Patent Publication Number: US-2003228595-A1

Title: Isolated human kinase proteins, nucleic acid molecules encoding human kinase proteins, and uses thereof

Description:
FIELD OF THE INVENTION  
       [0001] The present invention is in the field of kinase proteins that are related to the serine/threonine protein kinase subfamily, recombinant DNA molecules, and protein production. The present invention specifically provides novel peptides and proteins that effect protein phosphorylation and nucleic acid molecules encoding such peptide and protein molecules, all of which are useful in the development of human therapeutics and diagnostic compositions and methods.  
       BACKGROUND OF THE INVENTION  
       [0002] Protein Kinases  
       [0003] Kinases regulate many different cell proliferation, differentiation, and signaling processes by adding phosphate groups to proteins. Uncontrolled signaling has been implicated in a variety of disease conditions including inflammation, cancer, arteriosclerosis, and psoriasis. Reversible protein phosphorylation is the main strategy for controlling activities of eukaryotic cells. It is estimated that more than 1000 of the 10,000 proteins active in a typical mammalian cell are phosphorylated. The high-energy phosphate, which drives activation, is generally transferred from adenosine triphosphate molecules (ATP) to a particular protein by protein kinases and removed from that protein by protein phosphatases. Phosphorylation occurs in response to extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc), cell cycle checkpoints, and environmental or nutritional stresses and is roughly analogous to turning on a molecular switch. When the switch goes on, the appropriate protein kinase activates a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor.  
       [0004] The kinases comprise the largest known protein group, a superfamily of enzymes with widely varied functions and specificities. They are usually named after their substrate, their regulatory molecules, or some aspect of a mutant phenotype. With regard to substrates, the protein kinases may be roughly divided into two groups; those that phosphorylate tyrosine residues (protein tyrosine kinases, PTK) and those that phosphorylate serine or threonine residues (serine/threonine kinases, STK). A few protein kinases have dual specificity and phosphorylate threonine and tyrosine residues. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The N-terminal domain, which contains subdomains I-IV, generally folds into a two-lobed structure, which binds and orients the ATP (or GTP) donor molecule. The larger C terminal lobe, which contains subdomains VI A-XI, binds the protein substrate and carries out the transfer of the gamma phosphate from ATP to the hydroxyl group of a serine, threonine, or tyrosine residue. Subdomain V spans the two lobes.  
       [0005] The kinases may be categorized into families by the different amino acid sequences (generally between 5 and 100 residues) located on either side of, or inserted into loops of, the kinase domain. These added amino acid sequences allow the regulation of each kinase as it recognizes and interacts with its target protein. The primary structure of the kinase domains is conserved and can be further subdivided into 11 subdomains. Each of the 11 subdomains contains specific residues and motifs or patterns of amino acids that are characteristic of that subdomain and are highly conserved (Hardie, G. and Hanks, S. (1995)  The Protein Kinase Facts Books , Vol I:7-20 Academic Press, San Diego, Calif.).  
       [0006] The second messenger dependent protein kinases primarily mediate the effects of second messengers such as cyclic AMP (cAMP), cyclic GMP, inositol triphosphate, phosphatidylinositol, 3,4,5-triphosphate, cyclic-ADPribose, arachidonic acid, diacylglycerol and calcium-calmodulin. The cyclic-AMP dependent protein kinases (PKA) are important members of the STK family. Cyclic-AMP is an intracellular mediator of hormone action in all prokaryotic and animal cells that have been studied. Such hormone-induced cellular responses include thyroid hormone secretion, cortisol secretion, progesterone secretion, glycogen breakdown, bone resorption, and regulation of heart rate and force of heart muscle contraction. PKA is found in all animal cells and is thought to account for the effects of cyclic-AMP in most of these cells. Altered PKA expression is implicated in a variety of disorders and diseases including cancer, thyroid disorders, diabetes, atherosclerosis, and cardiovascular disease (Isselbacher, K. J. et al. (1994)  Harrison&#39;s Principles of Internal Medicine , McGraw-Hill, New York, N.Y., pp. 416-431, 1887).  
       [0007] Calcium-calmodulin (CaM) dependent protein kinases are also members of STK family. Calmodulin is a calcium receptor that mediates many calcium regulated processes by binding to target proteins in response to the binding of calcium. The principle target protein in these processes is CaM dependent protein kinases. CaM-kinases are involved in regulation of smooth muscle contraction (MLC kinase), glycogen breakdown (phosphorylase kinase), and neurotransmission (CaM kinase I and CaM kinase II). CaM kinase I phosphorylates a variety of substrates including the neurotransmitter related proteins synapsin I and II, the gene transcription regulator, CREB, and the cystic fibrosis conductance regulator protein, CFTR (Haribabu, B. et al. (1995)  EMBO Journal  14:3679-86). CaM II kinase also phosphorylates synapsin at different sites, and controls the synthesis of catecholamines in the brain through phosphorylation and activation of tyrosine hydroxylase. Many of the CaM kinases are activated by phosphorylation in addition to binding to CaM. The kinase may autophosphorylate itself, or be phosphorylated by another kinase as part of a “kinase cascade”.  
       [0008] Another ligand-activated protein kinase is 5′-AMP-activated protein kinase (AMPK) (Gao, G. et al. (1996)  J. Biol. Chem.  15:8675-81). Mammalian AMPK is a regulator of fatty acid and sterol synthesis through phosphorylation of the enzymes acetyl-CoA carboxylase and hydroxymethylglutaryl-CoA reductase and mediates responses of these pathways to cellular stresses such as heat shock and depletion of glucose and ATP. AMPK is a heterotrimeric complex comprised of a catalytic alpha subunit and two non-catalytic beta and gamma subunits that are believed to regulate the activity of the alpha subunit. Subunits of AMPK have a much wider distribution in non-lipogenic tissues such as brain, heart, spleen, and lung than expected. This distribution suggests that its role may extend beyond regulation of lipid metabolism alone.  
       [0009] The mitogen-activated protein kinases (MAP) are also members of the STK family. MAP kinases also regulate intracellular signaling pathways. They mediate signal transduction from the cell surface to the nucleus via phosphorylation cascades. Several subgroups have been identified, and each manifests different substrate specificities and responds to distinct extracellular stimuli (Egan, S. E. and Weinberg, R. A. (1993)  Nature  365:781-783). MAP kinase signaling pathways are present in mammalian cells as well as in yeast. The extracellular stimuli that activate mammalian pathways include epidermal growth factor (EGF), ultraviolet light, hyperosmolar medium, heat shock, endotoxic lipopolysaccharide (LPS), and pro-inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1(IL-1).  
       [0010] PRK (proliferation-related kinase) is a serum/cytokine inducible STK that is involved in regulation of the cell cycle and cell proliferation in human megakaroytic cells (Li, B. et al. (1996)  J. Biol. Chem.  271:19402-8). PRK is related to the polo (derived from humans polo gene) family of STKs implicated in cell division. PRK is downregulated in lung tumor tissue and may be a proto-oncogene whose deregulated expression in normal tissue leads to oncogenic transformation. Altered MAP kinase expression is implicated in a variety of disease conditions including cancer, inflammation, immune disorders, and disorders affecting growth and development.  
       [0011] The cyclin-dependent protein kinases (CDKs) are another group of STKs that control the progression of cells through the cell cycle. Cyclins are small regulatory proteins that act by binding to and activating CDKs that then trigger various phases of the cell cycle by phosphorylating and activating selected proteins involved in the mitotic process. CDKs are unique in that they require multiple inputs to become activated. In addition to the binding of cyclin, CDK activation requires the phosphorylation of a specific threonine residue and the dephosphorylation of a specific tyrosine residue.  
       [0012] Protein tyrosine kinases, PTKs, specifically phosphorylate tyrosine residues on their target proteins and may be divided into transmembrane, receptor PTKs and nontransmembrane, non-receptor PTKs. Transmembrane protein-tyrosine kinases are receptors for most growth factors. Binding of growth factor to the receptor activates the transfer of a phosphate group from ATP to selected tyrosine side chains of the receptor and other specific proteins. Growth factors (GF) associated with receptor PTKs include; epidermal GF, platelet-derived GF, fibroblast GF, hepatocyte GF, insulin and insulin-like GFs, nerve GF, vascular endothelial GF, and macrophage colony stimulating factor.  
       [0013] Non-receptor PTKs lack transmembrane regions and, instead, form complexes with the intracellular regions of cell surface receptors. Such receptors that function through non-receptor PTKs include those for cytokines, hormones (growth hormone and prolactin) and antigen-specific receptors on T and B lymphocytes.  
       [0014] Many of these PTKs were first identified as the products of mutant oncogenes in cancer cells where their activation was no longer subject to normal cellular controls. In fact, about one third of the known oncogenes encode PTKs, and it is well known that cellular transformation (oncogenesis) is often accompanied by increased tyrosine phosphorylation activity (Carbonneau H and Tonks N K (1992)  Annu. Rev. Cell. Biol.  8:463-93). Regulation of PTK activity may therefore be an important strategy in controlling some types of cancer.  
       [0015] Serine/Threonine Protein Kinases  
       [0016] The novel human protein, and encoding gene, provided by the present invention is related to the serine/threonine protein kinase subfamily, and shows the highest degree of similarity to striated muscle-specific serine/threonine protein kinases.  
       [0017] At least four isoforms related to striated muscle-specific serine/threonine protein kinases have been identified in the art: a 1.4-kb mRNA (aortic preferentially expressed gene (APEG)-1) expressed in vascular smooth muscle cells and down-regulated by vascular injury; 9-kb striated preferentially expressed gene (SPEG)alpha and 11-kb SPEGbeta, both of which are expressed in skeletal muscle and heart; and a 4-kb brain preferentially expressed gene (BPEG), which is expressed in the brain and aorta. All four isoforms share the middle three of the five exons of APEG-1 but have different alternative spliced 5′- and 3′-ends (Hsieh et al.,  J. Biol. Chem.  275 (47), 36966-36973 (2000)). SPEGbeta contains two serine/threonine kinase domains and is homologous to myosin light chain kinase proteins. At least one of the kinase domains in SPEGbeta is active and able to autophosphorylate (Hsieh et al.,  J. Biol. Chem.  275 (47), 36966-36973 (2000)). Hsieh et al ( J. Biol. Chem.  275 (47), 36966-36973 (2000)) showed that expression of SPEGalpha and SPEGbeta is developmentally regulated in the striated muscle during C2C12 myoblast to myotube differentiation in vitro and cardiomyocyte maturation in vivo. Hsieh et al suggested that this developmental regulation indicates that both SPEGalpha and SPEGbeta can serve as sensitive markers for striated muscle differentiation and that both SPEGalpha and SPEGbeta may play important roles in adult striated muscle function.  
       [0018] Kinase proteins, particularly members of the serine/threonine protein kinase subfamily, are a major target for drug action and development. Accordingly, it is valuable to the field of pharmaceutical development to identify and characterize previously unknown members of this subfamily of kinase proteins. The present invention advances the state of the art by providing previously unidentified human kinase proteins that have homology to members of the serine/threonine protein kinase subfamily.  
       SUMMARY OF THE INVENTION  
       [0019] The present invention is based in part on the identification of amino acid sequences of human kinase peptides and proteins that are related to the serine/threonine protein kinase subfamily, as well as allelic variants and other mammalian orthologs thereof. These unique peptide sequences, and nucleic acid sequences that encode these peptides, can be used as models for the development of human therapeutic targets, aid in the identification of therapeutic proteins, and serve as targets for the development of human therapeutic agents that modulate kinase activity in cells and tissues that express the kinase. Experimental data as provided in FIG. 1 indicates expression in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin). 
     
    
    
     DESCRIPTION OF THE FIGURE SHEETS  
     [0020]FIG. 1 provides the nucleotide sequence of a transcript sequence that encodes the kinase protein of the present invention. (SEQ ID NO:1) In addition, structure and functional information is provided, such as ATG start, stop and tissue distribution, where available, that allows one to readily determine specific uses of inventions based on this molecular sequence. Experimental data as provided in FIG. 1 indicates expression in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin).  
     [0021]FIG. 2 provides the predicted amino acid sequence of the kinase of the present invention. (SEQ ID NO:2) In addition structure and functional information such as protein family, function, and modification sites is provided where available, allowing one to readily determine specific uses of inventions based on this molecular sequence.  
     [0022]FIG. 3 provides genomic sequences that span the gene encoding the kinase protein of the present invention. (SEQ ID NO:3) In addition structure and functional information, such as intron/exon structure, promoter location, etc., is provided where available, allowing one to readily determine specific uses of inventions based on this molecular sequence. As illustrated in FIG. 3, SNPs were identified at 39 different nucleotide positions, including 2 non-synonymous coding SNPs.  
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
     [0023] General Description The present invention is based on the sequencing of the human genome. During the sequencing and assembly of the human genome, analysis of the sequence information revealed previously unidentified fragments of the human genome that encode peptides that share structural and/or sequence homology to protein/peptide/domains identified and characterized within the art as being a kinase protein or part of a kinase protein and are related to the serine/threonine protein kinase subfamily. Utilizing these sequences, additional genomic sequences were assembled and transcript and/or cDNA sequences were isolated and characterized. Based on this analysis, the present invention provides amino acid sequences of human kinase peptides and proteins that are related to the serine/threonine protein kinase subfamily, nucleic acid sequences in the form of transcript sequences, cDNA sequences and/or genomic sequences that encode these kinase peptides and proteins, nucleic acid variation (allelic information), tissue distribution of expression, and information about the closest art known protein/peptide/domain that has structural or sequence homology to the kinase of the present invention.  
     [0024] In addition to being previously unknown, the peptides that are provided in the present invention are selected based on their ability to be used for the development of commercially important products and services. Specifically, the present peptides are selected based on homology and/or structural relatedness to known kinase proteins of the serine/threonine protein kinase subfamily and the expression pattern observed. Experimental data as provided in FIG. 1 indicates expression in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin). The art has clearly established the commercial importance of members of this family of proteins and proteins that have expression patterns similar to that of the present gene. Some of the more specific features of the peptides of the present invention, and the uses thereof, are described herein, particularly in the Background of the Invention and in the annotation provided in the Figures, and/or are known within the art for each of the known serine/threonine protein kinase family or subfamily of kinase proteins.  
     [0025] Specific Embodiments  
     [0026] Peptide Molecules  
     [0027] The present invention provides nucleic acid sequences that encode protein molecules that have been identified as being members of the kinase family of proteins and are related to the serine/threonine protein kinase subfamily (protein sequences are provided in FIG. 2, transcript/cDNA sequences are provided in FIG. 1 and genomic sequences are provided in FIG. 3). The peptide sequences provided in FIG. 2, as well as the obvious variants described herein, particularly allelic variants as identified herein and using the information in FIG. 3, will be referred herein as the kinase peptides of the present invention, kinase peptides, or peptides/proteins of the present invention.  
     [0028] The present invention provides isolated peptide and protein molecules that consist of, consist essentially of, or comprise the amino acid sequences of the kinase peptides disclosed in the FIG. 2, (encoded by the nucleic acid molecule shown in FIG. 1, transcript/cDNA or FIG. 3, genomic sequence), as well as all obvious variants of these peptides that are within the art to make and use. Some of these variants are described in detail below.  
     [0029] As used herein, a peptide is said to be “isolated” or “purified” when it is substantially free of cellular material or free of chemical precursors or other chemicals. The peptides of the present invention can be purified to homogeneity or other degrees of purity. The level of purification will be based on the intended use. The critical feature is that the preparation allows for the desired function of the peptide, even if in the presence of considerable amounts of other components (the features of an isolated nucleic acid molecule is discussed below).  
     [0030] In some uses, “substantially free of cellular material” includes preparations of the peptide having less than about 30% (by dry weight) other proteins (i.e., contaminating protein), less than about 20% other proteins, less than about 10% other proteins, or less than about 5% other proteins. When the peptide is recombinantly produced, it can also be substantially free of culture medium, i.e., culture medium represents less than about 20% of the volume of the protein preparation.  
     [0031] The language “substantially free of chemical precursors or other chemicals” includes preparations of the peptide in which it is separated from chemical precursors or other chemicals that are involved in its synthesis. In one embodiment, the language “substantially free of chemical precursors or other chemicals” includes preparations of the kinase peptide having less than about 30% (by dry weight) chemical precursors or other chemicals, less than about 20% chemical precursors or other chemicals, less than about 10% chemical precursors or other chemicals, or less than about 5% chemical precursors or other chemicals.  
     [0032] The isolated kinase peptide can be purified from cells that naturally express it, purified from cells that have been altered to express it (recombinant), or synthesized using known protein synthesis methods. Experimental data as provided in FIG. 1 indicates expression in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin). For example, a nucleic acid molecule encoding the kinase peptide is cloned into an expression vector, the expression vector introduced into a host cell and the protein expressed in the host cell. The protein can then be isolated from the cells by an appropriate purification scheme using standard protein purification techniques. Many of these techniques are described in detail below.  
     [0033] Accordingly, the present invention provides proteins that consist of the amino acid sequences provided in FIG. 2 (SEQ ID NO:2), for example, proteins encoded by the transcript/cDNA nucleic acid sequences shown in FIG. 1 (SEQ ID NO:1) and the genomic sequences provided in FIG. 3 (SEQ ID NO:3). The amino acid sequence of such a protein is provided in FIG. 2. A protein consists of an amino acid sequence when the amino acid sequence is the final amino acid sequence of the protein.  
     [0034] The present invention further provides proteins that consist essentially of the amino acid sequences provided in FIG. 2 (SEQ ID NO:2), for example, proteins encoded by the transcript/cDNA nucleic acid sequences shown in FIG. 1 (SEQ ID NO:1) and the genomic sequences provided in FIG. 3 (SEQ ID NO:3). A protein consists essentially of an amino acid sequence when such an amino acid sequence is present with only a few additional amino acid residues, for example from about 1 to about 100 or so additional residues, typically from 1 to about 20 additional residues in the final protein.  
     [0035] The present invention further provides proteins that comprise the amino acid sequences provided in FIG. 2 (SEQ ID NO:2), for example, proteins encoded by the transcript/cDNA nucleic acid sequences shown in FIG. 1 (SEQ ID NO:1) and the genomic sequences provided in FIG. 3 (SEQ ID NO:3). A protein comprises an amino acid sequence when the amino acid sequence is at least part of the final amino acid sequence of the protein. In such a fashion, the protein can be only the peptide or have additional amino acid molecules, such as amino acid residues (contiguous encoded sequence) that are naturally associated with it or heterologous amino acid residues/peptide sequences. Such a protein can have a few additional amino acid residues or can comprise several hundred or more additional amino acids. The preferred classes of proteins that are comprised of the kinase peptides of the present invention are the naturally occurring mature proteins. A brief description of how various types of these proteins can be made/isolated is provided below.  
     [0036] The kinase peptides of the present invention can be attached to heterologous sequences to form chimeric or fusion proteins. Such chimeric and fusion proteins comprise a kinase peptide operatively linked to a heterologous protein having an amino acid sequence not substantially homologous to the kinase peptide. “Operatively linked” indicates that the kinase peptide and the heterologous protein are fused in-frame. The heterologous protein can be fused to the N-terminus or C-terminus of the kinase peptide.  
     [0037] In some uses, the fusion protein does not affect the activity of the kinase peptide per se. For example, the fusion protein can include, but is not limited to, enzymatic fusion proteins, for example beta-galactosidase fusions, yeast two-hybrid GAL fusions, poly-His fusions, MYC-tagged, HI-tagged and Ig fusions. Such fusion proteins, particularly poly-His fusions, can facilitate the purification of recombinant kinase peptide. In certain host cells (e.g., mammalian host cells), expression and/or secretion of a protein can be increased by using a heterologous signal sequence.  
     [0038] A chimeric or fusion protein can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different protein sequences are ligated together in-frame in accordance with conventional techniques. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and re-amplified to generate a chimeric gene sequence (see Ausubel et al.,  Current Protocols in Molecular Biology,  1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST protein). A kinase peptide-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the kinase peptide.  
     [0039] As mentioned above, the present invention also provides and enables obvious variants of the amino acid sequence of the proteins of the present invention, such as naturally occurring mature forms of the peptide, allelic/sequence variants of the peptides, non-naturally occurring recombinantly derived variants of the peptides, and orthologs and paralogs of the peptides. Such variants can readily be generated using art-known techniques in the fields of recombinant nucleic acid technology and protein biochemistry. It is understood, however, that variants exclude any amino acid sequences disclosed prior to the invention.  
     [0040] Such variants can readily be identified/made using molecular techniques and the sequence information disclosed herein. Further, such variants can readily be distinguished from other peptides based on sequence and/or structural homology to the kinase peptides of the present invention. The degree of homology/identity present will be based primarily on whether the peptide is a functional variant or non-functional variant, the amount of divergence present in the paralog family and the evolutionary distance between the orthologs.  
     [0041] To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of the length of a reference sequence is aligned for comparison purposes. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.  
     [0042] The comparison of sequences and determination of percent identity and similarity between two sequences can be accomplished using a mathematical algorithm. ( Computational Molecular Biology , Lesk, A. M., ed., Oxford University Press, New York, 1988;  Biocomputing: Informatics and Genome Projects , Smith, D. W., ed., Academic Press, New York, 1993;  Computer Analysis of Sequence Data, Part  1, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994;  Sequence Analysis in Molecular Biology , von Heinje, G., Academic Press, 1987; and  Sequence Analysis Primer , Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991). In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ( J. Mol. Biol.  (48):444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://www.gcg.com), using either a Blossom 62 matrix or a PAM 250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (Devereux, J., et al.,  Nucleic Acids Res.  12(1):387 (1984)) (available at http://www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. In another embodiment, the percent identity between two amino acid or nucleotide sequences is determined using the algorithm of E. Myers and W. Miller (CABIOS, 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM 120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.  
     [0043] The nucleic acid and protein sequences of the present invention can further be used as a “query sequence” to perform a search against sequence databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. ( J. Mol. Biol.  215:403-10 (1990)). BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the proteins of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al. ( Nucleic Acids Res.  25(17):3389-3402 (1997)). When utilizing BLAST and gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.  
     [0044] Full-length pre-processed forms, as well as mature processed forms, of proteins that comprise one of the peptides of the present invention can readily be identified as having complete sequence identity to one of the kinase peptides of the present invention as well as being encoded by the same genetic locus as the kinase peptide provided herein. As indicated in FIG. 3, the map position was determined to be on human chromosome 2.  
     [0045] Allelic variants of a kinase peptide can readily be identified as being a human protein having a high degree (significant) of sequence homology/identity to at least a portion of the kinase peptide as well as being encoded by the same genetic locus as the kinase peptide provided herein. Genetic locus can readily be determined based on the genomic information provided in FIG. 3, such as the genomic sequence mapped to the reference human. As indicated in FIG. 3, the map position was determined to be on human chromosome 2. As used herein, two proteins (or a region of the proteins) have significant homology when the amino acid sequences are typically at least about 70-80%, 80-90%, and more typically at least about 90-95% or more homologous. A significantly homologous amino acid sequence, according to the present invention, will be encoded by a nucleic acid sequence that will hybridize to a kinase peptide encoding nucleic acid molecule under stringent conditions as more fully described below.  
     [0046]FIG. 3 provides information on SNPs that have been found in the gene encoding the kinase proteins of the present invention. SNPs were identified at 39 different nucleotide positions, including five SNPs in coding regions, two of which (at nucleotide positions 52048 and 58826) change the encoded amino acid. The changes in the amino acid sequence that these SNPs cause is indicated in FIG. 3 and can readily be determined using the universal genetic code and the protein sequence provided in FIG. 2 as a reference.  
     [0047] Paralogs of a kinase peptide can readily be identified as having some degree of significant sequence homology/identity to at least a portion of the kinase peptide, as being encoded by a gene from humans, and as having similar activity or function. Two proteins will typically be considered paralogs when the amino acid sequences are typically at least about 60% or greater, and more typically at least about 70% or greater homology through a given region or domain. Such paralogs will be encoded by a nucleic acid sequence that will hybridize to a kinase peptide encoding nucleic acid molecule under moderate to stringent conditions as more fully described below.  
     [0048] Orthologs of a kinase peptide can readily be identified as having some degree of significant sequence homology/identity to at least a portion of the kinase peptide as well as being encoded by a gene from another organism. Preferred orthologs will be isolated from mammals, preferably primates, for the development of human therapeutic targets and agents. Such orthologs will be encoded by a nucleic acid sequence that will hybridize to a kinase peptide encoding nucleic acid molecule under moderate to stringent conditions, as more fully described below, depending on the degree of relatedness of the two organisms yielding the proteins.  
     [0049] Non-naturally occurring variants of the kinase peptides of the present invention can readily be generated using recombinant techniques. Such variants include, but are not limited to deletions, additions and substitutions in the amino acid sequence of the kinase peptide. For example, one class of substitutions are conserved amino acid substitution. Such substitutions are those that substitute a given amino acid in a kinase peptide by another amino acid of like characteristics. Typically seen as conservative substitutions are the replacements, one for another, among the aliphatic amino acids Ala, Val, Leu, and Ile; interchange of the hydroxyl residues Ser and Thr; exchange of the acidic residues Asp and Glu; substitution between the amide residues Asn and Gln; exchange of the basic residues Lys and Arg; and replacements among the aromatic residues Phe and Tyr. Guidance concerning which amino acid changes are likely to be phenotypically silent are found in Bowie et al.,  Science  247:1306-1310 (1990).  
     [0050] Variant kinase peptides can be filly functional or can lack function in one or more activities, e.g. ability to bind substrate, ability to phosphorylate substrate, ability to mediate signaling, etc. Fully functional variants typically contain only conservative variation or variation in non-critical residues or in non-critical regions. FIG. 2 provides the result of protein analysis and can be used to identify critical domains/regions. Functional variants can also contain substitution of similar amino acids that result in no change or an insignificant change in function. Alternatively, such substitutions may positively or negatively affect function to some degree.  
     [0051] Non-functional variants typically contain one or more non-conservative amino acid substitutions, deletions, insertions, inversions, or truncation or a substitution, insertion, inversion, or deletion in a critical residue or critical region.  
     [0052] Amino acids that are essential for function can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (Cunningham et al.,  Science  244:1081-1085 (1989)), particularly using the results provided in FIG. 2. The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity such as kinase activity or in assays such as an in vitro proliferative activity. Sites that are critical for binding partner/substrate binding can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith et al.,  J. Mol. Biol.  224:899-904 (1992); de Vos et al.  Science  255:306-312 (1992)).  
     [0053] The present invention further provides fragments of the kinase peptides, in addition to proteins and peptides that comprise and consist of such fragments, particularly those comprising the residues identified in FIG. 2. The fragments to which the invention pertains, however, are not to be construed as encompassing fragments that may be disclosed publicly prior to the present invention.  
     [0054] As used herein, a fragment comprises at least 8, 10, 12, 14, 16, or more contiguous amino acid residues from a kinase peptide. Such fragments can be chosen based on the ability to retain one or more of the biological activities of the kinase peptide or could be chosen for the ability to perform a function, e.g. bind a substrate or act as an immunogen. Particularly important fragments are biologically active fragments, peptides that are, for example, about 8 or more amino acids in length. Such fragments will typically comprise a domain or motif of the kinase peptide, e.g., active site, a transmembrane domain or a substrate-binding domain. Further, possible fragments include, but are not limited to, domain or motif containing fragments, soluble peptide fragments, and fragments containing immunogenic structures. Predicted domains and functional sites are readily identifiable by computer programs well known and readily available to those of skill in the art (e.g., PROSITE analysis). The results of one such analysis are provided in FIG. 2.  
     [0055] Polypeptides often contain amino acids other than the 20 amino acids commonly referred to as the 20 naturally occurring amino acids. Further, many amino acids, including the terminal amino acids, may be modified by natural processes, such as processing and other post-translational modifications, or by chemical modification techniques well known in the art. Common modifications that occur naturally in kinase peptides are described in basic texts, detailed monographs, and the research literature, and they are well known to those of skill in the art (some of these features are identified in FIG. 2).  
     [0056] Known modifications include, but are not limited to, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent crosslinks, formation of cystine, formation of pyroglutamate, formylation, gamma carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination.  
     [0057] Such modifications are well known to those of skill in the art and have been described in great detail in the scientific literature. Several particularly common modifications, glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, for instance, are described in most basic texts, such as  Proteins—Structure and Molecular Properties,  2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993). Many detailed reviews are available on this subject, such as by Wold, F.,  Posttranslational Covalent Modification of Proteins , B. C. Johnson, Ed., Academic Press, New York 1-12 (1983); Seifter et al. ( Meth. Enzymol.  182: 626-646 (1990)) and Rattan et al. ( Ann. N.Y Acad. Sci.  663:48-62 (1992)).  
     [0058] Accordingly, the kinase peptides of the present invention also encompass derivatives or analogs in which a substituted amino acid residue is not one encoded by the genetic code, in which a substituent group is included, in which the mature kinase peptide is fused with another compound, such as a compound to increase the half-life of the kinase peptide (for example, polyethylene glycol), or in which the additional amino acids are fused to the mature kinase peptide, such as a leader or secretory sequence or a sequence for purification of the mature kinase peptide or a pro-protein sequence.  
     [0059] Protein/Peptide Uses  
     [0060] The proteins of the present invention can be used in substantial and specific assays related to the functional information provided in the Figures; to raise antibodies or to elicit another immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the protein (or its binding partner or ligand) in biological fluids; and as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state). Where the protein binds or potentially binds to another protein or ligand (such as, for example, in a kinase-effector protein interaction or kinase-ligand interaction), the protein can be used to identify the binding partner/ligand so as to develop a system to identify inhibitors of the binding interaction. Any or all of these uses are capable of being developed into reagent grade or kit format for commercialization as commercial products.  
     [0061] Methods for performing the uses listed above are well known to those skilled in the art. References disclosing such methods include “Molecular Cloning: A Laboratory Manual”, 2d ed., Cold Spring Harbor Laboratory Press, Sambrook, J., E. F. Fritsch and T. Maniatis eds., 1989, and “Methods in Enzymology: Guide to Molecular Cloning Techniques”, Academic Press, Berger, S. L. and A. R. Kimmel eds., 1987.  
     [0062] The potential uses of the peptides of the present invention are based primarily on the source of the protein as well as the class/action of the protein. For example, kinases isolated from humans and their human/mammalian orthologs serve as targets for identifying agents for use in mammalian therapeutic applications, e.g. a human drug, particularly in modulating a biological or pathological response in a cell or tissue that expresses the kinase. Experimental data as provided in FIG. 1 indicates that kinase proteins of the present invention are expressed in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin), as indicated by virtual northern blot analysis. A large percentage of pharmaceutical agents are being developed that modulate the activity of kinase proteins, particularly members of the serine/threonine protein kinase subfamily (see Background of the Invention). The structural and functional information provided in the Background and Figures provide specific and substantial uses for the molecules of the present invention, particularly in combination with the expression information provided in FIG. 1. Experimental data as provided in FIG. 1 indicates expression in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin). Such uses can readily be determined using the information provided herein, that which is known in the art, and routine experimentation.  
     [0063] The proteins of the present invention (including variants and fragments that may have been disclosed prior to the present invention) are useful for biological assays related to kinases that are related to members of the serine/threonine protein kinase subfamily. Such assays involve any of the known kinase functions or activities or properties useful for diagnosis and treatment of kinase-related conditions that are specific for the subfamily of kinases that the one of the present invention belongs to, particularly in cells and tissues that express the kinase. Experimental data as provided in FIG. 1 indicates that kinase proteins of the present invention are expressed in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin), as indicated by virtual northern blot analysis.  
     [0064] The proteins of the present invention are also useful in drug screening assays, in cell-based or cell-free systems. Cell-based systems can be native, i.e., cells that normally express the kinase, as a biopsy or expanded in cell culture. Experimental data as provided in FIG. 1 indicates expression in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin). In an alternate embodiment, cell-based assays involve recombinant host cells expressing the kinase protein.  
     [0065] The polypeptides can be used to identify compounds that modulate kinase activity of the protein in its natural state or an altered form that causes a specific disease or pathology associated with the kinase. Both the kinases of the present invention and appropriate variants and fragments can be used in high-throughput screens to assay candidate compounds for the ability to bind to the kinase. These compounds can be further screened against a functional kinase to determine the effect of the compound on the kinase activity. Further, these compounds can be tested in animal or invertebrate systems to determine activity/effectiveness. Compounds can be identified that activate (agonist) or inactivate (antagonist) the kinase to a desired degree.  
     [0066] Further, the proteins of the present invention can be used to screen a compound for the ability to stimulate or inhibit interaction between the kinase protein and a molecule that normally interacts with the kinase protein, e.g. a substrate or a component of the signal pathway that the kinase protein normally interacts (for example, another kinase). Such assays typically include the steps of combining the kinase protein with a candidate compound under conditions that allow the kinase protein, or fragment, to interact with the target molecule, and to detect the formation of a complex between the protein and the target or to detect the biochemical consequence of the interaction with the kinase protein and the target, such as any of the associated effects of signal transduction such as protein phosphorylation, cAMP turnover, and adenylate cyclase activation, etc.  
     [0067] Candidate compounds include, for example, 1) peptides such as soluble peptides, including Ig-tailed fusion peptides and members of random peptide libraries (see, e.g., Lam et al.,  Nature  354:82-84 (1991); Houghten et al,  Nature  354:84-86 (1991)) and combinatorial chemistry-derived molecular libraries made of D- and/or L-configuration amino acids; 2) phosphopeptides (e.g., members of random and partially degenerate, directed phosphopeptide libraries, see, e.g., Songyang et al.,  Cell  72:767-778 (1993)); 3) antibodies (e.g., polyclonal, monoclonal, humanized, anti-idiotypic, chimeric, and single chain antibodies as well as Fab, F(ab′) 2 , Fab expression library fragments, and epitope-binding fragments of antibodies); and 4) small organic and inorganic molecules (e.g., molecules obtained from combinatorial and natural product libraries).  
     [0068] One candidate compound is a soluble fragment of the receptor that competes for substrate binding. Other candidate compounds include mutant kinases or appropriate fragments containing mutations that affect kinase function and thus compete for substrate. Accordingly, a fragment that competes for substrate, for example with a higher affinity, or a fragment that binds substrate but does not allow release, is encompassed by the invention.  
     [0069] The invention further includes other end point assays to identify compounds that modulate (stimulate or inhibit) kinase activity. The assays typically involve an assay of events in the signal transduction pathway that indicate kinase activity. Thus, the phosphorylation of a substrate, activation of a protein, a change in the expression of genes that are up- or down-regulated in response to the kinase protein dependent signal cascade can be assayed.  
     [0070] Any of the biological or biochemical functions mediated by the kinase can be used as an endpoint assay. These include all of the biochemical or biochemical/biological events described herein, in the references cited herein, incorporated by reference for these endpoint assay targets, and other functions known to those of ordinary skill in the art or that can be readily identified using the information provided in the Figures, particularly FIG. 2. Specifically, a biological function of a cell or tissues that expresses the kinase can be assayed. Experimental data as provided in FIG. 1 indicates that kinase proteins of the present invention are expressed in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin), as indicated by virtual northern blot analysis.  
     [0071] Binding and/or activating compounds can also be screened by using chimeric kinase proteins in which the amino terminal extracellular domain, or parts thereof, the entire transmembrane domain or subregions, such as any of the seven transmembrane segments or any of the intracellular or extracellular loops and the carboxy terminal intracellular domain, or parts thereof, can be replaced by heterologous domains or subregions. For example, a substrate-binding region can be used that interacts with a different substrate then that which is recognized by the native kinase. Accordingly, a different set of signal transduction components is available as an end-point assay for activation. This allows for assays to be performed in other than the specific host cell from which the kinase is derived.  
     [0072] The proteins of the present invention are also useful in competition binding assays in methods designed to discover compounds that interact with the kinase (e.g. binding partners and/or ligands). Thus, a compound is exposed to a kinase polypeptide under conditions that allow the compound to bind or to otherwise interact with the polypeptide. Soluble kinase polypeptide is also added to the mixture. If the test compound interacts with the soluble kinase polypeptide, it decreases the amount of complex formed or activity from the kinase target. This type of assay is particularly useful in cases in which compounds are sought that interact with specific regions of the kinase. Thus, the soluble polypeptide that competes with the target kinase region is designed to contain peptide sequences corresponding to the region of interest.  
     [0073] To perform cell free drug screening assays, it is sometimes desirable to immobilize either the kinase protein, or fragment, or its target molecule to facilitate separation of complexes from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay.  
     [0074] Techniques for immobilizing proteins on matrices can be used in the drug screening assays.  
     [0075] In one embodiment, a fusion protein can be provided which adds a domain that allows the protein to be bound to a matrix. For example, glutathione-S-transferase fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtitre plates, which are then combined with the cell lysates (e.g.,  35 S-labeled) and the candidate compound, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads are washed to remove any unbound label, and the matrix immobilized and radiolabel determined directly, or in the supernatant after the complexes are dissociated. Alternatively, the complexes can be dissociated from the matrix, separated by SDS-PAGE, and the level of kinase-binding protein found in the bead fraction quantitated from the gel using standard electrophoretic techniques. For example, either the polypeptide or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin using techniques well known in the art. Alternatively, antibodies reactive with the protein but which do not interfere with binding of the protein to its target molecule can be derivatized to the wells of the plate, and the protein trapped in the wells by antibody conjugation. Preparations of a kinase-binding protein and a candidate compound are incubated in the kinase protein-presenting wells and the amount of complex trapped in the well can be quantitated. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the kinase protein target molecule, or which are reactive with kinase protein and compete with the target molecule, as well as enzyme-linked assays which rely on detecting an enzymatic activity associated with the target molecule.  
     [0076] Agents that modulate one of the kinases of the present invention can be identified using one or more of the above assays, alone or in combination. It is generally preferable to use a cell-based or cell free system first and then confirm activity in an animal or other model system. Such model systems are well known in the art and can readily be employed in this context.  
     [0077] Modulators of kinase protein activity identified according to these drug screening assays can be used to treat a subject with a disorder mediated by the kinase pathway, by treating cells or tissues that express the kinase. Experimental data as provided in FIG. 1 indicates expression in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin). These methods of treatment include the steps of administering a modulator of kinase activity in a pharmaceutical composition to a subject in need of such treatment, the modulator being identified as described herein.  
     [0078] In yet another aspect of the invention, the kinase proteins can be used as “bait proteins” in a two-hybrid assay or three-hybrid assay (see, e.g., U.S. Pat. No. 5,283,317; Zervos et al. (1993)  Cell  72:223-232; Madura et al. (1993)  J. Biol. Chem.  268:12046-12054; Bartel et al. (1993)  Biotechniques  14:920-924; Iwabuchi et al. (1993) Oncogene 8:1693-1696; and Brent WO94/10300), to identify other proteins, which bind to or interact with the kinase and are involved in kinase activity. Such kinase-binding proteins are also likely to be involved in the propagation of signals by the kinase proteins or kinase targets as, for example, downstream elements of a kinase-mediated signaling pathway. Alternatively, such kinase-binding proteins are likely to be kinase inhibitors.  
     [0079] The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for a kinase protein is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein (“prey” or “sample”) is fused to a gene that codes for the activation domain of the known transcription factor. If the “bait” and the “prey” proteins are able to interact, in vivo, forming a kinase-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) which is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene which encodes the protein which interacts with the kinase protein.  
     [0080] This invention further pertains to novel agents identified by the above-described screening assays. Accordingly, it is within the scope of this invention to further use an agent identified as described herein in an appropriate animal model. For example, an agent identified as described herein (e.g., a kinase-modulating agent, an antisense kinase nucleic acid molecule, a kinase-specific antibody, or a kinase-binding partner) can be used in an animal or other model to determine the efficacy, toxicity, or side effects of treatment with such an agent. Alternatively, an agent identified as described herein can be used in an animal or other model to determine the mechanism of action of such an agent. Furthermore, this invention pertains to uses of novel agents identified by the above-described screening assays for treatments as described herein.  
     [0081] The kinase proteins of the present invention are also useful to provide a target for diagnosing a disease or predisposition to disease mediated by the peptide. Accordingly, the invention provides methods for detecting the presence, or levels of, the protein (or encoding mRNA) in a cell, tissue, or organism. Experimental data as provided in FIG. 1 indicates expression in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin). The method involves contacting a biological sample with a compound capable of interacting with the kinase protein such that the interaction can be detected. Such an assay can be provided in a single detection format or a multi-detection format such as an antibody chip array.  
     [0082] One agent for detecting a protein in a sample is an antibody capable of selectively binding to protein. A biological sample includes tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject.  
     [0083] The peptides of the present invention also provide targets for diagnosing active protein activity, disease, or predisposition to disease, in a patient having a variant peptide, particularly activities and conditions that are known for other members of the family of proteins to which the present one belongs. Thus, the peptide can be isolated from a biological sample and assayed for the presence of a genetic mutation that results in aberrant peptide. This includes amino acid substitution, deletion, insertion, rearrangement, (as the result of aberrant splicing events), and inappropriate post-translational modification. Analytic methods include altered electrophoretic mobility, altered tryptic peptide digest, altered kinase activity in cell-based or cell-free assay, alteration in substrate or antibody-binding pattern, altered isoelectric point, direct amino acid sequencing, and any other of the known assay techniques useful for detecting mutations in a protein. Such an assay can be provided in a single detection format or a multi-detection format such as an antibody chip array.  
     [0084] In vitro techniques for detection of peptide include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations and immunofluorescence using a detection reagent, such as an antibody or protein binding agent. Alternatively, the peptide can be detected in vivo in a subject by introducing into the subject a labeled anti-peptide antibody or other types of detection agent. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. Particularly useful are methods that detect the allelic variant of a peptide expressed in a subject and methods which detect fragments of a peptide in a sample.  
     [0085] The peptides are also useful in pharmacogenomic analysis. Pharmacogenomics deal with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See, e.g., Eichelbaum, M. ( Clin. Exp. Pharmacol. Physiol.  23(10-11):983-985(1996)), and Linder, M. W. ( Clin. Chem.  43(2):254-266 (1997)). The clinical outcomes of these variations result in severe toxicity of therapeutic drugs in certain individuals or therapeutic failure of drugs in certain individuals as a result of individual variation in metabolism. Thus, the genotype of the individual can determine the way a therapeutic compound acts on the body or the way the body metabolizes the compound. Further, the activity of drug metabolizing enzymes effects both the intensity and duration of drug action. Thus, the pharmacogenomics of the individual permit the selection of effective compounds and effective dosages of such compounds for prophylactic or therapeutic treatment based on the individual&#39;s genotype. The discovery of genetic polymorphisms in some drug metabolizing enzymes has explained why some patients do not obtain the expected drug effects, show an exaggerated drug effect, or experience serious toxicity from standard drug dosages. Polymorphisms can be expressed in the phenotype of the extensive metabolizer and the phenotype of the poor metabolizer. Accordingly, genetic polymorphism may lead to allelic protein variants of the kinase protein in which one or more of the kinase functions in one population is different from those in another population. The peptides thus allow a target to ascertain a genetic predisposition that can affect treatment modality. Thus, in a ligand-based treatment, polymorphism may give rise to amino terminal extracellular domains and/or other substrate-binding regions that are more or less active in substrate binding, and kinase activation. Accordingly, substrate dosage would necessarily be modified to maximize the therapeutic effect within a given population containing a polymorphism. As an alternative to genotyping, specific polymorphic peptides could be identified.  
     [0086] The peptides are also useful for treating a disorder characterized by an absence of, inappropriate, or unwanted expression of the protein. Experimental data as provided in FIG. 1 indicates expression in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin). Accordingly, methods for treatment include the use of the kinase protein or fragments.  
     [0087] Antibodies  
     [0088] The invention also provides antibodies that selectively bind to one of the peptides of the present invention, a protein comprising such a peptide, as well as variants and fragments thereof. As used herein, an antibody selectively binds a target peptide when it binds the target peptide and does not significantly bind to unrelated proteins. An antibody is still considered to selectively bind a peptide even if it also binds to other proteins that are not substantially homologous with the target peptide so long as such proteins share homology with a fragment or domain of the peptide target of the antibody. In this case, it would be understood that antibody binding to the peptide is still selective despite some degree of cross-reactivity.  
     [0089] As used herein, an antibody is defined in terms consistent with that recognized within the art: they are multi-subunit proteins produced by a mammalian organism in response to an antigen challenge. The antibodies of the present invention include polyclonal antibodies and monoclonal antibodies, as well as fragments of such antibodies, including, but not limited to, Fab or F(ab′) 2 , and Fv fragments.  
     [0090] Many methods are known for generating and/or identifying antibodies to a given target peptide. Several such methods are described by Harlow, Antibodies, Cold Spring Harbor Press, (1989).  
     [0091] In general, to generate antibodies, an isolated peptide is used as an immunogen and is administered to a mammalian organism, such as a rat, rabbit or mouse. The full-length protein, an antigenic peptide fragment or a fusion protein can be used. Particularly important fragments are those covering functional domains, such as the domains identified in FIG. 2, and domain of sequence homology or divergence amongst the family, such as those that can readily be identified using protein alignment methods and as presented in the Figures.  
     [0092] Antibodies are preferably prepared from regions or discrete fragments of the kinase proteins. Antibodies can be prepared from any region of the peptide as described herein. However, preferred regions will include those involved in function/activity and/or kinase/binding partner interaction. FIG. 2 can be used to identify particularly important regions while sequence alignment can be used to identify conserved and unique sequence fragments.  
     [0093] An antigenic fragment will typically comprise at least 8 contiguous amino acid residues. The antigenic peptide can comprise, however, at least 10, 12, 14, 16 or more amino acid residues. Such fragments can be selected on a physical property, such as fragments correspond to regions that are located on the surface of the protein, e.g., hydrophilic regions or can be selected based on sequence uniqueness (see FIG. 2).  
     [0094] Detection on an antibody of the present invention can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include  125 I,  131 I,  35 S or  3 H.  
     [0095] Antibody Uses  
     [0096] The antibodies can be used to isolate one of the proteins of the present invention by standard techniques, such as affinity chromatography or immunoprecipitation. The antibodies can facilitate the purification of the natural protein from cells and recombinantly produced protein expressed in host cells. In addition, such antibodies are useful to detect the presence of one of the proteins of the present invention in cells or tissues to determine the pattern of expression of the protein among various tissues in an organism and over the course of normal development. Experimental data as provided in FIG. 1 indicates that kinase proteins of the present invention are expressed in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin), as indicated by virtual northern blot analysis. Further, such antibodies can be used to detect protein in situ, in vitro, or in a cell lysate or supernatant in order to evaluate the abundance and pattern of expression. Also, such antibodies can be used to assess abnormal tissue distribution or abnormal expression during development or progression of a biological condition. Antibody detection of circulating fragments of the full length protein can be used to identify turnover.  
     [0097] Further, the antibodies can be used to assess expression in disease states such as in active stages of the disease or in an individual with a predisposition toward disease related to the protein&#39;s function. When a disorder is caused by an inappropriate tissue distribution, developmental expression, level of expression of the protein, or expressed/processed form, the antibody can be prepared against the normal protein. Experimental data as provided in FIG. 1 indicates expression in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin). If a disorder is characterized by a specific mutation in the protein, antibodies specific for this mutant protein can be used to assay for the presence of the specific mutant protein.  
     [0098] The antibodies can also be used to assess normal and aberrant subcellular localization of cells in the various tissues in an organism. Experimental data as provided in FIG. 1 indicates expression in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin). The diagnostic uses can be applied, not only in genetic testing, but also in monitoring a treatment modality. Accordingly, where treatment is ultimately aimed at correcting expression level or the presence of aberrant sequence and aberrant tissue distribution or developmental expression, antibodies directed against the protein or relevant fragments can be used to monitor therapeutic efficacy.  
     [0099] Additionally, antibodies are useful in pharmacogenomic analysis. Thus, antibodies prepared against polymorphic proteins can be used to identify individuals that require modified treatment modalities. The antibodies are also useful as diagnostic tools as an immunological marker for aberrant protein analyzed by electrophoretic mobility, isoelectric point, tryptic peptide digest, and other physical assays known to those in the art.  
     [0100] The antibodies are also useful for tissue typing. Experimental data as provided in FIG. 1 indicates expression in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin). Thus, where a specific protein has been correlated with expression in a specific tissue, antibodies that are specific for this protein can be used to identify a tissue type.  
     [0101] The antibodies are also useful for inhibiting protein function, for example, blocking the binding of the kinase peptide to a binding partner such as a substrate. These uses can also be applied in a therapeutic context in which treatment involves inhibiting the protein&#39;s function. An antibody can be used, for example, to block binding, thus modulating (agonizing or antagonizing) the peptides activity. Antibodies can be prepared against specific fragments containing sites required for function or against intact protein that is associated with a cell or cell membrane. See FIG. 2 for structural information relating to the proteins of the present invention.  
     [0102] The invention also encompasses kits for using antibodies to detect the presence of a protein in a biological sample. The kit can comprise antibodies such as a labeled or labelable antibody and a compound or agent for detecting protein in a biological sample; means for determining the amount of protein in the sample; means for comparing the amount of protein in the sample with a standard; and instructions for use. Such a kit can be supplied to detect a single protein or epitope or can be configured to detect one of a multitude of epitopes, such as in an antibody detection array. Arrays are described in detail below for nucleic acid arrays and similar methods have been developed for antibody arrays.  
     [0103] Nucleic Acid Molecules  
     [0104] The present invention further provides isolated nucleic acid molecules that encode a kinase peptide or protein of the present invention (cDNA, transcript and genomic sequence). Such nucleic acid molecules will consist of, consist essentially of, or comprise a nucleotide sequence that encodes one of the kinase peptides of the present invention, an allelic variant thereof, or an ortholog or paralog thereof  
     [0105] As used herein, an “isolated” nucleic acid molecule is one that is separated from other nucleic acid present in the natural source of the nucleic acid. Preferably, an “isolated”. nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5′ and 3′ ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. However, there can be some flanking nucleotide sequences, for example up to about 5KB, 4KB, 3KB, 2KB, or 1KB or less, particularly contiguous peptide encoding sequences and peptide encoding sequences within the same gene but separated by introns in the genomic sequence. The important point is that the nucleic acid is isolated from remote and unimportant flanking sequences such that it can be subjected to the specific manipulations described herein such as recombinant expression, preparation of probes and primers, and other uses specific to the nucleic acid sequences.  
     [0106] Moreover, an “isolated” nucleic acid molecule, such as a transcript/cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. However, the nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered isolated.  
     [0107] For example, recombinant DNA molecules contained in a vector are considered isolated. Further examples of isolated DNA molecules include recombinant DNA molecules maintained in heterologous host cells or purified (partially or substantially) DNA molecules in solution. Isolated RNA molecules include in vivo or in vitro. RNA transcripts of the isolated DNA molecules of the present invention. Isolated nucleic acid molecules according to the present invention further include such molecules produced synthetically.  
     [0108] Accordingly, the present invention provides nucleic acid molecules that consist of the nucleotide sequence shown in FIG. 1 or  3  (SEQ ID NO:1, transcript sequence and SEQ ID NO:3, genomic sequence), or any nucleic acid molecule that encodes the protein provided in FIG. 2, SEQ ID NO:2. A nucleic acid molecule consists of a nucleotide sequence when the nucleotide sequence is the complete nucleotide sequence of the nucleic acid molecule.  
     [0109] The present invention further provides nucleic acid molecules that consist essentially of the nucleotide sequence shown in FIG. 1 or  3  (SEQ ID NO:1, transcript sequence and SEQ ID NO:3, genomic sequence), or any nucleic acid molecule that encodes the protein provided in FIG. 2, SEQ ID NO:2. A nucleic acid molecule consists essentially of a nucleotide sequence when such a nucleotide sequence is present with only a few additional nucleic acid residues in the final nucleic acid molecule.  
     [0110] The present invention further provides nucleic acid molecules that comprise the nucleotide sequences shown in FIG. 1 or  3  (SEQ ID NO:1, transcript sequence and SEQ ID NO:3, genomic sequence), or any nucleic acid molecule that encodes the protein provided in FIG. 2, SEQ ID NO:2. A nucleic acid molecule comprises a nucleotide sequence when the nucleotide sequence is at least part of the final nucleotide sequence of the nucleic acid molecule. In such a fashion, the nucleic acid molecule can be only the nucleotide sequence or have additional nucleic acid residues, such as nucleic acid residues that are naturally associated with it or heterologous nucleotide sequences. Such a nucleic acid molecule can have a few additional nucleotides or can comprises several hundred or more additional nucleotides. A brief description of how various types of these nucleic acid molecules can be readily made/isolated is provided below.  
     [0111] In FIGS. 1 and 3, both coding and non-coding sequences are provided. Because of the source of the present invention, humans genomic sequence (FIG. 3) and cDNA/transcript sequences (FIG. 1), the nucleic acid molecules in the Figures will contain genomic intronic sequences, 5′ and 3′ non-coding sequences, gene regulatory regions and non-coding intergenic sequences. In general such sequence features are either noted in FIGS. 1 and 3 or can readily be identified using computational tools known in the art. As discussed below, some of the non-coding regions, particularly gene regulatory elements such as promoters, are useful for a variety of purposes, e.g. control of heterologous gene expression, target for identifying gene activity modulating compounds, and are particularly claimed as fragments of the genomic sequence provided herein.  
     [0112] The isolated nucleic acid molecules can encode the mature protein plus additional amino or carboxyl-terminal amino acids, or amino acids interior to the mature peptide (when the mature form has more than one peptide chain, for instance). Such sequences may play a role in processing of a protein from precursor to a mature form, facilitate protein trafficking, prolong or shorten protein half-life or facilitate manipulation of a protein for assay or production, among other things. As generally is the case in situ, the additional amino acids may be processed away from the mature protein by cellular enzymes.  
     [0113] As mentioned above, the isolated nucleic acid molecules include, but are not limited to, the sequence encoding the kinase peptide alone, the sequence encoding the mature peptide and additional coding sequences, such as a leader or secretory sequence (e.g., a pre-pro or pro-protein sequence), the sequence encoding the mature peptide, with or without the additional coding sequences, plus additional non-coding sequences, for example introns and non-coding 5′ and 3′ sequences such as transcribed but non-translated sequences that play a role in transcription, mRNA processing (including splicing and polyadenylation signals), ribosome binding and stability of mRNA. In addition, the nucleic acid molecule may be fused to a marker sequence encoding, for example, a peptide that facilitates purification.  
     [0114] Isolated nucleic acid molecules can be in the form of RNA, such as mRNA, or in the form DNA, including cDNA and genomic DNA obtained by cloning or produced by chemical synthetic techniques or by a combination thereof. The nucleic acid, especially DNA, can be double-stranded or single-stranded. Single-stranded nucleic acid can be the coding strand (sense strand) or the non-coding strand (anti-sense strand).  
     [0115] The invention further provides nucleic acid molecules that encode fragments of the peptides of the present invention as well as nucleic acid molecules that encode obvious variants of the kinase proteins of the present invention that are described above. Such nucleic acid molecules may be naturally occurring, such as allelic variants (same locus), paralogs (different locus), and orthologs (different organism), or may be constructed by recombinant DNA methods or by chemical synthesis. Such non-naturally occurring variants may be made by mutagenesis techniques, including those applied to nucleic acid molecules, cells, or organisms. Accordingly, as discussed above, the variants can contain nucleotide substitutions, deletions, inversions and insertions. Variation can occur in either or both the coding and non-coding regions. The variations can produce both conservative and non-conservative amino acid substitutions. The present invention further provides non-coding fragments of the nucleic acid molecules provided in FIGS. 1 and 3. Preferred non-coding fragments include, but are not limited to, promoter sequences, enhancer sequences, gene modulating sequences and gene termination sequences. Such fragments are useful in controlling heterologous gene expression and in developing screens to identify gene-modulating agents. A promoter can readily be identified as being 5′ to the ATG start site in the genomic sequence provided in FIG. 3.  
     [0116] A fragment comprises a contiguous nucleotide sequence greater than 12 or more nucleotides. Further, a fragment could at least 30, 40, 50, 100, 250 or 500 nucleotides in length. The length of the fragment will be based on its intended use. For example, the fragment can encode epitope bearing regions of the peptide, or can be useful as DNA probes and primers. Such fragments can be isolated using the known nucleotide sequence to synthesize an oligonucleotide probe. A labeled probe can then be used to screen a cDNA library, genomic DNA library, or mRNA to isolate nucleic acid corresponding to the coding region. Further, primers can be used in PCR reactions to clone specific regions of gene.  
     [0117] A probe/primer typically comprises substantially a purified oligonucleotide or oligonucleotide pair. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, 20, 25, 40, 50 or more consecutive nucleotides.  
     [0118] Orthologs, homologs, and allelic variants can be identified using methods well known in the art. As described in the Peptide Section, these variants comprise a nucleotide sequence encoding a peptide that is typically 60-70%, 70-80%, 80-90%, and more typically at least about 90-95% or more homologous to the nucleotide sequence shown in the Figure sheets or a fragment of this sequence. Such nucleic acid molecules can readily be identified as being able to hybridize under moderate to stringent conditions, to the nucleotide sequence shown in the Figure sheets or a fragment of the sequence. Allelic variants can readily be determined by genetic locus of the encoding gene. As indicated in FIG. 3, the map position was determined to be on human chromosome 2.  
     [0119]FIG. 3 provides information on SNPs that have been found in the gene encoding the kinase proteins of the present invention. SNPs were identified at 39 different nucleotide positions, including five SNPs in coding regions, two of which (at nucleotide positions 52048 and 58826) change the encoded amino acid. The changes in the amino acid sequence that these SNPs cause is indicated in FIG. 3 and can readily be determined using the universal genetic code and the protein sequence provided in FIG. 2 as a reference.  
     [0120] As used herein, the term “hybridizes under stringent conditions” is intended to describe conditions for hybridization and washing under which nucleotide sequences encoding a peptide at least 60-70% homologous to each other typically remain hybridized to each other. The conditions can be such that sequences at least about 60%, at least about 70%, or at least about 80% or more homologous to each other typically remain hybridized to each other. Such stringent conditions are known to those skilled in the art and can be found in  Current Protocols in Molecular Biology , John Wiley &amp; Sons, N.Y. (1989), 6.3.1-6.3.6. One example of stringent hybridization conditions are hybridization in 6× sodium chloride/sodium citrate (SSC) at about 45C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 50-65C. Examples of moderate to low stringency hybridization conditions are well known in the art.  
     [0121] Nucleic Acid Molecule Uses  
     [0122] The nucleic acid molecules of the present invention are useful for probes, primers, chemical intermediates, and in biological assays. The nucleic acid molecules are useful as a hybridization probe for messenger RNA, transcript/cDNA and genomic DNA to isolate full-length cDNA and genomic clones encoding the peptide described in FIG. 2 and to isolate cDNA and genomic clones that correspond to variants (alleles, orthologs, etc.) producing the same or related peptides shown in FIG. 2. As illustrated in FIG. 3, SNPs were identified at 39 different nucleotide positions, including 2 non-synonymous coding SNPs.  
     [0123] The probe can correspond to any sequence along the entire length of the nucleic acid molecules provided in the Figures. Accordingly, it could be derived from 5′ noncoding regions, the coding region, and 3′ noncoding regions. However, as discussed, fragments are not to be construed as encompassing fragments disclosed prior to the present invention.  
     [0124] The nucleic acid molecules are also useful as primers for PCR to amplify any given region of a nucleic acid molecule and are useful to synthesize antisense molecules of desired length and sequence.  
     [0125] The nucleic acid molecules are also useful for constructing recombinant vectors. Such vectors include expression vectors that express a portion of, or all of, the peptide sequences. Vectors also include insertion vectors, used to integrate into another nucleic acid molecule sequence, such as into the cellular genome, to alter in situ expression of a gene and/or gene product. For example, an endogenous coding sequence can be replaced via homologous recombination with all or part of the coding region containing one or more specifically introduced mutations.  
     [0126] The nucleic acid molecules are also useful for expressing antigenic portions of the proteins.  
     [0127] The nucleic acid molecules are also useful as probes for determining the chromosomal positions of the nucleic acid molecules by means of in situ hybridization methods. As indicated in FIG. 3, the map position was determined to be on human chromosome 2.  
     [0128] The nucleic acid molecules are also useful in making vectors containing the gene regulatory regions of the nucleic acid molecules of the present invention.  
     [0129] The nucleic acid molecules are also useful for designing ribozymes corresponding to all, or a part, of the mRNA produced from the nucleic acid molecules described herein.  
     [0130] The nucleic acid molecules are also useful for making vectors that express part, or all, of the peptides.  
     [0131] The nucleic acid molecules are also useful for constructing host cells expressing a part, or all, of the nucleic acid molecules and peptides.  
     [0132] The nucleic acid molecules are also useful for constructing transgenic animals expressing all, or a part, of the nucleic acid molecules and peptides.  
     [0133] The nucleic acid molecules are also useful as hybridization probes for determining the presence, level, form and distribution of nucleic acid expression. Experimental data as provided in FIG. 1 indicates that kinase proteins of the present invention are expressed in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin), as indicated by virtual northern blot analysis. Accordingly, the probes can be used to detect the presence of, or to determine levels of, a specific nucleic acid molecule in cells, tissues, and in organisms. The nucleic acid whose level is determined can be DNA or RNA. Accordingly, probes corresponding to the peptides described herein can be used to assess expression and/or gene copy number in a given cell, tissue, or organism. These uses are relevant for diagnosis of disorders involving an increase or decrease in kinase protein expression relative to normal results.  
     [0134] In vitro techniques for detection of mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detecting DNA includes Southern hybridizations and in situ hybridization.  
     [0135] Probes can be used as a part of a diagnostic test kit for identifying cells or tissues that express a kinase protein, such as by measuring a level of a kinase-encoding nucleic acid in a sample of cells from a subject e.g., mRNA or genomic DNA, or determining if a kinase gene has been mutated. Experimental data as provided in FIG. 1 indicates that kinase proteins of the. present invention are expressed in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin), as indicated by virtual northern blot analysis.  
     [0136] Nucleic acid expression assays are useful for drug screening to identify compounds that modulate kinase nucleic acid expression.  
     [0137] The invention thus provides a method for identifying a compound that can be used to treat a disorder associated with nucleic acid expression of the kinase gene, particularly biological and pathological processes that are mediated by the kinase in cells and tissues that express it. Experimental data as provided in FIG. 1 indicates expression in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin). The method typically includes assaying the ability of the compound to modulate the expression of the kinase nucleic acid and thus identifying a compound that can be used to treat a disorder characterized by undesired kinase nucleic acid expression. The assays can be performed in cell-based and cell-free systems. Cell-based assays include cells naturally expressing the kinase nucleic acid or recombinant cells genetically engineered to express specific nucleic acid sequences.  
     [0138] The assay for kinase nucleic acid expression can involve direct assay of nucleic acid levels, such as mRNA levels, or on collateral compounds involved in the signal pathway. Further, the expression of genes that are up- or down-regulated in response to the kinase protein signal pathway can also be assayed. In this embodiment the regulatory regions of these genes can be operably linked to a reporter gene such as luciferase.  
     [0139] Thus, modulators of kinase gene expression can be identified in a method wherein a cell is contacted with a candidate compound and the expression of mRNA determined. The level of expression of kinase mRNA in the presence of the candidate compound is compared to the level of expression of kinase mRNA in the absence of the candidate compound. The candidate compound can then be identified as a modulator of nucleic acid expression based on this comparison and be used, for example to treat a disorder characterized by aberrant nucleic acid expression. When expression of mRNA is statistically significantly greater in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of nucleic acid expression. When nucleic acid expression is statistically significantly less in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of nucleic acid expression.  
     [0140] The invention further provides methods of treatment, with the nucleic acid as a target, using a compound identified through drug screening as a gene modulator to modulate kinase nucleic acid expression in cells and tissues that express the kinase. Experimental data as provided in FIG. 1 indicates that kinase proteins of the present invention are expressed in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin), as indicated by virtual northern blot analysis. Modulation includes both up-regulation (i.e. activation or agonization) or down-regulation (suppression or antagonization) or nucleic acid expression.  
     [0141] Alternatively, a modulator for kinase nucleic acid expression can be a small molecule or drug identified using the screening assays described herein as long as the drug or small molecule inhibits the kinase nucleic acid expression in the cells and tissues that express the protein. Experimental data as provided in FIG. 1 indicates expression in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin).  
     [0142] The nucleic acid molecules are also useful for monitoring the effectiveness of modulating compounds on the expression or activity of the kinase gene in clinical trials or in a treatment regimen. Thus, the gene expression pattern can serve as a barometer for the continuing effectiveness of treatment with the compound, particularly with compounds to which a patient can develop resistance. The gene expression pattern can also serve as a marker indicative of a physiological response of the affected cells to the compound. Accordingly, such monitoring would allow either increased administration of the compound or the administration of alternative compounds to which the patient has not become resistant. Similarly, if the level of nucleic acid expression falls below a desirable level, administration of the compound could be commensurately decreased.  
     [0143] The nucleic acid molecules are also useful in diagnostic assays for qualitative changes in kinase nucleic acid expression, and particularly in qualitative changes that lead to pathology. The nucleic acid molecules can be used to detect mutations in kinase genes and gene expression products such as mRNA. The nucleic acid molecules can be used as hybridization probes to detect naturally occurring genetic mutations in the kinase gene and thereby to determine whether a subject with the mutation is at risk for a disorder caused by the mutation. Mutations include deletion, addition, or substitution of one or more nucleotides in the gene, chromosomal rearrangement, such as inversion or transposition, modification of genomic DNA, such as aberrant methylation patterns or changes in gene copy number, such as amplification. Detection of a mutated form of the kinase gene associated with a dysfunction provides a diagnostic tool for an active disease or susceptibility to disease when the disease results from overexpression, underexpression, or altered expression of a kinase protein.  
     [0144] Individuals carrying mutations in the kinase gene can be detected at the nucleic acid level by a variety of techniques. FIG. 3 provides information on SNPs that have been found in the gene encoding the kinase proteins of the present invention. SNPs were identified at 39 different nucleotide positions, including five SNPs in coding regions, two of which (at nucleotide positions 52048 and 58826) change the encoded amino acid. The changes in the amino acid sequence that these SNPs cause is indicated in FIG. 3 and can readily be determined using the universal genetic code and the protein sequence provided in FIG. 2 as a reference. As indicated in FIG. 3, the map position was determined to be on human chromosome 2. Genomic DNA can be analyzed directly or can be amplified by using PCR prior to analysis. RNA or cDNA can be used in the same way. In some uses, detection of the mutation involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g. U.S. Pat. Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran et al.,  Science  241:1077-1080 (1988); and Nakazawa et al.,  PNAS  91:360-364 (1994)), the latter of which can be particularly useful for detecting point mutations in the gene (see Abravaya et al.,  Nucleic Acids Res.  23:675-682 (1995)). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers which specifically hybridize to a gene under conditions such that hybridization and amplification of the gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. Deletions and insertions can be detected by a change in size of the amplified product compared to the normal genotype. Point mutations can be identified by hybridizing amplified DNA to normal RNA or antisense DNA sequences.  
     [0145] Alternatively, mutations in a kinase gene can be directly identified, for example, by alterations in restriction enzyme digestion patterns determined by gel electrophoresis.  
     [0146] Further, sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site. Perfectly matched sequences can be distinguished from mismatched sequences by nuclease cleavage digestion assays or by differences in melting temperature.  
     [0147] Sequence changes at specific locations can also be assessed by nuclease protection assays such as RNase and S1 protection or the chemical cleavage method. Furthermore, sequence differences between a mutant kinase gene and a wild-type gene can be determined by direct DNA sequencing. A variety of automated sequencing procedures can be utilized when performing the diagnostic assays (Naeve, C. W., (1995)  Biotechniques  19:448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO 94/16101; Cohen et al.,  Adv. Chromatogr.  36:127-162 (1996); and Griffin et al.,  Appl. Biochem. Biotechnol.,  38:147-159 (1993)).  
     [0148] Other methods for detecting mutations in the gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al.,  Science  230:1242 (1985)); Cotton et al.,  PNAS  85:4397(1988); Saleeba et al.,  Meth. Enzymol.  217:286-295 (1992)), electrophoretic mobility of mutant and wild type nucleic acid is compared (Orita et al.,  PNAS  86:2766 (1989); Cotton et al.,  Mutat. Res.  285:125-144 (1993); and Hayashi et al.,  Genet. Anal. Tech. Appl.  9:73-79 (1992)), and movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (Myers et al.,  Nature  313:495 (1985)). Examples of other techniques for detecting point mutations include selective oligonucleotide hybridization, selective amplification, and selective primer extension.  
     [0149] The nucleic acid molecules are also useful for testing an individual for a genotype that while not necessarily causing the disease, nevertheless affects the treatment modality. Thus, the nucleic acid molecules can be used to study the relationship between an individual&#39;s genotype and the individual&#39;s response to a compound used for treatment (pharmacogenomic relationship). Accordingly, the nucleic acid molecules described herein can be used to assess the mutation content of the kinase gene in an individual in order to select an appropriate compound or dosage regimen for treatment. FIG. 3 provides information on SNPs that have been found in the gene encoding the kinase proteins of the present invention. SNPs were identified at 39 different nucleotide positions, including five SNPs in coding regions, two of which (at nucleotide positions 52048 and 58826) change the encoded amino acid. The changes in the amino acid sequence that these SNPs cause is indicated in FIG. 3 and can readily be determined using the universal genetic code and the protein sequence provided in FIG. 2 as a reference.  
     [0150] Thus nucleic acid molecules displaying genetic variations that affect treatment provide a diagnostic target that can be used to tailor treatment in an individual. Accordingly, the production of recombinant cells and animals containing these polymorphisms allow effective clinical design of treatment compounds and dosage regimens.  
     [0151] The nucleic acid molecules are thus useful as antisense constructs to control kinase gene expression in cells, tissues, and organisms. A DNA antisense nucleic acid molecule is designed to be complementary to a region of the gene involved in transcription, preventing transcription and hence production of kinase protein. An antisense RNA or DNA nucleic acid molecule would hybridize to the mRNA and thus block translation of mRNA into kinase protein.  
     [0152] Alternatively, a class of antisense molecules can be used to inactivate mRNA in order to decrease expression of kinase nucleic acid. Accordingly, these molecules can treat a disorder characterized by abnormal or undesired kinase nucleic acid expression. This technique involves cleavage by means of ribozymes containing nucleotide sequences complementary to one or more regions in the mRNA that attenuate the ability of the mRNA to be translated. Possible regions include coding regions and particularly coding regions corresponding to the catalytic and other functional activities of the kinase protein, such as substrate binding.  
     [0153] The nucleic acid molecules also provide vectors for gene therapy in patients containing cells that are aberrant in kinase gene expression. Thus, recombinant cells, which include the patient&#39;s cells that have been engineered ex vivo and returned to the patient, are introduced into an individual where the cells produce the desired kinase protein to treat the individual.  
     [0154] The invention also encompasses kits for detecting the presence of a kinase nucleic acid in a biological sample. Experimental data as provided in FIG. 1 indicates that kinase proteins of the present invention are expressed in adult and fetal brain (including astrocytoma and neuroblastoma cells), lung/spleen, and squamous cell carcinoma (skin), as indicated by virtual northern blot analysis. For example, the kit can comprise reagents such as a labeled or labelable nucleic acid or agent capable of detecting kinase nucleic acid in a biological sample; means for determining the amount of kinase nucleic acid in the sample; and means for comparing the amount of kinase nucleic acid in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect kinase protein mRNA or DNA.  
     [0155] Nucleic Acid Arrays  
     [0156] The present invention further provides nucleic acid detection kits, such as arrays or microarrays of nucleic acid molecules that are based on the sequence information provided in FIGS. 1 and 3 (SEQ ID NOS: 1and 3).  
     [0157] As used herein “Arrays” or “Microarrays” refers to an array of distinct polynucleotides or oligonucleotides synthesized on a substrate, such as paper, nylon or other type of membrane, filter, chip, glass slide, or any other suitable solid support. In one embodiment, the microarray is prepared and used according to the methods described in U.S. Pat. No. 5,837,832, Chee et al., PCT application WO95/11995 (Chee et al.), Lockhart, D. J. et al. (1996; Nat. Biotech. 14: 1675-1680) and Schena, M. et al. (1996; Proc. Natl. Acad. Sci. 93: 10614-10619), all of which are incorporated herein in their entirety by reference. In other embodiments, such arrays are produced by the methods described by Brown et al., U.S. Pat. No. 5,807,522.  
     [0158] The microarray or detection kit is preferably composed of a large number of unique, single-stranded nucleic acid sequences, usually either synthetic antisense oligonucleotides or fragments of cDNAs, fixed to a solid support. The oligonucleotides are preferably about 6-60 nucleotides in length, more preferably 15-30 nucleotides in length, and most preferably about 20-25 nucleotides in length. For a certain type of microarray or detection kit, it may be preferable to use oligonucleotides that are only 7-20 nucleotides in length. The microarray or detection kit may contain oligonucleotides that cover the known 5′, or 3′, sequence, sequential oligonucleotides which cover the full length sequence; or unique oligonucleotides selected from particular areas along the length of the sequence. Polynucleotides used in the microarray or detection kit may be oligonucleotides that are specific to a gene or genes of interest.  
     [0159] In order to produce oligonucleotides to a known sequence for a microarray or detection kit, the gene(s) of interest (or an ORF identified from the contigs of the present invention) is typically examined using a computer algorithm which starts at the 5′ or at the 3′ end of the nucleotide sequence. Typical algorithms will then identify oligomers of defined length that are unique to the gene, have a GC content within a range suitable for hybridization, and lack predicted secondary structure that may interfere with hybridization. In certain situations it may be appropriate to use pairs of oligonucleotides on a microarray or detection kit. The “pairs” will be identical, except for one nucleotide that preferably is located in the center of the sequence. The second oligonucleotide in the pair (mismatched by one) serves as a control. The number of oligonucleotide pairs may range from two to one million. The oligomers are synthesized at designated areas on a substrate using a light-directed chemical process. The substrate may be paper, nylon or other type of membrane, filter, chip, glass slide or any other suitable solid support.  
     [0160] In another aspect, an oligonucleotide may be synthesized on the surface of the substrate by using a chemical coupling procedure and an ink jet application apparatus, as described in PCT application WO95/251116 (Baldeschweiler et al.) which is incorporated herein in its entirety by reference. In another aspect, a “gridded” array analogous to a dot (or slot) blot may be used to arrange and link cDNA fragments or oligonucleotides to the surface of a substrate using a vacuum system, thermal, UV, mechanical or chemical bonding procedures. An array, such as those described above, may be produced by hand or by using available devices (slot blot or dot blot apparatus), materials (any suitable solid support), and machines (including robotic instruments), and may contain 8, 24, 96, 384, 1536, 6144 or more oligonucleotides, or any other number between two and one million which lends itself to the efficient use of commercially available instrumentation.  
     [0161] In order to conduct sample analysis using a microarray or detection kit, the RNA or DNA from a biological sample is made into hybridization probes. The mRNA is isolated, and cDNA is produced and used as a template to make antisense RNA (aRNA). The aRNA is amplified in the presence of fluorescent nucleotides, and labeled probes are incubated with the microarray or detection kit so that the probe sequences hybridize to complementary oligonucleotides of the microarray or detection kit. Incubation conditions are adjusted so that hybridization occurs with precise complementary matches or with various degrees of less complementarity. After removal of nonhybridized probes, a scanner is used to determine the levels and patterns of fluorescence. The scanned images are examined to determine degree of complementarity and the relative abundance of each oligonucleotide sequence on the microarray or detection kit. The biological samples may be obtained from any bodily fluids (such as blood, urine, saliva, phlegm, gastric juices, etc.), cultured cells, biopsies, or other tissue preparations. A detection system may be used to measure the absence, presence, and amount of hybridization for all of the distinct sequences simultaneously. This data may be used for large-scale correlation studies on the sequences, expression patterns, mutations, variants, or polymorphisms among samples.  
     [0162] Using such arrays, the present invention provides methods to identify the expression of the kinase proteins/peptides of the present invention. In detail, such methods comprise incubating a test sample with one or more nucleic acid molecules and assaying for binding of the nucleic acid molecule with components within the test sample. Such assays will typically involve arrays comprising many genes, at least one of which is a gene of the present invention and or alleles of the kinase gene of the present invention. FIG. 3 provides information on SNPs that have been found in the gene encoding the kinase proteins of the present invention. SNPs were identified at 39. different nucleotide positions, including five SNPs in coding regions, two of which (at nucleotide positions 52048 and 58826) change the encoded amino acid. The changes in the amino acid sequence that these SNPs cause is indicated in FIG. 3 and can readily be determined using the universal genetic code and the protein sequence provided in FIG. 2 as a reference.  
     [0163] Conditions for incubating a nucleic acid molecule with a test sample vary. Incubation conditions depend on the format employed in the assay, the detection methods employed, and the type and nature of the nucleic acid molecule used in the assay. One skilled in the art will recognize that any one of the commonly available hybridization, amplification or array assay formats can readily be adapted to employ the novel fragments of the Human genome disclosed herein. Examples of such assays can be found in Chard, T,  An Introduction to Radioimmunoassay and Related Techniques , Elsevier Science Publishers, Amsterdam, The Netherlands (1986); Bullock, G. R. et al.,  Techniques in Immunocytochemistry , Academic Press, Orlando, Fla. Vol. 1 (1982), Vol. 2 (1983), Vol. 3 (1985); Tijssen, P.,  Practice and Theory of Enzyme Immunoassays: Laboratory Techniques in Biochemistry and Molecular Biology , Elsevier Science Publishers, Amsterdam, The Netherlands (1985).  
     [0164] The test samples of the present invention include cells, protein or membrane extracts of cells. The test sample used in the above-described method will vary based on the assay format, nature of the detection method and the tissues, cells or extracts used as the sample to be assayed. Methods for preparing nucleic acid extracts or of cells are well known in the art and can be readily be adapted in order to obtain a sample that is compatible with the system utilized.  
     [0165] In another embodiment of the present invention, kits are provided which contain the necessary reagents to carry out the assays of the present invention.  
     [0166] Specifically, the invention provides a compartmentalized kit to receive, in close confinement, one or more containers which comprises: (a) a first container comprising one of the nucleic acid molecules that can bind to a fragment of the Human genome disclosed herein; and (b) one or more other containers comprising one or more of the following: wash reagents, reagents capable of detecting presence of a bound nucleic acid.  
     [0167] In detail, a compartmentalized kit includes any kit in which reagents are contained in separate containers. Such containers include small glass containers, plastic containers, strips of plastic, glass or paper, or arraying material such as silica. Such containers allows one to efficiently transfer reagents from one compartment to another compartment such that the samples and reagents are not cross-contaminated, and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another. Such containers will include a container which will accept the test sample, a container which contains the nucleic acid probe, containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.), and containers which contain the reagents used to detect the bound probe. One skilled in the art will readily recognize that the previously unidentified kinase gene of the present invention can be routinely identified using the sequence information disclosed herein can be readily incorporated into one of the established kit formats which are well known in the art, particularly expression arrays.  
     [0168] Vectors/Host Cells  
     [0169] The invention also provides vectors containing the nucleic acid molecules described herein. The term “vector” refers to a vehicle, preferably a nucleic acid molecule, which can transport the nucleic acid molecules. When the vector is a nucleic acid molecule, the nucleic acid molecules are covalently linked to the vector nucleic acid. With this aspect of the invention, the vector includes a plasmid, single or double stranded phage, a single or double stranded RNA or DNA viral vector, or artificial chromosome, such as a BAC, PAC, YAC, OR MAC.  
     [0170] A vector can be maintained in the host cell as an extrachromosomal element where it replicates and produces additional copies of the nucleic acid molecules. Alternatively, the vector may integrate into the host cell genome and produce additional copies of the nucleic acid molecules when the host cell replicates.  
     [0171] The invention provides vectors for the maintenance (cloning vectors) or vectors for expression (expression vectors) of the nucleic acid molecules. The vectors can function in prokaryotic or eukaryotic cells or in both (shuttle vectors).  
     [0172] Expression vectors contain cis-acting regulatory regions that are operably linked in the vector to the nucleic acid molecules such that transcription of the nucleic acid molecules is allowed in a host cell. The nucleic acid molecules can be introduced into the host cell with a separate nucleic acid molecule capable of affecting transcription. Thus, the second nucleic acid molecule may provide a trans-acting factor interacting with the cis-regulatory control region to allow transcription of the nucleic acid molecules from the vector. Alternatively, a trans-acting factor may be supplied by the host cell. Finally, a trans-acting factor can be produced from the vector itself. It is understood, however, that in some embodiments, transcription and/or translation of the nucleic acid molecules can occur in a cell-free system.  
     [0173] The regulatory sequence to which the nucleic acid molecules described herein can be operably linked include promoters for directing mRNA transcription. These include, but are not limited to, the left promoter from bacteriophage λ, the lac, TRP, and TAC promoters from  E. coli , the early and late promoters from SV40, the CMV immediate early promoter, the adenovirus early and late promoters, and retrovirus long-terminal repeats.  
     [0174] In addition to control regions that promote transcription, expression vectors may also include regions that modulate transcription, such as repressor binding sites and enhancers. Examples include the SV40 enhancer, the cytomegalovirus immediate early enhancer, polyoma enhancer, adenovirus enhancers, and retrovirus LTR enhancers.  
     [0175] In addition to containing sites for transcription initiation and control, expression vectors can also contain sequences necessary for transcription termination and, in the transcribed region a ribosome binding site for translation. Other regulatory control elements for expression include initiation and termination codons as well as polyadenylation signals. The person of ordinary skill in the art would be aware of the numerous regulatory sequences that are useful in expression vectors. Such regulatory sequences are described, for example, in Sambrook et al.,  Molecular Cloning: A Laboratory Manual.  2nd. ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (1989).  
     [0176] A variety of expression vectors can be used to express a nucleic acid molecule. Such vectors include chromosomal, episomal, and virus-derived vectors, for example vectors derived from bacterial plasmids, from bacteriophage, from yeast episomes, from yeast chromosomal elements, including yeast artificial chromosomes, from viruses such as baculoviruses, papovaviruses such as SV40, Vaccinia viruses, adenoviruses, poxviruses, pseudorabies viruses, and retroviruses. Vectors may also be derived from combinations of these sources such as those derived from plasmid and bacteriophage genetic elements, e.g. cosmids and phagemids. Appropriate cloning and expression vectors for prokaryotic and eukaryotic hosts are described in Sambrook et al.,  Molecular Cloning:. A Laboratory Manual.  2nd. ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (1989).  
     [0177] The regulatory sequence may provide constitutive expression in one or more host cells (i.e. tissue specific) or may provide for inducible expression in one or more cell types such as by temperature, nutrient additive, or exogenous factor such as a hormone or other ligand. A variety of vectors providing for constitutive and inducible expression in prokaryotic and eukaryotic hosts are well known to those of ordinary skill in the art.  
     [0178] The nucleic acid molecules can be inserted into the vector nucleic acid by well-known methodology. Generally, the DNA sequence that will ultimately be expressed is joined to an expression vector by cleaving the DNA sequence and the expression vector with one or more restriction enzymes and then ligating the fragments together. Procedures for restriction enzyme digestion and ligation are well known to those of ordinary skill in the art.  
     [0179] The vector containing the appropriate nucleic acid molecule can be introduced into an appropriate host cell for propagation or expression using well-known techniques. Bacterial cells include, but are not limited to,  E. coli , Streptomyces, and  Salmonella typhimurium . Eukaryotic cells include, but are not limited to, yeast, insect cells such as Drosophila, animal cells such as COS and CHO cells, and plant cells.  
     [0180] As described herein, it may be desirable to express the peptide as a fusion protein. Accordingly, the invention provides fusion vectors that allow for the production of the peptides. Fusion vectors can increase the expression of a recombinant protein, increase the solubility of the recombinant protein, and aid in the purification of the protein by acting for example as a ligand for affinity purification. A proteolytic cleavage site may be introduced at the junction of the fusion moiety so that the desired peptide can ultimately be separated from the fusion moiety. Proteolytic enzymes include, but are not limited to, factor Xa, thrombin, and enterokinase. Typical fusion expression vectors include pGEX (Smith et al.,  Gene  67:31-40 (1988)), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion  E. coli  expression vectors include pTrc (Amann et al.,  Gene  69:301-315 (1988)) and pET 11d (Studier et al.,  Gene Expression Technology: Methods in Enzymology  185:60-89 (1990)).  
     [0181] Recombinant protein expression can be maximized in host bacteria by providing a genetic background wherein the host cell has an impaired capacity to proteolytically cleave the recombinant protein. (Gottesman, S.,  Gene Expression Technology: Methods in Enzymology  185, Academic Press, San Diego, Calif. (1990) 119-128). Alternatively, the sequence of the nucleic acid molecule of interest can be altered to provide preferential codon usage for a specific host cell, for example  E. coli . (Wada et al.,  Nucleic Acids Res.  20:2111-2118 (1992)).  
     [0182] The nucleic acid molecules can also be expressed by expression vectors that are operative in yeast. Examples of vectors for expression in yeast e.g.,  S. cerevisiae  include pYepSec1 (Baldari, et-al.,  EMBO J.  6:229-234 (1987)), pMFa (Kujan et al.,  Cell  30:933-943(1982)), pJRY88 (Schultz et al.,  Gene  54:113-123 (1987)), and pYES2 (Invitrogen Corporation, San Diego, Calif.).  
     [0183] The nucleic acid molecules can also be expressed in insect cells using, for example, baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., Sf9 cells) include the pAc series (Smith et al.,  Mol. Cell Biol.  3:2156-2165 (1983)) and the pVL series (Lucklow et al.,  Virology  170:31-39 (1989)).  
     [0184] In certain embodiments of the invention, the nucleic acid molecules described herein are expressed in mammalian cells using mammalian expression vectors. Examples of mammalian expression vectors include pCDM8 (Seed, B.  Nature  329:840(1987)) and pMT2PC (Kaufman et al.,  EMBO J.  6:187-195 (1987)).  
     [0185] The expression vectors listed herein are provided by way of example only of the well-known vectors available to those of ordinary skill in the art that would be useful to express the nucleic acid molecules. The person of ordinary skill in the art would be aware of other vectors suitable for maintenance propagation or expression of the nucleic acid molecules described herein. These are found for example in Sambrook, J., Fritsh, E. F., and Maniatis, T.  Molecular Cloning: A Laboratory Manual.  2nd., ed.,  Cold Spring Harbor Laboratory , Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989.  
     [0186] The invention also encompasses vectors in which the nucleic acid sequences described herein are cloned into the vector in reverse orientation, but operably linked to a regulatory sequence that permits transcription of antisense RNA. Thus, an antisense transcript can be produced to all, or to a portion, of the nucleic acid molecule sequences described herein, including both coding and non-coding regions. Expression of this antisense RNA is subject to each of the parameters described above in relation to expression of the sense RNA (regulatory sequences, constitutive or inducible expression, tissue-specific expression).  
     [0187] The invention also relates to recombinant host cells containing the vectors described herein. Host cells therefore include prokaryotic cells, lower eukaryotic cells such as yeast, other eukaryotic cells such as insect cells, and higher eukaryotic cells such as mammalian cells.  
     [0188] The recombinant host cells are prepared by introducing the vector constructs described herein into the cells by techniques readily available to the person of ordinary skill in the art. These include, but are not limited to, calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, lipofection, and other techniques such as those found in Sambrook, et al. ( Molecular Cloning: A Laboratory Manual.  2 nd, ed., Cold Spring Harbor Laboratory , Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989).  
     [0189] Host cells can contain more than one vector. Thus, different nucleotide sequences can be introduced on different vectors of the same cell. Similarly, the nucleic acid molecules can be introduced either alone or with other nucleic acid molecules that are not related to the nucleic acid molecules such as those providing trans-acting factors for expression vectors. When more than one vector is introduced into a cell, the vectors can be introduced independently, co-introduced or joined to the nucleic acid molecule vector.  
     [0190] In the case of bacteriophage and viral vectors, these can be introduced into cells as packaged or encapsulated virus by standard procedures for infection and transduction. Viral vectors can be replication-competent or replication-defective. In the case in which viral replication is defective, replication will occur in host cells providing functions that complement the defects.  
     [0191] Vectors generally include selectable markers that enable the selection of the subpopulation of cells that contain the recombinant vector constructs. The marker can be contained in the same vector that contains the nucleic acid molecules described herein or may be on a separate vector. Markers include tetracycline or ampicillin-resistance genes for prokaryotic host cells and dihydrofolate reductase or neomycin resistance for eukaryotic host cells. However, any marker that provides selection for a phenotypic trait will be effective.  
     [0192] While the mature proteins can be produced in bacteria, yeast, mammalian cells, and other cells under the control of the appropriate regulatory sequences, cell- free transcription and translation systems can also be used to produce these proteins using RNA derived from the DNA constructs described herein.  
     [0193] Where secretion of the peptide is desired, which is difficult to achieve with multi-transmembrane domain containing proteins such as kinases, appropriate secretion signals are incorporated into the vector. The signal sequence can be endogenous to the peptides or heterologous to these peptides.  
     [0194] Where the peptide is not secreted into the medium, which is typically the case with kinases, the protein can be isolated from the host cell by standard disruption procedures, including freeze thaw, sonication, mechanical disruption, use of lysing agents and the like. The peptide can then be recovered and purified by well-known purification methods including ammonium sulfate precipitation, acid extraction, anion or cationic exchange chromatography, phosphocellulose chromatography, hydrophobic-interaction chromatography, affinity chromatography, hydroxylapatite chromatography, lectin chromatography, or high performance liquid chromatography.  
     [0195] It is also understood that depending upon the host cell in recombinant production of the peptides described herein, the peptides can have various glycosylation patterns, depending upon the cell, or maybe non-glycosylated as when produced in bacteria. In addition, the peptides may include an initial modified methionine in some cases as a result of a host-mediated process.  
     [0196] Uses of Vectors and Host Cells  
     [0197] The recombinant host cells expressing the peptides described herein have a variety of uses. First, the cells are useful for producing a kinase protein or peptide that can be further purified to produce desired amounts of kinase protein or fragments. Thus, host cells containing expression vectors are useful for peptide production.  
     [0198] Host cells are also useful for conducting cell-based assays involving the kinase protein or kinase protein fragments, such as those described above as well as other formats known in the art. Thus, a recombinant host cell expressing a native kinase protein is useful for assaying compounds that stimulate or inhibit kinase protein function.  
     [0199] Host cells are also useful for identifying kinase protein mutants in which these functions are affected. If the mutants naturally occur and give rise to a pathology, host cells containing the mutations are useful to assay compounds that have a desired effect on the mutant kinase protein (for example, stimulating or inhibiting function) which may not be indicated by their effect on the native kinase protein.  
     [0200] Genetically engineered host cells can be further used to produce non-human transgenic animals. A transgenic animal is preferably a mammal, for example a rodent, such as a rat or mouse, in which one or more of the cells of the animal include a transgene. A transgene is exogenous DNA which is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal in one or more cell types or tissues of the transgenic animal. These animals are useful for studying the function of a kinase protein and identifying and evaluating modulators of kinase protein activity. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, and amphibians.  
     [0201] A transgenic animal can be produced by introducing nucleic acid into the male pronuclei of a fertilized oocyte, e.g., by microinjection, retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. Any of the kinase protein nucleotide sequences can be introduced as a transgene into the genome of a non-human animal, such as a mouse.  
     [0202] Any of the regulatory or other sequences useful in expression vectors can form part of the transgenic sequence. This includes intronic sequences and polyadenylation signals, if not already included. A tissue-specific regulatory sequence(s) can be operably linked to the transgene to direct expression of the kinase protein to particular cells.  
     [0203] Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009, both by Leder et al., U.S. Pat. No. 4,873,191 by Wagner et al. and in Hogan, B.,  Manipulating the Mouse Embryo , (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986). Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the transgene in its genome and/or expression of transgenic mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene can further be bred to other transgenic animals carrying other transgenes. A transgenic animal also includes animals in which the entire animal or tissues in the animal have been produced using the homologously recombinant host cells described herein.  
     [0204] In another embodiment, transgenic non-human animals can be produced which contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1. For a description of the cre/loxP recombinase system, see, e.g., Lakso et al. PNAS  89:6232-6236 (1992). Another example of a recombinase system is the FLP recombinase system of  S. cerevisiae  (O&#39;Gorman et al.  Science  251:1351-1355 (1991). If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein is required. Such animals can be provided through the construction of “double”transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.  
     [0205] Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, I. et al.  Nature  385:810-813(1997) and PCT International Publication Nos. WO 97/07668 and WO 97/07669. In brief, a cell, e.g., a somatic cell, from the transgenic animal can be isolated and induced to exit the growth cycle and enter G o . phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyst and then transferred to pseudopregnant female foster animal. The offspring born of this female foster animal will be a clone of the animal from which the cell, e.g., the somatic cell, is isolated.  
     [0206] Transgenic animals containing recombinant cells that express the peptides described herein are useful to conduct the assays described herein in an in vivo context. Accordingly, the various physiological factors that are present in vivo and that could effect substrate binding, kinase protein activation, and signal transduction, may not be evident from in vitro cell-free or cell-based assays. Accordingly, it is useful to provide non-human transgenic animals to assay in vivo kinase protein function, including substrate interaction, the effect of specific mutant kinase proteins on kinase protein function and substrate interaction, and the effect of chimeric kinase proteins. It is also possible to assess the effect of null mutations, that is, mutations that substantially or completely eliminate one or more kinase protein functions.  
     [0207] All publications and patents mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes for carrying out the invention which are obvious to those skilled in the field of molecular biology or related fields are intended to be within the scope of the following claims.  
    
     
       
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             DNA  
             Homo sapiens  
           
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atgcagaaag cccggggcac gcgaggcgag gatgcgggca cgagggcacc ccccagcccc     60 

ggagtgcccc cgaaaagggc caaggtgggg gccggcggcg gggctcctgt ggccgtggcc    120 

ggggcgccag tcttcctgcg gcccctgaag aacgcggcgg tgtgcgcggg cagcgacgtg    180 

cggctgcggg tggtggtgag cgggacgccc cagcccagcc tccgctggtt ccgggatggg    240 

cagctcctgc ccgcgccggc ccccgagccc agctgcctgt ggctgcggcg ctgcggggcg    300 

caggacgccg gcgtgtacag ctgcatggcc cagaacgagc ggggccgggc ctcctgcgag    360 

gcggtgctca cagtgctgga ggtcggagac tcagagacgg ctgaggatga catcagcgat    420 

gtgcagggaa cccagcgcct ggagcttcgg gatgacgggg ccttcagcac ccccacgggg    480 

ggttctgaca ccctggtggg cacctccctg gacacacccc cgacctccgt gacaggcacc    540 

tcagaggagc aagtgagctg gtggggcagc gggcagacgg tcctggagca ggaagcgggc    600 

agtgggggtg gcacccgccg cctcccgggc agcccaaggc aagcacaggc aaccggggcc    660 

gggccacggc acctgggggt ggagccgctg gtgcgggcat ctcgagctaa tctggtgggc    720 

gcaagctggg ggtcagagga tagcctttcc gtggccagtg acctgtacgg cagcgcattc    780 

agcctgtaca gaggacgggc gctctctatc cacgtgagcg tccctcagag cgggttgcgc    840 

agggaggagc ccgaccttca gcctcaactg gccagcgaag ccccacgccg ccctgcccag    900 

ccgcctcctt ccaaatccgc gctgctcccc ccaccgtccc ctcgggtcgg gaagcggtcc    960 

ccgccgggac ccccggccca gcccgcggcc acccccacgt cgccccaccg tcgcactcag   1020 

gagcctgtgc tgcccgagga caccaccacc gaagagaagc gagggaagaa gtccaagtcg   1080 

tccgggccct ccctggcggg caccgcggaa tcccgacccc agacgccact gagcgaggcc   1140 

tcaggccgcc tgtcggcgtt gggccgatcg cctaggctgg tgcgcgccgg ctcccgcatc   1200 

ctggacaagc tgcagttctt cgaggagcga cggcgcagcc tggagcgcag cgactcgccg   1260 

ccggcgcccc tgcggccctg ggtgcccctg cgcaaggccc gctctctgga gcagcccaag   1320 

tcggagcgcg gcgcaccgtg gggcaccccc ggggcctcgc aggaagaact gcgggcgcca   1380 

ggcagcgtgg ccgagcggcg ccgcctgttc cagcagaaag cggcctcgct ggacgagcgc   1440 

acgcgtcagc gcagcccggc ctcagacctc gagctgcgct tcgcccagga gctgggccgc   1500 

atccgccgct ccacgtcgcg ggaggagctg gtgcgctcgc acgagtccct gcgcgccacg   1560 

ctgcagcgtg ccccatcccc tcgagagccc ggcgagcccc cgctcttctc tcggccctcc   1620 

acccccaaga catcgcgggc cgtgagcccc gccgccgccc agccgccctc tccgagcagc   1680 

gcggagaagc cgggggacga gcctgggagg cccaggagcc gcgggccggc gggcaggaca   1740 

gagccggggg aaggcccgca gcaggaggtt aggcgtcggg accaattccc gctgacccgg   1800 

agcagagcca tccaggagtg caggagccct gtgccgcccc ccgccgccga tcccccagag   1860 

gccaggacga aagcaccccc cggtcggaag cgggagcccc cggcgcaggc cgtgcgcttc   1920 

ctgccctggg ccacgccggg cctggagggc gctgctgtac cccagacctt ggagaagaac   1980 

agggcggggc ctgaggcaga gaagaggctt cgcagagggc cggaggagga cggtccctgg   2040 

gggccctggg accgccgagg ggcccgcagc cagggcaaag gtcgccgggc ccggcccacc   2100 

tcccctgagc tcgagtcttc ggatgactcc tacgtgtccg ctggagaaga gcccctagag   2160 

gcccctgtgt ttgagatccc cctgcagaat gtggtggtgg caccaggggc agatgtgctg   2220 

ctcaagtgta tcatcactgc caaccccccg ccccaagtgt cctggcacaa ggatgggtca   2280 

gcgctgcgca gcgagggccg cctcctcctc cgggctgagg gtgagcggca caccctgctg   2340 

ctcagggagg ccagggcagc agatgccggg agctatatgg ccaccgccac caacgagctg   2400 

ggccaggcca cctgtgccgc ctcactgacc gtgagacccg gtgggtctac atcccctttc   2460 

agcagcccca tcacctccga cgaggaatac ctgagccccc cagaggagtt cccagagcct   2520 

ggggagacct ggccgcgaac ccccaccatg aagcccagtc ccagccagaa ccgccgttct   2580 

tctgacactg gctccaaggc accccccacc ttcaaggtct cacttatgga ccagtcagta   2640 

agagaaggcc aagatgtcat catgagcatc cgcgtgcagg gggagcccaa gcctgtggtc   2700 

tcctggctga gaaaccgcca gcccgtgcgc ccagaccagc ggcgctttgc ggaggaggct   2760 

gagggtgggc tgtgccggct gcggatcctg gctgcagagc gtggcgatgc tggtttctac   2820 

acttgcaaag cggtcaatga gtatggtgct cggcagtgcg aggcccgctt ggaggtccga   2880 

gcacaccctg aaagccggtc cctggccgtg ctggcccccc tgcaggacgt ggacgtgggg   2940 

gccggggaga tggcgctgtt tgagtgcctg gtggcggggc ccactgacgt ggaggtggat   3000 

tggctgtgcc gtggccgcct gctgcagcct gcactgctca aatgcaagat gcatttcgat   3060 

ggccgcaaat gcaagctgct acttacatct gtacatgagg acgacagtgg cgtctacacc   3120 

tgcaagctca gcacggccaa agatgagctg acctgcagtg cccggctgac cgtgcggccc   3180 

tcgttggcac ccctgttcac acggctgctg gaagatgtgg aggtgttgga gggccgagct   3240 

gcccgtttcg actgcaagat cagtggcacc ccgccccctg ttgttacctg gactcatttt   3300 

ggctgcccca tggaggagag tgagaacttg cggctgcggc aggacggggg tctgcactca   3360 

ctgcacattg cccatgtggg cagcgaggac gaggggctct atgcggtcag tgctgttaac   3420 

acccatggcc aggcccactg ctcagcccag ctgtatgtag aagagccccg gacagccgcc   3480 

tcaggcccca gctcgaagct ggagaagatg ccatccattc ccgaggagcc agagcagggt   3540 

gagctggagc ggctgtccat tcccgacttc ctgcggccac tgcaggacct ggaggtggga   3600 

ctggccaagg aggccatgct agagtgccag gtgaccggcc tgccctaccc caccatcagc   3660 

tggttccaca atggccaccg catccagagc agcgacgacc ggcgcatgac acagtacagg   3720 

gatgtccatc gcttggtgtt ccctgccgtg gggcctcagc acgccggtgt ctacaagagc   3780 

gtcattgcca acaagctggg caaagctgcc tgctatgccc acctgtatgt cacagatgtg   3840 

gtcccaggcc ctccagatgg cgccccgcag gtggtggctg tgacggggag gatggtcaca   3900 

ctcacatgga acccccccag gagtctggac atggccatcg acccggactc cctgacgtac   3960 

acagtgcagc accaggtgct gggctcggac cagtggacgg cactggtcac aggcctgcgg   4020 

gagccagggt gggcagccac agggctgcgt aagggggtcc agcacatctt ccgggtcctc   4080 

agcaccactg tcaagagcag cagcaagccc tcaccccctt ctgagcctgt gcagctgctg   4140 

gagcacggcc caaccctgga ggaggcccct gccatgctgg acaaaccaga catcgtgtat   4200 

gtggtggagg gacagcctgc cagcgtcacc gtcacattca accatgtgga ggcccaggtc   4260 

gtctggagga gctgccgagg ggccctccta gaggcacggg ccggtgtgta cgagctgagc   4320 

cagccagatg atgaccagta ctgtcttcgg atctgccggg tgagccgccg ggacatgggg   4380 

gccctcacct gcaccgcccg aaaccgtcac ggcacacaga cctgctcggt cacattggag   4440 

ctggcagagg cccctcggtt tgagtccatc atggaggacg tggaggtggg ggctggggaa   4500 

actgctcgct ttgcggtggt ggtcgaggga aaaccactgc cggacatcat gtggtacaag   4560 

gacgaggtgc tgctgaccga gagcagccat gtgagcttcg tgtacgagga gaatgagtgc   4620 

tccctggtgg tgctcagcac gggggcccag gatggaggcg tctacacctg caccgcccag   4680 

aacctggcgg gtgaggtctc ctgcaaagca gagttggctg tgcattcagc tcagacagct   4740 

atggaggtcg agggggtcgg ggaggatgag gaccatcgag gaaggagact cagcgacttt   4800 

tatgacatcc accaggagat cggcaggggt gctttctcct acttgcggcg catagtggag   4860 

cgtagctccg gcctggagtt tgcggccaag ttcatcccca gccaggccaa gccaaaggca   4920 

tcagcgcgtc gggaggcccg gctgctggcc aggctccagc acgactgtgt cctctacttc   4980 

catgaggcct tcgagaggcg ccggggactg gtcattgtca ccgagctctg cacagaggag   5040 

ctgctggagc gaatcgccag gaaacccacc gtgtgtgagt ctgagatccg ggcctatatg   5100 

cggcaggtgc tagagggaat acactacctg caccagagcc acgtgctgca cctcgatgtc   5160 

aagcctgaga acctgctggt gtgggatggt gctgcgggcg agcagcaggt gcggatctgt   5220 

gactttggga atgcccagga gctgactcca ggagagcccc agtactgcca gtatggcaca   5280 

cctgagtttg tagcacccga gattgtcaat cagagccccg tgtctggagt cactgacatc   5340 

tggcctgtgg gtgttgttgc cttcctctgt ctgacaggaa tctccccgtt tgttggggaa   5400 

aatgaccgga caacattgat gaacatccga aactacaacg tggccttcga ggagaccaca   5460 

ttcctgagcc tgagcaggga ggcccggggc ttcctcatca aagtgttggt gcaggaccgg   5520 

ctgagaccta ccgcagaaga gaccctagaa catccttggt tcaaaactca ggcaaagggc   5580 

gcagaggtga gcacggatca cctgaagcta ttcctctccc ggcggaggtg gcagcgctcc   5640 

cagatcagct acaaatgcca cctggtgctg cgccccatcc ccgagctgct gcgggccccc   5700 

ccagagcggg tgtgggtgac catgcccaga aggccacccc ccagtggggg gctctcatcc   5760 

tcctcggatt ctgaagagga agagctggaa gagctgccct cagtgccccg cccactgcag   5820 

cccgagttct ctggctcccg ggtgtccctc acagacattc ccactgagga tgaggccctg   5880 

gggaccccag agactggggc tgccaccccc atggactggc aggagcaggg aagggctccc   5940 

tctcaggacc aggaggctcc cagcccagag gccctcccct ccccaggcca ggagcccgca   6000 

gctggggcta gccccaggcg gggagagctc cgcaggggca gctcggctga gagcgccctg   6060 

ccccgggccg ggccgcggga gctgggccgg ggcctgcaca aggcggcgtc tgtggagctg   6120 

ccgcagcgcc ggagccccag cccgggagcc acccgcctgg cccggggagg cctgggtgag   6180 

ggcgagtatg cccagaggct gcaggccctg cgccagcggc tgctgcgggg aggccccgag   6240 

gatggcaagg tcagcggcct caggggtccc ctgctggaga gcctgggggg ccgtgctcgg   6300 

gacccccgga tggcacgagc tgcctccagc gaggcagcgc cccaccacca gcccccactc   6360 

gagaaccggg gcctgcaaaa gagcagcagc ttctcccagg gtgaggcgga gccccggggc   6420 

cggcaccgcc gagcgggggc gcccctcgag atccccgtgg ccaggcttgg ggcccgtagg   6480 

ctacaggagt ctccttccct gtctgccctc agcgaggccc agccatccag ccctgcacgg   6540 

cccagcgccc ccaaacccag tacccctaag tctgcagaac cttctgccac cacacctagt   6600 

gatgctccgc agccccccgc accccagcct gcccaagaca aggctccaga gcccaggcca   6660 

gaaccagtcc gagcctccaa gcctgcacca cccccccagg ccctgcaaac cctagcgctg   6720 

cccctcacac cctatgctca gatcattcag tccctccagc tgtcaggcca cgcccagggc   6780 

ccctcgcagg gccctgccgc gccgccttca gagcccaagc cccacgctgc tgtctttgcc   6840 

agggtggcct ccccacctcc gggagccccc gagaagcgcg tgccctcagc cgggggtccc   6900 

ccggtgctag ccgagaaagc ccgagttccc acggtgcccc ccaggccagg cagcagtctc   6960 

agtagcagca tcgaaaactt ggagtcggag gccgtgttcg aggccaagtt caagcgcagc   7020 

cgcgagtcgc ccctgtcgct ggggctgcgg ctgctgagcc gttcgcgctc ggaggagcgc   7080 

ggccccttcc gtggggccga ggaggaggat ggcatatacc ggcccagccc ggcggggacc   7140 

ccgctggagc tggtgcgacg gcctgagcgc tcacgctcgg tgcaggacct cagggctgtc   7200 

ggagagcctg gcctcgtccg ccgcctctcg ctgtcactgt cccagcggct gcggcggacc   7260 

cctcccgcgc agcgccaccc ggcctgggag gcccgcggcg gggacggaga gagctcggag   7320 

ggcgggagct cggcgcgggg ctccccggtg ctggcgatgc gcaggcggct gagcttcacc   7380 

ctggagcggc tgtccagccg attgcagcgc agtggcagca gcgaggactc ggggggcgcg   7440 

tcgggccgca gcacgccgct gttcggacgg cttcgcaggg ccacgtccga gggcgagagt   7500 

ctgcggcgcc ttggccttcc gcacaaccag ttggccgccc aggccggcgc caccacgcct   7560 

tccgccgagt ccctgggctc cgaggccagc gccacgtcgg gctcctcagc cccaggggaa   7620 

agccgaagcc ggctccgctg gggcttctct cggccgcgga aggacaaggg gttatcgcca   7680 

ccaaacctct ctgccagcgt ccaggaggag ttgggtcacc agtacgtgcg cagtgagtca   7740 

gacttccccc cagtcttcca catcaaactc aaggaccagg tgctgctgga gggggaggca   7800 

gccaccctgc tctgcctgcc agcggcctgc cctgcaccgc acatctcctg gatgaaagac   7860 

aagaagtcct tgaggtcaga gccctcagtg atcatcgtgt cctgcaaaga tgggcggcag   7920 

ctgctcagca tcccccgggc gggcaagcgg cacgccggtc tctatgagtg ctcggccacc   7980 

aacgtactgg gcagcatcac cagctcctgt accgtggctg tggcccgagt cccaggaaag   8040 

ctagctcctc cagaggtacc ccagacctac caggacacgg cgctggtgct gtggaagccg   8100 

ggagacagcc gggcaccttg cacgtatacg ctggagcggc gagtggatgg ggagtctgtg   8160 

tggcaccctg tgagctcagg catccccgac tgttactaca acgtgaccca cctgccagtt   8220 

ggcgtgactg tgaggttccg tgtggcctgt gccaaccgtg ctgggcaggg gcccttcagc   8280 

aactcttctg agaaggtctt tgtcaggggt actcaagatt cttcagctgt gccatctgct   8340 

gcccaccaag aggcccctgt cacctcaagg ccagccaggg cccggcctcc tgactctcct   8400 

acctcactgg ccccacccct agctcctgct gcccccacac ccccgtcagt cactgtcagc   8460 

ccctcatctc cccccacacc tcctagccag gccttgtcct cgctcaaggc tgtgggtcca   8520 

ccaccccaaa cccctccacg aagacacagg ggcctgcagg ctgcccggcc agcggagccc   8580 

accctaccca gtacccacgt caccccaagt gagcccaagc ctttcgtcct tgacactggg   8640 

accccgatcc cagcctccac tcctcaaggg gttaaaccag tgtcttcctc tactcctgtg   8700 

tatgtggtga cttcctttgt gtctgcacca ccagcccctg agcccccagc ccctgagccc   8760 

cctcctgagc ctaccaaggt gactgtgcag agcctcagcc cggccaagga ggtggtcagc   8820 

tcccctggga gcagtccccg aagctctccc aggcctgagg gtaccactct tcgacagggt   8880 

ccccctcaga aaccctacac cttcctggag gagaaagcca ggcagggccg ctttggtgtt   8940 

gtgcgagcgt gccgggagaa tgccacgggg cgaacgttcg tggccaagat cgtgccctat   9000 

gctgccgagg gcaagcggcg ggtcctgcag gagtacgagg tgctgcggac cctgcaccac   9060 

gagcggatca tgtccctgca cgaggcctac atcacccctc ggtacctcgt gctcattgct   9120 

gagagctgtg gcaaccggga actcctctgt gggctcagtg acaggttccg gtattctgag   9180 

gatgacgtgg ccacttacat ggtgcagctg ctacaaggcc tggactacct ccacggccac   9240 

cacgtgctcc acctagacat caagccagac aacctgctgc tggcccctga caatgccctc   9300 

aagattgtgg actttggcag tgcccagccc tacaaccccc aggcccttag gccccttggc   9360 

caccgcacgg gcacgctgga gttcatggct ccggagatgg tgaagggaga acccatcggc   9420 

tctgccacgg acatctgggg agcgggtgtg ctcacttaca ttatgctcag tggacgctcc   9480 

ccgttctatg agccagaccc ccaggaaacg gaggctcgga ttgtgggggg ccgctttgat   9540 

gccttccagc tgtaccccaa tacatcccag agcgccaccc tcttcttgcg aaaggttctc   9600 

tctgtacatc cctggagccg gccctccctg caggactgcc tggcccaccc atggttgcag   9660 

gacgcctacc tgatgaagct gcgccgccag acgctcacct tcaccaccaa ccggctcaag   9720 

gagttcctgg gcgagcagcg gcggcgccgg gctgaggctg ccacccgcca caaggtgctg   9780 

ctgcgctcct accctggcgg cccctag                                       9807 

 
           
             2  
             3268  
             PRT  
             Homo sapiens  
           
            2 

Met Gln Lys Ala Arg Gly Thr Arg Gly Glu Asp Ala Gly Thr Arg Ala 
 1               5                  10                  15 

Pro Pro Ser Pro Gly Val Pro Pro Lys Arg Ala Lys Val Gly Ala Gly 
            20                  25                  30 

Gly Gly Ala Pro Val Ala Val Ala Gly Ala Pro Val Phe Leu Arg Pro 
        35                  40                  45 

Leu Lys Asn Ala Ala Val Cys Ala Gly Ser Asp Val Arg Leu Arg Val 
    50                  55                  60 

Val Val Ser Gly Thr Pro Gln Pro Ser Leu Arg Trp Phe Arg Asp Gly 
65                  70                  75                  80 

Gln Leu Leu Pro Ala Pro Ala Pro Glu Pro Ser Cys Leu Trp Leu Arg 
                85                  90                  95 

Arg Cys Gly Ala Gln Asp Ala Gly Val Tyr Ser Cys Met Ala Gln Asn 
            100                 105                 110 

Glu Arg Gly Arg Ala Ser Cys Glu Ala Val Leu Thr Val Leu Glu Val 
        115                 120                 125 

Gly Asp Ser Glu Thr Ala Glu Asp Asp Ile Ser Asp Val Gln Gly Thr 
    130                 135                 140 

Gln Arg Leu Glu Leu Arg Asp Asp Gly Ala Phe Ser Thr Pro Thr Gly 
145                 150                 155                 160 

Gly Ser Asp Thr Leu Val Gly Thr Ser Leu Asp Thr Pro Pro Thr Ser 
                165                 170                 175 

Val Thr Gly Thr Ser Glu Glu Gln Val Ser Trp Trp Gly Ser Gly Gln 
            180                 185                 190 

Thr Val Leu Glu Gln Glu Ala Gly Ser Gly Gly Gly Thr Arg Arg Leu 
        195                 200                 205 

Pro Gly Ser Pro Arg Gln Ala Gln Ala Thr Gly Ala Gly Pro Arg His 
    210                 215                 220 

Leu Gly Val Glu Pro Leu Val Arg Ala Ser Arg Ala Asn Leu Val Gly 
225                 230                 235                 240 

Ala Ser Trp Gly Ser Glu Asp Ser Leu Ser Val Ala Ser Asp Leu Tyr 
                245                 250                 255 

Gly Ser Ala Phe Ser Leu Tyr Arg Gly Arg Ala Leu Ser Ile His Val 
            260                 265                 270 

Ser Val Pro Gln Ser Gly Leu Arg Arg Glu Glu Pro Asp Leu Gln Pro 
        275                 280                 285 

Gln Leu Ala Ser Glu Ala Pro Arg Arg Pro Ala Gln Pro Pro Pro Ser 
    290                 295                 300 

Lys Ser Ala Leu Leu Pro Pro Pro Ser Pro Arg Val Gly Lys Arg Ser 
305                 310                 315                 320 

Pro Pro Gly Pro Pro Ala Gln Pro Ala Ala Thr Pro Thr Ser Pro His 
                325                 330                 335 

Arg Arg Thr Gln Glu Pro Val Leu Pro Glu Asp Thr Thr Thr Glu Glu 
            340                 345                 350 

Lys Arg Gly Lys Lys Ser Lys Ser Ser Gly Pro Ser Leu Ala Gly Thr 
        355                 360                 365 

Ala Glu Ser Arg Pro Gln Thr Pro Leu Ser Glu Ala Ser Gly Arg Leu 
    370                 375                 380 

Ser Ala Leu Gly Arg Ser Pro Arg Leu Val Arg Ala Gly Ser Arg Ile 
385                 390                 395                 400 

Leu Asp Lys Leu Gln Phe Phe Glu Glu Arg Arg Arg Ser Leu Glu Arg 
                405                 410                 415 

Ser Asp Ser Pro Pro Ala Pro Leu Arg Pro Trp Val Pro Leu Arg Lys 
            420                 425                 430 

Ala Arg Ser Leu Glu Gln Pro Lys Ser Glu Arg Gly Ala Pro Trp Gly 
        435                 440                 445 

Thr Pro Gly Ala Ser Gln Glu Glu Leu Arg Ala Pro Gly Ser Val Ala 
    450                 455                 460 

Glu Arg Arg Arg Leu Phe Gln Gln Lys Ala Ala Ser Leu Asp Glu Arg 
465                 470                 475                 480 

Thr Arg Gln Arg Ser Pro Ala Ser Asp Leu Glu Leu Arg Phe Ala Gln 
                485                 490                 495 

Glu Leu Gly Arg Ile Arg Arg Ser Thr Ser Arg Glu Glu Leu Val Arg 
            500                 505                 510 

Ser His Glu Ser Leu Arg Ala Thr Leu Gln Arg Ala Pro Ser Pro Arg 
        515                 520                 525 

Glu Pro Gly Glu Pro Pro Leu Phe Ser Arg Pro Ser Thr Pro Lys Thr 
    530                 535                 540 

Ser Arg Ala Val Ser Pro Ala Ala Ala Gln Pro Pro Ser Pro Ser Ser 
545                 550                 555                 560 

Ala Glu Lys Pro Gly Asp Glu Pro Gly Arg Pro Arg Ser Arg Gly Pro 
                565                 570                 575 

Ala Gly Arg Thr Glu Pro Gly Glu Gly Pro Gln Gln Glu Val Arg Arg 
            580                 585                 590 

Arg Asp Gln Phe Pro Leu Thr Arg Ser Arg Ala Ile Gln Glu Cys Arg 
        595                 600                 605 

Ser Pro Val Pro Pro Pro Ala Ala Asp Pro Pro Glu Ala Arg Thr Lys 
    610                 615                 620 

Ala Pro Pro Gly Arg Lys Arg Glu Pro Pro Ala Gln Ala Val Arg Phe 
625                 630                 635                 640 

Leu Pro Trp Ala Thr Pro Gly Leu Glu Gly Ala Ala Val Pro Gln Thr 
                645                 650                 655 

Leu Glu Lys Asn Arg Ala Gly Pro Glu Ala Glu Lys Arg Leu Arg Arg 
            660                 665                 670 

Gly Pro Glu Glu Asp Gly Pro Trp Gly Pro Trp Asp Arg Arg Gly Ala 
        675                 680                 685 

Arg Ser Gln Gly Lys Gly Arg Arg Ala Arg Pro Thr Ser Pro Glu Leu 
    690                 695                 700 

Glu Ser Ser Asp Asp Ser Tyr Val Ser Ala Gly Glu Glu Pro Leu Glu 
705                 710                 715                 720 

Ala Pro Val Phe Glu Ile Pro Leu Gln Asn Val Val Val Ala Pro Gly 
                725                 730                 735 

Ala Asp Val Leu Leu Lys Cys Ile Ile Thr Ala Asn Pro Pro Pro Gln 
            740                 745                 750 

Val Ser Trp His Lys Asp Gly Ser Ala Leu Arg Ser Glu Gly Arg Leu 
        755                 760                 765 

Leu Leu Arg Ala Glu Gly Glu Arg His Thr Leu Leu Leu Arg Glu Ala 
    770                 775                 780 

Arg Ala Ala Asp Ala Gly Ser Tyr Met Ala Thr Ala Thr Asn Glu Leu 
785                 790                 795                 800 

Gly Gln Ala Thr Cys Ala Ala Ser Leu Thr Val Arg Pro Gly Gly Ser 
                805                 810                 815 

Thr Ser Pro Phe Ser Ser Pro Ile Thr Ser Asp Glu Glu Tyr Leu Ser 
            820                 825                 830 

Pro Pro Glu Glu Phe Pro Glu Pro Gly Glu Thr Trp Pro Arg Thr Pro 
        835                 840                 845 

Thr Met Lys Pro Ser Pro Ser Gln Asn Arg Arg Ser Ser Asp Thr Gly 
    850                 855                 860 

Ser Lys Ala Pro Pro Thr Phe Lys Val Ser Leu Met Asp Gln Ser Val 
865                 870                 875                 880 

Arg Glu Gly Gln Asp Val Ile Met Ser Ile Arg Val Gln Gly Glu Pro 
                885                 890                 895 

Lys Pro Val Val Ser Trp Leu Arg Asn Arg Gln Pro Val Arg Pro Asp 
            900                 905                 910 

Gln Arg Arg Phe Ala Glu Glu Ala Glu Gly Gly Leu Cys Arg Leu Arg 
        915                 920                 925 

Ile Leu Ala Ala Glu Arg Gly Asp Ala Gly Phe Tyr Thr Cys Lys Ala 
    930                 935                 940 

Val Asn Glu Tyr Gly Ala Arg Gln Cys Glu Ala Arg Leu Glu Val Arg 
945                 950                 955                 960 

Ala His Pro Glu Ser Arg Ser Leu Ala Val Leu Ala Pro Leu Gln Asp 
                965                 970                 975 

Val Asp Val Gly Ala Gly Glu Met Ala Leu Phe Glu Cys Leu Val Ala 
            980                 985                 990 

Gly Pro Thr Asp Val Glu Val Asp Trp Leu Cys Arg Gly Arg Leu Leu 
        995                 1000                1005 

Gln Pro Ala Leu Leu Lys Cys Lys Met His Phe Asp Gly Arg Lys Cys 
    1010                1015                1020 

Lys Leu Leu Leu Thr Ser Val His Glu Asp Asp Ser Gly Val Tyr Thr 
1025                1030                1035                1040 

Cys Lys Leu Ser Thr Ala Lys Asp Glu Leu Thr Cys Ser Ala Arg Leu 
                1045                1050                1055 

Thr Val Arg Pro Ser Leu Ala Pro Leu Phe Thr Arg Leu Leu Glu Asp 
            1060                1065                1070 

Val Glu Val Leu Glu Gly Arg Ala Ala Arg Phe Asp Cys Lys Ile Ser 
        1075                1080                1085 

Gly Thr Pro Pro Pro Val Val Thr Trp Thr His Phe Gly Cys Pro Met 
    1090                1095                1100 

Glu Glu Ser Glu Asn Leu Arg Leu Arg Gln Asp Gly Gly Leu His Ser 
1105                1110                1115                1120 

Leu His Ile Ala His Val Gly Ser Glu Asp Glu Gly Leu Tyr Ala Val 
                1125                1130                1135 

Ser Ala Val Asn Thr His Gly Gln Ala His Cys Ser Ala Gln Leu Tyr 
            1140                1145                1150 

Val Glu Glu Pro Arg Thr Ala Ala Ser Gly Pro Ser Ser Lys Leu Glu 
        1155                1160                1165 

Lys Met Pro Ser Ile Pro Glu Glu Pro Glu Gln Gly Glu Leu Glu Arg 
    1170                1175                1180 

Leu Ser Ile Pro Asp Phe Leu Arg Pro Leu Gln Asp Leu Glu Val Gly 
1185                1190                1195                1200 

Leu Ala Lys Glu Ala Met Leu Glu Cys Gln Val Thr Gly Leu Pro Tyr 
                1205                1210                1215 

Pro Thr Ile Ser Trp Phe His Asn Gly His Arg Ile Gln Ser Ser Asp 
            1220                1225                1230 

Asp Arg Arg Met Thr Gln Tyr Arg Asp Val His Arg Leu Val Phe Pro 
        1235                1240                1245 

Ala Val Gly Pro Gln His Ala Gly Val Tyr Lys Ser Val Ile Ala Asn 
    1250                1255                1260 

Lys Leu Gly Lys Ala Ala Cys Tyr Ala His Leu Tyr Val Thr Asp Val 
1265                1270                1275                1280 

Val Pro Gly Pro Pro Asp Gly Ala Pro Gln Val Val Ala Val Thr Gly 
                1285                1290                1295 

Arg Met Val Thr Leu Thr Trp Asn Pro Pro Arg Ser Leu Asp Met Ala 
            1300                1305                1310 

Ile Asp Pro Asp Ser Leu Thr Tyr Thr Val Gln His Gln Val Leu Gly 
        1315                1320                1325 

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

Ala Ala Thr Gly Leu Arg Lys Gly Val Gln His Ile Phe Arg Val Leu 
1345                1350                1355                1360 

Ser Thr Thr Val Lys Ser Ser Ser Lys Pro Ser Pro Pro Ser Glu Pro 
                1365                1370                1375 

Val Gln Leu Leu Glu His Gly Pro Thr Leu Glu Glu Ala Pro Ala Met 
            1380                1385                1390 

Leu Asp Lys Pro Asp Ile Val Tyr Val Val Glu Gly Gln Pro Ala Ser 
        1395                1400                1405 

Val Thr Val Thr Phe Asn His Val Glu Ala Gln Val Val Trp Arg Ser 
    1410                1415                1420 

Cys Arg Gly Ala Leu Leu Glu Ala Arg Ala Gly Val Tyr Glu Leu Ser 
1425                1430                1435                1440 

Gln Pro Asp Asp Asp Gln Tyr Cys Leu Arg Ile Cys Arg Val Ser Arg 
                1445                1450                1455 

Arg Asp Met Gly Ala Leu Thr Cys Thr Ala Arg Asn Arg His Gly Thr 
            1460                1465                1470 

Gln Thr Cys Ser Val Thr Leu Glu Leu Ala Glu Ala Pro Arg Phe Glu 
        1475                1480                1485 

Ser Ile Met Glu Asp Val Glu Val Gly Ala Gly Glu Thr Ala Arg Phe 
    1490                1495                1500 

Ala Val Val Val Glu Gly Lys Pro Leu Pro Asp Ile Met Trp Tyr Lys 
1505                1510                1515                1520 

Asp Glu Val Leu Leu Thr Glu Ser Ser His Val Ser Phe Val Tyr Glu 
                1525                1530                1535 

Glu Asn Glu Cys Ser Leu Val Val Leu Ser Thr Gly Ala Gln Asp Gly 
            1540                1545                1550 

Gly Val Tyr Thr Cys Thr Ala Gln Asn Leu Ala Gly Glu Val Ser Cys 
        1555                1560                1565 

Lys Ala Glu Leu Ala Val His Ser Ala Gln Thr Ala Met Glu Val Glu 
    1570                1575                1580 

Gly Val Gly Glu Asp Glu Asp His Arg Gly Arg Arg Leu Ser Asp Phe 
1585                1590                1595                1600 

Tyr Asp Ile His Gln Glu Ile Gly Arg Gly Ala Phe Ser Tyr Leu Arg 
                1605                1610                1615 

Arg Ile Val Glu Arg Ser Ser Gly Leu Glu Phe Ala Ala Lys Phe Ile 
            1620                1625                1630 

Pro Ser Gln Ala Lys Pro Lys Ala Ser Ala Arg Arg Glu Ala Arg Leu 
        1635                1640                1645 

Leu Ala Arg Leu Gln His Asp Cys Val Leu Tyr Phe His Glu Ala Phe 
    1650                1655                1660 

Glu Arg Arg Arg Gly Leu Val Ile Val Thr Glu Leu Cys Thr Glu Glu 
1665                1670                1675                1680 

Leu Leu Glu Arg Ile Ala Arg Lys Pro Thr Val Cys Glu Ser Glu Ile 
                1685                1690                1695 

Arg Ala Tyr Met Arg Gln Val Leu Glu Gly Ile His Tyr Leu His Gln 
            1700                1705                1710 

Ser His Val Leu His Leu Asp Val Lys Pro Glu Asn Leu Leu Val Trp 
        1715                1720                1725 

Asp Gly Ala Ala Gly Glu Gln Gln Val Arg Ile Cys Asp Phe Gly Asn 
    1730                1735                1740 

Ala Gln Glu Leu Thr Pro Gly Glu Pro Gln Tyr Cys Gln Tyr Gly Thr 
1745                1750                1755                1760 

Pro Glu Phe Val Ala Pro Glu Ile Val Asn Gln Ser Pro Val Ser Gly 
                1765                1770                1775 

Val Thr Asp Ile Trp Pro Val Gly Val Val Ala Phe Leu Cys Leu Thr 
            1780                1785                1790 

Gly Ile Ser Pro Phe Val Gly Glu Asn Asp Arg Thr Thr Leu Met Asn 
        1795                1800                1805 

Ile Arg Asn Tyr Asn Val Ala Phe Glu Glu Thr Thr Phe Leu Ser Leu 
    1810                1815                1820 

Ser Arg Glu Ala Arg Gly Phe Leu Ile Lys Val Leu Val Gln Asp Arg 
1825                1830                1835                1840 

Leu Arg Pro Thr Ala Glu Glu Thr Leu Glu His Pro Trp Phe Lys Thr 
                1845                1850                1855 

Gln Ala Lys Gly Ala Glu Val Ser Thr Asp His Leu Lys Leu Phe Leu 
            1860                1865                1870 

Ser Arg Arg Arg Trp Gln Arg Ser Gln Ile Ser Tyr Lys Cys His Leu 
        1875                1880                1885 

Val Leu Arg Pro Ile Pro Glu Leu Leu Arg Ala Pro Pro Glu Arg Val 
    1890                1895                1900 

Trp Val Thr Met Pro Arg Arg Pro Pro Pro Ser Gly Gly Leu Ser Ser 
1905                1910                1915                1920 

Ser Ser Asp Ser Glu Glu Glu Glu Leu Glu Glu Leu Pro Ser Val Pro 
                1925                1930                1935 

Arg Pro Leu Gln Pro Glu Phe Ser Gly Ser Arg Val Ser Leu Thr Asp 
            1940                1945                1950 

Ile Pro Thr Glu Asp Glu Ala Leu Gly Thr Pro Glu Thr Gly Ala Ala 
        1955                1960                1965 

Thr Pro Met Asp Trp Gln Glu Gln Gly Arg Ala Pro Ser Gln Asp Gln 
    1970                1975                1980 

Glu Ala Pro Ser Pro Glu Ala Leu Pro Ser Pro Gly Gln Glu Pro Ala 
1985                1990                1995                2000 

Ala Gly Ala Ser Pro Arg Arg Gly Glu Leu Arg Arg Gly Ser Ser Ala 
                2005                2010                2015 

Glu Ser Ala Leu Pro Arg Ala Gly Pro Arg Glu Leu Gly Arg Gly Leu 
            2020                2025                2030 

His Lys Ala Ala Ser Val Glu Leu Pro Gln Arg Arg Ser Pro Ser Pro 
        2035                2040                2045 

Gly Ala Thr Arg Leu Ala Arg Gly Gly Leu Gly Glu Gly Glu Tyr Ala 
    2050                2055                2060 

Gln Arg Leu Gln Ala Leu Arg Gln Arg Leu Leu Arg Gly Gly Pro Glu 
2065                2070                2075                2080 

Asp Gly Lys Val Ser Gly Leu Arg Gly Pro Leu Leu Glu Ser Leu Gly 
                2085                2090                2095 

Gly Arg Ala Arg Asp Pro Arg Met Ala Arg Ala Ala Ser Ser Glu Ala 
            2100                2105                2110 

Ala Pro His His Gln Pro Pro Leu Glu Asn Arg Gly Leu Gln Lys Ser 
        2115                2120                2125 

Ser Ser Phe Ser Gln Gly Glu Ala Glu Pro Arg Gly Arg His Arg Arg 
    2130                2135                2140 

Ala Gly Ala Pro Leu Glu Ile Pro Val Ala Arg Leu Gly Ala Arg Arg 
2145                2150                2155                2160 

Leu Gln Glu Ser Pro Ser Leu Ser Ala Leu Ser Glu Ala Gln Pro Ser 
                2165                2170                2175 

Ser Pro Ala Arg Pro Ser Ala Pro Lys Pro Ser Thr Pro Lys Ser Ala 
            2180                2185                2190 

Glu Pro Ser Ala Thr Thr Pro Ser Asp Ala Pro Gln Pro Pro Ala Pro 
        2195                2200                2205 

Gln Pro Ala Gln Asp Lys Ala Pro Glu Pro Arg Pro Glu Pro Val Arg 
    2210                2215                2220 

Ala Ser Lys Pro Ala Pro Pro Pro Gln Ala Leu Gln Thr Leu Ala Leu 
2225                2230                2235                2240 

Pro Leu Thr Pro Tyr Ala Gln Ile Ile Gln Ser Leu Gln Leu Ser Gly 
                2245                2250                2255 

His Ala Gln Gly Pro Ser Gln Gly Pro Ala Ala Pro Pro Ser Glu Pro 
            2260                2265                2270 

Lys Pro His Ala Ala Val Phe Ala Arg Val Ala Ser Pro Pro Pro Gly 
        2275                2280                2285 

Ala Pro Glu Lys Arg Val Pro Ser Ala Gly Gly Pro Pro Val Leu Ala 
    2290                2295                2300 

Glu Lys Ala Arg Val Pro Thr Val Pro Pro Arg Pro Gly Ser Ser Leu 
2305                2310                2315                2320 

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

Phe Lys Arg Ser Arg Glu Ser Pro Leu Ser Leu Gly Leu Arg Leu Leu 
            2340                2345                2350 

Ser Arg Ser Arg Ser Glu Glu Arg Gly Pro Phe Arg Gly Ala Glu Glu 
        2355                2360                2365 

Glu Asp Gly Ile Tyr Arg Pro Ser Pro Ala Gly Thr Pro Leu Glu Leu 
    2370                2375                2380 

Val Arg Arg Pro Glu Arg Ser Arg Ser Val Gln Asp Leu Arg Ala Val 
2385                2390                2395                2400 

Gly Glu Pro Gly Leu Val Arg Arg Leu Ser Leu Ser Leu Ser Gln Arg 
                2405                2410                2415 

Leu Arg Arg Thr Pro Pro Ala Gln Arg His Pro Ala Trp Glu Ala Arg 
            2420                2425                2430 

Gly Gly Asp Gly Glu Ser Ser Glu Gly Gly Ser Ser Ala Arg Gly Ser 
        2435                2440                2445 

Pro Val Leu Ala Met Arg Arg Arg Leu Ser Phe Thr Leu Glu Arg Leu 
    2450                2455                2460 

Ser Ser Arg Leu Gln Arg Ser Gly Ser Ser Glu Asp Ser Gly Gly Ala 
2465                2470                2475                2480 

Ser Gly Arg Ser Thr Pro Leu Phe Gly Arg Leu Arg Arg Ala Thr Ser 
                2485                2490                2495 

Glu Gly Glu Ser Leu Arg Arg Leu Gly Leu Pro His Asn Gln Leu Ala 
            2500                2505                2510 

Ala Gln Ala Gly Ala Thr Thr Pro Ser Ala Glu Ser Leu Gly Ser Glu 
        2515                2520                2525 

Ala Ser Ala Thr Ser Gly Ser Ser Ala Pro Gly Glu Ser Arg Ser Arg 
    2530                2535                2540 

Leu Arg Trp Gly Phe Ser Arg Pro Arg Lys Asp Lys Gly Leu Ser Pro 
2545                2550                2555                2560 

Pro Asn Leu Ser Ala Ser Val Gln Glu Glu Leu Gly His Gln Tyr Val 
                2565                2570                2575 

Arg Ser Glu Ser Asp Phe Pro Pro Val Phe His Ile Lys Leu Lys Asp 
            2580                2585                2590 

Gln Val Leu Leu Glu Gly Glu Ala Ala Thr Leu Leu Cys Leu Pro Ala 
        2595                2600                2605 

Ala Cys Pro Ala Pro His Ile Ser Trp Met Lys Asp Lys Lys Ser Leu 
    2610                2615                2620 

Arg Ser Glu Pro Ser Val Ile Ile Val Ser Cys Lys Asp Gly Arg Gln 
2625                2630                2635                2640 

Leu Leu Ser Ile Pro Arg Ala Gly Lys Arg His Ala Gly Leu Tyr Glu 
                2645                2650                2655 

Cys Ser Ala Thr Asn Val Leu Gly Ser Ile Thr Ser Ser Cys Thr Val 
            2660                2665                2670 

Ala Val Ala Arg Val Pro Gly Lys Leu Ala Pro Pro Glu Val Pro Gln 
        2675                2680                2685 

Thr Tyr Gln Asp Thr Ala Leu Val Leu Trp Lys Pro Gly Asp Ser Arg 
    2690                2695                2700 

Ala Pro Cys Thr Tyr Thr Leu Glu Arg Arg Val Asp Gly Glu Ser Val 
2705                2710                2715                2720 

Trp His Pro Val Ser Ser Gly Ile Pro Asp Cys Tyr Tyr Asn Val Thr 
                2725                2730                2735 

His Leu Pro Val Gly Val Thr Val Arg Phe Arg Val Ala Cys Ala Asn 
            2740                2745                2750 

Arg Ala Gly Gln Gly Pro Phe Ser Asn Ser Ser Glu Lys Val Phe Val 
        2755                2760                2765 

Arg Gly Thr Gln Asp Ser Ser Ala Val Pro Ser Ala Ala His Gln Glu 
    2770                2775                2780 

Ala Pro Val Thr Ser Arg Pro Ala Arg Ala Arg Pro Pro Asp Ser Pro 
2785                2790                2795                2800 

Thr Ser Leu Ala Pro Pro Leu Ala Pro Ala Ala Pro Thr Pro Pro Ser 
                2805                2810                2815 

Val Thr Val Ser Pro Ser Ser Pro Pro Thr Pro Pro Ser Gln Ala Leu 
            2820                2825                2830 

Ser Ser Leu Lys Ala Val Gly Pro Pro Pro Gln Thr Pro Pro Arg Arg 
        2835                2840                2845 

His Arg Gly Leu Gln Ala Ala Arg Pro Ala Glu Pro Thr Leu Pro Ser 
    2850                2855                2860 

Thr His Val Thr Pro Ser Glu Pro Lys Pro Phe Val Leu Asp Thr Gly 
2865                2870                2875                2880 

Thr Pro Ile Pro Ala Ser Thr Pro Gln Gly Val Lys Pro Val Ser Ser 
                2885                2890                2895 

Ser Thr Pro Val Tyr Val Val Thr Ser Phe Val Ser Ala Pro Pro Ala 
            2900                2905                2910 

Pro Glu Pro Pro Ala Pro Glu Pro Pro Pro Glu Pro Thr Lys Val Thr 
        2915                2920                2925 

Val Gln Ser Leu Ser Pro Ala Lys Glu Val Val Ser Ser Pro Gly Ser 
    2930                2935                2940 

Ser Pro Arg Ser Ser Pro Arg Pro Glu Gly Thr Thr Leu Arg Gln Gly 
2945                2950                2955                2960 

Pro Pro Gln Lys Pro Tyr Thr Phe Leu Glu Glu Lys Ala Arg Gln Gly 
                2965                2970                2975 

Arg Phe Gly Val Val Arg Ala Cys Arg Glu Asn Ala Thr Gly Arg Thr 
            2980                2985                2990 

Phe Val Ala Lys Ile Val Pro Tyr Ala Ala Glu Gly Lys Arg Arg Val 
        2995                3000                3005 

Leu Gln Glu Tyr Glu Val Leu Arg Thr Leu His His Glu Arg Ile Met 
    3010                3015                3020 

Ser Leu His Glu Ala Tyr Ile Thr Pro Arg Tyr Leu Val Leu Ile Ala 
3025                3030                3035                3040 

Glu Ser Cys Gly Asn Arg Glu Leu Leu Cys Gly Leu Ser Asp Arg Phe 
                3045                3050                3055 

Arg Tyr Ser Glu Asp Asp Val Ala Thr Tyr Met Val Gln Leu Leu Gln 
            3060                3065                3070 

Gly Leu Asp Tyr Leu His Gly His His Val Leu His Leu Asp Ile Lys 
        3075                3080                3085 

Pro Asp Asn Leu Leu Leu Ala Pro Asp Asn Ala Leu Lys Ile Val Asp 
    3090                3095                3100 

Phe Gly Ser Ala Gln Pro Tyr Asn Pro Gln Ala Leu Arg Pro Leu Gly 
3105                3110                3115                3120 

His Arg Thr Gly Thr Leu Glu Phe Met Ala Pro Glu Met Val Lys Gly 
                3125                3130                3135 

Glu Pro Ile Gly Ser Ala Thr Asp Ile Trp Gly Ala Gly Val Leu Thr 
            3140                3145                3150 

Tyr Ile Met Leu Ser Gly Arg Ser Pro Phe Tyr Glu Pro Asp Pro Gln 
        3155                3160                3165 

Glu Thr Glu Ala Arg Ile Val Gly Gly Arg Phe Asp Ala Phe Gln Leu 
    3170                3175                3180 

Tyr Pro Asn Thr Ser Gln Ser Ala Thr Leu Phe Leu Arg Lys Val Leu 
3185                3190                3195                3200 

Ser Val His Pro Trp Ser Arg Pro Ser Leu Gln Asp Cys Leu Ala His 
                3205                3210                3215 

Pro Trp Leu Gln Asp Ala Tyr Leu Met Lys Leu Arg Arg Gln Thr Leu 
            3220                3225                3230 

Thr Phe Thr Thr Asn Arg Leu Lys Glu Phe Leu Gly Glu Gln Arg Arg 
        3235                3240                3245 

Arg Arg Ala Glu Ala Ala Thr Arg His Lys Val Leu Leu Arg Ser Tyr 
    3250                3255                3260 

Pro Gly Gly Pro 
3265 

 
           
             3  
             62805  
             DNA  
             Homo sapiens  
           
            3 

ctttgtctgt tcactgctat atccctagtc cctagcacag tgccagtaca tagtagaaac     60 

tcaaaaatat ttgtggatga ataaataaaa aaattatgga tgaataaata attaaaaccc    120 

tgagttgtgc tacctccatt ctatagatga ggaaaccgag gcttagagat gctaggtaac    180 

ttgcttgaga tcgcatcgtt catttattca accaacttac taaccagcca acatttacag    240 

tctacccact gcattccaca cacatttaga ggcacagtgt tgggtggctt tgggttattt    300 

gtttttcgaa atactctcta ttcctttttt cttgatatac catctgtttg caatgacttc    360 

ccccatattg tcaccttcta gaattcaatt tacactttag aattcgattc atcatcagtg    420 

gttgccagag gttggtggag ggggtctatg gtagagtcta tgactccgaa gggggtacat    480 

gagctagtat ttggggtgat ggaattgttt gctctgtatg gtcctggagt ggcagataca    540 

tgattctatg catttgtcaa aacccagaga actgcacctc ataaaaaaat aaactttagg    600 

ccaggcacgg tggctcacac ctgtaatccc agtgctttag gaggctgagg caggcagatc    660 

acctgaggtc gggagttcga gaccagcccg accaaaatgg agaaaccccg tctctactaa    720 

aaatacaaaa ttagctgggt gtggtggtgc atgcctgtaa tcccagctac tcgggaggct    780 

gaggcaggag aattgctcga acccgggagg aggaggttgt ggtgagccga gatcacacca    840 

ttgcactccg gcctgggcaa caagagtgaa actccgtctc aaaaaaaaaa aaaaacttta    900 

atgtatgcaa actgtaaaaa aaattattcc tcaaggttct taacctctat ggatgtaatt    960 

cagtgtttaa atggttcctc ctataccttt tacacactgt ctctcgcgct ctctctcttt   1020 

ctctttgact tcagtatccc agaatgagga tggggaagag gaggcaaggg taagagtaac   1080 

attctctgcc tctgaatact catggctcct ctcagccctt cctgggtttc atccctcagg   1140 

gctcaaggtc aggcctgggt ctcctacttg gacttcttaa aaaatttttt actttatgat   1200 

aactgtagat tcacaggcaa ttataagaaa taatgcagag agatcctgaa ttaccttcac   1260 

ttggtttcct cctagggtaa catcttgtat gactatagta cagcatcaca accaggaaag   1320 

gggcattggt ataatccacc taccttctgc aagttttacc agtgttacat gtactgttag   1380 

tgttgcgtac aagtgcaaat gcacatttag ttctatgcaa ctttatcact tgtgtagatc   1440 

cacataacca ccaccattac cactgtcaag atacagaact gttctgtttt tgttttgttt   1500 

tgttttttga gacagagtct cactctgttg cccaggctgc agtgcagtgg tgccatctag   1560 

gctcactgca acctccacct cccaggttca agcgattctc ctgcctcagc ctcctgagta   1620 

gctgggacta caggcatgag ccactacacc tggctaattt tttgtatttt tagtagagac   1680 

aggtttcacc atgttggcca ggctggtgtt gaattcctga gttcaagtga tccacccacc   1740 

tcggcctccc aaagtgctgg aattacaggt gttagccacc gcgcccagcc aagatacaga   1800 

actgttctat cacaaaggtc tcatctggac tcttgatgtt tctcaacgtg caacacttag   1860 

gcacatcaga atcagttgag tcatttgtta aatgtgcaga ttcctcccag ctcagctgct   1920 

gaaccagtgt ggggcaagga ggctgggaat ctggccttta cttgaactgg ccgtcatttc   1980 

tatccatcct ccactttgtg gccgccaaga ggatcctcct aagacacagc tcccaccgtg   2040 

ttttttctgc cgcttaaagc tgtgtagtgg cgccccctgc tttcagggta gagaaaccaa   2100 

agccttagca aacaaagcct tctccaggcc ccacctccct tcttccactc accccaccca   2160 

ctacgcttca atccctccaa acctctctaa ttcccaggac gcctttgttt tcatcaggct   2220 

cattttgttc atgccgttcc ctctgcctgg aatgtcctgc ccactctttt ctgcctattg   2280 

caaccctatt ccaccaccca ttcttacaga tgaggacttg gaggttgaga gaggtttggt   2340 

gtcacccagc aagtaagggc agggcgcagt ggaggcccca atccacctga ctcccaggct   2400 

cctggtctta ctgttcgcca gctgtaatgg aggcgctggg ggaggccatg gtccctcttc   2460 

ggagctgtct gctcacctcc acttgggcct gcctccccat ccacctctca ggcatctcac   2520 

caggaccgtt cctcttcttc ccctcccagc gaagccgggc agggatgagg gttctgagat   2580 

gagggaggaa gggaaatggg attgagccca ggggtaacct gactccctgc agtgggtcgt   2640 

gtgggggcca ggcacactac ggaggggaaa gcctggaaca aataccgagg gactccctta   2700 

agccgggccg gcgatggggg ctcctggagg gagagaagga gccaagtgga gtcaagtccc   2760 

tcccctgctg ccccctccct ccacggctcc ctcgcaaccc gagccggggg gcctaaaaat   2820 

agcccccagg cgcaatcgcc tgccgccccg gtgaccttct gggtagcaca ggccgaaggc   2880 

gggcgggcag caggaaggca ggccgccggc cccccagact tgtctcctag ggcaccgtcc   2940 

cgcgggtgcc cccgtggccg cccagttccg gcgtcccccc agcccagctc tcagtggcca   3000 

tgcagaaagc ccggggcacg cgaggcgagg atgcgggcac gagggcaccc cccagccccg   3060 

gagtgccccc gaaaagggcc aaggtggggg ccggcggcgg ggctcctgtg gccgtggccg   3120 

gggcgccagt cttcctgcgg cccctgaaga acgcggcggt gtgcgcgggc agcgacgtgc   3180 

ggctgcgggt ggtggtgagc gggacgcccc agcccagcct ccgctggttc cgggatgggc   3240 

agctcctgcc cgcgccggcc cccgagccca gctgcctgtg gctgcggcgc tgcggggcgc   3300 

aggacgccgg cgtgtacagc tgcatggccc agaacgagcg gggccgggcc tcctgcgagg   3360 

cggtgctcac agtgctggag gtcggaggta aagggcaggt gggggccgcg cccggcaggg   3420 

gcggggtgct cagaggtaga aaagggctgc ccaggccacg cgggtaaggt actggatact   3480 

ggttccgccg ccttcttccc aggtgccctg gcttctcggc tgcccggccc cagaagtgag   3540 

acgaagagcc aagtgcaggg aatggggtgt caaggtagag aggctcccca caggaaggtc   3600 

agaggtcaag gggcagcaag cggttgataa gccaagcctg agacccactc ccacctctca   3660 

gggaattctg gggtggaagt tcttctcctc ctgtggagaa aagcctcctg ggggaaaggg   3720 

tgtccttcag ttccatgatt taaacttgag attgacactc cgatcagctc cttaacaggg   3780 

gagtccatgt ccgaaggagg gggccagctc ctctggtcca ggctgcactg ttgaagggat   3840 

ggctcagagc tccctgcagg ccattgccgt ggcagggttg atgtggtcag ctctaggtgg   3900 

ggtgtggaag aggcctatgg ttggccacgt gtgaacaggg tccagggtag gaggaggtgg   3960 

agcccgagcc agggccccat gggcatgaat ggaggtgagt gcttgagaat ccacatgcag   4020 

gtgtgtgcct gcatgggtgc tgtggagggc cctggattct gtgtggtggt gcaaacaggt   4080 

gaggtatggg cacgtggagc tggaatggga agctcctgga ccatgtctac ctgagcttcc   4140 

agagtggatg tttccagagc atggaagggg gatgctatgg accagtgctt gtcccccgcc   4200 

catagatttc caggtgcagt gtgaagaaaa ggctgagggt ctgaggcaga aggggagggc   4260 

aagaggctgg gcccagtgct catggtccag ctggggctac catggaggcc aggccagggc   4320 

cgttagcctt ggatccattt gggggcttcc tttttgattt cctcagtcct tgagtaagcc   4380 

aagtggtact tctctagcca aaggcagagc cttgggcagg ctgcgccttg agaaacagaa   4440 

ttctgaggaa gtaggctaca gctgggagag atggcaagga gctgggggtt cactcccttg   4500 

gacgtttcta agagggacat gtcactcccc tgggtgctgc tgtgtagggg taaatccttg   4560 

gaggctgggg aggaggcaca gggaggaaag ccctcagcag caggtgggca agaagtctct   4620 

aggacacagc caagtcagga gagggagccg ggctggcctc cctccatcgg catctcctcc   4680 

ccccagccct gctctgccca ccttcctgga gtctctgtgg ccaggcctgg gccagagagg   4740 

gccaaggctg gcgtctcctg gttggcctag cacctggaca agtacaggcc tcccgagcct   4800 

gggatcaggg gatggggtgc attctagcag acttcggagc tggggaaggt gtggactcct   4860 

tggggatctc agctctggtc cccccagggg caaagagggc tgaaaataga acatagatca   4920 

aagggtaaga tagatgagtt gatgagaata tgactggggg agagattagg gaagggaacg   4980 

aaagagctga caaggagagt aacagtcata atataagtta aggttggaaa ggaccacaga   5040 

gaactgcagc tccaaacaca tcctttcaca ggcaaggaca ctgtgggcca aagatcaggg   5100 

agctctgcct aagacgtact agtctagtta gagacatagc tagttatggc catcccagaa   5160 

ctaagaaccc agtcctcctg gttttggttc tgggggcctt gtactcctca agaagttctg   5220 

gagagagagg aaagagcgag agagggaggg agagtactgg gaaagtagct gtcacatgat   5280 

tggcccaggc ctggcatttc tcaagatgga tgtctcctgg cctgccttgg tccctcaaag   5340 

tggtaagtgg tgatgaggtg tgagagcccc cagcagggct gtttgctcag cctctctgca   5400 

gtcttggtgg tgtggtcagc agcgctgagc ctggctgggc gtacctagac agaggccagg   5460 

ctgacagtgt gcaggctggg ctgctctggt ggaacagcag gcttgagagg cttggggtaa   5520 

gaaaagggcc ctgggtgttg tggggctgga tcaggggccc tttgacattc atatgagaat   5580 

aggaagagga ctgggctgca gcaaataacc tttgagaaca tgtcctgatt gtgtagatag   5640 

aaggtggcag aacaggtgga ggcctcagtc tgtcccactg caaagaacca tgtgtgtaac   5700 

tattacacct atcccacatg ctttggagga gggaggggct ttgctttggt gatgctgggg   5760 

gactgactgg gtgaatctgg cttcctatcc cttctgttgc ccacccccac cagcccctgc   5820 

ccagtgatag ctcctgctcc agggcagccg ggcaagcagc tcggcattgc tcagacttac   5880 

tcatggaaaa ctttcttggt tggaaacaac agcaggagga cttcagggta ctcgaggaag   5940 

ccaagcaagg acctggctgc agacggaagg acatgctttc ctggctggga ttgctggctc   6000 

aataagacaa agtgatgcta ggttcctggc actcctgaag ccggatatgt tagctcaagg   6060 

atggaaggat ttgggcatgg ctctggaaag ttggggtcat gagaaggcaa gtgggctaca   6120 

gcctggaaaa tttggaggat gggaaactgg gggtggtggt gctgagattt gggggatgta   6180 

gaaatgaggg aagaatcgga aacaaaggag gtgaagatag cagaaatgca ggatacttgt   6240 

agaatcctta acatgcgtaa gtaccctgtc tcatttaatt atttaatctt ccaaacccta   6300 

ggttactgtt atgaccatta ttcatataga aaaactgggg ttcaaagagg aaatttacct   6360 

aagttcccat ggctagtgag gtgccagagc caggtctgaa agccaggtat ctgagtctgg   6420 

gtccatactg cttgtccaca gaaagagaag tgtgggaaga ctgtcaagga tttgtcatcg   6480 

tcaccatctt tctccgtcaa tatctccaaa tccatctctg gcctagtctc caagataggc   6540 

aggcattctt ctttttcaaa atatcaggct cccacttgca caggctgagg agccacatgc   6600 

aaatccagag accacagcaa gtgctaccct caaagctgtg ggtgtgcgtg tgtggctgaa   6660 

gagcagacct gcactaaagg gcagagggga agcaggagaa ggcacagccg agagaagagg   6720 

tgagctgatg atgctcacat ggtgtgttag ttggagcttc atagctaggg tctggaagat   6780 

tctggtgtta atcagaaggg ccaaagatca aaacatggta atgaaccatc ctggggactc   6840 

aaaggcttgg agaggagagc ttagagatag ggagagaggg ccaacttagg caaggaaagg   6900 

gtagaggaat gtaccagaac ctgtgttgag gaatattctg cagttattct ttttcacctg   6960 

gaatttagaa tgtctggcta gagaagccag gtggaaagta gtatggagct gggaatgggt   7020 

atggggagtg tcaacatgca tgcatgccaa gtgctgacca gtgagcggag gagaggccag   7080 

agtgggagca gagaggagct ctgggaccct ctccagggga atcctgagtg gaatgagaga   7140 

tggtcacttt tctggctaaa gacctctggg gacagaatat gggttaggac agagaagggg   7200 

gaaggctgga tgagtggaag ccgttgcagg aagatttact gtccccgttc ccatcactgc   7260 

ttaccctctc cacctgcagc tctgccaccc cctcccatat ttattgagtg cctactatgt   7320 

gcttttgata cacgagtcag ggggttgagg gagaccaaaa tttatgtcct ccaggggata   7380 

actttctagt gaggggagac agacaataca caataaacat agtaaatagg taaattacac   7440 

agtatgtcag aaatacagag cagggtcgta aatgagagaa gggagaaact gaactgaggc   7500 

aggaaagagg agacaaaagg gaggtggggt gggagcttgt ggcataggat ggagatttgg   7560 

attttctctg gttggaggga aatgctggca gtgcagaaat tggaagtctg ggtttggggg   7620 

agtggcaggg agacacagct gcccagctat gggagaaaaa tggggcaatc tggggccagc   7680 

tggggaggcc cacccagaga gcatgttcca ggccagccct tcaggagtga gcagtgccga   7740 

cccagagcag gaacacagaa tcctgccggc ccctcctggg cccagctgtc ccgtcactca   7800 

cgcccgctgc ccattggtta tttttgctac ggaatgtgcc agccccttgg attctcctgg   7860 

ggaacagggg ctcaagttac cccctctcat cactcagctc cccatctgtg agtgggtgtg   7920 

tttaggggtg tacatggaaa gtgcccatgg gtgtccaggg tcctctggct ggaacgagtg   7980 

tggacacaca tatgtgccct ctcagcacac gtccctgtgc atgtgtctgt acttgtaatt   8040 

tgctttgatg ctctaggaaa caagaacacc tgtatgcacc cagaatgtac aagacatgac   8100 

ctaaacttta gaataaaaga gcagccaggt gcggtggctc atgcctatca tcccagcatt   8160 

ttggaatgcc gaggcaggag aatagcttga gcccaggagt tcgagaccag cttgtgtaag   8220 

ataataagac ttcatctcta cttaatattt ttttaaaaat tagctgggca tgatggcatg   8280 

cacctgtagt ctcaggtaca aggggggctg aggtgggggg aatctcttga gcccaggtgg   8340 

tcaaggttgc agtgagccat gatggcaccg ctgcactcta gcctggacaa cagagtgaga   8400 

cctagtctct aaaacaataa agaaatctaa aataagataa aggggccaca gactcaaata   8460 

actgcagggg tcaagtagaa actgaaaatg agggaggtgc gctgagctca ggcatgattg   8520 

ctccagccca aacattgtgc aggctgaaca aaactcatca gtctgtccct gtatttattt   8580 

tattttattt atttatttat ttatttattt atttatttaa agcagagtct tgctctgtca   8640 

cccaggttgg agtacagtgg tgcgatctct gctcactaca acctcgcctc ctgggcataa   8700 

gtgattctca tgcatctgcc taggttggaa ttctggctcc ctcaatttat tggccatgtg   8760 

accttgggca agtaacctct ctgtgtctca gtcttcctct tgtcgtgagg attaaatgag   8820 

ctcattcaca tagagtgctt agcacaatgc ctggtacata ccaaacacgc aataactgtt   8880 

aatagttact tagtagtcac agctcagaaa tcaggattgg cactacctgt gctcactggg   8940 

atgataattc ccatctccag gacacatgga gtcctagaac ctgtatggct ttgactaagt   9000 

gataggactt ctctgagact cagtcacttg tcagttaaat gggtatagga ttattcataa   9060 

gggtttccag ctcatggggt tattgtaaat gaggtaacat ttgtaaagtg cctggcactt   9120 

agtaactgct aaacaaacat agctataatg gtcatgggga ggatagaatt ttgtgtatgc   9180 

aaagtgtgca tagtgctgaa tagggcaggg atcgggtgga acacacaaaa tatttggtga   9240 

gtgtgcttcc ctgtgattga gaacactggc caactttgtg aataatgggg gtacctctgt   9300 

gcacctttgc ttgtgtgtgt gaatgtacgg gggtaggggg ccgcgcatgg gacaatcgcg   9360 

aggtaaggca agataaagcc ctctctggct ttcttgagaa gccttagggt tttcacagtc   9420 

tgagtccatg ttaacacgca gtccacaccc gccaggaccc ttgccctgcg tttgacctag   9480 

gcgcccccac ccggcgctgt gcccttcggc gagttcggtt ctgcctggca cagtgtgtgt   9540 

gcgcgcatgt ttgtggaatg agcaagtcga gatgctgctg accttccaga gaggccccgc   9600 

gggaggaggt gagggtggga ggaggctgcg ctgggctgcc agaaagtggc ctgagctaga   9660 

ggccattgca cccctttctg tgcctcagtt tcctcatgtg cctagggctc cggaggcaga   9720 

tgcagggtgg gggtccgtgg ctctcggcgt taggaggtga ccggtggtcg tgtagggagg   9780 

caggtgaggg cctccccggg ggaagtaggg ggacaggaca aggaaggggc cccaggtggg   9840 

gtgcaggctg gcgagggagg ggcggactcc agcgccgccg ccgccgctgc tgccgccgcc   9900 

gtcgccgcct tacccccacc cggctcccga ggccccaggc tccttccgcc acccgcgccg   9960 

gctcccgccc gctccccagc tcgcccccgg ccccgcctcc gactccgccc cgcccccgcc  10020 

cgtcccctcc tcgcccggcc gccggcccgg ccccctcccc cgccatgaag aagctgtggg  10080 

tgaagaagcg tttccaggtg agggctccgg gggcgggcgg cgccgggagg gggcagggag  10140 

gcctgggcgc cccggaggga gggcgggtca ccgcagctgg gcccggtgga gggggcgctg  10200 

gatcggcgcc tgccccaccc gagccccgcc gagggcggcg ggccgggcgc gatctagggg  10260 

cgcccgggtc tgtgtcctga gcgcgcaggc ccctccccgc gctgaagggc agatcccccg  10320 

ctccccgatc gcccgcaatc cccgcgacca ccggggaagg cccccgctgc agcgttcggc  10380 

gtggagcgcc cacttgcttc tttgccacat cttctctctc ctctgtccaa cctcaacccc  10440 

gggccccggc cccccgcccg gcctgcccca gccccccact ctgaagcttt ccatcttccg  10500 

gagctcctga aagcaacgca cacggatccg cgctgagctc aatacattcc ccaagccctg  10560 

ccctgtcctc cgcgcacctg ggcctcctgc attcgtgagg ctctggccct ctgcccccat  10620 

catccctccc ccaccccctt gacacctacc caggtttctg tcctcccccc agcaggaatc  10680 

tgtgccctcg ttcctccatc tcccagtcac tcaagcaccc cgccccccgc atccccatct  10740 

tctccttctc ctcactgagc ctgactacct cgtcttctat cctctttctc tcgggctgtt  10800 

gccctggtcc cgggctgttg ccctggtccc gggctgtgag cctctgtcca gtgggatgtt  10860 

ccagcttcca cctgcagcct gcagttctct ccttcctccc ctgctcctcc caagagccca  10920 

gctgggtacc ctggaagaag gcaggggagt cattccctac aggggaagct ggtcactctg  10980 

ggtctctgcc cacctcccct ctcacacaca cactggccag ggaatgagtt tctgcttgat  11040 

gttgcaggtc tggatgggag gcacagggac cttaggaaca agcctccccc tcaactactc  11100 

attctggctt ttctctttca gaaaaccggc cattcccgcc gggcctttgg ccgactcacc  11160 

catggtgcgt ggaccgtggg cgtccttgct ctagcccatg cctactcctc ctcttggtcc  11220 

ctgtccctct gtgaggcatc gagttcctga agacagccca tgagatgtgg aaccctccca  11280 

ctcaccccca cacttatcta ccacccaccc gaccaggccc cctgtgccct acagctgaga  11340 

gaggacccag cagaagggag ggcggctcac tagcacaccc ctgcatggac tgggtgccct  11400 

gttctccatg tgaggcctaa tgggaaggag ttcattgcca tgctttggca accagtacgt  11460 

ggctcctgct tgtcatggca gccagaggga aactgaggca cagaacctgc tagaatctgg  11520 

gaaagttgaa aatactccca ggaacctttt ctcctaacct aaccactggg catttttgag  11580 

gacgattcaa cagtagaagg gagggacctt gaggaaggtg cctgtcacat catgatgcag  11640 

acagataagg ggttggtttg caaagagggg tcaaagcaca atgcaaatat tgtaatagag  11700 

ggtgggcctg actcctaatg ggaggcccag gtctgcggct ggactggaca caagcaggtg  11760 

tgtgtgtgtg tgtgtgcatg tgtgtgtgtg gccagtggca gcaccagtaa gtgccaagga  11820 

taccagaacc actggggcag ctggaataac aagcccaagt atgggggtcc cccgtgctgg  11880 

gcacatccca ggtatctccc tccccaccca ttgccacagg acacctctgg ggactgggtg  11940 

cctcacgccc cttctgtctt gactgccctc catgccctgc cccacaaacg ctctgataac  12000 

agtctgtccc tgtctctctc ctgctgctcc tatggaagcg aagttttccg ctcctgcaga  12060 

aagcaaagtt acggtaggaa actggctcct gctctagccc cccgcatccc cccctttccc  12120 

acccggcccc ggcctctcct caccctgcct cagctgcacc cgatgccttg cagctggttt  12180 

ggggtagagg acaggctggc cccgcggttg gtcgagtgcc ctggcagtac gactctgagg  12240 

tgactcctct ttgttcctgg ggtactggaa cccagacttt agagccttgg aacctaggac  12300 

ctgatgattt tggggctgca caggggctta agctttcact gacaagggga ggagggagaa  12360 

gggaggaggc tctgataatc cattaagata ttggcaggcg gggagggggt ggcagtttgg  12420 

agggccctac ggaggtaaac gtgagtaacc aggggcccag agatggagcc agggcactgg  12480 

catgggaggg gttatcctga gcagcccagg ctgggcaggg gatgtgggga gcaaaagaga  12540 

ggaggtgctg gcagccctgc cagtgataag atggagcctg ctgttggcag ggaggcagaa  12600 

ggcaataggg aagagttgga ggcagaggga ggagggccct gcccacacag accccttctt  12660 

ctccagactc agagacggct gaggatgaca tcagcgatgt gcagggaacc cagcgcctgg  12720 

agcttcggga tgacggggcc ttcagcaccc ccacgggtga gctcctgggg tgtacaaaga  12780 

gcaggcaggc gggttttcca taaggggtgc ctcagtctca cggtgctcct ttctctaggg  12840 

ggttctgaca ccctggtggg cacctccctg gacacacccc cgacctccgt gacaggcacc  12900 

tcagaggagc aagtgagctg gtggggcagc gggcagacgg tcctggagca ggaagcgggc  12960 

agtgggggtg gcacccgccg cctcccgggc agcccaaggc aagcacaggc aaccggggcc  13020 

gggccacggc acctgggggt ggagccgctg gtgcgggcat ctcgagctaa tctggtgggc  13080 

gcaagctggg ggtcagagga tagcctttcc gtggccagtg acctgtacgg cagcgcattc  13140 

agcctgtaca gaggacgggc gctctctatc cacgtgtaag taacggcctt acctgggcct  13200 

gaactgcccc atctcaccac gctgtcctgc gctgccctca ctgctcagtc agcctccacc  13260 

catcaccctg ccccatccat ctctctgtgc atttcttcac cccctgctgc cactccatct  13320 

tcccacactg ctccctcctc ctcctgagcc atcaccgccc acatccccct gctcccacct  13380 

gtcctggctc accatgccat ctccatggtc tcctggaccc tgctgtccct tccttgtctc  13440 

ctccaagatc tccagtttct caggggccct cttttgcctc acccatttgg gctccagttg  13500 

tccccaggat ccctcccccg acccgggggc ccccttggtg cctgctgtct cagcagctgc  13560 

tgccttttca tctctctgca cattcctgtt cccatgtggg cctttttctg ggaggaacag  13620 

aacctttcca cacggcagct cccgggagag caggagagag caggggaaca agccagcaag  13680 

caggagagag aagagagtga ggtggccagg ggcagatggg gcaaggggcc tgtgaaagca  13740 

ggaggccatg ggctgggggt ggcagggggc tgggaaaggg aggggctgga aatggggcca  13800 

ggccagaggg agagggcggg agtgatggtg gcagggggct tgcaatgatt tctctcatgg  13860 

gaaaccccta agtccctgag ggtgggattc aaggttgtcc caggaggggg tgtgaggagc  13920 

ggaggtgttg gaggcactgg agccattttt ggagatttgg ggctcgcaga tacaggaggg  13980 

agtgctatag tggaagaggg gagtggctga gaatagaggg actggggcat ttggggagct  14040 

gaggggggcc tggtttgtga tgggtatggg tgtgggggca gctaccaccg tgcaggagaa  14100 

agaaggggcc tggtggggga ggctgctttg agggtggtta gagcagggct agcggtgggc  14160 

aggggagagg gccagggctg ggccacggcc agggggaggc tcccttggct tatcttcttg  14220 

gccttacccg gtgttcctgt gccctggact tgcctttccc ttcctgcctt tctttaccag  14280 

gccccagcca gagcctggag ttgctatggc aacttcggag gaacccattt acttagtgat  14340 

gtctatggta cagagactgg cctggagctc agagctgccg gcaagaggcc tcctctgctg  14400 

tcctcaattt ctctccaggc ctcacccact tcccagaggc tcttccctgg ggactctgcg  14460 

gcccttcccc cagagaagac acttcctccc tgcaggtggc tggctggggt ttctgtctct  14520 

caggccactc tgcattgcca ccaccccttt tagccccagt cagaggtggg tctgtcatgt  14580 

gggtggctga ctcaggtagg ctaaaacatc cttaactcgg gacccctaga actgctcatg  14640 

gctggcaccc tactacttgt cctcccttct gtgcccctgg aaacccagac actttggagg  14700 

aaataagggc tcaggattct gactgcctgg gtttcaatcc tagcaccaat catttcccag  14760 

ctgtgtcacc ttggtaaggc atttaatctt ttttatgcct cagtttcttc atctgtaaat  14820 

gggggtgatc acagttctta cctcacaggg ctgttgtgag tattaaatga ctcaatgcat  14880 

tttaagcact tggtacaagc ctggcactca ggaaatattc aatgagccat tttacagatt  14940 

tttattaagc tctctctgat gtgtcaggta tgataataca tttaattcct tttttttttt  15000 

tttttgctta tctttatgtg tgatgtgccc cctcacccac cccctcctcc ccgcaagggt  15060 

ccagatgggg aaaactgaga cccagctctt gggcaccaaa gctctgttaa gtgaaaggga  15120 

tactctgggg tgaccggctc cttccctcct ccttttctcc cacactccct attcaggccc  15180 

acttagtagc tatttctgag ctgagttatt tcagagcata tccctgtggg ggggggcctt  15240 

ctgtacttct caggggggat ttctaaggac tcaaggtagc tttgccaggg gaagcacaag  15300 

tcaaaggcct atcggggggc agactgagca aggagagtag gagcctgggc atcccgttgc  15360 

cacctgctgt gtcccatcag tgctcggggt ggcggcaggt ataggctcag gtctacacag  15420 

cagctaggga atcctaggga tggggcactg ccccccaaaa ggcttgtgcc tggtccagga  15480 

ggctgttgct tggcttccag ggaccactag gaaggggtgt gccctgctga tgatgggcag  15540 

gggtgtgggg gccagctggg ggctggaatg agtgggtggc tgcattcctg agaacgcccc  15600 

tccccacccc accctcttgt cttccctccc cacttcatcc tttgggtcct aagcctcatt  15660 

cttttctctc cctcatgctc agttctgttt ccgctgtttc tcggcttcca gggctggggg  15720 

gaggaggctg gcccgagtcc tggggctgag tctgtaccaa gacccagcca ttagcccaat  15780 

cttgtggttc cagagccgcc ggcctctccc cagcacctgc tctggctgtg cgctcctcgt  15840 

gggggtgggg gtggggggca ggaggatctg gcccatgtca cccccaagcc tgcccagcat  15900 

gcccaccacc caattcctgt cacaagctaa gggtctagga gaggaggccc cctgaatcct  15960 

ctacccttct ccatcttggt tctgcagcag cgtccctcag agcgggttgc gcagggagga  16020 

gcccgacctt cagcctcaac tggccagcga agccccacgc cgccctgccc agccgcctcc  16080 

ttccaaatcc gcgctgctcc ccccaccgtc ccctcgggtc gggaagcggt ccccgccggg  16140 

acccccggcc cagcccgcgg ccacccccac gtcgccccac cgtcgcactc aggagcctgt  16200 

gctgcccgag gacaccacca ccgaagagaa gcgagggaag aagtccaagt cgtccgggcc  16260 

ctccctggcg ggcaccgcgg aatcccgacc ccagacgcca ctgagcgagg cctcaggccg  16320 

cctgtcggcg ttgggccgat cgcctaggct ggtgcgcgcc ggctcccgca tcctggacaa  16380 

gctgcagttc ttcgaggagc gacggcgcag cctggagcgc agcgactcgc cgccggcgcc  16440 

cctgcggccc tgggtgcccc tgcgcaaggc ccgctctctg gagcagccca agtcggagcg  16500 

cggcgcaccg tggggcaccc ccggggcctc gcaggaagaa ctgcgggcgc caggcagcgt  16560 

ggccgagcgg cgccgcctgt tccagcagaa agcggcctcg ctggacgagc gcacgcgtca  16620 

gcgcagcccg gcctcagacc tcgagctgcg cttcgcccag gagctgggcc gcatccgccg  16680 

ctccacgtcg cgggaggagc tggtgcgctc gcacgagtcc ctgcgcgcca cgctgcagcg  16740 

tgccccatcc cctcgagagc ccggcgagcc cccgctcttc tctcggccct ccacccccaa  16800 

gacatcgcgg gccgtgagcc ccgccgccgc ccagccgccc tctccgagca gcgcggagaa  16860 

gccgggggac gagcctggga ggcccaggag ccgcgggccg gcgggcagga cagagccggg  16920 

ggaaggcccg cagcaggagg ttaggcgtcg ggaccaattc ccgctgaccc ggagcagagc  16980 

catccaggag tgcaggagcc ctgtgccgcc ccccgccgcc gatcccccag aggccaggac  17040 

gaaagcaccc cccggtcgga agcgggagcc cccggcgcag gccgtgcgct tcctgccctg  17100 

ggccacgccg ggcctggagg gcgctgctgt accccagacc ttggagaaga acagggcggg  17160 

gcctgaggca gagaagaggc ttcgcagagg gccggaggag gacggtccct gggggccctg  17220 

ggaccgccga ggggcccgca gccagggcaa aggtcgccgg gcccggccca cctcccctga  17280 

gctcggtaag gcctcaggga gggctgacaa ggtgcctgaa cccccgtcgg ggggcgtttg  17340 

tggagagcaa gactgctcag caggagccgg ggggtcgggg gtttcgcctg gggctgctag  17400 

ccagctgcaa gggtgggttt gccaaagaag gcacagacac aggctcgact ttgagtgaag  17460 

gattgtcaaa gtccttgtgc taggactgct actggtgagg cagagcgtga gtgttgtgat  17520 

ggaggctagg tgaggctgag atgtgagcta agactggtgc ccagatgccc gccatagctc  17580 

ccctgggtcc agtggcctgc taggctgttg gatcaagaac cactactggg gggatgcact  17640 

ggtgggaacc taaggacccc cctccatacc cccaatccct ctgttgggga gagatggtag  17700 

atggtctgaa ataattttca aatccctgtt acagacacgc tttgtgccag ataactcttt  17760 

actctgcctc tcccacccgg gcaccatccc ctgacccatg tgtggccacc cagcctgccc  17820 

ttctagcctc ctcacctcag gcttacaccc cgcatggctg agctcactgt ggtccctaca  17880 

caatgcctgc ctgtgtgttg tctcccaacc ttcccatgga tgatgaccaa caccaccaac  17940 

aggagaatgg ctctgcaccc cacccctcat cctgcacatc aactcgaggc ccactcctgg  18000 

agagaggcag aggaaggcgt ccttgaccca cttccactgc tcctccagaa tagatgcctc  18060 

tacctgctgc tcctgggaga ccctgccagg atctctttca ttgcacttac catactgtat  18120 

ttttcttcat caaaattatt ttgcatttaa gtattaccac cttagaatct ttagagataa  18180 

ttaggcccct gtccatcatc ctcctggaca ccattattgc aaacacacaa ctatgtgcca  18240 

gcattgtgtt aactaggccc ttacagatgt tatttcattt cagcctatat gtcagtttca  18300 

gagggtcttt tcccctccat cttacagata acaaaactga ggctcagaga ggctaatttg  18360 

cccaaggttt tgtagctagg aaacagcaga attgggattt tcactgcttt tttggctatg  18420 

tacattgtcc tttatctagc ttatggaatg tcagagttgg agaatgccca gagacccatg  18480 

acagtggagt ttgtcatctc tctgtatgta tgagcttcct gtaagcaggg accactggtc  18540 

cttcctctag tgttcttggt acccatacag tactcagtat gccgggagta cagggtcact  18600 

atttggtgaa cggatgaaat caaatctgat cttcgtaggc ctctcagact gcctaccatt  18660 

cactcttttg aatctgacgg cttcacacat ttgacaattc acctcgtgtt gctctgtgac  18720 

accgctgtta ttgcttaagt cttgggttgc ttttagcttg ttctttgtct gtttgaaagc  18780 

ttgtgcccct ccaggtgcct tgcatagggc ctggtacgcc atacatgatg gctgacgtgt  18840 

taaagacata cacagtgcag tcctgtcttt ctccagaagc caacgctcta attgtggatg  18900 

aagttgagga acggccacac taacatggag tcaaggctgc cctgacctgt ttcgagaatg  18960 

ctccttctga cttccttttt tccctaagga cattcaggag gcagaccctc ttctccccaa  19020 

gtccctgctt tctagaagcc cctctgtctg ggtttggctt tctaggatgc aggccaccag  19080 

gactctctct cccgctgtca tccctgcagg gatcatggcc ccttaccccg ttattcctgt  19140 

gtccggcaga gtcttcggat gactcctacg tgtccgctgg agaagagccc ctagaggccc  19200 

ctgtgtttga gatccccctg cagaatgtgg tggtggcacc aggggcagat gtgctgctca  19260 

agtgtatcat cactgccaac cccccgcccc aaggtgagct ccagcactgg gccaaggtgc  19320 

ggtcgaggtt gggagggggt gtgtgagaag ggaaggggag gttcccccgg actcctccaa  19380 

gggaggggtg ggaaagaggg gaattatccc ctccacgggg gctgccctga cttgggtgtg  19440 

tgttcaggga catttctcag gacccccgag agaagggagg gcaacctgag cttcccaaaa  19500 

tgagggcgga ctcttccaga ttccctgggg tgctgagagg agaggtttgg tctcctgtgt  19560 

ggtgtgtggg gtaggagtag agattctcag tgggcgcctg tgggccgtgg cgagccgggt  19620 

ccctgtgcct ccccacagtg tcctggcaca aggatgggtc agcgctgcgc agcgagggcc  19680 

gcctcctcct ccgggctgag ggtgagcggc acaccctgct gctcagggag gccagggcag  19740 

cagatgccgg gagctatatg gccaccgcca ccaacgagct gggccaggcc acctgtgccg  19800 

cctcactgac cgtgagaccc ggtagggagc ccatcaaccc tggggctggg tgggggcaag  19860 

ccgtgactct tccctggccc aggccccagt ccacctccct tcccactctc agccttgagc  19920 

ttgggcaccc cgccagcata cttagtccat gcagtccctt ctgggtgtcg gcagctttgg  19980 

tgaaagcgtt ttaaatggcc ctggcctcag ggcaggggcc aaatccccaa ggcgcacaga  20040 

aggctggcca attcatgaag tcagtgaaat ttgtgtttag ccatcctcta aatgccatcc  20100 

tcccatggca tttccctgaa cagggtccta tggggaaagc aaattgtcct tgagtttccg  20160 

agaagaagaa tctctccgct cacagggttt aagagccacc acaagccttc tgaagtcatt  20220 

tcccctgtaa gacagtcccc cctcccagta aaaagagatg ctttcgagtg ccacaagcca  20280 

cttcccccct acttttcttg aacccaaagt tgtaaaaagg gtacagccaa gagcacttct  20340 

tgggctggca gtgccgaggc tgccttgttt tctatttttg tgaaagccct tacttggtgt  20400 

cagactactt tctttgggat tcagcccagt ttctttctgg ttcagctgga tcagtgtcgg  20460 

tgtacatggc cagttcagct cattcagctt gcggggcctg acaatgcact gaccccgggc  20520 

ctggggttcg gggaggtgag gatggtcagg gggtattaca gaaggaaaac acactcaacc  20580 

ctcaaggggg ttcccactgg gtgaccagac ctggatcaga ggacctaggt tgggggacag  20640 

tgcggagcag atggatctag tgccgaggac atccgagccg ttgcttagtg ttctgggatg  20700 

cctgcgctga gagacgttgg tgccctgaag gaggctggga ttttagaccg gcacggggaa  20760 

ggcgggacat gccaagaggg ggaacagcac atggtgttct gtcccttcct tccatgaagt  20820 

gctgcaggag acaagatggc agagcctgtg tgcccatccc agggcctcag cacctgagca  20880 

gtgagggagt tcttgatgca tctgatcata gtctcgtgct ccagtagagc ctttggttgc  20940 

acggtctggc ttgtgccact gcaggtcttc atcctcctta gctgcatatc cctcccgggg  21000 

cccattttcc aggctttctc ctcctcctac ccctcctacc ccgctgaatc atgcccgtcc  21060 

ctccaccaca tgcttctgtc cttccatcac ctccgggatc tggcttctga ctcagctccc  21120 

agctcccctg agggggccca ggcctggctc caggacccca gtcaatacct ggcttgggct  21180 

gaaatttggc gaggggtggg atgggggtgc cccgatactg gctcagggcc atttgggagc  21240 

cttttatggt tggaaaggca gcttggggcg aggcagttgt cagcccttga ctgagagttc  21300 

tgtatttgcg gcatagaacc tcctgagctt cagtttcctc atttgtaaac cggagataat  21360 

gacaccgtcc tcacggatga aagcgaatgt gtgaacgagc tttatgaact gtaaagctgt  21420 

agacaaatgt tagttgttag cgttattaac gggtgctgtt gtgtagaaga gctcaggttt  21480 

ctacaaggat ctgggaagtg ccttatcctt ctctgtccct ttcttcagcc catctgtgcc  21540 

ttagggactc cacctctccc cttggaaggc ccatatcctg cagaccctct gtatttccca  21600 

gcccctgtgt cctcagctca tcacagcatc tcggcacctc tgccctgggg agccagaaag  21660 

ccttcattgc attagtctgt tgcatcaggc attacagcaa gacagccacc tccttaagtc  21720 

aggctggctc gggggcccca gggcctgggg ggcaggcatg tgggtccaga cttggctctg  21780 

gctgttgtgg agcaagctga ctttcttacc ctacaaggca ctgtttagtc cagagtggct  21840 

ggatgggggc cagtggactt gagagcagca aaagtgggtg gaacctgggg atggcacaga  21900 

catctggcaa ggggtggtcc caggcctgga gtctgcaggc agtgaggggt ggggccaggg  21960 

gagggagtcc agcagtttgc ccgtaggcct ggtggggagc aggtagaggg aggcagtggg  22020 

cagtgtattg tgggaagagg cctgcgtgca gccaccgccc tctcttgctc cttcccctcc  22080 

ccctcttgct cttcacgctg cccctgccca gtgctatggt aaccagggct ggctgcccag  22140 

ttccctcttg gggtccaccc caacagggcc tgcttttgag gacccacaga tctcaattcc  22200 

tggttgggag ccatggtaac cagggaatgg ataactagag aatgcggccc catggaccat  22260 

ggtttagggg cagggtctgt gcggaaagga gctggtcctc accagctccc ctggtccctc  22320 

ccaccctttc caccccactg aatcattctg ttgagaccac agccattctc ccaaagcgga  22380 

tgtgtggatg ggggcaggtg gcttgggagt gtgagaagtg tgcttaacca aagcattccc  22440 

caccgctgcc cacatccatc acacaagtat ttattgagtg ccaaccaggt gccaagtgct  22500 

acagctctct aaacagtttc ttctgtttgg acagtgtcat agactttccc aagccctttc  22560 

acgtctcttc cctggcgata acattgtgcc atacatatcc cttggaggga cgtgtggcag  22620 

gtggggacat tcccatttta tggatgagaa gacaaaaatg tgaattgaaa agtgaggtag  22680 

agctagcacc aggccagcag cctttattta gcacttgcca tctgcctagg gatgttttca  22740 

gcaacaactg atttagggtg atggaaataa ctgcccatga agcaaataaa cttagtgtgg  22800 

ggtgcaaata aaagtaacat gactgggctg agtgtggtga atcacacttg taatcccagc  22860 

actttgggag gctgaggtgg gtggatcacc tgaggtcagg agttcgagac cagcctggcc  22920 

aacatggcaa aaccttgtct ctactaaaaa tacaaaaatt agccaggcgt ggtggcatat  22980 

gcctataatc ccagctactc tgggggctga aacaggagaa tcacttgaac ccaggaggcc  23040 

gaggttgcag taagccgaga tcgtgccact gcactccagc ctgggtgata aagtgagact  23100 

ctgtctcaaa ataaataaat aaataaataa ataaaaaata catgaccagg tagcacttat  23160 

tgagtgcttc atatatacca ggccctgtgt tgattggatt attttgttta atccagcctt  23220 

atgaggtagg ttctattatt atgcctatgt tacgaatgag gaaactgaga cttggaaaac  23280 

tttagccaat tgctctctgg acacagtggc tgacacctgt aatcccagca gttttgtctg  23340 

gagcagcatt gatcaataga catttctgtg atgatggaga tgctctatat gtgtgtggtc  23400 

cagtatggta gccctagcta catgtggtta gtgagcactt gaaatgcagc tgcggtgact  23460 

gaggaactgc attttaaatt taatttcatt ttaataactg cttttaaata gtctcaggtg  23520 

gctagtggct gccttcttgg gatggtcagc tctaggagct tagggccagc tggaggctgg  23580 

agctatgatt tgaaaccctg tctcggtctc tcaagcctac actcctaacc atgacactat  23640 

cccacccccc tttcctgttg ctctgaagaa gttcgaggtt gaggtagaac tgagctcatg  23700 

agctcactgg gagggcactg gtgatgccct ctgtgggtgg gtccgactgg gggctttctc  23760 

ttcttcctct attgactccc cacctccagc acagctgtgg tccttctgtt tccttgcatg  23820 

cctgatgtga gcacacccag cttccccacc gtgcgccccg agaggaggcc ctctgggtgc  23880 

tgggcaggag gaagtgggag tatgggaggc cccatgggcc tgggcctcat cctccccacc  23940 

tccagtcctt ccctcaacta caggtctcct atatttgagc ccaggattct tgcattttcc  24000 

agccaagacc ttggcctctt cattgtacct tagctggtca tggttttctt ggctgtaaag  24060 

tgaggatctt cacaccagcc aggccaccta cttggtgaga ttcctgaggg tctgtgagga  24120 

gggcaagttg gacacttggg acagaggata tatagctcat cgaagcccat tctggtccca  24180 

ctcatagaat caacatgacc acagcagaaa ataggttgtt tattgggggc catgaaaaca  24240 

aaaacaagga agaaaacctt agcatccatg tcagtccctg tcttctcttg cccctggtct  24300 

ctggccacct gtggcatagt tgcagattct cccttgtgat ggcagtggct gccgttgggg  24360 

aggatgccac atggccccca tcgtcagtcc tcgatggggg tttggacaac accagacaaa  24420 

gcagtgtggc atggtcccct tgcccaaact cagcccttcc tctaccctcc tgtctgccag  24480 

aaacaggcct gcctgacagg tggcctcccc gaagctggta cctagaacgg gggccatcac  24540 

tcacagcctg tcagaagaat tgagagctca tttactgttg ttgcagccac ttttcctcac  24600 

ctggagcaaa ctaacatagt catatataag aaattcatca tgaccgggtg cggtggctca  24660 

cgcctgtaat cccagcactt tgggaggcca agcagggtgg atcatgaggt caggagtatg  24720 

agaccagcct gaccaacata gtgaaaccct gtctctacca aaaatacaaa aaattagccg  24780 

ggtgtggtga tggacgtctc taattccagc tacttgggag gctgagacag gagaatcact  24840 

tgaatctggg aggcagaggt ctcagtgagc tgagatcata acattgcact ccggcctggg  24900 

cgacagtgcg agactctgtc tcaaaaaaaa aaaaaaaaga aaagaaaaag aaaaaaaaga  24960 

aaagaaaaaa gaaaaattaa tcacttctgg ggctaggtca ggctgaccat gtgaaatgat  25020 

ctgttggctt gtacattttg aactaagcct gaaacattct cagtccaagg ggaaacattc  25080 

atgtcagcac cctgtggaaa tgcccacctc ctggccagcc gtgtcctccc tttccctgac  25140 

ttttccgcag tggggttacc acagcagaca tttcaagaac tgcctgtgga ggacctactg  25200 

aaacagcaca tgtggagggc cagctgggaa gggccaagcc acaggcaaat gcttgctaac  25260 

ctgcagccta tcactccctt cctcaagaat cataaggagg aaaaaccgtt tatggactgg  25320 

gtgccgtggc tcacacctgt aatcctagca ctttgggagg ccaaggcagg tggaacactt  25380 

gagaccagga gtttgagacc agcctggcca acataatgaa accccgtctc tactaagaat  25440 

acaaaaatta gccaggtgtg gttgtgggag cctgtaatcc cagctactga gggaggccga  25500 

gccaggagaa tcgcttgaac ttcggaggtg gaggttgcag tgagctgaga ttacaccagt  25560 

gctttccagc ctggatgaca gactgagact gtctcaaaac aaaagcaaaa acaaacaaac  25620 

aaaagaattg taaagagtcc gccttgccta cagagtaaag gctgcacacc tttgtgtggc  25680 

ctctaccatc tgcacccata gggcaaaagg agccagaggc ctgaggctgg ccctcgggtg  25740 

gcagtgggag gcacctgctt gaacagtgga tgctccactc cttacttctt tacccagttt  25800 

atagacagac agttgagcta tagtcctctg cacacatggc ttttgcttca aacttttccg  25860 

catgcacttt cctctgcctg gaatactttt ccctttttcc tgcaaactgc aattccaata  25920 

ctgcctcttc cttcagttct ctctttttcc ctgggccaaa agtcatctcc cgccttctat  25980 

actcccacgc cccttacctg ctgctctctt gctacctcat acttcctgct tgctcttgta  26040 

gtcacttgtg tatctggttt gtcttcccca ccacccagaa ggctcctgag gacatgacca  26100 

tgtctttgcc actccttagc actggcagct gtgcctgggg gccctcctgg acagttaggg  26160 

gctgtgtgga ctgcagagct gtatgtgagg tggcagtgag taggcagaga gccccatgac  26220 

ttttcaagcc cttgagcaac gtgggtgaca cacagaggtg aggctaggca tgacacccag  26280 

ccacaagggt catgaggctc tgcctatgag gggagcttgg caaagagacc atggagcggt  26340 

ggtcctcaga gtgaggcccc cagaccagca gcatcagcat cacctgagta tgtgttagaa  26400 

atgcagtttc tttttttttt tttcccaata agcgttttgc actcttaaga aatgcagatt  26460 

attggcccca gccccgacct actgaatcgg aaattccgtg ggtggggccc agcactctat  26520 

ggtctaagga gccctccagg tgattccgat gcacagaaaa ccttgagaac cactgccata  26580 

gagttagaga ttgtgcccaa gatgggagac caggtcatgc caggggaagc acatgggctg  26640 

tgtagccaaa cctcctaggt tcaaagctct gctctgaggt tgaatggccc agtgaagggg  26700 

gcttagtgat accacctctt agggctgtcc tcctcccata aagatcagca gtggtcccta  26760 

agctttcatg tgcctaagag tcatctgggg tgctttttaa aatgcagttt cctgacatct  26820 

catttcagaa aatctaattc tgcaggctgg agtaaggttg aggaatctat attttaaata  26880 

agcccgaggt ggtcctgatg tgagtaggtc aagtaacatt ctgagaagcc ctgaagcaaa  26940 

gggctgtgtg cgacaccttt tatgtactag ataattcgca gtggtggctg caactctgtc  27000 

tattgtgaga acacatcagg ggacgctgaa acagttgggg tcggtggatg tgctggtctg  27060 

aggagaggga gttccctgtg tgcttcctaa cgccagtatt ttcatcaaat gagtttgacc  27120 

tgagagtgat gttgaaaggg cagacatgag catggggtca gcgtggggga ttgggagcca  27180 

gtgtgaaggg gcggtacttc cgtggtgggt tgttcggggc cattgagtgt atgtgcctat  27240 

taggtttagg ggggcacctg ccccctcctt cctggctggt gtaactgtgt ttgccacagt  27300 

gagagttggg cttgtgggtg cagcagggct gggatgtcag ggactggttc caaagatggt  27360 

ttttgctatg tggccaggga aaaaactagg tggcaccgga ttctggtatg gagcctcagg  27420 

aatcctcgat cagcttcctt ggtcactcac ttttggaggt atggaggggc agaggctact  27480 

gccttgtctg gaagaggcct gggctgctct gacagtctgt ctctccaagg ggcttgagga  27540 

tgggggtctg cttcatggct agatgccctc cagcatgctg ttcccctggg caccaccagg  27600 

ggtctctgag gctccctgca aaccttgacc atctggcctt cagctctgct tccgttccca  27660 

gtccctgggc ccgtgagcct cctcagtact gtccagcctg gaggtgaccc tggggcagga  27720 

ctccaggctc catagagggg taggaccgcc cacctgcgga gccatgcctg tgatctcagc  27780 

atcaaatgcc ttaagcacca aatgccattc tgacttccct ccccaaccct acctcaagac  27840 

agccagcctg aaccgtgggc ccctcctctg cccggccccc agccctcctt ccttactggc  27900 

catgctggga aacacaggtc atggcttggg aatgtggccc cgggttgcgg ggtgaggtga  27960 

taggaagagg gagaaggaca tgtgacccct gctcaacagc ccccttctct caggttctgt  28020 

gtccaaaccc tttccccatc ccagatacaa atgggttctc atgataaggg gccatttggg  28080 

ggaggcagcc cccgctgtcc tctttagcgg ggctaaggtg ggtggcgggc aagttgccaa  28140 

caggtgccct ggcggtttgg gtaggaaggc tggatgtggg cttaggccct gtggtggctg  28200 

ctggccagac cttccatggc agggatgagg gggcagaggt gggattctgg gccccctcag  28260 

attcttcccc cacctctgtg aaggagggca aagatcttga cagttctccg attttcgggg  28320 

ccaaagaaaa caggtatgcc ctggctctgt agtatttgag gctcgttagc gcattccccg  28380 

gtcagggatc ttggtggttc cgtcagagca aggggcaaca cagggaacat ttcccacggg  28440 

caccttcttt ggtggacgtg tcagaacaaa tgggtcaggg caagtgtccc tattggcaca  28500 

gcgcagtgcc acccctcccc tgtcttgctc ggggacggag gccccacacc ttgagtcaag  28560 

gcaccgcaga gcgggctttg ctcttgtcag ggtctgaagc tgtaaggaga agaaaggcag  28620 

atcccgcggc ttgggagtga gcagagtggc taaatccaga cggccgcgct ccgccctccc  28680 

tcccctctcc cctctcctcc ccctccacac cagggcccag gctgcctgtg gtctcggcag  28740 

gcaccacctt cctagccagc tgcctgccgg cctgccatcc aacctcctcc ttcccctcct  28800 

caggcgcctt cccctccccc agggccttct ccgtgcaggg cctcagctgg gtcagccgag  28860 

tgagtggggc tgggcaggct ggacaggctg ggctcctgct ccctggggag ccacgctggg  28920 

gtgggcagtg ggcaggcagc aggagggcct ggtgccaggg cagagccttc aggacaggca  28980 

caggctgggg tctgtgtgca gagcctcggg gtgagttggg gtacagccct gctgggggct  29040 

tggggtgggg ggaccctggg gagaacctag ggggctgtgg cagtttcatg tctgtatttg  29100 

gcagtcggat aggagccagc tcagcgagac tgggaccctg gccagttgca ggggagggcg  29160 

tcagggccct ggggacaccc ctcccccaag gctgactctg gtgcccccct cctcttcccc  29220 

caggctgagc tgcccttttt ggtggatgac tccagctctg ctttcctatc cctcgagcgt  29280 

ttgggggtgc aagctgtagg gctgtggcca acaggtgccc ctggggtttg cacggcagga  29340 

agctgagaag ggaaaggggg aggggcaggc tagatagtgc cgcctcattg gccctggacc  29400 

gaggtcggga tgtgacttgt ctgcggtgtg tgttcctctg caccaggccc agctcaccca  29460 

agaaatgggc gtcctagcca tgctgctcca gggttccata gacctgcttc ccctgctttt  29520 

ggagcctgca gttggtagtt taggtctcta gtccatgtca ggaatgtggg tgccctgctc  29580 

cagtggaatt ctcccaccag gcccaggagt ggcccctctg ctgcccgaac cctttgcccc  29640 

aggcctttcc ctatggtgtc ccctcctggg aggatcagca gggtcggtgt tggcagagcc  29700 

agtggcagag gaggttccag gggctcaggg aggggaagaa gctgggcgag gtcgcaggag  29760 

cctgggggtg aagtcagggc agggccggcc tgcggggagc tgccgcaact cctgggctct  29820 

gggcgacatt ccagccagct ctcccaggct ctctgctcgc cttcctccct ggtagctatc  29880 

tctgtctctc tccaggtggg tctacatccc ctttcagcag ccccatcacc tccgacgagg  29940 

aatacctgag ccccccagag gagttcccag agcctgggga gacctggccg cgaaccccca  30000 

ccatgaagcc cagtcccagc cagaaccgcc gttcttctga cactggctcc aaggcacccc  30060 

ccaccttcaa ggtcagaccc ctgaggctgg ggcctagcct cctgtgtgcc cccgttcctt  30120 

tgggtgcccc cttgttcttg gggccatgcc taggcaacat caagacctgg aactttgctc  30180 

ccattcaaac cctcttaccc agagccagtc tcagcctggc tgtggaagag tcctccgtct  30240 

cagattccac agcccccagg acccaaggct ctgccctgtc ttcccctgac actttggggt  30300 

acccccttca ggtctcactt atggaccagt cagtaagaga aggccaagat gtcatcatga  30360 

gcatccgcgt gcagggggag cccaagcctg tggtctcctg gtgagtagcc gcactttcca  30420 

ccacccacca gcgactctat gccaggcctg gctctgggag gtctggcttt gggtggaagg  30480 

aaatggaatc ttggtgggct tccccatgat ctgcctcagg ggcctcatct cagggacagc  30540 

agtgtactcc ccccggcacc ctgtcccttg ccccatgttc caggcttatt tagggcttcc  30600 

ccttctgggg aggggtttgg gtctcatgtc tgtccatttg ggataaatga ctgggtgcgg  30660 

tggctcacgc ctgtaatccc agcattttga gaggtgaggc gaatggatca cttgaggcca  30720 

ggagtttgag accagcctgg ccagcatggc gaagccctgt ctctactaaa aatacaaaaa  30780 

aattagccag atgtggtggt gcatgcttgt aatcccagct acttgggagg ctgaggcaag  30840 

aagattactt gaccctggga ggtggaagct gtagtgagct gagatcacac cattgcactc  30900 

cagcctgggt gacagagtga gaccctgtct caaaaataaa aataccccct tcccaaaatt  30960 

agcaaggagc aagacatttc agaggccaag gaaggaggat tgcttgagcc aaggagttga  31020 

agaccagctt gggcaacata gtgagactct gtctctacaa aaactttttt taaattagct  31080 

ggacgtggta gtacatgcct gtagacccag ctacttatga gggtgaggag gaggatcact  31140 

ggagcccagg agtttgaggt tgcagtgagc tatgatcata ccactgcact ccagcctgga  31200 

caatatagca agaccctatt gctgaaaaaa aaaagacatg caacaatttg tttctgagct  31260 

gccagcagcc ccgagttaaa tgtgggtcta agcagagggg cctcgctcat cccaggtgcc  31320 

tggaagatgg attactcagc ttgctaattt tttatggttt gaattctgtt tttcattttt  31380 

aattgattgt ctggtcccca ctgtgatttt tttttttttt tttttttttt tttttttttt  31440 

ttttagctgg agtttcactc tttgtcgccc aggctggagt gcagtggtgc gatctgggct  31500 

cactgcaacc tccgcctcct gggttcaagg gattctcctg cctcagcctc ctgagtagct  31560 

gggattacag gcatgtgcca ccacacccag ctaattttgt attttttgta gaggcagggt  31620 

ttctggtcag gctggtctcg aactcctgac ctcaggtgat ccacccacct cggcctccca  31680 

aagtgctggg attacaggca tgaaccaccg tgcccagccc ccactgtgat tttttttttt  31740 

aacattgtaa gttttttcat atcccttttg ggaagtggga aagctatctg tccattataa  31800 

ataaataaaa ataagacatg gggaagttta agaattatta agagctaaat agggtcaggc  31860 

atgagggctc aatgtctgta atcccagcac tttgggaagc caagagagga ggatcatttg  31920 

agcccagaag ttcaagacca gcgtggacaa catggtgaaa ccctgtatct acaaaaaata  31980 

caaaaattag ctgggcatgg tggcgtgtgc ctgtagtccc agctactcag gaggctgaga  32040 

tggggagatc gcttgagcct ggggaggtag aagctgcagt gagctgtgat tgtgccactg  32100 

cactccagcc tgggtgacag agggaaaccc tgtttaaaaa aaaaaaaaaa agacaagaaa  32160 

aaagagctaa atagcacggc tccactctga atgcagcagg gttccgagaa gggagagctg  32220 

caggcagtta gaagtgacct ggaagctcct agaggtgggt gggatggcag agtgggggta  32280 

aaaacctagc cctggaaacc agggatgccc acggtcagtg ggacagatct ggggactggg  32340 

caaactgcac agggaaggag aggcctgcac agtgctgcag ccccagttcc tgtgcacgca  32400 

catcaggccc ctgggccctg ggactgagtt cttgcccctc tgacaggctg agaaaccgcc  32460 

agcccgtgcg cccagaccag cggcgctttg cggaggaggc tgagggtggg ctgtgccggc  32520 

tgcggatcct ggctgcagag cgtggcgatg ctggtttcta cacttgcaaa gcggtcaatg  32580 

agtatggtgc tcggcagtgc gaggcccgct tggaggtccg aggtgagtac ctgatttctc  32640 

catgaatgcc cacctggccc tggccccttc cttcccccac tgtctgctct cacacagcct  32700 

cagttagagg atgccaccac tgaaagggcc ttaaggggcc cctagtccag ctgcttatat  32760 

tattgttgag tgaaccaaag cccagagaca ggaagtgacc tgcccaaagc tgcacagcac  32820 

attgttccgt gctcagctta ctacacaaca ccaccttccc tgttgctcca tcacggagcc  32880 

ctggcggcag ccagagaccc tgcacctgcc actggccaag ctctctctac actcttctga  32940 

gcctttgtca ccctgctctg cccaggaccc tccctcatcc ccctccccct ctcctctcgc  33000 

ccctttgccc accctcccat cccattgctg tgcagaagct actgtgaggt agcggtgggg  33060 

agagtctggt ggctggaccc gttcggaggg gcccttgggg tggcttaggc ttggagcatc  33120 

acagggaccc tagggtgcca gggtgagcac agctgtgacg tgtgaagagg cctgggcccc  33180 

cagagcctgg ggcatatgtg caggggccct ctcaggcagc agaaatgcca ggccctggct  33240 

agggggccct cgagggccat gggttttcct ccccaaaggc cacaaccgtt tatcttgcct  33300 

tccacctcac ccttcgcctc aatggctcct cgcttcctct cctcgcttct cactcagccc  33360 

ccagcccctg accttcccca aggctcagag ctcagaccct gacagtcatg gtccctctgc  33420 

tggcccccct gcctcagttc ccctcctctg tgcctgccgt tcctgtagtt gccacttcct  33480 

tggtctccag attcttcagc cctcctcccc ggcctgcttt ctctccaggg cctggctctg  33540 

cctcgcttct ctgtattaac ccatgtcttg gtgcttcttt ctcttgggga ttccttccga  33600 

cacccccagg ctttggggtg ctcctgatcc catgaatgcc tggttgcccg gggtctctgc  33660 

ctgcccagga accccgagga accagtctct ggctagctgc cggccctcgc agcccagagc  33720 

tgtccttggg ggagccaaga gtggcagtgc tgccctgacg gtgtgagagg cagccctcta  33780 

tgcagaaggg ccctagccag gtctgcgtgc ctgtgcgtgc atgtgtgcgt gtgcgtgcgc  33840 

atgcgtgcgt gtatgtgcat gcatgtgtgt gcatgtgtgt gcgtgtgtgc gtgcgtgtgc  33900 

atgtgtgcgt atgggtgtgt gcatgcgtgt gtgtgtgtgc gcgtgtgcgt gcgcgtgtgc  33960 

gtgcatgtgt gcgtgtgcat gcgtgtgtgt gcatgtgtgt gtgtgcgcgt gcgtgcgcgt  34020 

atgctgcact aacctgccgc ttgctgactg aggtttttgt ctgtacacag gcgagtgagc  34080 

tcagggggcc acctgcgctc cccccgctac cctccgagcc gcgcccctgt ctcaggcacc  34140 

tctcggacct cgctgtgttt cactgcctcc tgcccacaga cccaggcctg ccggcccgga  34200 

cccgtcccag cctcccctcc ccaccccatg cagcccccag ggggatagcc catgggcccc  34260 

tgtggaccct ccctccccaa gtggacacat ggctgtgcag gccaggaggc ccacagatgg  34320 

actgagtgct gggaaggggc ggctgcgagg ggtatcaacc ccccgagtct ctccctgaag  34380 

gggagcaccg ggcgagtgca tgtgctactg ctgctacagg cctgtctatc tgtttgtctg  34440 

tctgtgtgtc tgtgacagtc agggaaggat gcctcggagc tgaggtgggg tgagacagag  34500 

tgggagagat tacggcatgg catggagggg cccaaggagc aggggctgtt gacaaaggcc  34560 

ttaccaggaa gggttaggac actgaccatt ctagaaatgg gtttcgaatg gcacaacact  34620 

ttctatttca caaaagacca aaagccagag gccccaggct ctgtgctgat gaacagcctg  34680 

gctgagccct ggccctggca ggtttagggc ccatttgggg ccccctcctt ctctgtcagg  34740 

gctggggtgc tctgtctggg aatgagggag ttaaccaagt ttggtgcagg agcaggggca  34800 

gggggccact gtagtgagcg tggagaaatt tggaaacacc tatttcttaa ctcaaataaa  34860 

gtccagtttg tacctatctg gtgtgttgtg tttttttttt cccccgccga tgtctctgcc  34920 

accacgtggc cctctcagtt tcccctccct cagttccctc ttgcctccat gaatcaccct  34980 

ccctggccca gcttggattg ccatctcaaa gccaggtctg ggcatgcctt gctgtcctgg  35040 

ccaggtgggt gggctttccc catctccaga gaacaaaatg catctctctc tctgtgtctg  35100 

tctgtctctc tgtgcgtgcg tatgtgtgtc tccctcaccc tgtgtgtctc tgctctgtgc  35160 

gtggcccccg tggctgcttt cccctcagca caccctgaaa gccggtccct ggccgtgctg  35220 

gcccccctgc aggacgtgga cgtgggggcc ggggagatgg cgctgtttga gtgcctggtg  35280 

gcggggccca ctgacgtgga ggtggattgg ctgtgccgtg gccgcctgct gcagcctgca  35340 

ctgctcaaat gcaagatgca tttcgatggc cgcaaatgca agctgctact tacatctgta  35400 

catgaggacg acagtggcgt ctacacctgc aagctcagca cggccaaagg taactcccca  35460 

ctcaggcatt gggctgccgt gggtgcccaa gagctggagg gaggggactg ggggtgtaca  35520 

gtaagatgcc tgggaaacag agctccaacc ccgaggggaa gcgggggagg gtgggagcta  35580 

gtacattgcc ttggcctcaa taaaataagc acttagaata gtgcatagca caaaggaaag  35640 

gccgcaacag ggttaactgt tcctaggagg gagtgcatct gctgaggtga acgtgggttc  35700 

ccacgcctgc cctgcaagtc accagccata taactttgaa caagtcactt catctctctg  35760 

agctttagcc tgttcatctg tagaacaggg atggtgatca ttcctcctct gtagagggat  35820 

tggcaggatt aatgagatag tttatgtgaa gaacaaagca cagggcctgt caaagggcct  35880 

ttccaggaga gggtagggca ctgagcattc cagaaatggg tttcaaatgg cacacctgcc  35940 

taataaatgc cagccattgt taccactgat gctatctctg acctgggcct gcccacatgg  36000 

aagggcagag attatggcac ctgccttgct acgttgtggg tgatgaagac ctaagcggaa  36060 

gctggagggg ctttagaagc aggagggtgc atcgggtcaa cataagggac ccttatctcc  36120 

tccagaagct tctttgaggg ttggtaggtg gggccaaggg gcatctgctc tgggtctggg  36180 

gaaggtggct aggagcatgg gcatgacccc agcacagagg agaattctga gaagtagatg  36240 

gaggaggggt gggcttggct tctaggaccc tatcagagct gggctgtgct tcatccaggg  36300 

tgggcagggt gaggggagga ggggggagct ggggccaggc cctgggctca ggccctgggc  36360 

tcctatggag tccccagccc accatggcag tctgcaccca cccttgctga cctccaccct  36420 

ctcgaggtct agtctctgga tctgtgccca cttcctcccc tgagtaccca gagcctttgc  36480 

tgggctctgc ccaggctcca gcttcctgct cagccttagg tcaggagtgg tgggttggga  36540 

tgcctgggcc tccttagcct tccctatctc tgagctgccc cctgccccac agatgagctg  36600 

acctgcagtg cccggctgac cgtgcggccc tcgttggcac ccctgttcac acggctgctg  36660 

gaagatgtgg aggtgttgga gggccgagct gcccgtttcg actgcaagat cagtggcacc  36720 

ccgccccctg ttgttacctg gactcatttt ggtacggccc ctgtgctgca ggtgtttgag  36780 

ggccccccca agggcccagg cggcgatggg gtgcacccag agggcagggc ccctcactgt  36840 

gcctgctctg cattcccacc cctcctttct gcaggctgcc ccatggagga gagtgagaac  36900 

ttgcggctgc ggcaggacgg gggtctgcac tcactgcaca ttgcccatgt gggcagcgag  36960 

gacgaggggc tctatgcggt cagtgctgtt aacacccatg gccaggccca ctgctcagcc  37020 

cagctgtatg tagaagagcc ccggacagcc gcctcaggcc ccaggtacca ccggggcccc  37080 

aaatgatgct ggggctgcct gtgaggggcc agcccagccc tggggtggga ggcacggccc  37140 

tgggcctgtg ggcagctgtg tggtcttgca gctcgaagct ggagaagatg ccatccattc  37200 

ccgaggagcc agagcagggt gagctggagc ggctgtccat tcccgacttc ctgcggccac  37260 

tgcaggacct ggaggtggga ctggccaagg aggccatgct agagtgccag gtgaccggcc  37320 

tgccctaccc caccatcagc tggttccaca atggccaccg catccagagc agcgacgacc  37380 

ggcgcatgac acagtgtacg tgtctgggaa gttccccggg agtgtcccct gcagcaccca  37440 

cttggcttgc aatgccctgc ccctctcccc agctctcccc aggcctttcc tctgtagcct  37500 

gaccagggac agggtgcctg ggggaaggga acccggaggg actgtgaggt cattgcctcc  37560 

cctgcaagcc cacacagcac tcatctgctg agtcacccct cagtgcccgt tagcactgac  37620 

tgggcaggca gtactgcctg ctactaaccc gcatcgggcc catgagcaag ttacagaagc  37680 

cctctgtgcc tcagtttctc atctgtaatt gggttgttac gagactaaat cagttaatgc  37740 

atataagccc cagagcaggg cctggcacct ggcaagcagc tgggaggtgt gaagtctcag  37800 

tattcttgtt ttagtagcca ttatcatcag cggtggtact tcctggagac attgcaatga  37860 

aaaagcaggt gtgggcagtg tctggcatgg aagggatgct ctgtccaggg ttgctaacaa  37920 

atagcaaata acgaagaagg ggccagggga gacacagagg aacgtatttg ggttggtgtc  37980 

ctcttagcct gggatacttt cttatgggag catctcagtt ccatccttga aggaatctga  38040 

gtcttgtgtg agaaggtctg cccccctccc ataagacagt gcccactctt tgacccacga  38100 

tgatttcctc ttatggctgc aacatgacaa agatcacttt cattaagtgc tttctaagtg  38160 

ccaggtcctg agagctaaag gtatgacaag gaccatctta ccttgccaca ggcctataag  38220 

gcggatacta ttagccccat ttacagatgg ggaaactgag gcttagagag atacaggaag  38280 

ctgccaagag gcaagaaagg actgtctgac cctggtgccc agctcttaac caggatgtcc  38340 

ctgtcaccca tgctgcatcc tccctgccca cccgcctgcc catctccagt gatgccaccc  38400 

cggctccaac ccctgcccac agcctcccat gactgtcatt ctcagcagca ggcctccctg  38460 

tctcccagtc tgctctgagg ccctgggtga gtgtctgtct caggatctaa gctggcgtct  38520 

ccgcttctgc ctgtatctgg ggtcactggc agcccttggc ttctcttctc ttataaatag  38580 

tgtcagcaga gataaatgaa tgggtgactg ttctatgcag agataactgc aaagagaagg  38640 

gaagggtgtc tagggacagc cctgacatga aggaggacag tgcaggcctc ctctctgtgt  38700 

cttcgccaga gacagcctcc ttatcatcca gggagcaggg agtagggaaa gagctttgga  38760 

atcacatggt accaaggtca aactatcatt tattagccgt gggaccttga acaagtcaat  38820 

atctctgacc tcattggtaa aatggggata attttgtaga gttgttgcaa ggattcacga  38880 

gggggaaagc atgtcaggta cctggtatag gctgggcaca gagcaggcaa ctcttgtaat  38940 

atatcataga atgtatttgg tacttactgt gtgtgaggtt ctgggtctgg tgggacaagc  39000 

agatctgaca acgtcagccc tctctttaag gagcttgcag accaggtcag gagctatgac  39060 

tgatgcaaga ggaagagccc ccgcccatga aaagcagcgt gggccagtgc ccatcgatgt  39120 

gcaggcgaga gggttggggt cctgggagga gtcagaggat gaggggtaga gagcgggcca  39180 

ggggcagggg ggcttcatgg gctgtaccca cttaaactat gtcttgaagg acaaggaagc  39240 

cttaggtaag aggagagcat tccccaaggg aggaatgttg tgagcaatga cctgcagatg  39300 

gaactcggtg tctcgttcag gggcctgata gttagccagc atcaagatgc agaggagcaa  39360 

cagagacgtg gctggcaggg agtttgggtt gagggctttg ctgtcctcct ggagggcttc  39420 

cctgcagctg tgctggagac agaatggcag tggccttggg gatggagaag aagggcttag  39480 

gggaggggcc ttgggaacaa agctttgttc gagttttgac atagaggttg tgaccatgca  39540 

gaggtgggaa gacgaggggc cagtcaacag aggcagggac cccagagggt ggcccagtgt  39600 

aggaggaaga gaagatgata agttgcctgg cctgacacac tggagggaca gaccagaggg  39660 

gccagggcag atgtagactt ggaagccagc ccgggcccag acccagactt tgctgcacca  39720 

tggatgcact tcttgctgcc tgccccatcc ttgccccatc cttgcccact cgcctcctcc  39780 

ctgcagtgga tgggggtgag ggaccaggcc cgggatggca tgggcctacc cctcaaggta  39840 

tcctccgggc tcaggcccag tgtcactgtc cctcccctcc cagacaggga tgtccatcgc  39900 

ttggtgttcc ctgccgtggg gcctcagcac gccggtgtct acaagagcgt cattgccaac  39960 

aagctgggca aagctgcctg ctatgcccac ctgtatgtca caggtgaggc aggcaccctc  40020 

gtggtcagct gcacgcacag cctggcctct ggcactacgt gggggctcag ggaaaggggc  40080 

ctccacccag ctcccttccc ctccatcccc tggggaccct cttgccttgc ccctgcccct  40140 

gcggctgagc ccccaggccc tagcctcctg ccctgaggct cggtgatcct gtggggctgt  40200 

tgggcccttg gacccagcag acattcgaac tgcggctttc agatgtggtc ccaggccctc  40260 

cagatggcgc cccgcaggtg gtggctgtga cggggaggat ggtcacactc acatggaacc  40320 

cccccaggag tctggacatg gccatcggtg ggtcagggct gcacagggcc atgggtgggg  40380 

aaggggtgtg gagaaggcag gctcaggcag gacaccatgg gggccaggcc ccagaagcgg  40440 

atgggcaggg gcaggagctg atggaatgct ggtgggacca gctttgcccg tcttctctcc  40500 

acgttgcatg gggctcttgc tctgggtgag gagaggaggc acggggcact gccacattcc  40560 

cttcccatcc tcagagtggg tgcctgggtc aggacttgca aatgccctct cctcgtcttg  40620 

tccaggatct cctcccgctc tgcctcagtt tccctacctc aggtatcaag gaattagagt  40680 

tcaattccag ccccatctgt gcctgtactg gtaccttgtt ggctcttaac ctcccaggga  40740 

agtggctggg caagagcaga tggggggaca ggcaggaagc aacagcagag actgaggcac  40800 

gtcatcagag cagactaatg atgagttcca gggtcccggg ccagctggat ggggaggggt  40860 

tactgctcct gcaacagcag cctctagtag ctcctctccc gccagacccg gactccctga  40920 

cgtacacagt gcagcaccag gtgctgggct cggaccagtg gacggcactg gtcacaggcc  40980 

tgcgggagcc agggtgggca gccacagggc tgcgtaaggg ggtccagcac atcttccggg  41040 

tcctcagcac cactgtcaag agcagcagca agccctcacc cccttctgag cctgtgcagc  41100 

tgctggagca cggtgagcct gggtgctcct gtcgggtggg ggtgggagct gctgggatgg  41160 

ggaatggggg ccctgtggtg gaggctcaag ggatggcctg gacatggtaa ctggcaggag  41220 

cagcctagcc gggcgggacc ttggcccatc tgtacacttc cttctccctc ctgaaagcag  41280 

cagggcacgg tggctgaagc tcaggctttg ggatcgggcc tgctggggtc caaccccaca  41340 

acctcagctt tgctgctctc tggctgtgtt cccctgacaa atcgctaaac ctctctgagc  41400 

ttcagctttc ccatctgtaa aaacggaact caagtgttga tgaggggtgt tagaggagtg  41460 

gtgggtgctg aggacctgat gtcaagccca gcacagagcc tgcgctctcc tcctcccagg  41520 

cccaaccctg gaggaggccc ctgccatgct ggacaaacca gacatcgtgt atgtggtgga  41580 

gggacagcct gccagcgtca ccgtcacatt caaccatgtg gaggcccagg tcgtctggag  41640 

gaggtgggcc cctttcccac atgtggcagc ccaggtctgg cccagcctgg ccggaatgcc  41700 

ctggggcaag atctgggtga cctccctgtc atgtgtcccc tagctgccga ggggccctcc  41760 

tagaggcacg ggccggtgtg tacgagctga gccagccaga tgatgaccag tactgtcttc  41820 

ggatctgccg ggtgagccgc cgggacatgg gggccctcac ctgcaccgcc cgaaaccgtc  41880 

acggcacaca gacctgctcg gtcacattgg agctggcagg tgggtgacag cgggccttct  41940 

tcctagcctc cctccaaggc ccaaagctct ctactcacac ccccaggtac acaacctgcc  42000 

tgacactgct gcagatccaa acccatgtcc tctggtcagg cctgtccatg tcatggctat  42060 

acaaatacca tattagtaat aatgacaaca atcatactaa caagatttat tggccagacg  42120 

cggtggctca cacctgtaat ctcagcactt tgggaggccg acacaggtgg attacctgag  42180 

gtcaggagtt cgtgaccagc ctcgccaaca tggtgaaacc ccatctctac taaaaataca  42240 

aaaattagct gggtgtggcg gcaggtgcct gtagtcccag ctacttggga ggctgaggca  42300 

ggagaatcac ttgaacctgg gaggcagagg ttgcagtgag ccgagattgc tccattgcac  42360 

gctagcctgg gcaacaagag caaaactctg tctcaaaaaa aaaaaaaaaa aaagatgtat  42420 

tgagcctagt atgtgccagt ctcagtacta agcactttac atgtattgcc tcatttaatg  42480 

tttacatcag ccttgtgagt tggggttggt tattatcccc attttacaga tgaggagact  42540 

gaggccgagg ctaagagtaa ctggcccaag ttcacagaac ctaataagta caggagctgg  42600 

gttcaagtgt ggctgcctga ctcctagctc ctgtgttaaa cataatagga aatagtatct  42660 

cagatataac aaacatggga agaccaagtt ggtttttaaa gaaacccatg ggcacatctt  42720 

atcaccgaac tgccagccct gagaatcctg gccgcccttc ggcacaagcc tgtttgacag  42780 

agcctcccaa tgtttgcagc agcaaggatt cttttttttt tttttttttt tgagacagtc  42840 

atctcactct gtcacccaca ccatctcggc tcactgcaac ctccacctcc caggttcgag  42900 

tgattcttgt gcctcaggct gccaagtagc tgggactaca ggcttgcaca accacgccca  42960 

gcaaattttt tgtatttttt agtagagatg gggttttgct atgttggcca ggctggtctg  43020 

gaactcctgg cctcaagtaa tccgtccacc tcggcttccc aaagtgctga gattatagat  43080 

gtgagccacc gcctcgggcc ttaggattct ttttataatt tttcctttaa agatgtagtt  43140 

tctcaaacta gttactacct aatgcattag gtagtaactg tttggttttc taatttgtta  43200 

attaactcta gacatatgta accgccactc agaactcctg atcaacatgg gctaaacagg  43260 

gttacctgct gagtaaatac aattccaacc aaaagcaaag aaagtgacat tttacttagc  43320 

acaggcaatc ttatcatggg taaatggaca ttttctggtg ctttcaaaaa accattgaag  43380 

ctcacttgaa actttccggt gctttgacct tcatagactg cccccaccac ctcccagccc  43440 

atgggggaca ggattcctag aggcgagggg aggcgtctgt gaagtggaag ataagtggca  43500 

atagggtgtg taacaaagag acagggaacg cttctggccg tgctgtgaag atggtggggg  43560 

tgctgggcgc tcttttaagt gtctccctcc ttgcctgccc tgtccctagc actctccact  43620 

cagtcaccac tttactcctt gacagtccat cttcaggact cacctttctt cccagatata  43680 

ggaggagccc tgaagtttgg ggagcccctg gccctgagag ccctgcagca cagcctagct  43740 

ggaacagtga ccgatggagc cccatttgag cccagccagt cagggctctg atggggctgg  43800 

ggcttgcact gacaccccta ttccactaga ccccacccag ccacacccag acagggcaag  43860 

tggagtggtg gccccccttc ctccacgtca acctcactgc agtgtcttcc ccacccccgg  43920 

gatggcctcc cccgttgtct gtgtgcctgt gaagggtggg ggtccacacc cggccgccct  43980 

gccttcccaa gtgcctgact catcctactt ctcctcagtc tgagatgctc aaacacgctg  44040 

gggtgggggg tgggggctgg cgggggacac ctggaagtca caggctcctt tgcaaagcac  44100 

attgcaatgt gtatttaatt ccatcatgag aattagaagc tgctttacca ggaaatcata  44160 

tgaccatgtg atattatgga gaatgaaatc acaaccacat gtgggagata ctgagagtcc  44220 

atttctagat ggtttggtta gtatttgggg gttacttgtt tgttcatctt gccatctccc  44280 

agatgctatt aatagaagcc cctctaaaca tttttcaaag attcagtgaa aaaacttcaa  44340 

ggtagaggca atgccatcca tgagcttaat tcagggtcac aggctgagcc acctgcaggg  44400 

gccaagttca ggtagtcaga agccagcggg tggccctgtg aagaagggcg gccacccaca  44460 

gggggcagca ttgggccact cctctcccgc ggattcatgc agcgagggga gcgactcagg  44520 

atggccagtc ctgatttttc aagagaggca ggaaatccag atttcttttg tgtgtgaaaa  44580 

tctcctaatt tcaaagctgc caaattaata cagaaggtca aacaaagcaa gcctgcacct  44640 

tgtgccaggt ttcctcagat ttggagaaca tcacgtttgg atttacgggg cggggcgggg  44700 

cttggtccag gcagggaact ctgttgtccc agttggtggg ggtggggggt ggtggcttgc  44760 

agggaggcgg gggtctagcg ttctgactga gccagtcact gatgggggat cttgggaggg  44820 

gctgaggagg cagggtaaag ccagccccta gccccttctc ttcccacccc tatccccatg  44880 

tgtttcagag gcccctcggt ttgagtccat catggaggac gtggaggtgg gggctgggga  44940 

aactgctcgc tttgcggtgg tggtcgaggg aaaaccactg ccggacatca tgtggtacaa  45000 

ggtcagagtg tgctgctggc tgagcctggg ggagggagga ggggctccct gggggcgtgg  45060 

gagggtcctg gaaggcctta ggagggcgga gcccgggcag aggcgtggtt aggaggagga  45120 

aaggggctgc agaggactga ctagctgagg ggtgcagggc tttctgtggg agataaggga  45180 

ggagctgact ctgggtcctg gtgagagatg cgctgcccag agtaggagat gaggccctgg  45240 

ccccaaggta gagatgaggc caggcccagg ctgaaggtga gaccccactc tgcaggacga  45300 

ggtgctgctg accgagagca gccatgtgag cttcgtgtac gaggagaatg agtgctccct  45360 

ggtggtgctc agcacggggg cccaggatgg aggcgtctac acctgcaccg cccagaacct  45420 

ggcgggtgag gtctcctgca aagcagagtt ggctgtgcat tcaggtaggc aggagttccg  45480 

gagaaaggta aagcgcacac cccctggaat ctgatgtgac cctccatgct ctgcccagga  45540 

agcagccagc cctggactcg agccaccaca cccccagccc agcaccccgc cttgagcccc  45600 

caacattctt gcacctcttc tctcttcttc ttctgtccac ctgtcccagt ctctggcctg  45660 

cttgctttct tcccctccca cctaacacca tgacatctct gccccagctc agacagctat  45720 

ggaggtcgag ggggtcgggg aggatgagga ccatcgagga aggagactca gcgactttta  45780 

tgacatccac caggagatcg gcaggtgtgg ggctaggagg gaagccagtg ggggccgaga  45840 

gaggctgctg ggtctgaggg ttgggagggg tggagagggc cacagtgatg gctgatctct  45900 

gaccccctcc ctgtgtcaac caggggtgct ttctcctact tgcggcgcat agtggagcgt  45960 

agctccggcc tggagtttgc ggccaagttc atccccagcc aggccaagcc aaaggcatca  46020 

gcgcgtcggg aggcccggct gctggccagg ctccagcacg actgtgtcct ctacttccat  46080 

gaggccttcg agaggcgccg gggactggtc attgtcaccg agctgtatcc tgggacaggc  46140 

tgggggctag ggggatccat gcctaaatga ctggtccttg taacatccaa taggcaacat  46200 

gttttacagt ttacaaagta gtcccaattg acaattggga gggatacatc tggagacttc  46260 

tatgaaaacc aacagtttta agcccattgt tagcttaaat tttcatagca tttaatgtgt  46320 

gtgcctggca gtgttctaag agttttacaa atattaacct atttaatccc atatattcct  46380 

atctcctgga attttattat taacttgtat tatccccatt ttacagatga agagacaggc  46440 

atggagaggt taaataactt gcccaaggtc acagagctag cacatggcct atgcttttca  46500 

tcatgaaatg cagtacaatg catctgcata tttgtagtga ccccatttca gatcaatact  46560 

tggctttatt tagaggctgt tttcataagg aacagatttt accctttcat gaaggctgtg  46620 

gttaagcaaa ggcacattga ggtaaggatg ctgggtgatt ggctcatcac cccagtagca  46680 

gggtgaccgt aacctgcaca tgagcctcct gcctgcactg tttgaattca aacctcagca  46740 

aaatgacaaa ttattccatg tcatggatct tctaggtcat tctcaaatag agtcaagaag  46800 

ttccatccac agtcaacaaa attctgctgt aatttgatcc ctataaatgc tttacagggt  46860 

gggcaggaaa ggaaatgtta ttcccatatt actcctggga gaacctaggc tcagagaagt  46920 

gaagtgactt gtctgagatc ccatagaaag tgggagttca agcagggatg acccacctgt  46980 

gccctcagag gacaggaggt ggggaggggg tacacgtgga ggagcggaga ggcagtctct  47040 

ggctagtatc aagcattctg taaggggaag gagaaccccg tgctgagctg ggacctgccc  47100 

tgagcgctgg gctgggccgg gcagttggca ctgggcactg ttctccttga tctgggatgt  47160 

agctgcacag aggagctgct ggagcgaatc gccaggaaac ccaccgtgtg tgagtctgag  47220 

gtgagggcag tgggtggcag gggccaggtt gggcaccagc cttcacccac ctgagctttg  47280 

agaaccaaca aatgggtcct gagtgtgcca tctgtgccca caggaagcca ggggtggagg  47340 

tggagagcac tgttaggtag gcagcagagt ccccacccaa tgataccaga cccccatcta  47400 

tctgagactt gtgctattct ctctaaatct cagcaaaccc accccagctc ctaactgttg  47460 

tttcccactc ttcatcacat aaacatcccc caaacatttc tcctggaagg agccccacct  47520 

agattttatt gatctcactg cagtcctgcc acgtcaggct gtacatgttg tgcactgcac  47580 

aattctactt attaccacgc aatggctcct ccctataatt gtgctgtacc ctccggtgca  47640 

tatggtagcc ttggatcttt gcaaccccaa acctgtttca gccccttcca cgagccatct  47700 

gaaggctact ccacaggcac agccggaccg cttgccgccc tggaggtgtt cagacataca  47760 

ccacccttcc ccctcagact ctgggcccac tatttccaca gatccgggcc tatatgcggc  47820 

aggtgctaga gggaatacac tacctgcacc agagccacgt gctgcacctc gatgtcaagg  47880 

tgaggtgggg actggagagc agacagcccc tgtgggagcc aggaggtgaa gcatccttcc  47940 

ttgttcattt ggcccgcaca cctcgccttg tgtcttccag cctgagaacc tgctggtgtg  48000 

ggatggtgct gcgggcgagc agcaggtgcg gatctgtgac tttgggaatg cccaggagct  48060 

gactccagga gagccccagt actgccagta tggcacacct gagtttgtag cacccgagat  48120 

tgtcaatcag agccccgtgt ctggagtcac tgacatctgg taaggctggc atgctgggct  48180 

gggccgacca gggcagctgc ccttggggct gtgctgggga cgcgctcact ggcagggaga  48240 

tttaccgagc ctgaattcct cctgaaggtg ggctggaggc attgtttgca gggtctcctg  48300 

cccatgttac tccttgcccc ttgtgagtca gggctgcccc attctctcaa ggcctcagcc  48360 

ctgttagtcc ttgactcctt gtctcccctg gaagccgggc cttcccctca gcattcagcc  48420 

tgcctcctcc agtaaggcag gcatggtccc attggttccc aggcttccct gggcttcctg  48480 

ggccagccct gccatgaccc tggacttctc caggcatatc tggacctgta ggttcagggt  48540 

cctccctgaa gaagccactc ctgtgcccat tgtccatggc agtgttccca gggaggtaac  48600 

agctcactca ggtcagcagt agcaaagaac tgctcccttc cagtcagaga ggggcggtcc  48660 

tcttacctat cactctcctt ttcccacagg cctgtgggtg ttgttgcctt cctctggtaa  48720 

ggacccctct gcaatgtccc agcagtctcc tggcaggtct acccctaacc tttgcagggc  48780 

tgcagcccac ccccttctct tccgcacccc ccactccttc ttgcactgca aggagcctca  48840 

tgtgcatgaa ggtggacacc cctgtctgca tgcccacact ctgcctgtcc ccacacccct  48900 

ccataagagg tgggcaccct agatggagag agcccagcgc aggctcaggg ccatggaggc  48960 

agggaactcc ttggctctga gtgtccaaaa cttggactag atgggagtgg agctcagggt  49020 

gggcacatcc ccttggcaca gactcttcac tcatggagag gccacactgg aggagggatg  49080 

gaacaggtcc tctaaagcac aggccactag gccccaaggc agcaccacct ccctgcccat  49140 

caggggggct ggggagggga cagggcagga gagagtccgc agcctcacct cttacccaca  49200 

tttgcccagc ctctgtcatc ctcacaaccc cagagcctcc atctgtcccc agccctgtgc  49260 

ccccactgac attccccttt gtccccgcct gcccctcatg acagccctct tcacccctgc  49320 

agtctgacag gaatctcccc gtttgttggg gaaaatgacc ggacaacatt gatgaacatc  49380 

cgaaactaca acgtggcctt cgaggagacc acattcctga gcctgagcag ggaggcccgg  49440 

ggcttcctca tcaaagtgtt ggtgcaggac cggctgtgag tacaaggccc tgggagcccc  49500 

cacctgcagg gtcaccctca taccacctgc ctgctactcc caaactcctg cccctcgaca  49560 

tgcaagcccc caactcctta ggagccctgt ttgctcagtt attgactcac tgatgactga  49620 

acgataaatc ccttcttaat cctcattcat tcacaggaga cctaccgcag aagagaccct  49680 

agaacatcct tggttcaaag tgagtctagt ctgcaaagtg gtggcacaaa aggtggaggg  49740 

agagagaatg ttactaacag ctctatttat tgagtaccta ctgtgtgcag taaccacgtt  49800 

aggcattgta tgtacatatg acgtattagc ctcacaatag ctttgcaaag gaaggcatta  49860 

ttagtcccat tttgttgaca aggaaacagg ctttaatcag tgatggagtt gggggtatac  49920 

atactggact ccagggcata cgtctggacc tctccatcct gggcgtcctc agtggagttc  49980 

tcccccatgc ttgagaccag accctggtct tcctgacttc tgtctgtcca tctctgtcct  50040 

gcactggtcc cacacaatag cgttgggggt gaccaggcag tctcagcccc ttggttatga  50100 

gcttcatgtg ggcaggttct cggttctcac tcattcatct tcaaacccca gtgcctcagg  50160 

gcacagtgcc aggcattgat ggggtcttgg ggatttggga gggggggttc agcaaatgag  50220 

tctggaaaga gcgcctgaat aaactgttca tggagggttg tgccaggtca cttgaaggct  50280 

gaggtcattc gggtatcagg agttgaatta agagccttct ttctcagacc ggaaatgagc  50340 

tccagaagag agagcctggg tgggtagctg agggaagcat ccgtcttggt ctggaccacc  50400 

aaggctccag atgtctgggg tgttggccct acatggagac agaggggagc tggggagcca  50460 

ggacccgggt aaagggccta agatcacagg cctcccaggg cagctggttt accaggacag  50520 

ggccatgagc cctggtggaa gctcagaagc ctacctaggg gagccaccag tttcctgcct  50580 

ctcccctggg gggttcaggg gatttgtctt taggtgtgca tcttggctgt aggcattgtc  50640 

ctgacagacc cagggggaag gggaccccca ggagcccaga ctcagtgctg ctcgatccac  50700 

tctctcctgc caccccgccc catggacttt gtctctctgt tgccaaacct ggagggtcta  50760 

ggttgacagc tttccctcaa gccctctttc ctgggtttgc agactcaggc aaagggcgca  50820 

gaggtgagca cggatcacct gaagctattc ctctcccggc ggaggtggca ggtaagtgtg  50880 

gcaggccagc ctctgtgctt tccaccttct ccttttctct agcactgcct tccccctccc  50940 

gtgggccttc atctcctgct cctgtcttct cgctttcact ggctccatgc ctagcttcct  51000 

gcctgttccc tgaccctctg catgctcagg cctcttcccc agggctgagg tgggcctggg  51060 

ggggacaatc ctgccccagg ggtccctcag gtctgactcc agtaccctgt ctccagcgct  51120 

cccagatcag ctacaaatgc cacctggtgc tgcgccccat ccccgagctg ctgcgggccc  51180 

ccccagagcg ggtgtgggtg accatgccca gaaggccacc ccccagtggg gggctctcat  51240 

cctcctcgga ttctgaagag gaagagctgg aagagctgcc ctcagtgccc cgcccactgc  51300 

agcccgagtt ctctggctcc cgggtgtccc tcacagacat tcccactgag gatgaggccc  51360 

tggggacccc agagactggg gctgccaccc ccatggactg gcaggagcag ggaagggctc  51420 

cctctcagga ccaggaggct cccagcccag aggccctccc ctccccaggc caggagcccg  51480 

cagctggggc tagccccagg cggggagagc tccgcagggg cagctcggct gagagcgccc  51540 

tgccccgggc cgggccgcgg gagctgggcc ggggcctgca caaggcggcg tctgtggagc  51600 

tgccgcagcg ccggagcccc agcccgggag ccacccgcct ggcccgggga ggcctgggtg  51660 

agggcgagta tgcccagagg ctgcaggccc tgcgccagcg gctgctgcgg ggaggccccg  51720 

aggatggcaa ggtcagcggc ctcaggggtc ccctgctgga gagcctgggg ggccgtgctc  51780 

gggacccccg gatggcacga gctgcctcca gcgaggcagc gccccaccac cagcccccac  51840 

tcgagaaccg gggcctgcaa aagagcagca gcttctccca gggtgaggcg gagccccggg  51900 

gccggcaccg ccgagcgggg gcgcccctcg agatccccgt ggccaggctt ggggcccgta  51960 

ggctacagga gtctccttcc ctgtctgccc tcagcgaggc ccagccatcc agccctgcac  52020 

ggcccagcgc ccccaaaccc agtaccccta agtctgcaga accttctgcc accacaccta  52080 

gtgatgctcc gcagcccccc gcaccccagc ctgcccaaga caaggctcca gagcccaggc  52140 

cagaaccagt ccgagcctcc aagcctgcac caccccccca ggccctgcaa accctagcgc  52200 

tgcccctcac accctatgct cagatcattc agtccctcca gctgtcaggc cacgcccagg  52260 

gcccctcgca gggccctgcc gcgccgcctt cagagcccaa gccccacgct gctgtctttg  52320 

ccagggtggc ctccccacct ccgggagccc ccgagaagcg cgtgccctca gccgggggtc  52380 

ccccggtgct agccgagaaa gcccgagttc ccacggtgcc ccccaggcca ggcagcagtc  52440 

tcagtagcag catcgaaaac ttggagtcgg aggccgtgtt cgaggccaag ttcaagcgca  52500 

gccgcgagtc gcccctgtcg ctggggctgc ggctgctgag ccgttcgcgc tcggaggagc  52560 

gcggcccctt ccgtggggcc gaggaggagg atggcatata ccggcccagc ccggcgggga  52620 

ccccgctgga gctggtgcga cggcctgagc gctcacgctc ggtgcaggac ctcagggctg  52680 

tcggagagcc tggcctcgtc cgccgcctct cgctgtcact gtcccagcgg ctgcggcgga  52740 

cccctcccgc gcagcgccac ccggcctggg aggcccgcgg cggggacgga gagagctcgg  52800 

agggcgggag ctcggcgcgg ggctccccgg tgctggcgat gcgcaggcgg ctgagcttca  52860 

ccctggagcg gctgtccagc cgattgcagc gcagtggcag cagcgaggac tcggggggcg  52920 

cgtcgggccg cagcacgccg ctgttcggac ggcttcgcag ggccacgtcc gagggcgaga  52980 

gtctgcggcg ccttggcctt ccgcacaacc agttggccgc ccaggccggc gccaccacgc  53040 

cttccgccga gtccctgggc tccgaggcca gcgccacgtc gggctcctca ggtgaggagg  53100 

ggcaggggta gggcagcagg tgcagaggag ggtggggtgc gctggagaga ggctgtggga  53160 

ggagcagagg gctggggaca cccaccaggg gcaggctgag gccccgaggg tggaatcagc  53220 

agggctggag gggaggaaag caggaatggc ggcagggctg ggtgggctag gggttccttc  53280 

tggttctctg ggctgagggc tgcagagagg tgggaacttg ctggtactga ctgaacaaat  53340 

actcacgggc ctgagtcttc acagccccag gggaaagccg aagccggctc cgctggggct  53400 

tctctcggcc gcggaaggac aaggggttat cgccaccaaa cctctctgcc agcgtccagg  53460 

aggagttggg tcaccagtac gtgcgcagtg agtcaggtaa taagaggcct gctgggtgag  53520 

gaccctcctc ccctcctgcc ctcccctacc cccatcaggg agcagtcatg gctggtgaga  53580 

ggtgggccac cttgacaaac ctagtggaag gggtctgctc agacaactat aacaatagca  53640 

gtagctgaca ttcattagat aagctgagtg ttctattaaa cactttacaa gcactgcctc  53700 

attcaatcct gcagcactgt ttgggaaata ttagtatcat tgtctctatt gtacaggtga  53760 

ggaaacgggc ttagtgatgc taaggatctg tccaagtcgc agggctagta agtggagcag  53820 

ctgaagttgg actgtgtgac cttctgcagc caggtccctg aaacggcttc aggacaccac  53880 

ttatgtctgt cgggctggcc tcctctctcc tgggagaccc tagaatgttt ctgtaactgg  53940 

ctgtactttt caaggagctc aagatatagg gccctcctgc ctccacagtc cccctttaga  54000 

tgtgtgtgtg cttgggtgtg tacccaaaga cactcacttt ctctccagcc tagaggacca  54060 

cgacctggat tgtgccccct aagtctccat tgctctgcag ctccgaacac ctgactgccc  54120 

ctccctgacc cttctgcaca gaaaagcagc ctttggagct ctttgctagc tctttgccct  54180 

cttctgtttc tctgcctgag tgtcctggag ctccagatag ggaggcattc cccatgtggg  54240 

gtcaccccat cccccctgaa aaaggggcat tactcaagga cgacaagcaa aggcttcggg  54300 

aggttgggtt ttccaggcca gcatgcagga agggagcgag tccatgaagc caggctgtgt  54360 

gcaggatctt gacaagccac cagtcctgtt cttcccccat ttcctggtaa aactcagaat  54420 

agagtggctg tcgagtcttg cctcagctgg gcttataggg attgtgtcca gccttggcca  54480 

gggcaaaggg ggctgcagtg agagaaaagg atggagggaa gggctgctgg tggggagggg  54540 

agggtggaga gtgaggggga aagaaagcga tcagccagca gagaggcctg gggacagctg  54600 

atcccttccc acctggggcc tccctcccgg cccagttttg cttatgcagc tgatttcctg  54660 

ctgaggcagt gtccccttac ctcatccgct ccccgttccc tgcagaaaca aggctgtccc  54720 

aggctacttt aacaaccagg gctggcacct aggaatgggg gtggggctgg cggggctggc  54780 

agggctgggc ccgggtcact ttcacctctg agagaggtgg cctctctctc tctctccctg  54840 

ctacccagta ccctcacttg gcctggaggc agccattgag aaactgtgtt cacattgcct  54900 

tgttggaacc tcagtgtggg acccctcctt ggggagcagt ggggtacagc gggaaggggg  54960 

cacactgcca tcctgatcac cacacctgct gagtactcct cttctgcctg gctcatcccc  55020 

actcccagtc ccccacaatt cttcagacag gcagcagctg gggctcacaa ggctcctcag  55080 

ctttctcttc ccaggtgaat aaaatccacc cccaagtcct cccctatccc cacccttcac  55140 

ccaccacccc catggcccag ctgggattct tctaaaggga cattcccagg gatcatgcac  55200 

tcaaatcctc agggcactaa agaggcacag gctggctaca ttggaggaag gaaaactggt  55260 

cgcatcccta gccctgcatg tgcacagcca ccagctagct gtgaaggcag cttctctgct  55320 

ttgctggaac agcctttctc tgggggtctg tctgctccag gcttctctgc tggccatatt  55380 

attgagaaaa tgataacaac aagagaagtt agtatttatg atcagttact ctatggcaga  55440 

cactttacat gcctcgtaat tgtcacagca agcatcctgt gggcgtggga ttattttcct  55500 

tgatttacag attagaaatg gagcttctga gagagtaaat gacttgccca aggtcaggca  55560 

gatactgtct cttgcccctt caaaagctct caccacttaa ttgacctgaa ggagtataca  55620 

gaagacctac gaccctgtcc cccgatggca ggtgggaaga ggggccagga agccgacacg  55680 

cttccagggt ctgcccacag ttttcctaga ctgcagctct tttgagactg cacattctga  55740 

tagaacattc ctcatttggt cccatctcag ctcgggtcac taactcatct caattctctt  55800 

ctcacttgcc ctgtggtgcc ccagagaggg taggtcttgc aggatcttaa ccattatagt  55860 

ttttcagtat ttgtttgctt ttattttatt taacaaatgc ttatagacca cttacttagt  55920 

gccaggccct gctctaagtg atttacaaac ccatgacata agtagcattg tcagcagtca  55980 

gtgcaaggaa aaagcagttc tgcacacagt gagggcctgg ggaaagtgat gcttgcccca  56040 

aagaaaatta tcgaaggcat ggcgtggggt tccactttcc acatctgcct gggaagagac  56100 

aaagtttcat gctgcttcct gatggctgtt tgcaggcctt ctccacccct ccctcagcag  56160 

taagtgggcc agggtcccta cagatagatg gctgtctctg cttttcctcc agacttcccc  56220 

ccagtcttcc acatcaaact caaggaccag gtgctgctgg agggggaggc agccaccctg  56280 

ctctgcctgc cagcggcctg ccctgcaccg cacatctcct ggatgaaagg taaggagact  56340 

ctgtctccca cagagaggga ggccagcaag tggccctgag cccaggggat gggaggggct  56400 

aggccggagt ggggactgag cacggttagg ggggatgctg gagtggggag tgagtgaggg  56460 

ggcctggaca tgtgctgcct cactcagcag caactcctgc tcctccctgt ccccagacaa  56520 

gaagtccttg aggtcagagc cctcagtgat catcgtgtcc tgcaaagatg ggcggcagct  56580 

gctcagcatc ccccgggcgg gcaagcggca cgccggtctc tatgagtgct cggccaccaa  56640 

cgtactgggc agcatcacca gctcctgtac cgtggctgtg gcccgtgagc ctggggcagg  56700 

gccccagggg ggtagtgatg gggatggtgg gacagggctt gaggggttct tagctagggt  56760 

ataggggctc actgggactc ttctttctct tgccaggagt cccaggaaag ctagctcctc  56820 

cagaggtacc ccagacctac caggacacgg cgctggtgct gtggaagccg ggagacagcc  56880 

gggcaccttg cacgtatacg ctggagcggc gagtggatgg tgaggatggg gcagctggag  56940 

ggttggggga gcggcagggg gagggtagag gagtctggta aggccagtgc cctcccaggc  57000 

tccacagata gcaccgtggg agctggggcc accgcttctg tgacctcagc ccctccccca  57060 

tactgcctat aggggagtct gtgtggcacc ctgtgagctc aggcatcccc gactgttact  57120 

acaacgtgac ccacctgcca gttggcgtga ctgtgaggtt ccgtgtggcc tgtgccaacc  57180 

gtgctgggca ggggcccttc agcaactctt ctgagaaggt ctttgtcagg ggtactcaag  57240 

gtcagtgcaa tggtatgggg tgggaggagg aagggggctc tgagcctagg gttcttgtgg  57300 

agcaccatgg ccttgcccca aggcaccacg gtgatgattt tctctctctc ttagattctt  57360 

cagctgtgcc atctgctgcc caccaagagg cccctgtcac ctcaaggcca gccagggccc  57420 

ggcctcctga ctctcctacc tcactggccc cacccctagc tcctgctgcc cccacacccc  57480 

cgtcagtcac tgtcagcccc tcatctcccc ccacacctcc tagccaggcc ttgtcctcgc  57540 

tcaaggctgt gggtccacca ccccaaaccc ctccacgaag acacaggggc ctgcaggctg  57600 

cccggccagc ggagcccacc ctacccagta cccacgtcac cccaagtgag cccaagcctt  57660 

tcgtccttga cactgggacc ccgatcccag cctccactcc tcaaggggtt aaaccagtgt  57720 

cttcctctac tcctgtgtat gtggtgactt cctttgtgtc tgcaccacca gcccctgagc  57780 

ccccagcccc tgagccccct cctgagccta ccaaggtgac tgtgcagagc ctcagcccgg  57840 

ccaaggaggt ggtcagctcc cctgggagca gtccccgaag ctctcccagg cctgagggta  57900 

ccactcttcg acagggtccc cctcagaaac cctacacctt cctggaggag aaagccaggc  57960 

aagcagggct ggggaaggga agaggacaga ggggagtggg ccaaatgtct ggagcacatg  58020 

gcttcggaga gaagaccaga ctgtcctggc tggggtgggg ggaggtgctg agacctgggt  58080 

tattagaatg attgcgttca aatgtgccag acactgcact gcgtgcttta gccatatgat  58140 

ctcatcaaat cttcacaact ctgagagaca ctgcgctatt agcatcaccc atttcacagg  58200 

tggcaaagct gaggttagag aagctatggg atttacctaa ggtacagagc cagtgagtgg  58260 

cgaaggtggg actcgaaccc tggtttctag gattgaactc tggagcccac actggaacca  58320 

ctgcattctt gcccctaggg gtccctgctc tcctccgtta gccctcacta tggaagtgtc  58380 

cccctcctct cctctgagcc ggtggtgtcc ctccccccga cacacagggg ccgctttggt  58440 

gttgtgcgag cgtgccggga gaatgccacg gggcgaacgt tcgtggccaa gatcgtgccc  58500 

tatgctgccg agggcaagcg gcgggtcctg caggagtacg aggtgctgcg gaccctgcac  58560 

cacgagcgga tcatgtccct gcacgaggcc tacatcaccc ctcggtacct cgtgctcatt  58620 

gctgagagct gtggcaaccg ggaactcctc tgtgggctca gtgacaggta gctgggaatt  58680 

ctaggggagt agggaggaag aggtagggga ggctgggccg ggtatcatct gctccatccc  58740 

tgccctccca ggttccggta ttctgaggat gacgtggcca cttacatggt gcagctgcta  58800 

caaggcctgg actacctcca cggccaccac gtgctccacc tagacatcaa gccagacaac  58860 

ctgctgctgg cccctgacaa tgccctcaag attgtggact ttggcagtgc ccagccctac  58920 

aacccccagg cccttaggcc ccttggccac cgcacgggca cgctggagtt catgggtgag  58980 

gggaccagct gccagccagg gtggggacag ggccctgcca gagaggcagc agccagggct  59040 

caccccactt cacttacata tgtgccactt attgagtgat tactgtattc aagcaatgaa  59100 

cgaagtatgt ggattgatct ttacaataac cctggagtgt ggcataatat tagccccctt  59160 

ttacagatga ggaaactgag gggtactgat gttagggatt tgtgcaatca gacaattata  59220 

aatgctagag gcaggattca ctacagccaa aaagacagga gaatcaatta ttattttatt  59280 

taaataagga gaaccagcta ccatcgagca ccctgctaaa tgcttgacgt tcatgatctc  59340 

tcttccttgg tgtggttcta caggccacac tttacggatg aggctgtgga gagccaggca  59400 

ggtttagtaa atcgcccagg gtcccatagc tagaaggggc aggtctggga ttagagccag  59460 

ccaggctgat tttgaaggct tttaatcttg gtgtcagcca cactctttgt gaatgggagc  59520 

cataccttgg agccgatcca agggagcttg tcaccctgct tctcagcccc tctggagttc  59580 

tggggacccc gccattttgt gcctgggtta attcctcagg tgacccatat gtctcttggg  59640 

gtatgccacc acctctgtcc tgcctactgg ccttcagggc ctgccactct ggacattccc  59700 

atggtctggt gaccaggaca ttgtcctgct gctcaagcac ccagggacct cccccgcccc  59760 

cacttccctg ccaccaggaa gctgggtcag cttggcctct gtctcctgtc agctccggag  59820 

atggtgaagg gagaacccat cggctctgcc acggacatct ggggagcggg tgtgctcact  59880 

tacattatgt gagtgtcccc taccccaccg cagccctctc tgcccataca gtgagctccc  59940 

ggactcacct tctgccaaca ccctctcccc cgtgccccac ctcccctgta cacacatcca  60000 

cactgcacac tcacactcag gtgcacagta gcatggccct gagcactgtg cacctgacac  60060 

taatgtcctt ctgggtctgg gtgttggcct ccggtctgca tatgtcaatc aagctatctt  60120 

ccccaacagg ctcagtggac gctccccgtt ctatgagcca gacccccagg aaacggaggc  60180 

tcggattgtg gggggccgct ttgatgcctt ccagctgtac cccaatacat cccagagcgc  60240 

caccctcttc ttgcgaaagg ttctctctgt acatccctgg tgagtgagcc ccacacctgc  60300 

tatcccccag tgttacctgc ccctggcctg gcctgtgcca gagatctccc agctcctccc  60360 

ctgctcctag gaagaagtct gctgcttcta ctaaatggtc atactaccca ccatttaaag  60420 

cctgaggcag ccccgtgcaa ggcagactca ctgtccccat tccggagact ggggaactga  60480 

gctcttgagc tgcccaagat cacacatgta ggggtgggat ccaggactgg gacatgggtc  60540 

tgcgggagga cagagccccg gcagctccca gagcttcctt ccaggttcat catccctggc  60600 

tctgcctggc aggagccggc cctccctgca ggactgcctg gcccacccat ggttgcagga  60660 

cgcctacctg atgaagctgc gccgccagac gctcaccttc accaccaacc ggctcaagga  60720 

gttcctgggc gagcagcggc ggcgccgggc tgaggctgcc acccgccaca aggtgctgct  60780 

gcgctcctac cctggcggcc cctagaggca cggaccacag ccaggcctcg ggcttcaact  60840 

ggggttccca ccaatgccac gggacattcc agggcccacg ctgagccagg cgggcctggg  60900 

gcttcggtta ccaccagcag caacatctgg ctgggctctt acctcataga ccttcaagga  60960 

cagagacccc agggcctgga cctgatgcca ccccaggcca aagccagagt gggagaccca  61020 

ttggtcaggc tcagcagggt gggaacaggc agagggacaa gaggggaatg gagaagtgga  61080 

gaggaaaagg aatcgaggga caggaagggg gaggctctag gaaggttctg ggttgggggt  61140 

cagtgcatct cagggagaac caaggaaggt gggcatggct ggagaggagg aaaaggaagg  61200 

agccccaggt gtcagggcag taggctggga gtcagtgtgg caaagcgggg gcaggacaca  61260 

gatacagtgg caggggccca gggctgggac atgagagaag gcagcgaggc ggcagaggga  61320 

gaagagagga ctcaggtgga ggtggggtgg gtcagctgtc agcatccctc agaggagaaa  61380 

tgtggagagc tggaggccag cagtcactca cactcgctct gtcctcctgt ccagtggata  61440 

cagccctggg cgctctgctg gcccaaggat gtccccactg cccctccatg gcctctggcc  61500 

ttcttcccat tcatatttat ttatttattg acttttatga agtttcccct tccatccgat  61560 

ccctactgcc catgttgtcc tgaccatccc tcccagccat ccagctgtct gtctgtctgc  61620 

cacaaggaaa taaaaatggc aagcagcata acctgtgtgt ctattgggag ggatggctgg  61680 

aggggaagat ggctggtgag gggtgagtcc gggacagggg catttagccc tctctgggta  61740 

ttccccaaca cacacattca ggaatatacc agctagcact ttgggtcctt ccaaccccct  61800 

cccgtgaccc tcctggcccc tcacctctcc ttattcctgg agggagggga gactgtggtc  61860 

tgcttctccc cttgcagttt ccggaatgtt ggcagatcca ctgaacccct gcaaccaggc  61920 

tctagtagcc cccacctctt gtcacgtgtt ccctcatcac aatgtggggg atgctgggct  61980 

ctgaaatagg ccagccctca ccccaatcct ggctcagcct tgttcactct ccccagaaga  62040 

caggcaggag ctctggtcct gacccctgga gcagagtggg tttcatcctg atggttggtg  62100 

agagtaggta gtgtgaggag ctgcagaaga aaccaggaca gggaggctaa ggtggctgga  62160 

tcacctgagg tcaggagttc aagaccagcc tagccaacat gatgaaaccc cgtctctact  62220 

aaaaatacaa aaattagcca ggcgtggtgg tgcacacctg tgatctcagc tactcaggag  62280 

gctgaggcag gagaatcgct taaacctggg aggtgaaggt tgcaatgagc caagattgca  62340 

ccactgcgct ccagcctgga tgacagagtg agactccatc tcaaaaagaa acactaggac  62400 

aggctcacac cccttgccct ccatgtcaca gcacatatca gagcacatgg agagcaccag  62460 

ctgggagtgc tctagtctgc tgtgtccagc attttcctag ggctgaggga cacaccagcc  62520 

tggaccttct tgtccacatg gcaagttagg aggtctgctg ggtgctaaag cacctcaatt  62580 

ctagccacac ccgtgccata gaatggtcac tgggacctag gactgagctg ctctgccctg  62640 

aggttgggga cgagggattg gggggttggc agggacccag acctccttgt ctccagagga  62700 

aatgtttccc tcatccccac cttcaaaatt ctgttcttgg caaagtaaaa ggaacaaagc  62760 

ctctgaccag ggtagacaga gttgtcactg ctgtgttgct gatgg                  62805 

 
           
             4  
             3262  
             PRT  
             Mus musculus  
           
            4 

Met Gln Lys Ala Arg Gly Thr Arg Gly Glu Asp Ala Gly Thr Arg Ala 
 1               5                  10                  15 

Pro Pro Ser Pro Gly Val Pro Pro Lys Arg Ala Lys Val Gly Ala Gly 
            20                  25                  30 

Arg Gly Val Leu Val Thr Gly Asp Gly Ala Gly Ala Pro Val Phe Leu 
        35                  40                  45 

Arg Pro Leu Lys Asn Ala Ala Val Cys Ala Gly Ser Asp Val Arg Leu 
    50                  55                  60 

Arg Val Val Val Ser Gly Thr Pro Gln Pro Ser Leu Ser Trp Phe Arg 
65                  70                  75                  80 

Asp Gly Gln Leu Leu Pro Pro Pro Ala Pro Glu Pro Ser Cys Leu Trp 
                85                  90                  95 

Leu Arg Ser Cys Gly Ala Gln Asp Ala Gly Val Tyr Ser Cys Ser Ala 
            100                 105                 110 

Gln Asn Glu Arg Gly Gln Ala Ser Cys Glu Ala Val Leu Thr Val Leu 
        115                 120                 125 

Glu Val Arg Asp Ser Glu Thr Ala Glu Asp Asp Ile Ser Asp Val Pro 
    130                 135                 140 

Gly Thr Gln Arg Leu Glu Leu Arg Asp Asp Arg Ala Phe Ser Thr Pro 
145                 150                 155                 160 

Thr Gly Gly Ser Asp Thr Leu Val Gly Thr Ser Leu Asp Thr Pro Pro 
                165                 170                 175 

Thr Ser Val Thr Gly Thr Ser Glu Glu Gln Val Ser Trp Trp Gly Ser 
            180                 185                 190 

Gly Gln Thr Val Leu Glu Gln Glu Ala Gly Ser Gly Gly Gly Thr Arg 
        195                 200                 205 

Pro Leu Pro Gly Ser Pro Arg Gln Ala Gln Thr Thr Gly Ala Gly Pro 
    210                 215                 220 

Arg His Leu Gly Val Glu Pro Leu Val Arg Ala Ser Arg Ala Asn Leu 
225                 230                 235                 240 

Val Gly Ala Ser Trp Gly Ser Glu Asp Ser Leu Ser Val Ala Ser Asp 
                245                 250                 255 

Leu Tyr Gly Ser Ala Phe Ser Leu Tyr Arg Gly Arg Ala Leu Ser Ile 
            260                 265                 270 

His Val Ser Ile Pro Pro Ser Gly Leu His Arg Glu Glu Pro Asp Leu 
        275                 280                 285 

Gln Pro Gln Pro Ala Ser Asp Ala Leu Arg Pro Arg Pro Ala Leu Pro 
    290                 295                 300 

Pro Pro Ser Lys Ser Ala Leu Leu Pro Pro Pro Ser Pro Arg Val Gly 
305                 310                 315                 320 

Lys Arg Ala Leu Pro Gly Pro Ser Thr Gln Pro Pro Ala Thr Pro Thr 
                325                 330                 335 

Ser Pro His Arg Arg Ala Gln Glu Pro Ser Leu Pro Glu Asp Ile Thr 
            340                 345                 350 

Thr Thr Glu Glu Lys Arg Gly Lys Lys Pro Lys Ser Ser Gly Pro Ser 
        355                 360                 365 

Leu Ala Gly Thr Val Glu Ser Arg Pro Gln Thr Pro Leu Ser Glu Ala 
    370                 375                 380 

Ser Gly Arg Leu Ser Ala Leu Gly Arg Ser Pro Arg Leu Val Arg Ala 
385                 390                 395                 400 

Gly Ser Arg Ile Leu Asp Lys Leu Gln Phe Phe Glu Glu Arg Arg Arg 
                405                 410                 415 

Ser Leu Glu Arg Ser Asp Ser Pro Pro Ala Pro Leu Arg Pro Trp Val 
            420                 425                 430 

Pro Leu Arg Lys Ala Arg Ser Leu Glu Gln Pro Lys Ser Glu Gly Gly 
        435                 440                 445 

Ala Ala Trp Gly Thr Pro Glu Ala Ser Gln Glu Glu Leu Arg Ser Pro 
    450                 455                 460 

Arg Gly Ser Val Ala Glu Arg Arg Arg Leu Phe Gln Gln Lys Ala Ala 
465                 470                 475                 480 

Ser Leu Asp Glu Arg Thr Arg Gln Arg Ser Ala Thr Ser Asp Leu Glu 
                485                 490                 495 

Leu Arg Phe Ala Gln Glu Leu Gly Arg Ile Arg Arg Ser Thr Ser Arg 
            500                 505                 510 

Glu Glu Leu Val Arg Ser His Glu Ser Leu Arg Ala Thr Leu Gln Arg 
        515                 520                 525 

Ala Pro Ser Pro Arg Glu Pro Gly Glu Pro Pro Leu Phe Ser Arg Pro 
    530                 535                 540 

Ser Thr Pro Lys Thr Ser Arg Ala Val Ser Pro Ala Ala Thr Gln Pro 
545                 550                 555                 560 

Pro Pro Pro Ser Gly Ala Gly Lys Ser Gly Asp Glu Pro Gly Arg Pro 
                565                 570                 575 

Arg Ser Arg Gly Pro Val Gly Arg Thr Glu Pro Gly Glu Gly Pro Gln 
            580                 585                 590 

Gln Glu Ile Lys Arg Arg Asp Gln Phe Pro Leu Thr Arg Ser Arg Ala 
        595                 600                 605 

Ile Gln Glu Cys Arg Ser Pro Val Pro Pro Tyr Thr Ala Asp Pro Pro 
    610                 615                 620 

Glu Ser Arg Thr Lys Ala Pro Ser Gly Arg Lys Arg Glu Pro Pro Ala 
625                 630                 635                 640 

Gln Ala Val Arg Phe Leu Pro Trp Ala Thr Pro Gly Val Glu Asp Ser 
                645                 650                 655 

Val Leu Pro Gln Thr Leu Glu Lys Asn Arg Ala Gly Pro Glu Ala Glu 
            660                 665                 670 

Lys Arg Leu Arg Arg Gly Pro Glu Glu Asp Gly Pro Trp Gly Pro Trp 
        675                 680                 685 

Asp Arg Arg Gly Thr Arg Ser Gln Gly Lys Gly Arg Arg Ala Arg Pro 
    690                 695                 700 

Thr Ser Pro Glu Leu Glu Ser Ser Asp Asp Ser Tyr Val Ser Ala Gly 
705                 710                 715                 720 

Glu Glu Pro Leu Glu Ala Pro Val Phe Glu Ile Pro Leu Gln Asn Met 
                725                 730                 735 

Val Val Ala Pro Gly Ala Asp Val Leu Leu Lys Cys Ile Ile Thr Ala 
            740                 745                 750 

Asn Pro Pro Pro Gln Val Ser Trp Lys Lys Asp Gly Ser Met Leu His 
        755                 760                 765 

Ser Glu Gly Arg Leu Leu Ile Arg Ala Glu Gly Glu Arg His Thr Leu 
    770                 775                 780 

Leu Leu Arg Glu Ala Gln Ala Ala Asp Ala Gly Ser Tyr Thr Ala Thr 
785                 790                 795                 800 

Ala Thr Asn Glu Leu Gly Gln Ala Thr Cys Ala Ser Ser Leu Ala Val 
                805                 810                 815 

Arg Pro Gly Gly Ser Thr Ser Pro Phe Ser Ser Pro Ile Thr Ser Asp 
            820                 825                 830 

Glu Glu Tyr Leu Ser Pro Pro Glu Glu Phe Pro Glu Pro Gly Glu Thr 
        835                 840                 845 

Trp Pro Arg Thr Pro Thr Met Lys Leu Ser Pro Ser Gln Asp His Asp 
    850                 855                 860 

Ser Ser Asp Ser Ser Ser Lys Ala Pro Pro Thr Phe Lys Val Ser Leu 
865                 870                 875                 880 

Met Asp Gln Ser Val Arg Glu Gly Gln Asp Val Ile Met Ser Ile Arg 
                885                 890                 895 

Val Gln Gly Glu Pro Lys Pro Val Val Ser Trp Leu Arg Asn Arg Gln 
            900                 905                 910 

Pro Val Arg Pro Asp Gln Arg Arg Phe Ala Glu Glu Ala Glu Gly Gly 
        915                 920                 925 

Leu Cys Arg Leu Arg Ile Leu Ala Ala Glu Arg Gly Asp Ala Gly Phe 
    930                 935                 940 

Tyr Thr Cys Lys Ala Val Asn Glu Tyr Gly Ala Arg Gln Cys Glu Ala 
945                 950                 955                 960 

Arg Leu Glu Val Arg Ala His Pro Glu Ser Arg Ser Leu Ala Val Leu 
                965                 970                 975 

Ala Pro Leu Gln Asp Val Asp Val Gly Ala Gly Glu Met Ala Leu Phe 
            980                 985                 990 

Glu Cys Leu Val Ala Gly Pro Ala Asp Val Glu Val Asp Trp Leu Cys 
        995                 1000                1005 

Arg Gly Arg Leu Leu Gln Pro Ala Leu Leu Lys Cys Lys Met His Phe 
    1010                1015                1020 

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

Ser Gly Val Tyr Thr Cys Lys Leu Ser Thr Ala Lys Asp Glu Leu Thr 
                1045                1050                1055 

Cys Ser Ala Arg Leu Thr Val Arg Pro Ser Leu Ala Pro Leu Phe Thr 
            1060                1065                1070 

Arg Leu Leu Glu Asp Val Glu Val Leu Glu Gly Arg Ala Ala Arg Leu 
        1075                1080                1085 

Asp Cys Lys Ile Ser Gly Thr Pro Pro Pro Ser Val Thr Trp Thr His 
    1090                1095                1100 

Phe Gly His Pro Val Asn Glu Gly Asp Asn Leu Arg Leu Arg Gln Asp 
1105                1110                1115                1120 

Gly Gly Leu His Ser Leu His Ile Ala Arg Val Gly Ser Glu Asp Glu 
                1125                1130                1135 

Gly Leu Tyr Glu Val Ser Ala Thr Asn Thr His Gly Gln Ala His Cys 
            1140                1145                1150 

Ser Ala Gln Leu Tyr Val Glu Glu Pro Arg Thr Ala Ala Ser Gly Pro 
        1155                1160                1165 

Ser Ser Lys Leu Glu Lys Met Pro Ser Ile Pro Glu Glu Pro Glu His 
    1170                1175                1180 

Gly Asp Leu Glu Arg Leu Ser Ile Pro Asp Phe Leu Arg Pro Leu Gln 
1185                1190                1195                1200 

Asp Leu Glu Val Gly Leu Ala Lys Glu Ala Met Leu Glu Cys Gln Val 
                1205                1210                1215 

Thr Gly Leu Pro Tyr Pro Thr Ile Ser Trp Phe His Asn Gly His Arg 
            1220                1225                1230 

Ile Gln Ser Ser Asp Asp Arg Arg Met Thr Gln Tyr Arg Asp Ile His 
        1235                1240                1245 

Arg Leu Val Phe Pro Ala Val Gly Pro Gln His Ala Gly Val Tyr Lys 
    1250                1255                1260 

Ser Val Ile Ala Asn Lys Leu Gly Lys Ala Ala Cys Tyr Ala His Leu 
1265                1270                1275                1280 

Tyr Val Thr Asp Val Val Pro Gly Pro Pro Asp Gly Ala Pro Glu Val 
                1285                1290                1295 

Val Ala Val Thr Gly Arg Met Val Thr Leu Ser Trp Asn Pro Pro Arg 
            1300                1305                1310 

Ser Leu Asp Met Ala Ile Asp Pro Asp Ser Leu Thr Tyr Thr Val Gln 
        1315                1320                1325 

His Gln Val Leu Gly Ser Asp Gln Trp Thr Ala Leu Val Thr Gly Leu 
    1330                1335                1340 

Arg Glu Pro Ala Trp Ala Ala Thr Gly Leu Lys Lys Gly Ile Gln His 
1345                1350                1355                1360 

Ile Phe Arg Val Leu Ser Ser Ser Gly Lys Ser Ser Ser Lys Pro Ser 
                1365                1370                1375 

Ala Pro Ser Glu Pro Val Gln Leu Leu Glu His Gly Pro Pro Leu Glu 
            1380                1385                1390 

Glu Ala Pro Ala Val Leu Asp Lys Gln Asp Ile Val Tyr Val Val Glu 
        1395                1400                1405 

Gly Gln Pro Ala Cys Val Thr Val Thr Phe Asn His Val Glu Ala Gln 
    1410                1415                1420 

Val Val Trp Arg Ser Cys Arg Gly Ala Leu Leu Glu Ala Arg Thr Gly 
1425                1430                1435                1440 

Val Tyr Glu Leu Ser Gln Pro Asp Asp Asp Gln Tyr Cys Leu Arg Ile 
                1445                1450                1455 

Cys Arg Val Ser Arg Arg Asp Leu Gly Pro Leu Thr Cys Ser Ala Arg 
            1460                1465                1470 

Asn Arg His Gly Thr Lys Ala Cys Ser Val Thr Leu Glu Leu Ala Glu 
        1475                1480                1485 

Ala Pro Arg Phe Glu Ser Ile Met Glu Asp Val Glu Val Gly Pro Gly 
    1490                1495                1500 

Glu Thr Ala Arg Phe Ala Val Val Val Glu Gly Lys Pro Leu Pro Asp 
1505                1510                1515                1520 

Ile Met Trp Tyr Lys Asp Glu Val Leu Leu Ala Glu Ser Asn His Val 
                1525                1530                1535 

Ser Phe Val Tyr Glu Glu Asn Glu Cys Ser Leu Val Leu Leu Ser Ala 
            1540                1545                1550 

Gly Ser Gln Asp Gly Gly Val Tyr Thr Cys Thr Ala Arg Asn Leu Ala 
        1555                1560                1565 

Gly Glu Val Ser Cys Lys Ala Glu Leu Ser Val Leu Ser Ala Gln Thr 
    1570                1575                1580 

Ala Met Glu Val Glu Gly Val Gly Glu Asp Glu Glu His Arg Gly Arg 
1585                1590                1595                1600 

Arg Leu Ser Asp Tyr Tyr Asp Ile His Gln Glu Ile Gly Arg Gly Ala 
                1605                1610                1615 

Phe Ser Tyr Leu Arg Arg Val Val Glu Arg Ser Ser Gly Leu Glu Phe 
            1620                1625                1630 

Ala Ala Lys Phe Ile Pro Ser Gln Ala Lys Pro Lys Ala Ser Ala Arg 
        1635                1640                1645 

Arg Glu Ala Arg Leu Leu Ala Arg Leu Gln His Gly Cys Val Leu Tyr 
    1650                1655                1660 

Phe His Glu Ala Phe Glu Arg Arg Arg Gly Leu Val Ile Val Thr Glu 
1665                1670                1675                1680 

Leu Cys Thr Glu Glu Leu Leu Glu Arg Met Ala Arg Lys Pro Thr Val 
                1685                1690                1695 

Cys Glu Ser Glu Thr Arg Thr Tyr Met Arg Gln Val Leu Glu Gly Ile 
            1700                1705                1710 

Cys Tyr Leu His Gln Ser His Val Leu His Leu Asp Val Lys Pro Glu 
        1715                1720                1725 

Asn Leu Leu Val Trp Asp Gly Ala Gly Gly Glu Glu Gln Val Arg Ile 
    1730                1735                1740 

Cys Asp Phe Gly Asn Ala Gln Glu Leu Thr Pro Gly Glu Pro Gln Tyr 
1745                1750                1755                1760 

Cys Gln Tyr Gly Thr Pro Glu Phe Val Ala Pro Glu Ile Val Asn Gln 
                1765                1770                1775 

Ser Pro Val Ser Gly Val Thr Asp Ile Trp Pro Val Gly Val Val Ala 
            1780                1785                1790 

Phe Leu Cys Leu Thr Gly Ile Ser Pro Phe Val Gly Glu Asn Asp Arg 
        1795                1800                1805 

Thr Thr Leu Met Asn Ile Arg Asn Tyr Asn Val Ala Phe Glu Glu Thr 
    1810                1815                1820 

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

Leu Val Gln Asp Arg Leu Arg Pro Thr Ala Glu Glu Thr Leu Glu His 
                1845                1850                1855 

Pro Trp Phe Lys Thr Glu Ala Lys Gly Ala Glu Val Ser Thr Asp His 
            1860                1865                1870 

Leu Lys Leu Phe Leu Ser Arg Arg Arg Trp Gln Arg Ser Gln Ile Ser 
        1875                1880                1885 

Tyr Lys Cys His Leu Val Leu Arg Pro Ile Pro Glu Leu Leu Arg Ala 
    1890                1895                1900 

Pro Pro Glu Arg Val Trp Val Ala Met Pro Arg Arg Gln Pro Pro Ser 
1905                1910                1915                1920 

Gly Gly Leu Ser Ser Ser Ser Asp Ser Glu Glu Glu Glu Leu Glu Glu 
                1925                1930                1935 

Leu Pro Ser Val Pro Arg Pro Leu Gln Pro Glu Phe Ser Gly Ser Arg 
            1940                1945                1950 

Val Ser Leu Thr Asp Ile Pro Thr Glu Asp Glu Ala Leu Gly Thr Pro 
        1955                1960                1965 

Glu Ala Gly Ala Ala Thr Pro Met Asp Trp Gln Glu Gln Glu Arg Thr 
    1970                1975                1980 

Pro Ser Lys Asp Gln Glu Ala Pro Ser Pro Glu Ala Leu Pro Ser Pro 
1985                1990                1995                2000 

Gly Gln Glu Ser Pro Asp Gly Pro Ser Pro Arg Arg Pro Glu Leu Arg 
                2005                2010                2015 

Arg Gly Ser Ser Ala Glu Ser Ala Leu Pro Arg Val Gly Ser Arg Glu 
            2020                2025                2030 

Pro Gly Arg Ser Leu His Lys Ala Ala Ser Val Glu Leu Pro Gln Arg 
        2035                2040                2045 

Arg Ser Pro Ser Pro Gly Ala Thr Arg Leu Thr Arg Gly Gly Leu Gly 
    2050                2055                2060 

Glu Gly Glu Tyr Ala Gln Arg Leu Gln Ala Leu Arg Gln Arg Leu Leu 
2065                2070                2075                2080 

Arg Gly Gly Pro Glu Asp Gly Lys Val Ser Gly Leu Arg Gly Pro Leu 
                2085                2090                2095 

Leu Glu Ser Leu Gly Gly Arg Ala Arg Asp Pro Arg Met Ala Arg Ala 
            2100                2105                2110 

Ala Ser Ser Glu Ala Ala Pro His His Gln Pro Pro Pro Glu Ser Arg 
        2115                2120                2125 

Gly Leu Gln Lys Ser Ser Ser Phe Ser Gln Gly Glu Ala Glu Pro Arg 
    2130                2135                2140 

Gly Arg His Arg Arg Ala Gly Ala Pro Leu Glu Ile Pro Val Ala Arg 
2145                2150                2155                2160 

Leu Gly Ala Arg Arg Leu Gln Glu Ser Pro Ser Leu Ser Ala Leu Ser 
                2165                2170                2175 

Glu Thr Gln Pro Pro Ser Pro Ala Arg Pro Ser Val Pro Lys Leu Ser 
            2180                2185                2190 

Ile Thr Lys Ser Pro Glu Pro Ser Ala Val Thr Ser Arg Asp Ser Pro 
        2195                2200                2205 

Gln Pro Pro Glu Pro Gln Pro Val Pro Glu Lys Val Pro Glu Pro Lys 
    2210                2215                2220 

Pro Glu Pro Val Arg Ala Ala Lys Pro Ala Gln Pro Pro Leu Ala Leu 
2225                2230                2235                2240 

Gln Met Pro Thr Gln Pro Leu Thr Pro Tyr Ala Gln Ile Met Gln Ser 
                2245                2250                2255 

Leu Gln Leu Ser Ser Pro Thr Leu Ser Pro Gln Asp Pro Ala Val Pro 
            2260                2265                2270 

Pro Ser Glu Pro Lys Pro His Ala Ala Val Phe Ala Arg Val Ala Ser 
        2275                2280                2285 

Pro Pro Pro Gly Val Ser Glu Lys Arg Val Pro Ser Ala Arg Thr Pro 
    2290                2295                2300 

Pro Val Leu Ala Glu Lys Ala Arg Val Pro Thr Val Pro Pro Arg Pro 
2305                2310                2315                2320 

Gly Ser Ser Leu Ser Gly Ser Ile Glu Asn Leu Glu Ser Glu Ala Val 
                2325                2330                2335 

Phe Glu Ala Lys Phe Lys Arg Ser Arg Glu Ser Pro Leu Ser Arg Gly 
            2340                2345                2350 

Leu Arg Leu Leu Ser Arg Ser Arg Ser Glu Glu Arg Gly Pro Phe Arg 
        2355                2360                2365 

Gly Ala Glu Asp Asp Gly Ile Tyr Arg Pro Ser Pro Ala Gly Thr Pro 
    2370                2375                2380 

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

Arg Val Ala Gly Glu Pro Gly Leu Val Arg Arg Leu Ser Leu Ser Leu 
                2405                2410                2415 

Ser Gln Lys Leu Arg Arg Thr Pro Pro Gly Gln Arg His Pro Ala Trp 
            2420                2425                2430 

Glu Ser Arg Ser Gly Asp Gly Glu Ser Ser Glu Gly Gly Ser Ser Ala 
        2435                2440                2445 

Arg Ala Ser Pro Val Leu Ala Val Arg Arg Arg Leu Ser Ser Thr Leu 
    2450                2455                2460 

Glu Arg Leu Ser Ser Arg Leu Gln Arg Ser Gly Ser Ser Glu Asp Ser 
2465                2470                2475                2480 

Gly Gly Ala Ser Gly Arg Ser Thr Pro Leu Phe Gly Arg Leu Arg Arg 
                2485                2490                2495 

Ala Thr Ser Glu Gly Glu Ser Leu Arg Arg Leu Gly Val Pro His Asn 
            2500                2505                2510 

Gln Leu Gly Ser Gln Thr Gly Ala Thr Thr Pro Ser Ala Glu Ser Leu 
        2515                2520                2525 

Gly Ser Glu Ala Ser Gly Thr Ser Gly Ser Ser Ala Pro Gly Glu Ser 
    2530                2535                2540 

Arg Ser Arg His Arg Trp Gly Leu Ser Arg Leu Arg Lys Asp Lys Gly 
2545                2550                2555                2560 

Leu Ser Gln Pro Asn Leu Ser Ser Ser Val Gln Glu Asp Leu Gly His 
                2565                2570                2575 

Gln Tyr Val Pro Ser Glu Ser Asp Phe Pro Pro Val Phe His Ile Lys 
            2580                2585                2590 

Leu Lys Asp Gln Val Leu Leu Glu Gly Glu Ala Ala Thr Leu Leu Cys 
        2595                2600                2605 

Leu Pro Ala Ala Cys Pro Ala Pro Arg Ile Ser Trp Met Lys Asp Lys 
    2610                2615                2620 

Gln Ser Leu Arg Ser Glu Pro Ser Val Val Ile Val Ser Cys Lys Asp 
2625                2630                2635                2640 

Gly Arg Gln Leu Leu Ser Ile Pro Arg Ala Gly Lys Arg His Ala Gly 
                2645                2650                2655 

Leu Tyr Glu Cys Ser Ala Thr Asn Val Leu Gly Ser Ile Thr Ser Ser 
            2660                2665                2670 

Cys Thr Val Ala Val Ala Arg Ile Pro Gly Lys Leu Ala Pro Pro Glu 
        2675                2680                2685 

Val Pro Gln Thr Tyr His Asp Thr Ala Leu Val Val Trp Lys Pro Gly 
    2690                2695                2700 

Asp Gly Arg Ala Pro Cys Thr Tyr Thr Leu Glu Arg Arg Val Asp Gly 
2705                2710                2715                2720 

Glu Ser Val Trp His Pro Val Ser Ser Gly Ile Pro Asp Cys Tyr Tyr 
                2725                2730                2735 

Asn Val Thr Gln Leu Pro Val Gly Val Thr Val Arg Phe Arg Val Ala 
            2740                2745                2750 

Cys Ser Asn Arg Ala Gly Gln Gly Pro Phe Ser Asn Pro Ser Glu Lys 
        2755                2760                2765 

Val Phe Ile Arg Gly Thr Pro Asp Ser Pro Ala Gln Pro Ala Ala Ala 
    2770                2775                2780 

Pro Arg Asp Ala Pro Val Thr Ser Gly Pro Thr Arg Ala Pro Pro Pro 
2785                2790                2795                2800 

Asp Ser Pro Thr Ser Leu Ala Pro Thr Pro Ala Leu Ala Pro Pro Ala 
                2805                2810                2815 

Ser Gln Ala Ser Thr Leu Ser Pro Ser Thr Ser Ser Met Ser Ala Asn 
            2820                2825                2830 

Gln Ala Leu Ser Ser Leu Lys Ala Val Gly Pro Pro Pro Ala Thr Pro 
        2835                2840                2845 

Pro Arg Lys His Arg Gly Leu Leu Ala Thr Gln Gln Ala Glu Pro Ser 
    2850                2855                2860 

Pro Pro Ser Ile Val Val Thr Pro Ser Glu Pro Arg Ser Phe Val Pro 
2865                2870                2875                2880 

Asp Thr Gly Thr Leu Thr Pro Thr Ser Ser Pro Gln Gly Val Lys Pro 
                2885                2890                2895 

Ala Pro Ser Ser Thr Ser Leu Tyr Met Val Thr Ser Phe Val Ser Ala 
            2900                2905                2910 

Pro Pro Ala Pro Gln Ala Pro Ala Pro Glu Pro Pro Pro Glu Pro Thr 
        2915                2920                2925 

Lys Val Thr Val Arg Ser Leu Ser Pro Ala Lys Glu Val Val Ser Ser 
    2930                2935                2940 

Pro Thr Pro Glu Ser Thr Thr Leu Arg Gln Gly Pro Leu Arg Asn Pro 
2945                2950                2955                2960 

Thr Pro Ser Trp Arg Arg Arg Pro Gly Gly Ala Leu Ala Leu Cys Gly 
                2965                2970                2975 

His Ala Gly Arg Met Leu Arg Ala Glu Arg Leu Ser Pro Arg Phe Val 
            2980                2985                2990 

Pro Tyr Ala Ala Glu Gly Lys Arg Arg Val Leu Gln Glu Tyr Glu Val 
        2995                3000                3005 

Leu Arg Thr Leu His His Glu Arg Leu Met Ser Leu His Glu Ala Tyr 
    3010                3015                3020 

Ile Thr Pro Arg Tyr Leu Val Leu Ile Ala Glu Ser Cys Gly Asn Arg 
3025                3030                3035                3040 

Glu Leu Leu Cys Gly Leu Ser Asp Arg Phe Arg Tyr Ser Glu Asp Asp 
                3045                3050                3055 

Val Ala Thr Tyr Val Val Gln Leu Leu Gln Gly Leu Asp Tyr Leu His 
            3060                3065                3070 

Gly His His Val Leu His Leu Asp Ile Lys Pro Asp Asn Leu Leu Leu 
        3075                3080                3085 

Ala Ala Asp Asn Ala Leu Lys Ile Val Asp Phe Gly Ser Ala Gln Pro 
    3090                3095                3100 

Tyr Asn Pro Gln Ala Leu Lys Pro Leu Gly His Arg Thr Gly Thr Leu 
3105                3110                3115                3120 

Glu Phe Met Ala Pro Glu Met Val Lys Gly Asp Pro Ile Gly Ser Ala 
                3125                3130                3135 

Thr Asp Ile Trp Gly Ala Gly Val Leu Thr Tyr Ile Met Leu Ser Gly 
            3140                3145                3150 

Tyr Ser Pro Phe Tyr Glu Pro Asp Pro Gln Glu Thr Glu Ala Arg Ile 
        3155                3160                3165 

Val Gly Gly Arg Phe Asp Ala Phe Gln Leu Tyr Pro Asn Thr Ser Gln 
    3170                3175                3180 

Ser Ala Thr Leu Phe Leu Arg Lys Val Leu Ser Val His Pro Trp Ser 
3185                3190                3195                3200 

Arg Pro Ser Leu Gln Asp Cys Leu Ala His Pro Trp Leu Gln Asp Ala 
                3205                3210                3215 

Tyr Leu Met Lys Leu Arg Arg Gln Thr Leu Thr Phe Thr Thr Asn Arg 
            3220                3225                3230 

Leu Lys Glu Phe Leu Gly Glu Gln Arg Arg Arg Arg Ala Glu Ala Ala 
        3235                3240                3245 

Thr Arg His Lys Val Leu Leu Arg Ser Tyr Pro Gly Ser Pro 
    3250                3255                3260 

 
           
             5  
             2231  
             PRT  
             Homo sapiens  
           
            5 

Gly Glu Met Ala Leu Phe Glu Cys Leu Val Ala Gly Pro Thr Asp Val 
 1               5                  10                  15 

Glu Val Asp Trp Leu Cys Arg Gly Arg Leu Leu Gln Pro Ala Leu Leu 
            20                  25                  30 

Lys Cys Lys Met His Phe Asp Gly Arg Lys Cys Lys Leu Leu Leu Thr 
        35                  40                  45 

Ser Val His Glu Asp Asp Ser Gly Val Tyr Thr Cys Lys Leu Ser Thr 
    50                  55                  60 

Ala Lys Asp Glu Leu Thr Cys Ser Ala Arg Leu Thr Val Arg Pro Ser 
65                  70                  75                  80 

Leu Ala Pro Leu Phe Thr Arg Leu Leu Glu Asp Val Glu Val Leu Glu 
                85                  90                  95 

Gly Arg Ala Ala Arg Phe Asp Cys Lys Ile Ser Gly Thr Pro Pro Pro 
            100                 105                 110 

Val Val Thr Trp Thr His Phe Gly Cys Pro Met Glu Glu Ser Glu Asn 
        115                 120                 125 

Leu Arg Leu Arg Gln Asp Gly Gly Leu His Ser Leu His Ile Ala His 
    130                 135                 140 

Val Gly Ser Glu Asp Glu Gly Leu Tyr Ala Val Ser Ala Val Asn Thr 
145                 150                 155                 160 

His Gly Gln Ala His Cys Ser Ala Gln Leu Tyr Val Glu Glu Pro Arg 
                165                 170                 175 

Thr Ala Ala Ser Gly Pro Ser Ser Lys Leu Glu Lys Met Pro Ser Ile 
            180                 185                 190 

Pro Glu Glu Pro Glu Gln Gly Glu Leu Glu Arg Leu Ser Ile Pro Asp 
        195                 200                 205 

Phe Leu Arg Pro Leu Gln Asp Leu Glu Val Gly Leu Ala Lys Glu Ala 
    210                 215                 220 

Met Leu Glu Cys Gln Val Thr Gly Leu Pro Tyr Pro Thr Ile Ser Trp 
225                 230                 235                 240 

Phe His Asn Gly His Arg Ile Gln Ser Ser Asp Asp Arg Arg Met Thr 
                245                 250                 255 

Gln Tyr Arg Asp Val His Arg Leu Val Phe Pro Ala Val Gly Pro Gln 
            260                 265                 270 

His Ala Gly Val Tyr Lys Ser Val Ile Ala Asn Lys Leu Gly Lys Ala 
        275                 280                 285 

Ala Cys Tyr Ala His Leu Tyr Val Thr Asp Val Val Pro Gly Pro Pro 
    290                 295                 300 

Asp Gly Ala Pro Gln Val Val Ala Val Thr Gly Arg Met Val Thr Leu 
305                 310                 315                 320 

Thr Trp Asn Pro Pro Arg Ser Leu Asp Met Ala Ile Asp Pro Asp Ser 
                325                 330                 335 

Leu Thr Tyr Thr Val Gln His Gln Val Leu Gly Ser Asp Gln Trp Thr 
            340                 345                 350 

Ala Leu Val Thr Gly Leu Arg Glu Pro Gly Trp Ala Ala Thr Gly Leu 
        355                 360                 365 

Arg Lys Gly Val Gln His Ile Phe Arg Val Leu Ser Thr Thr Val Lys 
    370                 375                 380 

Ser Ser Ser Lys Pro Ser Pro Pro Ser Glu Pro Val Gln Leu Leu Glu 
385                 390                 395                 400 

His Gly Pro Thr Leu Glu Glu Ala Pro Ala Met Leu Asp Lys Pro Asp 
                405                 410                 415 

Ile Val Tyr Val Val Glu Gly Gln Pro Ala Ser Val Thr Val Thr Phe 
            420                 425                 430 

Asn His Val Glu Ala Gln Val Val Trp Arg Ser Cys Arg Gly Ala Leu 
        435                 440                 445 

Leu Glu Ala Arg Ala Gly Val Tyr Glu Leu Ser Gln Pro Asp Asp Asp 
    450                 455                 460 

Gln Tyr Cys Leu Arg Ile Cys Arg Val Ser Arg Arg Asp Met Gly Ala 
465                 470                 475                 480 

Leu Thr Cys Thr Ala Arg Asn Arg His Gly Thr Gln Thr Cys Ser Val 
                485                 490                 495 

Thr Leu Glu Leu Ala Glu Ala Pro Arg Phe Glu Ser Ile Met Glu Asp 
            500                 505                 510 

Val Glu Val Gly Ala Gly Glu Thr Ala Arg Phe Ala Val Val Val Glu 
        515                 520                 525 

Gly Lys Pro Leu Pro Asp Ile Met Trp Tyr Lys Asp Glu Val Leu Leu 
    530                 535                 540 

Thr Glu Ser Ser His Val Ser Phe Val Tyr Glu Glu Asn Glu Cys Ser 
545                 550                 555                 560 

Leu Val Val Leu Ser Thr Gly Ala Gln Asp Gly Gly Val Tyr Thr Cys 
                565                 570                 575 

Thr Ala Gln Asn Leu Ala Gly Glu Val Ser Cys Lys Ala Glu Leu Ala 
            580                 585                 590 

Val His Ser Ala Gln Thr Ala Met Glu Val Glu Gly Val Gly Glu Asp 
        595                 600                 605 

Glu Asp His Arg Gly Arg Arg Leu Ser Asp Phe Tyr Asp Ile His Gln 
    610                 615                 620 

Glu Ile Gly Arg Gly Ala Phe Ser Tyr Leu Arg Arg Ile Val Glu Arg 
625                 630                 635                 640 

Ser Ser Gly Leu Glu Phe Ala Ala Lys Phe Ile Pro Ser Gln Ala Lys 
                645                 650                 655 

Pro Lys Ala Ser Ala Arg Arg Glu Ala Arg Leu Leu Ala Arg Leu Gln 
            660                 665                 670 

His Asp Cys Val Leu Tyr Phe His Glu Ala Phe Glu Arg Arg Arg Gly 
        675                 680                 685 

Leu Val Ile Val Thr Glu Leu Cys Thr Glu Glu Leu Leu Glu Arg Ile 
    690                 695                 700 

Ala Arg Lys Pro Thr Val Cys Glu Ser Glu Ile Arg Ala Tyr Met Arg 
705                 710                 715                 720 

Gln Val Leu Glu Gly Ile His Tyr Leu His Gln Ser His Val Leu His 
                725                 730                 735 

Leu Asp Val Lys Pro Glu Asn Leu Leu Val Trp Asp Gly Ala Ala Gly 
            740                 745                 750 

Glu Gln Gln Val Arg Ile Cys Asp Phe Gly Asn Ala Gln Glu Leu Thr 
        755                 760                 765 

Pro Gly Glu Pro Gln Tyr Cys Gln Tyr Gly Thr Pro Glu Phe Val Ala 
    770                 775                 780 

Pro Glu Ile Val Asn Gln Ser Pro Val Ser Gly Val Thr Asp Ile Trp 
785                 790                 795                 800 

Pro Val Gly Val Val Ala Phe Leu Cys Leu Thr Gly Ile Ser Pro Phe 
                805                 810                 815 

Val Gly Glu Asn Asp Arg Thr Thr Leu Met Asn Ile Arg Asn Tyr Asn 
            820                 825                 830 

Val Ala Phe Glu Glu Thr Thr Phe Leu Ser Leu Ser Arg Glu Ala Arg 
        835                 840                 845 

Gly Phe Leu Ile Lys Val Leu Val Gln Asp Arg Leu Arg Pro Thr Ala 
    850                 855                 860 

Glu Glu Thr Leu Glu His Pro Trp Phe Lys Thr Gln Ala Lys Gly Ala 
865                 870                 875                 880 

Glu Val Ser Thr Asp His Leu Lys Leu Phe Leu Ser Arg Arg Arg Trp 
                885                 890                 895 

Gln Arg Ser Gln Ile Ser Tyr Lys Cys His Leu Val Leu Arg Pro Ile 
            900                 905                 910 

Pro Glu Leu Leu Arg Ala Pro Pro Glu Arg Val Trp Val Thr Met Pro 
        915                 920                 925 

Arg Arg Pro Pro Pro Ser Gly Gly Leu Ser Ser Ser Ser Asp Ser Glu 
    930                 935                 940 

Glu Glu Glu Leu Glu Glu Leu Pro Ser Val Pro Arg Pro Leu Gln Pro 
945                 950                 955                 960 

Glu Phe Ser Gly Ser Arg Val Ser Leu Thr Asp Ile Pro Thr Glu Asp 
                965                 970                 975 

Glu Ala Leu Gly Thr Pro Glu Thr Gly Ala Ala Thr Pro Met Asp Trp 
            980                 985                 990 

Gln Glu Gln Gly Arg Ala Pro Ser Gln Asp Gln Glu Ala Pro Ser Pro 
        995                 1000                1005 

Glu Ala Leu Pro Ser Pro Gly Gln Glu Pro Ala Ala Gly Ala Ser Pro 
    1010                1015                1020 

Arg Arg Gly Glu Leu Arg Arg Gly Ser Ser Ala Glu Ser Ala Leu Pro 
1025                1030                1035                1040 

Arg Ala Gly Pro Arg Glu Leu Gly Arg Gly Leu His Lys Ala Ala Ser 
                1045                1050                1055 

Val Glu Leu Pro Gln Arg Arg Ser Pro Gly Pro Gly Ala Thr Arg Leu 
            1060                1065                1070 

Ala Arg Gly Gly Leu Gly Glu Gly Glu Tyr Ala Gln Arg Leu Gln Ala 
        1075                1080                1085 

Leu Arg Gln Arg Leu Leu Arg Gly Gly Pro Glu Asp Gly Lys Val Ser 
    1090                1095                1100 

Gly Leu Arg Gly Pro Leu Leu Glu Ser Leu Gly Gly Arg Ala Arg Asp 
1105                1110                1115                1120 

Pro Arg Met Ala Arg Ala Ala Ser Ser Glu Ala Ala Pro His His Gln 
                1125                1130                1135 

Pro Pro Leu Glu Asn Arg Gly Leu Gln Lys Ser Ser Ser Phe Ser Gln 
            1140                1145                1150 

Gly Glu Ala Glu Pro Arg Gly Arg His Arg Arg Ala Gly Ala Pro Leu 
        1155                1160                1165 

Glu Ile Pro Val Ala Arg Leu Gly Ala Arg Arg Leu Gln Glu Ser Pro 
    1170                1175                1180 

Ser Leu Ser Ala Leu Ser Glu Ala Gln Pro Ser Ser Pro Ala Arg Pro 
1185                1190                1195                1200 

Ser Ala Pro Lys Pro Ser Thr Pro Lys Ser Ala Glu Pro Ser Ala Thr 
                1205                1210                1215 

Thr Pro Ser Asp Ala Pro Gln Pro Pro Ala Pro Gln Pro Ala Gln Asp 
            1220                1225                1230 

Lys Ala Pro Glu Pro Arg Pro Glu Pro Val Arg Ala Ser Lys Pro Ala 
        1235                1240                1245 

Pro Pro Pro Gln Ala Leu Gln Thr Leu Ala Leu Pro Leu Thr Pro Tyr 
    1250                1255                1260 

Ala Gln Ile Ile Gln Ser Leu Gln Leu Ser Gly His Ala Gln Gly Pro 
1265                1270                1275                1280 

Ser Gln Gly Pro Ala Ala Pro Pro Ser Glu Pro Lys Pro His Ala Ala 
                1285                1290                1295 

Val Phe Ala Arg Val Ala Ser Pro Pro Pro Gly Ala Pro Glu Lys Arg 
            1300                1305                1310 

Val Pro Ser Ala Gly Gly Pro Pro Val Leu Ala Glu Lys Ala Arg Val 
        1315                1320                1325 

Pro Thr Val Pro Pro Arg Pro Gly Ser Ser Leu Ser Ser Ser Ile Glu 
    1330                1335                1340 

Asn Leu Glu Ser Glu Ala Val Phe Glu Ala Lys Phe Lys Arg Ser Arg 
1345                1350                1355                1360 

Glu Ser Pro Leu Ser Leu Gly Leu Arg Leu Leu Ser Arg Ser Arg Ser 
                1365                1370                1375 

Glu Glu Arg Gly Pro Phe Arg Gly Ala Glu Glu Glu Asp Gly Ile Tyr 
            1380                1385                1390 

Arg Pro Ser Pro Ala Gly Thr Pro Leu Glu Leu Val Arg Arg Pro Glu 
        1395                1400                1405 

Arg Ser Arg Ser Val Gln Asp Leu Arg Ala Val Gly Glu Pro Gly Leu 
    1410                1415                1420 

Val Arg Arg Leu Ser Leu Ser Leu Ser Gln Arg Leu Arg Arg Thr Pro 
1425                1430                1435                1440 

Pro Ala Gln Arg His Pro Ala Trp Glu Ala Arg Gly Gly Asp Gly Glu 
                1445                1450                1455 

Ser Ser Glu Gly Gly Ser Ser Ala Arg Gly Ser Pro Val Leu Ala Met 
            1460                1465                1470 

Arg Arg Arg Leu Ser Phe Thr Leu Glu Arg Leu Ser Ser Arg Leu Gln 
        1475                1480                1485 

Arg Ser Gly Ser Ser Glu Asp Ser Gly Gly Ala Ser Gly Arg Ser Thr 
    1490                1495                1500 

Pro Leu Phe Gly Arg Leu Arg Arg Ala Thr Ser Glu Gly Glu Ser Leu 
1505                1510                1515                1520 

Arg Arg Leu Gly Leu Pro His Asn Gln Leu Ala Ala Gln Ala Gly Ala 
                1525                1530                1535 

Thr Thr Pro Ser Ala Glu Ser Leu Gly Ser Glu Ala Ser Ala Thr Ser 
            1540                1545                1550 

Gly Ser Ser Ala Pro Gly Glu Ser Arg Ser Arg Leu Arg Trp Gly Phe 
        1555                1560                1565 

Ser Arg Pro Arg Lys Asp Lys Gly Leu Ser Pro Pro Asn Leu Ser Ala 
    1570                1575                1580 

Ser Val Gln Glu Glu Leu Gly His Gln Tyr Val Arg Ser Glu Ser Asp 
1585                1590                1595                1600 

Phe Pro Pro Val Phe His Ile Lys Leu Lys Asp Gln Val Leu Leu Glu 
                1605                1610                1615 

Gly Glu Ala Ala Thr Leu Leu Cys Leu Pro Ala Ala Cys Pro Ala Pro 
            1620                1625                1630 

His Ile Ser Trp Met Lys Asp Lys Lys Ser Leu Arg Ser Glu Pro Ser 
        1635                1640                1645 

Val Ile Ile Val Ser Cys Lys Asp Gly Arg Gln Leu Leu Ser Ile Pro 
    1650                1655                1660 

Arg Ala Gly Lys Arg His Ala Gly Leu Tyr Glu Cys Ser Ala Thr Asn 
1665                1670                1675                1680 

Val Leu Gly Ser Ile Thr Ser Ser Cys Thr Val Ala Val Ala Arg Val 
                1685                1690                1695 

Pro Gly Lys Leu Ala Pro Pro Glu Val Thr Gln Thr Tyr Gln Asp Thr 
            1700                1705                1710 

Ala Leu Val Leu Trp Lys Pro Gly Asp Ser Arg Ala Pro Cys Thr Tyr 
        1715                1720                1725 

Thr Leu Glu Arg Arg Val Asp Gly Glu Ser Val Trp His Pro Val Ser 
    1730                1735                1740 

Ser Gly Ile Pro Asp Cys Tyr Tyr Asn Val Thr His Leu Pro Val Gly 
1745                1750                1755                1760 

Val Thr Val Arg Phe Arg Val Ala Cys Ala Asn Arg Ala Gly Gln Gly 
                1765                1770                1775 

Pro Phe Ser Asn Ser Ser Glu Lys Val Phe Val Arg Gly Thr Gln Asp 
            1780                1785                1790 

Ser Ser Ala Val Pro Ser Ala Ala His Gln Glu Ala Pro Val Thr Ser 
        1795                1800                1805 

Arg Pro Ala Arg Ala Arg Pro Pro Asp Ser Pro Thr Ser Leu Ala Pro 
    1810                1815                1820 

Pro Leu Ala Pro Ala Ala Pro Thr Pro Pro Ser Val Thr Val Ser Pro 
1825                1830                1835                1840 

Ser Ser Pro Pro Thr Pro Pro Ser Gln Ala Leu Ser Ser Leu Lys Ala 
                1845                1850                1855 

Val Gly Pro Pro Pro Gln Thr Pro Pro Arg Arg His Arg Gly Leu Gln 
            1860                1865                1870 

Ala Ala Arg Pro Ala Glu Pro Thr Leu Pro Ser Thr His Val Thr Pro 
        1875                1880                1885 

Ser Glu Pro Lys Pro Phe Val Leu Asp Thr Gly Thr Pro Ile Pro Ala 
    1890                1895                1900 

Ser Thr Pro Gln Gly Val Lys Pro Val Ser Ser Ser Thr Pro Val Tyr 
1905                1910                1915                1920 

Val Val Thr Ser Phe Val Ser Ala Pro Pro Ala Pro Glu Pro Pro Ala 
                1925                1930                1935 

Pro Glu Pro Pro Pro Glu Pro Thr Lys Val Thr Val Gln Ser Leu Ser 
            1940                1945                1950 

Pro Ala Lys Glu Val Val Ser Ser Pro Gly Ser Ser Pro Arg Ser Ser 
        1955                1960                1965 

Pro Arg Pro Glu Gly Thr Thr Leu Arg Gln Gly Pro Pro Gln Lys Pro 
    1970                1975                1980 

Tyr Thr Phe Leu Glu Glu Lys Ala Arg Gly Arg Phe Gly Val Val Arg 
1985                1990                1995                2000 

Ala Cys Arg Glu Asn Ala Thr Gly Arg Thr Phe Val Ala Lys Ile Val 
                2005                2010                2015 

Pro Tyr Ala Ala Glu Gly Lys Pro Arg Val Leu Gln Glu Tyr Glu Val 
            2020                2025                2030 

Leu Arg Thr Leu His His Glu Arg Ile Met Ser Leu His Glu Ala Tyr 
        2035                2040                2045 

Ile Thr Pro Arg Tyr Leu Val Leu Ile Ala Glu Ser Cys Gly Asn Arg 
    2050                2055                2060 

Glu Leu Leu Cys Gly Leu Ser Asp Arg Phe Arg Tyr Ser Glu Asp Asp 
2065                2070                2075                2080 

Val Ala Thr Tyr Met Val Gln Leu Leu Gln Gly Leu Asp Tyr Leu His 
                2085                2090                2095 

Gly His His Val Leu His Leu Asp Ile Lys Pro Asp Asn Leu Leu Leu 
            2100                2105                2110 

Ala Pro Asp Asn Ala Leu Lys Ile Val Asp Phe Gly Ser Ala Gln Pro 
        2115                2120                2125 

Tyr Asn Pro Gln Ala Leu Arg Pro Leu Gly His Arg Thr Gly Thr Leu 
    2130                2135                2140 

Glu Phe Met Ala Pro Glu Met Val Lys Gly Glu Pro Ile Gly Ser Ala 
2145                2150                2155                2160 

Thr Asp Ile Trp Gly Ala Gly Val Leu Thr Tyr Ile Met Leu Ser Gly 
                2165                2170                2175 

Arg Ser Pro Phe Tyr Glu Pro Asp Pro Gln Glu Thr Glu Ala Arg Ile 
            2180                2185                2190 

Val Gly Gly Arg Phe Asp Ala Phe Gln Leu Tyr Pro Asn Thr Ser Gln 
        2195                2200                2205 

Ser Ala Thr Leu Phe Leu Arg Lys Val Leu Ser Val His Pro Trp Ser 
    2210                2215                2220 

Arg Pro Ser Ser Cys Leu Ser 
2225                2230