) induced by steroids such as glucocortocoid and estrogen (Lee et al.,  Nature,  294:228-232 (1981); and heat shock promoters inducible by temperature changes.  
     [0047] In addition, viral vectors such as retroviral, adenovirus, adeno-associated virus, lentivirus, and herpesvirus vectors can be used to express ATX polypeptides into a cell. Viral based systems provide the advantage of being able to introduce relatively high levels of a heterologous nucleic acid into a variety of cells. Additionally, such viruses can introduce heterologous DNA into nondividing cells. Viral vectors include, for example, Herpes simplex virus vectors (U.S. Pat. No. 5,501,979), Vaccinia virus vectors (U.S. Pat. No. 5,506,138), Cytomegalovirus vectors (U.S. Pat. No. 5,561,063), Modified Moloney murine leukemia virus vectors (U.S. Pat. No. 5,693,508), adenovirus vectors (U.S. Pat. Nos. 5,700,470 and 5,731,172), adeno-associated virus vectors (U.S. Pat. No. 5,604,090), constitutive and regulatable retrovirus vectors (U.S. Pat. Nos. 4,405,712; 4,650,764 and 5,739,018, respectively), papilloma virus vectors (U.S. Pat. Nos. 5,674,703 and 5,719,054), and the like.  
     [0048] The invention further provides a host cell containing an ATX-encoding vector as described above. For example, the invention provides a host cell that contains a vector which contains an isolated nucleic acid molecule having substantially the same nucleotide sequence as SEQ ID NO:1. Host cells include prokaryotic and eukaryotic cells. Nucleic acids of the invention can be introduced into the host cell as part of a circular plasmid, or as linear DNA having an isolated protein coding region or a viral vector. Methods for introducing DNA into the host cell are well known in the art and include transformation, transfection, electroporation, nuclear injection, or fusion with carriers such as liposomes, micelles, ghost cells, protoplasts, and other transformed cells. Detailed procedures for these methods can be found in Sambrook et al.,  Molecular Cloning: A Laboratory Manual  (Cold Spring Harbor Laboratory Press, 1989) and the references cited therein). Expression systems of the invention include bacterial, yeast, fungal, plant, insect, invertebrate, and mammalian cells systems.  
     [0049] Useful mammalian expression vectors and methods of introducing such vectors into mammalian cells either ex vivo or in vivo, for expression of the encoded polypeptide, are well known in the art. For example, a plasmid expression vector can be introduced into a cell by calcium-phosphate mediated transfection, DEAE-Dextran-mediated transfection, lipofection, polybrene- or polylysine-mediated transfection, electroporation, or by conjugation to an antibody, gramacidin S, artificial viral envelopes or other intracellular carriers. A viral expression vector can be introduced into a cell in an expressible form by infection or transduction, for example, or by encapsulation in a liposome.  
     [0050] The invention also provides a method of producing an ATX polypeptide by a) growing the host cell described above under conditions appropriate for expression of the ATX polypeptide, and b) isolating the ATX polypeptide from the host cell or host cell growth medium. This method can be used to produce ATX polypeptide, for example, as a source of immunogen for the development of antibodies specifically reactive with ATX.  
     [0051] ATX polypeptide isolated from the cells or from the medium in which the cells are grown by purification methods known in the art, for example, conventional chromatographic methods including immunoaffinity chromatography, receptor affinity chromatography, hydrophobic interaction chromatography, lectin affinity chromatography, size exclusion filtration, cation or anion exchange chromatography, high pressure liquid chromatography (HPLC), reverse phase HPLC, and the like. Still other methods of purification include those wherein the desired protein is expressed and purified as a fusion protein having a specific tag, label, or chelating moiety that is recognized by a specific binding partner or agent. The purified protein can be cleaved to yield the desired protein, or be left as an intact fusion protein.  
     [0052] The DNA sequence information provided by the present invention also makes possible the development through, for example, homologous recombination or “knock-out” strategies of animals that fail to express functional ATX or that express a variant of ATX (Capecchi,  Science  244:1288-1292 (1989)). Such animals are useful as models for studying the in vivo activities of ATX and modulators of ATX.  
     [0053] The invention provides an isolated polypeptide containing substantially the same amino acid sequence as SEQ ID NO:2. For example, the invention provides a polypeptide containing an amino acid sequence as referenced in SEQ ID NO:2. The sequence shown in SEQ ID NO:2 corresponds to the “long form” of ATX (FIG. 1A).  
     [0054] As described further above, an isolated ATX polypeptide includes conservative and non-conservative amino acid changes to the sequence shown in SEQ ID NO:2. In addition, an isolated ATX polypeptide includes species homologs and fragments of ATX. For example, the invention provides an isolated ATX polypeptide fragment as referenced in SEQ ID NO:6. Alternatively, the invention provides ATX polypeptide fragments other than the fragment as referenced in SEQ ID NO:6. For example, the invention provides ATX polypeptide fragments that contain carboxyl terminal deletions of a full length ATX polypeptide. Furthermore, an ATX polypeptide can contain polypeptide modifications or heterologous sequences such as an epitope tag. Polypeptides of the invention can be isolated from natural cell sources, chemically synthesized, or produced by recombinant procedures involving the host cells of the invention.  
     [0055] The invention provides an antibody, or antigen binding fragment thereof, which specifically binds to an ATX polypeptide containing an amino acid sequence as referenced in SEQ ID NO:2. Antibodies include, for example, monoclonal and polyclonal antibodies, single chain antibodies, chimeric antibodies, bifunctional or bispecific antibodies, humanized antibodies, human antibodies, and complementary determining region (CDR)-grafted antibodies, including compounds which include CDR or antigen-binding sequences, which specifically bind to a polypeptide of the invention. Antibody fragments, including Fab, Fab′, F(ab′) 2 , and Fv, are also provided by the invention. Screening assays to determine binding specificity or exclusivity of an antibody of the invention are well known in the art (see Harlow et al. (Eds), Antibodies A Laboratory Manual; Cold Spring Harbor Laboratory; Cold Spring Harbor, N.Y. (1988)).  
     [0056] Antibodies that recognize and bind fragments of the ATX polypeptides of the invention are also contemplated, provided that the antibodies specifically bind ATX polypeptides. As with antibodies that are specific for full length ATX polypeptides, antibodies of the invention that recognize ATX fragments are those which can distinguish ATX polypeptides from other PIKK polypeptides despite inherent sequence identity, homology, or similarity found in the family of proteins.  
     [0057] Antibodies of the invention can be produced using any method well known in the art, using any polypeptide, or immunogenic fragment thereof, of the invention. Immunogenic polypeptides can be isolated from natural sources, from recombinant host cells, or can be chemically synthesized. For example, as disclosed herein, antibodies specifically reactive with ATX were generated using glutathione S-transferase (GST) fusion proteins containing ATX amino acids 2281-2339 (anti-ATX-Ab-1) or amino acids 1691-1790 (anti-ATX-Ab-2) (Example 2). Polypeptide of the invention can also be conjugated to a hapten such as keyhole limpet hemocyanin (KLH) in order to increase immunogenicity. Methods for synthesizing such peptides are known in the art, for example, as in R. P. Merrifield,  J. Amer. Chem. Soc.  85: 2149-2154 (1963); J. L. Krstenansky, et al.,  FEBS Lett.  211:10 (1987). Antibodies to a polypeptide of the invention can also be prepared through immunization using a nucleic acid of the invention, as described in Fan et al.,  Nat. Biotech.  17:870-872 (1999). DNA encoding a polypeptide can be used to generate antibodies against the encoded polypetide following topical administration of naked plasmid DNA or following injection, for example, intramuscular injection, of the DNA.  
     [0058] Non-human antibodies can be humanized by any methods known in the art. In one method, the non-human CDRs are inserted into a human antibody or consensus antibody framework sequence. Further changes can then be introduced into the antibody framework to modulate affinity or immunogenicity. Antibodies of the invention further include plastic antibodies or molecularly imprinted polymers (MIPs) (Haupt and Mosbauch,  TIBTech  16:468-475 (1998)). Antibodies of this type can be useful in immunoaffinity separation, chromatography, solid phase extraction, immunoassays, for use as immunosensors, and for screening chemical or biological libraries. Advantages of antibodies of this type are that no animal immunization is required, the antibodies are relatively inexpensive to produce, they are resistant to organic solvents, and they are reusable over long period of time.  
     [0059] The invention provides a method for detecting ATX polypeptide in a sample by contacting the sample with an ATX antibody under conditions that allow specific binding of the antibody to the polypeptide and detecting the bound antibody. Antibodies of the invention can also include one or more labels that permit detection of the antibody and antibody binding. Labels can include, for example, radioactivity, fluorescence (or chemiluminescence), one of a high affinity binding pair (such as biotin/avidin), enzymes, or combinations of one or more of these labels. Antibodies of the invention are also useful, for example, for therapeutic purposes (by modulating activity of ATX), diagnostic purposes to detect or quantitate ATX, as well as purification of ATX. Kits containing an antibody or antibodies of the invention are also provided.  
     [0060] The DNA and amino acid sequence information provided by the present invention also makes possible the systematic analysis of the structure and function of ATX. DNA and amino acid sequence information for ATX also permits identification of compounds with which an ATX polypeptide or nucleic acid will interact. Methods to identify compounds that bind to ATX include solution assays, in vitro assays where ATX polypeptides are immobilized, and cell based assays. Identification of compounds that bind ATX polypeptides provides potential targets for therapeutic or prophylactic intervention in pathologies associated with ATX biological activity.  
     [0061] The invention provides a method for identifying a compound that specifically binds to an ATX polypeptide of the invention, by a) contacting the ATX polypeptide with a compound, and b) determining specific binding of the compound to said ATX polypeptide. As described further above, the term compound includes macromolecules of natural or synthetic origin including, for example, a polypeptide, peptidomimetic, non-peptidyl compound, carbohydrate, lipid, and antibody or antibody fragment, a small organic or inorganic molecule, or a nucleic acid including an aptamer.  
     [0062] Identification of compounds that bind the ATX polypeptide can be achieved by isolating the ATX polypeptide/binding complex, and separating the ATX polypeptide from the binding compound. An additional step of characterizing the physical, biological, or biochemical properties of the binding compound can also be performed. In one embodiment, the ATX polypeptide/binding complex can be isolated using a antibody immunospecific for either the ATX polypeptide or the candidate binding compound. In another embodiment, the complex can be isolated using a second binding compound that interacts with either the ATX polypeptide or the candidate binding compound. In still another embodiment, either the polypeptide ATX or the candidate binding compound comprises a label or tag that facilitates its isolation, and methods of the invention to identify binding compounds include a step of isolating the ATX polypeptide/binding complex through interaction with the label or tag. An exemplary tag of this type is a poly-histidine sequence, generally around six histidine residues, that permits isolation of a compound so labeled using nickel chelation. Other labels and tags, such as the FLAG tag, thioredoxin, and GST, each of which is well known in the art.  
     [0063] An in vitro assay can be performed where the ATX polypeptide can be immobilized and then contacted with a candidate binding compound. In an alternative embodiment, the candidate binding compound can be immobilized and binding of the ATX polypeptide is detected. Immobilization can be accomplished using any of the methods well known in the art, including covalent bonding to a support, a bead, or a chromatographic resin, as well as non-covalent, high affinity interaction such as antibody binding, or use of streptavidin/biotin binding wherein the immobilized compound includes a biotin or streptavidin moiety. Detection of binding can be accomplished, for example, (i) using a radioactive label on the compound that is not immobilized, (ii) using of a fluorescent label on the non-immobilized compound, (iii) using an antibody immunospecific for the non-immobilized compound, (iv) using a label on the non-immobilized compound that excites a fluorescent support to which the immobilized compound is attached, as well as other techniques well known in the art.  
     [0064] A cell based assay that can be used in the method of the invention for detecting an ATX binding compound is a yeast or mammalian two-hybrid assay (Fields and Song,  Nature  340:245-246 (1989); Fields,  Methods: A Companion to Methods in Enzymology  5:116-124 (1993); U.S. Pat. No. 5,283,173 issued Feb. 1, 1994 to Fields, et al.). Modifications and variations on the two-hybrid assay have previously been described (Colas and Brent,  TIBTECH  16:355-363 (1998)).  
     [0065] The invention also provides a method for identifying an ATX-modulatory compound by measuring the level of an ATX polypeptide in the presence of a test compound, where a difference in the level of the ATX polypeptide in the presence of the test compound compared to in the absence of the test compound indicating that the test compound is an ATX-modulatory compound. In addition, the invention provides a method for identifying an ATX-modulatory compound by measuring the level of an ATX polypeptide in the presence of a test compound, where a difference in the level of the ATX polypeptide in the presence of the test compound compared to in the absence of the test compound indicating that the test compound is an ATX-modulatory compound, and where the ATX-modulatory compound is not caffeine or wortmannin. The ATX-modulatory compound can decrease or increase the level of ATX polypeptide.  
     [0066] Agents that modulate, for example, increase, decrease, or block the level of ATX can be identified by incubating a test compound with an ATX polypeptide or nucleic acid and determining the effect of the test compound on ATX activity or expression. The level of ATX can include the expression level of ATX or an activity level of ATX. The selectivity, or specificity, of an ATX-modulatory compound can be evaluated by comparing its effects on ATX or an ATX-encoding nucleic acids to its effect on other polypeptides or compounds. Cell based methods, such as two-hybrid assays to identify DNAs encoding binding compounds and split hybrid assays to identify inhibitors of ATX polypeptide interaction with a known binding polypeptide, as well as in vitro methods, including assays where an ATX polypeptide, ATX-encoding nucleic acid, or a binding compound are immobilized, and solution assays are included in this method of the invention.  
     [0067] As understood by those of skill in the art, assay methods for identifying compounds that modulate an activity generally require comparison to a “control.” One type of a control is a reaction or cell that is treated substantially the same as the test reaction or cell exposed to the compound, with the distinction that the control reaction or cell is not exposed to the compound.  
     [0068] As disclosed herein, the compounds wortmannin and caffeine can modulate (inhibit) the level of ATX (Example 3 and Example 7). Wortmannin is known to inhibit ATM kinase and is an irreversible inhibitor of PIKKs. Caffeine is a known inhibitor of the G2 cell cycle checkpoint. As disclosed herein, caffeine reversed the accumulation of G2/M phase cells induced by ATX anti-sense treatment, indicating that ATX deficiency can trigger the activation of a caffeine-sensitive G2 checkpoint (Example 7).  
     [0069] The invention provides a method for identifying an ATX-modulatory compound where the level of ATX polypeptide is measured by determining the kinase activity of the ATX polypeptide. The kinase activity of ATX can be measured using methods well known in the art such as kinase assays and immune complex kinase assays as performed herein in Example 3. These assays contain ATX, a substrate, and a suitable buffer including [g-32 P]ATP and Mn 2+ . Phosphorylated substrates can also be detected using phospho-specific antibodies.  
     [0070] In addition, the invention provides a method for identifying an ATX-modulatory compound where the level of ATX polypeptide is measured by determining the phosphorylation of a p53 polypeptide or fragment. For example, a GST fusion protein containing the first 70 amino acids of p53 (GST-p53 1-70 ) can be used as a substrate to measure the level of ATX polypeptide by its kinase activity (Example 3). In addition to p53, the phosphorylation of hUpf1, a helicase, can be used to measure the level of ATX polypeptide (Example 3).  
     [0071] The invention also provides a method for identifying an ATX-modulatory compound where the level of ATX polypeptide is measured by determining the level of p53 polypeptide accumulation. As shown herein, a decrease in ATX polypeptide, such as results from the use of an anti-sense oligonucleotide, leads to a reduction in p53 polypeptide accumulation (Example 6). Thus, the level of p53 can be used as a measure of ATX polypeptide level.  
     [0072] The invention further provides a method for identifying an ATX-modulatory compound where the level of ATX polypeptide is measured by determining the level of non-sense mediated messenger RNA (mRNA) decay (NMD). NMD is a surveillance mechanism within cells whereby imperfect mRNAs that contain premature translation termination codons are preferentially degraded. As disclosed herein, treatment of cells with an ATX anti-sense oligonucleotide, which reduced endogenous ATX expression, demonstrated that ATX expression is required for maximal NMD activity (Example 9). The level of NMD is correlated to the level of ATX in the cell and so the level of NMD can be used as a measure of ATX polypeptide level.  
     [0073] ATX-modulatory compounds can be identified that decrease or increase the level of ATX polypeptide or nucleic acid. A decrease in the level of ATX can be a partial reduction or a total blockage of the level of ATX, and an increase in the level of ATX can be a partial increase or an induction of the level of ATX from a previously undetectable level. For example, an ATX-modulatory compound can increase the level of NMD activity in a cell. It can be desirable to increase the level of NMD activity in a cell in order to protect the cell from deleterious gain-of-function mutations caused by truncated polypeptides resulting from the translation of imperfect mRNAs that contain premature translation termination. Alternatively, an ATX-modulatory compound can decrease the level of NMD activity in a cell. It can be desirable to decrease the level of NMD activity in a cell in some cases where the truncated polypeptide does not have a deleterious effect but instead retains some activity that can compensate for the normal gene function.  
     [0074] ATX-modulatory compounds can include, for example, antibodies and other proteins or peptides which specifically bind to an ATX polypeptide or an ATX-encoding nucleic acid, oligonucleotides which bind to an ATX polypeptide or an ATX gene sequence, and other non-peptide compounds, for example, isolated or synthetic organic and inorganic molecules, which specifically react with an ATX polypeptide or underlying nucleic acid. ATX-modulatory compounds of the invention can interact specifically or exclusively to an ATX polypeptide or ATX-encoding nucleic acid, however, modulators that interact with an ATX polypeptide or an ATX-encoding nucleic acid with higher affinity or avidity compared to other compounds are also included in the invention. Mutant ATX polypeptides which affect the enzymatic activity or cellular localization of the wild-type ATX polypeptides are also contemplated by the invention. Targets for the development of ATX-modulatory compounds can include, for example: (1) regions of an ATX polypeptide which contact other proteins, (2) regions that localize an ATX polypeptide within a cell, (3) regions of an ATX polypeptide which bind substrate, (4) allosteric regulatory binding site(s) of an ATX polypeptide, (5) phosphorylation site(s) of an ATX polypeptide as well as other regions of the protein where covalent modification regulates biological activity and (6) regions of an ATX polypeptide which are involved in multimerization of subunits. Still other ATX-modulatory compounds include those that recognize specific ATX-encoding and regulatory nucleic acid sequences. ATX-modulatory compounds that modulate the level of ATX can be therapeutically useful in treatment of diseases and physiological conditions in which ATX is known or suspected to be involved.  
     [0075] Methods of the invention to identify ATX-modulatory compounds include variations on any of the methods described above to identify ATX binding compounds, the variations including techniques where a binding compound has been identified and the binding assay is carried out in the presence and absence of a candidate ATX-modulatory compound. A modulatory compound is identified in those instances where the level of binding between an ATX polypeptide and a binding compound changes in the presence of the candidate modulatory compound compared to the level of binding in the absence of the candidate modulatory compound. An ATX-modulatory compound that increases binding between an ATX polypeptide and the binding compound is described as an enhancer or activator, and a modulatory compound that decreases binding between the ATX polypeptide and the binding compound is described as an inhibitor. In vitro methods of the invention are amenable to high throughput assays as described below.  
     [0076] In addition to the assays described above which can be modified to identify binding compounds, other methods are contemplated to identify modulatory compounds. In one embodiment, methods of the invention can include use of the split hybrid assay as generally described in WO98/13502 and variations on this method as described in WO95/20652.  
     [0077] The methods of the invention can also utilize high throughput screening (HTS) assays to identify compounds that interact with or inhibit biological activity of an ATX polypeptide. HTS assays permit screening of large numbers of compounds in an efficient manner. Cell-based HTS systems include melanophore assays, yeast-based assay systems, and mammalian cell expression systems (Jayawickreme and Kost, Curr. Opin. Biotechnol. 8:629-634 (1997)). Automated (robotic) and miniaturized HTS assays are also embraced (Houston and Banks, Curr. Opin. Biotechnol. 8:734-740 (1997)). HTS assays are designed to identify “hits” or “lead compounds” having the desired property, from which modifications can be designed to improve the desired property. Chemical modification of the “hit” or “lead compound” is often based on an identifiable structure/activity relationship (SAR) between the “hit” and the ATX polypeptide.  
     [0078] There are a number of different libraries used for the identification of small molecule modulators, including, (1) chemical libraries, (2) natural product libraries, and (3) combinatorial libraries comprised of random peptides, oligonucleotides or organic molecules.  
     [0079] Chemical libraries consist of structural analogs of known compounds or compounds that are identified as “hits” or “leads” via natural product screening. Natural product libraries are collections from microorganisms, animals, plants, or marine organisms which are used to create mixtures for screening by, for example, (1) fermentation and extraction of broths from soil, plant or marine microorganisms or (2) extraction of plants or marine organisms. Natural product libraries include polyketides, non-ribosomal peptides, and variants (non-naturally occurring) variants thereof. Combinatorial libraries are composed of large numbers of peptides, oligonucleotides or organic compounds as a mixture. They can be prepared by traditional automated synthesis methods, PCR, cloning or proprietary synthetic methods. Libraries that can be utilized by the invention include peptide and oligonucleotide combinatorial libraries. Still other libraries of interest include protein, peptidomimetic, multiparallel synthetic collection, recombinatorial, and polypeptide libraries. For a review of combinatorial chemistry and libraries created therefrom, see Myers,  Curr. Opin. Biotechnol.  8:701-707 (1997). Identification of modulators through use of the various libraries described herein permits modification of the candidate “hit” (or “lead”) to optimize the capacity of the “hit” to modulate activity.  
     [0080] Anti-sense oligonucleotides which recognize and hybridize to nucleic acid encoding ATX can also be utilized by the methods of the invention. Full length and fragment anti-sense oligonucleotides are provided. One skilled in the art of will appreciate that fragment anti-sense molecules of the invention include (i) those which specifically or exclusively recognize and hybridize to ATX-encoding RNA (as determined by sequence comparison of DNA encoding ATX to DNA encoding other molecules) as well as (ii) those which recognize and hybridize to RNA encoding variants of the ATX family of proteins. Antisense oligonucleotides that hybridize to RNA encoding other members of the PIKK family of proteins are also identifiable through sequence comparison to identify characteristic, or signature, sequences for the family of molecules. Identification of sequences unique to ATX-encoding nucleic acids, as well as sequences common to the family of PIKK-encoding nucleic acids, can be deduced through use of any publicly available sequence database, or through use of commercially available sequence comparison programs. After identification of the desired sequences, isolation through restriction digestion or amplification using any of the various polymerase chain reaction techniques well known in the art can be performed. Anti-sense oligonucleotides can be used for regulating expression of ATX by those cells expressing ATX mRNA. Antisense molecules are generally from about 5 to about 100 nucleotide in length, and preferably are about 10 to 20 nucleotides in length. Antisense nucleic acids capable of specifically binding to ATX expression control sequences or ATX RNA are introduced into cells, for example, by a viral vector or colloidal dispersion system such as a liposome.  
     [0081] The anti-sense nucleic acid binds to the ATX-encoding target nucleotide sequence in the cell and prevents transcription or translation of the target sequence. Phosphorothioate and methylphosphonate anti-sense oligonucleotides are specifically contemplated for therapeutic use by the invention. The anti-sense oligonucleotides may be further modified by poly-L-lysine, transferrin polylysine, or cholesterol moieties at their 5′ end.  
     [0082] The invention also provides methods to modulate ATX expression through the use of RNA interference (RNAi) (Brummelkamp et al.,  Science  296:550-553 (2002); Elbashir et al.,  Nature  411:494-498 (2002)). RNAi is a process of sequence-specific gene silencing by post-transcriptional RNA degradation, which is initiated by double-stranded RNA (dsRNA) homologous in sequence to the silenced gene. A double-stranded RNA (dsRNA) that is used for RNAi is referred to herein as an “interfering RNA.” For example, a suitable dsRNA for RNAi can contain sense and antisense strands of about 21 contiguous nucleotides corresponding to the gene to be targeted that form 19 RNA base pairs, leaving overhangs of two nucleotides at each 3′ end (Elbashir et al., supra; Bass,  Nature  411:428-429 (2001); Zamore,  Nat. Struct. Biol.  8:746-750 (2001)). dsRNAs of about 25-30 nucleotides have also been used successfully for RNai (Karabinos et al.,  Proc. Natl. Acad. Sci.  98:7863-7868 (2001). dsRNA can be synthesized in vitro and introduced into a cell by methods known in the art. By using RNAi methods, the targeted RNA is degraded, and translation of the target polypeptide is decreased or abolished.  
     [0083] The invention further provides methods to modulate ATX expression through the use of ribozymes (Gibson and Shillitoe,  Mol. Biotech.  7:125-137 (1997)). Ribozyme technology can be utilized to inhibit translation of ATX mRNA in a sequence specific manner through (i) the hybridization of a complementary RNA to a target mRNA and (ii) cleavage of the hybridized mRNA through nuclease activity inherent to the complementary strand. Ribozymes can be identified by empirical methods or be specifically designed based on accessible sites on the target mRNA (Bramlage, et al.,  Trends in Biotech  16:434-438 (1998)). Delivery of ribozymes to target cells can be accomplished using either exogenous or endogenous delivery techniques well known in the art. Exogenous delivery methods can include use of targeting liposomes or direct local injection. Endogenous methods include use of viral vectors and non-viral plasmids. Ribozymes can be ATX-modulatory compounds and specifically modulate expression of ATX when designed to be complementary to regions unique to a nucleic acid encoding ATX. Specifically modulate means that ribozymes of the invention exclusively recognize a nucleic acid encoding ATX.  
     [0084] The invention further provides methods to modulate transcription of ATX through use of oligonucleotide-directed triple helix formation (Lavrovsky, et al.,  Biochem. Mol. Med.  62:11-22 (1997)). Triple helix formation is accomplished using sequence specific oligonucleotides which hybridize to double stranded DNA in the major groove as defined in the Watson-Crick model. Hybridization of a sequence specific oligonucleotide can thereafter modulate activity of DNA-binding proteins, including, for example, transcription factors and polymerases. Target sequences for hybridization include promoter and enhancer regions to permit transcriptional regulation of ATX expression. In addition to use of oligonucleotides, triple helix formation techniques of the invention also include use of peptide nucleic acids as described in Corey,  TIBTECH  15:224-229 (1997). Oligonucleotides which are capable of triple helix formation are also useful for site-specific covalent modification of target DNA sequences. Oligonucleotides useful for covalent modification can be coupled to various DNA damaging agents as described in Lavrovsky, et al. (supra)  
     [0085] Mutations in the ATX gene can result in loss of normal function of the ATX gene product and underlie ATX-related human disease states. The invention therefore provides gene therapy methods to restore ATX activity in treating those disease states described herein. Delivery of a functional ATX gene to appropriate cells is effected ex vivo, in situ, or in vivo by use of vectors, for example, viral vectors such as adenovirus, adeno-associated virus, or a retrovirus, or ex vivo by use of physical DNA transfer methods such as liposomes or chemical treatments (Anderson,  Nature,  supplement to vol. 392, no. 6679, pp.25-20 (1998)). Alternatively, in some human disease states, preventing the expression of, or inhibiting the activity of, ATX can be useful in treating the disease states. In this case, anti-sense therapy or gene therapy, for example, where a dominant negative ATX mutant is introduced into a target cell type, can be applied to negatively regulate the expression of ATX.  
     [0086] The invention provides a method for modulating cell survival by introducing an ATX-modulatory compound identified by the methods described above into a cell in an amount effective to modulate survival of the cell. For example, the ATX-modulatory compound can decrease or increase cell survival.  
     [0087] A level of cell death or cell survival can be measured by any of a variety of methods known to one skilled in the art. For example, trypan blue staining can be used to measure the level of cell death in a cell. In addition, clonogenic assays, as described herein, can be used (Example 5). Other staining methods, for example, propidium iodide and Alomar Blue, also can be used to measure cell death. The stained cells can be visualized in any way that is convenient, for example, by microscopy or flow cytometry (FACS). In addition, cell viability and cell proliferation assays such as the lactose dehydrogenase (LDH) assay and the MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay are commercially available and can be used to measure cell viability. In addition, the uptake of 3H thymidine can be used to access the viability of cells.  
     [0088] The invention further provides a method for modulating cell survival by introducing an ATX-modulatory compound into a cell where the cell is exposed to a stressor agent. As described further above, a stressor agent is any agent that can induce a stress response pathway within a cell. A stressor agent can include, for example, UV light, ionizing radiation, reactive oxygen intermediates, or a chemical agent such as a cytotoxic or chemotherapeutic agent. In addition, environmental conditions such as excessive heat can induce a stress response pathway within a cell resulting in, for example, the induction of heat shock proteins. Stress response pathways include DNA repair pathways, non-sense mediated mRNA decay (NMD), heat shock pathways, the induction of apoptosis, activation of the NFkB transcription factor, activation of the stress-activated MAP kinase pathways including, for example, JNK and p38 pathways, and activation of ubiquitin-dependent proteolysis.  
     [0089] An example of an ATX-modulatory compound of the invention is an antisense oligonucleotide. The invention provides a method for decreasing cell survival by introducing an antisense oligonucleotide, such as SEQ ID NO: 11 into a cell in an amount effective to decrease survival of the cell.  
     [0090] Association of ATX with cell cycle progression makes compositions of the invention, including for example an ATX polypeptide, an inhibitor thereof, an antibody, or other modulator of ATX expression or biological activity, useful for treating a number of conditions. For example, the invention provides a method for treating a condition characterized by excessive cell survival or cell growth by administering to a patient having such a condition an effective amount of an ATX-modulatory compound where the effective amount of the compound increases cell death. For example, an ATX-modultory compound can be given to a patient with a neoplastic condition.  
     [0091] An ATX-modulatory compound that decreases the level of ATX can enhance the radiosensitivity or chemosensitivity of neoplastic cells. Therefore, it is contemplated that an ATX-modulatory compound can be given alone or in combination with another agent such as a cytotoxic or chemotherapeutic agent. Several cytotoxic agents, such as radiation, and chemotherapeutic agents, such as cis-platin, are well known in the art. An appropriate agent can be chosen based on several factors, such as the particular type of neoplastic condition at issue or the ability of the patient to tolerate the agent. For example, focused radiation therapy, including brachytherapy, can be used in conjunction with an ATX inhibitory compound in order to induce tumor cell death while minimizing cytotoxic effects on normal tissue.  
     [0092] A “neoplastic condition,” refers to a condition associated with hyperproliferation of cells and includes benign and malignant expanding lesions of proliferating cells. Neoplastic conditions include benign and malignant hyperproliferative disorders. A benign neoplasm grows in an expansile manner, displacing or compressing surrounding tissues rather than invading them. A malignant neoplasm refers to a large group of diseases characterized by uncontrolled growth and spread of abnormal cells. Cancer, for example, is a malignant neoplastic condition that encompasses many sub-conditions that are characterized by insufficient death of abnormal cells. Tumors of the colon, prostate, lung, cervix, stomach, breast and skin are examples of neoplastic conditions.  
     [0093] Aberrant ATX activity can be associated with various forms of cancer in, for example, adult and pediatric oncology, including growth of solid tumors/malignancies, myxiod and round cell carcinoma, locally advanced tumors, metastatic cancer, human soft tissue sarcomas, cancer metastases, including lymphatic metastases, squamous cell carcinoma of the head and neck, esophageal squamous cell carcinoma, oral carcinoma, blood cell malignancies, including multiple myeloma, leukemias, effusion lymphomas (body cavity based lymphomas), thymic lymphoma lung cancer, including small cell carcinoma, non-small cell cancers, breast cancer, including small cell carcinoma and ductal carcinoma, gastrointestinal cancers, including stomach cancer, colon cancer, colorectal cancer, polyps associated with colorectal neoplasia, pancreatic cancer, liver cancer, urological cancers, including bladder cancer, including primary superficial bladder tumors, invasive transitional cell carcinoma of the bladder, and muscle-invasive bladder cancer, prostate cancer, malignancies of the female genital tract, including ovarian carcinoma, primary peritoneal epithelial neoplasms, cervical carcinoma, uterine endometrial cancers, and solid tumors in the ovarian follicle, kidney cancer, including renal cell carcinoma, brain cancer, including intrinsic brain tumors, neuroblastoma, astrocytic brain tumors, gliomas, metastatic tumor cell invasion in the central nervous system, bone cancers, including osteomas, skin cancers, including malignant melanoma, tumor progression of human skin keratinocytes, and squamous cell cancer, hemangiopericytoma, and Kaposi&#39;s sarcoma.  
     [0094] Aberrant ATX activity also can be associated with other conditions which include aberrant apoptotic mechanisms, including abnormal caspase activity; aberrant enzyme activity associated with cell cycle progression, including for example cyclins A, B, D and E; alterations in viral (such as Epstein-Barr virus, papillomavirus) replication in latently infected cells; chromosome structure abnormalities, including genomic stability in general, unrepaired chromosome damage, telomere erosion (and telomerase activity), breakage syndromes including for example, Sjogren&#39;s syndrome and Nijimegen breakage syndrome; embryonic stem cell lethality; abnormal embyonic development; sensitivity to ionizing radiation; acute immune complex alveolitis; and Fanconi anemia. ATX-modulatory compounds can be used alone or in combination with another agent in the treatment of these conditions.  
     [0095] The invention also provides a method for treating a condition characterized by excessive cell death by administering to a patient having such a condition an effective amount of an ATX-modulatory compound where the effective amount of the compound increases cell survival. For example, an ATX-modultory compound can be given to a patient with a neurodegnerative condition in order to increase neuronal cell survival. In addition the invention provides a method of prolonging the in vivo survival of transplanted cells for the treatment of a disease or pathological condition. Also, for example, a compound that increases the level of ATX can be given to a patient who is exposed to stressors such as UV light in order to protect against genetic mutations.  
     [0096] The effective compounds of the invention described herein can optionally be formulated together with a pharmaceutically acceptable carrier for delivery to a cultured cell or to a subject. Suitable pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous or organic solvents such as physiologically buffered saline, glycols, glycerol, oils or injectable organic esters. A pharmaceutically acceptable carrier can also contain a physiologically acceptable compound that acts, for example, to stabilize or increase the solubility of a pharmaceutical composition. Such a physiologically acceptable compound can be, for example, a carbohydrate, such as glucose, sucrose or dextrans; an antioxidant, such as ascorbic acid or glutathione; a chelating agent; a low molecular weight polypeptide; or another stabilizer or excipient. Pharmaceutically acceptable carriers, including solvents, stabilizers, solubilizers and preservatives, are described, for example, in Martin,  Remington&#39;s Pharm. Sci.,  15th Ed. (Mack Publ. Co., Easton, 1975).  
     [0097] Those skilled in the art can formulate the therapeutic molecules to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) excludes many highly hydrophilic compounds. To ensure that the effective compounds of the invention cross the BBB, if desired, they can be formulated, for example, in liposomes, or chemically derivatized. For a review of strategies for increasing bioavailability of polypeptide drugs in the brain, and of methods for determining the permeability of polypeptides through the BBB using in vitro and in vivo assays, see Engleton et al.,  Peptides  9:1431-1439 (1997). Strategies that have been successfully used to increase the permeability of other neuropeptides through the BBB are particularly contemplated. Modifications to a polypeptide of the invention that can increase its BBB penetration include conjugating the peptide to a lipophilic moiety, such as a lipophilic amino acid or methyldihydropyridine. Similar modifications to invention polypeptides or peptidomimetics are likewise expected to be advantageous.  
     [0098] Methods of ensuring appropriate distribution in vivo can also be provided by rechargeable or biodegradable devices, particularly where gradients of concentrations of drug in a tissue are desired. Various slow release polymeric devices are known in the art for the controlled delivery of drugs, and include both biodegradable and non-degradable polymers and hydrogels. Those skilled in the art understand that the choice of the pharmaceutical formulation and the appropriate preparation of the composition will depend on the intended use and mode of administration.  
     [0099] The effective compounds of the invention can be administered to a subject by any effective route. Suitable routes for delivering the therapeutic molecules of the invention include topically, intraocularly, intradermally, parenterally, orally, intranasally, intravenously, intramuscularly, intraspinally, intracerebrally and subcutaneously. The present invention also provides compounds containing an acceptable carrier such as any of the standard pharmaceutical carriers, including phosphate buffered saline solution, water and emulsions such as an oil and water emulsion, and various types of wetting agents.  
     [0100] An effective dose of an effective compound of the invention can be determined, for example, by extrapolation from the concentration required in the ATX binding or ATX activity assays described herein; or from the dose required to modulate cell proliferation. An effective dose of an effective compound of the invention for the treatment of a pathology can also be determined from appropriate animal models, such as transgenic mice. Animal models for pathologies such as tumors are well-known in the art. An effective dose for treating this disease is a dose that results in either partial or complete regression of the tumor, reduction in metastasis, reduced discomfort, or prolonged life span. The appropriate dose for treatment of a human subject with a therapeutic molecule of the invention can be determined by those skilled in the art, and is dependent on the nature and bioactivity of the particular compound, the desired route of administration, the gender, age and health of the individual, the number of doses and duration of treatment, and the particular condition being treated.  
     [0101] It is understood that modifications which do not substantially affect the activity of the various embodiments of this invention are also included within the definition of the invention provided herein. Accordingly, the following examples are intended to illustrate but not limit the present invention.  
     EXAMPLE 1  
     Molecular Cloning of ATX  
     [0102] This example shows the cloning of ATX nucleic acids. During a BLAST search for mTOR-related proteins, it was noted that an expressed sequence tag (EST) (KIAA0421) contained a 5′-terminus with an open reading frame (ORF) that bore clear homology to a conserved region in the catalytic domains of PIKK family members. To access the full-length cDNA, the EST was used to generate a primer for 5′-RACE with human brain cDNA as the template. The initial 5′-RACE product extended the region of homology with the PIKK catalytic domain. Sequential screens of human brain (Clontech #HL1128a) and Jurkat T cell cDNA libraries (Stratagene #936219), combined with 5′-RACE of brain and Jurkat cDNA, resulted in the isolation of several overlapping DNA fragments that were assembled into approximately 12 kb of contiguous nucleotide sequence. This cDNA contains an ORF of 10,563 nucleotides with an additional 1.8 kb of 3′-UTR, and encodes a 3,521 amino acid polypeptide with a deduced molecular mass of 395 kDa. The first nucleotide of the ATG translation initiation codon in exon 6 as has been designated as nucleotide “1”, and nucleotides upstream of this ATG are identified in the 3′ to 5′ direction with negative numbers. The conclusion that this sequence was derived from a single mRNA transcript was confirmed by PCR with primers that were complementary to the extreme 5′-terminus (nucleotides −90 to −67) and 3′-terminus (nucleotides 10,553 to 10,570) of the corresponding cDNA. The cloned cDNA sequence is contained in a genomic BAC clone (AC020716), which allowed localization of the gene encoding this putative PIKK family member to human chromosome 16. Based on its functional overlap with ATM, this new PIKK family member was named “ATX”.  
     [0103] The collective results of the 5′-RACE and RT-PCR assays of mRNA derived from Jurkat T cell, human brain, and other human cell lines indicated that the ATX locus gives rise to several mRNA transcripts (FIG. 1A). One repetitively isolated ATX cDNA clone contains exon 4 spliced directly to exon 6, and yields the 3,521 amino acid polypeptide described above. This mRNA transcript and encoded polypeptide has been designated “long ATX”, to distinguish it from a “short ATX” polypeptide (3,031 amino acids) produced as a result of allelic variation in exon 15, which leads to the insertion of 27 nucleotides beginning at nucleotide 1427 (FIG. 1A). This sequence alteration causes the insertion of two in-frame stop codons, and use of the next available ATG codon (in exon 16) as the translational start site gives rise to the amino-terminally truncated, short form of ATX. The 5′ end of the ATX allele that encodes short ATX is contained within a second genomic BAC clone (AC003007) derived from human chromosome 16. Yamashita et al. have identified two human cDNA clones, both designated hSMG-1, one of which (FIG. 1A, second from bottom, SEQ ID NO: 7) was similar to the long ATX cDNA clone (SEQ ID NO:1) (Yamashita et al.,  Genes and Development  15:2215-2228 (2001)). Exon 5 was not included in our long cDNA clone due to the infrequent appearance of this exon during our 5′-RACE and RT-PCR analyses of human cell line-derived mRNA. Furthermore, the minority of cDNAs that did include the exon 5 sequence frequently contained exon 3, which placed an in-frame stop codon at the 5′-end of this cDNA (FIG. 1A). The longest ATX cDNA clone (ORF beginning at exon 2, SEQ ID NO:9) identified by Yamashita et al. (Yamashita et al., supra, 2001) was also isolated in our screening procedure. However, it was repeatedly found that the exon 3-associated stop codon was present in this transcript.  
     EXAMPLE 2  
     Expression of Endoqenous and Recombinant ATX  
     [0104] In order to examine the expression of ATX mRNA in various tissues, a multiple tissue Northern blot was hybridized with a 32P-labelled, ATX cDNA probe that spanned exons 38-39(nucleotides 5,071-5,370). The ATX probe detected a major mRNA species that, based on its electrophoretic mobility, was significantly larger the 9.5 kb calibration marker, and could reasonably accommodate the predicted ORF (10.5 kb) of long ATX (data not shown). This ATX transcript was widely expressed in human tissues, with the highest levels observed in heart and skeletal muscle. These results are consistent with those obtained in immunoblot analyses with ATX-specific antibodies, which showed that ATX protein was uniformly expressed in hematopoietic, mesenchymal, and epithelial cell lines (data not shown). Database searches with the ATX amino acid sequence revealed the highest degree of homology to  C. elegans  SMG1, a protein required for NMD in the worm. Both ATX and CeSMG1 contain the PI 3-kinase related catalytic domain, which identifies these proteins as members of the PIKK family (FIG. 1B). Outside of the catalytic domain, the regional sequence homology between ATX and other PIKK family members was limited to the FKBP-12rapamycin binding (FRB, designated NH2 in FIG. 1B) domain of mTOR, and to the NH1 and NH2 domains of CeSMG1. The FRB domain mediates the high-affinity interaction between mTOR and the antiproliferative FKBP12rapamycin complex (Chen et al.,  Proc. Natl. Acad. Sci. USA,  92:4947-4951 (1995)). However, the FRB-related domain of ATX does not confer any detectable binding affinity for FKBP12rapamycin (data not shown); hence, it is unlikely that ATX is a relevant target for rapamycin in intact cells. The expression of the short and long forms of ATX were compared after transient transfection of the respective cDNAs into human embryonic kidney 293T cells. The short ATX polypeptide was poorly expressed relative to long ATX (data not shown). However, these results do not exclude the possibility that the shorter form of ATX is expressed and contributes to the overall functions of ATX in mammalian cells.  
     [0105] In order to compare the translation product derived from the long ATX cDNA with the endogenously expressed ATX polypeptide, HEK 293T cells were transfected with HA-tagged expression plasmids encoding either wild-type ATX (HA-ATXWT) or a catalytically inactive ATX mutant (HA-ATXKI). The HA-ATXKI mutant contains an Asp&gt;Ala substitution at a conserved residue (Asp-2195) in the ATX catalytic domain. Similar mutations in the catalytic domains of ATM, ATR, and DNA-PKCS have been shown to generate kinase-inactive (KI) versions of these PIKK family members (Canman et al.,  Science,  281:1677-1679 (1998); Cliby et al.,  EMBO Journal,  17:159-169 (1998); Hunter, supra, 1995).  
     [0106] For analyses of the endogenous ATX protein, two different rabbit polyclonal antibodies were prepared against GST fusion proteins containing peptide fragments derived from ATX. The first antibody (α-ATX Ab-1) was generated against a GST fusion protein containing amino acids 2281-2339 of ATX, while the second (α-ATX Ab-2) was obtained from immunizations with GST fused to amino acids 1691-1790 of ATX. The α-ATX Ab1 immunoblot analyses of whole cell extracts from non-transfected or HA-ATX-transfected HEK 293T cells revealed a single major immunoreactive band migrating, at the predicted molecular mass of ˜395 kDa (data not shown). An immunoreactive protein bearing a nearly identical electrophoretic mobility was detected in α-HA immunoprecipitates from transfected 293T cells. These results indicate that the molecular mass of the recombinant protein produced from the long ATX cDNA corresponds closely to that of the endogenous ATX protein. Consistent with the predicted size of ATX, the band recognized by the α-ATX antibodies migrated with a significantly lower electrophoretic mobility than either ATM (molecular mass, 370 kDa) or ATR (molecular mass, 305 kDa).  
     [0107] Methods:  
     [0108] Cloning  
     [0109] The longer ATX ORF was appended with an amino-terminal hemagglutinin (HA) epitope tag sequence (CYPYDVPDYASL), and was subsequently amplified as two partially overlapping fragments from Jurkat cDNA. The nucleotide at position 4,620 was mutated in each of the two PCR products to create a SacII site that could be utilized to ligate the two ATX fragments, which were inserted into the XhoI and NotI sites of pcDNA3.1 (Invitrogen) (HA-ATX). The mutation used to generate the SacII did not alter the ATX polypeptide sequence. The expression vector encoding the catalytically inactive ATX mutant (HA-ATXKI) contains an Ala substitution at Asp-2195, which was generated by site-directed mutagenesis with the QuickChange kit (Stratagene). All plasmid constructs were sequenced to insure the fidelity of the PCR and cloning procedures.  
     [0110] Cell Lines  
     [0111] U2OS osterosarcoma and human embryonic kidney (HEK) 293T cells were cultured in low-glucose Dulbecco&#39;s Modified Eagle&#39;s Medium (DMEM), supplemented with 10% fetal bovine serum. The ATM-deficient human fibroblast line, AT4BI, was maintained in DMEM/F-12 medium supplemented with 10% fetal bovine serum. Where indicated, cells were γ-irradiated with a 137Cs source or UV irradiated with a UV-B source (λmax, 305 nm).  
     [0112] Antibodies  
     [0113] ATX-specific antibodies were raised by immunizing rabbits (Cocalico Biologicals, Inc.) with the indicated glutathione S-transferase (GST) fusion protein. Anti-ATX Ab-1 was raised against a GST fusion protein containing ATX amino acids 2281-2339, and α-ATX Ab-2 was raised against a GST fusion protein containing ATX amino acids 1691-1790. For purification of α-ATX Ab-2, GST-reactive antibodies were first absorbed on GSH-agarose. The flow-through fraction was then affinity purified over Affi-Gel 15 (BIO-RAD) coupled to the GST-ATX1691-1790 fusion protein. The α-PLC-γ1 antiserum was prepared as described (Secrist et al.,  J. Biol. Chem.,  268: 5886-5893 (1993)). The α-ATM (Ab-3), α-ATR (Ab-1), α-phospho-Ser15-p53, and α-p53 (Ab-6) reagents were obtained from Oncogene Science Research Products. Additional antibodies were obtained from (sources in parentheses): α-HA (clone 12CA5; BabCo), α-FLAG-M2 and α-tubulin (Sigma), α-Cds1/Chk2 (Upstate Biotechnology), and α-GAL4 (clone RK5C1; Santa Cruz Biotechnology).  
     [0114] Two-Dimensional Page  
     [0115] HEK 293 cells were lysed and protein analyzed as described {Pal, 2001 #1360}, except that cellular extracts were incubated for 2 h with α-FLAG-M2 mAb, followed by 2 h with protein G agarose (Sigma) to immunoprecipitate the FLAG-hUpf1 protein. Prior to elution, the immunoprecipitates were washed in lysis buffer as described {Pal et al., Rna  7:5-15 (2001) #1360}.  
     [0116] Immunofluorescence  
     [0117] For immunofluorescence microscopy of endogenous ATX, 6× 104  U2OS cells were plated onto 22-mm2 glass coverslips. After 40 h, cells were exposed to 400 J/m2 UV-B, then fixed 1, 4 or 8 hrs later in phosphate-buffered saline (PBS) containing 4% paraformaldehyde for 20 min, and incubated in methanol at −20° for 15 min. The coverslips were rehydrated in phosphate-buffered saline (PBS) and incubated overnight at 4° C. in blocking solution (PBS containing 3% BSA and 2% goat serum). Coverslips were subsequently overlayed for 1 h with affinity purified α-ATX Ab-2 (1 μg per ml) in blocking solution at room temperature. Coverslips were washed with PBS, 0.2% Tween-20, and overlayed for 45 min at room temperature with fluorescein isothiocyanate (FITC)—conjugated goat anti-rabbit IgG (Caltag) (1:2000 in blocking solution). Samples were then washed and incubated with 100 μg per ml RNaseA in PBS for 30 min, followed by 1 μg per ml propidium iodide for 5 min. After extensive washing in PBS containing 0.2% Tween-20, coverslips were mounted on slides with an aqueous anti-fade mounting reagent (Vectashield, Vector Laboratories). Immunofluorescence images were generated with a Carl Zeiss LSM410 scanning laser confocal microscope.  
     EXAMPLE 3  
     Characterization of ATX Kinase Activity  
     [0118] With the exception of the TOR proteins, the PIKK family members that bear functional catalytic domains phosphorylate substrates bearing the Ser/Thr-Gln motif (Tibbetts and Abraham, supra, 2000). To determine whether the ATX kinase domain displayed a similar phosphorylation site selectivity, HEK 293T cells were transfected with a plasmid vector encoding HA-tagged ATXWT, ATXKI, or, for comparative purposes, HA-ATMWT. Detergent extracts from the transfected cell populations were immunoprecipitated with α-HA antibody, and protein kinase assays were performed in buffer containing Mn2+, [γ-32P]ATP, and a GST fusion protein containing the first 70 amino acids of p53 (GST-p53 1-70 ) as the substrate (FIG. 1C). The GST-p53 1-70  protein was previously identified as a substrate for ATM and ATR in immune complex kinase assays (Tibbetts et al.,  Genes and Development  13:152-157 (1999)). Interestingly, the specific kinase activity of HA-ATXWT towards GST-p53 1-70  was significantly higher than that of HA-ATM (FIG. 1C, left panel). Based on the ratios of 32P incorporation into substrate to levels of HA-tagged protein kinase, it can be estimated that the specific kinase activity of ATXWT was approximately 3.5-fold higher than that of ATMWT. As observed with ATM as the test kinase (Banin et al.,  Science  281:1674-1677 (1998); Canman et al.,  Science  281:1677-1679 (1998); Tibbetts et al., supra, 1999), phosphorylation of GST-p53 1-70  by ATXWT was nearly abolished by substitution of the Ser-15 residue in p53 with Ala (FIG. 1C, right panel). Because Ser-15 resides in the optimal sequence (LSQE) for phosphorylation by ATM (O&#39;Neill et al.,  J. Biol. Chem.  275:22719-22727 (2000)), this finding indicates that ATX is a Ser/Thr-Gln-directed kinase, with the potential to phosphorylate a set of substrates that overlaps with those modified by ATM. In contrast to the amino-terminal fragment, of p53, the PHAS-I/4E-BP1 protein, which is the prototypical substrate for mTOR, was poorly phosphorylated by HA-ATXWT in immune complex kinase assays (data not shown).  
     [0119] The amino acid sequences surrounding the four phosphorylation sites (LSQP, LSQD, LSQD, and LSQY) identified in this study resemble the consensus site for phosphorylation by ATM (O&#39;Neill et al., supra, 2000). A GST fusion protein that contained the carboxyl-terminal region of hUpf1 (amino acids 1019-1118), including all four of the ATX phosphorylation sites was constructed. This GST-hUpf11019-1118 protein was tested as a substrate for HA-ATXWT versus HA-ATMWT in immune complex kinase assays. Once again, this substrate was phosphorylated by both ATM and ATX, with the latter protein kinase showing the higher specific catalytic activity under these in vitro assay conditions (FIG. 1C, left panel). Furthermore, the results of repeated assays indicated that GST-p53 1-70  was more avidly phosphorylated by ATX than was the GST-hUpf11019-1118 substrate.  
     [0120] The protein kinase activities of the mammalian PIKKs characteristically display a strong dependence on Mn2+ as a cofactor for the phosphotransferase reaction, and variable sensitivity to inhibition by wortmannin (Abraham,  Genes and Development  15:2177-2196 (2001)). In our studies, the protein kinase activity of ATX was also dependent on the addition of Mn2+ the kinase reaction buffer (data not shown). In addition, pretreatment of the immunoprecipitated HA-ATXWT protein with wortmannin resulted in a concentration-dependent inhibition of GST-p53 1-70  phosphorylation. The drug concentration required for 50% inhibition (IC50) of ATX activity in vitro was between 10 and 100 nM (FIG. 1D), which is comparable to the previously published IC50 (80 nM) for wortmannin as an ATM inhibitor (Sarkaria et al.,  Cancer Res.  58:4375-4382 (1998)). Wortmannin is an irreversible inhibitor of PIKKs (Walker et al.,  Molecular Cells  6:909-919 (2000)) and can be used to assess the potency of this drug as an ATX inhibitor in intact cells. To this end, U2OS osteosarcoma cells were pretreated for 30 min with the indicated concentrations of wortmannin, followed by the preparation of cellular extracts for immunoprecipitation of endogenous ATX with α-ATX Ab-2. Under these conditions, wortmannin inhibited ATX kinase activity with an IC50 of 1-3 μM, which is considerably higher than that observed following direct treatment of the immunoprecipitated protein kinase with this drug (FIG. 1D). A similarly dramatic decrease in the inhibitory potency of wortmannin was observed with ATM as the target enzyme in intact cells (Sarkaria et al., supra, 1998).  
     [0121] Immune Complex Kinase Assays  
     [0122] Native or recombinant ATX proteins were immunoprecipitated from cell extracts as described above, and the immunoprecipitates were washed twice in lysis buffer, once in high-salt buffer (100 mM Tris-HCl, pH 7.4, 500 mM LiCl) and once in kinase buffer (10 mM Hepes, pH 7.4, 50 mM NaCl, 50 mM β-glycerol phosphate). Forty μl kinase buffer (containing 10% glycerol, 1 mM DTT, 10 mM MnCl 2 , 20 nM microcystin, protease inhibitors, 1 μg of the indicated substrate, 10 μM ATP, and 10 μCi [γ-32P]ATP (6000 Ci/mmole) (NEN)] was added to each sample, and kinase reactions were performed for 30 min at 30° C. Reactions were terminated by addition of 40 μl of 4×-SDS-PAGE sample buffer, and heating to 100□C.  
     EXAMPLE4  
     Subcellular Localization of ATX  
     [0123] The subcellular localization of ATX was examined by biochemical fractionation of U2OS cells, followed by immunoprecipitation of crude nuclear and cytoplasmic fractions with α-ATX Ab-2. Comparable levels of ATX were found in the nuclear and cytoplasmic extracts from U2OS cells (data not shown). The integrity of these subcellular fractions was confirmed by immunoprecipitation and immunoblotting of parallel samples with antibodies specific for PLCγ1 and ATR, which are localized to the cytoplasm and nucleus, respectively. The presence of ATX in both the cytoplasmic and nuclear compartments was further documented by immunostaining of U2OS cells with affinity-purified α-ATX Ab-2. Exposure of cells to genotoxic agents triggers the appearance of DNA damage-induced nuclear foci containing either ATM or ATR (Andegeko et al.,  J. Biol. Chem.  276:38334-38230 (2001); Tibbetts et al.,  Genes and Development  14:2989-3002 (2000)). To determine whether ATX undergoes similar changes in subcellular localization in response to genotoxic stress, U2OS cells were treated with 400 J/m2 UV-B, and stained with α-ATX Ab-2. Exposure to UV triggered the appearance of ATX-containing nuclear foci. The ATX-positive foci were evident within 1 h after UV treatment, and continued to accumulate in the cells until at least 8 h post-treatment, at which time greater than 50% of the cells exhibited multiple ATX-containing foci. In contrast, the formation of ATX foci after treatment of U2OS cells with 20 Gy IR was not detected.  
     [0124] In addition, the effect of genotoxic stress on the protein kinase activity of ATX in immune complex assays was determined. Consistent with the results of the immunofluorescence staining experiments, treatment of the cells with IR failed to induce a reproducible increase in the protein kinase activity observed in α-ATX immunoprecipitates (data not shown). On the other hand, UV exposure caused a modest but consistent increase in ATX kinase activity that reached a maximal level at 4 h post-irradiation. Collectively, the results of the nuclear localization and protein kinase activity studies indicated that, like ATM and ATR, ATX participated in cellular responses to DNA damage or other forms of stress induced by UV irradiation.  
     [0125] Methods:  
     [0126] Cell Fractionation, Immunoprecipitation, and Immunoblotting  
     [0127] For subcellular fractionations, U2OS cells were resuspended in cold homogenization buffer (25 mM Hepes, pH 7.4, 250 mM sucrose, 1 mM EGTA, 5 mM MgCl2, 50 mM NaF, 1 mM DTT, plus protease inhibitors) and Dounce homogenized on ice with 40 strokes in a Tefloncoated homogenizer. The nuclei were pelleted at 500×g, and the supernatant was collected as the crude cytoplasmic fraction. Prior to immunoprecipitation, 150 mM NaCl and 1% (wt/vol) NP-40 (final concentration) were added to the crude cytoplasmic fractions. Nuclear extracts were prepared by suspending the nuclear pellets in extraction buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 1% NP-40, 1 mM dithiothreitol), supplemented with protease inhibitors (10 μg per ml leupeptin, 10 μg per ml aprotinin, 1 μM pepstatin). After 15 min on ice, the samples were centrifuged, and the supernatant was collected for analysis. For immunoprecipitations, cell extracts were prepared by resuspending washed cell pellets in lysis buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 1% NP-40, 1 mM dithiothreitol) plus protease inhibitors. When samples were prepared for immune complex kinase assays, the lysis buffer was modified to contain 1% Tween-20 detergent in place of NP-40, and additional phosphatase inhibitors (20 mM β-glycerol phosphate and 50 nM microcystin). Samples were incubated on ice for 15 min, and then clarified by centrifugation. HA-tagged recombinant proteins were immunoprecipitated from cell extracts with 4 μg of α-HA antibody. Endogenous ATX protein was immunoprecipitated with 8 μg of α-ATX Ab-2. After separation by SDS-PAGE, the proteins were detected by autoradiography (for kinase reaction products) or by immunoblotting. Proteins immunoblotted with rabbit and mouse antibodies were detected with protein A-horseradish peroxidase (HRP) (Amersham), and sheep anti-mouse IgG-HRP (Amersham), respectively. Immunoreactive proteins were illuminated with Renaissance chemiluminescence system (NEN).  
     EXAMPLE 5  
     Effect of Decreased ATX Function on Cellular Sensitivity to UV and IR  
     [0128] In order to gain further insights into the role of ATX in stress responses, U2OS cells were transfected with the kinase-inactive ATXKI mutant, and the UV- and IR-sensitivities of the transfected cells in clonogenic survival assays was examined. Control cell populations were transfected with either empty plasmid (pcDNA3.1) or with ATXWT-encoding plasmid. At 48 h post-transfection, the cells were treated with various doses of UV-B (FIG. 2A) or IR (FIG. 2B). The treated cells were then cultured in G418-containing medium in order to select for stably transfected cells. Cellular survival was determined after 10 days in culture by staining emergent colonies with Coomassie blue, followed by calorimetric quantitation of the amount of dye-bound protein present in each sample. Expression of ATXKI, but not ATXWT, reduced the basal survival of otherwise untreated U2OS cells (FIG. 2B, top panel). These results indicate that endogenous ATX function is required for the maintenance of normal cell viability or growth in culture. Furthermore, expression of ATXKI dramatically increased the sensitivity of U2OS cells to the cytostatic/cytotoxic effects of both UV and IR in these clonogenic survival assays.  
     [0129] To address concerns related to potential non-specific effects of ATXKI expression on cellular functions, an antisense oligonucleotide-based approach to reduce the level of ATX expression in U2OS cells was developed. The cells were mock transfected, or transfected with sense (S) or antisense (AS) oligonucleotides, and then treated for 24 h with various genotoxic agents. The cells were then trypsinized and replated, and clonogenic survival was analyzed after 10 days in culture. The results obtained with AS-treated cells were strikingly similar to those obtained with the ATXKI-expressing cells (FIGS.  2 A-C). While transfection of U2OS cells with the S oligonucleotide reduced the basal level of colony outgrowth by 25%, treatment with the AS oligonucleotide decreased basal clonogenic activity by 75% (FIG. 2C, right panel). Hence, the AS-induced decrease in ATX protein expression was accompanied by a reduction in cell viability or proliferation in the absence of environmental stress. Furthermore, the AS-treated cells were significantly more sensitive to the suppressive effects of IR (FIG. 2C, left panel) and UV treatments (data not shown) on clonogenic survival. The reduction in ATX protein caused by AS treatment ranged from 50-90% in over 10 independent trials.  
     [0130] Methods:  
     [0131] Cell Transfections  
     [0132] To prepare recombinant HA-tagged ATX and ATM proteins, HEK 293T cells were plated onto 60-mm dishes (9×105 cells per dish), and were transfected with 5 μg pcDNA3.1 (empty vector), HA-ATXWT, HA-ATXKI, or HA-ATMWT plasmid DNAS. Transfections were performed with the Fugene 6 transfection reagent (Roche), according to the manufacturer&#39;s instructions. For NMD assays (see Example 9, below), U2OS cells were seeded onto 100 mm dishes (1×106 cells per dish). After 20 h, cells were transfected with 1.5 μg of pmCMV-Gl test plasmid, either Norm or 39Ter (Ishigaki et al., 2001); 1.5 μg of phCMV-MUP reference plasmid (Ishigaki et al.,  Cell  106:607-617 (2001)); and 7 μg of empty plasmid (pcDNA 3.1), plasmids encoding HA-ATMWT, HA-ATMKI, HA-ATXWT or HA-ATXKI. For antisense transfection experiments, U2OS cells were seeded onto 60 mm dishes (1×10 5  cells per dish) in complete medium supplemented with penicillin/streptomycin. After 30 h, cells were either mock transfected or transfected with sense (S) or antisense (AS) phosphorothioate oligonucleotides (Genset Oligos, La Jolla, Calif.). The S oligonucleotide spans ATX nucleotides 210-229 (5′-GAGACAGGAGGGAGCTTGCT-3′), and the AS oligonucleotide is complementary to this sequence (5′-AGCAAGCTCCCTCCTGTCTC-3′). The cells were transfected with oligonucleotides at final concentrations of 8 μg/ml, with Fugene 6:DNA ratio of 1.6:1. Forty-eight hours after transfection, dishes were exposed to IR, UV-B, or 5-FU, and then harvested for immunoblotting, cell-cycle distribution, or cell survival assays. To examine ATX protein levels in oligonucleotide-treated cells, whole cell extracts were resolved by SDS-PAGE and immunoblotted with α-ATX Ab-1. When oligonucleotide-transfected cells were used for NMD assays, U2OS cells were seeded in culture dishes as described above. The cells were transfected using the Fugene reagent, with 1.5 μg of pmCMV-Gl test plasmid, 0.7 μg of phCMV-MUP reference plasmid, and 24 μg of S or AS oligonucleotide.  
     [0133] Clonogenic and G418 Survival Assays  
     [0134] U2OS cells were seeded into 60 mm dishes (1×105 cells per dish) in complete medium. After 48 h, cells were transfected as described above. Forty-eight hours after transfection, dishes were exposed to IR or UV-B, and G418 was added at 1 mg per ml in complete medium. G418-resistant cells were stained 10 days later with Coomassie Blue. To quantitate the outgrowth of drug-resistant cells, the Coomassie Blue-bound protein was solubilized at 37° C. with 0.1 M NaOH, and the soluble material was analyzed by absorbance spectroscopy at a wavelength of 590 nm. For AT4BI cell survival assays, cells were transfected with pcDNA3.1, pcDNA3.1-FLAG-ATM, or HA-ATX. After 48 h, the transfected cells were exposed to the indicated doses of IR, and G418 was added at 8 hours post-irradiation. Drug-resistant colonies were stained with Coomassie Blue after 10 days in culture, and the samples were analyzed with Image Pro Plus software to quantitate cell density. For clonogenic assays where oligonucleotides were used, the cells were plated and transfected with S or AS oligonucleotides as described above. Forty-eight hours after transfection, cells were exposed to IR or UV. Twenty-four hours after exposure to damaging agents, cells were replated at 1000 cells per 60 mm dish and colonies allowed to form for 10 days. Dishes were stained with Coomassie Blue, and the number of colonies (minimum size, 50 cells per colony) was counted by visual examination.  
     EXAMPLE 6  
     Role of ATX in p53 Activation  
     [0135] A major mediator of stress-induced signaling in mammalian cells is the tumor suppressor protein, p53 (Ko and Prives,  Genes and Development  10:1054-1072, (1996); Ryan et al.,  Curr. Opin. Cell Biol.  13:332-337 (2001)). ATX phosphorylates p53 on Ser-15 (FIG. 1C), a site implicated in the regulation of p53 stability and transcriptional activity (Dumaz and Meek,  Curr. Opin. Cell Biol.  13:225-231 (1999); Zhang and Xiong,  Science  292:1910-1915 (2001)). Therefore, the possibility that these two proteins are functionally linked during cellular stress responses was investigated. U2OS cells were transiently transfected with a HA-ATXWT or HA-ATXKI expression plasmid, together with a GFP-encoding plasmid to allow for FACS-based enrichment of the transfected cells. The GFP+ cells were then examined for IR-induced stabilization of p53, as well as for specific phosphorylation of this protein on Ser-15. Expression of ATXKI strongly suppressed both the phosphorylation of Ser-15 and the overall accumulation of p53 in IR-treated cells (FIG. 3A). In contrast, overexpression of ATXWT enhanced both of these responses in cells exposed to IR. Consistent with findings presented above, treatment of U2OS cells with the AS oligonucleotide led to a decrease in endogenous ATX expression, and concomitantly reduced both the phosphorylation and stabilization of p53 induced by IR exposure (FIG. 3B). These results indicated that ATX exhibits functional overlap with ATM during IR-induced p53 activation.  
     [0136] Recent findings point toward ATM as a critical upstream regulator of the activity of the checkpoint kinase, hChk2, in IR-damaged cells (Ahn et al.,  Cancer Res.  60:5934-5936 (2000); Melchionna et al.,  Nat. Cell Biol.  2:762-765 (2000)). To determine whether ATX was also involved in hChk2 activation, the effect of AS oligonucleotide treatment on the IR-dependent phosphorylation of hChk2 was examined. In contrast to the p53 results, the AS-treated cells retained the ability to phosphorylate hChk2 in response to IR-induced stress (FIG. 3B). These results indicate that, while ATM and ATX serve as positive regulators of p53 function, ATX plays no identifiable role as an upstream activator of a distinct ATM target protein, the hChk2 kinase. Moreover, the differential effects of AS treatment on p53 expression versus hChk2 activation argue against the possibility that AS exposure leads to nonspecific inhibition of checkpoint signaling responses to IR-induced DNA damage.  
     [0137] Additional studies with AS oligonucleotide-treated cells demonstrated that, in contrast to ATM (Canman et al.,  Science  281, 1677-1679. 1998; Siliciano et al.,  Genes Dev  11, 3471-3481 (1997)), ATX plays a role in the phosphorylation and stabilization of p53 in cells exposed to UV light (FIG. 3C). As observed with IR as the stress-inducing agent, a reduction in ATX protein expression severely impaired both Ser-15 phosphorylation and p53 protein accumulation in UV-damaged cells. The recognition of UV light-induced DNA damage occurs primarily during S phase, when pyrimidine dimers and other bulky lesions interfere with replication fork progression (Friedberg,  DNA Repair and Mutagenesis  (Washington, D.C., ASM Press) (1995); Lindahl and Wood,  Cell  103:1121-1131 (1999)).  
     [0138] In order to further define the potential linkage between DNA replicational stress and ATX, the response of AS-treated cells to 5-fluorouracil (5-FU), an S-phase specific cytotoxic agent was examined (Danenberg et al.,  Seminars in Oncology  26:621-631 (1999); Grem,  Investigational New Drugs  18:299-313 (2000)). Previous findings indicated that the cytotoxic effects of 5-FU are strongly p53-dependent (Bunz et al.,  J. Clin. Invest.  104:263-269 (1999)). Treatment of U2OS cells with 5-FU increased p53 expression to levels similar to those observed in UV-irradiated cells (FIG. 3C). However, the accumulation of p53 induced by 5-FU exposure was not accompanied by an increase in Ser-15 phosphorylation. These findings indicate that the mechanism of p53 stabilization triggered by 5-FU does not involve upstream protein kinases that modify the Ser-15 site. Consistent with this conclusion, the level of p53 induction by 5-FU in AS-treated cells was identical to that observed in their S-treated counterparts. These results indicate that the inhibitory effect of the AS treatment on p53 activation is selective for those forms of stress that induce the phosphorylation of p53 at Ser-15.  
     [0139] Changes in phosphorylation at Ser-15 are typically accompanied by alterations in the expression of the p53 protein, which complicates the interpretation of results obtained by immunoblotting of whole cell extracts with phospho-Ser-15-specific antibodies. In order to confirm that reduced ATX expression interferes with stress-induced Ser-15 phosphorylation, U2OS cells were transfected with either the S or AS oligonucleotide, and then were pretreated with the proteasome inhibitor, LLnV, to stabilize p53. In the presence of LLnV, the p53 level in each test population was relatively unaffected by UV exposure (data not shown). However, the ratio of phospho-Ser-15 to total p53 protein was increased by UV irradiation of both the mock-transfected and S oligonucleotide-treated cells. Although AS treatment partially interfered with the accumulation of p53 under these conditions, the reduction in ATX expression effectively blocked the stoichiometric increase in Ser-15 phosphorylation triggered by UV-induced stress.  
     EXAMPLE 7  
     Role of ATX in IR-Induced Cell Cycle Arrest  
     [0140] Since p53 plays a central role in activation of the G1 checkpoint, and influences S, G2, and M checkpoints as well (Giaccia and Kastan,  Genes  &amp;  Development  12:2973-2983 (1998); Ko and Prives, supra, 1996), a functional deficiency of ATX might alter the cell-cycle arrest responses to IR and other genotoxic agents. To test this possibility, U2OS cells were pre-treated with S or AS oligonucleotides, exposed to IR, and cell-cycle distributions at 24 h post-irradiation were determined. In the absence of IR, AS treatment led to a reduction in the percentage of G1 phase cells, and a concomitant accumulation of G2/M phase cells, when compared to their S oligonucleotide-treated counterparts (FIG. 3D). The AS-treated cells also contained an increased subpopulation with &lt;2N DNA content, which is indicative of apoptotic cells. After IR exposure, cells treated with the S oligonucleotide accumulated in both G1 and G2/M phases and were cleared out of S phase, a profile typical of p53-positive cells that retain G1 checkpoint function. In contrast, the AS-treated cells arrested primarily in G2/M phase after IR exposure. The cell-cycle distribution of the AS-treated cells was reminiscent of that observed in cells that have lost p53-dependent checkpoint function (North and Hainaut,  Pathol. Biol.  48:255-270 (2000); Waldman et al.,  Cancer Res.  55:5187-5190 (1995)). Immunoblot analyses of the same cell populations confirmed that AS exposure led to a profound reduction in ATX protein levels in U2OS cells. In contrast, AS exposure caused no significant change in the expression levels of two control proteins, ATM and PLC-γ1.  
     [0141] The cell-cycle distribution results described in FIG. 3D demonstrated that ATX-deficient cells accumulate with 4N DNA content under both basal culture conditions and after IR-induced stress. This arrest state could reflect the activation of either a G2 or a mitotic checkpoint (or both checkpoints). To distinguish between these possibilities, the effects of caffeine, a known inhibitor of the G2 checkpoint (Powell et al.,  Cancer Res.  55:1643-1648 (1995); Russell et al.,  Cancer Res.  55:1639-1642 (1995); Yao et al.,  Nat, Med.  2:1140-1143 (1996)), on the cell cycle distribution of the AS-treated cells were examined. The G2 checkpoint inhibitor was added to the culture medium at 8 h prior to harvest for determination of cell-cycle distributions (FIG. 3E, left panel), and immunoblotting for ATX expression (right panel). Caffeine completely reversed the accumulation of G2/M phase cells induced by AS treatment, indicating that ATX deficiency triggered the activation of a caffeine-sensitive G2 checkpoint. The immunoblotting results confirmed that AS-treated cells displayed a marked, specific reduction in ATX protein expression. In addition, treatment of the AS cells with caffeine also resulted in an increase in the percentage of hypodiploid cells, which indicates that an intact G2 checkpoint partially protects the ATX-deficient cells from apoptotic death, for example, by preventing a catastrophic entry into M phase.  
     EXAMPLE 8  
     ATX Overexpression Complements IR Sensitivity in ATM-Deficient Cells  
     [0142] Based on the finding that ATM and ATX display overlapping functions as activators of p53, it was investigated whether ATX overexpression can complement the phenotypic defects found in cells from A-T patients. One characteristic defect of cells from A-T patients is reduced clonogenic survival in culture, even in the absence of DNA dsb-inducing agents (Rotman and Shiloh,  Oncogene  18:6135-6144 (1998)). As shown in FIG. 4A, transient transfection of ATM-null AT4BI cells with an ATM expression plasmid increased the outgrowth of G418-resistant colonies by approximately 2-fold, relative to cells transfected with empty vector. The clonogenic defect of AT4BI cells was partially rescued (approximately 1.5-fold increase in colony survival) by transient expression of ATX. Thus, ATX overexpression partially complements the intrinsic clonogenic survival defect of ATM-null cells. Furthermore, low-dose (1 Gy) IR treatment sharply reduced the clonogenic survival of mock-transfected AT4BI cells, and this radiosensitive phenotype was rescued to equivalent degrees by transfection of the cells with ATM or ATX (FIG. 4B). Thus, overexpression of ATX complements, at least in part, the stress response defects observed in cells from A-T patients.  
     EXAMPLE 9  
     Roles of ATX and ATM in hUpf1 Phosphorylation and NMD  
     [0143] The Upf1 helicase undergoes serum-inducible phosphorylation in intact cells, as demonstrated by two-dimensional(2-D) gel electrophoresis (Pal et al., supra, 2001). Based on the evidence disclosed herein that ATX is a UV-responsive kinase, the possibility that UV light exposure triggers the phosphorylation of hUpf1 in ATXWT-transfected U2OS cells was investigated. Serum stimulation or UV treatment induced virtually identical shifts in the 2-D electrophoretic mobility of hUpf1, which indicates that these agents provoke the phosphorylation of this protein at similar sites (data not shown). In contrast, expression of the catalytically-inactive ATXKI protein blocked the appearance of the most highly shifted form of hUpf1, and caused the accumulation of a broad band with intermediate electrophoretic mobility. The latter hUpf1 species can be less phosphorylated forms of the protein. Thus, overexpression of ATXKI interferes with both the serum- and UV-induced phosphorylation of hUpf1; however, these results also indicate that the hUpf1 is targeted by at least one additional protein kinase in these cells.  
     [0144] Based on the functional overlap between ATM and ATX during stress-induced p53 activation, it was possible that these PIKKs might also share the ability to regulate the RNA surveillance pathway leading to NMD. To focus our studies of hUpf1 phosphorylation on the Ser-Gln-rich region, a mammalian expression vector encoding GAL4 fused to the carboxyl terminus (amino acids 1019-1118) of hUpf1 (GAL4-hUpf11019-1118) was generated. Expression of GAL4-hUpf11019-1118 in U2OS cells generates a major immunoreactive band that migrates with a molecular mass of ˜35 kDa in serum-starved cells. Stimulation of the transfected cells with 10% fetal bovine serum or UV light leads to the increased expression of forms of GAL4-hUpf11019-1118 that display reduced electrophoretic mobility (FIG. 5A, left panel). In this experiment, cells were harvested at 6 h after serum or UV exposure; however, the GAL4-hUpf11019-1118 mobility shifts could be detected as early as 2 h after cellular stimulation with either agent. The appearance of these shifted GAL4-hUpf11019-1118 bands is due to phosphorylation, as treatment of the cell extracts with λ phosphatase collapses the complex pattern of α-Gal4-reactive species into the major ˜35 kDa band, which represents non-phosphorylated GAL4-hUpf11019-1118 (FIG. 5A, right panel). Moreover, the observed GAL4-hUpf11019-1118 mobility shifts were due to phosphorylation of the hUpf1 fragment, as the electrophoretic mobility GAL4 alone was not altered by cellular exposure to serum or UV (FIG. 5A, lower panel). In the experiment shown in FIG. 5A (left panel), selected samples were pretreated with 20 μM wortmannin in order to inhibit endogenous ATX and ATM kinase activities (Sarkaria et al., supra, 1998)). In the wortmannin-treated cells, the FBS- or UV-induced generation of the most slowly migrating form of GAL4-hUpf11019-1118 (indicated with an arrow) was preferentially inhibited. This drug effect was accompanied by an increase in the abundance of the less shifted bands, which can represent less phosphorylated forms of GAL4-hUpf11019-1118. These results indicate that, although a wortmannin-sensitive protein kinase(s) contributes to the inducible phosphorylation of the GAL4-hUpf11019-1118 reporter protein, the hUpf1 carboxyl-terminal region is also targeted for modification by at least one additional, wortmannin-resistant protein kinase.  
     [0145] To further examine the contributions of ATM and ATX to the phosphorylation of GAL4-hUpf11019-1118, U2OS cells were cotransfected with wild-type (WT) or kinase-inactive (KI) versions of HA-ATM or HA-ATX. Expression of either HA-ATMKI or HA-ATXKI strongly suppressed the phosphorylation of GAL4-hUpf11019-1118 in cells treated with UV light (FIG. 5B) or serum (data not shown). Expression of the catalytically active HA-ATMWT or HA-ATXWT proteins enhanced the phosphorylation of GAL4-hUpf11019-1118 in both unstimulated and stimulated cells. The latter results add further support to the notion that ATX and ATM are capable of phosphorylating hUpf1 carboxyl-terminal region in intact cells. In these experiments, the HA-tagged ATM and ATX proteins were overexpressed by approximately 2- and 1.5-fold, respectively, when compared to their endogenous counterparts (data not shown).  
     [0146] In addition, the effects of HA-ATXKI and HA-ATMKI overexpression on NMD were comparatively examined using an established assay (Sun et al.,  Proc. Natl. Acad. Sci. USA  95:10009-1998). U2OS cells were transfected with a plasmid encoding either the normal human β-globin gene (Norm) or a mutated β-globin gene bearing a premature termination codon (Ter), together with a reference plasmid encoding the mouse urinary protein (MUP). Where indicated, the cells were co-transfected with empty vector, or expression vectors encoding wild-type or kinase-inactive versions of ATM (HA-ATMWT, HA-ATMKI) or ATX (HA-ATXWT, HA-ATXKI) (FIG. 6A). Expression of the kinase-inactive HA-ATMKI or HA-ATXKI proteins abrogated NMD of the Ter-containing β-globin mRNA. Furthermore, treatment of the cells with the AS oligonucleotide to reduce endogenous ATX expression confirmed that ATX expression is required for maximal NMD activity under these assay conditions (FIG. 6B). Collectively, these results indicate that ATM and ATX function as shared components of the pathways leading to both NMD and p53 activation during UV- and IR-induced stress.  
     [0147] Methods:  
     [0148] Construction of GST and GAL4-hUpf1 Fusion Proteins  
     [0149] The hUpf11019-1118-BamHI fragment was generated by PCR amplification of full-length hUpf1 using the following primers: 5′-AGGAGGGGATCCGGACGCCAGAAGAACCGCTTTGGG-3′, 5′-AGGAGGGGATCCATACTGGGACAGCCCCGTCAC-3′. This fragment was subcloned into the BamHI site of pGEX-2T and pCMX-GAL4(N) to generate the GSThUpf11019-1118 and GAL4-hUpf11019-1118 fusion proteins, respectively.  
     [0150] GAL4-hUpf1 Mobility Shift Assays  
     [0151] U2OS cells were plated in 60 mm dishes (4×105 cells per dish), and then transfected with 0.5 μg pCMX-GAL4 or pCMX-GAL4-hUpf11019-1118, together with 4.5 μg pcDNA3.1-, HA-ATXWT, HA-ATXKI, HA-ATMWT, or HA-ATMKI plasmid DNAs. The HA-ATMKI protein contains an Asp-2870&gt;Ala mutation that inactivates the kinase domain. Twenty hours after transfection, serum was removed from the medium, and the cells were cultured for an additional 24 h. The cells were then treated with 10% fetal bovine serum or 100 J/m2 UV-B. Where indicated, the serum-starved cells were pretreated for 30 min with 20 μM wortmannin prior to treatment with serum or UV. Cells were harvested in lysis buffer containing 25 mM Hepes, pH 7.4, 300 mM NaCl, 1.5 mM MgCl2, 1 mM EGTA, 1% Triton X-100, 20 mM β-glycerophosphate, 20 nM microcystin, 0.1 mM sodium orthovanadate, 1 mM DTT, plus protease inhibitors. For phosphatase treatment, 600 U λphosphatase was added to cellular extracts (New England Biolabs). Cell extracts were resolved on by SDS-PAGE, and were immunoblotted with α-GAL4 antibody.  
     [0152] RNA Isolation and Assays of NMD  
     [0153] Total or nuclear RNA was isolated using Trizol (Invitrogen) or the NE-PER kit (Pierce), respectively. The extent of NMD was determined by using RT-PCR to quantitate the levels of Globin and MUP mRNA as described previously (Ishigaki et al.,  Cell  83: 1-4 (2001)), except that 21 cycles of PCR were used when analyzing the effects of ATX-specific S and AS oligonucleotides.  
     [0154] Throughout this application various publications have been referenced within parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in this application in order to more fully describe the state of the art to which this invention pertains.  
     [0155] Although the invention has been described with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention.  
    
     
       
         1 
         
           
             11  
           
           
             1  
             12464  
             DNA  
             Homo sapiens  
             
               CDS  
               (91)...(10656)  
             
           
            1 

caaccttcaa attcagctgt ggtgtctcgg caaaggcacg atgataccag agtccacgct     60 

gacatacaga atgacgaaaa ggagagatcg atg tct tat tgt gat gag tct cga     114 
                                  Met Ser Tyr Cys Asp Glu Ser Arg 
                                   1               5 

ctg tcg aat ctt ctt cgg agg atc acc cgg gaa gac gac aga gac cga      162 
Leu Ser Asn Leu Leu Arg Arg Ile Thr Arg Glu Asp Asp Arg Asp Arg 
     10                  15                  20 

aga ttg gct act gta aag cag ttg aaa gaa ttt att cag caa cca gaa      210 
Arg Leu Ala Thr Val Lys Gln Leu Lys Glu Phe Ile Gln Gln Pro Glu 
 25                  30                  35                  40 

aat aag ctg gta cta gtt aaa caa ttg gat aat atc ttg gct gct gta      258 
Asn Lys Leu Val Leu Val Lys Gln Leu Asp Asn Ile Leu Ala Ala Val 
                 45                  50                  55 

cat gac gtg ctt aat gaa agt agc aaa ttg ctt cag gag ttg aga cag      306 
His Asp Val Leu Asn Glu Ser Ser Lys Leu Leu Gln Glu Leu Arg Gln 
             60                  65                  70 

gag gga gct tgc tgt ctt ggc ctt ctt tgt gct tct ctg agc tat gag      354 
Glu Gly Ala Cys Cys Leu Gly Leu Leu Cys Ala Ser Leu Ser Tyr Glu 
         75                  80                  85 

gct gag aag atc ttc aag tgg att ttt agc aaa ttt agc tca tct gca      402 
Ala Glu Lys Ile Phe Lys Trp Ile Phe Ser Lys Phe Ser Ser Ser Ala 
     90                  95                 100 

aaa gat gaa gtt aaa ctc ctc tac tta tgt gcc acc tac aaa gca cta      450 
Lys Asp Glu Val Lys Leu Leu Tyr Leu Cys Ala Thr Tyr Lys Ala Leu 
105                 110                 115                 120 

gag act gta gga gaa aag aaa gcc ttt tca tct gta atg cag ctt gta      498 
Glu Thr Val Gly Glu Lys Lys Ala Phe Ser Ser Val Met Gln Leu Val 
                125                 130                 135 

atg acc agc ctg cag tct att ctt gaa aat gtg gat aca cca gaa ttg      546 
Met Thr Ser Leu Gln Ser Ile Leu Glu Asn Val Asp Thr Pro Glu Leu 
            140                 145                 150 

ctt tgt aaa tgt gtt aag tgc att ctt ttg gtg gct cga tgt tac cct      594 
Leu Cys Lys Cys Val Lys Cys Ile Leu Leu Val Ala Arg Cys Tyr Pro 
        155                 160                 165 

cat att ttc agc act aat ttt agg gat aca gtt gat ata tta gtt gga      642 
His Ile Phe Ser Thr Asn Phe Arg Asp Thr Val Asp Ile Leu Val Gly 
    170                 175                 180 

tgg cat ata gat cat act cag aaa cct tcg ctc acg cag cag gta tct      690 
Trp His Ile Asp His Thr Gln Lys Pro Ser Leu Thr Gln Gln Val Ser 
185                 190                 195                 200 

ggg tgg ttg cag agt ttg gag cca ttt tgg gta gct gat ctt gca ttt      738 
Gly Trp Leu Gln Ser Leu Glu Pro Phe Trp Val Ala Asp Leu Ala Phe 
                205                 210                 215 

tct act act ctt ctt ggt cag ttt ctg gaa gac atg gaa gca tat gct      786 
Ser Thr Thr Leu Leu Gly Gln Phe Leu Glu Asp Met Glu Ala Tyr Ala 
            220                 225                 230 

gag gac ctc agc cat gtg gcc tct ggg gaa tca gtg gat gaa gat gtc      834 
Glu Asp Leu Ser His Val Ala Ser Gly Glu Ser Val Asp Glu Asp Val 
        235                 240                 245 

cct cct cca tca gtg tca tta cca aag ctg gct gca ctt ctc cgg gta      882 
Pro Pro Pro Ser Val Ser Leu Pro Lys Leu Ala Ala Leu Leu Arg Val 
    250                 255                 260 

ttt agt act gtg gtg agg agc att ggg gaa cgc ttc agc cca att cgg      930 
Phe Ser Thr Val Val Arg Ser Ile Gly Glu Arg Phe Ser Pro Ile Arg 
265                 270                 275                 280 

ggt cct cca att act gag gca tat gta aca gat gtt ctg tac aga gta      978 
Gly Pro Pro Ile Thr Glu Ala Tyr Val Thr Asp Val Leu Tyr Arg Val 
                285                 290                 295 

atg aga tgt gtg acg gct gca aac cag gtg ttt ttt tct gag gct gtg     1026 
Met Arg Cys Val Thr Ala Ala Asn Gln Val Phe Phe Ser Glu Ala Val 
            300                 305                 310 

ttg aca gct gct aat gag tgt gtt ggt gtt ttg ctc ggc agc ttg gat     1074 
Leu Thr Ala Ala Asn Glu Cys Val Gly Val Leu Leu Gly Ser Leu Asp 
        315                 320                 325 

cct agc atg act ata cat tgt gac atg gtc att aca tat gga tta gac     1122 
Pro Ser Met Thr Ile His Cys Asp Met Val Ile Thr Tyr Gly Leu Asp 
    330                 335                 340 

caa ctg gag aat tgc cag act tgt ggt acc gat tat atc atc tca gtc     1170 
Gln Leu Glu Asn Cys Gln Thr Cys Gly Thr Asp Tyr Ile Ile Ser Val 
345                 350                 355                 360 

ttg aat tta ctc acg ctg att gtt gaa cag ata aat acg aaa ctg cca     1218 
Leu Asn Leu Leu Thr Leu Ile Val Glu Gln Ile Asn Thr Lys Leu Pro 
                365                 370                 375 

tca tca ttt gta gaa aaa ctg ttt ata cca tca tct aaa cta cta ttc     1266 
Ser Ser Phe Val Glu Lys Leu Phe Ile Pro Ser Ser Lys Leu Leu Phe 
            380                 385                 390 

ttg cgt tat cat aaa gaa aaa gag gtt gtt gct gta gcc cat gct gtt     1314 
Leu Arg Tyr His Lys Glu Lys Glu Val Val Ala Val Ala His Ala Val 
        395                 400                 405 

tat caa gca gtg ctc agc ttg aag aat att cct gtt ttg gag act gcc     1362 
Tyr Gln Ala Val Leu Ser Leu Lys Asn Ile Pro Val Leu Glu Thr Ala 
    410                 415                 420 

tat aag tta ata ttg gga gaa atg act tgt gcc cta aac aac ctc cta     1410 
Tyr Lys Leu Ile Leu Gly Glu Met Thr Cys Ala Leu Asn Asn Leu Leu 
425                 430                 435                 440 

cac agt cta caa ctt cct gag gcc tgt tct gaa ata aaa cat gag gct     1458 
His Ser Leu Gln Leu Pro Glu Ala Cys Ser Glu Ile Lys His Glu Ala 
                445                 450                 455 

ttt aag aat cat gtg ttc aat gta gac aat gca aaa ttt gta gtt ata     1506 
Phe Lys Asn His Val Phe Asn Val Asp Asn Ala Lys Phe Val Val Ile 
            460                 465                 470 

ttt gac ctc agt gcc ctg act aca att gga aat gcc aaa aac tca cta     1554 
Phe Asp Leu Ser Ala Leu Thr Thr Ile Gly Asn Ala Lys Asn Ser Leu 
        475                 480                 485 

ata ggg atg tgg gcg cta tct cca act gtc ttt gca ctt ctg agt aag     1602 
Ile Gly Met Trp Ala Leu Ser Pro Thr Val Phe Ala Leu Leu Ser Lys 
    490                 495                 500 

aat ctg atg att gtg cac agt gac ctg gct gtt cac ttc cct gcc att     1650 
Asn Leu Met Ile Val His Ser Asp Leu Ala Val His Phe Pro Ala Ile 
505                 510                 515                 520 

cag tat gct gtg ctc tac aca ttg tat tct cat tgt acc agg cat gat     1698 
Gln Tyr Ala Val Leu Tyr Thr Leu Tyr Ser His Cys Thr Arg His Asp 
                525                 530                 535 

cac ttt atc tct agt agc ctc agt tct tcc tct cct tct ttg ttt gat     1746 
His Phe Ile Ser Ser Ser Leu Ser Ser Ser Ser Pro Ser Leu Phe Asp 
            540                 545                 550 

gga gct gtg att agc act gta act acg gct aca aag aaa cat ttc tca     1794 
Gly Ala Val Ile Ser Thr Val Thr Thr Ala Thr Lys Lys His Phe Ser 
        555                 560                 565 

att ata tta aat ctt ctg gga ata tta ctt aag aaa gat aac ctt aac     1842 
Ile Ile Leu Asn Leu Leu Gly Ile Leu Leu Lys Lys Asp Asn Leu Asn 
    570                 575                 580 

cag gac acg agg aaa ctg tta atg act tgg gct ttg gaa gca gct gtt     1890 
Gln Asp Thr Arg Lys Leu Leu Met Thr Trp Ala Leu Glu Ala Ala Val 
585                 590                 595                 600 

tta atg aag aag tct gaa aca tac gca cct tta ttc tct ctt ccg tct     1938 
Leu Met Lys Lys Ser Glu Thr Tyr Ala Pro Leu Phe Ser Leu Pro Ser 
                605                 610                 615 

ttc cat aaa ttt tgc aaa ggc ctt tta gcc aac act ctc gtt gaa gat     1986 
Phe His Lys Phe Cys Lys Gly Leu Leu Ala Asn Thr Leu Val Glu Asp 
            620                 625                 630 

gtg aat atc tgt ctg cag gca tgc agc agt cta cat gct ctg tcc tct     2034 
Val Asn Ile Cys Leu Gln Ala Cys Ser Ser Leu His Ala Leu Ser Ser 
        635                 640                 645 

tcc ttg cca gat gat ctt tta cag aga tgt gtc gat gtt tgc cgt gtt     2082 
Ser Leu Pro Asp Asp Leu Leu Gln Arg Cys Val Asp Val Cys Arg Val 
    650                 655                 660 

caa cta gtg cac agt gga act cgt att cga caa gca ttt gga aaa ctg     2130 
Gln Leu Val His Ser Gly Thr Arg Ile Arg Gln Ala Phe Gly Lys Leu 
665                 670                 675                 680 

ttg aaa tca att cct tta gat gtt gtc cta agc aat aac aat cac aca     2178 
Leu Lys Ser Ile Pro Leu Asp Val Val Leu Ser Asn Asn Asn His Thr 
                685                 690                 695 

gaa att caa gaa att tct tta gca tta aga agt cac atg agt aaa gca     2226 
Glu Ile Gln Glu Ile Ser Leu Ala Leu Arg Ser His Met Ser Lys Ala 
            700                 705                 710 

cca agt aat aca ttc cac ccc caa gat ttc tct gat gtt att agt ttt     2274 
Pro Ser Asn Thr Phe His Pro Gln Asp Phe Ser Asp Val Ile Ser Phe 
        715                 720                 725 

att ttg tat ggg aac tct cat aga aca ggg aag gac aat tgg ttg gaa     2322 
Ile Leu Tyr Gly Asn Ser His Arg Thr Gly Lys Asp Asn Trp Leu Glu 
    730                 735                 740 

aga ctg ttc tat agc tgc cag aga ctg gat aag cgt gac cag tca aca     2370 
Arg Leu Phe Tyr Ser Cys Gln Arg Leu Asp Lys Arg Asp Gln Ser Thr 
745                 750                 755                 760 

att cca cgc aat ctc ctg aag aca gat gct gtc ctt tgg cag tgg gcc     2418 
Ile Pro Arg Asn Leu Leu Lys Thr Asp Ala Val Leu Trp Gln Trp Ala 
                765                 770                 775 

ata tgg gaa gct gca caa ttc act gtt ctt tct aag ctg aga acc cca     2466 
Ile Trp Glu Ala Ala Gln Phe Thr Val Leu Ser Lys Leu Arg Thr Pro 
            780                 785                 790 

ctg ggc aga gct caa gac acc ttc cag aca att gaa ggt atc att cga     2514 
Leu Gly Arg Ala Gln Asp Thr Phe Gln Thr Ile Glu Gly Ile Ile Arg 
        795                 800                 805 

agt ctc gca gct cac aca tta aac cct gat cag gat gtt agt cag tgg     2562 
Ser Leu Ala Ala His Thr Leu Asn Pro Asp Gln Asp Val Ser Gln Trp 
    810                 815                 820 

aca act gca gac aat gat gaa ggc cat ggt aac aac caa ctt aga ctt     2610 
Thr Thr Ala Asp Asn Asp Glu Gly His Gly Asn Asn Gln Leu Arg Leu 
825                 830                 835                 840 

gtt ctt ctt ctg cag tat ctg gaa aat ctg gag aaa tta atg tat aat     2658 
Val Leu Leu Leu Gln Tyr Leu Glu Asn Leu Glu Lys Leu Met Tyr Asn 
                845                 850                 855 

gca tac gag gga tgt gct aat gca tta act tca cct ccc aag gtc att     2706 
Ala Tyr Glu Gly Cys Ala Asn Ala Leu Thr Ser Pro Pro Lys Val Ile 
            860                 865                 870 

aga act ttt ttc tat acc aat cgc caa act tgt cag gac tgg cta acg     2754 
Arg Thr Phe Phe Tyr Thr Asn Arg Gln Thr Cys Gln Asp Trp Leu Thr 
        875                 880                 885 

cgg att cga ctc tcc atc atg agg gta gga ttg ttg gca ggc cag cct     2802 
Arg Ile Arg Leu Ser Ile Met Arg Val Gly Leu Leu Ala Gly Gln Pro 
    890                 895                 900 

gca gtg aca gtg aga cat ggc ttt gac ttg ctt aca gag atg aaa aca     2850 
Ala Val Thr Val Arg His Gly Phe Asp Leu Leu Thr Glu Met Lys Thr 
905                 910                 915                 920 

acc agc cta tct cag ggg aat gaa ttg gaa gta acc att atg atg gtg     2898 
Thr Ser Leu Ser Gln Gly Asn Glu Leu Glu Val Thr Ile Met Met Val 
                925                 930                 935 

gta gaa gca tta tgt gaa ctt cat tgt cct gaa gct ata cag gga att     2946 
Val Glu Ala Leu Cys Glu Leu His Cys Pro Glu Ala Ile Gln Gly Ile 
            940                 945                 950 

gct gtc tgg tca tca tct att gtt gga aaa aat ctt ctg tgg att aac     2994 
Ala Val Trp Ser Ser Ser Ile Val Gly Lys Asn Leu Leu Trp Ile Asn 
        955                 960                 965 

tca gtg gct caa cag gct gaa ggg agg ttt gaa aag gcc tct gtg gag     3042 
Ser Val Ala Gln Gln Ala Glu Gly Arg Phe Glu Lys Ala Ser Val Glu 
    970                 975                 980 

tac cag gaa cac ctg tgt gcc atg aca ggt gtt gat tgc tgc atc tcc     3090 
Tyr Gln Glu His Leu Cys Ala Met Thr Gly Val Asp Cys Cys Ile Ser 
 985                 990                 995                1000 

agc ttt gac aaa tcg gtg ctc acc tta gcc aat gct ggg cgt aac agt     3138 
Ser Phe Asp Lys Ser Val Leu Thr Leu Ala Asn Ala Gly Arg Asn Ser 
                1005                1010                1015 

gcc agc ccg aaa cat tct ctg aat ggt gaa tcc aga aaa act gtg ctg     3186 
Ala Ser Pro Lys His Ser Leu Asn Gly Glu Ser Arg Lys Thr Val Leu 
            1020                1025                1030 

tcc aaa ccg act gac tct tcc cct gag gtt ata aat tat tta gga aat     3234 
Ser Lys Pro Thr Asp Ser Ser Pro Glu Val Ile Asn Tyr Leu Gly Asn 
        1035                1040                1045 

aaa gca tgt gag tgc tac atc tca att gcc gat tgg gct gct gtg cag     3282 
Lys Ala Cys Glu Cys Tyr Ile Ser Ile Ala Asp Trp Ala Ala Val Gln 
    1050                1055                1060 

gaa tgg cag aac gct atc cat gac ttg aaa aag agt acc agt agc act     3330 
Glu Trp Gln Asn Ala Ile His Asp Leu Lys Lys Ser Thr Ser Ser Thr 
1065                1070                1075                1080 

tcc ctc aac ctg aaa gct gac ttc aac tat ata aaa tca tta agc agc     3378 
Ser Leu Asn Leu Lys Ala Asp Phe Asn Tyr Ile Lys Ser Leu Ser Ser 
                1085                1090                1095 

ttt gag tct gga aaa ttt gtt gaa tgt acc gag caa tta gaa ttg tta     3426 
Phe Glu Ser Gly Lys Phe Val Glu Cys Thr Glu Gln Leu Glu Leu Leu 
            1100                1105                1110 

cca gga gaa aat atc aat cta ctt gct gga gga tca aaa gaa aaa ata     3474 
Pro Gly Glu Asn Ile Asn Leu Leu Ala Gly Gly Ser Lys Glu Lys Ile 
        1115                1120                1125 

gac atg aaa aaa ctg ctt cct aac atg tta agt ccg gat ccg agg gaa     3522 
Asp Met Lys Lys Leu Leu Pro Asn Met Leu Ser Pro Asp Pro Arg Glu 
    1130                1135                1140 

ctt cag aaa tcc att gaa gtt caa ttg tta aga agt tct gtt tgt ttg     3570 
Leu Gln Lys Ser Ile Glu Val Gln Leu Leu Arg Ser Ser Val Cys Leu 
1145                1150                1155                1160 

gca act gct tta aac ccg ata gaa caa gat cag aag tgg cag tct ata     3618 
Ala Thr Ala Leu Asn Pro Ile Glu Gln Asp Gln Lys Trp Gln Ser Ile 
                1165                1170                1175 

act gaa aat gtg gta aag tac ttg aag caa aca tcc cgc atc gct att     3666 
Thr Glu Asn Val Val Lys Tyr Leu Lys Gln Thr Ser Arg Ile Ala Ile 
            1180                1185                1190 

gga cct ctg aga ctt tct act tta aca gtt tca cag tct ttg cca gtt     3714 
Gly Pro Leu Arg Leu Ser Thr Leu Thr Val Ser Gln Ser Leu Pro Val 
        1195                1200                1205 

cta agt acc ttg cag ctg tat tgc tca tct gct ttg gag aac aca gtt     3762 
Leu Ser Thr Leu Gln Leu Tyr Cys Ser Ser Ala Leu Glu Asn Thr Val 
    1210                1215                1220 

tct aac aga ctt tca aca gag gac tgt ctt att cca ctc ttc agt gaa     3810 
Ser Asn Arg Leu Ser Thr Glu Asp Cys Leu Ile Pro Leu Phe Ser Glu 
1225                1230                1235                1240 

gct tta cgt tca tgt aaa cag cat gac gtg agg cca tgg atg cag gca     3858 
Ala Leu Arg Ser Cys Lys Gln His Asp Val Arg Pro Trp Met Gln Ala 
                1245                1250                1255 

tta agg tat act atg tac cag aat cag ttg ttg gag aaa att aaa gaa     3906 
Leu Arg Tyr Thr Met Tyr Gln Asn Gln Leu Leu Glu Lys Ile Lys Glu 
            1260                1265                1270 

caa aca gtc cca att aga agc cat ctc atg gaa tta ggt cta aca gca     3954 
Gln Thr Val Pro Ile Arg Ser His Leu Met Glu Leu Gly Leu Thr Ala 
        1275                1280                1285 

gca aaa ttt gct aga aaa cga ggg aat gtg tcc ctt gca aca aga ctg     4002 
Ala Lys Phe Ala Arg Lys Arg Gly Asn Val Ser Leu Ala Thr Arg Leu 
    1290                1295                1300 

ctg gca cag tgc agt gaa gtt cag ctg gga aag acc acc act gca cag     4050 
Leu Ala Gln Cys Ser Glu Val Gln Leu Gly Lys Thr Thr Thr Ala Gln 
1305                1310                1315                1320 

gat tta gtc caa cat ttt aaa aaa cta tca acc caa ggt caa gtg gat     4098 
Asp Leu Val Gln His Phe Lys Lys Leu Ser Thr Gln Gly Gln Val Asp 
                1325                1330                1335 

gaa aaa tgg ggg ccc gaa ctt gat att gaa aaa acc aaa ttg ctt tat     4146 
Glu Lys Trp Gly Pro Glu Leu Asp Ile Glu Lys Thr Lys Leu Leu Tyr 
            1340                1345                1350 

aca gca ggc cag tca aca cat gca atg gaa atg ttg agt tct tgt gcc     4194 
Thr Ala Gly Gln Ser Thr His Ala Met Glu Met Leu Ser Ser Cys Ala 
        1355                1360                1365 

ata tct ttc tgc aag tct gtg aaa gct gaa tat gca gtt gct aaa tca     4242 
Ile Ser Phe Cys Lys Ser Val Lys Ala Glu Tyr Ala Val Ala Lys Ser 
    1370                1375                1380 

att ctg aca ctg gct aaa tgg atc cag gca gaa tgg aaa gag att tca     4290 
Ile Leu Thr Leu Ala Lys Trp Ile Gln Ala Glu Trp Lys Glu Ile Ser 
1385                1390                1395                1400 

gga cag ctg aaa cag gtt tac aga gct cag cac caa cag aac ttc aca     4338 
Gly Gln Leu Lys Gln Val Tyr Arg Ala Gln His Gln Gln Asn Phe Thr 
                1405                1410                1415 

ggt ctt tct act ttg tct aaa aac ata ctc act cta ata gaa ctg cca     4386 
Gly Leu Ser Thr Leu Ser Lys Asn Ile Leu Thr Leu Ile Glu Leu Pro 
            1420                1425                1430 

tct gtt aat acg atg gaa gaa gag tat cct cgg atc gag agt gaa tct     4434 
Ser Val Asn Thr Met Glu Glu Glu Tyr Pro Arg Ile Glu Ser Glu Ser 
        1435                1440                1445 

aca gtg cat att gga gtt gga gaa cct gac ttc att ttg gga cag ttg     4482 
Thr Val His Ile Gly Val Gly Glu Pro Asp Phe Ile Leu Gly Gln Leu 
    1450                1455                1460 

tat cac ctg tct tca gta cag gca cct gaa gta gcc aaa tct tgg gca     4530 
Tyr His Leu Ser Ser Val Gln Ala Pro Glu Val Ala Lys Ser Trp Ala 
1465                1470                1475                1480 

gcg ttg gcc agc tgg gct tat agg tgg ggc aga aag gtg gtt gac aat     4578 
Ala Leu Ala Ser Trp Ala Tyr Arg Trp Gly Arg Lys Val Val Asp Asn 
                1485                1490                1495 

gcc agt cag gga gaa ggt gtt cgt ctg ctg cct aga gaa aaa tct gaa     4626 
Ala Ser Gln Gly Glu Gly Val Arg Leu Leu Pro Arg Glu Lys Ser Glu 
            1500                1505                1510 

gtt cag aat cta ctt cca gac act ata act gag gaa gag aaa gag aga     4674 
Val Gln Asn Leu Leu Pro Asp Thr Ile Thr Glu Glu Glu Lys Glu Arg 
        1515                1520                1525 

ata tat ggt att ctt gga cag gct gtg tgt cgg ccg gcg ggg att cag     4722 
Ile Tyr Gly Ile Leu Gly Gln Ala Val Cys Arg Pro Ala Gly Ile Gln 
    1530                1535                1540 

gat gaa gat ata aca ctt cag ata act gag agt gaa gac aac gaa gaa     4770 
Asp Glu Asp Ile Thr Leu Gln Ile Thr Glu Ser Glu Asp Asn Glu Glu 
1545                1550                1555                1560 

gat gac atg gtt gat gtt atc tgg cgt cag ttg ata tca agc tgc cca     4818 
Asp Asp Met Val Asp Val Ile Trp Arg Gln Leu Ile Ser Ser Cys Pro 
                1565                1570                1575 

tgg ctt tca gaa ctt gat gaa agt gca act gaa gga gtt att aaa gtg     4866 
Trp Leu Ser Glu Leu Asp Glu Ser Ala Thr Glu Gly Val Ile Lys Val 
            1580                1585                1590 

tgg agg aaa gtt gta gat aga ata ttc agc ctg tac aaa ctc tct tgc     4914 
Trp Arg Lys Val Val Asp Arg Ile Phe Ser Leu Tyr Lys Leu Ser Cys 
        1595                1600                1605 

agt gca tac ttt act ttc ctt aaa ctc aac gct ggt caa att cct tta     4962 
Ser Ala Tyr Phe Thr Phe Leu Lys Leu Asn Ala Gly Gln Ile Pro Leu 
    1610                1615                1620 

gat gag gat gac cct agg ctg cat tta agt cac aga gtg gaa cag agc     5010 
Asp Glu Asp Asp Pro Arg Leu His Leu Ser His Arg Val Glu Gln Ser 
1625                1630                1635                1640 

act gat gac atg att gtg atg gcc aca ttg cgc ctg ctg cgg ttg ctc     5058 
Thr Asp Asp Met Ile Val Met Ala Thr Leu Arg Leu Leu Arg Leu Leu 
                1645                1650                1655 

gtg aag cat gct ggt gag ctt cgg cag tat ctg gag cac ggc ttg gag     5106 
Val Lys His Ala Gly Glu Leu Arg Gln Tyr Leu Glu His Gly Leu Glu 
            1660                1665                1670 

aca aca ccc act gca cca tgg aga gga att att ccg caa ctt ttc tca     5154 
Thr Thr Pro Thr Ala Pro Trp Arg Gly Ile Ile Pro Gln Leu Phe Ser 
        1675                1680                1685 

cgc tta aac cac cct gaa gtg tat gtg cgc caa agt att tgt aac ctt     5202 
Arg Leu Asn His Pro Glu Val Tyr Val Arg Gln Ser Ile Cys Asn Leu 
    1690                1695                1700 

ctc tgc cgt gtg gct caa gat tcc cca cat ctc ata ttg tat cct gca     5250 
Leu Cys Arg Val Ala Gln Asp Ser Pro His Leu Ile Leu Tyr Pro Ala 
1705                1710                1715                1720 

ata gtg ggt acc ata tcg ctt agt agt gaa tcc cag gct tca gga aat     5298 
Ile Val Gly Thr Ile Ser Leu Ser Ser Glu Ser Gln Ala Ser Gly Asn 
                1725                1730                1735 

aaa ttt tcc act gca att cca act tta ctt ggc aat att caa gga gaa     5346 
Lys Phe Ser Thr Ala Ile Pro Thr Leu Leu Gly Asn Ile Gln Gly Glu 
            1740                1745                1750 

gaa ttg ctg gtt tct gaa tgt gag gga gga agt cct cct gca tct cag     5394 
Glu Leu Leu Val Ser Glu Cys Glu Gly Gly Ser Pro Pro Ala Ser Gln 
        1755                1760                1765 

gat agc aat aag gat gaa cct aaa agt gga tta aat gaa gac caa gcc     5442 
Asp Ser Asn Lys Asp Glu Pro Lys Ser Gly Leu Asn Glu Asp Gln Ala 
    1770                1775                1780 

atg atg cag gat tgt tac agc aaa att gta gat aag ctg tcc tct gca     5490 
Met Met Gln Asp Cys Tyr Ser Lys Ile Val Asp Lys Leu Ser Ser Ala 
1785                1790                1795                1800 

aac ccc acc atg gta tta cag gtt cag atg ctc gtg gct gaa ctg cgc     5538 
Asn Pro Thr Met Val Leu Gln Val Gln Met Leu Val Ala Glu Leu Arg 
                1805                1810                1815 

agg gtc act gtg ctc tgg gat gag ctc tgg ctg gga gtt ttg ctg caa     5586 
Arg Val Thr Val Leu Trp Asp Glu Leu Trp Leu Gly Val Leu Leu Gln 
            1820                1825                1830 

caa cac atg tat gtc ctg aga cga att cag cag ctt gaa gat gag gtg     5634 
Gln His Met Tyr Val Leu Arg Arg Ile Gln Gln Leu Glu Asp Glu Val 
        1835                1840                1845 

aag aga gtc cag aac aac aac acc tta cgc aaa gaa gag aaa att gca     5682 
Lys Arg Val Gln Asn Asn Asn Thr Leu Arg Lys Glu Glu Lys Ile Ala 
    1850                1855                1860 

atc atg agg gag aag cac aca gct ttg atg aag ccc atc gta ttt gct     5730 
Ile Met Arg Glu Lys His Thr Ala Leu Met Lys Pro Ile Val Phe Ala 
1865                1870                1875                1880 

ttg gag cat gtg agg agt atc aca gcg gct cct gca gaa aca cct cat     5778 
Leu Glu His Val Arg Ser Ile Thr Ala Ala Pro Ala Glu Thr Pro His 
                1885                1890                1895 

gaa aaa tgg ttt cag gat aac tat ggt gat gcc att gaa aat gcc cta     5826 
Glu Lys Trp Phe Gln Asp Asn Tyr Gly Asp Ala Ile Glu Asn Ala Leu 
            1900                1905                1910 

gaa aaa ctg aag act cca ttg aac cct gca aag cct ggg agc agc tgg     5874 
Glu Lys Leu Lys Thr Pro Leu Asn Pro Ala Lys Pro Gly Ser Ser Trp 
        1915                1920                1925 

att cca ttt aaa gag ata atg cta agt ttg caa cag aga gca cag aaa     5922 
Ile Pro Phe Lys Glu Ile Met Leu Ser Leu Gln Gln Arg Ala Gln Lys 
    1930                1935                1940 

cgt gca agt tac atc ttg cgt ctt gaa gaa atc agt cca tgg ttg gct     5970 
Arg Ala Ser Tyr Ile Leu Arg Leu Glu Glu Ile Ser Pro Trp Leu Ala 
1945                1950                1955                1960 

gcc atg act aac act gaa att gct ctt cct ggg gaa gtc tca gcc aga     6018 
Ala Met Thr Asn Thr Glu Ile Ala Leu Pro Gly Glu Val Ser Ala Arg 
                1965                1970                1975 

gac act gtc aca atc cat agt gtg ggc gga acc atc aca atc tta ccg     6066 
Asp Thr Val Thr Ile His Ser Val Gly Gly Thr Ile Thr Ile Leu Pro 
            1980                1985                1990 

act aaa acc aag cca aag aaa ctt ctc ttt ctt gga tca gat ggg aag     6114 
Thr Lys Thr Lys Pro Lys Lys Leu Leu Phe Leu Gly Ser Asp Gly Lys 
        1995                2000                2005 

agc tat cct tat ctt ttc aaa gga ctg gag gat tta cat ctg gat gag     6162 
Ser Tyr Pro Tyr Leu Phe Lys Gly Leu Glu Asp Leu His Leu Asp Glu 
    2010                2015                2020 

aga ata atg cag ttc cta tct att gtg aat acc atg ttt gct aca att     6210 
Arg Ile Met Gln Phe Leu Ser Ile Val Asn Thr Met Phe Ala Thr Ile 
2025                2030                2035                2040 

aat cgc caa gaa aca ccc cgg ttc cat gct cga cac tat tct gta aca     6258 
Asn Arg Gln Glu Thr Pro Arg Phe His Ala Arg His Tyr Ser Val Thr 
                2045                2050                2055 

cca cta gga aca aga tca gga cta atc cag tgg gta gat gga gcc aca     6306 
Pro Leu Gly Thr Arg Ser Gly Leu Ile Gln Trp Val Asp Gly Ala Thr 
            2060                2065                2070 

ccc tta ttt ggt ctt tac aaa cga tgg caa caa cgg gaa gct gcc tta     6354 
Pro Leu Phe Gly Leu Tyr Lys Arg Trp Gln Gln Arg Glu Ala Ala Leu 
        2075                2080                2085 

caa gca caa aag gcc caa gat tcc tac caa act cct cag aat cct gga     6402 
Gln Ala Gln Lys Ala Gln Asp Ser Tyr Gln Thr Pro Gln Asn Pro Gly 
    2090                2095                2100 

att gta ccc cgt cct agt gaa ctt tat tac agt aaa att ggc cct gct     6450 
Ile Val Pro Arg Pro Ser Glu Leu Tyr Tyr Ser Lys Ile Gly Pro Ala 
2105                2110                2115                2120 

ttg aaa aca gtt ggg ctt agc ctg gat gtg tcc cgt cgg gat tgg cct     6498 
Leu Lys Thr Val Gly Leu Ser Leu Asp Val Ser Arg Arg Asp Trp Pro 
                2125                2130                2135 

ctt cat gta atg aag gca gta ttg gaa gag tta atg gag gcc aca ccc     6546 
Leu His Val Met Lys Ala Val Leu Glu Glu Leu Met Glu Ala Thr Pro 
            2140                2145                2150 

ccg aat ctc ctt gcc aaa gag ctc tgg tca tct tgc aca aca cct gat     6594 
Pro Asn Leu Leu Ala Lys Glu Leu Trp Ser Ser Cys Thr Thr Pro Asp 
        2155                2160                2165 

gaa tgg tgg aga gtt acg cag tct tat gca aga tct act gca gtc atg     6642 
Glu Trp Trp Arg Val Thr Gln Ser Tyr Ala Arg Ser Thr Ala Val Met 
    2170                2175                2180 

tct atg gtt gga tac ata att ggc ctt gga gac aga cat ctg gat aat     6690 
Ser Met Val Gly Tyr Ile Ile Gly Leu Gly Asp Arg His Leu Asp Asn 
2185                2190                2195                2200 

gtt ctt ata gat atg acg act gga gaa gtt gtt cac ata gat tac aat     6738 
Val Leu Ile Asp Met Thr Thr Gly Glu Val Val His Ile Asp Tyr Asn 
                2205                2210                2215 

gtt tgc ttt gaa aaa ggt aaa agc ctt aga gtt cct gag aaa gta cct     6786 
Val Cys Phe Glu Lys Gly Lys Ser Leu Arg Val Pro Glu Lys Val Pro 
            2220                2225                2230 

ttt cga atg aca caa aac att gaa aca gca ctg ggt gta act gga gta     6834 
Phe Arg Met Thr Gln Asn Ile Glu Thr Ala Leu Gly Val Thr Gly Val 
        2235                2240                2245 

gaa ggt gta ttt agg ctt tca tgt gag cag gtt tta cac att atg cgg     6882 
Glu Gly Val Phe Arg Leu Ser Cys Glu Gln Val Leu His Ile Met Arg 
    2250                2255                2260 

cgt ggc aga gag acc ctg ctg acg ctg ctg gag gcc ttt gtg tac gac     6930 
Arg Gly Arg Glu Thr Leu Leu Thr Leu Leu Glu Ala Phe Val Tyr Asp 
2265                2270                2275                2280 

cct ctg gtg gac tgg aca gca gga ggc gag gct ggg ttt gct ggt gct     6978 
Pro Leu Val Asp Trp Thr Ala Gly Gly Glu Ala Gly Phe Ala Gly Ala 
                2285                2290                2295 

gtc tat ggt gga ggt ggc cag cag gcc gag agc aag cag agc aag aga     7026 
Val Tyr Gly Gly Gly Gly Gln Gln Ala Glu Ser Lys Gln Ser Lys Arg 
            2300                2305                2310 

gag atg gag cga gag atc acc cgc agc ctg ttt tct tct aga gta gct     7074 
Glu Met Glu Arg Glu Ile Thr Arg Ser Leu Phe Ser Ser Arg Val Ala 
        2315                2320                2325 

gag att aag gtg aac tgg ttt aag aat aga gat gag atg ctg gtt gtg     7122 
Glu Ile Lys Val Asn Trp Phe Lys Asn Arg Asp Glu Met Leu Val Val 
    2330                2335                2340 

ctt ccc aag ttg gac ggt agc tta gat gaa tac cta agc ttg caa gag     7170 
Leu Pro Lys Leu Asp Gly Ser Leu Asp Glu Tyr Leu Ser Leu Gln Glu 
2345                2350                2355                2360 

caa ctg aca gat gtg gaa aaa ctg cag ggc aaa cta ctg gag gaa ata     7218 
Gln Leu Thr Asp Val Glu Lys Leu Gln Gly Lys Leu Leu Glu Glu Ile 
                2365                2370                2375 

gag ttt cta gaa gga gct gaa ggg gtg gat cat cct tct cat act ctg     7266 
Glu Phe Leu Glu Gly Ala Glu Gly Val Asp His Pro Ser His Thr Leu 
            2380                2385                2390 

caa cac agg tat tct gag cac acc caa cta cag act cag caa aga gct     7314 
Gln His Arg Tyr Ser Glu His Thr Gln Leu Gln Thr Gln Gln Arg Ala 
        2395                2400                2405 

gtt cag gaa gca atc cag gtg aag ctg aat gaa ttt gaa caa tgg ata     7362 
Val Gln Glu Ala Ile Gln Val Lys Leu Asn Glu Phe Glu Gln Trp Ile 
    2410                2415                2420 

aca cat tat cag gct gca ttc aat aat tta gaa gca aca cag ctt gca     7410 
Thr His Tyr Gln Ala Ala Phe Asn Asn Leu Glu Ala Thr Gln Leu Ala 
2425                2430                2435                2440 

agc ttg ctt caa gag ata agc aca caa atg gac ctt ggt cct cca agt     7458 
Ser Leu Leu Gln Glu Ile Ser Thr Gln Met Asp Leu Gly Pro Pro Ser 
                2445                2450                2455 

tac gtg cca gca aca gcc ttt ctg cag aat gct ggt cag gcc cac ttg     7506 
Tyr Val Pro Ala Thr Ala Phe Leu Gln Asn Ala Gly Gln Ala His Leu 
            2460                2465                2470 

att agc cag tgc gag cag ctg gag ggg gag gtt ggt gct ctc ctg cag     7554 
Ile Ser Gln Cys Glu Gln Leu Glu Gly Glu Val Gly Ala Leu Leu Gln 
        2475                2480                2485 

cag agg cgc tcc gtg ctc cgt ggc tgt ctg gag caa ctg cat cac tat     7602 
Gln Arg Arg Ser Val Leu Arg Gly Cys Leu Glu Gln Leu His His Tyr 
    2490                2495                2500 

gca acc gtg gcc ctg cag tat ccg aag gcc ata ttt cag aaa cat cga     7650 
Ala Thr Val Ala Leu Gln Tyr Pro Lys Ala Ile Phe Gln Lys His Arg 
2505                2510                2515                2520 

att gaa cag tgg aag acc tgg atg gaa gag ctc atc tgt aac acc aca     7698 
Ile Glu Gln Trp Lys Thr Trp Met Glu Glu Leu Ile Cys Asn Thr Thr 
                2525                2530                2535 

gta gag cgt tgt caa gag ctc tat agg aaa tat gaa atg caa tat gct     7746 
Val Glu Arg Cys Gln Glu Leu Tyr Arg Lys Tyr Glu Met Gln Tyr Ala 
            2540                2545                2550 

ccc cag cca ccc cca aca gtg tgt cag ttc atc act gcc act gaa atg     7794 
Pro Gln Pro Pro Pro Thr Val Cys Gln Phe Ile Thr Ala Thr Glu Met 
        2555                2560                2565 

acc ctg cag cga tac gca gca gac atc aac agc aga ctt att aga caa     7842 
Thr Leu Gln Arg Tyr Ala Ala Asp Ile Asn Ser Arg Leu Ile Arg Gln 
    2570                2575                2580 

gtg gaa cgc ttg aaa cag gaa gct gtc act gtg cca gtt tgt gaa gat     7890 
Val Glu Arg Leu Lys Gln Glu Ala Val Thr Val Pro Val Cys Glu Asp 
2585                2590                2595                2600 

cag ttg aaa gaa att gaa cgt tgc att aaa gtt ttc ctt cat gag aat     7938 
Gln Leu Lys Glu Ile Glu Arg Cys Ile Lys Val Phe Leu His Glu Asn 
                2605                2610                2615 

gga gaa gaa gga tct ttg agt cta gca agt gtt att att tct gcc ctt     7986 
Gly Glu Glu Gly Ser Leu Ser Leu Ala Ser Val Ile Ile Ser Ala Leu 
            2620                2625                2630 

tgt acc ctt aca agg cgt aac ctg atg atg gaa ggt gca gcg tca agt     8034 
Cys Thr Leu Thr Arg Arg Asn Leu Met Met Glu Gly Ala Ala Ser Ser 
        2635                2640                2645 

gct gga gaa cag ctg gtt gat ctg act tct cgg gat gga gcc tgg ttc     8082 
Ala Gly Glu Gln Leu Val Asp Leu Thr Ser Arg Asp Gly Ala Trp Phe 
    2650                2655                2660 

ttg gag gaa ctc tgc agt atg agc gga aac gtc acc tgc ttg gtt cag     8130 
Leu Glu Glu Leu Cys Ser Met Ser Gly Asn Val Thr Cys Leu Val Gln 
2665                2670                2675                2680 

tta ctg aag cag tgc cac ctg gtg cca cag gac tta gat atc ccg aac     8178 
Leu Leu Lys Gln Cys His Leu Val Pro Gln Asp Leu Asp Ile Pro Asn 
                2685                2690                2695 

ccc atg gaa gcg tct gag aca gtt cac tta gcc aat gga gtg tat acc     8226 
Pro Met Glu Ala Ser Glu Thr Val His Leu Ala Asn Gly Val Tyr Thr 
            2700                2705                2710 

tca ctt cag gaa ttg aat tcg aat ttc cgg caa atc ata ttt cca gaa     8274 
Ser Leu Gln Glu Leu Asn Ser Asn Phe Arg Gln Ile Ile Phe Pro Glu 
        2715                2720                2725 

gca ctt cga tgt tta atg aaa ggg gaa tac acg tta gaa agt atg ctg     8322 
Ala Leu Arg Cys Leu Met Lys Gly Glu Tyr Thr Leu Glu Ser Met Leu 
    2730                2735                2740 

cat gaa ctg gac ggt ctt att gag cag acc acc gat ggc gtt ccc ctg     8370 
His Glu Leu Asp Gly Leu Ile Glu Gln Thr Thr Asp Gly Val Pro Leu 
2745                2750                2755                2760 

cag act cta gtg gaa tct ctt cag gcc tac tta aga aac gca gct atg     8418 
Gln Thr Leu Val Glu Ser Leu Gln Ala Tyr Leu Arg Asn Ala Ala Met 
                2765                2770                2775 

gga ctg gaa gaa gaa aca cat gct cat tac atc gat gtt gcc aga cta     8466 
Gly Leu Glu Glu Glu Thr His Ala His Tyr Ile Asp Val Ala Arg Leu 
            2780                2785                2790 

cta cat gct cag tac ggt gaa tta atc caa ccg aga aat ggt tca gtt     8514 
Leu His Ala Gln Tyr Gly Glu Leu Ile Gln Pro Arg Asn Gly Ser Val 
        2795                2800                2805 

gat gaa aca ccc aaa atg tca gct ggc cag atg ctt ttg gta gca ttc     8562 
Asp Glu Thr Pro Lys Met Ser Ala Gly Gln Met Leu Leu Val Ala Phe 
    2810                2815                2820 

gat ggc atg ttt gct caa gtt gaa act gct ttc agc tta tta gtt gaa     8610 
Asp Gly Met Phe Ala Gln Val Glu Thr Ala Phe Ser Leu Leu Val Glu 
2825                2830                2835                2840 

aag ttg aac aag atg gaa att ccc ata gct tgg cga aag att gac atc     8658 
Lys Leu Asn Lys Met Glu Ile Pro Ile Ala Trp Arg Lys Ile Asp Ile 
                2845                2850                2855 

ata agg gaa gcc agg agt act caa gtt aat ttt ttt gat gat gat aat     8706 
Ile Arg Glu Ala Arg Ser Thr Gln Val Asn Phe Phe Asp Asp Asp Asn 
            2860                2865                2870 

cac cgg cag gtg cta gaa gag att ttc ttt cta aaa aga cta cag act     8754 
His Arg Gln Val Leu Glu Glu Ile Phe Phe Leu Lys Arg Leu Gln Thr 
        2875                2880                2885 

att aag gag ttc ttc agg ctc tgt ggt acc ttt tct aaa aca ttg tca     8802 
Ile Lys Glu Phe Phe Arg Leu Cys Gly Thr Phe Ser Lys Thr Leu Ser 
    2890                2895                2900 

gga tca agt tca ctt gaa gat cag aat act gtg aat ggg cct gta cag     8850 
Gly Ser Ser Ser Leu Glu Asp Gln Asn Thr Val Asn Gly Pro Val Gln 
2905                2910                2915                2920 

att gtc aat gtg aaa acc ctt ttt aga aac tct tgt ttc agt gaa gac     8898 
Ile Val Asn Val Lys Thr Leu Phe Arg Asn Ser Cys Phe Ser Glu Asp 
                2925                2930                2935 

caa atg gcc aaa cct atc aag gca ttc aca gct gac ttt gtg agg cag     8946 
Gln Met Ala Lys Pro Ile Lys Ala Phe Thr Ala Asp Phe Val Arg Gln 
            2940                2945                2950 

ctc ttg ata ggg cta ccc aac caa gcc ctc gga ctc aca ctg tgc agt     8994 
Leu Leu Ile Gly Leu Pro Asn Gln Ala Leu Gly Leu Thr Leu Cys Ser 
        2955                2960                2965 

ttt atc agt gct ctg ggt gta gac atc att gct caa gta gag gca aag     9042 
Phe Ile Ser Ala Leu Gly Val Asp Ile Ile Ala Gln Val Glu Ala Lys 
    2970                2975                2980 

gac ttt ggt gcc gaa agc aaa gtt tct gtt gat gat ctc tgt aag aaa     9090 
Asp Phe Gly Ala Glu Ser Lys Val Ser Val Asp Asp Leu Cys Lys Lys 
2985                2990                2995                3000 

gcg gtg gaa cat aac atc cag ata ggg aag ttc tct cag ctg gtt atg     9138 
Ala Val Glu His Asn Ile Gln Ile Gly Lys Phe Ser Gln Leu Val Met 
                3005                3010                3015 

aac agg gca act gtg tta gca agt tct tac gac act gcc tgg aag aag     9186 
Asn Arg Ala Thr Val Leu Ala Ser Ser Tyr Asp Thr Ala Trp Lys Lys 
            3020                3025                3030 

cat gac ttg gtg cga agg cta gaa acc agt att tct tct tgt aag aca     9234 
His Asp Leu Val Arg Arg Leu Glu Thr Ser Ile Ser Ser Cys Lys Thr 
        3035                3040                3045 

agc ctg cag cgg gtt cag ctg cat att gcc atg ttt cag tgg caa cat     9282 
Ser Leu Gln Arg Val Gln Leu His Ile Ala Met Phe Gln Trp Gln His 
    3050                3055                3060 

gaa gat cta ctt atc aat aga cca caa gcc atg tca gtc aca cct ccc     9330 
Glu Asp Leu Leu Ile Asn Arg Pro Gln Ala Met Ser Val Thr Pro Pro 
3065                3070                3075                3080 

cca cgg tct gct atc cta acc agc atg aaa aag aag ctg cat acc ctg     9378 
Pro Arg Ser Ala Ile Leu Thr Ser Met Lys Lys Lys Leu His Thr Leu 
                3085                3090                3095 

agc cag att gaa act tct att gca aca gtt cag gag aag cta gct gca     9426 
Ser Gln Ile Glu Thr Ser Ile Ala Thr Val Gln Glu Lys Leu Ala Ala 
            3100                3105                3110 

ctt gaa tca agt att gaa cag cga ctc aag tgg gca ggt ggt gcc aac     9474 
Leu Glu Ser Ser Ile Glu Gln Arg Leu Lys Trp Ala Gly Gly Ala Asn 
        3115                3120                3125 

cct gca ttg gcc cct gta cta caa gat ttt gaa gca acg ata gct gaa     9522 
Pro Ala Leu Ala Pro Val Leu Gln Asp Phe Glu Ala Thr Ile Ala Glu 
    3130                3135                3140 

aga aga aat ctt gtc ctt aaa gag agc caa aga gca agt cag gtc aca     9570 
Arg Arg Asn Leu Val Leu Lys Glu Ser Gln Arg Ala Ser Gln Val Thr 
3145                3150                3155                3160 

ttt ctc tgc agc aat atc att cat ttt gaa agt tta cga aca aga act     9618 
Phe Leu Cys Ser Asn Ile Ile His Phe Glu Ser Leu Arg Thr Arg Thr 
                3165                3170                3175 

gca gaa gcc tta aac ctg gat gcg gcg tta ttt gaa cta atc aag cga     9666 
Ala Glu Ala Leu Asn Leu Asp Ala Ala Leu Phe Glu Leu Ile Lys Arg 
            3180                3185                3190 

tgt cag cag atg tgt tcg ttt gca tca cag ttt aac agt tca gtg tct     9714 
Cys Gln Gln Met Cys Ser Phe Ala Ser Gln Phe Asn Ser Ser Val Ser 
        3195                3200                3205 

gag tta gag ctt cgt tta tta cag aga gtg gac act ggt ctt gaa cat     9762 
Glu Leu Glu Leu Arg Leu Leu Gln Arg Val Asp Thr Gly Leu Glu His 
    3210                3215                3220 

cct att ggc agc tct gaa tgg ctt ttg tca gca cac aaa cag ttg acc     9810 
Pro Ile Gly Ser Ser Glu Trp Leu Leu Ser Ala His Lys Gln Leu Thr 
3225                3230                3235                3240 

cag gat atg tct act cag agg gca att cag aca gag aaa gag cag cag     9858 
Gln Asp Met Ser Thr Gln Arg Ala Ile Gln Thr Glu Lys Glu Gln Gln 
                3245                3250                3255 

ata gaa acg gtc tgt gaa aca att cag aat ctg gtt gat aat ata aag     9906 
Ile Glu Thr Val Cys Glu Thr Ile Gln Asn Leu Val Asp Asn Ile Lys 
            3260                3265                3270 

act gtg ctc act ggt cat aac cga cag ctt gga gat gtc aaa cat ctc     9954 
Thr Val Leu Thr Gly His Asn Arg Gln Leu Gly Asp Val Lys His Leu 
        3275                3280                3285 

ttg aaa gct atg gct aag gat gaa gaa gct gct ctg gca gat ggt gaa    10002 
Leu Lys Ala Met Ala Lys Asp Glu Glu Ala Ala Leu Ala Asp Gly Glu 
    3290                3295                3300 

gat gtt ccc tat gag aac agt gtt agg cag ttt ttg ggt gaa tat aaa    10050 
Asp Val Pro Tyr Glu Asn Ser Val Arg Gln Phe Leu Gly Glu Tyr Lys 
3305                3310                3315                3320 

tca tgg caa gac aac att caa aca gtt cta ttt aca tta gtc cag gct    10098 
Ser Trp Gln Asp Asn Ile Gln Thr Val Leu Phe Thr Leu Val Gln Ala 
                3325                3330                3335 

atg ggt cag gtt cga agt caa gaa cac gtt gaa atg ctc cag gaa atc    10146 
Met Gly Gln Val Arg Ser Gln Glu His Val Glu Met Leu Gln Glu Ile 
            3340                3345                3350 

act ccc acc ttg aaa gaa ctg aaa aca caa agt cag agt atc tat aat    10194 
Thr Pro Thr Leu Lys Glu Leu Lys Thr Gln Ser Gln Ser Ile Tyr Asn 
        3355                3360                3365 

aat tta gtg agt ttt gca tca ccc tta gtc acc gat gca aca aat gaa    10242 
Asn Leu Val Ser Phe Ala Ser Pro Leu Val Thr Asp Ala Thr Asn Glu 
    3370                3375                3380 

tgt tcg agt cca acg tca tct gct act tat cag cca tcc ttc gct gca    10290 
Cys Ser Ser Pro Thr Ser Ser Ala Thr Tyr Gln Pro Ser Phe Ala Ala 
3385                3390                3395                3400 

gca gtc cgg agt aac act ggc cag aag act cag cct gat gtc atg tca    10338 
Ala Val Arg Ser Asn Thr Gly Gln Lys Thr Gln Pro Asp Val Met Ser 
                3405                3410                3415 

cag aat gct aga aag ctg atc cag aaa aat ctt gct aca tca gct gat    10386 
Gln Asn Ala Arg Lys Leu Ile Gln Lys Asn Leu Ala Thr Ser Ala Asp 
            3420                3425                3430 

act cca cca agc acc gtt cca gga act ggc aag agt gtt gct tgt agt    10434 
Thr Pro Pro Ser Thr Val Pro Gly Thr Gly Lys Ser Val Ala Cys Ser 
        3435                3440                3445 

cct aaa aag gca gtc aga gac cct aaa act ggg aaa gcg gtg caa gag    10482 
Pro Lys Lys Ala Val Arg Asp Pro Lys Thr Gly Lys Ala Val Gln Glu 
    3450                3455                3460 

aga aac tcc tat gca gtg agt gtg tgg aag aga gtg aaa gcc aag tta    10530 
Arg Asn Ser Tyr Ala Val Ser Val Trp Lys Arg Val Lys Ala Lys Leu 
3465                3470                3475                3480 

gag ggc cga gat gtt gat ccg aat agg agg atg tca gtt gct gaa cag    10578 
Glu Gly Arg Asp Val Asp Pro Asn Arg Arg Met Ser Val Ala Glu Gln 
                3485                3490                3495 

gtt gac tat gtc att aag gaa gca act aat cta gat aac ttg gct cag    10626 
Val Asp Tyr Val Ile Lys Glu Ala Thr Asn Leu Asp Asn Leu Ala Gln 
            3500                3505                3510 

ctg tat gaa ggt tgg aca gcc tgg gtg tga atggcaagac agtagatgag      10676 
Leu Tyr Glu Gly Trp Thr Ala Trp Val  * 
        3515                3520 

tctggttaag cgaggtcaga catccaccag aatcaactca gcctcaggca tccaaagcca  10736 

caccacagtc ggtggtgatg caactggggg cttactctga ggaaacctag gaaatctcgg  10796 

tgcactagga agtgaatccc gcaggacagc tgcactcagg gatacgccca acaccatggc  10856 

ctgcaacccc agggtcaagg gtgaaggaaa gcaagctcac cgcctgaaca cggagattgt  10916 

ctttctgcca cagaacagca gcagacgtgt cgggaggtta gctgcggaaa gaaatcggga  10976 

tgccgcggag cacagagtga tttggaactc cattccacct gaccctgtgt gtacaatcca  11036 

ggaaaaaaac aaaccccact cagaaacaga gaaaactggg gtcgcgaaga aatcacagcc  11096 

aaggaagatt tgatgcattc agattctcgt gtaacacttg ttgcttggca acagtactgg  11156 

ttgggttgac cagtaagtag aaaaaggcta aaggctatgc gatatgaatt tcagaaatgg  11216 

actgaaaatg gagagctatg taacagatac actacagtag aagaacttac ttctgaaatg  11276 

aagggaaaaa aaccacccca tcgttcccta ctcctcccca ccacttaccc gttccccctt  11336 

tacctaatct agtagattag ccatctttca aattcacttt tatttcagtc cttatatttc  11396 

atatacttcc gtctcgatgc tgttaacaac ttctgataac atggaaaatt caaggattgt  11456 

ttaaaggtct gatgatcaca cacaaaatgt aattccggtt atttaagtca tttctgtgat  11516 

tctatcatgt acagtttcca gaattgtcac tgtgcattca aaagtaatga atctaacaga  11576 

catttgattt aatgtacact cccttttgct tatagtgtgc attttttttg gaggtcattc  11636 

aaattttccc tcttctgtga tagctgtagt ttctttcata gaaagtagct aatccagtgt  11696 

aatcttttac ctttttaaaa accaagatag agtatctatt agagttttac attgttgatg  11756 

atagattaac aataaagtga tgttctggtg gaggtagact gaaatttttt taattcatgt  11816 

ttttcatttg atacttttaa tttacactta gtaaattaaa agttgtttaa tttacttggc  11876 

attttaggac atgtacatga aacagtgaaa atgagatcca ccaacatctt ttattaagtt  11936 

cagttattag tctgtgaagt gctttacttt ttgcacaatt ttaatagctt gctattcagt  11996 

aatacattat agtgaattca tgatcaaggt ttccttaaat ttagcattgc atttcagtac  12056 

tgactgtgta agctaaattg ctgatccaaa ataaaaaccc agactagaat agggttctta  12116 

aaatcaagta tcaatacaaa atagaacaca attaaaatct taattgttgg ctgggcacag  12176 

tggctcacgc ctgtaatccc agcactttgg gaggccgagg cgggcggatc atgaggttag  12236 

gagagcgaga ccatcctggc taacacggtg aaaccccgtc tttactaaaa tacaaaaaaa  12296 

attagccggg tgtggtggcg ggcgcctgta gtcccagcta ctcgggaggc tgaggcagga  12356 

gaatggcgtg aacccaggag gcggagcttg cagtgagccg agattgtgcc actgcactcc  12416 

agcctgggca acagagctag actctgtgtc aaaaataaat gactagat               12464 

 
           
             2  
             3521  
             PRT  
             Homo sapiens  
           
            2 

Met Ser Tyr Cys Asp Glu Ser Arg Leu Ser Asn Leu Leu Arg Arg Ile 
 1               5                  10                  15 

Thr Arg Glu Asp Asp Arg Asp Arg Arg Leu Ala Thr Val Lys Gln Leu 
            20                  25                  30 

Lys Glu Phe Ile Gln Gln Pro Glu Asn Lys Leu Val Leu Val Lys Gln 
        35                  40                  45 

Leu Asp Asn Ile Leu Ala Ala Val His Asp Val Leu Asn Glu Ser Ser 
    50                  55                  60 

Lys Leu Leu Gln Glu Leu Arg Gln Glu Gly Ala Cys Cys Leu Gly Leu 
65                  70                  75                  80 

Leu Cys Ala Ser Leu Ser Tyr Glu Ala Glu Lys Ile Phe Lys Trp Ile 
                85                  90                  95 

Phe Ser Lys Phe Ser Ser Ser Ala Lys Asp Glu Val Lys Leu Leu Tyr 
            100                 105                 110 

Leu Cys Ala Thr Tyr Lys Ala Leu Glu Thr Val Gly Glu Lys Lys Ala 
        115                 120                 125 

Phe Ser Ser Val Met Gln Leu Val Met Thr Ser Leu Gln Ser Ile Leu 
    130                 135                 140 

Glu Asn Val Asp Thr Pro Glu Leu Leu Cys Lys Cys Val Lys Cys Ile 
145                 150                 155                 160 

Leu Leu Val Ala Arg Cys Tyr Pro His Ile Phe Ser Thr Asn Phe Arg 
                165                 170                 175 

Asp Thr Val Asp Ile Leu Val Gly Trp His Ile Asp His Thr Gln Lys 
            180                 185                 190 

Pro Ser Leu Thr Gln Gln Val Ser Gly Trp Leu Gln Ser Leu Glu Pro 
        195                 200                 205 

Phe Trp Val Ala Asp Leu Ala Phe Ser Thr Thr Leu Leu Gly Gln Phe 
    210                 215                 220 

Leu Glu Asp Met Glu Ala Tyr Ala Glu Asp Leu Ser His Val Ala Ser 
225                 230                 235                 240 

Gly Glu Ser Val Asp Glu Asp Val Pro Pro Pro Ser Val Ser Leu Pro 
                245                 250                 255 

Lys Leu Ala Ala Leu Leu Arg Val Phe Ser Thr Val Val Arg Ser Ile 
            260                 265                 270 

Gly Glu Arg Phe Ser Pro Ile Arg Gly Pro Pro Ile Thr Glu Ala Tyr 
        275                 280                 285 

Val Thr Asp Val Leu Tyr Arg Val Met Arg Cys Val Thr Ala Ala Asn 
    290                 295                 300 

Gln Val Phe Phe Ser Glu Ala Val Leu Thr Ala Ala Asn Glu Cys Val 
305                 310                 315                 320 

Gly Val Leu Leu Gly Ser Leu Asp Pro Ser Met Thr Ile His Cys Asp 
                325                 330                 335 

Met Val Ile Thr Tyr Gly Leu Asp Gln Leu Glu Asn Cys Gln Thr Cys 
            340                 345                 350 

Gly Thr Asp Tyr Ile Ile Ser Val Leu Asn Leu Leu Thr Leu Ile Val 
        355                 360                 365 

Glu Gln Ile Asn Thr Lys Leu Pro Ser Ser Phe Val Glu Lys Leu Phe 
    370                 375                 380 

Ile Pro Ser Ser Lys Leu Leu Phe Leu Arg Tyr His Lys Glu Lys Glu 
385                 390                 395                 400 

Val Val Ala Val Ala His Ala Val Tyr Gln Ala Val Leu Ser Leu Lys 
                405                 410                 415 

Asn Ile Pro Val Leu Glu Thr Ala Tyr Lys Leu Ile Leu Gly Glu Met 
            420                 425                 430 

Thr Cys Ala Leu Asn Asn Leu Leu His Ser Leu Gln Leu Pro Glu Ala 
        435                 440                 445 

Cys Ser Glu Ile Lys His Glu Ala Phe Lys Asn His Val Phe Asn Val 
    450                 455                 460 

Asp Asn Ala Lys Phe Val Val Ile Phe Asp Leu Ser Ala Leu Thr Thr 
465                 470                 475                 480 

Ile Gly Asn Ala Lys Asn Ser Leu Ile Gly Met Trp Ala Leu Ser Pro 
                485                 490                 495 

Thr Val Phe Ala Leu Leu Ser Lys Asn Leu Met Ile Val His Ser Asp 
            500                 505                 510 

Leu Ala Val His Phe Pro Ala Ile Gln Tyr Ala Val Leu Tyr Thr Leu 
        515                 520                 525 

Tyr Ser His Cys Thr Arg His Asp His Phe Ile Ser Ser Ser Leu Ser 
    530                 535                 540 

Ser Ser Ser Pro Ser Leu Phe Asp Gly Ala Val Ile Ser Thr Val Thr 
545                 550                 555                 560 

Thr Ala Thr Lys Lys His Phe Ser Ile Ile Leu Asn Leu Leu Gly Ile 
                565                 570                 575 

Leu Leu Lys Lys Asp Asn Leu Asn Gln Asp Thr Arg Lys Leu Leu Met 
            580                 585                 590 

Thr Trp Ala Leu Glu Ala Ala Val Leu Met Lys Lys Ser Glu Thr Tyr 
        595                 600                 605 

Ala Pro Leu Phe Ser Leu Pro Ser Phe His Lys Phe Cys Lys Gly Leu 
    610                 615                 620 

Leu Ala Asn Thr Leu Val Glu Asp Val Asn Ile Cys Leu Gln Ala Cys 
625                 630                 635                 640 

Ser Ser Leu His Ala Leu Ser Ser Ser Leu Pro Asp Asp Leu Leu Gln 
                645                 650                 655 

Arg Cys Val Asp Val Cys Arg Val Gln Leu Val His Ser Gly Thr Arg 
            660                 665                 670 

Ile Arg Gln Ala Phe Gly Lys Leu Leu Lys Ser Ile Pro Leu Asp Val 
        675                 680                 685 

Val Leu Ser Asn Asn Asn His Thr Glu Ile Gln Glu Ile Ser Leu Ala 
    690                 695                 700 

Leu Arg Ser His Met Ser Lys Ala Pro Ser Asn Thr Phe His Pro Gln 
705                 710                 715                 720 

Asp Phe Ser Asp Val Ile Ser Phe Ile Leu Tyr Gly Asn Ser His Arg 
                725                 730                 735 

Thr Gly Lys Asp Asn Trp Leu Glu Arg Leu Phe Tyr Ser Cys Gln Arg 
            740                 745                 750 

Leu Asp Lys Arg Asp Gln Ser Thr Ile Pro Arg Asn Leu Leu Lys Thr 
        755                 760                 765 

Asp Ala Val Leu Trp Gln Trp Ala Ile Trp Glu Ala Ala Gln Phe Thr 
    770                 775                 780 

Val Leu Ser Lys Leu Arg Thr Pro Leu Gly Arg Ala Gln Asp Thr Phe 
785                 790                 795                 800 

Gln Thr Ile Glu Gly Ile Ile Arg Ser Leu Ala Ala His Thr Leu Asn 
                805                 810                 815 

Pro Asp Gln Asp Val Ser Gln Trp Thr Thr Ala Asp Asn Asp Glu Gly 
            820                 825                 830 

His Gly Asn Asn Gln Leu Arg Leu Val Leu Leu Leu Gln Tyr Leu Glu 
        835                 840                 845 

Asn Leu Glu Lys Leu Met Tyr Asn Ala Tyr Glu Gly Cys Ala Asn Ala 
    850                 855                 860 

Leu Thr Ser Pro Pro Lys Val Ile Arg Thr Phe Phe Tyr Thr Asn Arg 
865                 870                 875                 880 

Gln Thr Cys Gln Asp Trp Leu Thr Arg Ile Arg Leu Ser Ile Met Arg 
                885                 890                 895 

Val Gly Leu Leu Ala Gly Gln Pro Ala Val Thr Val Arg His Gly Phe 
            900                 905                 910 

Asp Leu Leu Thr Glu Met Lys Thr Thr Ser Leu Ser Gln Gly Asn Glu 
        915                 920                 925 

Leu Glu Val Thr Ile Met Met Val Val Glu Ala Leu Cys Glu Leu His 
    930                 935                 940 

Cys Pro Glu Ala Ile Gln Gly Ile Ala Val Trp Ser Ser Ser Ile Val 
945                 950                 955                 960 

Gly Lys Asn Leu Leu Trp Ile Asn Ser Val Ala Gln Gln Ala Glu Gly 
                965                 970                 975 

Arg Phe Glu Lys Ala Ser Val Glu Tyr Gln Glu His Leu Cys Ala Met 
            980                 985                 990 

Thr Gly Val Asp Cys Cys Ile Ser Ser Phe Asp Lys Ser Val Leu Thr 
        995                 1000                1005 

Leu Ala Asn Ala Gly Arg Asn Ser Ala Ser Pro Lys His Ser Leu Asn 
    1010                1015                1020 

Gly Glu Ser Arg Lys Thr Val Leu Ser Lys Pro Thr Asp Ser Ser Pro 
1025                1030                1035                1040 

Glu Val Ile Asn Tyr Leu Gly Asn Lys Ala Cys Glu Cys Tyr Ile Ser 
                1045                1050                1055 

Ile Ala Asp Trp Ala Ala Val Gln Glu Trp Gln Asn Ala Ile His Asp 
            1060                1065                1070 

Leu Lys Lys Ser Thr Ser Ser Thr Ser Leu Asn Leu Lys Ala Asp Phe 
        1075                1080                1085 

Asn Tyr Ile Lys Ser Leu Ser Ser Phe Glu Ser Gly Lys Phe Val Glu 
    1090                1095                1100 

Cys Thr Glu Gln Leu Glu Leu Leu Pro Gly Glu Asn Ile Asn Leu Leu 
1105                1110                1115                1120 

Ala Gly Gly Ser Lys Glu Lys Ile Asp Met Lys Lys Leu Leu Pro Asn 
                1125                1130                1135 

Met Leu Ser Pro Asp Pro Arg Glu Leu Gln Lys Ser Ile Glu Val Gln 
            1140                1145                1150 

Leu Leu Arg Ser Ser Val Cys Leu Ala Thr Ala Leu Asn Pro Ile Glu 
        1155                1160                1165 

Gln Asp Gln Lys Trp Gln Ser Ile Thr Glu Asn Val Val Lys Tyr Leu 
    1170                1175                1180 

Lys Gln Thr Ser Arg Ile Ala Ile Gly Pro Leu Arg Leu Ser Thr Leu 
1185                1190                1195                1200 

Thr Val Ser Gln Ser Leu Pro Val Leu Ser Thr Leu Gln Leu Tyr Cys 
                1205                1210                1215 

Ser Ser Ala Leu Glu Asn Thr Val Ser Asn Arg Leu Ser Thr Glu Asp 
            1220                1225                1230 

Cys Leu Ile Pro Leu Phe Ser Glu Ala Leu Arg Ser Cys Lys Gln His 
        1235                1240                1245 

Asp Val Arg Pro Trp Met Gln Ala Leu Arg Tyr Thr Met Tyr Gln Asn 
    1250                1255                1260 

Gln Leu Leu Glu Lys Ile Lys Glu Gln Thr Val Pro Ile Arg Ser His 
1265                1270                1275                1280 

Leu Met Glu Leu Gly Leu Thr Ala Ala Lys Phe Ala Arg Lys Arg Gly 
                1285                1290                1295 

Asn Val Ser Leu Ala Thr Arg Leu Leu Ala Gln Cys Ser Glu Val Gln 
            1300                1305                1310 

Leu Gly Lys Thr Thr Thr Ala Gln Asp Leu Val Gln His Phe Lys Lys 
        1315                1320                1325 

Leu Ser Thr Gln Gly Gln Val Asp Glu Lys Trp Gly Pro Glu Leu Asp 
    1330                1335                1340 

Ile Glu Lys Thr Lys Leu Leu Tyr Thr Ala Gly Gln Ser Thr His Ala 
1345                1350                1355                1360 

Met Glu Met Leu Ser Ser Cys Ala Ile Ser Phe Cys Lys Ser Val Lys 
                1365                1370                1375 

Ala Glu Tyr Ala Val Ala Lys Ser Ile Leu Thr Leu Ala Lys Trp Ile 
            1380                1385                1390 

Gln Ala Glu Trp Lys Glu Ile Ser Gly Gln Leu Lys Gln Val Tyr Arg 
        1395                1400                1405 

Ala Gln His Gln Gln Asn Phe Thr Gly Leu Ser Thr Leu Ser Lys Asn 
    1410                1415                1420 

Ile Leu Thr Leu Ile Glu Leu Pro Ser Val Asn Thr Met Glu Glu Glu 
1425                1430                1435                1440 

Tyr Pro Arg Ile Glu Ser Glu Ser Thr Val His Ile Gly Val Gly Glu 
                1445                1450                1455 

Pro Asp Phe Ile Leu Gly Gln Leu Tyr His Leu Ser Ser Val Gln Ala 
            1460                1465                1470 

Pro Glu Val Ala Lys Ser Trp Ala Ala Leu Ala Ser Trp Ala Tyr Arg 
        1475                1480                1485 

Trp Gly Arg Lys Val Val Asp Asn Ala Ser Gln Gly Glu Gly Val Arg 
    1490                1495                1500 

Leu Leu Pro Arg Glu Lys Ser Glu Val Gln Asn Leu Leu Pro Asp Thr 
1505                1510                1515                1520 

Ile Thr Glu Glu Glu Lys Glu Arg Ile Tyr Gly Ile Leu Gly Gln Ala 
                1525                1530                1535 

Val Cys Arg Pro Ala Gly Ile Gln Asp Glu Asp Ile Thr Leu Gln Ile 
            1540                1545                1550 

Thr Glu Ser Glu Asp Asn Glu Glu Asp Asp Met Val Asp Val Ile Trp 
        1555                1560                1565 

Arg Gln Leu Ile Ser Ser Cys Pro Trp Leu Ser Glu Leu Asp Glu Ser 
    1570                1575                1580 

Ala Thr Glu Gly Val Ile Lys Val Trp Arg Lys Val Val Asp Arg Ile 
1585                1590                1595                1600 

Phe Ser Leu Tyr Lys Leu Ser Cys Ser Ala Tyr Phe Thr Phe Leu Lys 
                1605                1610                1615 

Leu Asn Ala Gly Gln Ile Pro Leu Asp Glu Asp Asp Pro Arg Leu His 
            1620                1625                1630 

Leu Ser His Arg Val Glu Gln Ser Thr Asp Asp Met Ile Val Met Ala 
        1635                1640                1645 

Thr Leu Arg Leu Leu Arg Leu Leu Val Lys His Ala Gly Glu Leu Arg 
    1650                1655                1660 

Gln Tyr Leu Glu His Gly Leu Glu Thr Thr Pro Thr Ala Pro Trp Arg 
1665                1670                1675                1680 

Gly Ile Ile Pro Gln Leu Phe Ser Arg Leu Asn His Pro Glu Val Tyr 
                1685                1690                1695 

Val Arg Gln Ser Ile Cys Asn Leu Leu Cys Arg Val Ala Gln Asp Ser 
            1700                1705                1710 

Pro His Leu Ile Leu Tyr Pro Ala Ile Val Gly Thr Ile Ser Leu Ser 
        1715                1720                1725 

Ser Glu Ser Gln Ala Ser Gly Asn Lys Phe Ser Thr Ala Ile Pro Thr 
    1730                1735                1740 

Leu Leu Gly Asn Ile Gln Gly Glu Glu Leu Leu Val Ser Glu Cys Glu 
1745                1750                1755                1760 

Gly Gly Ser Pro Pro Ala Ser Gln Asp Ser Asn Lys Asp Glu Pro Lys 
                1765                1770                1775 

Ser Gly Leu Asn Glu Asp Gln Ala Met Met Gln Asp Cys Tyr Ser Lys 
            1780                1785                1790 

Ile Val Asp Lys Leu Ser Ser Ala Asn Pro Thr Met Val Leu Gln Val 
        1795                1800                1805 

Gln Met Leu Val Ala Glu Leu Arg Arg Val Thr Val Leu Trp Asp Glu 
    1810                1815                1820 

Leu Trp Leu Gly Val Leu Leu Gln Gln His Met Tyr Val Leu Arg Arg 
1825                1830                1835                1840 

Ile Gln Gln Leu Glu Asp Glu Val Lys Arg Val Gln Asn Asn Asn Thr 
                1845                1850                1855 

Leu Arg Lys Glu Glu Lys Ile Ala Ile Met Arg Glu Lys His Thr Ala 
            1860                1865                1870 

Leu Met Lys Pro Ile Val Phe Ala Leu Glu His Val Arg Ser Ile Thr 
        1875                1880                1885 

Ala Ala Pro Ala Glu Thr Pro His Glu Lys Trp Phe Gln Asp Asn Tyr 
    1890                1895                1900 

Gly Asp Ala Ile Glu Asn Ala Leu Glu Lys Leu Lys Thr Pro Leu Asn 
1905                1910                1915                1920 

Pro Ala Lys Pro Gly Ser Ser Trp Ile Pro Phe Lys Glu Ile Met Leu 
                1925                1930                1935 

Ser Leu Gln Gln Arg Ala Gln Lys Arg Ala Ser Tyr Ile Leu Arg Leu 
            1940                1945                1950 

Glu Glu Ile Ser Pro Trp Leu Ala Ala Met Thr Asn Thr Glu Ile Ala 
        1955                1960                1965 

Leu Pro Gly Glu Val Ser Ala Arg Asp Thr Val Thr Ile His Ser Val 
    1970                1975                1980 

Gly Gly Thr Ile Thr Ile Leu Pro Thr Lys Thr Lys Pro Lys Lys Leu 
1985                1990                1995                2000 

Leu Phe Leu Gly Ser Asp Gly Lys Ser Tyr Pro Tyr Leu Phe Lys Gly 
                2005                2010                2015 

Leu Glu Asp Leu His Leu Asp Glu Arg Ile Met Gln Phe Leu Ser Ile 
            2020                2025                2030 

Val Asn Thr Met Phe Ala Thr Ile Asn Arg Gln Glu Thr Pro Arg Phe 
        2035                2040                2045 

His Ala Arg His Tyr Ser Val Thr Pro Leu Gly Thr Arg Ser Gly Leu 
    2050                2055                2060 

Ile Gln Trp Val Asp Gly Ala Thr Pro Leu Phe Gly Leu Tyr Lys Arg 
2065                2070                2075                2080 

Trp Gln Gln Arg Glu Ala Ala Leu Gln Ala Gln Lys Ala Gln Asp Ser 
                2085                2090                2095 

Tyr Gln Thr Pro Gln Asn Pro Gly Ile Val Pro Arg Pro Ser Glu Leu 
            2100                2105                2110 

Tyr Tyr Ser Lys Ile Gly Pro Ala Leu Lys Thr Val Gly Leu Ser Leu 
        2115                2120                2125 

Asp Val Ser Arg Arg Asp Trp Pro Leu His Val Met Lys Ala Val Leu 
    2130                2135                2140 

Glu Glu Leu Met Glu Ala Thr Pro Pro Asn Leu Leu Ala Lys Glu Leu 
2145                2150                2155                2160 

Trp Ser Ser Cys Thr Thr Pro Asp Glu Trp Trp Arg Val Thr Gln Ser 
                2165                2170                2175 

Tyr Ala Arg Ser Thr Ala Val Met Ser Met Val Gly Tyr Ile Ile Gly 
            2180                2185                2190 

Leu Gly Asp Arg His Leu Asp Asn Val Leu Ile Asp Met Thr Thr Gly 
        2195                2200                2205 

Glu Val Val His Ile Asp Tyr Asn Val Cys Phe Glu Lys Gly Lys Ser 
    2210                2215                2220 

Leu Arg Val Pro Glu Lys Val Pro Phe Arg Met Thr Gln Asn Ile Glu 
2225                2230                2235                2240 

Thr Ala Leu Gly Val Thr Gly Val Glu Gly Val Phe Arg Leu Ser Cys 
                2245                2250                2255 

Glu Gln Val Leu His Ile Met Arg Arg Gly Arg Glu Thr Leu Leu Thr 
            2260                2265                2270 

Leu Leu Glu Ala Phe Val Tyr Asp Pro Leu Val Asp Trp Thr Ala Gly 
        2275                2280                2285 

Gly Glu Ala Gly Phe Ala Gly Ala Val Tyr Gly Gly Gly Gly Gln Gln 
    2290                2295                2300 

Ala Glu Ser Lys Gln Ser Lys Arg Glu Met Glu Arg Glu Ile Thr Arg 
2305                2310                2315                2320 

Ser Leu Phe Ser Ser Arg Val Ala Glu Ile Lys Val Asn Trp Phe Lys 
                2325                2330                2335 

Asn Arg Asp Glu Met Leu Val Val Leu Pro Lys Leu Asp Gly Ser Leu 
            2340                2345                2350 

Asp Glu Tyr Leu Ser Leu Gln Glu Gln Leu Thr Asp Val Glu Lys Leu 
        2355                2360                2365 

Gln Gly Lys Leu Leu Glu Glu Ile Glu Phe Leu Glu Gly Ala Glu Gly 
    2370                2375                2380 

Val Asp His Pro Ser His Thr Leu Gln His Arg Tyr Ser Glu His Thr 
2385                2390                2395                2400 

Gln Leu Gln Thr Gln Gln Arg Ala Val Gln Glu Ala Ile Gln Val Lys 
                2405                2410                2415 

Leu Asn Glu Phe Glu Gln Trp Ile Thr His Tyr Gln Ala Ala Phe Asn 
            2420                2425                2430 

Asn Leu Glu Ala Thr Gln Leu Ala Ser Leu Leu Gln Glu Ile Ser Thr 
        2435                2440                2445 

Gln Met Asp Leu Gly Pro Pro Ser Tyr Val Pro Ala Thr Ala Phe Leu 
    2450                2455                2460 

Gln Asn Ala Gly Gln Ala His Leu Ile Ser Gln Cys Glu Gln Leu Glu 
2465                2470                2475                2480 

Gly Glu Val Gly Ala Leu Leu Gln Gln Arg Arg Ser Val Leu Arg Gly 
                2485                2490                2495 

Cys Leu Glu Gln Leu His His Tyr Ala Thr Val Ala Leu Gln Tyr Pro 
            2500                2505                2510 

Lys Ala Ile Phe Gln Lys His Arg Ile Glu Gln Trp Lys Thr Trp Met 
        2515                2520                2525 

Glu Glu Leu Ile Cys Asn Thr Thr Val Glu Arg Cys Gln Glu Leu Tyr 
    2530                2535                2540 

Arg Lys Tyr Glu Met Gln Tyr Ala Pro Gln Pro Pro Pro Thr Val Cys 
2545                2550                2555                2560 

Gln Phe Ile Thr Ala Thr Glu Met Thr Leu Gln Arg Tyr Ala Ala Asp 
                2565                2570                2575 

Ile Asn Ser Arg Leu Ile Arg Gln Val Glu Arg Leu Lys Gln Glu Ala 
            2580                2585                2590 

Val Thr Val Pro Val Cys Glu Asp Gln Leu Lys Glu Ile Glu Arg Cys 
        2595                2600                2605 

Ile Lys Val Phe Leu His Glu Asn Gly Glu Glu Gly Ser Leu Ser Leu 
    2610                2615                2620 

Ala Ser Val Ile Ile Ser Ala Leu Cys Thr Leu Thr Arg Arg Asn Leu 
2625                2630                2635                2640 

Met Met Glu Gly Ala Ala Ser Ser Ala Gly Glu Gln Leu Val Asp Leu 
                2645                2650                2655 

Thr Ser Arg Asp Gly Ala Trp Phe Leu Glu Glu Leu Cys Ser Met Ser 
            2660                2665                2670 

Gly Asn Val Thr Cys Leu Val Gln Leu Leu Lys Gln Cys His Leu Val 
        2675                2680                2685 

Pro Gln Asp Leu Asp Ile Pro Asn Pro Met Glu Ala Ser Glu Thr Val 
    2690                2695                2700 

His Leu Ala Asn Gly Val Tyr Thr Ser Leu Gln Glu Leu Asn Ser Asn 
2705                2710                2715                2720 

Phe Arg Gln Ile Ile Phe Pro Glu Ala Leu Arg Cys Leu Met Lys Gly 
                2725                2730                2735 

Glu Tyr Thr Leu Glu Ser Met Leu His Glu Leu Asp Gly Leu Ile Glu 
            2740                2745                2750 

Gln Thr Thr Asp Gly Val Pro Leu Gln Thr Leu Val Glu Ser Leu Gln 
        2755                2760                2765 

Ala Tyr Leu Arg Asn Ala Ala Met Gly Leu Glu Glu Glu Thr His Ala 
    2770                2775                2780 

His Tyr Ile Asp Val Ala Arg Leu Leu His Ala Gln Tyr Gly Glu Leu 
2785                2790                2795                2800 

Ile Gln Pro Arg Asn Gly Ser Val Asp Glu Thr Pro Lys Met Ser Ala 
                2805                2810                2815 

Gly Gln Met Leu Leu Val Ala Phe Asp Gly Met Phe Ala Gln Val Glu 
            2820                2825                2830 

Thr Ala Phe Ser Leu Leu Val Glu Lys Leu Asn Lys Met Glu Ile Pro 
        2835                2840                2845 

Ile Ala Trp Arg Lys Ile Asp Ile Ile Arg Glu Ala Arg Ser Thr Gln 
    2850                2855                2860 

Val Asn Phe Phe Asp Asp Asp Asn His Arg Gln Val Leu Glu Glu Ile 
2865                2870                2875                2880 

Phe Phe Leu Lys Arg Leu Gln Thr Ile Lys Glu Phe Phe Arg Leu Cys 
                2885                2890                2895 

Gly Thr Phe Ser Lys Thr Leu Ser Gly Ser Ser Ser Leu Glu Asp Gln 
            2900                2905                2910 

Asn Thr Val Asn Gly Pro Val Gln Ile Val Asn Val Lys Thr Leu Phe 
        2915                2920                2925 

Arg Asn Ser Cys Phe Ser Glu Asp Gln Met Ala Lys Pro Ile Lys Ala 
    2930                2935                2940 

Phe Thr Ala Asp Phe Val Arg Gln Leu Leu Ile Gly Leu Pro Asn Gln 
2945                2950                2955                2960 

Ala Leu Gly Leu Thr Leu Cys Ser Phe Ile Ser Ala Leu Gly Val Asp 
                2965                2970                2975 

Ile Ile Ala Gln Val Glu Ala Lys Asp Phe Gly Ala Glu Ser Lys Val 
            2980                2985                2990 

Ser Val Asp Asp Leu Cys Lys Lys Ala Val Glu His Asn Ile Gln Ile 
        2995                3000                3005 

Gly Lys Phe Ser Gln Leu Val Met Asn Arg Ala Thr Val Leu Ala Ser 
    3010                3015                3020 

Ser Tyr Asp Thr Ala Trp Lys Lys His Asp Leu Val Arg Arg Leu Glu 
3025                3030                3035                3040 

Thr Ser Ile Ser Ser Cys Lys Thr Ser Leu Gln Arg Val Gln Leu His 
                3045                3050                3055 

Ile Ala Met Phe Gln Trp Gln His Glu Asp Leu Leu Ile Asn Arg Pro 
            3060                3065                3070 

Gln Ala Met Ser Val Thr Pro Pro Pro Arg Ser Ala Ile Leu Thr Ser 
        3075                3080                3085 

Met Lys Lys Lys Leu His Thr Leu Ser Gln Ile Glu Thr Ser Ile Ala 
    3090                3095                3100 

Thr Val Gln Glu Lys Leu Ala Ala Leu Glu Ser Ser Ile Glu Gln Arg 
3105                3110                3115                3120 

Leu Lys Trp Ala Gly Gly Ala Asn Pro Ala Leu Ala Pro Val Leu Gln 
                3125                3130                3135 

Asp Phe Glu Ala Thr Ile Ala Glu Arg Arg Asn Leu Val Leu Lys Glu 
            3140                3145                3150 

Ser Gln Arg Ala Ser Gln Val Thr Phe Leu Cys Ser Asn Ile Ile His 
        3155                3160                3165 

Phe Glu Ser Leu Arg Thr Arg Thr Ala Glu Ala Leu Asn Leu Asp Ala 
    3170                3175                3180 

Ala Leu Phe Glu Leu Ile Lys Arg Cys Gln Gln Met Cys Ser Phe Ala 
3185                3190                3195                3200 

Ser Gln Phe Asn Ser Ser Val Ser Glu Leu Glu Leu Arg Leu Leu Gln 
                3205                3210                3215 

Arg Val Asp Thr Gly Leu Glu His Pro Ile Gly Ser Ser Glu Trp Leu 
            3220                3225                3230 

Leu Ser Ala His Lys Gln Leu Thr Gln Asp Met Ser Thr Gln Arg Ala 
        3235                3240                3245 

Ile Gln Thr Glu Lys Glu Gln Gln Ile Glu Thr Val Cys Glu Thr Ile 
    3250                3255                3260 

Gln Asn Leu Val Asp Asn Ile Lys Thr Val Leu Thr Gly His Asn Arg 
3265                3270                3275                3280 

Gln Leu Gly Asp Val Lys His Leu Leu Lys Ala Met Ala Lys Asp Glu 
                3285                3290                3295 

Glu Ala Ala Leu Ala Asp Gly Glu Asp Val Pro Tyr Glu Asn Ser Val 
            3300                3305                3310 

Arg Gln Phe Leu Gly Glu Tyr Lys Ser Trp Gln Asp Asn Ile Gln Thr 
        3315                3320                3325 

Val Leu Phe Thr Leu Val Gln Ala Met Gly Gln Val Arg Ser Gln Glu 
    3330                3335                3340 

His Val Glu Met Leu Gln Glu Ile Thr Pro Thr Leu Lys Glu Leu Lys 
3345                3350                3355                3360 

Thr Gln Ser Gln Ser Ile Tyr Asn Asn Leu Val Ser Phe Ala Ser Pro 
                3365                3370                3375 

Leu Val Thr Asp Ala Thr Asn Glu Cys Ser Ser Pro Thr Ser Ser Ala 
            3380                3385                3390 

Thr Tyr Gln Pro Ser Phe Ala Ala Ala Val Arg Ser Asn Thr Gly Gln 
        3395                3400                3405 

Lys Thr Gln Pro Asp Val Met Ser Gln Asn Ala Arg Lys Leu Ile Gln 
    3410                3415                3420 

Lys Asn Leu Ala Thr Ser Ala Asp Thr Pro Pro Ser Thr Val Pro Gly 
3425                3430                3435                3440 

Thr Gly Lys Ser Val Ala Cys Ser Pro Lys Lys Ala Val Arg Asp Pro 
                3445                3450                3455 

Lys Thr Gly Lys Ala Val Gln Glu Arg Asn Ser Tyr Ala Val Ser Val 
            3460                3465                3470 

Trp Lys Arg Val Lys Ala Lys Leu Glu Gly Arg Asp Val Asp Pro Asn 
        3475                3480                3485 

Arg Arg Met Ser Val Ala Glu Gln Val Asp Tyr Val Ile Lys Glu Ala 
    3490                3495                3500 

Thr Asn Leu Asp Asn Leu Ala Gln Leu Tyr Glu Gly Trp Thr Ala Trp 
3505                3510                3515                3520 

Val 

 
           
             3  
             2629  
             DNA  
             Homo sapiens  
             
               CDS  
               (252)...(1433)  
             
           
            3 

acttgtcatg gcgactgtcc agctttgtgc caggagcctc gcaggggttg atgggattgg     60 

ggttttcccc tcccatgtgc tcaagactgg cgctaaaagt tttgagcttc tcaaaagtct    120 

agagccaccg tccagggagc aggtagctgc tgggctccgg ggacactttg cgttcgggct    180 

gggagcgtgc tttccacgac ggtgacacgc ttccctggat tggcagccag actgccttcc    240 

gggtcactgc c atg gag gag ccg cag tca gat cct agc gtc gag ccc cct     290 
             Met Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro 
              1               5                   10 

ctg agt cag gaa aca ttt tca gac cta tgg aaa cta ctt cct gaa aac      338 
Leu Ser Gln Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn 
     15                  20                  25 

aac gtt ctg tcc ccc ttg ccg tcc caa gca atg gat gat ttg atg ctg      386 
Asn Val Leu Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu 
 30                  35                  40                  45 

tcc ccg gac gat att gaa caa tgg ttc act gaa gac cca ggt cca gat      434 
Ser Pro Asp Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp 
                 50                  55                  60 

gaa gct ccc aga atg cca gag gct gct ccc cgc gtg gcc cct gca cca      482 
Glu Ala Pro Arg Met Pro Glu Ala Ala Pro Arg Val Ala Pro Ala Pro 
             65                  70                  75 

gca gct cct aca ccg gcg gcc cct gca cca gcc ccc tcc tgg ccc ctg      530 
Ala Ala Pro Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu 
         80                  85                  90 

tca tct tct gtc cct tcc cag aaa acc tac cag ggc agc tac ggt ttc      578 
Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe 
     95                 100                 105 

cgt ctg ggc ttc ttg cat tct ggg aca gcc aag tct gtg act tgc acg      626 
Arg Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr 
110                 115                 120                 125 

tac tcc cct gcc ctc aac aag atg ttt tgc caa ctg gcc aag acc tgc      674 
Tyr Ser Pro Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys 
                130                 135                 140 

cct gtg cag ctg tgg gtt gat tcc aca ccc ccg ccc ggc acc cgc gtc      722 
Pro Val Gln Leu Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val 
            145                 150                 155 

cgc gcc atg gcc atc tac aag cag tca cag cac atg acg gag gtt gtg      770 
Arg Ala Met Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val 
        160                 165                 170 

agg cgc tgc ccc cac cat gag cgc tgc tca gat agc gat ggt ctg gcc      818 
Arg Arg Cys Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala 
    175                 180                 185 

cct cct cag cat ctt atc cga gtg gaa gga aat ttg cgt gtg gag tat      866 
Pro Pro Gln His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr 
190                 195                 200                 205 

ttg gat gac aga aac act ttt cga cat agt gtg gtg gtg ccc tat gag      914 
Leu Asp Asp Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu 
                210                 215                 220 

ccg cct gag gtt ggc tct gac tgt acc acc atc cac tac aac tac atg      962 
Pro Pro Glu Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met 
            225                 230                 235 

tgt aac agt tcc tgc atg ggc ggc atg aac cgg agg ccc atc ctc acc     1010 
Cys Asn Ser Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr 
        240                 245                 250 

atc atc aca ctg gaa gac tcc agt ggt aat cta ctg gga cgg aac agc     1058 
Ile Ile Thr Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser 
    255                 260                 265 

ttt gag gtg cgt gtt tgt gcc tgt cct ggg aga gac cgg cgc aca gag     1106 
Phe Glu Val Arg Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu 
270                 275                 280                 285 

gaa gag aat ctc cgc aag aaa ggg gag cct cac cac gag ctg ccc cca     1154 
Glu Glu Asn Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro 
                290                 295                 300 

ggg agc act aag cga gca ctg ccc aac aac acc agc tcc tct ccc cag     1202 
Gly Ser Thr Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln 
            305                 310                 315 

cca aag aag aaa cca ctg gat gga gaa tat ttc acc ctt cag atc cgt     1250 
Pro Lys Lys Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg 
        320                 325                 330 

ggg cgt gag cgc ttc gag atg ttc cga gag ctg aat gag gcc ttg gaa     1298 
Gly Arg Glu Arg Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu 
    335                 340                 345 

ctc aag gat gcc cag gct ggg aag gag cca ggg ggg agc agg gct cac     1346 
Leu Lys Asp Ala Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His 
350                 355                 360                 365 

tcc agc cac ctg aag tcc aaa aag ggt cag tct acc tcc cgc cat aaa     1394 
Ser Ser His Leu Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys 
                370                 375                 380 

aaa ctc atg ttc aag aca gaa ggg cct gac tca gac tga cattctccac      1443 
Lys Leu Met Phe Lys Thr Glu Gly Pro Asp Ser Asp  * 
            385                 390 

ttcttgttcc ccactgacag cctcccaccc ccatctctcc ctcccctgcc attttgggtt   1503 

ttgggtcttt gaacccttgc ttgcaatagg tgtgcgtcag aagcacccag gacttccatt   1563 

tgctttgtcc cggggctcca ctgaacaagt tggcctgcac tggtgttttg ttgtggggag   1623 

gaggatgggg agtaggacat accagcttag attttaaggt ttttactgtg agggatgttt   1683 

gggagatgta agaaatgttc ttgcagttaa gggttagttt acaatcagcc acattctagg   1743 

taggtagggg cccacttcac cgtactaacc agggaagctg tccctcatgt tgaattttct   1803 

ctaacttcaa ggcccatatc tgtgaaatgc tggcatttgc acctacctca cagagtgcat   1863 

tgtgagggtt aatgaaataa tgtacatctg gccttgaaac caccttttat tacatggggt   1923 

ctaaaacttg acccccttga gggtgcctgt tccctctccc tctccctgtt ggctggtggg   1983 

ttggtagttt ctacagttgg gcagctggtt aggtagaggg agttgtcaag tcttgctggc   2043 

ccagccaaac cctgtctgac aacctcttgg tcgaccttag tacctaaaag gaaatctcac   2103 

cccatcccac accctggagg atttcatctc ttgtatatga tgatctggat ccaccaagac   2163 

ttgttttatg ctcagggtca atttcttttt tctttttttt tttttttttt ctttttcttt   2223 

gagactgggt ctcgctttgt tgcccaggct ggagtggagt ggcgtgatct tggcttactg   2283 

cagcctttgc ctccccggct cgagcagtcc tgcctcagcc tccggagtag ctgggaccac   2343 

aggttcatgc caccatggcc agccaacttt tgcatgtttt gtagagatgg ggtctcacag   2403 

tgttgcccag gctggtctca aactcctggg ctcaggcgat ccacctgtct cagcctccca   2463 

gagtgctggg attacaattg tgagccacca cgtggagctg gaagggtcaa catcttttac   2523 

attctgcaag cacatctgca ttttcacccc acccttcccc tccttctccc tttttatatc   2583 

ccatttttat atcgatctct tattttacaa taaaactttg ctgcca                  2629 

 
           
             4  
             393  
             PRT  
             Homo sapiens  
           
            4 

Met Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln 
 1               5                  10                  15 

Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu 
            20                  25                  30 

Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp 
        35                  40                  45 

Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro 
    50                  55                  60 

Arg Met Pro Glu Ala Ala Pro Arg Val Ala Pro Ala Pro Ala Ala Pro 
65                  70                  75                  80 

Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser 
                85                  90                  95 

Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly 
            100                 105                 110 

Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro 
        115                 120                 125 

Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln 
    130                 135                 140 

Leu Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met 
145                 150                 155                 160 

Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys 
                165                 170                 175 

Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln 
            180                 185                 190 

His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp 
        195                 200                 205 

Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu 
    210                 215                 220 

Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser 
225                 230                 235                 240 

Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr 
                245                 250                 255 

Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val 
            260                 265                 270 

Arg Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn 
        275                 280                 285 

Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr 
    290                 295                 300 

Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys 
305                 310                 315                 320 

Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu 
                325                 330                 335 

Arg Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp 
            340                 345                 350 

Ala Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His 
        355                 360                 365 

Leu Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met 
    370                 375                 380 

Phe Lys Thr Glu Gly Pro Asp Ser Asp 
385                 390 

 
           
             5  
             12606  
             DNA  
             Homo sapiens  
             
               CDS  
               (1703)...(10798)  
             
           
            5 

attgacttga tgcacaacat cacaaaggcg atttttgaga actgatagtg catcagccga     60 

cccaggtaat ttaaaatatt cttcatccag agatagaggt ggttcttcct cttacggact    120 

gcaaccttca aattcagctg tggtgtctcg gcaaaggcac gatgatacca gagtccacgc    180 

tgacatacag aatgacgaaa aggagagatc gatgtcttat tgtgatgagt ctcgactgtc    240 

gaatcttctt cggaggatca cccgggaaga cgacagagac cgaagattgg ctactgtaaa    300 

gcagttgaaa gaatttattc agcaaccaga aaataagctg gtactagtta aacaattgga    360 

taatatcttg gctgctgtac atgacgtgct taatgaaagt agcaaattgc ttcaggagtt    420 

gagacaggag ggagcttgct gtcttggcct tctttgtgct tctctgagct atgaggctga    480 

gaagatcttc aagtggattt ttagcaaatt tagctcatct gcaaaagatg aagttaaact    540 

cctctactta tgtgccacct acaaagcact agagactgta ggagaaaaga aagccttttc    600 

atctgtaatg cagcttgtaa tgaccagcct gcagtctatt cttgaaaatg tggatacacc    660 

agaattgctt tgtaaatgtg ttaagtgcat tcttttggtg gctcgatgtt accctcatat    720 

tttcagcact aattttaggg atacagttga tatattagtt ggatggcata tagatcatac    780 

tcagaaacct tcgctcacgc agcaggtatc tgggtggttg cagagtttgg agccattttg    840 

ggtagctgat cttgcatttt ctactactct tcttggtcag tttctggaag acatggaagc    900 

atatgctgag gacctcagcc atgtggcctc tggggaatca gtggatgaag atgtccctcc    960 

tccatcagtg tcattaccaa agctggctgc acttctccgg gtatttagta ctgtggtgag   1020 

gagcattggg gaacgcttca gcccaattcg gggtcctcca attactgagg catatgtaac   1080 

agatgttctg tacagagtaa tgagatgtgt gacggctgca aaccaggtgt ttttttctga   1140 

ggctgtgttg acagctgcta atgagtgtgt tggtgttttg ctcggcagct tggatcctag   1200 

catgactata cattgtgaca tggtcattac atatggatta gaccaactgg agaattgcca   1260 

gacttgtggt accgattata tcatctcagt cttgaattta ctcacgctga ttgttgaaca   1320 

gataaatacg aaactgccat catcatttgt agaaaaactg tttataccat catctaaact   1380 

actattcttg cgttatcata aagaaaaaga ggttgttgct gtagcccatg ctgtttatca   1440 

agcagtgctc agcttgaaga atattcctgt tttggagact gcctataagt taatattggg   1500 

agaaatgact tgtgccctaa acaacctcct acacagtcta caacttcctg aggcctgttc   1560 

tgaaataaaa catgaggctt ttaagaatca tgtgttcaat gtagacaatg caaaatttgt   1620 

agttatattt gacctcaatt gactacaaaa tttgtagtta aatttgacta caattggaaa   1680 

tgccaaaaac tcactaatag gg atg tgg gcg cta tct cca act gtc ttt gca    1732 
                         Met Trp Ala Leu Ser Pro Thr Val Phe Ala 
                          1               5                   10 

ctt ctg agt aag aat ctg atg att gtg cac agt gac ctg gct gtt cac     1780 
Leu Leu Ser Lys Asn Leu Met Ile Val His Ser Asp Leu Ala Val His 
                 15                  20                  25 

ttc cct gcc att cag tat gct gtg ctc tac aca ttg tat tct cat tgt     1828 
Phe Pro Ala Ile Gln Tyr Ala Val Leu Tyr Thr Leu Tyr Ser His Cys 
             30                  35                  40 

acc agg cat gat cac ttt atc tct agt agc ctc agt tct tcc tct cct     1876 
Thr Arg His Asp His Phe Ile Ser Ser Ser Leu Ser Ser Ser Ser Pro 
         45                  50                  55 

tct ttg ttt gat gga gct gtg att agc act gta act acg gct aca aag     1924 
Ser Leu Phe Asp Gly Ala Val Ile Ser Thr Val Thr Thr Ala Thr Lys 
     60                  65                  70 

aaa cat ttc tca att ata tta aat ctt ctg gga ata tta ctt aag aaa     1972 
Lys His Phe Ser Ile Ile Leu Asn Leu Leu Gly Ile Leu Leu Lys Lys 
 75                  80                  85                  90 

gat aac ctt aac cag gac acg agg aaa ctg tta atg act tgg gct ttg     2020 
Asp Asn Leu Asn Gln Asp Thr Arg Lys Leu Leu Met Thr Trp Ala Leu 
                 95                 100                 105 

gaa gca gct gtt tta atg aag aag tct gaa aca tac gca cct tta ttc     2068 
Glu Ala Ala Val Leu Met Lys Lys Ser Glu Thr Tyr Ala Pro Leu Phe 
            110                 115                 120 

tct ctt ccg tct ttc cat aaa ttt tgc aaa ggc ctt tta gcc aac act     2116 
Ser Leu Pro Ser Phe His Lys Phe Cys Lys Gly Leu Leu Ala Asn Thr 
        125                 130                 135 

ctc gtt gaa gat gtg aat atc tgt ctg cag gca tgc agc agt cta cat     2164 
Leu Val Glu Asp Val Asn Ile Cys Leu Gln Ala Cys Ser Ser Leu His 
    140                 145                 150 

gct ctg tcc tct tcc ttg cca gat gat ctt tta cag aga tgt gtc gat     2212 
Ala Leu Ser Ser Ser Leu Pro Asp Asp Leu Leu Gln Arg Cys Val Asp 
155                 160                 165                 170 

gtt tgc cgt gtt caa cta gtg cac agt gga act cgt att cga caa gca     2260 
Val Cys Arg Val Gln Leu Val His Ser Gly Thr Arg Ile Arg Gln Ala 
                175                 180                 185 

ttt gga aaa ctg ttg aaa tca att cct tta gat gtt gtc cta agc aat     2308 
Phe Gly Lys Leu Leu Lys Ser Ile Pro Leu Asp Val Val Leu Ser Asn 
            190                 195                 200 

aac aat cac aca gaa att caa gaa att tct tta gca tta aga agt cac     2356 
Asn Asn His Thr Glu Ile Gln Glu Ile Ser Leu Ala Leu Arg Ser His 
        205                 210                 215 

atg agt aaa gca cca agt aat aca ttc cac ccc caa gat ttc tct gat     2404 
Met Ser Lys Ala Pro Ser Asn Thr Phe His Pro Gln Asp Phe Ser Asp 
    220                 225                 230 

gtt att agt ttt att ttg tat ggg aac tct cat aga aca ggg aag gac     2452 
Val Ile Ser Phe Ile Leu Tyr Gly Asn Ser His Arg Thr Gly Lys Asp 
235                 240                 245                 250 

aat tgg ttg gaa aga ctg ttc tat agc tgc cag aga ctg gat aag cgt     2500 
Asn Trp Leu Glu Arg Leu Phe Tyr Ser Cys Gln Arg Leu Asp Lys Arg 
                255                 260                 265 

gac cag tca aca att cca cgc aat ctc ctg aag aca gat gct gtc ctt     2548 
Asp Gln Ser Thr Ile Pro Arg Asn Leu Leu Lys Thr Asp Ala Val Leu 
            270                 275                 280 

tgg cag tgg gcc ata tgg gaa gct gca caa ttc act gtt ctt tct aag     2596 
Trp Gln Trp Ala Ile Trp Glu Ala Ala Gln Phe Thr Val Leu Ser Lys 
        285                 290                 295 

ctg aga acc cca ctg ggc aga gct caa gac acc ttc cag aca att gaa     2644 
Leu Arg Thr Pro Leu Gly Arg Ala Gln Asp Thr Phe Gln Thr Ile Glu 
    300                 305                 310 

ggt atc att cga agt ctc gca gct cac aca tta aac cct gat cag gat     2692 
Gly Ile Ile Arg Ser Leu Ala Ala His Thr Leu Asn Pro Asp Gln Asp 
315                 320                 325                 330 

gtt agt cag tgg aca act gca gac aat gat gaa ggc cat ggt aac aac     2740 
Val Ser Gln Trp Thr Thr Ala Asp Asn Asp Glu Gly His Gly Asn Asn 
                335                 340                 345 

caa ctt aga ctt gtt ctt ctt ctg cag tat ctg gaa aat ctg gag aaa     2788 
Gln Leu Arg Leu Val Leu Leu Leu Gln Tyr Leu Glu Asn Leu Glu Lys 
            350                 355                 360 

tta atg tat aat gca tac gag gga tgt gct aat gca tta act tca cct     2836 
Leu Met Tyr Asn Ala Tyr Glu Gly Cys Ala Asn Ala Leu Thr Ser Pro 
        365                 370                 375 

ccc aag gtc att aga act ttt ttc tat acc aat cgc caa act tgt cag     2884 
Pro Lys Val Ile Arg Thr Phe Phe Tyr Thr Asn Arg Gln Thr Cys Gln 
    380                 385                 390 

gac tgg cta acg cgg att cga ctc tcc atc atg agg gta gga ttg ttg     2932 
Asp Trp Leu Thr Arg Ile Arg Leu Ser Ile Met Arg Val Gly Leu Leu 
395                 400                 405                 410 

gca ggc cag cct gca gtg aca gtg aga cat ggc ttt gac ttg ctt aca     2980 
Ala Gly Gln Pro Ala Val Thr Val Arg His Gly Phe Asp Leu Leu Thr 
                415                 420                 425 

gag atg aaa aca acc agc cta tct cag ggg aat gaa ttg gaa gta acc     3028 
Glu Met Lys Thr Thr Ser Leu Ser Gln Gly Asn Glu Leu Glu Val Thr 
            430                 435                 440 

att atg atg gtg gta gaa gca tta tgt gaa ctt cat tgt cct gaa gct     3076 
Ile Met Met Val Val Glu Ala Leu Cys Glu Leu His Cys Pro Glu Ala 
        445                 450                 455 

ata cag gga att gct gtc tgg tca tca tct att gtt gga aaa aat ctt     3124 
Ile Gln Gly Ile Ala Val Trp Ser Ser Ser Ile Val Gly Lys Asn Leu 
    460                 465                 470 

ctg tgg att aac tca gtg gct caa cag gct gaa ggg agg ttt gaa aag     3172 
Leu Trp Ile Asn Ser Val Ala Gln Gln Ala Glu Gly Arg Phe Glu Lys 
475                 480                 485                 490 

gcc tct gtg gag tac cag gaa cac ctg tgt gcc atg aca ggt gtt gat     3220 
Ala Ser Val Glu Tyr Gln Glu His Leu Cys Ala Met Thr Gly Val Asp 
                495                 500                 505 

tgc tgc atc tcc agc ttt gac aaa tcg gtg ctc acc tta gcc aat gct     3268 
Cys Cys Ile Ser Ser Phe Asp Lys Ser Val Leu Thr Leu Ala Asn Ala 
            510                 515                 520 

ggg cgt aac agt gcc agc ccg aaa cat tct ctg aat ggt gaa tcc aga     3316 
Gly Arg Asn Ser Ala Ser Pro Lys His Ser Leu Asn Gly Glu Ser Arg 
        525                 530                 535 

aaa act gtg ctg tcc aaa ccg act gac tct tcc cct gag gtt ata aat     3364 
Lys Thr Val Leu Ser Lys Pro Thr Asp Ser Ser Pro Glu Val Ile Asn 
    540                 545                 550 

tat tta gga aat aaa gca tgt gag tgc tac atc tca att gcc gat tgg     3412 
Tyr Leu Gly Asn Lys Ala Cys Glu Cys Tyr Ile Ser Ile Ala Asp Trp 
555                 560                 565                 570 

gct gct gtg cag gaa tgg cag aac gct atc cat gac ttg aaa aag agt     3460 
Ala Ala Val Gln Glu Trp Gln Asn Ala Ile His Asp Leu Lys Lys Ser 
                575                 580                 585 

acc agt agc act tcc ctc aac ctg aaa gct gac ttc aac tat ata aaa     3508 
Thr Ser Ser Thr Ser Leu Asn Leu Lys Ala Asp Phe Asn Tyr Ile Lys 
            590                 595                 600 

tca tta agc agc ttt gag tct gga aaa ttt gtt gaa tgt acc gag caa     3556 
Ser Leu Ser Ser Phe Glu Ser Gly Lys Phe Val Glu Cys Thr Glu Gln 
        605                 610                 615 

tta gaa ttg tta cca gga gaa aat atc aat cta ctt gct gga gga tca     3604 
Leu Glu Leu Leu Pro Gly Glu Asn Ile Asn Leu Leu Ala Gly Gly Ser 
    620                 625                 630 

aaa gaa aaa ata gac atg aaa aaa ctg ctt cct aac atg tta agt ccg     3652 
Lys Glu Lys Ile Asp Met Lys Lys Leu Leu Pro Asn Met Leu Ser Pro 
635                 640                 645                 650 

gat ccg agg gaa ctt cag aaa tcc att gaa gtt caa ttg tta aga agt     3700 
Asp Pro Arg Glu Leu Gln Lys Ser Ile Glu Val Gln Leu Leu Arg Ser 
                655                 660                 665 

tct gtt tgt ttg gca act gct tta aac ccg ata gaa caa gat cag aag     3748 
Ser Val Cys Leu Ala Thr Ala Leu Asn Pro Ile Glu Gln Asp Gln Lys 
            670                 675                 680 

tgg cag tct ata act gaa aat gtg gta aag tac ttg aag caa aca tcc     3796 
Trp Gln Ser Ile Thr Glu Asn Val Val Lys Tyr Leu Lys Gln Thr Ser 
        685                 690                 695 

cgc atc gct att gga cct ctg aga ctt tct act tta aca gtt tca cag     3844 
Arg Ile Ala Ile Gly Pro Leu Arg Leu Ser Thr Leu Thr Val Ser Gln 
    700                 705                 710 

tct ttg cca gtt cta agt acc ttg cag ctg tat tgc tca tct gct ttg     3892 
Ser Leu Pro Val Leu Ser Thr Leu Gln Leu Tyr Cys Ser Ser Ala Leu 
715                 720                 725                 730 

gag aac aca gtt tct aac aga ctt tca aca gag gac tgt ctt att cca     3940 
Glu Asn Thr Val Ser Asn Arg Leu Ser Thr Glu Asp Cys Leu Ile Pro 
                735                 740                 745 

ctc ttc agt gaa gct tta cgt tca tgt aaa cag cat gac gtg agg cca     3988 
Leu Phe Ser Glu Ala Leu Arg Ser Cys Lys Gln His Asp Val Arg Pro 
            750                 755                 760 

tgg atg cag gca tta agg tat act atg tac cag aat cag ttg ttg gag     4036 
Trp Met Gln Ala Leu Arg Tyr Thr Met Tyr Gln Asn Gln Leu Leu Glu 
        765                 770                 775 

aaa att aaa gaa caa aca gtc cca att aga agc cat ctc atg gaa tta     4084 
Lys Ile Lys Glu Gln Thr Val Pro Ile Arg Ser His Leu Met Glu Leu 
    780                 785                 790 

ggt cta aca gca gca aaa ttt gct aga aaa cga ggg aat gtg tcc ctt     4132 
Gly Leu Thr Ala Ala Lys Phe Ala Arg Lys Arg Gly Asn Val Ser Leu 
795                 800                 805                 810 

gca aca aga ctg ctg gca cag tgc agt gaa gtt cag ctg gga aag acc     4180 
Ala Thr Arg Leu Leu Ala Gln Cys Ser Glu Val Gln Leu Gly Lys Thr 
                815                 820                 825 

acc act gca cag gat tta gtc caa cat ttt aaa aaa cta tca acc caa     4228 
Thr Thr Ala Gln Asp Leu Val Gln His Phe Lys Lys Leu Ser Thr Gln 
            830                 835                 840 

ggt caa gtg gat gaa aaa tgg ggg ccc gaa ctt gat att gaa aaa acc     4276 
Gly Gln Val Asp Glu Lys Trp Gly Pro Glu Leu Asp Ile Glu Lys Thr 
        845                 850                 855 

aaa ttg ctt tat aca gca ggc cag tca aca cat gca atg gaa atg ttg     4324 
Lys Leu Leu Tyr Thr Ala Gly Gln Ser Thr His Ala Met Glu Met Leu 
    860                 865                 870 

agt tct tgt gcc ata tct ttc tgc aag tct gtg aaa gct gaa tat gca     4372 
Ser Ser Cys Ala Ile Ser Phe Cys Lys Ser Val Lys Ala Glu Tyr Ala 
875                 880                 885                 890 

gtt gct aaa tca att ctg aca ctg gct aaa tgg atc cag gca gaa tgg     4420 
Val Ala Lys Ser Ile Leu Thr Leu Ala Lys Trp Ile Gln Ala Glu Trp 
                895                 900                 905 

aaa gag att tca gga cag ctg aaa cag gtt tac aga gct cag cac caa     4468 
Lys Glu Ile Ser Gly Gln Leu Lys Gln Val Tyr Arg Ala Gln His Gln 
            910                 915                 920 

cag aac ttc aca ggt ctt tct act ttg tct aaa aac ata ctc act cta     4516 
Gln Asn Phe Thr Gly Leu Ser Thr Leu Ser Lys Asn Ile Leu Thr Leu 
        925                 930                 935 

ata gaa ctg cca tct gtt aat acg atg gaa gaa gag tat cct cgg atc     4564 
Ile Glu Leu Pro Ser Val Asn Thr Met Glu Glu Glu Tyr Pro Arg Ile 
    940                 945                 950 

gag agt gaa tct aca gtg cat att gga gtt gga gaa cct gac ttc att     4612 
Glu Ser Glu Ser Thr Val His Ile Gly Val Gly Glu Pro Asp Phe Ile 
955                 960                 965                 970 

ttg gga cag ttg tat cac ctg tct tca gta cag gca cct gaa gta gcc     4660 
Leu Gly Gln Leu Tyr His Leu Ser Ser Val Gln Ala Pro Glu Val Ala 
                975                 980                 985 

aaa tct tgg gca gcg ttg gcc agc tgg gct tat agg tgg ggc aga aag     4708 
Lys Ser Trp Ala Ala Leu Ala Ser Trp Ala Tyr Arg Trp Gly Arg Lys 
             990                 995                1000 

gtg gtt gac aat gcc agt cag gga gaa ggt gtt cgt ctg ctg cct aga     4756 
Val Val Asp Asn Ala Ser Gln Gly Glu Gly Val Arg Leu Leu Pro Arg 
        1005                1010                1015 

gaa aaa tct gaa gtt cag aat cta ctt cca gac act ata act gag gaa     4804 
Glu Lys Ser Glu Val Gln Asn Leu Leu Pro Asp Thr Ile Thr Glu Glu 
    1020                1025                1030 

gag aaa gag aga ata tat ggt att ctt gga cag gct gtg tgt cgg ccg     4852 
Glu Lys Glu Arg Ile Tyr Gly Ile Leu Gly Gln Ala Val Cys Arg Pro 
1035                1040                1045                1050 

gcg ggg att cag gat gaa gat ata aca ctt cag ata act gag agt gaa     4900 
Ala Gly Ile Gln Asp Glu Asp Ile Thr Leu Gln Ile Thr Glu Ser Glu 
                1055                1060                1065 

gac aac gaa gaa gat gac atg gtt gat gtt atc tgg cgt cag ttg ata     4948 
Asp Asn Glu Glu Asp Asp Met Val Asp Val Ile Trp Arg Gln Leu Ile 
            1070                1075                1080 

tca agc tgc cca tgg ctt tca gaa ctt gat gaa agt gca act gaa gga     4996 
Ser Ser Cys Pro Trp Leu Ser Glu Leu Asp Glu Ser Ala Thr Glu Gly 
        1085                1090                1095 

gtt att aaa gtg tgg agg aaa gtt gta gat aga ata ttc agc ctg tac     5044 
Val Ile Lys Val Trp Arg Lys Val Val Asp Arg Ile Phe Ser Leu Tyr 
    1100                1105                1110 

aaa ctc tct tgc agt gca tac ttt act ttc ctt aaa ctc aac gct ggt     5092 
Lys Leu Ser Cys Ser Ala Tyr Phe Thr Phe Leu Lys Leu Asn Ala Gly 
1115                1120                1125                1130 

caa att cct tta gat gag gat gac cct agg ctg cat tta agt cac aga     5140 
Gln Ile Pro Leu Asp Glu Asp Asp Pro Arg Leu His Leu Ser His Arg 
                1135                1140                1145 

gtg gaa cag agc act gat gac atg att gtg atg gcc aca ttg cgc ctg     5188 
Val Glu Gln Ser Thr Asp Asp Met Ile Val Met Ala Thr Leu Arg Leu 
            1150                1155                1160 

ctg cgg ttg ctc gtg aag cat gct ggt gag ctt cgg cag tat ctg gag     5236 
Leu Arg Leu Leu Val Lys His Ala Gly Glu Leu Arg Gln Tyr Leu Glu 
        1165                1170                1175 

cac ggc ttg gag aca aca ccc act gca cca tgg aga gga att att ccg     5284 
His Gly Leu Glu Thr Thr Pro Thr Ala Pro Trp Arg Gly Ile Ile Pro 
    1180                1185                1190 

caa ctt ttc tca cgc tta aac cac cct gaa gtg tat gtg cgc caa agt     5332 
Gln Leu Phe Ser Arg Leu Asn His Pro Glu Val Tyr Val Arg Gln Ser 
1195                1200                1205                1210 

att tgt aac ctt ctc tgc cgt gtg gct caa gat tcc cca cat ctc ata     5380 
Ile Cys Asn Leu Leu Cys Arg Val Ala Gln Asp Ser Pro His Leu Ile 
                1215                1220                1225 

ttg tat cct gca ata gtg ggt acc ata tcg ctt agt agt gaa tcc cag     5428 
Leu Tyr Pro Ala Ile Val Gly Thr Ile Ser Leu Ser Ser Glu Ser Gln 
            1230                1235                1240 

gct tca gga aat aaa ttt tcc act gca att cca act tta ctt ggc aat     5476 
Ala Ser Gly Asn Lys Phe Ser Thr Ala Ile Pro Thr Leu Leu Gly Asn 
        1245                1250                1255 

att caa gga gaa gaa ttg ctg gtt tct gaa tgt gag gga gga agt cct     5524 
Ile Gln Gly Glu Glu Leu Leu Val Ser Glu Cys Glu Gly Gly Ser Pro 
    1260                1265                1270 

cct gca tct cag gat agc aat aag gat gaa cct aaa agt gga tta aat     5572 
Pro Ala Ser Gln Asp Ser Asn Lys Asp Glu Pro Lys Ser Gly Leu Asn 
1275                1280                1285                1290 

gaa gac caa gcc atg atg cag gat tgt tac agc aaa att gta gat aag     5620 
Glu Asp Gln Ala Met Met Gln Asp Cys Tyr Ser Lys Ile Val Asp Lys 
                1295                1300                1305 

ctg tcc tct gca aac ccc acc atg gta tta cag gtt cag atg ctc gtg     5668 
Leu Ser Ser Ala Asn Pro Thr Met Val Leu Gln Val Gln Met Leu Val 
            1310                1315                1320 

gct gaa ctg cgc agg gtc act gtg ctc tgg gat gag ctc tgg ctg gga     5716 
Ala Glu Leu Arg Arg Val Thr Val Leu Trp Asp Glu Leu Trp Leu Gly 
        1325                1330                1335 

gtt ttg ctg caa caa cac atg tat gtc ctg aga cga att cag cag ctt     5764 
Val Leu Leu Gln Gln His Met Tyr Val Leu Arg Arg Ile Gln Gln Leu 
    1340                1345                1350 

gaa gat gag gtg aag aga gtc cag aac aac aac acc tta cgc aaa gaa     5812 
Glu Asp Glu Val Lys Arg Val Gln Asn Asn Asn Thr Leu Arg Lys Glu 
1355                1360                1365                1370 

gag aaa att gca atc atg agg gag aag cac aca gct ttg atg aag ccc     5860 
Glu Lys Ile Ala Ile Met Arg Glu Lys His Thr Ala Leu Met Lys Pro 
                1375                1380                1385 

atc gta ttt gct ttg gag cat gtg agg agt atc aca gcg gct cct gca     5908 
Ile Val Phe Ala Leu Glu His Val Arg Ser Ile Thr Ala Ala Pro Ala 
            1390                1395                1400 

gaa aca cct cat gaa aaa tgg ttt cag gat aac tat ggt gat gcc att     5956 
Glu Thr Pro His Glu Lys Trp Phe Gln Asp Asn Tyr Gly Asp Ala Ile 
        1405                1410                1415 

gaa aat gcc cta gaa aaa ctg aag act cca ttg aac cct gca aag cct     6004 
Glu Asn Ala Leu Glu Lys Leu Lys Thr Pro Leu Asn Pro Ala Lys Pro 
    1420                1425                1430 

ggg agc agc tgg att cca ttt aaa gag ata atg cta agt ttg caa cag     6052 
Gly Ser Ser Trp Ile Pro Phe Lys Glu Ile Met Leu Ser Leu Gln Gln 
1435                1440                1445                1450 

aga gca cag aaa cgt gca agt tac atc ttg cgt ctt gaa gaa atc agt     6100 
Arg Ala Gln Lys Arg Ala Ser Tyr Ile Leu Arg Leu Glu Glu Ile Ser 
                1455                1460                1465 

cca tgg ttg gct gcc atg act aac act gaa att gct ctt cct ggg gaa     6148 
Pro Trp Leu Ala Ala Met Thr Asn Thr Glu Ile Ala Leu Pro Gly Glu 
            1470                1475                1480 

gtc tca gcc aga gac act gtc aca atc cat agt gtg ggc gga acc atc     6196 
Val Ser Ala Arg Asp Thr Val Thr Ile His Ser Val Gly Gly Thr Ile 
        1485                1490                1495 

aca atc tta ccg act aaa acc aag cca aag aaa ctt ctc ttt ctt gga     6244 
Thr Ile Leu Pro Thr Lys Thr Lys Pro Lys Lys Leu Leu Phe Leu Gly 
    1500                1505                1510 

tca gat ggg aag agc tat cct tat ctt ttc aaa gga ctg gag gat tta     6292 
Ser Asp Gly Lys Ser Tyr Pro Tyr Leu Phe Lys Gly Leu Glu Asp Leu 
1515                1520                1525                1530 

cat ctg gat gag aga ata atg cag ttc cta tct att gtg aat acc atg     6340 
His Leu Asp Glu Arg Ile Met Gln Phe Leu Ser Ile Val Asn Thr Met 
                1535                1540                1545 

ttt gct aca att aat cgc caa gaa aca ccc cgg ttc cat gct cga cac     6388 
Phe Ala Thr Ile Asn Arg Gln Glu Thr Pro Arg Phe His Ala Arg His 
            1550                1555                1560 

tat tct gta aca cca cta gga aca aga tca gga cta atc cag tgg gta     6436 
Tyr Ser Val Thr Pro Leu Gly Thr Arg Ser Gly Leu Ile Gln Trp Val 
        1565                1570                1575 

gat gga gcc aca ccc tta ttt ggt ctt tac aaa cga tgg caa caa cgg     6484 
Asp Gly Ala Thr Pro Leu Phe Gly Leu Tyr Lys Arg Trp Gln Gln Arg 
    1580                1585                1590 

gaa gct gcc tta caa gca caa aag gcc caa gat tcc tac caa act cct     6532 
Glu Ala Ala Leu Gln Ala Gln Lys Ala Gln Asp Ser Tyr Gln Thr Pro 
1595                1600                1605                1610 

cag aat cct gga att gta ccc cgt cct agt gaa ctt tat tac agt aaa     6580 
Gln Asn Pro Gly Ile Val Pro Arg Pro Ser Glu Leu Tyr Tyr Ser Lys 
                1615                1620                1625 

att ggc cct gct ttg aaa aca gtt ggg ctt agc ctg gat gtg tcc cgt     6628 
Ile Gly Pro Ala Leu Lys Thr Val Gly Leu Ser Leu Asp Val Ser Arg 
            1630                1635                1640 

cgg gat tgg cct ctt cat gta atg aag gca gta ttg gaa gag tta atg     6676 
Arg Asp Trp Pro Leu His Val Met Lys Ala Val Leu Glu Glu Leu Met 
        1645                1650                1655 

gag gcc aca ccc ccg aat ctc ctt gcc aaa gag ctc tgg tca tct tgc     6724 
Glu Ala Thr Pro Pro Asn Leu Leu Ala Lys Glu Leu Trp Ser Ser Cys 
    1660                1665                1670 

aca aca cct gat gaa tgg tgg aga gtt acg cag tct tat gca aga tct     6772 
Thr Thr Pro Asp Glu Trp Trp Arg Val Thr Gln Ser Tyr Ala Arg Ser 
1675                1680                1685                1690 

act gca gtc atg tct atg gtt gga tac ata att ggc ctt gga gac aga     6820 
Thr Ala Val Met Ser Met Val Gly Tyr Ile Ile Gly Leu Gly Asp Arg 
                1695                1700                1705 

cat ctg gat aat gtt ctt ata gat atg acg act gga gaa gtt gtt cac     6868 
His Leu Asp Asn Val Leu Ile Asp Met Thr Thr Gly Glu Val Val His 
            1710                1715                1720 

ata gat tac aat gtt tgc ttt gaa aaa ggt aaa agc ctt aga gtt cct     6916 
Ile Asp Tyr Asn Val Cys Phe Glu Lys Gly Lys Ser Leu Arg Val Pro 
        1725                1730                1735 

gag aaa gta cct ttt cga atg aca caa aac att gaa aca gca ctg ggt     6964 
Glu Lys Val Pro Phe Arg Met Thr Gln Asn Ile Glu Thr Ala Leu Gly 
    1740                1745                1750 

gta act gga gta gaa ggt gta ttt agg ctt tca tgt gag cag gtt tta     7012 
Val Thr Gly Val Glu Gly Val Phe Arg Leu Ser Cys Glu Gln Val Leu 
1755                1760                1765                1770 

cac att atg cgg cgt ggc aga gag acc ctg ctg acg ctg ctg gag gcc     7060 
His Ile Met Arg Arg Gly Arg Glu Thr Leu Leu Thr Leu Leu Glu Ala 
                1775                1780                1785 

ttt gtg tac gac cct ctg gtg gac tgg aca gca gga ggc gag gct ggg     7108 
Phe Val Tyr Asp Pro Leu Val Asp Trp Thr Ala Gly Gly Glu Ala Gly 
            1790                1795                1800 

ttt gct ggt gct gtc tat ggt gga ggt ggc cag cag gcc gag agc aag     7156 
Phe Ala Gly Ala Val Tyr Gly Gly Gly Gly Gln Gln Ala Glu Ser Lys 
        1805                1810                1815 

cag agc aag aga gag atg gag cga gag atc acc cgc agc ctg ttt tct     7204 
Gln Ser Lys Arg Glu Met Glu Arg Glu Ile Thr Arg Ser Leu Phe Ser 
    1820                1825                1830 

tct aga gta gct gag att aag gtg aac tgg ttt aag aat aga gat gag     7252 
Ser Arg Val Ala Glu Ile Lys Val Asn Trp Phe Lys Asn Arg Asp Glu 
1835                1840                1845                1850 

atg ctg gtt gtg ctt ccc aag ttg gac ggt agc tta gat gaa tac cta     7300 
Met Leu Val Val Leu Pro Lys Leu Asp Gly Ser Leu Asp Glu Tyr Leu 
                1855                1860                1865 

agc ttg caa gag caa ctg aca gat gtg gaa aaa ctg cag ggc aaa cta     7348 
Ser Leu Gln Glu Gln Leu Thr Asp Val Glu Lys Leu Gln Gly Lys Leu 
            1870                1875                1880 

ctg gag gaa ata gag ttt cta gaa gga gct gaa ggg gtg gat cat cct     7396 
Leu Glu Glu Ile Glu Phe Leu Glu Gly Ala Glu Gly Val Asp His Pro 
        1885                1890                1895 

tct cat act ctg caa cac agg tat tct gag cac acc caa cta cag act     7444 
Ser His Thr Leu Gln His Arg Tyr Ser Glu His Thr Gln Leu Gln Thr 
    1900                1905                1910 

cag caa aga gct gtt cag gaa gca atc cag gtg aag ctg aat gaa ttt     7492 
Gln Gln Arg Ala Val Gln Glu Ala Ile Gln Val Lys Leu Asn Glu Phe 
1915                1920                1925                1930 

gaa caa tgg ata aca cat tat cag gct gca ttc aat aat tta gaa gca     7540 
Glu Gln Trp Ile Thr His Tyr Gln Ala Ala Phe Asn Asn Leu Glu Ala 
                1935                1940                1945 

aca cag ctt gca agc ttg ctt caa gag ata agc aca caa atg gac ctt     7588 
Thr Gln Leu Ala Ser Leu Leu Gln Glu Ile Ser Thr Gln Met Asp Leu 
            1950                1955                1960 

ggt cct cca agt tac gtg cca gca aca gcc ttt ctg cag aat gct ggt     7636 
Gly Pro Pro Ser Tyr Val Pro Ala Thr Ala Phe Leu Gln Asn Ala Gly 
        1965                1970                1975 

cag gcc cac ttg att agc cag tgc gag cag ctg gag ggg gag gtt ggt     7684 
Gln Ala His Leu Ile Ser Gln Cys Glu Gln Leu Glu Gly Glu Val Gly 
    1980                1985                1990 

gct ctc ctg cag cag agg cgc tcc gtg ctc cgt ggc tgt ctg gag caa     7732 
Ala Leu Leu Gln Gln Arg Arg Ser Val Leu Arg Gly Cys Leu Glu Gln 
1995                2000                2005                2010 

ctg cat cac tat gca acc gtg gcc ctg cag tat ccg aag gcc ata ttt     7780 
Leu His His Tyr Ala Thr Val Ala Leu Gln Tyr Pro Lys Ala Ile Phe 
                2015                2020                2025 

cag aaa cat cga att gaa cag tgg aag acc tgg atg gaa gag ctc atc     7828 
Gln Lys His Arg Ile Glu Gln Trp Lys Thr Trp Met Glu Glu Leu Ile 
            2030                2035                2040 

tgt aac acc aca gta gag cgt tgt caa gag ctc tat agg aaa tat gaa     7876 
Cys Asn Thr Thr Val Glu Arg Cys Gln Glu Leu Tyr Arg Lys Tyr Glu 
        2045                2050                2055 

atg caa tat gct ccc cag cca ccc cca aca gtg tgt cag ttc atc act     7924 
Met Gln Tyr Ala Pro Gln Pro Pro Pro Thr Val Cys Gln Phe Ile Thr 
    2060                2065                2070 

gcc act gaa atg acc ctg cag cga tac gca gca gac atc aac agc aga     7972 
Ala Thr Glu Met Thr Leu Gln Arg Tyr Ala Ala Asp Ile Asn Ser Arg 
2075                2080                2085                2090 

ctt att aga caa gtg gaa cgc ttg aaa cag gaa gct gtc act gtg cca     8020 
Leu Ile Arg Gln Val Glu Arg Leu Lys Gln Glu Ala Val Thr Val Pro 
                2095                2100                2105 

gtt tgt gaa gat cag ttg aaa gaa att gaa cgt tgc att aaa gtt ttc     8068 
Val Cys Glu Asp Gln Leu Lys Glu Ile Glu Arg Cys Ile Lys Val Phe 
            2110                2115                2120 

ctt cat gag aat gga gaa gaa gga tct ttg agt cta gca agt gtt att     8116 
Leu His Glu Asn Gly Glu Glu Gly Ser Leu Ser Leu Ala Ser Val Ile 
        2125                2130                2135 

att tct gcc ctt tgt acc ctt aca agg cgt aac ctg atg atg gaa ggt     8164 
Ile Ser Ala Leu Cys Thr Leu Thr Arg Arg Asn Leu Met Met Glu Gly 
    2140                2145                2150 

gca gcg tca agt gct gga gaa cag ctg gtt gat ctg act tct cgg gat     8212 
Ala Ala Ser Ser Ala Gly Glu Gln Leu Val Asp Leu Thr Ser Arg Asp 
2155                2160                2165                2170 

gga gcc tgg ttc ttg gag gaa ctc tgc agt atg agc gga aac gtc acc     8260 
Gly Ala Trp Phe Leu Glu Glu Leu Cys Ser Met Ser Gly Asn Val Thr 
                2175                2180                2185 

tgc ttg gtt cag tta ctg aag cag tgc cac ctg gtg cca cag gac tta     8308 
Cys Leu Val Gln Leu Leu Lys Gln Cys His Leu Val Pro Gln Asp Leu 
            2190                2195                2200 

gat atc ccg aac ccc atg gaa gcg tct gag aca gtt cac tta gcc aat     8356 
Asp Ile Pro Asn Pro Met Glu Ala Ser Glu Thr Val His Leu Ala Asn 
        2205                2210                2215 

gga gtg tat acc tca ctt cag gaa ttg aat tcg aat ttc cgg caa atc     8404 
Gly Val Tyr Thr Ser Leu Gln Glu Leu Asn Ser Asn Phe Arg Gln Ile 
    2220                2225                2230 

ata ttt cca gaa gca ctt cga tgt tta atg aaa ggg gaa tac acg tta     8452 
Ile Phe Pro Glu Ala Leu Arg Cys Leu Met Lys Gly Glu Tyr Thr Leu 
2235                2240                2245                2250 

gaa agt atg ctg cat gaa ctg gac ggt ctt att gag cag acc acc gat     8500 
Glu Ser Met Leu His Glu Leu Asp Gly Leu Ile Glu Gln Thr Thr Asp 
                2255                2260                2265 

ggc gtt ccc ctg cag act cta gtg gaa tct ctt cag gcc tac tta aga     8548 
Gly Val Pro Leu Gln Thr Leu Val Glu Ser Leu Gln Ala Tyr Leu Arg 
            2270                2275                2280 

aac gca gct atg gga ctg gaa gaa gaa aca cat gct cat tac atc gat     8596 
Asn Ala Ala Met Gly Leu Glu Glu Glu Thr His Ala His Tyr Ile Asp 
        2285                2290                2295 

gtt gcc aga cta cta cat gct cag tac ggt gaa tta atc caa ccg aga     8644 
Val Ala Arg Leu Leu His Ala Gln Tyr Gly Glu Leu Ile Gln Pro Arg 
    2300                2305                2310 

aat ggt tca gtt gat gaa aca ccc aaa atg tca gct ggc cag atg ctt     8692 
Asn Gly Ser Val Asp Glu Thr Pro Lys Met Ser Ala Gly Gln Met Leu 
2315                2320                2325                2330 

ttg gta gca ttc gat ggc atg ttt gct caa gtt gaa act gct ttc agc     8740 
Leu Val Ala Phe Asp Gly Met Phe Ala Gln Val Glu Thr Ala Phe Ser 
                2335                2340                2345 

tta tta gtt gaa aag ttg aac aag atg gaa att ccc ata gct tgg cga     8788 
Leu Leu Val Glu Lys Leu Asn Lys Met Glu Ile Pro Ile Ala Trp Arg 
            2350                2355                2360 

aag att gac atc ata agg gaa gcc agg agt act caa gtt aat ttt ttt     8836 
Lys Ile Asp Ile Ile Arg Glu Ala Arg Ser Thr Gln Val Asn Phe Phe 
        2365                2370                2375 

gat gat gat aat cac cgg cag gtg cta gaa gag att ttc ttt cta aaa     8884 
Asp Asp Asp Asn His Arg Gln Val Leu Glu Glu Ile Phe Phe Leu Lys 
    2380                2385                2390 

aga cta cag act att aag gag ttc ttc agg ctc tgt ggt acc ttt tct     8932 
Arg Leu Gln Thr Ile Lys Glu Phe Phe Arg Leu Cys Gly Thr Phe Ser 
2395                2400                2405                2410 

aaa aca ttg tca gga tca agt tca ctt gaa gat cag aat act gtg aat     8980 
Lys Thr Leu Ser Gly Ser Ser Ser Leu Glu Asp Gln Asn Thr Val Asn 
                2415                2420                2425 

ggg cct gta cag att gtc aat gtg aaa acc ctt ttt aga aac tct tgt     9028 
Gly Pro Val Gln Ile Val Asn Val Lys Thr Leu Phe Arg Asn Ser Cys 
            2430                2435                2440 

ttc agt gaa gac caa atg gcc aaa cct atc aag gca ttc aca gct gac     9076 
Phe Ser Glu Asp Gln Met Ala Lys Pro Ile Lys Ala Phe Thr Ala Asp 
        2445                2450                2455 

ttt gtg agg cag ctc ttg ata ggg cta ccc aac caa gcc ctc gga ctc     9124 
Phe Val Arg Gln Leu Leu Ile Gly Leu Pro Asn Gln Ala Leu Gly Leu 
    2460                2465                2470 

aca ctg tgc agt ttt atc agt gct ctg ggt gta gac atc att gct caa     9172 
Thr Leu Cys Ser Phe Ile Ser Ala Leu Gly Val Asp Ile Ile Ala Gln 
2475                2480                2485                2490 

gta gag gca aag gac ttt ggt gcc gaa agc aaa gtt tct gtt gat gat     9220 
Val Glu Ala Lys Asp Phe Gly Ala Glu Ser Lys Val Ser Val Asp Asp 
                2495                2500                2505 

ctc tgt aag aaa gcg gtg gaa cat aac atc cag ata ggg aag ttc tct     9268 
Leu Cys Lys Lys Ala Val Glu His Asn Ile Gln Ile Gly Lys Phe Ser 
            2510                2515                2520 

cag ctg gtt atg aac agg gca act gtg tta gca agt tct tac gac act     9316 
Gln Leu Val Met Asn Arg Ala Thr Val Leu Ala Ser Ser Tyr Asp Thr 
        2525                2530                2535 

gcc tgg aag aag cat gac ttg gtg cga agg cta gaa acc agt att tct     9364 
Ala Trp Lys Lys His Asp Leu Val Arg Arg Leu Glu Thr Ser Ile Ser 
    2540                2545                2550 

tct tgt aag aca agc ctg cag cgg gtt cag ctg cat att gcc atg ttt     9412 
Ser Cys Lys Thr Ser Leu Gln Arg Val Gln Leu His Ile Ala Met Phe 
2555                2560                2565                2570 

cag tgg caa cat gaa gat cta ctt atc aat aga cca caa gcc atg tca     9460 
Gln Trp Gln His Glu Asp Leu Leu Ile Asn Arg Pro Gln Ala Met Ser 
                2575                2580                2585 

gtc aca cct ccc cca cgg tct gct atc cta acc agc atg aaa aag aag     9508 
Val Thr Pro Pro Pro Arg Ser Ala Ile Leu Thr Ser Met Lys Lys Lys 
            2590                2595                2600 

ctg cat acc ctg agc cag att gaa act tct att gca aca gtt cag gag     9556 
Leu His Thr Leu Ser Gln Ile Glu Thr Ser Ile Ala Thr Val Gln Glu 
        2605                2610                2615 

aag cta gct gca ctt gaa tca agt att gaa cag cga ctc aag tgg gca     9604 
Lys Leu Ala Ala Leu Glu Ser Ser Ile Glu Gln Arg Leu Lys Trp Ala 
    2620                2625                2630 

ggt ggt gcc aac cct gca ttg gcc cct gta cta caa gat ttt gaa gca     9652 
Gly Gly Ala Asn Pro Ala Leu Ala Pro Val Leu Gln Asp Phe Glu Ala 
2635                2640                2645                2650 

acg ata gct gaa aga aga aat ctt gtc ctt aaa gag agc caa aga gca     9700 
Thr Ile Ala Glu Arg Arg Asn Leu Val Leu Lys Glu Ser Gln Arg Ala 
                2655                2660                2665 

agt cag gtc aca ttt ctc tgc agc aat atc att cat ttt gaa agt tta     9748 
Ser Gln Val Thr Phe Leu Cys Ser Asn Ile Ile His Phe Glu Ser Leu 
            2670                2675                2680 

cga aca aga act gca gaa gcc tta aac ctg gat gcg gcg tta ttt gaa     9796 
Arg Thr Arg Thr Ala Glu Ala Leu Asn Leu Asp Ala Ala Leu Phe Glu 
        2685                2690                2695 

cta atc aag cga tgt cag cag atg tgt tcg ttt gca tca cag ttt aac     9844 
Leu Ile Lys Arg Cys Gln Gln Met Cys Ser Phe Ala Ser Gln Phe Asn 
    2700                2705                2710 

agt tca gtg tct gag tta gag ctt cgt tta tta cag aga gtg gac act     9892 
Ser Ser Val Ser Glu Leu Glu Leu Arg Leu Leu Gln Arg Val Asp Thr 
2715                2720                2725                2730 

ggt ctt gaa cat cct att ggc agc tct gaa tgg ctt ttg tca gca cac     9940 
Gly Leu Glu His Pro Ile Gly Ser Ser Glu Trp Leu Leu Ser Ala His 
                2735                2740                2745 

aaa cag ttg acc cag gat atg tct act cag agg gca att cag aca gag     9988 
Lys Gln Leu Thr Gln Asp Met Ser Thr Gln Arg Ala Ile Gln Thr Glu 
            2750                2755                2760 

aaa gag cag cag ata gaa acg gtc tgt gaa aca att cag aat ctg gtt    10036 
Lys Glu Gln Gln Ile Glu Thr Val Cys Glu Thr Ile Gln Asn Leu Val 
        2765                2770                2775 

gat aat ata aag act gtg ctc act ggt cat aac cga cag ctt gga gat    10084 
Asp Asn Ile Lys Thr Val Leu Thr Gly His Asn Arg Gln Leu Gly Asp 
    2780                2785                2790 

gtc aaa cat ctc ttg aaa gct atg gct aag gat gaa gaa gct gct ctg    10132 
Val Lys His Leu Leu Lys Ala Met Ala Lys Asp Glu Glu Ala Ala Leu 
2795                2800                2805                2810 

gca gat ggt gaa gat gtt ccc tat gag aac agt gtt agg cag ttt ttg    10180 
Ala Asp Gly Glu Asp Val Pro Tyr Glu Asn Ser Val Arg Gln Phe Leu 
                2815                2820                2825 

ggt gaa tat aaa tca tgg caa gac aac att caa aca gtt cta ttt aca    10228 
Gly Glu Tyr Lys Ser Trp Gln Asp Asn Ile Gln Thr Val Leu Phe Thr 
            2830                2835                2840 

tta gtc cag gct atg ggt cag gtt cga agt caa gaa cac gtt gaa atg    10276 
Leu Val Gln Ala Met Gly Gln Val Arg Ser Gln Glu His Val Glu Met 
        2845                2850                2855 

ctc cag gaa atc act ccc acc ttg aaa gaa ctg aaa aca caa agt cag    10324 
Leu Gln Glu Ile Thr Pro Thr Leu Lys Glu Leu Lys Thr Gln Ser Gln 
    2860                2865                2870 

agt atc tat aat aat tta gtg agt ttt gca tca ccc tta gtc acc gat    10372 
Ser Ile Tyr Asn Asn Leu Val Ser Phe Ala Ser Pro Leu Val Thr Asp 
2875                2880                2885                2890 

gca aca aat gaa tgt tcg agt cca acg tca tct gct act tat cag cca    10420 
Ala Thr Asn Glu Cys Ser Ser Pro Thr Ser Ser Ala Thr Tyr Gln Pro 
                2895                2900                2905 

tcc ttc gct gca gca gtc cgg agt aac act ggc cag aag act cag cct    10468 
Ser Phe Ala Ala Ala Val Arg Ser Asn Thr Gly Gln Lys Thr Gln Pro 
            2910                2915                2920 

gat gtc atg tca cag aat gct aga aag ctg atc cag aaa aat ctt gct    10516 
Asp Val Met Ser Gln Asn Ala Arg Lys Leu Ile Gln Lys Asn Leu Ala 
        2925                2930                2935 

aca tca gct gat act cca cca agc acc gtt cca gga act ggc aag agt    10564 
Thr Ser Ala Asp Thr Pro Pro Ser Thr Val Pro Gly Thr Gly Lys Ser 
    2940                2945                2950 

gtt gct tgt agt cct aaa aag gca gtc aga gac cct aaa act ggg aaa    10612 
Val Ala Cys Ser Pro Lys Lys Ala Val Arg Asp Pro Lys Thr Gly Lys 
2955                2960                2965                2970 

gcg gtg caa gag aga aac tcc tat gca gtg agt gtg tgg aag aga gtg    10660 
Ala Val Gln Glu Arg Asn Ser Tyr Ala Val Ser Val Trp Lys Arg Val 
                2975                2980                2985 

aaa gcc aag tta gag ggc cga gat gtt gat ccg aat agg agg atg tca    10708 
Lys Ala Lys Leu Glu Gly Arg Asp Val Asp Pro Asn Arg Arg Met Ser 
            2990                2995                3000 

gtt gct gaa cag gtt gac tat gtc att aag gaa gca act aat cta gat    10756 
Val Ala Glu Gln Val Asp Tyr Val Ile Lys Glu Ala Thr Asn Leu Asp 
        3005                3010                3015 

aac ttg gct cag ctg tat gaa ggt tgg aca gcc tgg gtg tga            10798 
Asn Leu Ala Gln Leu Tyr Glu Gly Trp Thr Ala Trp Val  * 
    3020                3025                3030 

atggcaagac agtagatgag tctggttaag cgaggtcaga catccaccag aatcaactca  10858 

gcctcaggca tccaaagcca caccacagtc ggtggtgatg caactggggg cttactctga  10918 

ggaaacctag gaaatctcgg tgcactagga agtgaatccc gcaggacagc tgcactcagg  10978 

gatacgccca acaccatggc ctgcaacccc agggtcaagg gtgaaggaaa gcaagctcac  11038 

cgcctgaaca cggagattgt ctttctgcca cagaacagca gcagacgtgt cgggaggtta  11098 

gctgcggaaa gaaatcggga tgccgcggag cacagagtga tttggaactc cattccacct  11158 

gaccctgtgt gtacaatcca ggaaaaaaac aaaccccact cagaaacaga gaaaactggg  11218 

gtcgcgaaga aatcacagcc aaggaagatt tgatgcattc agattctcgt gtaacacttg  11278 

ttgcttggca acagtactgg ttgggttgac cagtaagtag aaaaaggcta aaggctatgc  11338 

gatatgaatt tcagaaatgg actgaaaatg gagagctatg taacagatac actacagtag  11398 

aagaacttac ttctgaaatg aagggaaaaa aaccacccca tcgttcccta ctcctcccca  11458 

ccacttaccc gttccccctt tacctaatct agtagattag ccatctttca aattcacttt  11518 

tatttcagtc cttatatttc atatacttcc gtctcgatgc tgttaacaac ttctgataac  11578 

atggaaaatt caaggattgt ttaaaggtct gatgatcaca cacaaaatgt aattccggtt  11638 

atttaagtca tttctgtgat tctatcatgt acagtttcca gaattgtcac tgtgcattca  11698 

aaagtaatga atctaacaga catttgattt aatgtacact cccttttgct tatagtgtgc  11758 

attttttttg gaggtcattc aaattttccc tcttctgtga tagctgtagt ttctttcata  11818 

gaaagtagct aatccagtgt aatcttttac ctttttaaaa accaagatag agtatctatt  11878 

agagttttac attgttgatg atagattaac aataaagtga tgttctggtg gaggtagact  11938 

gaaatttttt taattcatgt ttttcatttg atacttttaa tttacactta gtaaattaaa  11998 

agttgtttaa tttacttggc attttaggac atgtacatga aacagtgaaa atgagatcca  12058 

ccaacatctt ttattaagtt cagttattag tctgtgaagt gctttacttt ttgcacaatt  12118 

ttaatagctt gctattcagt aatacattat agtgaattca tgatcaaggt ttccttaaat  12178 

ttagcattgc atttcagtac tgactgtgta agctaaattg ctgatccaaa ataaaaaccc  12238 

agactagaat agggttctta aaatcaagta tcaatacaaa atagaacaca attaaaatct  12298 

taattgttgg ctgggcacag tggctcacgc ctgtaatccc agcactttgg gaggccgagg  12358 

cgggcggatc atgaggttag gagagcgaga ccatcctggc taacacggtg aaaccccgtc  12418 

tttactaaaa tacaaaaaaa attagccggg tgtggtggcg ggcgcctgta gtcccagcta  12478 

ctcgggaggc tgaggcagga gaatggcgtg aacccaggag gcggagcttg cagtgagccg  12538 

agattgtgcc actgcactcc agcctgggca acagagctag actctgtgtc aaaaataaat  12598 

gactagat                                                           12606 

 
           
             6  
             3031  
             PRT  
             Homo sapiens  
           
            6 

Met Trp Ala Leu Ser Pro Thr Val Phe Ala Leu Leu Ser Lys Asn Leu 
 1               5                  10                  15 

Met Ile Val His Ser Asp Leu Ala Val His Phe Pro Ala Ile Gln Tyr 
            20                  25                  30 

Ala Val Leu Tyr Thr Leu Tyr Ser His Cys Thr Arg His Asp His Phe 
        35                  40                  45 

Ile Ser Ser Ser Leu Ser Ser Ser Ser Pro Ser Leu Phe Asp Gly Ala 
    50                  55                  60 

Val Ile Ser Thr Val Thr Thr Ala Thr Lys Lys His Phe Ser Ile Ile 
65                  70                  75                  80 

Leu Asn Leu Leu Gly Ile Leu Leu Lys Lys Asp Asn Leu Asn Gln Asp 
                85                  90                  95 

Thr Arg Lys Leu Leu Met Thr Trp Ala Leu Glu Ala Ala Val Leu Met 
            100                 105                 110 

Lys Lys Ser Glu Thr Tyr Ala Pro Leu Phe Ser Leu Pro Ser Phe His 
        115                 120                 125 

Lys Phe Cys Lys Gly Leu Leu Ala Asn Thr Leu Val Glu Asp Val Asn 
    130                 135                 140 

Ile Cys Leu Gln Ala Cys Ser Ser Leu His Ala Leu Ser Ser Ser Leu 
145                 150                 155                 160 

Pro Asp Asp Leu Leu Gln Arg Cys Val Asp Val Cys Arg Val Gln Leu 
                165                 170                 175 

Val His Ser Gly Thr Arg Ile Arg Gln Ala Phe Gly Lys Leu Leu Lys 
            180                 185                 190 

Ser Ile Pro Leu Asp Val Val Leu Ser Asn Asn Asn His Thr Glu Ile 
        195                 200                 205 

Gln Glu Ile Ser Leu Ala Leu Arg Ser His Met Ser Lys Ala Pro Ser 
    210                 215                 220 

Asn Thr Phe His Pro Gln Asp Phe Ser Asp Val Ile Ser Phe Ile Leu 
225                 230                 235                 240 

Tyr Gly Asn Ser His Arg Thr Gly Lys Asp Asn Trp Leu Glu Arg Leu 
                245                 250                 255 

Phe Tyr Ser Cys Gln Arg Leu Asp Lys Arg Asp Gln Ser Thr Ile Pro 
            260                 265                 270 

Arg Asn Leu Leu Lys Thr Asp Ala Val Leu Trp Gln Trp Ala Ile Trp 
        275                 280                 285 

Glu Ala Ala Gln Phe Thr Val Leu Ser Lys Leu Arg Thr Pro Leu Gly 
    290                 295                 300 

Arg Ala Gln Asp Thr Phe Gln Thr Ile Glu Gly Ile Ile Arg Ser Leu 
305                 310                 315                 320 

Ala Ala His Thr Leu Asn Pro Asp Gln Asp Val Ser Gln Trp Thr Thr 
                325                 330                 335 

Ala Asp Asn Asp Glu Gly His Gly Asn Asn Gln Leu Arg Leu Val Leu 
            340                 345                 350 

Leu Leu Gln Tyr Leu Glu Asn Leu Glu Lys Leu Met Tyr Asn Ala Tyr 
        355                 360                 365 

Glu Gly Cys Ala Asn Ala Leu Thr Ser Pro Pro Lys Val Ile Arg Thr 
    370                 375                 380 

Phe Phe Tyr Thr Asn Arg Gln Thr Cys Gln Asp Trp Leu Thr Arg Ile 
385                 390                 395                 400 

Arg Leu Ser Ile Met Arg Val Gly Leu Leu Ala Gly Gln Pro Ala Val 
                405                 410                 415 

Thr Val Arg His Gly Phe Asp Leu Leu Thr Glu Met Lys Thr Thr Ser 
            420                 425                 430 

Leu Ser Gln Gly Asn Glu Leu Glu Val Thr Ile Met Met Val Val Glu 
        435                 440                 445 

Ala Leu Cys Glu Leu His Cys Pro Glu Ala Ile Gln Gly Ile Ala Val 
    450                 455                 460 

Trp Ser Ser Ser Ile Val Gly Lys Asn Leu Leu Trp Ile Asn Ser Val 
465                 470                 475                 480 

Ala Gln Gln Ala Glu Gly Arg Phe Glu Lys Ala Ser Val Glu Tyr Gln 
                485                 490                 495 

Glu His Leu Cys Ala Met Thr Gly Val Asp Cys Cys Ile Ser Ser Phe 
            500                 505                 510 

Asp Lys Ser Val Leu Thr Leu Ala Asn Ala Gly Arg Asn Ser Ala Ser 
        515                 520                 525 

Pro Lys His Ser Leu Asn Gly Glu Ser Arg Lys Thr Val Leu Ser Lys 
    530                 535                 540 

Pro Thr Asp Ser Ser Pro Glu Val Ile Asn Tyr Leu Gly Asn Lys Ala 
545                 550                 555                 560 

Cys Glu Cys Tyr Ile Ser Ile Ala Asp Trp Ala Ala Val Gln Glu Trp 
                565                 570                 575 

Gln Asn Ala Ile His Asp Leu Lys Lys Ser Thr Ser Ser Thr Ser Leu 
            580                 585                 590 

Asn Leu Lys Ala Asp Phe Asn Tyr Ile Lys Ser Leu Ser Ser Phe Glu 
        595                 600                 605 

Ser Gly Lys Phe Val Glu Cys Thr Glu Gln Leu Glu Leu Leu Pro Gly 
    610                 615                 620 

Glu Asn Ile Asn Leu Leu Ala Gly Gly Ser Lys Glu Lys Ile Asp Met 
625                 630                 635                 640 

Lys Lys Leu Leu Pro Asn Met Leu Ser Pro Asp Pro Arg Glu Leu Gln 
                645                 650                 655 

Lys Ser Ile Glu Val Gln Leu Leu Arg Ser Ser Val Cys Leu Ala Thr 
            660                 665                 670 

Ala Leu Asn Pro Ile Glu Gln Asp Gln Lys Trp Gln Ser Ile Thr Glu 
        675                 680                 685 

Asn Val Val Lys Tyr Leu Lys Gln Thr Ser Arg Ile Ala Ile Gly Pro 
    690                 695                 700 

Leu Arg Leu Ser Thr Leu Thr Val Ser Gln Ser Leu Pro Val Leu Ser 
705                 710                 715                 720 

Thr Leu Gln Leu Tyr Cys Ser Ser Ala Leu Glu Asn Thr Val Ser Asn 
                725                 730                 735 

Arg Leu Ser Thr Glu Asp Cys Leu Ile Pro Leu Phe Ser Glu Ala Leu 
            740                 745                 750 

Arg Ser Cys Lys Gln His Asp Val Arg Pro Trp Met Gln Ala Leu Arg 
        755                 760                 765 

Tyr Thr Met Tyr Gln Asn Gln Leu Leu Glu Lys Ile Lys Glu Gln Thr 
    770                 775                 780 

Val Pro Ile Arg Ser His Leu Met Glu Leu Gly Leu Thr Ala Ala Lys 
785                 790                 795                 800 

Phe Ala Arg Lys Arg Gly Asn Val Ser Leu Ala Thr Arg Leu Leu Ala 
                805                 810                 815 

Gln Cys Ser Glu Val Gln Leu Gly Lys Thr Thr Thr Ala Gln Asp Leu 
            820                 825                 830 

Val Gln His Phe Lys Lys Leu Ser Thr Gln Gly Gln Val Asp Glu Lys 
        835                 840                 845 

Trp Gly Pro Glu Leu Asp Ile Glu Lys Thr Lys Leu Leu Tyr Thr Ala 
    850                 855                 860 

Gly Gln Ser Thr His Ala Met Glu Met Leu Ser Ser Cys Ala Ile Ser 
865                 870                 875                 880 

Phe Cys Lys Ser Val Lys Ala Glu Tyr Ala Val Ala Lys Ser Ile Leu 
                885                 890                 895 

Thr Leu Ala Lys Trp Ile Gln Ala Glu Trp Lys Glu Ile Ser Gly Gln 
            900                 905                 910 

Leu Lys Gln Val Tyr Arg Ala Gln His Gln Gln Asn Phe Thr Gly Leu 
        915                 920                 925 

Ser Thr Leu Ser Lys Asn Ile Leu Thr Leu Ile Glu Leu Pro Ser Val 
    930                 935                 940 

Asn Thr Met Glu Glu Glu Tyr Pro Arg Ile Glu Ser Glu Ser Thr Val 
945                 950                 955                 960 

His Ile Gly Val Gly Glu Pro Asp Phe Ile Leu Gly Gln Leu Tyr His 
                965                 970                 975 

Leu Ser Ser Val Gln Ala Pro Glu Val Ala Lys Ser Trp Ala Ala Leu 
            980                 985                 990 

Ala Ser Trp Ala Tyr Arg Trp Gly Arg Lys Val Val Asp Asn Ala Ser 
        995                 1000                1005 

Gln Gly Glu Gly Val Arg Leu Leu Pro Arg Glu Lys Ser Glu Val Gln 
    1010                1015                1020 

Asn Leu Leu Pro Asp Thr Ile Thr Glu Glu Glu Lys Glu Arg Ile Tyr 
1025                1030                1035                1040 

Gly Ile Leu Gly Gln Ala Val Cys Arg Pro Ala Gly Ile Gln Asp Glu 
                1045                1050                1055 

Asp Ile Thr Leu Gln Ile Thr Glu Ser Glu Asp Asn Glu Glu Asp Asp 
            1060                1065                1070 

Met Val Asp Val Ile Trp Arg Gln Leu Ile Ser Ser Cys Pro Trp Leu 
        1075                1080                1085 

Ser Glu Leu Asp Glu Ser Ala Thr Glu Gly Val Ile Lys Val Trp Arg 
    1090                1095                1100 

Lys Val Val Asp Arg Ile Phe Ser Leu Tyr Lys Leu Ser Cys Ser Ala 
1105                1110                1115                1120 

Tyr Phe Thr Phe Leu Lys Leu Asn Ala Gly Gln Ile Pro Leu Asp Glu 
                1125                1130                1135 

Asp Asp Pro Arg Leu His Leu Ser His Arg Val Glu Gln Ser Thr Asp 
            1140                1145                1150 

Asp Met Ile Val Met Ala Thr Leu Arg Leu Leu Arg Leu Leu Val Lys 
        1155                1160                1165 

His Ala Gly Glu Leu Arg Gln Tyr Leu Glu His Gly Leu Glu Thr Thr 
    1170                1175                1180 

Pro Thr Ala Pro Trp Arg Gly Ile Ile Pro Gln Leu Phe Ser Arg Leu 
1185                1190                1195                1200 

Asn His Pro Glu Val Tyr Val Arg Gln Ser Ile Cys Asn Leu Leu Cys 
                1205                1210                1215 

Arg Val Ala Gln Asp Ser Pro His Leu Ile Leu Tyr Pro Ala Ile Val 
            1220                1225                1230 

Gly Thr Ile Ser Leu Ser Ser Glu Ser Gln Ala Ser Gly Asn Lys Phe 
        1235                1240                1245 

Ser Thr Ala Ile Pro Thr Leu Leu Gly Asn Ile Gln Gly Glu Glu Leu 
    1250                1255                1260 

Leu Val Ser Glu Cys Glu Gly Gly Ser Pro Pro Ala Ser Gln Asp Ser 
1265                1270                1275                1280 

Asn Lys Asp Glu Pro Lys Ser Gly Leu Asn Glu Asp Gln Ala Met Met 
                1285                1290                1295 

Gln Asp Cys Tyr Ser Lys Ile Val Asp Lys Leu Ser Ser Ala Asn Pro 
            1300                1305                1310 

Thr Met Val Leu Gln Val Gln Met Leu Val Ala Glu Leu Arg Arg Val 
        1315                1320                1325 

Thr Val Leu Trp Asp Glu Leu Trp Leu Gly Val Leu Leu Gln Gln His 
    1330                1335                1340 

Met Tyr Val Leu Arg Arg Ile Gln Gln Leu Glu Asp Glu Val Lys Arg 
1345                1350                1355                1360 

Val Gln Asn Asn Asn Thr Leu Arg Lys Glu Glu Lys Ile Ala Ile Met 
                1365                1370                1375 

Arg Glu Lys His Thr Ala Leu Met Lys Pro Ile Val Phe Ala Leu Glu 
            1380                1385                1390 

His Val Arg Ser Ile Thr Ala Ala Pro Ala Glu Thr Pro His Glu Lys 
        1395                1400                1405 

Trp Phe Gln Asp Asn Tyr Gly Asp Ala Ile Glu Asn Ala Leu Glu Lys 
    1410                1415                1420 

Leu Lys Thr Pro Leu Asn Pro Ala Lys Pro Gly Ser Ser Trp Ile Pro 
1425                1430                1435                1440 

Phe Lys Glu Ile Met Leu Ser Leu Gln Gln Arg Ala Gln Lys Arg Ala 
                1445                1450                1455 

Ser Tyr Ile Leu Arg Leu Glu Glu Ile Ser Pro Trp Leu Ala Ala Met 
            1460                1465                1470 

Thr Asn Thr Glu Ile Ala Leu Pro Gly Glu Val Ser Ala Arg Asp Thr 
        1475                1480                1485 

Val Thr Ile His Ser Val Gly Gly Thr Ile Thr Ile Leu Pro Thr Lys 
    1490                1495                1500 

Thr Lys Pro Lys Lys Leu Leu Phe Leu Gly Ser Asp Gly Lys Ser Tyr 
1505                1510                1515                1520 

Pro Tyr Leu Phe Lys Gly Leu Glu Asp Leu His Leu Asp Glu Arg Ile 
                1525                1530                1535 

Met Gln Phe Leu Ser Ile Val Asn Thr Met Phe Ala Thr Ile Asn Arg 
            1540                1545                1550 

Gln Glu Thr Pro Arg Phe His Ala Arg His Tyr Ser Val Thr Pro Leu 
        1555                1560                1565 

Gly Thr Arg Ser Gly Leu Ile Gln Trp Val Asp Gly Ala Thr Pro Leu 
    1570                1575                1580 

Phe Gly Leu Tyr Lys Arg Trp Gln Gln Arg Glu Ala Ala Leu Gln Ala 
1585                1590                1595                1600 

Gln Lys Ala Gln Asp Ser Tyr Gln Thr Pro Gln Asn Pro Gly Ile Val 
                1605                1610                1615 

Pro Arg Pro Ser Glu Leu Tyr Tyr Ser Lys Ile Gly Pro Ala Leu Lys 
            1620                1625                1630 

Thr Val Gly Leu Ser Leu Asp Val Ser Arg Arg Asp Trp Pro Leu His 
        1635                1640                1645 

Val Met Lys Ala Val Leu Glu Glu Leu Met Glu Ala Thr Pro Pro Asn 
    1650                1655                1660 

Leu Leu Ala Lys Glu Leu Trp Ser Ser Cys Thr Thr Pro Asp Glu Trp 
1665                1670                1675                1680 

Trp Arg Val Thr Gln Ser Tyr Ala Arg Ser Thr Ala Val Met Ser Met 
                1685                1690                1695 

Val Gly Tyr Ile Ile Gly Leu Gly Asp Arg His Leu Asp Asn Val Leu 
            1700                1705                1710 

Ile Asp Met Thr Thr Gly Glu Val Val His Ile Asp Tyr Asn Val Cys 
        1715                1720                1725 

Phe Glu Lys Gly Lys Ser Leu Arg Val Pro Glu Lys Val Pro Phe Arg 
    1730                1735                1740 

Met Thr Gln Asn Ile Glu Thr Ala Leu Gly Val Thr Gly Val Glu Gly 
1745                1750                1755                1760 

Val Phe Arg Leu Ser Cys Glu Gln Val Leu His Ile Met Arg Arg Gly 
                1765                1770                1775 

Arg Glu Thr Leu Leu Thr Leu Leu Glu Ala Phe Val Tyr Asp Pro Leu 
            1780                1785                1790 

Val Asp Trp Thr Ala Gly Gly Glu Ala Gly Phe Ala Gly Ala Val Tyr 
        1795                1800                1805 

Gly Gly Gly Gly Gln Gln Ala Glu Ser Lys Gln Ser Lys Arg Glu Met 
    1810                1815                1820 

Glu Arg Glu Ile Thr Arg Ser Leu Phe Ser Ser Arg Val Ala Glu Ile 
1825                1830                1835                1840 

Lys Val Asn Trp Phe Lys Asn Arg Asp Glu Met Leu Val Val Leu Pro 
                1845                1850                1855 

Lys Leu Asp Gly Ser Leu Asp Glu Tyr Leu Ser Leu Gln Glu Gln Leu 
            1860                1865                1870 

Thr Asp Val Glu Lys Leu Gln Gly Lys Leu Leu Glu Glu Ile Glu Phe 
        1875                1880                1885 

Leu Glu Gly Ala Glu Gly Val Asp His Pro Ser His Thr Leu Gln His 
    1890                1895                1900 

Arg Tyr Ser Glu His Thr Gln Leu Gln Thr Gln Gln Arg Ala Val Gln 
1905                1910                1915                1920 

Glu Ala Ile Gln Val Lys Leu Asn Glu Phe Glu Gln Trp Ile Thr His 
                1925                1930                1935 

Tyr Gln Ala Ala Phe Asn Asn Leu Glu Ala Thr Gln Leu Ala Ser Leu 
            1940                1945                1950 

Leu Gln Glu Ile Ser Thr Gln Met Asp Leu Gly Pro Pro Ser Tyr Val 
        1955                1960                1965 

Pro Ala Thr Ala Phe Leu Gln Asn Ala Gly Gln Ala His Leu Ile Ser 
    1970                1975                1980 

Gln Cys Glu Gln Leu Glu Gly Glu Val Gly Ala Leu Leu Gln Gln Arg 
1985                1990                1995                2000 

Arg Ser Val Leu Arg Gly Cys Leu Glu Gln Leu His His Tyr Ala Thr 
                2005                2010                2015 

Val Ala Leu Gln Tyr Pro Lys Ala Ile Phe Gln Lys His Arg Ile Glu 
            2020                2025                2030 

Gln Trp Lys Thr Trp Met Glu Glu Leu Ile Cys Asn Thr Thr Val Glu 
        2035                2040                2045 

Arg Cys Gln Glu Leu Tyr Arg Lys Tyr Glu Met Gln Tyr Ala Pro Gln 
    2050                2055                2060 

Pro Pro Pro Thr Val Cys Gln Phe Ile Thr Ala Thr Glu Met Thr Leu 
2065                2070                2075                2080 

Gln Arg Tyr Ala Ala Asp Ile Asn Ser Arg Leu Ile Arg Gln Val Glu 
                2085                2090                2095 

Arg Leu Lys Gln Glu Ala Val Thr Val Pro Val Cys Glu Asp Gln Leu 
            2100                2105                2110 

Lys Glu Ile Glu Arg Cys Ile Lys Val Phe Leu His Glu Asn Gly Glu 
        2115                2120                2125 

Glu Gly Ser Leu Ser Leu Ala Ser Val Ile Ile Ser Ala Leu Cys Thr 
    2130                2135                2140 

Leu Thr Arg Arg Asn Leu Met Met Glu Gly Ala Ala Ser Ser Ala Gly 
2145                2150                2155                2160 

Glu Gln Leu Val Asp Leu Thr Ser Arg Asp Gly Ala Trp Phe Leu Glu 
                2165                2170                2175 

Glu Leu Cys Ser Met Ser Gly Asn Val Thr Cys Leu Val Gln Leu Leu 
            2180                2185                2190 

Lys Gln Cys His Leu Val Pro Gln Asp Leu Asp Ile Pro Asn Pro Met 
        2195                2200                2205 

Glu Ala Ser Glu Thr Val His Leu Ala Asn Gly Val Tyr Thr Ser Leu 
    2210                2215                2220 

Gln Glu Leu Asn Ser Asn Phe Arg Gln Ile Ile Phe Pro Glu Ala Leu 
2225                2230                2235                2240 

Arg Cys Leu Met Lys Gly Glu Tyr Thr Leu Glu Ser Met Leu His Glu 
                2245                2250                2255 

Leu Asp Gly Leu Ile Glu Gln Thr Thr Asp Gly Val Pro Leu Gln Thr 
            2260                2265                2270 

Leu Val Glu Ser Leu Gln Ala Tyr Leu Arg Asn Ala Ala Met Gly Leu 
        2275                2280                2285 

Glu Glu Glu Thr His Ala His Tyr Ile Asp Val Ala Arg Leu Leu His 
    2290                2295                2300 

Ala Gln Tyr Gly Glu Leu Ile Gln Pro Arg Asn Gly Ser Val Asp Glu 
2305                2310                2315                2320 

Thr Pro Lys Met Ser Ala Gly Gln Met Leu Leu Val Ala Phe Asp Gly 
                2325                2330                2335 

Met Phe Ala Gln Val Glu Thr Ala Phe Ser Leu Leu Val Glu Lys Leu 
            2340                2345                2350 

Asn Lys Met Glu Ile Pro Ile Ala Trp Arg Lys Ile Asp Ile Ile Arg 
        2355                2360                2365 

Glu Ala Arg Ser Thr Gln Val Asn Phe Phe Asp Asp Asp Asn His Arg 
    2370                2375                2380 

Gln Val Leu Glu Glu Ile Phe Phe Leu Lys Arg Leu Gln Thr Ile Lys 
2385                2390                2395                2400 

Glu Phe Phe Arg Leu Cys Gly Thr Phe Ser Lys Thr Leu Ser Gly Ser 
                2405                2410                2415 

Ser Ser Leu Glu Asp Gln Asn Thr Val Asn Gly Pro Val Gln Ile Val 
            2420                2425                2430 

Asn Val Lys Thr Leu Phe Arg Asn Ser Cys Phe Ser Glu Asp Gln Met 
        2435                2440                2445 

Ala Lys Pro Ile Lys Ala Phe Thr Ala Asp Phe Val Arg Gln Leu Leu 
    2450                2455                2460 

Ile Gly Leu Pro Asn Gln Ala Leu Gly Leu Thr Leu Cys Ser Phe Ile 
2465                2470                2475                2480 

Ser Ala Leu Gly Val Asp Ile Ile Ala Gln Val Glu Ala Lys Asp Phe 
                2485                2490                2495 

Gly Ala Glu Ser Lys Val Ser Val Asp Asp Leu Cys Lys Lys Ala Val 
            2500                2505                2510 

Glu His Asn Ile Gln Ile Gly Lys Phe Ser Gln Leu Val Met Asn Arg 
        2515                2520                2525 

Ala Thr Val Leu Ala Ser Ser Tyr Asp Thr Ala Trp Lys Lys His Asp 
    2530                2535                2540 

Leu Val Arg Arg Leu Glu Thr Ser Ile Ser Ser Cys Lys Thr Ser Leu 
2545                2550                2555                2560 

Gln Arg Val Gln Leu His Ile Ala Met Phe Gln Trp Gln His Glu Asp 
                2565                2570                2575 

Leu Leu Ile Asn Arg Pro Gln Ala Met Ser Val Thr Pro Pro Pro Arg 
            2580                2585                2590 

Ser Ala Ile Leu Thr Ser Met Lys Lys Lys Leu His Thr Leu Ser Gln 
        2595                2600                2605 

Ile Glu Thr Ser Ile Ala Thr Val Gln Glu Lys Leu Ala Ala Leu Glu 
    2610                2615                2620 

Ser Ser Ile Glu Gln Arg Leu Lys Trp Ala Gly Gly Ala Asn Pro Ala 
2625                2630                2635                2640 

Leu Ala Pro Val Leu Gln Asp Phe Glu Ala Thr Ile Ala Glu Arg Arg 
                2645                2650                2655 

Asn Leu Val Leu Lys Glu Ser Gln Arg Ala Ser Gln Val Thr Phe Leu 
            2660                2665                2670 

Cys Ser Asn Ile Ile His Phe Glu Ser Leu Arg Thr Arg Thr Ala Glu 
        2675                2680                2685 

Ala Leu Asn Leu Asp Ala Ala Leu Phe Glu Leu Ile Lys Arg Cys Gln 
    2690                2695                2700 

Gln Met Cys Ser Phe Ala Ser Gln Phe Asn Ser Ser Val Ser Glu Leu 
2705                2710                2715                2720 

Glu Leu Arg Leu Leu Gln Arg Val Asp Thr Gly Leu Glu His Pro Ile 
                2725                2730                2735 

Gly Ser Ser Glu Trp Leu Leu Ser Ala His Lys Gln Leu Thr Gln Asp 
            2740                2745                2750 

Met Ser Thr Gln Arg Ala Ile Gln Thr Glu Lys Glu Gln Gln Ile Glu 
        2755                2760                2765 

Thr Val Cys Glu Thr Ile Gln Asn Leu Val Asp Asn Ile Lys Thr Val 
    2770                2775                2780 

Leu Thr Gly His Asn Arg Gln Leu Gly Asp Val Lys His Leu Leu Lys 
2785                2790                2795                2800 

Ala Met Ala Lys Asp Glu Glu Ala Ala Leu Ala Asp Gly Glu Asp Val 
                2805                2810                2815 

Pro Tyr Glu Asn Ser Val Arg Gln Phe Leu Gly Glu Tyr Lys Ser Trp 
            2820                2825                2830 

Gln Asp Asn Ile Gln Thr Val Leu Phe Thr Leu Val Gln Ala Met Gly 
        2835                2840                2845 

Gln Val Arg Ser Gln Glu His Val Glu Met Leu Gln Glu Ile Thr Pro 
    2850                2855                2860 

Thr Leu Lys Glu Leu Lys Thr Gln Ser Gln Ser Ile Tyr Asn Asn Leu 
2865                2870                2875                2880 

Val Ser Phe Ala Ser Pro Leu Val Thr Asp Ala Thr Asn Glu Cys Ser 
                2885                2890                2895 

Ser Pro Thr Ser Ser Ala Thr Tyr Gln Pro Ser Phe Ala Ala Ala Val 
            2900                2905                2910 

Arg Ser Asn Thr Gly Gln Lys Thr Gln Pro Asp Val Met Ser Gln Asn 
        2915                2920                2925 

Ala Arg Lys Leu Ile Gln Lys Asn Leu Ala Thr Ser Ala Asp Thr Pro 
    2930                2935                2940 

Pro Ser Thr Val Pro Gly Thr Gly Lys Ser Val Ala Cys Ser Pro Lys 
2945                2950                2955                2960 

Lys Ala Val Arg Asp Pro Lys Thr Gly Lys Ala Val Gln Glu Arg Asn 
                2965                2970                2975 

Ser Tyr Ala Val Ser Val Trp Lys Arg Val Lys Ala Lys Leu Glu Gly 
            2980                2985                2990 

Arg Asp Val Asp Pro Asn Arg Arg Met Ser Val Ala Glu Gln Val Asp 
        2995                3000                3005 

Tyr Val Ile Lys Glu Ala Thr Asn Leu Asp Asn Leu Ala Gln Leu Tyr 
    3010                3015                3020 

Glu Gly Trp Thr Ala Trp Val 
3025                3030 

 
           
             7  
             12539  
             DNA  
             Homo sapiens  
             
               CDS  
               (141)...(10730)  
             
           
            7 

gtggctacag tgtcaatgga ggatctgggg aaaatactta tggtcggaag tcgttggggc     60 

aagagctgag ggttaacaat gtgaccagcc ctgagttcac cagtgttcag catggcagtc    120 

gtgctttagc caccaaagac atg agg aaa tca cag gag aga tcg atg tct tat    173 
                       Met Arg Lys Ser Gln Glu Arg Ser Met Ser Tyr 
                        1               5                   10 

tct gat gag tct cga ctg tcg aat ctt ctt cgg agg atc acc cgg gaa      221 
Ser Asp Glu Ser Arg Leu Ser Asn Leu Leu Arg Arg Ile Thr Arg Glu 
             15                  20                  25 

gac gac aga gac cga aga ttg gct act gta aag cag ttg aaa gaa ttt      269 
Asp Asp Arg Asp Arg Arg Leu Ala Thr Val Lys Gln Leu Lys Glu Phe 
         30                  35                  40 

att cag caa cca gaa aat aag ctg gta cta gtt aaa caa ttg gat aat      317 
Ile Gln Gln Pro Glu Asn Lys Leu Val Leu Val Lys Gln Leu Asp Asn 
     45                  50                  55 

atc ttg gct gct gta cat gac gtg ctt aat gaa agt agc aaa ttg ctt      365 
Ile Leu Ala Ala Val His Asp Val Leu Asn Glu Ser Ser Lys Leu Leu 
 60                  65                  70                  75 

cag gag ttg aga cag gag gga gct tgc tgt ctt ggc ctt ctt tgt gct      413 
Gln Glu Leu Arg Gln Glu Gly Ala Cys Cys Leu Gly Leu Leu Cys Ala 
                 80                  85                  90 

tct ctg agc tat gag gct gag aag atc ttc aag tgg att ttt agc aaa      461 
Ser Leu Ser Tyr Glu Ala Glu Lys Ile Phe Lys Trp Ile Phe Ser Lys 
             95                 100                 105 

ttt agc tca tct gca aaa gat gaa gtt aaa ctc ctc tac tta tgt gcc      509 
Phe Ser Ser Ser Ala Lys Asp Glu Val Lys Leu Leu Tyr Leu Cys Ala 
        110                 115                 120 

acc tac aaa gca cta gag act gta gga gaa aag aaa gcc ttt tca tct      557 
Thr Tyr Lys Ala Leu Glu Thr Val Gly Glu Lys Lys Ala Phe Ser Ser 
    125                 130                 135 

gta atg cag ctt gta atg acc agc ctg cag tct att ctt gaa aat gtg      605 
Val Met Gln Leu Val Met Thr Ser Leu Gln Ser Ile Leu Glu Asn Val 
140                 145                 150                 155 

gat aca cca gaa ttg ctt tgt aaa tgt gtt aag tgc att ctt ttg gtg      653 
Asp Thr Pro Glu Leu Leu Cys Lys Cys Val Lys Cys Ile Leu Leu Val 
                160                 165                 170 

gct cga tgt tac cct cat att ttc agc act aat ttt agg gat aca gtt      701 
Ala Arg Cys Tyr Pro His Ile Phe Ser Thr Asn Phe Arg Asp Thr Val 
            175                 180                 185 

gat ata tta gtt gga tgg cat ata gat cat act cag aaa cct tcg ctc      749 
Asp Ile Leu Val Gly Trp His Ile Asp His Thr Gln Lys Pro Ser Leu 
        190                 195                 200 

acg cag cag gta tct ggg tgg ttg cag agt ttg gag cca ttt tgg gta      797 
Thr Gln Gln Val Ser Gly Trp Leu Gln Ser Leu Glu Pro Phe Trp Val 
    205                 210                 215 

gct gat ctt gca ttt tct act act ctt ctt ggt cag ttt ctg gaa gac      845 
Ala Asp Leu Ala Phe Ser Thr Thr Leu Leu Gly Gln Phe Leu Glu Asp 
220                 225                 230                 235 

atg gaa gca tat gct gag gac ctc agc cat gtg gcc tct ggg gaa tca      893 
Met Glu Ala Tyr Ala Glu Asp Leu Ser His Val Ala Ser Gly Glu Ser 
                240                 245                 250 

gtg gat gaa gat gtc cct cct cca tca gtg tca tta cca aag ctg gct      941 
Val Asp Glu Asp Val Pro Pro Pro Ser Val Ser Leu Pro Lys Leu Ala 
            255                 260                 265 

gca ctt ctc cgg gta ttt agt act gtg gtg agg agc att ggg gaa cgc      989 
Ala Leu Leu Arg Val Phe Ser Thr Val Val Arg Ser Ile Gly Glu Arg 
        270                 275                 280 

ttc agc cca att cgg ggt cct cca att act gag gca tat gta aca gat     1037 
Phe Ser Pro Ile Arg Gly Pro Pro Ile Thr Glu Ala Tyr Val Thr Asp 
    285                 290                 295 

gtt ctg tac aga gta atg aga tgt gtg acg gct gca aac cag gtg ttt     1085 
Val Leu Tyr Arg Val Met Arg Cys Val Thr Ala Ala Asn Gln Val Phe 
300                 305                 310                 315 

ttt tct gag gct gtg ttg aca gct gct aat gag tgt gtt ggt gtt ttg     1133 
Phe Ser Glu Ala Val Leu Thr Ala Ala Asn Glu Cys Val Gly Val Leu 
                320                 325                 330 

ctc ggc agc ttg gat cct agc atg act ata cat tgt gac atg gtc att     1181 
Leu Gly Ser Leu Asp Pro Ser Met Thr Ile His Cys Asp Met Val Ile 
            335                 340                 345 

aca tat gga tta gac caa ctg gag aat tgc cag act tgt ggt acc gat     1229 
Thr Tyr Gly Leu Asp Gln Leu Glu Asn Cys Gln Thr Cys Gly Thr Asp 
        350                 355                 360 

tat atc atc tca gtc ttg aat tta ctc acg ctg att gtt gaa cag ata     1277 
Tyr Ile Ile Ser Val Leu Asn Leu Leu Thr Leu Ile Val Glu Gln Ile 
    365                 370                 375 

aat acg aaa ctg cca tca tca ttt gta gaa aaa ctg ttt ata cca tca     1325 
Asn Thr Lys Leu Pro Ser Ser Phe Val Glu Lys Leu Phe Ile Pro Ser 
380                 385                 390                 395 

tct aaa cta cta ttc ttg cgt tat cat aaa gaa aaa gag gtt gtt gct     1373 
Ser Lys Leu Leu Phe Leu Arg Tyr His Lys Glu Lys Glu Val Val Ala 
                400                 405                 410 

gta gcc cat gct gtt tat caa gca gtg ctc agc ttg aag aat att cct     1421 
Val Ala His Ala Val Tyr Gln Ala Val Leu Ser Leu Lys Asn Ile Pro 
            415                 420                 425 

gtt ttg gag act gcc tat aag tta ata ttg gga gaa atg act tgt gcc     1469 
Val Leu Glu Thr Ala Tyr Lys Leu Ile Leu Gly Glu Met Thr Cys Ala 
        430                 435                 440 

cta aac aac ctc cta cac agt cta caa ctt cct gag gcc tgt tct gaa     1517 
Leu Asn Asn Leu Leu His Ser Leu Gln Leu Pro Glu Ala Cys Ser Glu 
    445                 450                 455 

ata aaa cat gag gct ttt aag aat cat gtg ttc aat gta gac aat gca     1565 
Ile Lys His Glu Ala Phe Lys Asn His Val Phe Asn Val Asp Asn Ala 
460                 465                 470                 475 

aaa ttt gta gtt aaa ttt gac ctc agt gcc ctg act aca att gga aat     1613 
Lys Phe Val Val Lys Phe Asp Leu Ser Ala Leu Thr Thr Ile Gly Asn 
                480                 485                 490 

gcc aaa aac tca cta ata ggg atg tgg gcg cta tct cca act gtc ttt     1661 
Ala Lys Asn Ser Leu Ile Gly Met Trp Ala Leu Ser Pro Thr Val Phe 
            495                 500                 505 

gca ctt ctg agt aag aat ctg atg att gtg cac agt gac ctg gct gtt     1709 
Ala Leu Leu Ser Lys Asn Leu Met Ile Val His Ser Asp Leu Ala Val 
        510                 515                 520 

cac ttc cct gcc att cag tat gct gtg ctc tac aca ttg tat tct cat     1757 
His Phe Pro Ala Ile Gln Tyr Ala Val Leu Tyr Thr Leu Tyr Ser His 
    525                 530                 535 

tgt acc agg cat gat cac ttt atc tct agt agc ctc agt tct gcc tct     1805 
Cys Thr Arg His Asp His Phe Ile Ser Ser Ser Leu Ser Ser Ala Ser 
540                 545                 550                 555 

cct tct ttg ttt gat gga gct gtg att agc act gta act acg gct aca     1853 
Pro Ser Leu Phe Asp Gly Ala Val Ile Ser Thr Val Thr Thr Ala Thr 
                560                 565                 570 

aag aaa cat ttc tca att ata tta aat ctt ctg gga ata tta ctt aag     1901 
Lys Lys His Phe Ser Ile Ile Leu Asn Leu Leu Gly Ile Leu Leu Lys 
            575                 580                 585 

aaa gat aac ctt aac cag gac acg agg aaa ctg tta atg act tgg gct     1949 
Lys Asp Asn Leu Asn Gln Asp Thr Arg Lys Leu Leu Met Thr Trp Ala 
        590                 595                 600 

ttg gaa gca gct gtt tta atg agg aag tct gaa aca tac gca cct tta     1997 
Leu Glu Ala Ala Val Leu Met Arg Lys Ser Glu Thr Tyr Ala Pro Leu 
    605                 610                 615 

ttc tct ctt ccg tct ttc cat aaa ttt tgc aaa ggc ctt tta gcc aac     2045 
Phe Ser Leu Pro Ser Phe His Lys Phe Cys Lys Gly Leu Leu Ala Asn 
620                 625                 630                 635 

act ctc gtt gaa gat gtg aat atc tgt ctg cag gca tgc agc agt cta     2093 
Thr Leu Val Glu Asp Val Asn Ile Cys Leu Gln Ala Cys Ser Ser Leu 
                640                 645                 650 

cat gct ctg tcc tct tcc ttg cca gat gat ctt tta cag aga tgt gtc     2141 
His Ala Leu Ser Ser Ser Leu Pro Asp Asp Leu Leu Gln Arg Cys Val 
            655                 660                 665 

gat gtt tgc cgt gtt caa cta gtg cac agt gga act cgt att cga caa     2189 
Asp Val Cys Arg Val Gln Leu Val His Ser Gly Thr Arg Ile Arg Gln 
        670                 675                 680 

gca ttt gga aaa ctg ttg aaa tca att cct tta gat gtt gtc cta agc     2237 
Ala Phe Gly Lys Leu Leu Lys Ser Ile Pro Leu Asp Val Val Leu Ser 
    685                 690                 695 

aat aac aat cac aca gaa att caa gaa att tct tta gca tta aga agt     2285 
Asn Asn Asn His Thr Glu Ile Gln Glu Ile Ser Leu Ala Leu Arg Ser 
700                 705                 710                 715 

cac atg agt aaa gca cca agt aat aca ttc cac ccc caa gat ttc tct     2333 
His Met Ser Lys Ala Pro Ser Asn Thr Phe His Pro Gln Asp Phe Ser 
                720                 725                 730 

gat gtt att agt ttt att ttg tat ggg aac tct cat aga aca ggg aag     2381 
Asp Val Ile Ser Phe Ile Leu Tyr Gly Asn Ser His Arg Thr Gly Lys 
            735                 740                 745 

gac aat tgg ttg gaa aga ctg ttc tat agc tgc cag aga ctg gat aag     2429 
Asp Asn Trp Leu Glu Arg Leu Phe Tyr Ser Cys Gln Arg Leu Asp Lys 
        750                 755                 760 

cgt gac cag tca aca att cca cgc aat ctc ctg aag aca gat gct gtc     2477 
Arg Asp Gln Ser Thr Ile Pro Arg Asn Leu Leu Lys Thr Asp Ala Val 
    765                 770                 775 

ctt tgg cag tgg gcc ata tgg gaa gct gca caa ttc act gtt ctt tct     2525 
Leu Trp Gln Trp Ala Ile Trp Glu Ala Ala Gln Phe Thr Val Leu Ser 
780                 785                 790                 795 

aag ctg aga acc cca ctg ggc aga gct caa gac acc ttc cag aca att     2573 
Lys Leu Arg Thr Pro Leu Gly Arg Ala Gln Asp Thr Phe Gln Thr Ile 
                800                 805                 810 

gaa ggt atc att cga agt ctc gca gct cac aca tta aac cct gat cag     2621 
Glu Gly Ile Ile Arg Ser Leu Ala Ala His Thr Leu Asn Pro Asp Gln 
            815                 820                 825 

gat gtt agt cag tgg aca act gca gac aat gat gaa ggc cat ggt aac     2669 
Asp Val Ser Gln Trp Thr Thr Ala Asp Asn Asp Glu Gly His Gly Asn 
        830                 835                 840 

aac caa ctt aga ctt gtt ctt ctt ctg cag tat ctg gaa aat ctg gag     2717 
Asn Gln Leu Arg Leu Val Leu Leu Leu Gln Tyr Leu Glu Asn Leu Glu 
    845                 850                 855 

aaa tta atg tat aat gca tac gag gga tgt gct aat gca tta act tca     2765 
Lys Leu Met Tyr Asn Ala Tyr Glu Gly Cys Ala Asn Ala Leu Thr Ser 
860                 865                 870                 875 

cct ccc aag gtc att aga act ttt ttc tat acc aat cgc caa act tgt     2813 
Pro Pro Lys Val Ile Arg Thr Phe Phe Tyr Thr Asn Arg Gln Thr Cys 
                880                 885                 890 

cag gac tgg cta acg cgg att cga ctc tcc atc atg agg gta gga ttg     2861 
Gln Asp Trp Leu Thr Arg Ile Arg Leu Ser Ile Met Arg Val Gly Leu 
            895                 900                 905 

ttg gca ggc cag cct gca gtg aca gtg aga cat ggc ttt gac ttg ctt     2909 
Leu Ala Gly Gln Pro Ala Val Thr Val Arg His Gly Phe Asp Leu Leu 
        910                 915                 920 

aca gag atg aaa aca acc agc cta tct cag ggg aat gaa ttg gaa gta     2957 
Thr Glu Met Lys Thr Thr Ser Leu Ser Gln Gly Asn Glu Leu Glu Val 
    925                 930                 935 

acc att atg atg gtg gta gaa gca tta tgt gaa ctt cat tgt cct gaa     3005 
Thr Ile Met Met Val Val Glu Ala Leu Cys Glu Leu His Cys Pro Glu 
940                 945                 950                 955 

gct ata cag gga att gct gtc tgg tca tca tct att gtt gga aaa aat     3053 
Ala Ile Gln Gly Ile Ala Val Trp Ser Ser Ser Ile Val Gly Lys Asn 
                960                 965                 970 

ctt ctg tgg att aac tca gtg gct caa cag gct gaa ggg agg ttt gaa     3101 
Leu Leu Trp Ile Asn Ser Val Ala Gln Gln Ala Glu Gly Arg Phe Glu 
            975                 980                 985 

aag gcc tct gtg gag tac cag gaa cac ctg tgt gcc atg aca ggt gtt     3149 
Lys Ala Ser Val Glu Tyr Gln Glu His Leu Cys Ala Met Thr Gly Val 
         990                 995                1000 

gat tgc tgc atc tcc agc ttt gac aaa tcg gtg ctc acc tta gcc aat     3197 
Asp Cys Cys Ile Ser Ser Phe Asp Lys Ser Val Leu Thr Leu Ala Asn 
    1005                1010                1015 

gct ggg cgt aac agt gcc agc ccg aaa cat tct ctg aat ggt gaa tcc     3245 
Ala Gly Arg Asn Ser Ala Ser Pro Lys His Ser Leu Asn Gly Glu Ser 
1020                1025                1030                1035 

aga aaa act gtg ctg tcc aaa ccg act gac tct tcc cct gag gtt ata     3293 
Arg Lys Thr Val Leu Ser Lys Pro Thr Asp Ser Ser Pro Glu Val Ile 
                1040                1045                1050 

aat tat tta gga aat aaa gca tgt gag ttc tac atc tca att gcc gat     3341 
Asn Tyr Leu Gly Asn Lys Ala Cys Glu Phe Tyr Ile Ser Ile Ala Asp 
            1055                1060                1065 

tgg gct gct gtg cag gaa tgg cag aac gct atc cat gac ttg aaa aag     3389 
Trp Ala Ala Val Gln Glu Trp Gln Asn Ala Ile His Asp Leu Lys Lys 
        1070                1075                1080 

agt acc agt agc act tcc ctc aac ctg aaa gct gac ttc aac tat ata     3437 
Ser Thr Ser Ser Thr Ser Leu Asn Leu Lys Ala Asp Phe Asn Tyr Ile 
    1085                1090                1095 

aaa tca tta agc agc ttt gag tct gga aaa ttt gtt gaa tgt acc gag     3485 
Lys Ser Leu Ser Ser Phe Glu Ser Gly Lys Phe Val Glu Cys Thr Glu 
1100                1105                1110                1115 

cag tta gaa ttg tta cca gga gaa aat atc aat cta ctt gct gga gga     3533 
Gln Leu Glu Leu Leu Pro Gly Glu Asn Ile Asn Leu Leu Ala Gly Gly 
                1120                1125                1130 

tca aaa gaa aaa ata gac atg aaa aaa ctg ctt cct aac atg tta agt     3581 
Ser Lys Glu Lys Ile Asp Met Lys Lys Leu Leu Pro Asn Met Leu Ser 
            1135                1140                1145 

ccg gat ccg agg gaa ctt cag aaa tcc att gaa gtt caa ttg tta aga     3629 
Pro Asp Pro Arg Glu Leu Gln Lys Ser Ile Glu Val Gln Leu Leu Arg 
        1150                1155                1160 

agt tct gtt tgt ttg gca act gct tta aac ccg ata gaa caa gat cag     3677 
Ser Ser Val Cys Leu Ala Thr Ala Leu Asn Pro Ile Glu Gln Asp Gln 
    1165                1170                1175 

aag tgg cag tct ata act gaa aat gtg gta aag tac ttg aag caa aca     3725 
Lys Trp Gln Ser Ile Thr Glu Asn Val Val Lys Tyr Leu Lys Gln Thr 
1180                1185                1190                1195 

tcc cgc atc gct att gga cct ctg aga ctt tct act tta aca gtt tca     3773 
Ser Arg Ile Ala Ile Gly Pro Leu Arg Leu Ser Thr Leu Thr Val Ser 
                1200                1205                1210 

cag tct ttg cca gtt cta agt acc ttg cag ctg tat tgc tca tct gct     3821 
Gln Ser Leu Pro Val Leu Ser Thr Leu Gln Leu Tyr Cys Ser Ser Ala 
            1215                1220                1225 

ttg gag aac aca gtt tct aac aga ctt tca aca gag gac tgt ctt att     3869 
Leu Glu Asn Thr Val Ser Asn Arg Leu Ser Thr Glu Asp Cys Leu Ile 
        1230                1235                1240 

cca ctc ttc agt gaa gct tta cgt tca tgt aaa cag cat gac gtg agg     3917 
Pro Leu Phe Ser Glu Ala Leu Arg Ser Cys Lys Gln His Asp Val Arg 
    1245                1250                1255 

cca tgg atg cag gca tta agg tat act atg tac cag aat cag ttg ttg     3965 
Pro Trp Met Gln Ala Leu Arg Tyr Thr Met Tyr Gln Asn Gln Leu Leu 
1260                1265                1270                1275 

gag aaa att aaa gaa caa aca gtc cca att aga agc cat ctc atg gaa     4013 
Glu Lys Ile Lys Glu Gln Thr Val Pro Ile Arg Ser His Leu Met Glu 
                1280                1285                1290 

tta ggt cta aca gca gca aaa ttt gct aga aaa cga ggg aat gtg tcc     4061 
Leu Gly Leu Thr Ala Ala Lys Phe Ala Arg Lys Arg Gly Asn Val Ser 
            1295                1300                1305 

ctt gca aca aga ctg ctg gca cag tgc agt gaa gtt cag ctg gga aag     4109 
Leu Ala Thr Arg Leu Leu Ala Gln Cys Ser Glu Val Gln Leu Gly Lys 
        1310                1315                1320 

acc acc act gca cag gat tta gtc caa cat ttt aaa aaa cta tca acc     4157 
Thr Thr Thr Ala Gln Asp Leu Val Gln His Phe Lys Lys Leu Ser Thr 
    1325                1330                1335 

caa ggt caa gtg gat gaa aaa tgg ggg ccc gaa ctt gat att gaa aaa     4205 
Gln Gly Gln Val Asp Glu Lys Trp Gly Pro Glu Leu Asp Ile Glu Lys 
1340                1345                1350                1355 

acc aaa ttg ctt tat aca gca ggc cag tca aca cat gca atg gaa atg     4253 
Thr Lys Leu Leu Tyr Thr Ala Gly Gln Ser Thr His Ala Met Glu Met 
                1360                1365                1370 

ttg agt tct tgt gcc ata tct ttc tgc aag tct gtg aaa gct gaa tat     4301 
Leu Ser Ser Cys Ala Ile Ser Phe Cys Lys Ser Val Lys Ala Glu Tyr 
            1375                1380                1385 

gca gtt gct aaa tca att ctg aca ctg gct aaa tgg atc cag gca gaa     4349 
Ala Val Ala Lys Ser Ile Leu Thr Leu Ala Lys Trp Ile Gln Ala Glu 
        1390                1395                1400 

tgg aaa gag att tca gga cag ctg aaa cag gtt tac aga gct cag cac     4397 
Trp Lys Glu Ile Ser Gly Gln Leu Lys Gln Val Tyr Arg Ala Gln His 
    1405                1410                1415 

caa cag aac ttc aca ggt ctt tct act ttg tct aaa aac ata ctc act     4445 
Gln Gln Asn Phe Thr Gly Leu Ser Thr Leu Ser Lys Asn Ile Leu Thr 
1420                1425                1430                1435 

cta ata gaa ctg cca tct gtt aat acg atg gaa gaa gag tat cct cgg     4493 
Leu Ile Glu Leu Pro Ser Val Asn Thr Met Glu Glu Glu Tyr Pro Arg 
                1440                1445                1450 

atc gag agt gaa tct aca gtg cat att gga gtt gga gaa cct gac ttc     4541 
Ile Glu Ser Glu Ser Thr Val His Ile Gly Val Gly Glu Pro Asp Phe 
            1455                1460                1465 

att ttg gga cag ttg tat cac ctg tct tca gta cag gca cct gaa gta     4589 
Ile Leu Gly Gln Leu Tyr His Leu Ser Ser Val Gln Ala Pro Glu Val 
        1470                1475                1480 

gcc aaa tct tgg gca gcg ttg gcc agc tgg gct tat agg tgg ggc aga     4637 
Ala Lys Ser Trp Ala Ala Leu Ala Ser Trp Ala Tyr Arg Trp Gly Arg 
    1485                1490                1495 

aag gtg gtt gac aat gcc agt cag gga gaa ggt gtt cgt ctg ctg cct     4685 
Lys Val Val Asp Asn Ala Ser Gln Gly Glu Gly Val Arg Leu Leu Pro 
1500                1505                1510                1515 

aga gaa aaa tct gaa gtt cag aat cta ctt cca gac act ata act gag     4733 
Arg Glu Lys Ser Glu Val Gln Asn Leu Leu Pro Asp Thr Ile Thr Glu 
                1520                1525                1530 

gaa gag aaa gag aga ata tat ggt att ctt gga cag gct gtg tgt cgg     4781 
Glu Glu Lys Glu Arg Ile Tyr Gly Ile Leu Gly Gln Ala Val Cys Arg 
            1535                1540                1545 

ccg gcg ggg att cag gat gaa gat ata aca ctt cag ata act gag agt     4829 
Pro Ala Gly Ile Gln Asp Glu Asp Ile Thr Leu Gln Ile Thr Glu Ser 
        1550                1555                1560 

gaa gac aac gaa gaa gat gac atg gtt gat gtt atc tgg cgt cag ttg     4877 
Glu Asp Asn Glu Glu Asp Asp Met Val Asp Val Ile Trp Arg Gln Leu 
    1565                1570                1575 

ata tca agc tgc cca tgg ctt tca gaa ctt gat gaa agt gca act gaa     4925 
Ile Ser Ser Cys Pro Trp Leu Ser Glu Leu Asp Glu Ser Ala Thr Glu 
1580                1585                1590                1595 

gga gtt att aaa gtg tgg agg aaa gtt gta gat aga ata ttc agc ctg     4973 
Gly Val Ile Lys Val Trp Arg Lys Val Val Asp Arg Ile Phe Ser Leu 
                1600                1605                1610 

tac aaa ctc tct tgc agt gca tac ttt act ttc ctt aaa ctc aac gct     5021 
Tyr Lys Leu Ser Cys Ser Ala Tyr Phe Thr Phe Leu Lys Leu Asn Ala 
            1615                1620                1625 

ggt caa att cct tta gat gag gat gac cct agg ctg cat tta agt cac     5069 
Gly Gln Ile Pro Leu Asp Glu Asp Asp Pro Arg Leu His Leu Ser His 
        1630                1635                1640 

aga gtg gaa cag agc act gat gac atg att gtg atg gcc aca ttg cgc     5117 
Arg Val Glu Gln Ser Thr Asp Asp Met Ile Val Met Ala Thr Leu Arg 
    1645                1650                1655 

ctg ctg cgg ttg ctc gtg aag cat gct ggt gag ctt cgg cag tat ctg     5165 
Leu Leu Arg Leu Leu Val Lys His Ala Gly Glu Leu Arg Gln Tyr Leu 
1660                1665                1670                1675 

gag cac ggc ttg gag aca aca ccc act gca cca tgg agg gga att att     5213 
Glu His Gly Leu Glu Thr Thr Pro Thr Ala Pro Trp Arg Gly Ile Ile 
                1680                1685                1690 

ccg caa ctt ttc tca cgc tta aac cac cct gaa gtg tat gtg cgc caa     5261 
Pro Gln Leu Phe Ser Arg Leu Asn His Pro Glu Val Tyr Val Arg Gln 
            1695                1700                1705 

agt att tgt aac ctt ctc tgc cgt gtg gct caa gat tcc cca cat ctc     5309 
Ser Ile Cys Asn Leu Leu Cys Arg Val Ala Gln Asp Ser Pro His Leu 
        1710                1715                1720 

ata ttg tat cct gca ata gtg ggt acc ata tcg ctt agt agt gaa tcc     5357 
Ile Leu Tyr Pro Ala Ile Val Gly Thr Ile Ser Leu Ser Ser Glu Ser 
    1725                1730                1735 

cag gct tca gga aat aaa ttt tcc act gca att cca act tta ctt ggc     5405 
Gln Ala Ser Gly Asn Lys Phe Ser Thr Ala Ile Pro Thr Leu Leu Gly 
1740                1745                1750                1755 

aat att caa gga gaa gaa ttg ctg gtt tct gaa tgt gag gga gga agt     5453 
Asn Ile Gln Gly Glu Glu Leu Leu Val Ser Glu Cys Glu Gly Gly Ser 
                1760                1765                1770 

cct cct gca tct cag gat agc aat aag gat gaa cct aaa agt gga tta     5501 
Pro Pro Ala Ser Gln Asp Ser Asn Lys Asp Glu Pro Lys Ser Gly Leu 
            1775                1780                1785 

aat gaa gac caa gcc atg atg cag gat tgt tac agc aaa att gta gat     5549 
Asn Glu Asp Gln Ala Met Met Gln Asp Cys Tyr Ser Lys Ile Val Asp 
        1790                1795                1800 

aag ctg tcc tct gca aac ccc acc atg gta tta cag gtt cag atg ctc     5597 
Lys Leu Ser Ser Ala Asn Pro Thr Met Val Leu Gln Val Gln Met Leu 
    1805                1810                1815 

gtg gct gaa ctg cgc agg gtc act gtg ctc tgg gat gag ctc tgg ctg     5645 
Val Ala Glu Leu Arg Arg Val Thr Val Leu Trp Asp Glu Leu Trp Leu 
1820                1825                1830                1835 

gga gtt ttg ctg caa caa cac atg tat gtc ctg aga cga att cag cag     5693 
Gly Val Leu Leu Gln Gln His Met Tyr Val Leu Arg Arg Ile Gln Gln 
                1840                1845                1850 

ctt gaa gat gag gtg aag aga gtc cag aac aac aac acc tta cgc aaa     5741 
Leu Glu Asp Glu Val Lys Arg Val Gln Asn Asn Asn Thr Leu Arg Lys 
            1855                1860                1865 

gaa gag aaa att gca atc atg agg gag agg cac aca gct ttg atg aag     5789 
Glu Glu Lys Ile Ala Ile Met Arg Glu Arg His Thr Ala Leu Met Lys 
        1870                1875                1880 

ccc atc gta ttt gct ttg gag cat gtg agg agt atc aca gcg gct cct     5837 
Pro Ile Val Phe Ala Leu Glu His Val Arg Ser Ile Thr Ala Ala Pro 
    1885                1890                1895 

gca gaa aca cct cat gaa aaa tgg ttt cag gat aac tat ggt gat gcc     5885 
Ala Glu Thr Pro His Glu Lys Trp Phe Gln Asp Asn Tyr Gly Asp Ala 
1900                1905                1910                1915 

att gaa aat gcc cta gaa aaa ctg aag act cca ttg aac cct gca aag     5933 
Ile Glu Asn Ala Leu Glu Lys Leu Lys Thr Pro Leu Asn Pro Ala Lys 
                1920                1925                1930 

cct ggg agc agc tgg att cca ttt aaa gag ata atg cta agt ttg caa     5981 
Pro Gly Ser Ser Trp Ile Pro Phe Lys Glu Ile Met Leu Ser Leu Gln 
            1935                1940                1945 

cag aga gca cag aaa cgt gca agt tac atc ttg cgt ctt gaa gaa atc     6029 
Gln Arg Ala Gln Lys Arg Ala Ser Tyr Ile Leu Arg Leu Glu Glu Ile 
        1950                1955                1960 

agt cca tgg ttg gct gcc atg act aac act gaa att gct ctt cct ggg     6077 
Ser Pro Trp Leu Ala Ala Met Thr Asn Thr Glu Ile Ala Leu Pro Gly 
    1965                1970                1975 

gaa gtc tca gcc aga gac act gtc aca atc cat agt gtg ggc gga acc     6125 
Glu Val Ser Ala Arg Asp Thr Val Thr Ile His Ser Val Gly Gly Thr 
1980                1985                1990                1995 

atc aca atc tta ccg act aaa acc aag cca aag aaa ctt ctc ttt ctt     6173 
Ile Thr Ile Leu Pro Thr Lys Thr Lys Pro Lys Lys Leu Leu Phe Leu 
                2000                2005                2010 

gga tca gat ggg aag agc tat cct tat ctt ttc aaa gga ctg gag gat     6221 
Gly Ser Asp Gly Lys Ser Tyr Pro Tyr Leu Phe Lys Gly Leu Glu Asp 
            2015                2020                2025 

tta cat ctg gat gag aga ata atg cag ttc cta tct att gtg aat acc     6269 
Leu His Leu Asp Glu Arg Ile Met Gln Phe Leu Ser Ile Val Asn Thr 
        2030                2035                2040 

atg ttt gct aca att aat cgc caa gaa aca ccc cgg ttc cat gct cga     6317 
Met Phe Ala Thr Ile Asn Arg Gln Glu Thr Pro Arg Phe His Ala Arg 
    2045                2050                2055 

cac tat tct gta aca cca cta gga aca aga tca gga cta atc cag tgg     6365 
His Tyr Ser Val Thr Pro Leu Gly Thr Arg Ser Gly Leu Ile Gln Trp 
2060                2065                2070                2075 

gta gat gga gcc aca ccc tta ttt ggt ctt tac aaa cga tgg caa caa     6413 
Val Asp Gly Ala Thr Pro Leu Phe Gly Leu Tyr Lys Arg Trp Gln Gln 
                2080                2085                2090 

cgg gaa gct gcc tta caa gca caa aag gcc caa gat tcc tac caa act     6461 
Arg Glu Ala Ala Leu Gln Ala Gln Lys Ala Gln Asp Ser Tyr Gln Thr 
            2095                2100                2105 

cct cag aat cct gga att gta ccc cgt cct agt gaa ctt tat tac agt     6509 
Pro Gln Asn Pro Gly Ile Val Pro Arg Pro Ser Glu Leu Tyr Tyr Ser 
        2110                2115                2120 

aaa att ggc cct gct ttg aaa aca gtt ggg ctt agc ctg gat gtg tcc     6557 
Lys Ile Gly Pro Ala Leu Lys Thr Val Gly Leu Ser Leu Asp Val Ser 
    2125                2130                2135 

cgt cgg gat tgg cct ctt cat gta atg aag gca gta ttg gaa gag tta     6605 
Arg Arg Asp Trp Pro Leu His Val Met Lys Ala Val Leu Glu Glu Leu 
2140                2145                2150                2155 

atg gag gcc aca ccc ccg aat ctc ctt gcc aaa gag ctc tgg tca tct     6653 
Met Glu Ala Thr Pro Pro Asn Leu Leu Ala Lys Glu Leu Trp Ser Ser 
                2160                2165                2170 

tgc aca aca cct gat gaa tgg tgg aga gtt acg cag tct tat gca aga     6701 
Cys Thr Thr Pro Asp Glu Trp Trp Arg Val Thr Gln Ser Tyr Ala Arg 
            2175                2180                2185 

tct act gca gtc atg tct atg gtt gga tac ata att ggc ctt gga gac     6749 
Ser Thr Ala Val Met Ser Met Val Gly Tyr Ile Ile Gly Leu Gly Asp 
        2190                2195                2200 

aga cat ctg gat aat gtt ctt ata gat atg acg act gga gaa gtt gtt     6797 
Arg His Leu Asp Asn Val Leu Ile Asp Met Thr Thr Gly Glu Val Val 
    2205                2210                2215 

cac ata gat tac aat gtt tgc ttt gaa aaa ggt aaa agc ctt aga gtt     6845 
His Ile Asp Tyr Asn Val Cys Phe Glu Lys Gly Lys Ser Leu Arg Val 
2220                2225                2230                2235 

cct gag aaa gta cct ttt cga atg aca caa aac att gaa aca gca ctg     6893 
Pro Glu Lys Val Pro Phe Arg Met Thr Gln Asn Ile Glu Thr Ala Leu 
                2240                2245                2250 

ggt gta act gga gta gaa ggt gta ttt agg ctt tca tgt gag cag gtt     6941 
Gly Val Thr Gly Val Glu Gly Val Phe Arg Leu Ser Cys Glu Gln Val 
            2255                2260                2265 

tta cac att atg cgg cgt ggc aga gag acc ctg ctg acg ctg ctg gag     6989 
Leu His Ile Met Arg Arg Gly Arg Glu Thr Leu Leu Thr Leu Leu Glu 
        2270                2275                2280 

gcc ttt gtg tac gac cct ctg gtg gac tgg aca gca gga ggc gag gct     7037 
Ala Phe Val Tyr Asp Pro Leu Val Asp Trp Thr Ala Gly Gly Glu Ala 
    2285                2290                2295 

ggg ttt gct ggt gct gtc tat ggt gga ggt ggc cag cag gcc gag agc     7085 
Gly Phe Ala Gly Ala Val Tyr Gly Gly Gly Gly Gln Gln Ala Glu Ser 
2300                2305                2310                2315 

aag cag agc aag aga gag atg gag cga gag atc acc cgc agc ctg ttt     7133 
Lys Gln Ser Lys Arg Glu Met Glu Arg Glu Ile Thr Arg Ser Leu Phe 
                2320                2325                2330 

tct tct aga gta gct gag att aag gtg aac tgg ttt aag aat aga gat     7181 
Ser Ser Arg Val Ala Glu Ile Lys Val Asn Trp Phe Lys Asn Arg Asp 
            2335                2340                2345 

gag atg ctg gtt gtg ctt ccc aag ttg gac ggt agc tta gat gaa tac     7229 
Glu Met Leu Val Val Leu Pro Lys Leu Asp Gly Ser Leu Asp Glu Tyr 
        2350                2355                2360 

cta agc ttg caa gag caa ctg aca gat gtg gaa aaa ctg cag ggc aaa     7277 
Leu Ser Leu Gln Glu Gln Leu Thr Asp Val Glu Lys Leu Gln Gly Lys 
    2365                2370                2375 

cta ctg gag gaa ata gag ttt cta gaa gga gct gaa ggg gtg gat cat     7325 
Leu Leu Glu Glu Ile Glu Phe Leu Glu Gly Ala Glu Gly Val Asp His 
2380                2385                2390                2395 

cct tct cat act ctg caa cac agg tat tct gag cac acc caa cta cag     7373 
Pro Ser His Thr Leu Gln His Arg Tyr Ser Glu His Thr Gln Leu Gln 
                2400                2405                2410 

act cag caa aga gct gtt cag gaa gca atc cag gtg aag ctg aat gaa     7421 
Thr Gln Gln Arg Ala Val Gln Glu Ala Ile Gln Val Lys Leu Asn Glu 
            2415                2420                2425 

ttt gaa caa tgg ata aca cat tat cag gct gca ttc aat aat tta gaa     7469 
Phe Glu Gln Trp Ile Thr His Tyr Gln Ala Ala Phe Asn Asn Leu Glu 
        2430                2435                2440 

gca aca cag ctt gca agc ttg ctt caa gag ata agc aca caa atg gac     7517 
Ala Thr Gln Leu Ala Ser Leu Leu Gln Glu Ile Ser Thr Gln Met Asp 
    2445                2450                2455 

ctt ggt cct cca agt tac gtg cca gca aca gcc ttt ctg cag aat gct     7565 
Leu Gly Pro Pro Ser Tyr Val Pro Ala Thr Ala Phe Leu Gln Asn Ala 
2460                2465                2470                2475 

ggt cag gcc cac ttg att agc cag tgc gag cag ctg gag ggg gag gtt     7613 
Gly Gln Ala His Leu Ile Ser Gln Cys Glu Gln Leu Glu Gly Glu Val 
                2480                2485                2490 

ggt gct ctc ctg cag cag agg cgc tcc gtg ctc cgt ggc tgt ctg gag     7661 
Gly Ala Leu Leu Gln Gln Arg Arg Ser Val Leu Arg Gly Cys Leu Glu 
            2495                2500                2505 

caa ctg cat cac tat gca acc gtg gcc ctg cag tat ccg aag gcc ata     7709 
Gln Leu His His Tyr Ala Thr Val Ala Leu Gln Tyr Pro Lys Ala Ile 
        2510                2515                2520 

ttt cag aaa cat cga att gaa cag tgg aag acc tgg atg gaa gag ctc     7757 
Phe Gln Lys His Arg Ile Glu Gln Trp Lys Thr Trp Met Glu Glu Leu 
    2525                2530                2535 

atc tgt aac acc aca gta gag cgt tgt caa gag ctc tat agg aaa tat     7805 
Ile Cys Asn Thr Thr Val Glu Arg Cys Gln Glu Leu Tyr Arg Lys Tyr 
2540                2545                2550                2555 

gaa atg caa tat gct ccc cag cca ccc cca aca gtg tgt cag ttc atc     7853 
Glu Met Gln Tyr Ala Pro Gln Pro Pro Pro Thr Val Cys Gln Phe Ile 
                2560                2565                2570 

act gcc act gaa atg acc ctg cag cga tac gca gca gac atc aac agc     7901 
Thr Ala Thr Glu Met Thr Leu Gln Arg Tyr Ala Ala Asp Ile Asn Ser 
            2575                2580                2585 

aga ctt att aga caa gtg gaa cgc ttg aaa cag gaa gct gtc act gtg     7949 
Arg Leu Ile Arg Gln Val Glu Arg Leu Lys Gln Glu Ala Val Thr Val 
        2590                2595                2600 

cca gtt tgt gaa gat cag ttg aaa gaa att gaa cgt tgc att aaa gtt     7997 
Pro Val Cys Glu Asp Gln Leu Lys Glu Ile Glu Arg Cys Ile Lys Val 
    2605                2610                2615 

ttc ctt cat gag aat gga gaa gaa gga tct ttg agt cta gca agt gtt     8045 
Phe Leu His Glu Asn Gly Glu Glu Gly Ser Leu Ser Leu Ala Ser Val 
2620                2625                2630                2635 

att att tct gcc ctt tgt acc ctt aca agg cgt aac ctg atg atg gaa     8093 
Ile Ile Ser Ala Leu Cys Thr Leu Thr Arg Arg Asn Leu Met Met Glu 
                2640                2645                2650 

ggt gca gcg tca agt gct gga gaa cag ctg gtt gat ctg act tct cgg     8141 
Gly Ala Ala Ser Ser Ala Gly Glu Gln Leu Val Asp Leu Thr Ser Arg 
            2655                2660                2665 

gat gga gcc tgg ttc ttg gag gaa ctc tgc agt atg agc gga aac gtc     8189 
Asp Gly Ala Trp Phe Leu Glu Glu Leu Cys Ser Met Ser Gly Asn Val 
        2670                2675                2680 

acc tgc ttg gtt cag tta ctg aag cag tgc cac ctg gtg cca cag gac     8237 
Thr Cys Leu Val Gln Leu Leu Lys Gln Cys His Leu Val Pro Gln Asp 
    2685                2690                2695 

tta gat atc ccg aac ccc atg gaa gcg tct gag aca gtt cac tta gcc     8285 
Leu Asp Ile Pro Asn Pro Met Glu Ala Ser Glu Thr Val His Leu Ala 
2700                2705                2710                2715 

aat gga gtg tat acc tca ctt cag gaa ttg aat tcg aat ttc cgg caa     8333 
Asn Gly Val Tyr Thr Ser Leu Gln Glu Leu Asn Ser Asn Phe Arg Gln 
                2720                2725                2730 

atc ata ttt cca gaa gca ctt cga tgt tta atg aaa ggg gaa tac acg     8381 
Ile Ile Phe Pro Glu Ala Leu Arg Cys Leu Met Lys Gly Glu Tyr Thr 
            2735                2740                2745 

tta gaa agt atg ctg cat gaa ctg gac ggt ctt att gag cag acc acc     8429 
Leu Glu Ser Met Leu His Glu Leu Asp Gly Leu Ile Glu Gln Thr Thr 
        2750                2755                2760 

gat ggc gtt ccc ctg cag act cta gtg gaa tct ctt cag gcc tac tta     8477 
Asp Gly Val Pro Leu Gln Thr Leu Val Glu Ser Leu Gln Ala Tyr Leu 
    2765                2770                2775 

aga aac gca gct atg gga ctg gaa gaa gaa aca cat gct cat tac atc     8525 
Arg Asn Ala Ala Met Gly Leu Glu Glu Glu Thr His Ala His Tyr Ile 
2780                2785                2790                2795 

gat gtt gcc aga cta cta cat gct cag tac ggt gaa tta atc caa ccg     8573 
Asp Val Ala Arg Leu Leu His Ala Gln Tyr Gly Glu Leu Ile Gln Pro 
                2800                2805                2810 

aga aat ggt tca gtt gat gaa aca ccc aaa atg tca gct ggc cag atg     8621 
Arg Asn Gly Ser Val Asp Glu Thr Pro Lys Met Ser Ala Gly Gln Met 
            2815                2820                2825 

ctt ttg gta gca ttc gat ggc atg ttt gct caa gtt gaa act gct ttc     8669 
Leu Leu Val Ala Phe Asp Gly Met Phe Ala Gln Val Glu Thr Ala Phe 
        2830                2835                2840 

agc tta tta gtt gaa aag ttg aac aag atg gaa att ccc ata gct tgg     8717 
Ser Leu Leu Val Glu Lys Leu Asn Lys Met Glu Ile Pro Ile Ala Trp 
    2845                2850                2855 

cga aag att gac atc ata agg gaa gcc agg agt act caa gtt aat ttt     8765 
Arg Lys Ile Asp Ile Ile Arg Glu Ala Arg Ser Thr Gln Val Asn Phe 
2860                2865                2870                2875 

ttt gat gat gat aat cac cgg cag gtg cta gaa gag att ttc ttt cta     8813 
Phe Asp Asp Asp Asn His Arg Gln Val Leu Glu Glu Ile Phe Phe Leu 
                2880                2885                2890 

aaa aga cta cag act att aag gag ttc ttc agg ctc tgt ggt acc ttt     8861 
Lys Arg Leu Gln Thr Ile Lys Glu Phe Phe Arg Leu Cys Gly Thr Phe 
            2895                2900                2905 

tct aaa aca ttg tca gga tca agt tca ctt gaa gat cag aat act gtg     8909 
Ser Lys Thr Leu Ser Gly Ser Ser Ser Leu Glu Asp Gln Asn Thr Val 
        2910                2915                2920 

aat ggg cct gta cag att gtc aat gtg aaa acc ctt ttt aga aac tct     8957 
Asn Gly Pro Val Gln Ile Val Asn Val Lys Thr Leu Phe Arg Asn Ser 
    2925                2930                2935 

tgt ttc agt gaa gac caa atg gcc aaa cct atc aag gca ttc aca gct     9005 
Cys Phe Ser Glu Asp Gln Met Ala Lys Pro Ile Lys Ala Phe Thr Ala 
2940                2945                2950                2955 

gac ttt gtg agg cag ctc ttg ata ggg cta ccc aac caa gcc ctc gga     9053 
Asp Phe Val Arg Gln Leu Leu Ile Gly Leu Pro Asn Gln Ala Leu Gly 
                2960                2965                2970 

ctc aca ctg tgc agt ttt atc agt gct ctg ggt gta gac atc att gct     9101 
Leu Thr Leu Cys Ser Phe Ile Ser Ala Leu Gly Val Asp Ile Ile Ala 
            2975                2980                2985 

caa gta gag gca aag gac ttt ggt gcc gaa agc aaa gtt tct gtt gat     9149 
Gln Val Glu Ala Lys Asp Phe Gly Ala Glu Ser Lys Val Ser Val Asp 
        2990                2995                3000 

gat ctc tgt aag aaa gcg gtg gaa cat aac atc cag ata ggg aag ttc     9197 
Asp Leu Cys Lys Lys Ala Val Glu His Asn Ile Gln Ile Gly Lys Phe 
    3005                3010                3015 

tct cag ctg gtt atg aac agg gca act gtg tta gca agt tct tac gac     9245 
Ser Gln Leu Val Met Asn Arg Ala Thr Val Leu Ala Ser Ser Tyr Asp 
3020                3025                3030                3035 

act gcc tgg aag aag cat gac ttg gtg cga agg cta gaa acc agt att     9293 
Thr Ala Trp Lys Lys His Asp Leu Val Arg Arg Leu Glu Thr Ser Ile 
                3040                3045                3050 

tct tct tgt aag aca agc ctg cag cgg gtt cag ctg cat att gcc atg     9341 
Ser Ser Cys Lys Thr Ser Leu Gln Arg Val Gln Leu His Ile Ala Met 
            3055                3060                3065 

ttt cag tgg caa cat gaa gat cta ctt atc aat aga cca caa gcc atg     9389 
Phe Gln Trp Gln His Glu Asp Leu Leu Ile Asn Arg Pro Gln Ala Met 
        3070                3075                3080 

tca gtc aca cct ccc cca cgg tct gct atc cta acc agc atg aaa aag     9437 
Ser Val Thr Pro Pro Pro Arg Ser Ala Ile Leu Thr Ser Met Lys Lys 
    3085                3090                3095 

aag ctg cat acc ctg agc cag att gaa act tct att gcg aca gtt cag     9485 
Lys Leu His Thr Leu Ser Gln Ile Glu Thr Ser Ile Ala Thr Val Gln 
3100                3105                3110                3115 

gag aag cta gct gca ctt gaa tca agt att gaa cag cga ctc aag tgg     9533 
Glu Lys Leu Ala Ala Leu Glu Ser Ser Ile Glu Gln Arg Leu Lys Trp 
                3120                3125                3130 

gca ggt ggt gcc aac cct gca ttg gcc cct gta cta caa gat ttt gaa     9581 
Ala Gly Gly Ala Asn Pro Ala Leu Ala Pro Val Leu Gln Asp Phe Glu 
            3135                3140                3145 

gca acg ata gct gaa aga aga aat ctt gtc ctt aaa gag agc caa aga     9629 
Ala Thr Ile Ala Glu Arg Arg Asn Leu Val Leu Lys Glu Ser Gln Arg 
        3150                3155                3160 

gca agt cag gtc aca ttt ctc tgc agc aat atc att cat ttt gaa agt     9677 
Ala Ser Gln Val Thr Phe Leu Cys Ser Asn Ile Ile His Phe Glu Ser 
    3165                3170                3175 

tta cga aca aga act gca gaa gcc tta aac ctg gat gcg gcg tta ttt     9725 
Leu Arg Thr Arg Thr Ala Glu Ala Leu Asn Leu Asp Ala Ala Leu Phe 
3180                3185                3190                3195 

gaa cta atc aag cga tgt cag cag atg tgt tcg ttt gca tca cag ttt     9773 
Glu Leu Ile Lys Arg Cys Gln Gln Met Cys Ser Phe Ala Ser Gln Phe 
                3200                3205                3210 

aac agt tca gtg tct gag tta gag ctt cgt tta tta cag aga gtg gac     9821 
Asn Ser Ser Val Ser Glu Leu Glu Leu Arg Leu Leu Gln Arg Val Asp 
            3215                3220                3225 

act ggt ctt gaa cat cct att ggc agc tct gaa tgg ctt ttg tca gca     9869 
Thr Gly Leu Glu His Pro Ile Gly Ser Ser Glu Trp Leu Leu Ser Ala 
        3230                3235                3240 

cac aaa cag ttg acc cag gat atg tct act cag agg gca att cag aca     9917 
His Lys Gln Leu Thr Gln Asp Met Ser Thr Gln Arg Ala Ile Gln Thr 
    3245                3250                3255 

gag aaa gag cag cag ata gaa acg gtc tgt gaa aca att cag aat ctg     9965 
Glu Lys Glu Gln Gln Ile Glu Thr Val Cys Glu Thr Ile Gln Asn Leu 
3260                3265                3270                3275 

gtt gat aat ata aag act gtg ctc act ggt cat aac cga cag ctt gga    10013 
Val Asp Asn Ile Lys Thr Val Leu Thr Gly His Asn Arg Gln Leu Gly 
                3280                3285                3290 

gat gtc aaa cat ctc ttg aaa gct atg gct aag gat gaa gaa gct gct    10061 
Asp Val Lys His Leu Leu Lys Ala Met Ala Lys Asp Glu Glu Ala Ala 
            3295                3300                3305 

ctg gca gat ggt gaa gat gtt ccc tat gag aac agt gtt agg cag ttt    10109 
Leu Ala Asp Gly Glu Asp Val Pro Tyr Glu Asn Ser Val Arg Gln Phe 
        3310                3315                3320 

ttg ggt gaa tat aaa tca tgg caa gac aac att caa aca gtt cta ttt    10157 
Leu Gly Glu Tyr Lys Ser Trp Gln Asp Asn Ile Gln Thr Val Leu Phe 
    3325                3330                3335 

aca tta gtc cag gct atg ggt cag gtt cga agt caa gaa cac gtt gaa    10205 
Thr Leu Val Gln Ala Met Gly Gln Val Arg Ser Gln Glu His Val Glu 
3340                3345                3350                3355 

atg ctc cag gaa atc act ccc acc ttg aaa gaa ctg aaa aca caa agt    10253 
Met Leu Gln Glu Ile Thr Pro Thr Leu Lys Glu Leu Lys Thr Gln Ser 
                3360                3365                3370 

cag agt atc tat aat aat tta gtg agt ttt gca tca ccc tta gtc acc    10301 
Gln Ser Ile Tyr Asn Asn Leu Val Ser Phe Ala Ser Pro Leu Val Thr 
            3375                3380                3385 

gat gca aca aat gaa tgt tcg agt cca acg tca tct gct act tat cag    10349 
Asp Ala Thr Asn Glu Cys Ser Ser Pro Thr Ser Ser Ala Thr Tyr Gln 
        3390                3395                3400 

cca tcc ttc gct gca gca gtc cgg agt aac act ggc cag aag act cag    10397 
Pro Ser Phe Ala Ala Ala Val Arg Ser Asn Thr Gly Gln Lys Thr Gln 
    3405                3410                3415 

cct gat gtc atg tca cag aat gct aga aag ctg atc cag aaa aat ctt    10445 
Pro Asp Val Met Ser Gln Asn Ala Arg Lys Leu Ile Gln Lys Asn Leu 
3420                3425                3430                3435 

gct aca tca gct gat act cca cca agc acc gtt cca gga act ggc aag    10493 
Ala Thr Ser Ala Asp Thr Pro Pro Ser Thr Val Pro Gly Thr Gly Lys 
                3440                3445                3450 

agt gtt gct tgt agt cct aaa aag gca gtc aga gac cct aaa act ggg    10541 
Ser Val Ala Cys Ser Pro Lys Lys Ala Val Arg Asp Pro Lys Thr Gly 
            3455                3460                3465 

aaa gcg gtg caa gag aga aac tcc tat gca gtg agt gtg tgg aag aga    10589 
Lys Ala Val Gln Glu Arg Asn Ser Tyr Ala Val Ser Val Trp Lys Arg 
        3470                3475                3480 

gtg aaa gcc aag tta gag ggc cga gat gtt gat ccg aat agg agg atg    10637 
Val Lys Ala Lys Leu Glu Gly Arg Asp Val Asp Pro Asn Arg Arg Met 
    3485                3490                3495 

tca gtt gct gaa cag gtt gac tat gtc att aag gaa gca act aat cta    10685 
Ser Val Ala Glu Gln Val Asp Tyr Val Ile Lys Glu Ala Thr Asn Leu 
3500                3505                3510                3515 

gat aac ttg gct cag ctg tat gaa ggt tgg aca gcc tgg gtg tga        10730 
Asp Asn Leu Ala Gln Leu Tyr Glu Gly Trp Thr Ala Trp Val  * 
                3520                3525 

atggcaagac agtagatgag tctggttaag cgaggtcaga catccaccag aatcaactca  10790 

gcctcaggca tccaaagcca caccacagtc ggtggtgatg caactggggg cttactctga  10850 

ggaaacctag gaaatctcgg tgcactagga agtgaatccc gcaggacagc tgcactcagg  10910 

gatacgccca acaccatggc ctgcaacccc agggtcaagg gtgaaggaaa gcaaagctca  10970 

ccgcctgaac acggagattg tctttctgcc acagaacagc agcagacgtg tcgggaggtt  11030 

agctgcggaa agaaatcggg atgccgcgga gcacagagtg atttggaact ccattccacc  11090 

tgaccctgtg tgtacaatcc aggaaaaaaa caaaccccac tcagaaacag agaaaactgg  11150 

ggtcgcgaag aaatcacagc caaggaagat ttgatgcatt cagattctcg tgtaacactt  11210 

gttgcttggc aacagtactg gttgggttga ccagtaagta gaaaaaggct aaaggctatg  11270 

cgatatgaat ttcagaaatg gactgaaaat ggagagctat gtaacagata cactacagta  11330 

gaagaactta cttctgaaat gaagggaaaa aaaccacccc atcgttccct actcctcccc  11390 

accacttacc cgttccccct ttacctaatc tagtagatta gccatctttc aaattcactt  11450 

ttatttcagt ccttatattt catatacttc cgtctcgatg ctgttaacaa cttctgataa  11510 

catggaaaat tcaaggattg tttaaaggtc tgatgatcac acacaaaatg taattccggt  11570 

tatttaagtc atttctgtga ttctatcatg tacagtttcc agaattgtca ctgtgcattc  11630 

aaaagtaatg aatctaacag acatttgatt taatgtacac tcccttttgc ttatagtgtg  11690 

catttttttt ggaggtcatt caaattttcc ctcttctgtg atagctgtag tttctttcat  11750 

agaaagtagc taatccagtg taatctttta cctttttaaa aaccaagata gagtatctat  11810 

tagagtttta cattgttgat gatagattaa caataaagtg atgttctggt ggaggtagac  11870 

tgaaattttt ttaattcatg tttttcattt gatactttta atttacactt agtaaattaa  11930 

aagttgttta atttacttgg cattttagga catgtacatg aaacagtgaa aatgagatcc  11990 

accaacatct tttattaagt tcagttatta gtctgtgaag tgctttactt tttgcacaat  12050 

tttaatagct tgctattcag taatacatta tagtgaattc atgatcaagg tttccttaaa  12110 

tttagcattg catttcagta ctgactgtgt aagctaaatt gctgatccaa aataaaaacc  12170 

cagactagaa tagggttctt aaaatcaagt atcaatacaa aatagaacac aattaaaatc  12230 

ttaattgttg gctgggcaca gtggctcacg cctgtaatcc cagcactttg ggaggccgag  12290 

gcgggcggat catgaggtta ggagagcgag accatcctgg ctaacacggt gaaaccccgt  12350 

ctttactaaa atacaaaaaa aattagccgg gtgtggtggc gggcgcctgt agtcccagct  12410 

actcgggagg ctgaggcagg agaatggcgt gaacccagga ggcggagctt gcagtgagcc  12470 

gagattgtgc cactgcactc cagcctgggc aacagagcta gactctgtgt caaaaataaa  12530 

tgactagat                                                          12539 

 
           
             8  
             3529  
             PRT  
             Homo sapiens  
           
            8 

Met Arg Lys Ser Gln Glu Arg Ser Met Ser Tyr Ser Asp Glu Ser Arg 
 1               5                  10                  15 

Leu Ser Asn Leu Leu Arg Arg Ile Thr Arg Glu Asp Asp Arg Asp Arg 
            20                  25                  30 

Arg Leu Ala Thr Val Lys Gln Leu Lys Glu Phe Ile Gln Gln Pro Glu 
        35                  40                  45 

Asn Lys Leu Val Leu Val Lys Gln Leu Asp Asn Ile Leu Ala Ala Val 
    50                  55                  60 

His Asp Val Leu Asn Glu Ser Ser Lys Leu Leu Gln Glu Leu Arg Gln 
65                  70                  75                  80 

Glu Gly Ala Cys Cys Leu Gly Leu Leu Cys Ala Ser Leu Ser Tyr Glu 
                85                  90                  95 

Ala Glu Lys Ile Phe Lys Trp Ile Phe Ser Lys Phe Ser Ser Ser Ala 
            100                 105                 110 

Lys Asp Glu Val Lys Leu Leu Tyr Leu Cys Ala Thr Tyr Lys Ala Leu 
        115                 120                 125 

Glu Thr Val Gly Glu Lys Lys Ala Phe Ser Ser Val Met Gln Leu Val 
    130                 135                 140 

Met Thr Ser Leu Gln Ser Ile Leu Glu Asn Val Asp Thr Pro Glu Leu 
145                 150                 155                 160 

Leu Cys Lys Cys Val Lys Cys Ile Leu Leu Val Ala Arg Cys Tyr Pro 
                165                 170                 175 

His Ile Phe Ser Thr Asn Phe Arg Asp Thr Val Asp Ile Leu Val Gly 
            180                 185                 190 

Trp His Ile Asp His Thr Gln Lys Pro Ser Leu Thr Gln Gln Val Ser 
        195                 200                 205 

Gly Trp Leu Gln Ser Leu Glu Pro Phe Trp Val Ala Asp Leu Ala Phe 
    210                 215                 220 

Ser Thr Thr Leu Leu Gly Gln Phe Leu Glu Asp Met Glu Ala Tyr Ala 
225                 230                 235                 240 

Glu Asp Leu Ser His Val Ala Ser Gly Glu Ser Val Asp Glu Asp Val 
                245                 250                 255 

Pro Pro Pro Ser Val Ser Leu Pro Lys Leu Ala Ala Leu Leu Arg Val 
            260                 265                 270 

Phe Ser Thr Val Val Arg Ser Ile Gly Glu Arg Phe Ser Pro Ile Arg 
        275                 280                 285 

Gly Pro Pro Ile Thr Glu Ala Tyr Val Thr Asp Val Leu Tyr Arg Val 
    290                 295                 300 

Met Arg Cys Val Thr Ala Ala Asn Gln Val Phe Phe Ser Glu Ala Val 
305                 310                 315                 320 

Leu Thr Ala Ala Asn Glu Cys Val Gly Val Leu Leu Gly Ser Leu Asp 
                325                 330                 335 

Pro Ser Met Thr Ile His Cys Asp Met Val Ile Thr Tyr Gly Leu Asp 
            340                 345                 350 

Gln Leu Glu Asn Cys Gln Thr Cys Gly Thr Asp Tyr Ile Ile Ser Val 
        355                 360                 365 

Leu Asn Leu Leu Thr Leu Ile Val Glu Gln Ile Asn Thr Lys Leu Pro 
    370                 375                 380 

Ser Ser Phe Val Glu Lys Leu Phe Ile Pro Ser Ser Lys Leu Leu Phe 
385                 390                 395                 400 

Leu Arg Tyr His Lys Glu Lys Glu Val Val Ala Val Ala His Ala Val 
                405                 410                 415 

Tyr Gln Ala Val Leu Ser Leu Lys Asn Ile Pro Val Leu Glu Thr Ala 
            420                 425                 430 

Tyr Lys Leu Ile Leu Gly Glu Met Thr Cys Ala Leu Asn Asn Leu Leu 
        435                 440                 445 

His Ser Leu Gln Leu Pro Glu Ala Cys Ser Glu Ile Lys His Glu Ala 
    450                 455                 460 

Phe Lys Asn His Val Phe Asn Val Asp Asn Ala Lys Phe Val Val Lys 
465                 470                 475                 480 

Phe Asp Leu Ser Ala Leu Thr Thr Ile Gly Asn Ala Lys Asn Ser Leu 
                485                 490                 495 

Ile Gly Met Trp Ala Leu Ser Pro Thr Val Phe Ala Leu Leu Ser Lys 
            500                 505                 510 

Asn Leu Met Ile Val His Ser Asp Leu Ala Val His Phe Pro Ala Ile 
        515                 520                 525 

Gln Tyr Ala Val Leu Tyr Thr Leu Tyr Ser His Cys Thr Arg His Asp 
    530                 535                 540 

His Phe Ile Ser Ser Ser Leu Ser Ser Ala Ser Pro Ser Leu Phe Asp 
545                 550                 555                 560 

Gly Ala Val Ile Ser Thr Val Thr Thr Ala Thr Lys Lys His Phe Ser 
                565                 570                 575 

Ile Ile Leu Asn Leu Leu Gly Ile Leu Leu Lys Lys Asp Asn Leu Asn 
            580                 585                 590 

Gln Asp Thr Arg Lys Leu Leu Met Thr Trp Ala Leu Glu Ala Ala Val 
        595                 600                 605 

Leu Met Arg Lys Ser Glu Thr Tyr Ala Pro Leu Phe Ser Leu Pro Ser 
    610                 615                 620 

Phe His Lys Phe Cys Lys Gly Leu Leu Ala Asn Thr Leu Val Glu Asp 
625                 630                 635                 640 

Val Asn Ile Cys Leu Gln Ala Cys Ser Ser Leu His Ala Leu Ser Ser 
                645                 650                 655 

Ser Leu Pro Asp Asp Leu Leu Gln Arg Cys Val Asp Val Cys Arg Val 
            660                 665                 670 

Gln Leu Val His Ser Gly Thr Arg Ile Arg Gln Ala Phe Gly Lys Leu 
        675                 680                 685 

Leu Lys Ser Ile Pro Leu Asp Val Val Leu Ser Asn Asn Asn His Thr 
    690                 695                 700 

Glu Ile Gln Glu Ile Ser Leu Ala Leu Arg Ser His Met Ser Lys Ala 
705                 710                 715                 720 

Pro Ser Asn Thr Phe His Pro Gln Asp Phe Ser Asp Val Ile Ser Phe 
                725                 730                 735 

Ile Leu Tyr Gly Asn Ser His Arg Thr Gly Lys Asp Asn Trp Leu Glu 
            740                 745                 750 

Arg Leu Phe Tyr Ser Cys Gln Arg Leu Asp Lys Arg Asp Gln Ser Thr 
        755                 760                 765 

Ile Pro Arg Asn Leu Leu Lys Thr Asp Ala Val Leu Trp Gln Trp Ala 
    770                 775                 780 

Ile Trp Glu Ala Ala Gln Phe Thr Val Leu Ser Lys Leu Arg Thr Pro 
785                 790                 795                 800 

Leu Gly Arg Ala Gln Asp Thr Phe Gln Thr Ile Glu Gly Ile Ile Arg 
                805                 810                 815 

Ser Leu Ala Ala His Thr Leu Asn Pro Asp Gln Asp Val Ser Gln Trp 
            820                 825                 830 

Thr Thr Ala Asp Asn Asp Glu Gly His Gly Asn Asn Gln Leu Arg Leu 
        835                 840                 845 

Val Leu Leu Leu Gln Tyr Leu Glu Asn Leu Glu Lys Leu Met Tyr Asn 
    850                 855                 860 

Ala Tyr Glu Gly Cys Ala Asn Ala Leu Thr Ser Pro Pro Lys Val Ile 
865                 870                 875                 880 

Arg Thr Phe Phe Tyr Thr Asn Arg Gln Thr Cys Gln Asp Trp Leu Thr 
                885                 890                 895 

Arg Ile Arg Leu Ser Ile Met Arg Val Gly Leu Leu Ala Gly Gln Pro 
            900                 905                 910 

Ala Val Thr Val Arg His Gly Phe Asp Leu Leu Thr Glu Met Lys Thr 
        915                 920                 925 

Thr Ser Leu Ser Gln Gly Asn Glu Leu Glu Val Thr Ile Met Met Val 
    930                 935                 940 

Val Glu Ala Leu Cys Glu Leu His Cys Pro Glu Ala Ile Gln Gly Ile 
945                 950                 955                 960 

Ala Val Trp Ser Ser Ser Ile Val Gly Lys Asn Leu Leu Trp Ile Asn 
                965                 970                 975 

Ser Val Ala Gln Gln Ala Glu Gly Arg Phe Glu Lys Ala Ser Val Glu 
            980                 985                 990 

Tyr Gln Glu His Leu Cys Ala Met Thr Gly Val Asp Cys Cys Ile Ser 
        995                 1000                1005 

Ser Phe Asp Lys Ser Val Leu Thr Leu Ala Asn Ala Gly Arg Asn Ser 
    1010                1015                1020 

Ala Ser Pro Lys His Ser Leu Asn Gly Glu Ser Arg Lys Thr Val Leu 
1025                1030                1035                1040 

Ser Lys Pro Thr Asp Ser Ser Pro Glu Val Ile Asn Tyr Leu Gly Asn 
                1045                1050                1055 

Lys Ala Cys Glu Phe Tyr Ile Ser Ile Ala Asp Trp Ala Ala Val Gln 
            1060                1065                1070 

Glu Trp Gln Asn Ala Ile His Asp Leu Lys Lys Ser Thr Ser Ser Thr 
        1075                1080                1085 

Ser Leu Asn Leu Lys Ala Asp Phe Asn Tyr Ile Lys Ser Leu Ser Ser 
    1090                1095                1100 

Phe Glu Ser Gly Lys Phe Val Glu Cys Thr Glu Gln Leu Glu Leu Leu 
1105                1110                1115                1120 

Pro Gly Glu Asn Ile Asn Leu Leu Ala Gly Gly Ser Lys Glu Lys Ile 
                1125                1130                1135 

Asp Met Lys Lys Leu Leu Pro Asn Met Leu Ser Pro Asp Pro Arg Glu 
            1140                1145                1150 

Leu Gln Lys Ser Ile Glu Val Gln Leu Leu Arg Ser Ser Val Cys Leu 
        1155                1160                1165 

Ala Thr Ala Leu Asn Pro Ile Glu Gln Asp Gln Lys Trp Gln Ser Ile 
    1170                1175                1180 

Thr Glu Asn Val Val Lys Tyr Leu Lys Gln Thr Ser Arg Ile Ala Ile 
1185                1190                1195                1200 

Gly Pro Leu Arg Leu Ser Thr Leu Thr Val Ser Gln Ser Leu Pro Val 
                1205                1210                1215 

Leu Ser Thr Leu Gln Leu Tyr Cys Ser Ser Ala Leu Glu Asn Thr Val 
            1220                1225                1230 

Ser Asn Arg Leu Ser Thr Glu Asp Cys Leu Ile Pro Leu Phe Ser Glu 
        1235                1240                1245 

Ala Leu Arg Ser Cys Lys Gln His Asp Val Arg Pro Trp Met Gln Ala 
    1250                1255                1260 

Leu Arg Tyr Thr Met Tyr Gln Asn Gln Leu Leu Glu Lys Ile Lys Glu 
1265                1270                1275                1280 

Gln Thr Val Pro Ile Arg Ser His Leu Met Glu Leu Gly Leu Thr Ala 
                1285                1290                1295 

Ala Lys Phe Ala Arg Lys Arg Gly Asn Val Ser Leu Ala Thr Arg Leu 
            1300                1305                1310 

Leu Ala Gln Cys Ser Glu Val Gln Leu Gly Lys Thr Thr Thr Ala Gln 
        1315                1320                1325 

Asp Leu Val Gln His Phe Lys Lys Leu Ser Thr Gln Gly Gln Val Asp 
    1330                1335                1340 

Glu Lys Trp Gly Pro Glu Leu Asp Ile Glu Lys Thr Lys Leu Leu Tyr 
1345                1350                1355                1360 

Thr Ala Gly Gln Ser Thr His Ala Met Glu Met Leu Ser Ser Cys Ala 
                1365                1370                1375 

Ile Ser Phe Cys Lys Ser Val Lys Ala Glu Tyr Ala Val Ala Lys Ser 
            1380                1385                1390 

Ile Leu Thr Leu Ala Lys Trp Ile Gln Ala Glu Trp Lys Glu Ile Ser 
        1395                1400                1405 

Gly Gln Leu Lys Gln Val Tyr Arg Ala Gln His Gln Gln Asn Phe Thr 
    1410                1415                1420 

Gly Leu Ser Thr Leu Ser Lys Asn Ile Leu Thr Leu Ile Glu Leu Pro 
1425                1430                1435                1440 

Ser Val Asn Thr Met Glu Glu Glu Tyr Pro Arg Ile Glu Ser Glu Ser 
                1445                1450                1455 

Thr Val His Ile Gly Val Gly Glu Pro Asp Phe Ile Leu Gly Gln Leu 
            1460                1465                1470 

Tyr His Leu Ser Ser Val Gln Ala Pro Glu Val Ala Lys Ser Trp Ala 
        1475                1480                1485 

Ala Leu Ala Ser Trp Ala Tyr Arg Trp Gly Arg Lys Val Val Asp Asn 
    1490                1495                1500 

Ala Ser Gln Gly Glu Gly Val Arg Leu Leu Pro Arg Glu Lys Ser Glu 
1505                1510                1515                1520 

Val Gln Asn Leu Leu Pro Asp Thr Ile Thr Glu Glu Glu Lys Glu Arg 
                1525                1530                1535 

Ile Tyr Gly Ile Leu Gly Gln Ala Val Cys Arg Pro Ala Gly Ile Gln 
            1540                1545                1550 

Asp Glu Asp Ile Thr Leu Gln Ile Thr Glu Ser Glu Asp Asn Glu Glu 
        1555                1560                1565 

Asp Asp Met Val Asp Val Ile Trp Arg Gln Leu Ile Ser Ser Cys Pro 
    1570                1575                1580 

Trp Leu Ser Glu Leu Asp Glu Ser Ala Thr Glu Gly Val Ile Lys Val 
1585                1590                1595                1600 

Trp Arg Lys Val Val Asp Arg Ile Phe Ser Leu Tyr Lys Leu Ser Cys 
                1605                1610                1615 

Ser Ala Tyr Phe Thr Phe Leu Lys Leu Asn Ala Gly Gln Ile Pro Leu 
            1620                1625                1630 

Asp Glu Asp Asp Pro Arg Leu His Leu Ser His Arg Val Glu Gln Ser 
        1635                1640                1645 

Thr Asp Asp Met Ile Val Met Ala Thr Leu Arg Leu Leu Arg Leu Leu 
    1650                1655                1660 

Val Lys His Ala Gly Glu Leu Arg Gln Tyr Leu Glu His Gly Leu Glu 
1665                1670                1675                1680 

Thr Thr Pro Thr Ala Pro Trp Arg Gly Ile Ile Pro Gln Leu Phe Ser 
                1685                1690                1695 

Arg Leu Asn His Pro Glu Val Tyr Val Arg Gln Ser Ile Cys Asn Leu 
            1700                1705                1710 

Leu Cys Arg Val Ala Gln Asp Ser Pro His Leu Ile Leu Tyr Pro Ala 
        1715                1720                1725 

Ile Val Gly Thr Ile Ser Leu Ser Ser Glu Ser Gln Ala Ser Gly Asn 
    1730                1735                1740 

Lys Phe Ser Thr Ala Ile Pro Thr Leu Leu Gly Asn Ile Gln Gly Glu 
1745                1750                1755                1760 

Glu Leu Leu Val Ser Glu Cys Glu Gly Gly Ser Pro Pro Ala Ser Gln 
                1765                1770                1775 

Asp Ser Asn Lys Asp Glu Pro Lys Ser Gly Leu Asn Glu Asp Gln Ala 
            1780                1785                1790 

Met Met Gln Asp Cys Tyr Ser Lys Ile Val Asp Lys Leu Ser Ser Ala 
        1795                1800                1805 

Asn Pro Thr Met Val Leu Gln Val Gln Met Leu Val Ala Glu Leu Arg 
    1810                1815                1820 

Arg Val Thr Val Leu Trp Asp Glu Leu Trp Leu Gly Val Leu Leu Gln 
1825                1830                1835                1840 

Gln His Met Tyr Val Leu Arg Arg Ile Gln Gln Leu Glu Asp Glu Val 
                1845                1850                1855 

Lys Arg Val Gln Asn Asn Asn Thr Leu Arg Lys Glu Glu Lys Ile Ala 
            1860                1865                1870 

Ile Met Arg Glu Arg His Thr Ala Leu Met Lys Pro Ile Val Phe Ala 
        1875                1880                1885 

Leu Glu His Val Arg Ser Ile Thr Ala Ala Pro Ala Glu Thr Pro His 
    1890                1895                1900 

Glu Lys Trp Phe Gln Asp Asn Tyr Gly Asp Ala Ile Glu Asn Ala Leu 
1905                1910                1915                1920 

Glu Lys Leu Lys Thr Pro Leu Asn Pro Ala Lys Pro Gly Ser Ser Trp 
                1925                1930                1935 

Ile Pro Phe Lys Glu Ile Met Leu Ser Leu Gln Gln Arg Ala Gln Lys 
            1940                1945                1950 

Arg Ala Ser Tyr Ile Leu Arg Leu Glu Glu Ile Ser Pro Trp Leu Ala 
        1955                1960                1965 

Ala Met Thr Asn Thr Glu Ile Ala Leu Pro Gly Glu Val Ser Ala Arg 
    1970                1975                1980 

Asp Thr Val Thr Ile His Ser Val Gly Gly Thr Ile Thr Ile Leu Pro 
1985                1990                1995                2000 

Thr Lys Thr Lys Pro Lys Lys Leu Leu Phe Leu Gly Ser Asp Gly Lys 
                2005                2010                2015 

Ser Tyr Pro Tyr Leu Phe Lys Gly Leu Glu Asp Leu His Leu Asp Glu 
            2020                2025                2030 

Arg Ile Met Gln Phe Leu Ser Ile Val Asn Thr Met Phe Ala Thr Ile 
        2035                2040                2045 

Asn Arg Gln Glu Thr Pro Arg Phe His Ala Arg His Tyr Ser Val Thr 
    2050                2055                2060 

Pro Leu Gly Thr Arg Ser Gly Leu Ile Gln Trp Val Asp Gly Ala Thr 
2065                2070                2075                2080 

Pro Leu Phe Gly Leu Tyr Lys Arg Trp Gln Gln Arg Glu Ala Ala Leu 
                2085                2090                2095 

Gln Ala Gln Lys Ala Gln Asp Ser Tyr Gln Thr Pro Gln Asn Pro Gly 
            2100                2105                2110 

Ile Val Pro Arg Pro Ser Glu Leu Tyr Tyr Ser Lys Ile Gly Pro Ala 
        2115                2120                2125 

Leu Lys Thr Val Gly Leu Ser Leu Asp Val Ser Arg Arg Asp Trp Pro 
    2130                2135                2140 

Leu His Val Met Lys Ala Val Leu Glu Glu Leu Met Glu Ala Thr Pro 
2145                2150                2155                2160 

Pro Asn Leu Leu Ala Lys Glu Leu Trp Ser Ser Cys Thr Thr Pro Asp 
                2165                2170                2175 

Glu Trp Trp Arg Val Thr Gln Ser Tyr Ala Arg Ser Thr Ala Val Met 
            2180                2185                2190 

Ser Met Val Gly Tyr Ile Ile Gly Leu Gly Asp Arg His Leu Asp Asn 
        2195                2200                2205 

Val Leu Ile Asp Met Thr Thr Gly Glu Val Val His Ile Asp Tyr Asn 
    2210                2215                2220 

Val Cys Phe Glu Lys Gly Lys Ser Leu Arg Val Pro Glu Lys Val Pro 
2225                2230                2235                2240 

Phe Arg Met Thr Gln Asn Ile Glu Thr Ala Leu Gly Val Thr Gly Val 
                2245                2250                2255 

Glu Gly Val Phe Arg Leu Ser Cys Glu Gln Val Leu His Ile Met Arg 
            2260                2265                2270 

Arg Gly Arg Glu Thr Leu Leu Thr Leu Leu Glu Ala Phe Val Tyr Asp 
        2275                2280                2285 

Pro Leu Val Asp Trp Thr Ala Gly Gly Glu Ala Gly Phe Ala Gly Ala 
    2290                2295                2300 

Val Tyr Gly Gly Gly Gly Gln Gln Ala Glu Ser Lys Gln Ser Lys Arg 
2305                2310                2315                2320 

Glu Met Glu Arg Glu Ile Thr Arg Ser Leu Phe Ser Ser Arg Val Ala 
                2325                2330                2335 

Glu Ile Lys Val Asn Trp Phe Lys Asn Arg Asp Glu Met Leu Val Val 
            2340                2345                2350 

Leu Pro Lys Leu Asp Gly Ser Leu Asp Glu Tyr Leu Ser Leu Gln Glu 
        2355                2360                2365 

Gln Leu Thr Asp Val Glu Lys Leu Gln Gly Lys Leu Leu Glu Glu Ile 
    2370                2375                2380 

Glu Phe Leu Glu Gly Ala Glu Gly Val Asp His Pro Ser His Thr Leu 
2385                2390                2395                2400 

Gln His Arg Tyr Ser Glu His Thr Gln Leu Gln Thr Gln Gln Arg Ala 
                2405                2410                2415 

Val Gln Glu Ala Ile Gln Val Lys Leu Asn Glu Phe Glu Gln Trp Ile 
            2420                2425                2430 

Thr His Tyr Gln Ala Ala Phe Asn Asn Leu Glu Ala Thr Gln Leu Ala 
        2435                2440                2445 

Ser Leu Leu Gln Glu Ile Ser Thr Gln Met Asp Leu Gly Pro Pro Ser 
    2450                2455                2460 

Tyr Val Pro Ala Thr Ala Phe Leu Gln Asn Ala Gly Gln Ala His Leu 
2465                2470                2475                2480 

Ile Ser Gln Cys Glu Gln Leu Glu Gly Glu Val Gly Ala Leu Leu Gln 
                2485                2490                2495 

Gln Arg Arg Ser Val Leu Arg Gly Cys Leu Glu Gln Leu His His Tyr 
            2500                2505                2510 

Ala Thr Val Ala Leu Gln Tyr Pro Lys Ala Ile Phe Gln Lys His Arg 
        2515                2520                2525 

Ile Glu Gln Trp Lys Thr Trp Met Glu Glu Leu Ile Cys Asn Thr Thr 
    2530                2535                2540 

Val Glu Arg Cys Gln Glu Leu Tyr Arg Lys Tyr Glu Met Gln Tyr Ala 
2545                2550                2555                2560 

Pro Gln Pro Pro Pro Thr Val Cys Gln Phe Ile Thr Ala Thr Glu Met 
                2565                2570                2575 

Thr Leu Gln Arg Tyr Ala Ala Asp Ile Asn Ser Arg Leu Ile Arg Gln 
            2580                2585                2590 

Val Glu Arg Leu Lys Gln Glu Ala Val Thr Val Pro Val Cys Glu Asp 
        2595                2600                2605 

Gln Leu Lys Glu Ile Glu Arg Cys Ile Lys Val Phe Leu His Glu Asn 
    2610                2615                2620 

Gly Glu Glu Gly Ser Leu Ser Leu Ala Ser Val Ile Ile Ser Ala Leu 
2625                2630                2635                2640 

Cys Thr Leu Thr Arg Arg Asn Leu Met Met Glu Gly Ala Ala Ser Ser 
                2645                2650                2655 

Ala Gly Glu Gln Leu Val Asp Leu Thr Ser Arg Asp Gly Ala Trp Phe 
            2660                2665                2670 

Leu Glu Glu Leu Cys Ser Met Ser Gly Asn Val Thr Cys Leu Val Gln 
        2675                2680                2685 

Leu Leu Lys Gln Cys His Leu Val Pro Gln Asp Leu Asp Ile Pro Asn 
    2690                2695                2700 

Pro Met Glu Ala Ser Glu Thr Val His Leu Ala Asn Gly Val Tyr Thr 
2705                2710                2715                2720 

Ser Leu Gln Glu Leu Asn Ser Asn Phe Arg Gln Ile Ile Phe Pro Glu 
                2725                2730                2735 

Ala Leu Arg Cys Leu Met Lys Gly Glu Tyr Thr Leu Glu Ser Met Leu 
            2740                2745                2750 

His Glu Leu Asp Gly Leu Ile Glu Gln Thr Thr Asp Gly Val Pro Leu 
        2755                2760                2765 

Gln Thr Leu Val Glu Ser Leu Gln Ala Tyr Leu Arg Asn Ala Ala Met 
    2770                2775                2780 

Gly Leu Glu Glu Glu Thr His Ala His Tyr Ile Asp Val Ala Arg Leu 
2785                2790                2795                2800 

Leu His Ala Gln Tyr Gly Glu Leu Ile Gln Pro Arg Asn Gly Ser Val 
                2805                2810                2815 

Asp Glu Thr Pro Lys Met Ser Ala Gly Gln Met Leu Leu Val Ala Phe 
            2820                2825                2830 

Asp Gly Met Phe Ala Gln Val Glu Thr Ala Phe Ser Leu Leu Val Glu 
        2835                2840                2845 

Lys Leu Asn Lys Met Glu Ile Pro Ile Ala Trp Arg Lys Ile Asp Ile 
    2850                2855                2860 

Ile Arg Glu Ala Arg Ser Thr Gln Val Asn Phe Phe Asp Asp Asp Asn 
2865                2870                2875                2880 

His Arg Gln Val Leu Glu Glu Ile Phe Phe Leu Lys Arg Leu Gln Thr 
                2885                2890                2895 

Ile Lys Glu Phe Phe Arg Leu Cys Gly Thr Phe Ser Lys Thr Leu Ser 
            2900                2905                2910 

Gly Ser Ser Ser Leu Glu Asp Gln Asn Thr Val Asn Gly Pro Val Gln 
        2915                2920                2925 

Ile Val Asn Val Lys Thr Leu Phe Arg Asn Ser Cys Phe Ser Glu Asp 
    2930                2935                2940 

Gln Met Ala Lys Pro Ile Lys Ala Phe Thr Ala Asp Phe Val Arg Gln 
2945                2950                2955                2960 

Leu Leu Ile Gly Leu Pro Asn Gln Ala Leu Gly Leu Thr Leu Cys Ser 
                2965                2970                2975 

Phe Ile Ser Ala Leu Gly Val Asp Ile Ile Ala Gln Val Glu Ala Lys 
            2980                2985                2990 

Asp Phe Gly Ala Glu Ser Lys Val Ser Val Asp Asp Leu Cys Lys Lys 
        2995                3000                3005 

Ala Val Glu His Asn Ile Gln Ile Gly Lys Phe Ser Gln Leu Val Met 
    3010                3015                3020 

Asn Arg Ala Thr Val Leu Ala Ser Ser Tyr Asp Thr Ala Trp Lys Lys 
3025                3030                3035                3040 

His Asp Leu Val Arg Arg Leu Glu Thr Ser Ile Ser Ser Cys Lys Thr 
                3045                3050                3055 

Ser Leu Gln Arg Val Gln Leu His Ile Ala Met Phe Gln Trp Gln His 
            3060                3065                3070 

Glu Asp Leu Leu Ile Asn Arg Pro Gln Ala Met Ser Val Thr Pro Pro 
        3075                3080                3085 

Pro Arg Ser Ala Ile Leu Thr Ser Met Lys Lys Lys Leu His Thr Leu 
    3090                3095                3100 

Ser Gln Ile Glu Thr Ser Ile Ala Thr Val Gln Glu Lys Leu Ala Ala 
3105                3110                3115                3120 

Leu Glu Ser Ser Ile Glu Gln Arg Leu Lys Trp Ala Gly Gly Ala Asn 
                3125                3130                3135 

Pro Ala Leu Ala Pro Val Leu Gln Asp Phe Glu Ala Thr Ile Ala Glu 
            3140                3145                3150 

Arg Arg Asn Leu Val Leu Lys Glu Ser Gln Arg Ala Ser Gln Val Thr 
        3155                3160                3165 

Phe Leu Cys Ser Asn Ile Ile His Phe Glu Ser Leu Arg Thr Arg Thr 
    3170                3175                3180 

Ala Glu Ala Leu Asn Leu Asp Ala Ala Leu Phe Glu Leu Ile Lys Arg 
3185                3190                3195                3200 

Cys Gln Gln Met Cys Ser Phe Ala Ser Gln Phe Asn Ser Ser Val Ser 
                3205                3210                3215 

Glu Leu Glu Leu Arg Leu Leu Gln Arg Val Asp Thr Gly Leu Glu His 
            3220                3225                3230 

Pro Ile Gly Ser Ser Glu Trp Leu Leu Ser Ala His Lys Gln Leu Thr 
        3235                3240                3245 

Gln Asp Met Ser Thr Gln Arg Ala Ile Gln Thr Glu Lys Glu Gln Gln 
    3250                3255                3260 

Ile Glu Thr Val Cys Glu Thr Ile Gln Asn Leu Val Asp Asn Ile Lys 
3265                3270                3275                3280 

Thr Val Leu Thr Gly His Asn Arg Gln Leu Gly Asp Val Lys His Leu 
                3285                3290                3295 

Leu Lys Ala Met Ala Lys Asp Glu Glu Ala Ala Leu Ala Asp Gly Glu 
            3300                3305                3310 

Asp Val Pro Tyr Glu Asn Ser Val Arg Gln Phe Leu Gly Glu Tyr Lys 
        3315                3320                3325 

Ser Trp Gln Asp Asn Ile Gln Thr Val Leu Phe Thr Leu Val Gln Ala 
    3330                3335                3340 

Met Gly Gln Val Arg Ser Gln Glu His Val Glu Met Leu Gln Glu Ile 
3345                3350                3355                3360 

Thr Pro Thr Leu Lys Glu Leu Lys Thr Gln Ser Gln Ser Ile Tyr Asn 
                3365                3370                3375 

Asn Leu Val Ser Phe Ala Ser Pro Leu Val Thr Asp Ala Thr Asn Glu 
            3380                3385                3390 

Cys Ser Ser Pro Thr Ser Ser Ala Thr Tyr Gln Pro Ser Phe Ala Ala 
        3395                3400                3405 

Ala Val Arg Ser Asn Thr Gly Gln Lys Thr Gln Pro Asp Val Met Ser 
    3410                3415                3420 

Gln Asn Ala Arg Lys Leu Ile Gln Lys Asn Leu Ala Thr Ser Ala Asp 
3425                3430                3435                3440 

Thr Pro Pro Ser Thr Val Pro Gly Thr Gly Lys Ser Val Ala Cys Ser 
                3445                3450                3455 

Pro Lys Lys Ala Val Arg Asp Pro Lys Thr Gly Lys Ala Val Gln Glu 
            3460                3465                3470 

Arg Asn Ser Tyr Ala Val Ser Val Trp Lys Arg Val Lys Ala Lys Leu 
        3475                3480                3485 

Glu Gly Arg Asp Val Asp Pro Asn Arg Arg Met Ser Val Ala Glu Gln 
    3490                3495                3500 

Val Asp Tyr Val Ile Lys Glu Ala Thr Asn Leu Asp Asn Leu Ala Gln 
3505                3510                3515                3520 

Leu Tyr Glu Gly Trp Thr Ala Trp Val 
                3525 

 
           
             9  
             13110  
             DNA  
             Homo sapiens  
             
               CDS  
               (328)...(11301)  
             
           
            9 

ggggaagcag tggccgtgtg agcgtgagga gctgccgcca ccgcctgctc ctcgtcctcc     60 

tcgtcctccg gggccccagc gtcgtgggcc gcgcacggcc ctggaagaga cgtcgcctcg    120 

ccttcatccg cctctctcac cgcgccgctc cctcgtcctg ccctgcgggc tcaggcggaa    180 

cccggaacgg ccgtcctctt cccccgccct ccgccgccgc ctcctcctcc tccttctcgg    240 

cttcctcctc agccccgggc cggagcgggg tgtcggcggc ggccggttcg ggcggcggcg    300 

cttggccatg tcgtgtcggg gaaggta atg agc cgc aga gcc ccg ggg tct cgg    354 
                              Met Ser Arg Arg Ala Pro Gly Ser Arg 
                               1               5 

ctg agc agc ggc ggc acc aac tat tcg cgg agc tgg aat gac tgg caa      402 
Leu Ser Ser Gly Gly Thr Asn Tyr Ser Arg Ser Trp Asn Asp Trp Gln 
 10                  15                  20                  25 

ccc aga act gat agt gca tca gct gac cca ggt aat tta aaa tat tct      450 
Pro Arg Thr Asp Ser Ala Ser Ala Asp Pro Gly Asn Leu Lys Tyr Ser 
                 30                  35                  40 

tca tcc aga gat aga ggt ggt tct tcc tct tac gga ctg caa cct tca      498 
Ser Ser Arg Asp Arg Gly Gly Ser Ser Ser Tyr Gly Leu Gln Pro Ser 
             45                  50                  55 

aat tca gct gtg gtg tct cgg caa agg cac gat gat acc aga gtc cac      546 
Asn Ser Ala Val Val Ser Arg Gln Arg His Asp Asp Thr Arg Val His 
         60                  65                  70 

gct gac ata cag aat gac gaa aag ggt ggc tac agt gtc aat gga gga      594 
Ala Asp Ile Gln Asn Asp Glu Lys Gly Gly Tyr Ser Val Asn Gly Gly 
     75                  80                  85 

tct ggg gaa aat act tat ggt cgg aag tcg ttg ggg caa gag ctg agg      642 
Ser Gly Glu Asn Thr Tyr Gly Arg Lys Ser Leu Gly Gln Glu Leu Arg 
 90                  95                 100                 105 

gtt aac aat gtg acc agc cct gag ttc acc agt gtt cag cat ggc agt      690 
Val Asn Asn Val Thr Ser Pro Glu Phe Thr Ser Val Gln His Gly Ser 
                110                 115                 120 

cgt gct tta gcc acc aaa gac atg agg aaa tca cag gag aga tcg atg      738 
Arg Ala Leu Ala Thr Lys Asp Met Arg Lys Ser Gln Glu Arg Ser Met 
            125                 130                 135 

tct tat tct gat gag tct cga ctg tcg aat ctt ctt cgg agg atc acc      786 
Ser Tyr Ser Asp Glu Ser Arg Leu Ser Asn Leu Leu Arg Arg Ile Thr 
        140                 145                 150 

cgg gaa gac gac aga gac cga aga ttg gct act gta aag cag ttg aaa      834 
Arg Glu Asp Asp Arg Asp Arg Arg Leu Ala Thr Val Lys Gln Leu Lys 
    155                 160                 165 

gaa ttt att cag caa cca gaa aat aag ctg gta cta gtt aaa caa ttg      882 
Glu Phe Ile Gln Gln Pro Glu Asn Lys Leu Val Leu Val Lys Gln Leu 
170                 175                 180                 185 

gat aat atc ttg gct gct gta cat gac gtg ctt aat gaa agt agc aaa      930 
Asp Asn Ile Leu Ala Ala Val His Asp Val Leu Asn Glu Ser Ser Lys 
                190                 195                 200 

ttg ctt cag gag ttg aga cag gag gga gct tgc tgt ctt ggc ctt ctt      978 
Leu Leu Gln Glu Leu Arg Gln Glu Gly Ala Cys Cys Leu Gly Leu Leu 
            205                 210                 215 

tgt gct tct ctg agc tat gag gct gag aag atc ttc aag tgg att ttt     1026 
Cys Ala Ser Leu Ser Tyr Glu Ala Glu Lys Ile Phe Lys Trp Ile Phe 
        220                 225                 230 

agc aaa ttt agc tca tct gca aaa gat gaa gtt aaa ctc ctc tac tta     1074 
Ser Lys Phe Ser Ser Ser Ala Lys Asp Glu Val Lys Leu Leu Tyr Leu 
    235                 240                 245 

tgt gcc acc tac aaa gca cta gag act gta gga gaa aag aaa gcc ttt     1122 
Cys Ala Thr Tyr Lys Ala Leu Glu Thr Val Gly Glu Lys Lys Ala Phe 
250                 255                 260                 265 

tca tct gta atg cag ctt gta atg acc agc ctg cag tct att ctt gaa     1170 
Ser Ser Val Met Gln Leu Val Met Thr Ser Leu Gln Ser Ile Leu Glu 
                270                 275                 280 

aat gtg gat aca cca gaa ttg ctt tgt aaa tgt gtt aag tgc att ctt     1218 
Asn Val Asp Thr Pro Glu Leu Leu Cys Lys Cys Val Lys Cys Ile Leu 
            285                 290                 295 

ttg gtg gct cga tgt tac cct cat att ttc agc act aat ttt agg gat     1266 
Leu Val Ala Arg Cys Tyr Pro His Ile Phe Ser Thr Asn Phe Arg Asp 
        300                 305                 310 

aca gtt gat ata tta gtt gga tgg cat ata gat cat act cag aaa cct     1314 
Thr Val Asp Ile Leu Val Gly Trp His Ile Asp His Thr Gln Lys Pro 
    315                 320                 325 

tcg ctc acg cag cag gta tct ggg tgg ttg cag agt ttg gag cca ttt     1362 
Ser Leu Thr Gln Gln Val Ser Gly Trp Leu Gln Ser Leu Glu Pro Phe 
330                 335                 340                 345 

tgg gta gct gat ctt gca ttt tct act act ctt ctt ggt cag ttt ctg     1410 
Trp Val Ala Asp Leu Ala Phe Ser Thr Thr Leu Leu Gly Gln Phe Leu 
                350                 355                 360 

gaa gac atg gaa gca tat gct gag gac ctc agc cat gtg gcc tct ggg     1458 
Glu Asp Met Glu Ala Tyr Ala Glu Asp Leu Ser His Val Ala Ser Gly 
            365                 370                 375 

gaa tca gtg gat gaa gat gtc cct cct cca tca gtg tca tta cca aag     1506 
Glu Ser Val Asp Glu Asp Val Pro Pro Pro Ser Val Ser Leu Pro Lys 
        380                 385                 390 

ctg gct gca ctt ctc cgg gta ttt agt act gtg gtg agg agc att ggg     1554 
Leu Ala Ala Leu Leu Arg Val Phe Ser Thr Val Val Arg Ser Ile Gly 
    395                 400                 405 

gaa cgc ttc agc cca att cgg ggt cct cca att act gag gca tat gta     1602 
Glu Arg Phe Ser Pro Ile Arg Gly Pro Pro Ile Thr Glu Ala Tyr Val 
410                 415                 420                 425 

aca gat gtt ctg tac aga gta atg aga tgt gtg acg gct gca aac cag     1650 
Thr Asp Val Leu Tyr Arg Val Met Arg Cys Val Thr Ala Ala Asn Gln 
                430                 435                 440 

gtg ttt ttt tct gag gct gtg ttg aca gct gct aat gag tgt gtt ggt     1698 
Val Phe Phe Ser Glu Ala Val Leu Thr Ala Ala Asn Glu Cys Val Gly 
            445                 450                 455 

gtt ttg ctc ggc agc ttg gat cct agc atg act ata cat tgt gac atg     1746 
Val Leu Leu Gly Ser Leu Asp Pro Ser Met Thr Ile His Cys Asp Met 
        460                 465                 470 

gtc att aca tat gga tta gac caa ctg gag aat tgc cag act tgt ggt     1794 
Val Ile Thr Tyr Gly Leu Asp Gln Leu Glu Asn Cys Gln Thr Cys Gly 
    475                 480                 485 

acc gat tat atc atc tca gtc ttg aat tta ctc acg ctg att gtt gaa     1842 
Thr Asp Tyr Ile Ile Ser Val Leu Asn Leu Leu Thr Leu Ile Val Glu 
490                 495                 500                 505 

cag ata aat acg aaa ctg cca tca tca ttt gta gaa aaa ctg ttt ata     1890 
Gln Ile Asn Thr Lys Leu Pro Ser Ser Phe Val Glu Lys Leu Phe Ile 
                510                 515                 520 

cca tca tct aaa cta cta ttc ttg cgt tat cat aaa gaa aaa gag gtt     1938 
Pro Ser Ser Lys Leu Leu Phe Leu Arg Tyr His Lys Glu Lys Glu Val 
            525                 530                 535 

gtt gct gta gcc cat gct gtt tat caa gca gtg ctc agc ttg aag aat     1986 
Val Ala Val Ala His Ala Val Tyr Gln Ala Val Leu Ser Leu Lys Asn 
        540                 545                 550 

att cct gtt ttg gag act gcc tat aag tta ata ttg gga gaa atg act     2034 
Ile Pro Val Leu Glu Thr Ala Tyr Lys Leu Ile Leu Gly Glu Met Thr 
    555                 560                 565 

tgt gcc cta aac aac ctc cta cac agt cta caa ctt cct gag gcc tgt     2082 
Cys Ala Leu Asn Asn Leu Leu His Ser Leu Gln Leu Pro Glu Ala Cys 
570                 575                 580                 585 

tct gaa ata aaa cat gag gct ttt aag aat cat gtg ttc aat gta gac     2130 
Ser Glu Ile Lys His Glu Ala Phe Lys Asn His Val Phe Asn Val Asp 
                590                 595                 600 

aat gca aaa ttt gta gtt aaa ttt gac ctc agt gcc ctg act aca att     2178 
Asn Ala Lys Phe Val Val Lys Phe Asp Leu Ser Ala Leu Thr Thr Ile 
            605                 610                 615 

gga aat gcc aaa aac tca cta ata ggg atg tgg gcg cta tct cca act     2226 
Gly Asn Ala Lys Asn Ser Leu Ile Gly Met Trp Ala Leu Ser Pro Thr 
        620                 625                 630 

gtc ttt gca ctt ctg agt aag aat ctg atg att gtg cac agt gac ctg     2274 
Val Phe Ala Leu Leu Ser Lys Asn Leu Met Ile Val His Ser Asp Leu 
    635                 640                 645 

gct gtt cac ttc cct gcc att cag tat gct gtg ctc tac aca ttg tat     2322 
Ala Val His Phe Pro Ala Ile Gln Tyr Ala Val Leu Tyr Thr Leu Tyr 
650                 655                 660                 665 

tct cat tgt acc agg cat gat cac ttt atc tct agt agc ctc agt tct     2370 
Ser His Cys Thr Arg His Asp His Phe Ile Ser Ser Ser Leu Ser Ser 
                670                 675                 680 

gcc tct cct tct ttg ttt gat gga gct gtg att agc act gta act acg     2418 
Ala Ser Pro Ser Leu Phe Asp Gly Ala Val Ile Ser Thr Val Thr Thr 
            685                 690                 695 

gct aca aag aaa cat ttc tca att ata tta aat ctt ctg gga ata tta     2466 
Ala Thr Lys Lys His Phe Ser Ile Ile Leu Asn Leu Leu Gly Ile Leu 
        700                 705                 710 

ctt aag aaa gat aac ctt aac cag gac acg agg aaa ctg tta atg act     2514 
Leu Lys Lys Asp Asn Leu Asn Gln Asp Thr Arg Lys Leu Leu Met Thr 
    715                 720                 725 

tgg gct ttg gaa gca gct gtt tta atg agg aag tct gaa aca tac gca     2562 
Trp Ala Leu Glu Ala Ala Val Leu Met Arg Lys Ser Glu Thr Tyr Ala 
730                 735                 740                 745 

cct tta ttc tct ctt ccg tct ttc cat aaa ttt tgc aaa ggc ctt tta     2610 
Pro Leu Phe Ser Leu Pro Ser Phe His Lys Phe Cys Lys Gly Leu Leu 
                750                 755                 760 

gcc aac act ctc gtt gaa gat gtg aat atc tgt ctg cag gca tgc agc     2658 
Ala Asn Thr Leu Val Glu Asp Val Asn Ile Cys Leu Gln Ala Cys Ser 
            765                 770                 775 

agt cta cat gct ctg tcc tct tcc ttg cca gat gat ctt tta cag aga     2706 
Ser Leu His Ala Leu Ser Ser Ser Leu Pro Asp Asp Leu Leu Gln Arg 
        780                 785                 790 

tgt gtc gat gtt tgc cgt gtt caa cta gtg cac agt gga act cgt att     2754 
Cys Val Asp Val Cys Arg Val Gln Leu Val His Ser Gly Thr Arg Ile 
    795                 800                 805 

cga caa gca ttt gga aaa ctg ttg aaa tca att cct tta gat gtt gtc     2802 
Arg Gln Ala Phe Gly Lys Leu Leu Lys Ser Ile Pro Leu Asp Val Val 
810                 815                 820                 825 

cta agc aat aac aat cac aca gaa att caa gaa att tct tta gca tta     2850 
Leu Ser Asn Asn Asn His Thr Glu Ile Gln Glu Ile Ser Leu Ala Leu 
                830                 835                 840 

aga agt cac atg agt aaa gca cca agt aat aca ttc cac ccc caa gat     2898 
Arg Ser His Met Ser Lys Ala Pro Ser Asn Thr Phe His Pro Gln Asp 
            845                 850                 855 

ttc tct gat gtt att agt ttt att ttg tat ggg aac tct cat aga aca     2946 
Phe Ser Asp Val Ile Ser Phe Ile Leu Tyr Gly Asn Ser His Arg Thr 
        860                 865                 870 

ggg aag gac aat tgg ttg gaa aga ctg ttc tat agc tgc cag aga ctg     2994 
Gly Lys Asp Asn Trp Leu Glu Arg Leu Phe Tyr Ser Cys Gln Arg Leu 
    875                 880                 885 

gat aag cgt gac cag tca aca att cca cgc aat ctc ctg aag aca gat     3042 
Asp Lys Arg Asp Gln Ser Thr Ile Pro Arg Asn Leu Leu Lys Thr Asp 
890                 895                 900                 905 

gct gtc ctt tgg cag tgg gcc ata tgg gaa gct gca caa ttc act gtt     3090 
Ala Val Leu Trp Gln Trp Ala Ile Trp Glu Ala Ala Gln Phe Thr Val 
                910                 915                 920 

ctt tct aag ctg aga acc cca ctg ggc aga gct caa gac acc ttc cag     3138 
Leu Ser Lys Leu Arg Thr Pro Leu Gly Arg Ala Gln Asp Thr Phe Gln 
            925                 930                 935 

aca att gaa ggt atc att cga agt ctc gca gct cac aca tta aac cct     3186 
Thr Ile Glu Gly Ile Ile Arg Ser Leu Ala Ala His Thr Leu Asn Pro 
        940                 945                 950 

gat cag gat gtt agt cag tgg aca act gca gac aat gat gaa ggc cat     3234 
Asp Gln Asp Val Ser Gln Trp Thr Thr Ala Asp Asn Asp Glu Gly His 
    955                 960                 965 

ggt aac aac caa ctt aga ctt gtt ctt ctt ctg cag tat ctg gaa aat     3282 
Gly Asn Asn Gln Leu Arg Leu Val Leu Leu Leu Gln Tyr Leu Glu Asn 
970                 975                 980                 985 

ctg gag aaa tta atg tat aat gca tac gag gga tgt gct aat gca tta     3330 
Leu Glu Lys Leu Met Tyr Asn Ala Tyr Glu Gly Cys Ala Asn Ala Leu 
                 990                 995                1000 

act tca cct ccc aag gtc att aga act ttt ttc tat acc aat cgc caa     3378 
Thr Ser Pro Pro Lys Val Ile Arg Thr Phe Phe Tyr Thr Asn Arg Gln 
            1005                1010                1015 

act tgt cag gac tgg cta acg cgg att cga ctc tcc atc atg agg gta     3426 
Thr Cys Gln Asp Trp Leu Thr Arg Ile Arg Leu Ser Ile Met Arg Val 
        1020                1025                1030 

gga ttg ttg gca ggc cag cct gca gtg aca gtg aga cat ggc ttt gac     3474 
Gly Leu Leu Ala Gly Gln Pro Ala Val Thr Val Arg His Gly Phe Asp 
    1035                1040                1045 

ttg ctt aca gag atg aaa aca acc agc cta tct cag ggg aat gaa ttg     3522 
Leu Leu Thr Glu Met Lys Thr Thr Ser Leu Ser Gln Gly Asn Glu Leu 
1050                1055                1060                1065 

gaa gta acc att atg atg gtg gta gaa gca tta tgt gaa ctt cat tgt     3570 
Glu Val Thr Ile Met Met Val Val Glu Ala Leu Cys Glu Leu His Cys 
                1070                1075                1080 

cct gaa gct ata cag gga att gct gtc tgg tca tca tct att gtt gga     3618 
Pro Glu Ala Ile Gln Gly Ile Ala Val Trp Ser Ser Ser Ile Val Gly 
            1085                1090                1095 

aaa aat ctt ctg tgg att aac tca gtg gct caa cag gct gaa ggg agg     3666 
Lys Asn Leu Leu Trp Ile Asn Ser Val Ala Gln Gln Ala Glu Gly Arg 
        1100                1105                1110 

ttt gaa aag gcc tct gtg gag tac cag gaa cac ctg tgt gcc atg aca     3714 
Phe Glu Lys Ala Ser Val Glu Tyr Gln Glu His Leu Cys Ala Met Thr 
    1115                1120                1125 

ggt gtt gat tgc tgc atc tcc agc ttt gac aaa tcg gtg ctc acc tta     3762 
Gly Val Asp Cys Cys Ile Ser Ser Phe Asp Lys Ser Val Leu Thr Leu 
1130                1135                1140                1145 

gcc aat gct ggg cgt aac agt gcc agc ccg aaa cat tct ctg aat ggt     3810 
Ala Asn Ala Gly Arg Asn Ser Ala Ser Pro Lys His Ser Leu Asn Gly 
                1150                1155                1160 

gaa tcc aga aaa act gtg ctg tcc aaa ccg act gac tct tcc cct gag     3858 
Glu Ser Arg Lys Thr Val Leu Ser Lys Pro Thr Asp Ser Ser Pro Glu 
            1165                1170                1175 

gtt ata aat tat tta gga aat aaa gca tgt gag ttc tac atc tca att     3906 
Val Ile Asn Tyr Leu Gly Asn Lys Ala Cys Glu Phe Tyr Ile Ser Ile 
        1180                1185                1190 

gcc gat tgg gct gct gtg cag gaa tgg cag aac gct atc cat gac ttg     3954 
Ala Asp Trp Ala Ala Val Gln Glu Trp Gln Asn Ala Ile His Asp Leu 
    1195                1200                1205 

aaa aag agt acc agt agc act tcc ctc aac ctg aaa gct gac ttc aac     4002 
Lys Lys Ser Thr Ser Ser Thr Ser Leu Asn Leu Lys Ala Asp Phe Asn 
1210                1215                1220                1225 

tat ata aaa tca tta agc agc ttt gag tct gga aaa ttt gtt gaa tgt     4050 
Tyr Ile Lys Ser Leu Ser Ser Phe Glu Ser Gly Lys Phe Val Glu Cys 
                1230                1235                1240 

acc gag cag tta gaa ttg tta cca gga gaa aat atc aat cta ctt gct     4098 
Thr Glu Gln Leu Glu Leu Leu Pro Gly Glu Asn Ile Asn Leu Leu Ala 
            1245                1250                1255 

gga gga tca aaa gaa aaa ata gac atg aaa aaa ctg ctt cct aac atg     4146 
Gly Gly Ser Lys Glu Lys Ile Asp Met Lys Lys Leu Leu Pro Asn Met 
        1260                1265                1270 

tta agt ccg gat ccg agg gaa ctt cag aaa tcc att gaa gtt caa ttg     4194 
Leu Ser Pro Asp Pro Arg Glu Leu Gln Lys Ser Ile Glu Val Gln Leu 
    1275                1280                1285 

tta aga agt tct gtt tgt ttg gca act gct tta aac ccg ata gaa caa     4242 
Leu Arg Ser Ser Val Cys Leu Ala Thr Ala Leu Asn Pro Ile Glu Gln 
1290                1295                1300                1305 

gat cag aag tgg cag tct ata act gaa aat gtg gta aag tac ttg aag     4290 
Asp Gln Lys Trp Gln Ser Ile Thr Glu Asn Val Val Lys Tyr Leu Lys 
                1310                1315                1320 

caa aca tcc cgc atc gct att gga cct ctg aga ctt tct act tta aca     4338 
Gln Thr Ser Arg Ile Ala Ile Gly Pro Leu Arg Leu Ser Thr Leu Thr 
            1325                1330                1335 

gtt tca cag tct ttg cca gtt cta agt acc ttg cag ctg tat tgc tca     4386 
Val Ser Gln Ser Leu Pro Val Leu Ser Thr Leu Gln Leu Tyr Cys Ser 
        1340                1345                1350 

tct gct ttg gag aac aca gtt tct aac aga ctt tca aca gag gac tgt     4434 
Ser Ala Leu Glu Asn Thr Val Ser Asn Arg Leu Ser Thr Glu Asp Cys 
    1355                1360                1365 

ctt att cca ctc ttc agt gaa gct tta cgt tca tgt aaa cag cat gac     4482 
Leu Ile Pro Leu Phe Ser Glu Ala Leu Arg Ser Cys Lys Gln His Asp 
1370                1375                1380                1385 

gtg agg cca tgg atg cag gca tta agg tat act atg tac cag aat cag     4530 
Val Arg Pro Trp Met Gln Ala Leu Arg Tyr Thr Met Tyr Gln Asn Gln 
                1390                1395                1400 

ttg ttg gag aaa att aaa gaa caa aca gtc cca att aga agc cat ctc     4578 
Leu Leu Glu Lys Ile Lys Glu Gln Thr Val Pro Ile Arg Ser His Leu 
            1405                1410                1415 

atg gaa tta ggt cta aca gca gca aaa ttt gct aga aaa cga ggg aat     4626 
Met Glu Leu Gly Leu Thr Ala Ala Lys Phe Ala Arg Lys Arg Gly Asn 
        1420                1425                1430 

gtg tcc ctt gca aca aga ctg ctg gca cag tgc agt gaa gtt cag ctg     4674 
Val Ser Leu Ala Thr Arg Leu Leu Ala Gln Cys Ser Glu Val Gln Leu 
    1435                1440                1445 

gga aag acc acc act gca cag gat tta gtc caa cat ttt aaa aaa cta     4722 
Gly Lys Thr Thr Thr Ala Gln Asp Leu Val Gln His Phe Lys Lys Leu 
1450                1455                1460                1465 

tca acc caa ggt caa gtg gat gaa aaa tgg ggg ccc gaa ctt gat att     4770 
Ser Thr Gln Gly Gln Val Asp Glu Lys Trp Gly Pro Glu Leu Asp Ile 
                1470                1475                1480 

gaa aaa acc aaa ttg ctt tat aca gca ggc cag tca aca cat gca atg     4818 
Glu Lys Thr Lys Leu Leu Tyr Thr Ala Gly Gln Ser Thr His Ala Met 
            1485                1490                1495 

gaa atg ttg agt tct tgt gcc ata tct ttc tgc aag tct gtg aaa gct     4866 
Glu Met Leu Ser Ser Cys Ala Ile Ser Phe Cys Lys Ser Val Lys Ala 
        1500                1505                1510 

gaa tat gca gtt gct aaa tca att ctg aca ctg gct aaa tgg atc cag     4914 
Glu Tyr Ala Val Ala Lys Ser Ile Leu Thr Leu Ala Lys Trp Ile Gln 
    1515                1520                1525 

gca gaa tgg aaa gag att tca gga cag ctg aaa cag gtt tac aga gct     4962 
Ala Glu Trp Lys Glu Ile Ser Gly Gln Leu Lys Gln Val Tyr Arg Ala 
1530                1535                1540                1545 

cag cac caa cag aac ttc aca ggt ctt tct act ttg tct aaa aac ata     5010 
Gln His Gln Gln Asn Phe Thr Gly Leu Ser Thr Leu Ser Lys Asn Ile 
                1550                1555                1560 

ctc act cta ata gaa ctg cca tct gtt aat acg atg gaa gaa gag tat     5058 
Leu Thr Leu Ile Glu Leu Pro Ser Val Asn Thr Met Glu Glu Glu Tyr 
            1565                1570                1575 

cct cgg atc gag agt gaa tct aca gtg cat att gga gtt gga gaa cct     5106 
Pro Arg Ile Glu Ser Glu Ser Thr Val His Ile Gly Val Gly Glu Pro 
        1580                1585                1590 

gac ttc att ttg gga cag ttg tat cac ctg tct tca gta cag gca cct     5154 
Asp Phe Ile Leu Gly Gln Leu Tyr His Leu Ser Ser Val Gln Ala Pro 
    1595                1600                1605 

gaa gta gcc aaa tct tgg gca gcg ttg gcc agc tgg gct tat agg tgg     5202 
Glu Val Ala Lys Ser Trp Ala Ala Leu Ala Ser Trp Ala Tyr Arg Trp 
1610                1615                1620                1625 

ggc aga aag gtg gtt gac aat gcc agt cag gga gaa ggt gtt cgt ctg     5250 
Gly Arg Lys Val Val Asp Asn Ala Ser Gln Gly Glu Gly Val Arg Leu 
                1630                1635                1640 

ctg cct aga gaa aaa tct gaa gtt cag aat cta ctt cca gac act ata     5298 
Leu Pro Arg Glu Lys Ser Glu Val Gln Asn Leu Leu Pro Asp Thr Ile 
            1645                1650                1655 

act gag gaa gag aaa gag aga ata tat ggt att ctt gga cag gct gtg     5346 
Thr Glu Glu Glu Lys Glu Arg Ile Tyr Gly Ile Leu Gly Gln Ala Val 
        1660                1665                1670 

tgt cgg ccg gcg ggg att cag gat gaa gat ata aca ctt cag ata act     5394 
Cys Arg Pro Ala Gly Ile Gln Asp Glu Asp Ile Thr Leu Gln Ile Thr 
    1675                1680                1685 

gag agt gaa gac aac gaa gaa gat gac atg gtt gat gtt atc tgg cgt     5442 
Glu Ser Glu Asp Asn Glu Glu Asp Asp Met Val Asp Val Ile Trp Arg 
1690                1695                1700                1705 

cag ttg ata tca agc tgc cca tgg ctt tca gaa ctt gat gaa agt gca     5490 
Gln Leu Ile Ser Ser Cys Pro Trp Leu Ser Glu Leu Asp Glu Ser Ala 
                1710                1715                1720 

act gaa gga gtt att aaa gtg tgg agg aaa gtt gta gat aga ata ttc     5538 
Thr Glu Gly Val Ile Lys Val Trp Arg Lys Val Val Asp Arg Ile Phe 
            1725                1730                1735 

agc ctg tac aaa ctc tct tgc agt gca tac ttt act ttc ctt aaa ctc     5586 
Ser Leu Tyr Lys Leu Ser Cys Ser Ala Tyr Phe Thr Phe Leu Lys Leu 
        1740                1745                1750 

aac gct ggt caa att cct tta gat gag gat gac cct agg ctg cat tta     5634 
Asn Ala Gly Gln Ile Pro Leu Asp Glu Asp Asp Pro Arg Leu His Leu 
    1755                1760                1765 

agt cac aga gtg gaa cag agc act gat gac atg att gtg atg gcc aca     5682 
Ser His Arg Val Glu Gln Ser Thr Asp Asp Met Ile Val Met Ala Thr 
1770                1775                1780                1785 

ttg cgc ctg ctg cgg ttg ctc gtg aag cat gct ggt gag ctt cgg cag     5730 
Leu Arg Leu Leu Arg Leu Leu Val Lys His Ala Gly Glu Leu Arg Gln 
                1790                1795                1800 

tat ctg gag cac ggc ttg gag aca aca ccc act gca cca tgg agg gga     5778 
Tyr Leu Glu His Gly Leu Glu Thr Thr Pro Thr Ala Pro Trp Arg Gly 
            1805                1810                1815 

att att ccg caa ctt ttc tca cgc tta aac cac cct gaa gtg tat gtg     5826 
Ile Ile Pro Gln Leu Phe Ser Arg Leu Asn His Pro Glu Val Tyr Val 
        1820                1825                1830 

cgc caa agt att tgt aac ctt ctc tgc cgt gtg gct caa gat tcc cca     5874 
Arg Gln Ser Ile Cys Asn Leu Leu Cys Arg Val Ala Gln Asp Ser Pro 
    1835                1840                1845 

cat ctc ata ttg tat cct gca ata gtg ggt acc ata tcg ctt agt agt     5922 
His Leu Ile Leu Tyr Pro Ala Ile Val Gly Thr Ile Ser Leu Ser Ser 
1850                1855                1860                1865 

gaa tcc cag gct tca gga aat aaa ttt tcc act gca att cca act tta     5970 
Glu Ser Gln Ala Ser Gly Asn Lys Phe Ser Thr Ala Ile Pro Thr Leu 
                1870                1875                1880 

ctt ggc aat att caa gga gaa gaa ttg ctg gtt tct gaa tgt gag gga     6018 
Leu Gly Asn Ile Gln Gly Glu Glu Leu Leu Val Ser Glu Cys Glu Gly 
            1885                1890                1895 

gga agt cct cct gca tct cag gat agc aat aag gat gaa cct aaa agt     6066 
Gly Ser Pro Pro Ala Ser Gln Asp Ser Asn Lys Asp Glu Pro Lys Ser 
        1900                1905                1910 

gga tta aat gaa gac caa gcc atg atg cag gat tgt tac agc aaa att     6114 
Gly Leu Asn Glu Asp Gln Ala Met Met Gln Asp Cys Tyr Ser Lys Ile 
    1915                1920                1925 

gta gat aag ctg tcc tct gca aac ccc acc atg gta tta cag gtt cag     6162 
Val Asp Lys Leu Ser Ser Ala Asn Pro Thr Met Val Leu Gln Val Gln 
1930                1935                1940                1945 

atg ctc gtg gct gaa ctg cgc agg gtc act gtg ctc tgg gat gag ctc     6210 
Met Leu Val Ala Glu Leu Arg Arg Val Thr Val Leu Trp Asp Glu Leu 
                1950                1955                1960 

tgg ctg gga gtt ttg ctg caa caa cac atg tat gtc ctg aga cga att     6258 
Trp Leu Gly Val Leu Leu Gln Gln His Met Tyr Val Leu Arg Arg Ile 
            1965                1970                1975 

cag cag ctt gaa gat gag gtg aag aga gtc cag aac aac aac acc tta     6306 
Gln Gln Leu Glu Asp Glu Val Lys Arg Val Gln Asn Asn Asn Thr Leu 
        1980                1985                1990 

cgc aaa gaa gag aaa att gca atc atg agg gag agg cac aca gct ttg     6354 
Arg Lys Glu Glu Lys Ile Ala Ile Met Arg Glu Arg His Thr Ala Leu 
    1995                2000                2005 

atg aag ccc atc gta ttt gct ttg gag cat gtg agg agt atc aca gcg     6402 
Met Lys Pro Ile Val Phe Ala Leu Glu His Val Arg Ser Ile Thr Ala 
2010                2015                2020                2025 

gct cct gca gaa aca cct cat gaa aaa tgg ttt cag gat aac tat ggt     6450 
Ala Pro Ala Glu Thr Pro His Glu Lys Trp Phe Gln Asp Asn Tyr Gly 
                2030                2035                2040 

gat gcc att gaa aat gcc cta gaa aaa ctg aag act cca ttg aac cct     6498 
Asp Ala Ile Glu Asn Ala Leu Glu Lys Leu Lys Thr Pro Leu Asn Pro 
            2045                2050                2055 

gca aag cct ggg agc agc tgg att cca ttt aaa gag ata atg cta agt     6546 
Ala Lys Pro Gly Ser Ser Trp Ile Pro Phe Lys Glu Ile Met Leu Ser 
        2060                2065                2070 

ttg caa cag aga gca cag aaa cgt gca agt tac atc ttg cgt ctt gaa     6594 
Leu Gln Gln Arg Ala Gln Lys Arg Ala Ser Tyr Ile Leu Arg Leu Glu 
    2075                2080                2085 

gaa atc agt cca tgg ttg gct gcc atg act aac act gaa att gct ctt     6642 
Glu Ile Ser Pro Trp Leu Ala Ala Met Thr Asn Thr Glu Ile Ala Leu 
2090                2095                2100                2105 

cct ggg gaa gtc tca gcc aga gac act gtc aca atc cat agt gtg ggc     6690 
Pro Gly Glu Val Ser Ala Arg Asp Thr Val Thr Ile His Ser Val Gly 
                2110                2115                2120 

gga acc atc aca atc tta ccg act aaa acc aag cca aag aaa ctt ctc     6738 
Gly Thr Ile Thr Ile Leu Pro Thr Lys Thr Lys Pro Lys Lys Leu Leu 
            2125                2130                2135 

ttt ctt gga tca gat ggg aag agc tat cct tat ctt ttc aaa gga ctg     6786 
Phe Leu Gly Ser Asp Gly Lys Ser Tyr Pro Tyr Leu Phe Lys Gly Leu 
        2140                2145                2150 

gag gat tta cat ctg gat gag aga ata atg cag ttc cta tct att gtg     6834 
Glu Asp Leu His Leu Asp Glu Arg Ile Met Gln Phe Leu Ser Ile Val 
    2155                2160                2165 

aat acc atg ttt gct aca att aat cgc caa gaa aca ccc cgg ttc cat     6882 
Asn Thr Met Phe Ala Thr Ile Asn Arg Gln Glu Thr Pro Arg Phe His 
2170                2175                2180                2185 

gct cga cac tat tct gta aca cca cta gga aca aga tca gga cta atc     6930 
Ala Arg His Tyr Ser Val Thr Pro Leu Gly Thr Arg Ser Gly Leu Ile 
                2190                2195                2200 

cag tgg gta gat gga gcc aca ccc tta ttt ggt ctt tac aaa cga tgg     6978 
Gln Trp Val Asp Gly Ala Thr Pro Leu Phe Gly Leu Tyr Lys Arg Trp 
            2205                2210                2215 

caa caa cgg gaa gct gcc tta caa gca caa aag gcc caa gat tcc tac     7026 
Gln Gln Arg Glu Ala Ala Leu Gln Ala Gln Lys Ala Gln Asp Ser Tyr 
        2220                2225                2230 

caa act cct cag aat cct gga att gta ccc cgt cct agt gaa ctt tat     7074 
Gln Thr Pro Gln Asn Pro Gly Ile Val Pro Arg Pro Ser Glu Leu Tyr 
    2235                2240                2245 

tac agt aaa att ggc cct gct ttg aaa aca gtt ggg ctt agc ctg gat     7122 
Tyr Ser Lys Ile Gly Pro Ala Leu Lys Thr Val Gly Leu Ser Leu Asp 
2250                2255                2260                2265 

gtg tcc cgt cgg gat tgg cct ctt cat gta atg aag gca gta ttg gaa     7170 
Val Ser Arg Arg Asp Trp Pro Leu His Val Met Lys Ala Val Leu Glu 
                2270                2275                2280 

gag tta atg gag gcc aca ccc ccg aat ctc ctt gcc aaa gag ctc tgg     7218 
Glu Leu Met Glu Ala Thr Pro Pro Asn Leu Leu Ala Lys Glu Leu Trp 
            2285                2290                2295 

tca tct tgc aca aca cct gat gaa tgg tgg aga gtt acg cag tct tat     7266 
Ser Ser Cys Thr Thr Pro Asp Glu Trp Trp Arg Val Thr Gln Ser Tyr 
        2300                2305                2310 

gca aga tct act gca gtc atg tct atg gtt gga tac ata att ggc ctt     7314 
Ala Arg Ser Thr Ala Val Met Ser Met Val Gly Tyr Ile Ile Gly Leu 
    2315                2320                2325 

gga gac aga cat ctg gat aat gtt ctt ata gat atg acg act gga gaa     7362 
Gly Asp Arg His Leu Asp Asn Val Leu Ile Asp Met Thr Thr Gly Glu 
2330                2335                2340                2345 

gtt gtt cac ata gat tac aat gtt tgc ttt gaa aaa ggt aaa agc ctt     7410 
Val Val His Ile Asp Tyr Asn Val Cys Phe Glu Lys Gly Lys Ser Leu 
                2350                2355                2360 

aga gtt cct gag aaa gta cct ttt cga atg aca caa aac att gaa aca     7458 
Arg Val Pro Glu Lys Val Pro Phe Arg Met Thr Gln Asn Ile Glu Thr 
            2365                2370                2375 

gca ctg ggt gta act gga gta gaa ggt gta ttt agg ctt tca tgt gag     7506 
Ala Leu Gly Val Thr Gly Val Glu Gly Val Phe Arg Leu Ser Cys Glu 
        2380                2385                2390 

cag gtt tta cac att atg cgg cgt ggc aga gag acc ctg ctg acg ctg     7554 
Gln Val Leu His Ile Met Arg Arg Gly Arg Glu Thr Leu Leu Thr Leu 
    2395                2400                2405 

ctg gag gcc ttt gtg tac gac cct ctg gtg gac tgg aca gca gga ggc     7602 
Leu Glu Ala Phe Val Tyr Asp Pro Leu Val Asp Trp Thr Ala Gly Gly 
2410                2415                2420                2425 

gag gct ggg ttt gct ggt gct gtc tat ggt gga ggt ggc cag cag gcc     7650 
Glu Ala Gly Phe Ala Gly Ala Val Tyr Gly Gly Gly Gly Gln Gln Ala 
                2430                2435                2440 

gag agc aag cag agc aag aga gag atg gag cga gag atc acc cgc agc     7698 
Glu Ser Lys Gln Ser Lys Arg Glu Met Glu Arg Glu Ile Thr Arg Ser 
            2445                2450                2455 

ctg ttt tct tct aga gta gct gag att aag gtg aac tgg ttt aag aat     7746 
Leu Phe Ser Ser Arg Val Ala Glu Ile Lys Val Asn Trp Phe Lys Asn 
        2460                2465                2470 

aga gat gag atg ctg gtt gtg ctt ccc aag ttg gac ggt agc tta gat     7794 
Arg Asp Glu Met Leu Val Val Leu Pro Lys Leu Asp Gly Ser Leu Asp 
    2475                2480                2485 

gaa tac cta agc ttg caa gag caa ctg aca gat gtg gaa aaa ctg cag     7842 
Glu Tyr Leu Ser Leu Gln Glu Gln Leu Thr Asp Val Glu Lys Leu Gln 
2490                2495                2500                2505 

ggc aaa cta ctg gag gaa ata gag ttt cta gaa gga gct gaa ggg gtg     7890 
Gly Lys Leu Leu Glu Glu Ile Glu Phe Leu Glu Gly Ala Glu Gly Val 
                2510                2515                2520 

gat cat cct tct cat act ctg caa cac agg tat tct gag cac acc caa     7938 
Asp His Pro Ser His Thr Leu Gln His Arg Tyr Ser Glu His Thr Gln 
            2525                2530                2535 

cta cag act cag caa aga gct gtt cag gaa gca atc cag gtg aag ctg     7986 
Leu Gln Thr Gln Gln Arg Ala Val Gln Glu Ala Ile Gln Val Lys Leu 
        2540                2545                2550 

aat gaa ttt gaa caa tgg ata aca cat tat cag gct gca ttc aat aat     8034 
Asn Glu Phe Glu Gln Trp Ile Thr His Tyr Gln Ala Ala Phe Asn Asn 
    2555                2560                2565 

tta gaa gca aca cag ctt gca agc ttg ctt caa gag ata agc aca caa     8082 
Leu Glu Ala Thr Gln Leu Ala Ser Leu Leu Gln Glu Ile Ser Thr Gln 
2570                2575                2580                2585 

atg gac ctt ggt cct cca agt tac gtg cca gca aca gcc ttt ctg cag     8130 
Met Asp Leu Gly Pro Pro Ser Tyr Val Pro Ala Thr Ala Phe Leu Gln 
                2590                2595                2600 

aat gct ggt cag gcc cac ttg att agc cag tgc gag cag ctg gag ggg     8178 
Asn Ala Gly Gln Ala His Leu Ile Ser Gln Cys Glu Gln Leu Glu Gly 
            2605                2610                2615 

gag gtt ggt gct ctc ctg cag cag agg cgc tcc gtg ctc cgt ggc tgt     8226 
Glu Val Gly Ala Leu Leu Gln Gln Arg Arg Ser Val Leu Arg Gly Cys 
        2620                2625                2630 

ctg gag caa ctg cat cac tat gca acc gtg gcc ctg cag tat ccg aag     8274 
Leu Glu Gln Leu His His Tyr Ala Thr Val Ala Leu Gln Tyr Pro Lys 
    2635                2640                2645 

gcc ata ttt cag aaa cat cga att gaa cag tgg aag acc tgg atg gaa     8322 
Ala Ile Phe Gln Lys His Arg Ile Glu Gln Trp Lys Thr Trp Met Glu 
2650                2655                2660                2665 

gag ctc atc tgt aac acc aca gta gag cgt tgt caa gag ctc tat agg     8370 
Glu Leu Ile Cys Asn Thr Thr Val Glu Arg Cys Gln Glu Leu Tyr Arg 
                2670                2675                2680 

aaa tat gaa atg caa tat gct ccc cag cca ccc cca aca gtg tgt cag     8418 
Lys Tyr Glu Met Gln Tyr Ala Pro Gln Pro Pro Pro Thr Val Cys Gln 
            2685                2690                2695 

ttc atc act gcc act gaa atg acc ctg cag cga tac gca gca gac atc     8466 
Phe Ile Thr Ala Thr Glu Met Thr Leu Gln Arg Tyr Ala Ala Asp Ile 
        2700                2705                2710 

aac agc aga ctt att aga caa gtg gaa cgc ttg aaa cag gaa gct gtc     8514 
Asn Ser Arg Leu Ile Arg Gln Val Glu Arg Leu Lys Gln Glu Ala Val 
    2715                2720                2725 

act gtg cca gtt tgt gaa gat cag ttg aaa gaa att gaa cgt tgc att     8562 
Thr Val Pro Val Cys Glu Asp Gln Leu Lys Glu Ile Glu Arg Cys Ile 
2730                2735                2740                2745 

aaa gtt ttc ctt cat gag aat gga gaa gaa gga tct ttg agt cta gca     8610 
Lys Val Phe Leu His Glu Asn Gly Glu Glu Gly Ser Leu Ser Leu Ala 
                2750                2755                2760 

agt gtt att att tct gcc ctt tgt acc ctt aca agg cgt aac ctg atg     8658 
Ser Val Ile Ile Ser Ala Leu Cys Thr Leu Thr Arg Arg Asn Leu Met 
            2765                2770                2775 

atg gaa ggt gca gcg tca agt gct gga gaa cag ctg gtt gat ctg act     8706 
Met Glu Gly Ala Ala Ser Ser Ala Gly Glu Gln Leu Val Asp Leu Thr 
        2780                2785                2790 

tct cgg gat gga gcc tgg ttc ttg gag gaa ctc tgc agt atg agc gga     8754 
Ser Arg Asp Gly Ala Trp Phe Leu Glu Glu Leu Cys Ser Met Ser Gly 
    2795                2800                2805 

aac gtc acc tgc ttg gtt cag tta ctg aag cag tgc cac ctg gtg cca     8802 
Asn Val Thr Cys Leu Val Gln Leu Leu Lys Gln Cys His Leu Val Pro 
2810                2815                2820                2825 

cag gac tta gat atc ccg aac ccc atg gaa gcg tct gag aca gtt cac     8850 
Gln Asp Leu Asp Ile Pro Asn Pro Met Glu Ala Ser Glu Thr Val His 
                2830                2835                2840 

tta gcc aat gga gtg tat acc tca ctt cag gaa ttg aat tcg aat ttc     8898 
Leu Ala Asn Gly Val Tyr Thr Ser Leu Gln Glu Leu Asn Ser Asn Phe 
            2845                2850                2855 

cgg caa atc ata ttt cca gaa gca ctt cga tgt tta atg aaa ggg gaa     8946 
Arg Gln Ile Ile Phe Pro Glu Ala Leu Arg Cys Leu Met Lys Gly Glu 
        2860                2865                2870 

tac acg tta gaa agt atg ctg cat gaa ctg gac ggt ctt att gag cag     8994 
Tyr Thr Leu Glu Ser Met Leu His Glu Leu Asp Gly Leu Ile Glu Gln 
    2875                2880                2885 

acc acc gat ggc gtt ccc ctg cag act cta gtg gaa tct ctt cag gcc     9042 
Thr Thr Asp Gly Val Pro Leu Gln Thr Leu Val Glu Ser Leu Gln Ala 
2890                2895                2900                2905 

tac tta aga aac gca gct atg gga ctg gaa gaa gaa aca cat gct cat     9090 
Tyr Leu Arg Asn Ala Ala Met Gly Leu Glu Glu Glu Thr His Ala His 
                2910                2915                2920 

tac atc gat gtt gcc aga cta cta cat gct cag tac ggt gaa tta atc     9138 
Tyr Ile Asp Val Ala Arg Leu Leu His Ala Gln Tyr Gly Glu Leu Ile 
            2925                2930                2935 

caa ccg aga aat ggt tca gtt gat gaa aca ccc aaa atg tca gct ggc     9186 
Gln Pro Arg Asn Gly Ser Val Asp Glu Thr Pro Lys Met Ser Ala Gly 
        2940                2945                2950 

cag atg ctt ttg gta gca ttc gat ggc atg ttt gct caa gtt gaa act     9234 
Gln Met Leu Leu Val Ala Phe Asp Gly Met Phe Ala Gln Val Glu Thr 
    2955                2960                2965 

gct ttc agc tta tta gtt gaa aag ttg aac aag atg gaa att ccc ata     9282 
Ala Phe Ser Leu Leu Val Glu Lys Leu Asn Lys Met Glu Ile Pro Ile 
2970                2975                2980                2985 

gct tgg cga aag att gac atc ata agg gaa gcc agg agt act caa gtt     9330 
Ala Trp Arg Lys Ile Asp Ile Ile Arg Glu Ala Arg Ser Thr Gln Val 
                2990                2995                3000 

aat ttt ttt gat gat gat aat cac cgg cag gtg cta gaa gag att ttc     9378 
Asn Phe Phe Asp Asp Asp Asn His Arg Gln Val Leu Glu Glu Ile Phe 
            3005                3010                3015 

ttt cta aaa aga cta cag act att aag gag ttc ttc agg ctc tgt ggt     9426 
Phe Leu Lys Arg Leu Gln Thr Ile Lys Glu Phe Phe Arg Leu Cys Gly 
        3020                3025                3030 

acc ttt tct aaa aca ttg tca gga tca agt tca ctt gaa gat cag aat     9474 
Thr Phe Ser Lys Thr Leu Ser Gly Ser Ser Ser Leu Glu Asp Gln Asn 
    3035                3040                3045 

act gtg aat ggg cct gta cag att gtc aat gtg aaa acc ctt ttt aga     9522 
Thr Val Asn Gly Pro Val Gln Ile Val Asn Val Lys Thr Leu Phe Arg 
3050                3055                3060                3065 

aac tct tgt ttc agt gaa gac caa atg gcc aaa cct atc aag gca ttc     9570 
Asn Ser Cys Phe Ser Glu Asp Gln Met Ala Lys Pro Ile Lys Ala Phe 
                3070                3075                3080 

aca gct gac ttt gtg agg cag ctc ttg ata ggg cta ccc aac caa gcc     9618 
Thr Ala Asp Phe Val Arg Gln Leu Leu Ile Gly Leu Pro Asn Gln Ala 
            3085                3090                3095 

ctc gga ctc aca ctg tgc agt ttt atc agt gct ctg ggt gta gac atc     9666 
Leu Gly Leu Thr Leu Cys Ser Phe Ile Ser Ala Leu Gly Val Asp Ile 
        3100                3105                3110 

att gct caa gta gag gca aag gac ttt ggt gcc gaa agc aaa gtt tct     9714 
Ile Ala Gln Val Glu Ala Lys Asp Phe Gly Ala Glu Ser Lys Val Ser 
    3115                3120                3125 

gtt gat gat ctc tgt aag aaa gcg gtg gaa cat aac atc cag ata ggg     9762 
Val Asp Asp Leu Cys Lys Lys Ala Val Glu His Asn Ile Gln Ile Gly 
3130                3135                3140                3145 

aag ttc tct cag ctg gtt atg aac agg gca act gtg tta gca agt tct     9810 
Lys Phe Ser Gln Leu Val Met Asn Arg Ala Thr Val Leu Ala Ser Ser 
                3150                3155                3160 

tac gac act gcc tgg aag aag cat gac ttg gtg cga agg cta gaa acc     9858 
Tyr Asp Thr Ala Trp Lys Lys His Asp Leu Val Arg Arg Leu Glu Thr 
            3165                3170                3175 

agt att tct tct tgt aag aca agc ctg cag cgg gtt cag ctg cat att     9906 
Ser Ile Ser Ser Cys Lys Thr Ser Leu Gln Arg Val Gln Leu His Ile 
        3180                3185                3190 

gcc atg ttt cag tgg caa cat gaa gat cta ctt atc aat aga cca caa     9954 
Ala Met Phe Gln Trp Gln His Glu Asp Leu Leu Ile Asn Arg Pro Gln 
    3195                3200                3205 

gcc atg tca gtc aca cct ccc cca cgg tct gct atc cta acc agc atg    10002 
Ala Met Ser Val Thr Pro Pro Pro Arg Ser Ala Ile Leu Thr Ser Met 
3210                3215                3220                3225 

aaa aag aag ctg cat acc ctg agc cag att gaa act tct att gcg aca    10050 
Lys Lys Lys Leu His Thr Leu Ser Gln Ile Glu Thr Ser Ile Ala Thr 
                3230                3235                3240 

gtt cag gag aag cta gct gca ctt gaa tca agt att gaa cag cga ctc    10098 
Val Gln Glu Lys Leu Ala Ala Leu Glu Ser Ser Ile Glu Gln Arg Leu 
            3245                3250                3255 

aag tgg gca ggt ggt gcc aac cct gca ttg gcc cct gta cta caa gat    10146 
Lys Trp Ala Gly Gly Ala Asn Pro Ala Leu Ala Pro Val Leu Gln Asp 
        3260                3265                3270 

ttt gaa gca acg ata gct gaa aga aga aat ctt gtc ctt aaa gag agc    10194 
Phe Glu Ala Thr Ile Ala Glu Arg Arg Asn Leu Val Leu Lys Glu Ser 
    3275                3280                3285 

caa aga gca agt cag gtc aca ttt ctc tgc agc aat atc att cat ttt    10242 
Gln Arg Ala Ser Gln Val Thr Phe Leu Cys Ser Asn Ile Ile His Phe 
3290                3295                3300                3305 

gaa agt tta cga aca aga act gca gaa gcc tta aac ctg gat gcg gcg    10290 
Glu Ser Leu Arg Thr Arg Thr Ala Glu Ala Leu Asn Leu Asp Ala Ala 
                3310                3315                3320 

tta ttt gaa cta atc aag cga tgt cag cag atg tgt tcg ttt gca tca    10338 
Leu Phe Glu Leu Ile Lys Arg Cys Gln Gln Met Cys Ser Phe Ala Ser 
            3325                3330                3335 

cag ttt aac agt tca gtg tct gag tta gag ctt cgt tta tta cag aga    10386 
Gln Phe Asn Ser Ser Val Ser Glu Leu Glu Leu Arg Leu Leu Gln Arg 
        3340                3345                3350 

gtg gac act ggt ctt gaa cat cct att ggc agc tct gaa tgg ctt ttg    10434 
Val Asp Thr Gly Leu Glu His Pro Ile Gly Ser Ser Glu Trp Leu Leu 
    3355                3360                3365 

tca gca cac aaa cag ttg acc cag gat atg tct act cag agg gca att    10482 
Ser Ala His Lys Gln Leu Thr Gln Asp Met Ser Thr Gln Arg Ala Ile 
3370                3375                3380                3385 

cag aca gag aaa gag cag cag ata gaa acg gtc tgt gaa aca att cag    10530 
Gln Thr Glu Lys Glu Gln Gln Ile Glu Thr Val Cys Glu Thr Ile Gln 
                3390                3395                3400 

aat ctg gtt gat aat ata aag act gtg ctc act ggt cat aac cga cag    10578 
Asn Leu Val Asp Asn Ile Lys Thr Val Leu Thr Gly His Asn Arg Gln 
            3405                3410                3415 

ctt gga gat gtc aaa cat ctc ttg aaa gct atg gct aag gat gaa gaa    10626 
Leu Gly Asp Val Lys His Leu Leu Lys Ala Met Ala Lys Asp Glu Glu 
        3420                3425                3430 

gct gct ctg gca gat ggt gaa gat gtt ccc tat gag aac agt gtt agg    10674 
Ala Ala Leu Ala Asp Gly Glu Asp Val Pro Tyr Glu Asn Ser Val Arg 
    3435                3440                3445 

cag ttt ttg ggt gaa tat aaa tca tgg caa gac aac att caa aca gtt    10722 
Gln Phe Leu Gly Glu Tyr Lys Ser Trp Gln Asp Asn Ile Gln Thr Val 
3450                3455                3460                3465 

cta ttt aca tta gtc cag gct atg ggt cag gtt cga agt caa gaa cac    10770 
Leu Phe Thr Leu Val Gln Ala Met Gly Gln Val Arg Ser Gln Glu His 
                3470                3475                3480 

gtt gaa atg ctc cag gaa atc act ccc acc ttg aaa gaa ctg aaa aca    10818 
Val Glu Met Leu Gln Glu Ile Thr Pro Thr Leu Lys Glu Leu Lys Thr 
            3485                3490                3495 

caa agt cag agt atc tat aat aat tta gtg agt ttt gca tca ccc tta    10866 
Gln Ser Gln Ser Ile Tyr Asn Asn Leu Val Ser Phe Ala Ser Pro Leu 
        3500                3505                3510 

gtc acc gat gca aca aat gaa tgt tcg agt cca acg tca tct gct act    10914 
Val Thr Asp Ala Thr Asn Glu Cys Ser Ser Pro Thr Ser Ser Ala Thr 
    3515                3520                3525 

tat cag cca tcc ttc gct gca gca gtc cgg agt aac act ggc cag aag    10962 
Tyr Gln Pro Ser Phe Ala Ala Ala Val Arg Ser Asn Thr Gly Gln Lys 
3530                3535                3540                3545 

act cag cct gat gtc atg tca cag aat gct aga aag ctg atc cag aaa    11010 
Thr Gln Pro Asp Val Met Ser Gln Asn Ala Arg Lys Leu Ile Gln Lys 
                3550                3555                3560 

aat ctt gct aca tca gct gat act cca cca agc acc gtt cca gga act    11058 
Asn Leu Ala Thr Ser Ala Asp Thr Pro Pro Ser Thr Val Pro Gly Thr 
            3565                3570                3575 

ggc aag agt gtt gct tgt agt cct aaa aag gca gtc aga gac cct aaa    11106 
Gly Lys Ser Val Ala Cys Ser Pro Lys Lys Ala Val Arg Asp Pro Lys 
        3580                3585                3590 

act ggg aaa gcg gtg caa gag aga aac tcc tat gca gtg agt gtg tgg    11154 
Thr Gly Lys Ala Val Gln Glu Arg Asn Ser Tyr Ala Val Ser Val Trp 
    3595                3600                3605 

aag aga gtg aaa gcc aag tta gag ggc cga gat gtt gat ccg aat agg    11202 
Lys Arg Val Lys Ala Lys Leu Glu Gly Arg Asp Val Asp Pro Asn Arg 
3610                3615                3620                3625 

agg atg tca gtt gct gaa cag gtt gac tat gtc att aag gaa gca act    11250 
Arg Met Ser Val Ala Glu Gln Val Asp Tyr Val Ile Lys Glu Ala Thr 
                3630                3635                3640 

aat cta gat aac ttg gct cag ctg tat gaa ggt tgg aca gcc tgg gtg    11298 
Asn Leu Asp Asn Leu Ala Gln Leu Tyr Glu Gly Trp Thr Ala Trp Val 
            3645                3650                3655 

tga atggcaagac agtagatgag tctggttaag cgaggtcaga catccaccag         11351 
 * 

aatcaactca gcctcaggca tccaaagcca caccacagtc ggtggtgatg caactggggg  11411 

cttactctga ggaaacctag gaaatctcgg tgcactagga agtgaatccc gcaggacagc  11471 

tgcactcagg gatacgccca acaccatggc ctgcaacccc agggtcaagg gtgaaggaaa  11531 

gcaaagctca ccgcctgaac acggagattg tctttctgcc acagaacagc agcagacgtg  11591 

tcgggaggtt agctgcggaa agaaatcggg atgccgcgga gcacagagtg atttggaact  11651 

ccattccacc tgaccctgtg tgtacaatcc aggaaaaaaa caaaccccac tcagaaacag  11711 

agaaaactgg ggtcgcgaag aaatcacagc caaggaagat ttgatgcatt cagattctcg  11771 

tgtaacactt gttgcttggc aacagtactg gttgggttga ccagtaagta gaaaaaggct  11831 

aaaggctatg cgatatgaat ttcagaaatg gactgaaaat ggagagctat gtaacagata  11891 

cactacagta gaagaactta cttctgaaat gaagggaaaa aaaccacccc atcgttccct  11951 

actcctcccc accacttacc cgttccccct ttacctaatc tagtagatta gccatctttc  12011 

aaattcactt ttatttcagt ccttatattt catatacttc cgtctcgatg ctgttaacaa  12071 

cttctgataa catggaaaat tcaaggattg tttaaaggtc tgatgatcac acacaaaatg  12131 

taattccggt tatttaagtc atttctgtga ttctatcatg tacagtttcc agaattgtca  12191 

ctgtgcattc aaaagtaatg aatctaacag acatttgatt taatgtacac tcccttttgc  12251 

ttatagtgtg catttttttt ggaggtcatt caaattttcc ctcttctgtg atagctgtag  12311 

tttctttcat agaaagtagc taatccagtg taatctttta cctttttaaa aaccaagata  12371 

gagtatctat tagagtttta cattgttgat gatagattaa caataaagtg atgttctggt  12431 

ggaggtagac tgaaattttt ttaattcatg tttttcattt gatactttta atttacactt  12491 

agtaaattaa aagttgttta atttacttgg cattttagga catgtacatg aaacagtgaa  12551 

aatgagatcc accaacatct tttattaagt tcagttatta gtctgtgaag tgctttactt  12611 

tttgcacaat tttaatagct tgctattcag taatacatta tagtgaattc atgatcaagg  12671 

tttccttaaa tttagcattg catttcagta ctgactgtgt aagctaaatt gctgatccaa  12731 

aataaaaacc cagactagaa tagggttctt aaaatcaagt atcaatacaa aatagaacac  12791 

aattaaaatc ttaattgttg gctgggcaca gtggctcacg cctgtaatcc cagcactttg  12851 

ggaggccgag gcgggcggat catgaggtta ggagagcgag accatcctgg ctaacacggt  12911 

gaaaccccgt ctttactaaa atacaaaaaa aattagccgg gtgtggtggc gggcgcctgt  12971 

agtcccagct actcgggagg ctgaggcagg agaatggcgt gaacccagga ggcggagctt  13031 

gcagtgagcc gagattgtgc cactgcactc cagcctgggc aacagagcta gactctgtgt  13091 

caaaaataaa tgactagat                                               13110 

 
           
             10  
             3657  
             PRT  
             Homo sapiens  
           
            10 

Met Ser Arg Arg Ala Pro Gly Ser Arg Leu Ser Ser Gly Gly Thr Asn 
 1               5                  10                  15 

Tyr Ser Arg Ser Trp Asn Asp Trp Gln Pro Arg Thr Asp Ser Ala Ser 
            20                  25                  30 

Ala Asp Pro Gly Asn Leu Lys Tyr Ser Ser Ser Arg Asp Arg Gly Gly 
        35                  40                  45 

Ser Ser Ser Tyr Gly Leu Gln Pro Ser Asn Ser Ala Val Val Ser Arg 
    50                  55                  60 

Gln Arg His Asp Asp Thr Arg Val His Ala Asp Ile Gln Asn Asp Glu 
65                  70                  75                  80 

Lys Gly Gly Tyr Ser Val Asn Gly Gly Ser Gly Glu Asn Thr Tyr Gly 
                85                  90                  95 

Arg Lys Ser Leu Gly Gln Glu Leu Arg Val Asn Asn Val Thr Ser Pro 
            100                 105                 110 

Glu Phe Thr Ser Val Gln His Gly Ser Arg Ala Leu Ala Thr Lys Asp 
        115                 120                 125 

Met Arg Lys Ser Gln Glu Arg Ser Met Ser Tyr Ser Asp Glu Ser Arg 
    130                 135                 140 

Leu Ser Asn Leu Leu Arg Arg Ile Thr Arg Glu Asp Asp Arg Asp Arg 
145                 150                 155                 160 

Arg Leu Ala Thr Val Lys Gln Leu Lys Glu Phe Ile Gln Gln Pro Glu 
                165                 170                 175 

Asn Lys Leu Val Leu Val Lys Gln Leu Asp Asn Ile Leu Ala Ala Val 
            180                 185                 190 

His Asp Val Leu Asn Glu Ser Ser Lys Leu Leu Gln Glu Leu Arg Gln 
        195                 200                 205 

Glu Gly Ala Cys Cys Leu Gly Leu Leu Cys Ala Ser Leu Ser Tyr Glu 
    210                 215                 220 

Ala Glu Lys Ile Phe Lys Trp Ile Phe Ser Lys Phe Ser Ser Ser Ala 
225                 230                 235                 240 

Lys Asp Glu Val Lys Leu Leu Tyr Leu Cys Ala Thr Tyr Lys Ala Leu 
                245                 250                 255 

Glu Thr Val Gly Glu Lys Lys Ala Phe Ser Ser Val Met Gln Leu Val 
            260                 265                 270 

Met Thr Ser Leu Gln Ser Ile Leu Glu Asn Val Asp Thr Pro Glu Leu 
        275                 280                 285 

Leu Cys Lys Cys Val Lys Cys Ile Leu Leu Val Ala Arg Cys Tyr Pro 
    290                 295                 300 

His Ile Phe Ser Thr Asn Phe Arg Asp Thr Val Asp Ile Leu Val Gly 
305                 310                 315                 320 

Trp His Ile Asp His Thr Gln Lys Pro Ser Leu Thr Gln Gln Val Ser 
                325                 330                 335 

Gly Trp Leu Gln Ser Leu Glu Pro Phe Trp Val Ala Asp Leu Ala Phe 
            340                 345                 350 

Ser Thr Thr Leu Leu Gly Gln Phe Leu Glu Asp Met Glu Ala Tyr Ala 
        355                 360                 365 

Glu Asp Leu Ser His Val Ala Ser Gly Glu Ser Val Asp Glu Asp Val 
    370                 375                 380 

Pro Pro Pro Ser Val Ser Leu Pro Lys Leu Ala Ala Leu Leu Arg Val 
385                 390                 395                 400 

Phe Ser Thr Val Val Arg Ser Ile Gly Glu Arg Phe Ser Pro Ile Arg 
                405                 410                 415 

Gly Pro Pro Ile Thr Glu Ala Tyr Val Thr Asp Val Leu Tyr Arg Val 
            420                 425                 430 

Met Arg Cys Val Thr Ala Ala Asn Gln Val Phe Phe Ser Glu Ala Val 
        435                 440                 445 

Leu Thr Ala Ala Asn Glu Cys Val Gly Val Leu Leu Gly Ser Leu Asp 
    450                 455                 460 

Pro Ser Met Thr Ile His Cys Asp Met Val Ile Thr Tyr Gly Leu Asp 
465                 470                 475                 480 

Gln Leu Glu Asn Cys Gln Thr Cys Gly Thr Asp Tyr Ile Ile Ser Val 
                485                 490                 495 

Leu Asn Leu Leu Thr Leu Ile Val Glu Gln Ile Asn Thr Lys Leu Pro 
            500                 505                 510 

Ser Ser Phe Val Glu Lys Leu Phe Ile Pro Ser Ser Lys Leu Leu Phe 
        515                 520                 525 

Leu Arg Tyr His Lys Glu Lys Glu Val Val Ala Val Ala His Ala Val 
    530                 535                 540 

Tyr Gln Ala Val Leu Ser Leu Lys Asn Ile Pro Val Leu Glu Thr Ala 
545                 550                 555                 560 

Tyr Lys Leu Ile Leu Gly Glu Met Thr Cys Ala Leu Asn Asn Leu Leu 
                565                 570                 575 

His Ser Leu Gln Leu Pro Glu Ala Cys Ser Glu Ile Lys His Glu Ala 
            580                 585                 590 

Phe Lys Asn His Val Phe Asn Val Asp Asn Ala Lys Phe Val Val Lys 
        595                 600                 605 

Phe Asp Leu Ser Ala Leu Thr Thr Ile Gly Asn Ala Lys Asn Ser Leu 
    610                 615                 620 

Ile Gly Met Trp Ala Leu Ser Pro Thr Val Phe Ala Leu Leu Ser Lys 
625                 630                 635                 640 

Asn Leu Met Ile Val His Ser Asp Leu Ala Val His Phe Pro Ala Ile 
                645                 650                 655 

Gln Tyr Ala Val Leu Tyr Thr Leu Tyr Ser His Cys Thr Arg His Asp 
            660                 665                 670 

His Phe Ile Ser Ser Ser Leu Ser Ser Ala Ser Pro Ser Leu Phe Asp 
        675                 680                 685 

Gly Ala Val Ile Ser Thr Val Thr Thr Ala Thr Lys Lys His Phe Ser 
    690                 695                 700 

Ile Ile Leu Asn Leu Leu Gly Ile Leu Leu Lys Lys Asp Asn Leu Asn 
705                 710                 715                 720 

Gln Asp Thr Arg Lys Leu Leu Met Thr Trp Ala Leu Glu Ala Ala Val 
                725                 730                 735 

Leu Met Arg Lys Ser Glu Thr Tyr Ala Pro Leu Phe Ser Leu Pro Ser 
            740                 745                 750 

Phe His Lys Phe Cys Lys Gly Leu Leu Ala Asn Thr Leu Val Glu Asp 
        755                 760                 765 

Val Asn Ile Cys Leu Gln Ala Cys Ser Ser Leu His Ala Leu Ser Ser 
    770                 775                 780 

Ser Leu Pro Asp Asp Leu Leu Gln Arg Cys Val Asp Val Cys Arg Val 
785                 790                 795                 800 

Gln Leu Val His Ser Gly Thr Arg Ile Arg Gln Ala Phe Gly Lys Leu 
                805                 810                 815 

Leu Lys Ser Ile Pro Leu Asp Val Val Leu Ser Asn Asn Asn His Thr 
            820                 825                 830 

Glu Ile Gln Glu Ile Ser Leu Ala Leu Arg Ser His Met Ser Lys Ala 
        835                 840                 845 

Pro Ser Asn Thr Phe His Pro Gln Asp Phe Ser Asp Val Ile Ser Phe 
    850                 855                 860 

Ile Leu Tyr Gly Asn Ser His Arg Thr Gly Lys Asp Asn Trp Leu Glu 
865                 870                 875                 880 

Arg Leu Phe Tyr Ser Cys Gln Arg Leu Asp Lys Arg Asp Gln Ser Thr 
                885                 890                 895 

Ile Pro Arg Asn Leu Leu Lys Thr Asp Ala Val Leu Trp Gln Trp Ala 
            900                 905                 910 

Ile Trp Glu Ala Ala Gln Phe Thr Val Leu Ser Lys Leu Arg Thr Pro 
        915                 920                 925 

Leu Gly Arg Ala Gln Asp Thr Phe Gln Thr Ile Glu Gly Ile Ile Arg 
    930                 935                 940 

Ser Leu Ala Ala His Thr Leu Asn Pro Asp Gln Asp Val Ser Gln Trp 
945                 950                 955                 960 

Thr Thr Ala Asp Asn Asp Glu Gly His Gly Asn Asn Gln Leu Arg Leu 
                965                 970                 975 

Val Leu Leu Leu Gln Tyr Leu Glu Asn Leu Glu Lys Leu Met Tyr Asn 
            980                 985                 990 

Ala Tyr Glu Gly Cys Ala Asn Ala Leu Thr Ser Pro Pro Lys Val Ile 
        995                 1000                1005 

Arg Thr Phe Phe Tyr Thr Asn Arg Gln Thr Cys Gln Asp Trp Leu Thr 
    1010                1015                1020 

Arg Ile Arg Leu Ser Ile Met Arg Val Gly Leu Leu Ala Gly Gln Pro 
1025                1030                1035                1040 

Ala Val Thr Val Arg His Gly Phe Asp Leu Leu Thr Glu Met Lys Thr 
                1045                1050                1055 

Thr Ser Leu Ser Gln Gly Asn Glu Leu Glu Val Thr Ile Met Met Val 
            1060                1065                1070 

Val Glu Ala Leu Cys Glu Leu His Cys Pro Glu Ala Ile Gln Gly Ile 
        1075                1080                1085 

Ala Val Trp Ser Ser Ser Ile Val Gly Lys Asn Leu Leu Trp Ile Asn 
    1090                1095                1100 

Ser Val Ala Gln Gln Ala Glu Gly Arg Phe Glu Lys Ala Ser Val Glu 
1105                1110                1115                1120 

Tyr Gln Glu His Leu Cys Ala Met Thr Gly Val Asp Cys Cys Ile Ser 
                1125                1130                1135 

Ser Phe Asp Lys Ser Val Leu Thr Leu Ala Asn Ala Gly Arg Asn Ser 
            1140                1145                1150 

Ala Ser Pro Lys His Ser Leu Asn Gly Glu Ser Arg Lys Thr Val Leu 
        1155                1160                1165 

Ser Lys Pro Thr Asp Ser Ser Pro Glu Val Ile Asn Tyr Leu Gly Asn 
    1170                1175                1180 

Lys Ala Cys Glu Phe Tyr Ile Ser Ile Ala Asp Trp Ala Ala Val Gln 
1185                1190                1195                1200 

Glu Trp Gln Asn Ala Ile His Asp Leu Lys Lys Ser Thr Ser Ser Thr 
                1205                1210                1215 

Ser Leu Asn Leu Lys Ala Asp Phe Asn Tyr Ile Lys Ser Leu Ser Ser 
            1220                1225                1230 

Phe Glu Ser Gly Lys Phe Val Glu Cys Thr Glu Gln Leu Glu Leu Leu 
        1235                1240                1245 

Pro Gly Glu Asn Ile Asn Leu Leu Ala Gly Gly Ser Lys Glu Lys Ile 
    1250                1255                1260 

Asp Met Lys Lys Leu Leu Pro Asn Met Leu Ser Pro Asp Pro Arg Glu 
1265                1270                1275                1280 

Leu Gln Lys Ser Ile Glu Val Gln Leu Leu Arg Ser Ser Val Cys Leu 
                1285                1290                1295 

Ala Thr Ala Leu Asn Pro Ile Glu Gln Asp Gln Lys Trp Gln Ser Ile 
            1300                1305                1310 

Thr Glu Asn Val Val Lys Tyr Leu Lys Gln Thr Ser Arg Ile Ala Ile 
        1315                1320                1325 

Gly Pro Leu Arg Leu Ser Thr Leu Thr Val Ser Gln Ser Leu Pro Val 
    1330                1335                1340 

Leu Ser Thr Leu Gln Leu Tyr Cys Ser Ser Ala Leu Glu Asn Thr Val 
1345                1350                1355                1360 

Ser Asn Arg Leu Ser Thr Glu Asp Cys Leu Ile Pro Leu Phe Ser Glu 
                1365                1370                1375 

Ala Leu Arg Ser Cys Lys Gln His Asp Val Arg Pro Trp Met Gln Ala 
            1380                1385                1390 

Leu Arg Tyr Thr Met Tyr Gln Asn Gln Leu Leu Glu Lys Ile Lys Glu 
        1395                1400                1405 

Gln Thr Val Pro Ile Arg Ser His Leu Met Glu Leu Gly Leu Thr Ala 
    1410                1415                1420 

Ala Lys Phe Ala Arg Lys Arg Gly Asn Val Ser Leu Ala Thr Arg Leu 
1425                1430                1435                1440 

Leu Ala Gln Cys Ser Glu Val Gln Leu Gly Lys Thr Thr Thr Ala Gln 
                1445                1450                1455 

Asp Leu Val Gln His Phe Lys Lys Leu Ser Thr Gln Gly Gln Val Asp 
            1460                1465                1470 

Glu Lys Trp Gly Pro Glu Leu Asp Ile Glu Lys Thr Lys Leu Leu Tyr 
        1475                1480                1485 

Thr Ala Gly Gln Ser Thr His Ala Met Glu Met Leu Ser Ser Cys Ala 
    1490                1495                1500 

Ile Ser Phe Cys Lys Ser Val Lys Ala Glu Tyr Ala Val Ala Lys Ser 
1505                1510                1515                1520 

Ile Leu Thr Leu Ala Lys Trp Ile Gln Ala Glu Trp Lys Glu Ile Ser 
                1525                1530                1535 

Gly Gln Leu Lys Gln Val Tyr Arg Ala Gln His Gln Gln Asn Phe Thr 
            1540                1545                1550 

Gly Leu Ser Thr Leu Ser Lys Asn Ile Leu Thr Leu Ile Glu Leu Pro 
        1555                1560                1565 

Ser Val Asn Thr Met Glu Glu Glu Tyr Pro Arg Ile Glu Ser Glu Ser 
    1570                1575                1580 

Thr Val His Ile Gly Val Gly Glu Pro Asp Phe Ile Leu Gly Gln Leu 
1585                1590                1595                1600 

Tyr His Leu Ser Ser Val Gln Ala Pro Glu Val Ala Lys Ser Trp Ala 
                1605                1610                1615 

Ala Leu Ala Ser Trp Ala Tyr Arg Trp Gly Arg Lys Val Val Asp Asn 
            1620                1625                1630 

Ala Ser Gln Gly Glu Gly Val Arg Leu Leu Pro Arg Glu Lys Ser Glu 
        1635                1640                1645 

Val Gln Asn Leu Leu Pro Asp Thr Ile Thr Glu Glu Glu Lys Glu Arg 
    1650                1655                1660 

Ile Tyr Gly Ile Leu Gly Gln Ala Val Cys Arg Pro Ala Gly Ile Gln 
1665                1670                1675                1680 

Asp Glu Asp Ile Thr Leu Gln Ile Thr Glu Ser Glu Asp Asn Glu Glu 
                1685                1690                1695 

Asp Asp Met Val Asp Val Ile Trp Arg Gln Leu Ile Ser Ser Cys Pro 
            1700                1705                1710 

Trp Leu Ser Glu Leu Asp Glu Ser Ala Thr Glu Gly Val Ile Lys Val 
        1715                1720                1725 

Trp Arg Lys Val Val Asp Arg Ile Phe Ser Leu Tyr Lys Leu Ser Cys 
    1730                1735                1740 

Ser Ala Tyr Phe Thr Phe Leu Lys Leu Asn Ala Gly Gln Ile Pro Leu 
1745                1750                1755                1760 

Asp Glu Asp Asp Pro Arg Leu His Leu Ser His Arg Val Glu Gln Ser 
                1765                1770                1775 

Thr Asp Asp Met Ile Val Met Ala Thr Leu Arg Leu Leu Arg Leu Leu 
            1780                1785                1790 

Val Lys His Ala Gly Glu Leu Arg Gln Tyr Leu Glu His Gly Leu Glu 
        1795                1800                1805 

Thr Thr Pro Thr Ala Pro Trp Arg Gly Ile Ile Pro Gln Leu Phe Ser 
    1810                1815                1820 

Arg Leu Asn His Pro Glu Val Tyr Val Arg Gln Ser Ile Cys Asn Leu 
1825                1830                1835                1840 

Leu Cys Arg Val Ala Gln Asp Ser Pro His Leu Ile Leu Tyr Pro Ala 
                1845                1850                1855 

Ile Val Gly Thr Ile Ser Leu Ser Ser Glu Ser Gln Ala Ser Gly Asn 
            1860                1865                1870 

Lys Phe Ser Thr Ala Ile Pro Thr Leu Leu Gly Asn Ile Gln Gly Glu 
        1875                1880                1885 

Glu Leu Leu Val Ser Glu Cys Glu Gly Gly Ser Pro Pro Ala Ser Gln 
    1890                1895                1900 

Asp Ser Asn Lys Asp Glu Pro Lys Ser Gly Leu Asn Glu Asp Gln Ala 
1905                1910                1915                1920 

Met Met Gln Asp Cys Tyr Ser Lys Ile Val Asp Lys Leu Ser Ser Ala 
                1925                1930                1935 

Asn Pro Thr Met Val Leu Gln Val Gln Met Leu Val Ala Glu Leu Arg 
            1940                1945                1950 

Arg Val Thr Val Leu Trp Asp Glu Leu Trp Leu Gly Val Leu Leu Gln 
        1955                1960                1965 

Gln His Met Tyr Val Leu Arg Arg Ile Gln Gln Leu Glu Asp Glu Val 
    1970                1975                1980 

Lys Arg Val Gln Asn Asn Asn Thr Leu Arg Lys Glu Glu Lys Ile Ala 
1985                1990                1995                2000 

Ile Met Arg Glu Arg His Thr Ala Leu Met Lys Pro Ile Val Phe Ala 
                2005                2010                2015 

Leu Glu His Val Arg Ser Ile Thr Ala Ala Pro Ala Glu Thr Pro His 
            2020                2025                2030 

Glu Lys Trp Phe Gln Asp Asn Tyr Gly Asp Ala Ile Glu Asn Ala Leu 
        2035                2040                2045 

Glu Lys Leu Lys Thr Pro Leu Asn Pro Ala Lys Pro Gly Ser Ser Trp 
    2050                2055                2060 

Ile Pro Phe Lys Glu Ile Met Leu Ser Leu Gln Gln Arg Ala Gln Lys 
2065                2070                2075                2080 

Arg Ala Ser Tyr Ile Leu Arg Leu Glu Glu Ile Ser Pro Trp Leu Ala 
                2085                2090                2095 

Ala Met Thr Asn Thr Glu Ile Ala Leu Pro Gly Glu Val Ser Ala Arg 
            2100                2105                2110 

Asp Thr Val Thr Ile His Ser Val Gly Gly Thr Ile Thr Ile Leu Pro 
        2115                2120                2125 

Thr Lys Thr Lys Pro Lys Lys Leu Leu Phe Leu Gly Ser Asp Gly Lys 
    2130                2135                2140 

Ser Tyr Pro Tyr Leu Phe Lys Gly Leu Glu Asp Leu His Leu Asp Glu 
2145                2150                2155                2160 

Arg Ile Met Gln Phe Leu Ser Ile Val Asn Thr Met Phe Ala Thr Ile 
                2165                2170                2175 

Asn Arg Gln Glu Thr Pro Arg Phe His Ala Arg His Tyr Ser Val Thr 
            2180                2185                2190 

Pro Leu Gly Thr Arg Ser Gly Leu Ile Gln Trp Val Asp Gly Ala Thr 
        2195                2200                2205 

Pro Leu Phe Gly Leu Tyr Lys Arg Trp Gln Gln Arg Glu Ala Ala Leu 
    2210                2215                2220 

Gln Ala Gln Lys Ala Gln Asp Ser Tyr Gln Thr Pro Gln Asn Pro Gly 
2225                2230                2235                2240 

Ile Val Pro Arg Pro Ser Glu Leu Tyr Tyr Ser Lys Ile Gly Pro Ala 
                2245                2250                2255 

Leu Lys Thr Val Gly Leu Ser Leu Asp Val Ser Arg Arg Asp Trp Pro 
            2260                2265                2270 

Leu His Val Met Lys Ala Val Leu Glu Glu Leu Met Glu Ala Thr Pro 
        2275                2280                2285 

Pro Asn Leu Leu Ala Lys Glu Leu Trp Ser Ser Cys Thr Thr Pro Asp 
    2290                2295                2300 

Glu Trp Trp Arg Val Thr Gln Ser Tyr Ala Arg Ser Thr Ala Val Met 
2305                2310                2315                2320 

Ser Met Val Gly Tyr Ile Ile Gly Leu Gly Asp Arg His Leu Asp Asn 
                2325                2330                2335 

Val Leu Ile Asp Met Thr Thr Gly Glu Val Val His Ile Asp Tyr Asn 
            2340                2345                2350 

Val Cys Phe Glu Lys Gly Lys Ser Leu Arg Val Pro Glu Lys Val Pro 
        2355                2360                2365 

Phe Arg Met Thr Gln Asn Ile Glu Thr Ala Leu Gly Val Thr Gly Val 
    2370                2375                2380 

Glu Gly Val Phe Arg Leu Ser Cys Glu Gln Val Leu His Ile Met Arg 
2385                2390                2395                2400 

Arg Gly Arg Glu Thr Leu Leu Thr Leu Leu Glu Ala Phe Val Tyr Asp 
                2405                2410                2415 

Pro Leu Val Asp Trp Thr Ala Gly Gly Glu Ala Gly Phe Ala Gly Ala 
            2420                2425                2430 

Val Tyr Gly Gly Gly Gly Gln Gln Ala Glu Ser Lys Gln Ser Lys Arg 
        2435                2440                2445 

Glu Met Glu Arg Glu Ile Thr Arg Ser Leu Phe Ser Ser Arg Val Ala 
    2450                2455                2460 

Glu Ile Lys Val Asn Trp Phe Lys Asn Arg Asp Glu Met Leu Val Val 
2465                2470                2475                2480 

Leu Pro Lys Leu Asp Gly Ser Leu Asp Glu Tyr Leu Ser Leu Gln Glu 
                2485                2490                2495 

Gln Leu Thr Asp Val Glu Lys Leu Gln Gly Lys Leu Leu Glu Glu Ile 
            2500                2505                2510 

Glu Phe Leu Glu Gly Ala Glu Gly Val Asp His Pro Ser His Thr Leu 
        2515                2520                2525 

Gln His Arg Tyr Ser Glu His Thr Gln Leu Gln Thr Gln Gln Arg Ala 
    2530                2535                2540 

Val Gln Glu Ala Ile Gln Val Lys Leu Asn Glu Phe Glu Gln Trp Ile 
2545                2550                2555                2560 

Thr His Tyr Gln Ala Ala Phe Asn Asn Leu Glu Ala Thr Gln Leu Ala 
                2565                2570                2575 

Ser Leu Leu Gln Glu Ile Ser Thr Gln Met Asp Leu Gly Pro Pro Ser 
            2580                2585                2590 

Tyr Val Pro Ala Thr Ala Phe Leu Gln Asn Ala Gly Gln Ala His Leu 
        2595                2600                2605 

Ile Ser Gln Cys Glu Gln Leu Glu Gly Glu Val Gly Ala Leu Leu Gln 
    2610                2615                2620 

Gln Arg Arg Ser Val Leu Arg Gly Cys Leu Glu Gln Leu His His Tyr 
2625                2630                2635                2640 

Ala Thr Val Ala Leu Gln Tyr Pro Lys Ala Ile Phe Gln Lys His Arg 
                2645                2650                2655 

Ile Glu Gln Trp Lys Thr Trp Met Glu Glu Leu Ile Cys Asn Thr Thr 
            2660                2665                2670 

Val Glu Arg Cys Gln Glu Leu Tyr Arg Lys Tyr Glu Met Gln Tyr Ala 
        2675                2680                2685 

Pro Gln Pro Pro Pro Thr Val Cys Gln Phe Ile Thr Ala Thr Glu Met 
    2690                2695                2700 

Thr Leu Gln Arg Tyr Ala Ala Asp Ile Asn Ser Arg Leu Ile Arg Gln 
2705                2710                2715                2720 

Val Glu Arg Leu Lys Gln Glu Ala Val Thr Val Pro Val Cys Glu Asp 
                2725                2730                2735 

Gln Leu Lys Glu Ile Glu Arg Cys Ile Lys Val Phe Leu His Glu Asn 
            2740                2745                2750 

Gly Glu Glu Gly Ser Leu Ser Leu Ala Ser Val Ile Ile Ser Ala Leu 
        2755                2760                2765 

Cys Thr Leu Thr Arg Arg Asn Leu Met Met Glu Gly Ala Ala Ser Ser 
    2770                2775                2780 

Ala Gly Glu Gln Leu Val Asp Leu Thr Ser Arg Asp Gly Ala Trp Phe 
2785                2790                2795                2800 

Leu Glu Glu Leu Cys Ser Met Ser Gly Asn Val Thr Cys Leu Val Gln 
                2805                2810                2815 

Leu Leu Lys Gln Cys His Leu Val Pro Gln Asp Leu Asp Ile Pro Asn 
            2820                2825                2830 

Pro Met Glu Ala Ser Glu Thr Val His Leu Ala Asn Gly Val Tyr Thr 
        2835                2840                2845 

Ser Leu Gln Glu Leu Asn Ser Asn Phe Arg Gln Ile Ile Phe Pro Glu 
    2850                2855                2860 

Ala Leu Arg Cys Leu Met Lys Gly Glu Tyr Thr Leu Glu Ser Met Leu 
2865                2870                2875                2880 

His Glu Leu Asp Gly Leu Ile Glu Gln Thr Thr Asp Gly Val Pro Leu 
                2885                2890                2895 

Gln Thr Leu Val Glu Ser Leu Gln Ala Tyr Leu Arg Asn Ala Ala Met 
            2900                2905                2910 

Gly Leu Glu Glu Glu Thr His Ala His Tyr Ile Asp Val Ala Arg Leu 
        2915                2920                2925 

Leu His Ala Gln Tyr Gly Glu Leu Ile Gln Pro Arg Asn Gly Ser Val 
    2930                2935                2940 

Asp Glu Thr Pro Lys Met Ser Ala Gly Gln Met Leu Leu Val Ala Phe 
2945                2950                2955                2960 

Asp Gly Met Phe Ala Gln Val Glu Thr Ala Phe Ser Leu Leu Val Glu 
                2965                2970                2975 

Lys Leu Asn Lys Met Glu Ile Pro Ile Ala Trp Arg Lys Ile Asp Ile 
            2980                2985                2990 

Ile Arg Glu Ala Arg Ser Thr Gln Val Asn Phe Phe Asp Asp Asp Asn 
        2995                3000                3005 

His Arg Gln Val Leu Glu Glu Ile Phe Phe Leu Lys Arg Leu Gln Thr 
    3010                3015                3020 

Ile Lys Glu Phe Phe Arg Leu Cys Gly Thr Phe Ser Lys Thr Leu Ser 
3025                3030                3035                3040 

Gly Ser Ser Ser Leu Glu Asp Gln Asn Thr Val Asn Gly Pro Val Gln 
                3045                3050                3055 

Ile Val Asn Val Lys Thr Leu Phe Arg Asn Ser Cys Phe Ser Glu Asp 
            3060                3065                3070 

Gln Met Ala Lys Pro Ile Lys Ala Phe Thr Ala Asp Phe Val Arg Gln 
        3075                3080                3085 

Leu Leu Ile Gly Leu Pro Asn Gln Ala Leu Gly Leu Thr Leu Cys Ser 
    3090                3095                3100 

Phe Ile Ser Ala Leu Gly Val Asp Ile Ile Ala Gln Val Glu Ala Lys 
3105                3110                3115                3120 

Asp Phe Gly Ala Glu Ser Lys Val Ser Val Asp Asp Leu Cys Lys Lys 
                3125                3130                3135 

Ala Val Glu His Asn Ile Gln Ile Gly Lys Phe Ser Gln Leu Val Met 
            3140                3145                3150 

Asn Arg Ala Thr Val Leu Ala Ser Ser Tyr Asp Thr Ala Trp Lys Lys 
        3155                3160                3165 

His Asp Leu Val Arg Arg Leu Glu Thr Ser Ile Ser Ser Cys Lys Thr 
    3170                3175                3180 

Ser Leu Gln Arg Val Gln Leu His Ile Ala Met Phe Gln Trp Gln His 
3185                3190                3195                3200 

Glu Asp Leu Leu Ile Asn Arg Pro Gln Ala Met Ser Val Thr Pro Pro 
                3205                3210                3215 

Pro Arg Ser Ala Ile Leu Thr Ser Met Lys Lys Lys Leu His Thr Leu 
            3220                3225                3230 

Ser Gln Ile Glu Thr Ser Ile Ala Thr Val Gln Glu Lys Leu Ala Ala 
        3235                3240                3245 

Leu Glu Ser Ser Ile Glu Gln Arg Leu Lys Trp Ala Gly Gly Ala Asn 
    3250                3255                3260 

Pro Ala Leu Ala Pro Val Leu Gln Asp Phe Glu Ala Thr Ile Ala Glu 
3265                3270                3275                3280 

Arg Arg Asn Leu Val Leu Lys Glu Ser Gln Arg Ala Ser Gln Val Thr 
                3285                3290                3295 

Phe Leu Cys Ser Asn Ile Ile His Phe Glu Ser Leu Arg Thr Arg Thr 
            3300                3305                3310 

Ala Glu Ala Leu Asn Leu Asp Ala Ala Leu Phe Glu Leu Ile Lys Arg 
        3315                3320                3325 

Cys Gln Gln Met Cys Ser Phe Ala Ser Gln Phe Asn Ser Ser Val Ser 
    3330                3335                3340 

Glu Leu Glu Leu Arg Leu Leu Gln Arg Val Asp Thr Gly Leu Glu His 
3345                3350                3355                3360 

Pro Ile Gly Ser Ser Glu Trp Leu Leu Ser Ala His Lys Gln Leu Thr 
                3365                3370                3375 

Gln Asp Met Ser Thr Gln Arg Ala Ile Gln Thr Glu Lys Glu Gln Gln 
            3380                3385                3390 

Ile Glu Thr Val Cys Glu Thr Ile Gln Asn Leu Val Asp Asn Ile Lys 
        3395                3400                3405 

Thr Val Leu Thr Gly His Asn Arg Gln Leu Gly Asp Val Lys His Leu 
    3410                3415                3420 

Leu Lys Ala Met Ala Lys Asp Glu Glu Ala Ala Leu Ala Asp Gly Glu 
3425                3430                3435                3440 

Asp Val Pro Tyr Glu Asn Ser Val Arg Gln Phe Leu Gly Glu Tyr Lys 
                3445                3450                3455 

Ser Trp Gln Asp Asn Ile Gln Thr Val Leu Phe Thr Leu Val Gln Ala 
            3460                3465                3470 

Met Gly Gln Val Arg Ser Gln Glu His Val Glu Met Leu Gln Glu Ile 
        3475                3480                3485 

Thr Pro Thr Leu Lys Glu Leu Lys Thr Gln Ser Gln Ser Ile Tyr Asn 
    3490                3495                3500 

Asn Leu Val Ser Phe Ala Ser Pro Leu Val Thr Asp Ala Thr Asn Glu 
3505                3510                3515                3520 

Cys Ser Ser Pro Thr Ser Ser Ala Thr Tyr Gln Pro Ser Phe Ala Ala 
                3525                3530                3535 

Ala Val Arg Ser Asn Thr Gly Gln Lys Thr Gln Pro Asp Val Met Ser 
            3540                3545                3550 

Gln Asn Ala Arg Lys Leu Ile Gln Lys Asn Leu Ala Thr Ser Ala Asp 
        3555                3560                3565 

Thr Pro Pro Ser Thr Val Pro Gly Thr Gly Lys Ser Val Ala Cys Ser 
    3570                3575                3580 

Pro Lys Lys Ala Val Arg Asp Pro Lys Thr Gly Lys Ala Val Gln Glu 
3585                3590                3595                3600 

Arg Asn Ser Tyr Ala Val Ser Val Trp Lys Arg Val Lys Ala Lys Leu 
                3605                3610                3615 

Glu Gly Arg Asp Val Asp Pro Asn Arg Arg Met Ser Val Ala Glu Gln 
            3620                3625                3630 

Val Asp Tyr Val Ile Lys Glu Ala Thr Asn Leu Asp Asn Leu Ala Gln 
        3635                3640                3645 

Leu Tyr Glu Gly Trp Thr Ala Trp Val 
    3650                3655 

 
           
             11  
             20  
             DNA  
             Artificial Sequence  
             
               synthetic oligonucleotide  
             
           
            11 

agcaagctcc ctcctgtctc                                                 20