Abstract:
A new galanin receptor, GALR2, is described. Also provided are nucleic acids encoding same and various assays to identify ligands particular to said receptor. Ligands so identified are useful for the treatment of obesity, treatment of pain, and treatment of cognitive disorders.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     The present application claims priority to application Ser. No. 60/033,851, filed Dec. 27, 1996. 
    
    
     FIELD OF THE INVENTION 
     This invention relates to a novel galanin receptor, designated GALR2, to nucleotides encoding it, and to assays which use it. 
     BACKGROUND OF THE INVENTION 
     Although first isolated from porcine intestine, galanin is widely distributed in the central and peripheral nervous system. Galanin in most species is a 29 amino acid peptide with an amidated carboxyl terminus. Human galanin is unique in that it is longer, 30 amino acids, and is not amidated. There is strong conservation of the galanin sequence with the amino terminal fifteen residues being absolutely conserved in all species. Galanin immunoreactivity and binding is abundant in the hypothalamus, the locus coeruleus, the hippocampus and the anterior pituitary, as well as regions of the spinal cord, the pancreas and the gastrointestinal tract. 
     Like neuropeptide Y (NPY), injection of galanin into the paraventricular nucleus (PVN) of the hypothalamus produces a dose-dependent increase in feeding in satiated rats. While galanin, like norepinephrine, enhances carbohydrate ingestion, some studies have shown that it profoundly increases fat intake. It has been suggested that galanin shifts macronutrient preference from carbohydrate to fat. The same injections that increase feeding reduce energy expenditure and inhibit insulin secretion. There is enhanced galanin expression in the hypothalamus of genetically obese rats compared with their lean littermate controls. Injection of peptide receptor antagonists into the PVN blocks the galanin-specific induction of increased fat intake. Specific galanin antisense oligonucleotides when injected into the PVN produce a specific decrease in galanin expression associated with a decrease in fat ingestion and total caloric intake while hardly affecting either protein or carbohydrate intake. Thus galanin appears to be one potential neurochemical marker related to the behavior of fat ingestion. 
     Galanin inhibits cholinergic function and impairs working memory in rats. Lesions that destroy cholinergic neurons result in deficits in spatial learning tasks. While locally administered acetylcholine (ACh) reverses some of this deficit, galanin blocks this ACh-mediated improvement. Evidence from autopsy samples from Alzheimer&#39;s disease-afflicted brains suggests an increased galinergic innervation of the nucleus basilis. Thus, if galinergic overactivity contributes to the decline in cognitive performance in Alzheimer&#39;s disease, galanin antagonists may be therapeutically useful in alleviating cognitive impairment. 
     In the rat, administration of galanin intracerebroventricularly, subcutaneously or intravenously increases plasma growth hormone. Infusion of human galanin into healthy subjects also increases plasma growth hormone and potently enhances the growth hormone response to GHRH. 
     Galanin levels are particularly high in dorsal root ganglia. Sciatic nerve resection dramatically up-regulates galanin peptide and mRNA levels. Chronic administration of galanin receptor antagonists (M35, M15) after axotomy results in a marked increase in self mutilation behavior in rats, generally considered to be a response to pain. Application of antisense oligonucleotides specific for galanin to the proximal end of a transected sciatic nerve suppressed the increase in galanin peptide levels with a parallel increase in autotomy. Galanin injected intrathecally acts synergistically with morphine to produce analgesia, this antinociceptive effect of morphine is blocked by galanin receptor antagonists. Thus, galanin agonists may have some utility in relieving neural pain. 
     The actions of galanin are mediated by high affinity galanin receptors that are coupled by pertussis toxin sensitive G i /G o  proteins to inhibition of adenylate cyclase activity, closure of L-type Ca ++  channels and opening of ATP-sensitive K +  channels. Specific binding of  125 I-galanin (Kd approximately 1 nM) has been demonstrated in areas paralleling localization of galanin immunoreactivity: hypothalamus, ventral hippocampus, basal forebrain, spinal cord, pancreas and pituitary. In most tissues the amino terminus (GAL 1-15) is sufficient for high affinity binding and agonist activity. 
     Recently, a galanin receptor cDNA was isolated by expression cloning from a human Bowes melanoma cell line. (Habert-Ortoli, et al. 1994.  Proc. Nat. Acad. Sci,,  USA 91: 9780-9783). This receptor, GALR1, is expressed in human fetal brain and small intestine, but little else is known of its distribution. Gal(1-16) is at least 1000 times more active than pGAL(3-29) as an inhibitor of  125 I-porcine galanin binding to this receptor transiently expressed in COS cells. It remains to be determined whether this receptor subtype represents the hypothalamic receptor that mediates the galanin specific feeding behavior. 
     It would be desirable to identify further galanin receptors so that they can be used to further characterize this biological system and to identify galanin receptor subtype selective agonists and antagonists. 
     SUMMARY OF THE INVENTION 
     This invention relates to a novel galanin receptor, designated GALR2, substantially free from associated proteins, and to GALR2-like receptors which are at least about 40% homologous and which have substantially the same biological activity. In preferred embodiments of this invention, the GALR2-like receptors are at least about 60%, and more preferably at least about 75%, and even more preferably at least about 85% homologous to a GALR2 receptor. This invention also relates specifically to rat, human and mouse GALR2, substantially free from associated proteins, and to receptors which are at least about 50% homologous and which have substantially the same biological activity. 
     Another aspect of this invention are primate and non-primate GALR2 proteins which are encoded by substantially the same nucleic acid sequences, but which have undergone changes in splicing or other RNA processing-derived modifications or mutagenesis-induced changes, so that the expressed protein has a homologous, but different amino acid sequence from the native forms. These variant forms may have different and/or additional functions in human and animal physiology or in vitro in cell based assays. 
     A further aspect of this invention are nucleic acids which encode a galanin receptor or a functional equivalent from rat, human, mouse, swine, or other species. These nucleic acids may be free from associated nucleic adds, or they may be isolated or purified. The nucleic acids which encode a receptor of this invention may be any type of nucleic acid. Preferred forms are DNAs, including genomic and cDNA, although this invention specifically includes RNAs as well. Nucleic acid constructs may also contain regions which control transcription and translation such as one or more promoter regions, termination regions, and if desired enhancer regions. The nucleic acids may be inserted into any known vector including plasmids, and used to transfect suitable host cells using techniques generally available to one of ordinary skill in the art. 
     Another aspect of this invention are vectors comprising nucleic acids which encode GALR2, and host cells which contain these vectors. Still another aspect of this invention is a method of making GALR2 comprising introducing a vector comprising nucleic acids encoding GALR2 into a host cell under culturing conditions. 
     Yet another aspect of this invention are assays for GALR2 ligands which utilize the receptors and/or nucleic acids of this invention. Preferred assays of this embodiment compare the binding of the putative GALR2 ligand to the binding of galanin to GALR2. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIGS. 1A and 1B provide the nucleic acid sequence of rat GALR2 (clone 27A) containing 5′ and 3′ untranslated regions (SEQ ID NO:1). 
     FIGS. 2A and 2B provide the nucleic acid sequence of GALR2 (clone 27A) from initiator Met to polyadenylation (positions 296-2,200 of SEQ ID NO: 1). 
     FIGS. 3A and 3B provide a schematic representation of GALR2 (clone 27A) and the nucleic acid (positions 296-1,904 of SEQ ID NO: 1). and deduced amino acid (SEQ ID NO:2) sequence of GALR2 (clone 27A). 
     FIG. 4 is the deduced amino acid sequence of GALR2 (clone 27A) (SEQ ID NO: 2). 
     FIGS. 5A and 5B provide a comparison (PileUp alignment) of amino acid sequences for rat GALR1 (SEQ ID. NO: 3) and rat GALR2 (SEQ ID. NO:2). 
     FIG. 6 is the nucleic acid sequence of the cDNA probe used to isolate GALR2 (SEQ ID NO:4). 
     FIGS. 7A and 7B provide the DNA sequence of human GALR2 gene (SEQ ID NO:5). 
     FIG. 8 is the DNA sequence (open reading frame only) of human GALR2 gene (SEQ ID NO:6). 
     FIGS. 9A and 9B provide the deduced amino acid sequence of human GALR2 (SEQ ID NO:7). 
     FIG. 10 demonstrates the pharmacology of human and rat GALR2. 
     FIG. 11 illustrates G q  or G s  coupled response (pigment dispersion) as well as G i -coupled response (pigment aggregation). 
     FIG. 12 is the DNA sequence of mouse GALR2 gene (SEQ ID. NO:8). 
     FIG. 13 is the amino acid sequence for mouse GALR2 gene (SEQ ID NO:9). 
     FIGS. 14A and 14B,  14 C and  14 D provide a comparison of human, rat and mouse GALR1 and GALR2 protein sequences showing strong sequence conservation among members of the GALR gene family mGALR1 is SEQ ID NO: 10; rGALR1 is SEQ ID NO: 3; hGALR1 is SEQ ID NO: 11; mGALR2 is SEQ ID NO: 9; rGALR2 is SEQ ID NO: 2; hGALR2 is SEQ ID NO: 7. 
     FIG. 15 is the RNA expression profile of human GALR2. 
     FIG. 16 illustrates the expression of rat GALR2 in the brain. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     As used throughout the specification and claims, the following definitions apply: 
     “Substantially free from associated proteins” means that the receptor is at least about 90%, and preferably at least about 95% free from other cell membrane proteins which are normally found in a living mammalian cell which expresses a galanin receptor. 
     “Substantially free from associated nucleic acids” means that the nucleic acid is at least about 90%, and preferably at least about 95%, free from other nucleic acids which are normally found in a living mammalian cell which naturally expresses a galanin receptor gene. 
     “Substantially the same biological activity” means that the receptor-galanin binding constant is within 5-fold of the binding constant of GALR2 and galanin, and preferably within 2-fold of the binding constant of GALR2 and galanin. 
     “Stringent post-hybridizational washing conditions” means 0.1×standard saline citrate (SSC) at 65° C. 
     “Standard post-hybridizational washing conditions” means 6×SSC at 55° C. 
     “Relaxed post-hybridizational washing conditions” means 6×SSC at 30° C., or 1 to 2×SSC at 55° C. 
     “Functional equivalent” means that a receptor which does not have the exact same amino acid sequence of a naturally occurring GALR2 protein due to alternative splicing, deletions, mutations, or additions, but retains at least 1%, preferably 10%, and more preferably 25% of the biological activity of the naturally occurring receptor. Such derivatives will have a significant homology with a natural GALR2 and can be detected by reduced stringency hybridization with a DNA sequence obtained from a GALR2. The nucleic acid encoding a functional equivalent has at least about 60% homology at the nucleotide level to a naturally occurring receptor nucleic acid. 
     It has been found, in accordance with this invention, that there is a second galanin receptor, which is designated GALR2. The rat, human and mouse GALR2 sequences are given in FIGS. 4,  9  and  13 , respectively, and are referenced in the Examples; however it is to be understood that this invention specifically includes GALR2 without regard to the species and, in particular, specifically includes rodent (including rat and mouse), rhesus, swine, chicken, cow and human. The galanin 2 receptors are highly conserved throughout species, and one of ordinary skill in the art, given the rat, human and/or mouse sequences presented herein, can easily design probes to obtain the GALR2 from other species. 
     GALR2 proteins contain various functional domains, including one or more domains which anchor the receptor in the cell membrane, and at least one ligand binding domain. As with many receptor proteins, it is possible to modify many of the amino acids, particularly those which are not found in the ligand binding domain, and still retain at least a percentage of the biological activity of the original receptor. Thus this invention specifically includes modified functionally equivalent GALR2s which have deleted, truncated, or mutated N-terminal portions. This invention also specifically includes modified functionally equivalent GALR2s which contain modifications and/or deletions in other domains, which are not accompanied by a loss of functional activity. 
     Additionally, it is possible to modify other functional domains such as those that interact with second messenger effector systems, by altering binding specificity and/or selectivity. Such functionally equivalent mutant receptors are also within the scope of this invention. 
     The proteins of this invention were found to have structural features which are typical of the 7-transmembrane domain (TM) containing G-protein linked receptor superfamily (GPC-R&#39;s or 7-TM receptors). Thus GALR2 proteins make up new members of the GPC-R family of receptors. The intact GALR2 of this invention was found to have the general features of GPC-R&#39;s, including seven transmembrane regions, three intra- and extracellular loops, and the GPC-R protein signature sequence. The TM domains and GPC-R protein signature sequence are noted in the protein sequences of the GALR2. Not all regions are required for functioning, and therefore this invention also comprises functional receptors which lack one or more non-essential domains. 
     Determination of the nucleotide sequence indicated that the GALR2 belongs to the intron-containing class of GPC-R&#39;s. Clone 27A, a precursor mRNA terminating in a poly (A) tract, encodes a 1119 bp open reading frame divided into two exons by a single intron of approximately 500 bp (FIG.  4 ). Exon 1 encodes the N-terminal extracellular domain through predicted TM-3, while exon 2 encodes the second predicted extracellular loop through the C-terminal intracellular domain. A perfectly conserved splice donor site (G/gt) is found at nucleotide 368 which coincides with the second residue of the G protein-coupled receptor signature aromatic triplet, (D,E) RY. 
     Removal of the intron indicates that clone 27A encodes a full-length rat galanin receptor polypeptide of 372-amino acids with 7 predicted TM domains, as underlined in FIG.  4 . Searches of nucleic acid and protein sequence databases revealed that the open reading frame sequence is unique and most closely related to rat galanin 1 receptor (GALR1) with 55% nucleic acid and 38% protein sequence identity. An alignment of the protein sequences for rat GALR1 and GALR2 is given in FIG.  5 . Several conserved features ascribed to GPC-R&#39;s were also identified in the rat GALR2: the signature aromatic triplet sequence (Glu-Arg-Tyr) adjacent to TM-3, Cys-98 and Cys-153 in the first two extracellular loops capable of disulfide bonding, putative amino-terminal N-glycosylation sites (Asn-Xaa-Ser/Thr), phosphorylation sites in the carboxyl-terminus and the third cytoplasmic loop, and conserved proline residues in TM-4, 5, 6 and 7. 
     A second cDNA clone was isolated, termed clone 16.6, which does not contain an intron and is therefore a contiguous cDNA containing the complete open reading frame of GALR2. Like clone 27A, Clone 16.6 contains a 5′ untranslated region of approximately 500 bp, a contiguous GALR2 open reading frame encoding 7-TM domains (1119 bp), a 3′ untranslated region of about 320 bp, and a poly (A) tract. The open reading frame sequence is identical for clones 27A (SEQ ID NO:18) and 16.6 (SEQ ID NO:19) except for nucleotide 109 of the open reading frame (located in predicted TM-1). Clone 27A contains a C while Clone 16.6 contains a T in position 109. Thus, amino acid 37 of the GALR2 protein is phenylalanine in Clone 16.6 (SEQ ID NO:20) and leucine in Clone 27A. Both the DNAs of clones 27A and Clone 16.6 form aspects of this invention, as do their respective proteins. 
     The human GALR2 protein bears strong sequence identity and similarity to the rat GALR2 ortholog. One notable difference between the human and rat forms is the presence of an additional 15 amino acids in the C-terminal intracellular domain of human GALR2. The mouse protein sequence, as well, bears very strong identity and similarity with the GALR gene family. 
     This invention also relates to truncated forms of GALR2, particularly those which encompass the extracellular portion of the receptor, but lack the intracellular signaling portion of the receptor, and to nucleic acids encoding these truncated forms. Such truncated receptors are useful in various binding assays. Thus this invention specifically includes modified functionally equivalent GALR2s which have deleted, truncated, or mutated N-terminal portions. This invention also specifically includes modified functionally equivalent GALR2s including receptor chimeras which contain modifications and/or deletions in other domains, which are not accompanied by a loss of functional activity. 
     Additionally, it is possible to modify other functional domains such as those that interact with second messenger effector systems, by altering binding specificity and/or selectivity. Such functionally equivalent mutant receptors are also within the scope of this invention. 
     Assays which make up further aspects of this invention include binding assays (competition for  125 I-galanin binding), coupling assays (including galanin-mediated inhibition of forskolin-stimulated adenylate cyclase in cells expressing galanin receptors), measurement of galanin-stimulated calcium release in cells expressing galanin receptors (such as aequorin assays), stimulation of inward rectifying potassium channels (GIRK channels, measured by voltage changes) in cells expressing galanin receptors, and measurement of pH changes upon galanin stimulation of cells expressing galanin receptors as measured with a microphysiometer. 
     Host cells may be cultured under suitable conditions to produce GALR2. An expression vector containing DNA encoding the receptor may be used for expression of receptor in a recombinant host cell. Recombinant host cells may be prokaryotic or eukaryotic, including but not limited to bacteria such as  E. coli,  fungal cells such as yeast, mammalian cells including but not limited to cell lines of human, bovine, porcine, monkey and rodent origin, and insect cells including but not limited to Drosophila, Spodoptera, and silkworm derived cell lines. Cell lines derived from mammalian species which are suitable and which are commercially available include, but are not limited to, L cells L-M(TK − ) (ATCC CCL 1.3), L cells L-M (ATCC CCL 1.2), 293 (ATCC CRL 1573), Raji (ATCC CCL 86), CV-1 (ATCC CCL 70), COS-1 (ATCC CRL 1650), COS-7 (ATCC CRL 1651), CHO-K1 (ATCC CCL 61), 3T3 (ATCC CCL 92), NIH/3T3 (ATCC CRL 1658), HeLa (ATCC CCL 2), C127I (ATCC CRL 1616), BS-C-1 (ATCC CCL 26) and MRC-5 (ATCC CCL 171). 
     The specificity of binding of compounds showing affinity for the receptor is shown by measuring the affinity of the compounds for cells transfected with the cloned receptor or for membranes from these cells. Expression of the cloned receptor and screening for compounds that inhibit the binding of radiolabeled ligand to these cells provides a rational way for rapid selection of compounds with high affinity for the receptor. These compounds identified by the above assays may be agonists or antagonists of the receptor and may be peptides, proteins, or non-proteinaceous organic molecules. Alternatively, functional assays of the receptor may be used to screen for compounds which affect the activity of the receptor. Such functional assays range from ex vivo muscle contraction assays to assays which determine second messenger levels in cells expressing the receptor. The second messenger assays include, but are not limited to, assays to measure cyclic AMP or calcium levels or assays to measure adenyl cyclase activity. These compounds identified by the above assays may be agonists, antagonists, suppressors, or inducers of the receptor. The functional activity of these compounds is best assessed by using the receptor either natively expressed in tissues or cloned and exogenously expressed. 
     Using the assays of this invention, galanin agonists and antagonists may be identified. A galanin agonist is a compound which binds to the GALR2, such as a galanin mimetic, and produces a cellular response which is at least about equivalent to that of galanin, and which may be greater than that of galanin. Such compounds would be useful in situations where galanin insufficiency causes anorexia, or for treatment of pain. 
     Also using this embodiment of the assay, galanin antagonists may be identified. A galanin antagonist is a compound which can bind to the GALR2, but produces a lesser response than that of native galanin. Such compounds would be useful in the treatment of obesity. 
     One assay of this invention is a method of identifying a compound which modulates GALR2 receptor comprising: a) culturing cells expressing the GALR2 receptor in the presence of the compound and b) measuring GALR2 receptor activity or second messenger activity. If desired, the determined activity can be compared to a standard, such as that measured using galanin as the compound. In preferred embodiments, the cells are transformed and express the GALR2 receptor. 
     The consultant cDNA clone (or shorter portions of, for instance, only 15 nucleotides long) may be used to probe libraries under hybridization conditions to find other receptors which are similar enough so that the nucleic acids can hybridize, and is particularly useful for screening libraries from other species. In this step, one of ordinary skill in the art will appreciate that the hybridization conditions can vary from very stringent to relaxed. Proper temperature, salt concentrations, and buffers are well known. 
     The following non-limiting Examples are presented to better illustrate the invention. 
     EXAMPLE 1 
     A cDNA library from rat hypothalamus was constructed in the plasmid-based mammalian vector pcDNA-3 (InVitrogen, San Diego, Calif.). Total RNA was isolated from freshly-dissected rat hypothalami (flash-frozen in liquid nitrogen) using the RNagents total RNA isolation kit (Promega Biotech, Madison, Wis.) with a yield of approximately 0.5 mg from 1 g (wet weight) of hypothalamic tissue. Poly (A) +  mRNA was selected using the Poly A tract mRNA Isolation System III (Promega Biotech) with a yield of approximately 6 μg from 0.5 μg total RNA. 3 μg of poly (A) +  was then utilized as a template for cDNA synthesis using a kit (Choice Superscript, Life Technologies, Gaithersberg, Md.) with both random hexamer and oligo (dT)-Not I priming. The double-stranded cDNA was adapted for insertion into the BstXI site of pcDNA-3 using EcoRI/BstXI adapters and transformed by electroporation into the  E. coli  strain HB101. The resulting library contained approximately 750,000 primary transformants with 90% of the clones containing inserts (average size 1-2 kb). The library (approximately 700,000 cfu) was plated onto LB plates containing ampicillin and chloramphenicol and probed with an approximately 280 bp PCR fragment (SEQ ID NO:4). Hybridization was conducted at 32° C. for 18 hrs. in 5×SSPE buffer containing 50% formamide, 4×Denhardt&#39;s solution, 0.1% SDS, 10% dextran sulfate, 30 μg/ml sheared salmon-sperm DNA with 2×10 6  cpm/ml of  32 P-labeled probe. The probe was radiolabeled by random-priming with [α] 32 P-dCTP to a specific activity of greater than 10 9  dpm/μg. The filters were then washed in 1×SSC, 0.1% SDS at 55° C. and exposed to film (Kodak X-omat) for 48 hrs. Two independent positive clones were identified (clones 27A and 16.6) and subjected to further analysis. 
     EXAMPLE 2 
     Sequence Analysis of GALR2 
     DNA was prepared from overnight cultures using the Wizard DNA Purification System (Promega Corp., Madison, Wis.) and subjected to automated sequence analysis using the PRISM Dye Deoxy terminator cycle sequencing kit (Applied Biosystems, Foster City, Calif.) on an ABI 377 instrument. Initial sequencing primers were complementary to the T7 and SP6 promoter sites in pcDNA-3, additional primers were made complementary to the insert DNA. Database searches (Genbank, EMBL, Swiss-Prot, PIR, dEST, Prosite, dbGPCR), sequence alignments, and analysis of the galanin receptor nucleotide and protein sequences were carried out using the GCG Sequence Analysis Software Package (Madison, Wis.; pileup, peptide structure and motif programs), FASTA and BLAST search programs, and the PC/Gene software suite from Intelligenetics (San Francisco, Calif.; protein analysis programs). 
     EXAMPLE 3 
     Construction of a Vector for Expression of GALR2 
     Five μg of the mammalian expression vector pCI.neo (Promega Biotech, Madison, Wis.) was digested with 20 units of EcoRI for 2 hours at 37° C. The digest was then treated with calf intestinal phosphatase and then electrophoresed on 1% Seaplaque gel in 1×TAE buffer and the band corresponding to linearized vector was cut out. DNA was recovered from the slice after melting at 65° C. using the Promega Wizard PCR system (Promega Biotech). DNA was quantitated by electrophoresis with standards on a 1% TBE gel. 100 ng of the 2200 bp EcoRI insert (including the intron) from pcDNA-3/27A was ligated to 50 ng of the vector pCI.neo in a 10 ml reaction at room temperature for 1 hour. 1 μl of this ligation mixture was used to transform 50 μl competent DH5a cells (Life Technologies). Clones in the correct orientation were selected following a digest with BamHI. Transfection-quality DNA was then prepared using the Qiagen Maxi protocol (Qiagen, Chatsworth, Calif.). Mammalian COS-7 cells were transfected by electroporation. COS-7 cells (1×10 7 ) were suspended in 0.85 ml of Ringers&#39; buffer and 15 mg of the pCI.neo/27A clone was added to a 0.4 mm electroporation cuvette (Bio-Rad, Hercules, Calif.). Current was applied (960 μF, 260 V) using a Bio-Rad Electroporator device and the cells were transferred to a T-180 flask (Corning). Expression was allowed to proceed for 72 hrs. 
     EXAMPLE 4 
     Pharmacology of GALR2 
     Membranes were prepared from transfected cells following dissociation in enzyme-free dissociation solution (Specialty Media, Lavallette, N.J.) by disruption in a Dounce homogenizer in ice-cold membrane buffer (10 mM Tris, pH 7.4, 10 mM PMSF, 10 μM phosphoramidon, and 40 μg/ml bacitracin). After a low speed (1100×g for 10 min. at 4° C.) and a high speed centrifugation (38,700×g for 15 min. at 4° C.), membranes were resuspended in buffer and protein concentration determined (Bio-Rad assay kit). Binding of  125 I-human galanin (specific activity of 2200 Ci/mmol, DuPont NEN) was measured in membranes using a buffer of 25 mM Tris pH 7.4, 0.5% BSA, 2 mM MgCl 2 , 40 μg/ml bacitracin, 4 μg/ml phosphoramidon, and 10 μM leupeptin in a total volume of 250 μl. 70 pM  125 I-human galanin was used. Reactions were initiated by the addition of membranes and the incubation was allowed to proceed at room temperature for 1 hour. Nonspecific binding was defined as the amount of radioactivity remaining bound in the presence of 1 μM cold galanin. In competition studies various concentrations of peptides (hGal, pGal, hGal(1-16), rGAL(2-29), rGAL(3-29), hGal (1-19) or chimeric peptides (C7, M15, M40, M35) were included along with  125 I-hGal (70 pmol). Incubations were terminated by rapid filtration through GF/C filters which had been presoaked with 0.1% polyethylamine using a TOMTEC (Orange, Conn.) cell harvester. The results were analyzed using the Prism software package (GraphPad, San Diego, Calif.). Shown in the table below is the ligand binding profiles of both rat GALR1 and rat GALR2 proteins (clone 27A shown; clone 16.6 gave similar results). The K D  for binding of  125 I-labeled human galanin against rat GALR2 was 0.2 nM. 
     
       
         
               
               
             
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 IC50 (nM) 
               
             
          
           
               
                   
                 rat GALR1 
                 rat GALR2 (clone 27A) 
               
               
                   
                   
               
             
          
           
               
                   
                 pig Galanin 
                 0.06 
                 0.46 
               
               
                   
                 human Galanin 
                 0.07 ± 0.01 
                 1.3 ± 0.5 
               
               
                   
                 rat Gal (2-29) 
                 7.2 
                 2.9 ± 1.3 
               
               
                   
                 rat Gal (3-29) 
                 &gt;1000 
                 &gt;1000 
               
               
                   
                 human Gal (1-19) 
                 0.86 
               
               
                   
                 pig Gal (1-16) 
                 0.27 ± 0.18 
                 3.0 
               
               
                   
                 galantide (M15) 
                 1.0 ± 1.1 
                  28 ± 3.5 
               
               
                   
                 C7 
                 4.9 ± 3   
                 23 ± 13 
               
               
                   
                 M40 
                 0.01 
                  1.9 ± 0.14 
               
               
                   
                 M35 
                 0.9 ± 0.6 
                 0.43 ± 0.18 
               
               
                   
                   
               
             
          
         
       
     
     EXAMPLE 5 
     Expression of Rat GALR2 
     In situ hybidization was conducted to map the distribution of GALR2 mRNA in rat brain using a  32 P-labeled GALR2 ORF fragment as a hybridization probe; see O&#39;Dowd, B. F. et al. 1995 Genomics 28:84-91. Specific hybridization was detected in a number of brain nuclei and regions, most notably supra-, pre-(PMD/PMV), med- and lateral mammillary nuclei, the dendate gyrus (DG), cingulate gyrus (CG), posterior hypothalamic (PH), supraoptic and arcuate nuclei (Arc) as shown in FIG.  16 . Both frontal and parietal cortical regions were also labeled. 
     Clone Isolation of Human GALR2: Cloning of Partial GalR2 Gene by Degenerate PCR 
     Human genomic DNA was amplified by PCR using degenerate oligonucleotides designed based on the sequences encoding transmembranes (TM) regions TM3 (P1: 5′ CTG ACC GYC ATG RSC ATT GAC SGC TAC, SEQ ID NO:16, wherein Y=C or T, R=A or G, S=C or G) and TM7 (P2: 5′-GGG GTT GRS GCA GCT GTT GGC RTA, SEQ ID NO:17) of somatostatin receptors and the receptor encoded by the somatostatin-related gene, SLC-1. The PCR conditions were as follows: denaturation at 95° C. for 1 min, annealing at either 55° C., 45° C., or 38° C. for 1 min and extension at 72° C. for 2.5 min for 30 cycles, followed by a 7 min extension at 72° C. The resultant PCR products were phenol/chloroform extracted, precipitated with ethanol, phosphorylated with T4 polynucleotide kinase, and blunt-ended with Klenow enzyme. Subsequently, they were electrophoresed on a 0.5% low-melting point agarose and a fragment of the expected size was subcloned into the EcoRV site of pBluescript SK(−) (Stratagene, La Jolla, Calif.). Colonies were selected, plasmid DNA was purified, and the inserts sequenced. 
     EXAMPLE 6 
     Gene Sequence and Structure: Cloning and Sequencing of Human GalR2 Genomic DNA 
     DNA fragments radiolabelled with [32P]dCTP by nick translation (Amersham) were used as a probe to screen a EMBL3 SP6/T7 human genomic library (Clontech, Palo Alto, Calif.). Positive phage clones were plaque purified, DNA was prepared, restriction enzyme digested, electrophoresed on an agarose gel, transferred to nylon membrane, and hybridized with the same probe used to screen the library, as described by Marchese et al, 1994 [Genomics 23, 609-618]. Positive phage were subcloned by digesting phage DNA, and subcloning the resultant fragment into the pBluescript vector. The DNA sequence of the done was determined using standard methods on an ABI 372 automated sequencer (Perkin-Elmer-Applied Biosystems, Foster City, Calif.). As shown in FIG. 7, the sequence determined shows a gene with a total of two exons interrupted by an 1800 bp intron. The deduced amino acid sequence (FIG. 9) of the complete open reading frame (FIG. 8) gives a protein of 387 amino acids with features typical of G protein-coupled receptors including 7 transmembrane alpha helical domains. FIG. 14 shows an alignment of GALR1 and GALR2 protein sequences with the seven transmembrane domains underlined. The human GALR2 protein bears strong sequence identity and similarity to the rat GALR2 ortholog. One notable difference between the human and rat forms is the presence of an additional 15 amino acids in the C-terminal intracellular domain of human GALR2. 
     EXAMPLE 7 
     Receptor Expression: Human and Rat GALR2: Construction of Human GalR2 Expression Plasmid 
     The human GalR2 expression construct was assembled from the human genomic clone by PCR. Each exon was PCR amplified using standard conditions. The primers for exon I were: Forward, Exon I (5′-CCG GAA TTC GGT ACC ATG AAC GTC TCG GGC TGC CC-3′; SEQ ID NO:12) and Reverse, Exon I (5′-GGT AGC GGA TGG CCA GAT ACC TGT CTA GAG AGA CGG CGG CC-3′; SEQ ID NO:13). The primers for exon II were: Forward, Exon II (5′-GGC CGC CGT CTC TCT AGA CAG GTA TCT GGC CAT CCG CTA CC- 3′; SEQ ID NO:14) and Reverse, Exon II (5′-GGC CGC CGT CTC TCT AGA CAG GTA TCT GGC CAT CCG CTA CC-3′; SEQ ID NO:15). PCR products were subcloned in to pBluescript and sequenced. Exon I product was subcloned into the EcoRI and XbaI sites of plasmid pCINeo (Promega, Madison, Wis.). Exon II was then cloned into the XbaI site and the orientation determined by appropriate restriction digests and DNA sequencing. 
     EXAMPLE 8 
     Radioligand Binding Assay 
     Plasmid DNA was prepared using the Qiagen Maxi protocol (Qiagen, Chatsworth, Calif.) and transfected into COS-7 cells by electroporation. Briefly, 0.85 μl COS-7 cells in Ringers&#39; buffer (1.2×10 7 /ml) and 20 μg of DNA were mixed in a 0.4 mm electroporation cuvette (Bio-Rad, Hercules, Calif.) and current (960 μF, 260 V) was applied using a Bio-Rad Electroporator device. Cells were transferred to a T-180 flask (Corning) with fresh media and expression was allowed to proceed for 72 hrs. Membranes were prepared from transfected cells following disruption in enzyme-free dissociation solution (Specialty Media, Lavallette, N.J.) in a Dounce homogenizer in ice-cold membrane buffer (10 mM Tris, pH 7.4, 10 mM PMSF, 10 μM phosphoramidon, and 40 μg/ml bacitracin). After a low speed (1100×g, 10 min. at 4° C.) and a high speed centrifugation (38,700×g for 15 min. at 4° C.), membranes were suspended in buffer and the protein concentration determined (Bio-Rad assay kit). Binding of  125 I-human galanin (sp. act=2200 Ci/mmol, DuPont NEN) was measured in membranes using a buffer of 25 mM Tris pH 7.4, 0.5% BSA, 2 mM MgCl 2 , 40 μg/ml bacitracin, 4 μg/ml phosphoramidon, and 10 μM leupeptin in a total volume of 0.25 ml. 70 pm  125 I-human galanin was used. Reactions were initiated by the addition of membranes and the incubation was allowed to proceed at room temperature for 1 hour. Non-specific binding was defined as the amount of membrane bound radioactivity remaining in the presence of 1 μM cold galanin. In competition studies various concentrations of peptides (hGal, pGal, hGal(1-16), rGAL(2-29), rGAL(3-29), hGal (1-19) or chimeric peptides (C7, M15, M40, M35) were included along with  125 I-hGal (70 pmol). Incubations were terminated by rapid filtration through GF/C filters which had been presoaked with 0.1% polyethylamine using a TOMTEC (Orange, Conn.) cell harvester. The results were analyzed using the Prism software package (GraphPad, San Diego, Calif.). 
     Recombinant expression of human GALR2 binding sites in transiently transfected COS-7 permitted the determation of pharmacology of the cloned receptor.  125 I-human galanin bound to the cloned GALR2 receptor with high affinity in a saturable and specific manner with a K D  of 5 nM. As summarized in FIG. 10, competition of  125 I-human galanin with a variety of galanin-derived peptides and chimeric peptide antagonist/partial agonists showed that the human GALR2 receptor has a similar pharmacology of binding to that of the rat GALR2. 
     EXAMPLE 9 
     Functional Characterization: Post-receptor Signalling Mechanism Frog Melanophore Assay 
     Growth of  Xenopus laevis  melanophores and fibroblasts was performed as described previously (Potenza, M. N. et al, 1992,  Pigment Cell Res.  3:38-43). Briefly, melanophores were grown in fibroblast-conditioned growth medium. The fibroblast-conditioned growth medium was prepared by growing fibroblasts in 70% L-15 medium (Sigma), pH 7.3, supplemented with 20% heat-inactivated fetal bovine serum (Gibco), 100 μg/ml streptomycin, 100 units/ml penicillin and 2 mM glutamine at 27.5° C. The medium from growing fibroblasts was collected, passed through a 0.2 μm filter (fibroblast-conditioned growth medium) and used to culture melanophores at 27.5° C. 
     Plasmid DNA was transiently transfected into melanophores by electroporation using a BTX ECM600 electroporator (Genetronics, Inc. San Diego, Calif.). Melanophores were incubated in the presence of fresh fibroblast-conditioned frog medium for 1 hour prior to harvesting of cells. Melanophore monolayers were detached by trypsinization (0.25% trypsin, JHR Biosciences), followed by inactivation of the trypsin with fibroblast-conditioned frog medium. The cells were collected by centrifugation at 200×g for 5 minutes at 4° C. Cells were washed once in fibroblast conditioned frog medium, centrifuged again and resuspended at 5×10 6  cells per ml in ice cold 70% PBS pH 7.0. 400 μl aliquots of cells in PBS were added to prechilled eppendorf tubes containing 2 μg of pcIneo:human Galanin 2 receptor plasmid DNA mixed with control receptor cDNA and naked vector DNA for a total of 20 μg DNA (2 μg each of pcDNA1amp:cannabinoid 2 and pcDNA3: thromboxane A2 receptor plasmid DNA, and 18 μg of pcDNA3.1 plasmid DNA in 40 μl total volume, or 2 μg each of pcDNA1amp: cannabinoid 2 and pcDNA3:thromboxane A2 receptor plasmid DNA, and 20 μg of pcDNA3.1 plasmid DNA in 40 μl total volume, as a control). Samples were incubated on ice for 20 min, and mixed every 7 minutes. Cell and DNA mixes were transferred to prechilled 2 mM gap electroporation cuvettes (BTX) and electroporated with the following settings: capacitance of 325 microfarad, voltage of 450 volts and resistance of 720 ohms. Immediately following electroporation, cells were mixed with fibroblast-conditioned frog medium (7.85 mls per cuvette) and plated onto flat bottom 96 well microtiter plates (NUNC). Electroporations from multiple cuvettes were pooled together prior to plating to ensure homogenous transfection efficiency. On the day following transfection, medium was removed and fresh fibroblast-conditioned frog medium was added to the melanophore monolayer and cell were incubated at 27° C. 
     Cells were assayed for receptor expression 2 days following transfection in 96-well plate format. On the day of ligand stimulation, medium was removed by aspiration and cells were washed with 70% L-15 containing 15 mM HEPES pH 7.3 (Sigma). Assays were dividing into two separate parts in order to examine Gs/Gq functional coupling which results in pigment dispersion in melanophores, or Gi functional coupling which results in pigment aggregation. For Gs/Gq functional coupling responses, assays were performed as follows. Cells were incubated in 100 μl of 70% L-15 containing 15 mM HEPES for 1 hour in the dark at room temperature, and then incubated in the presence of melatonin (2 nM final concentration) for 1 hour in the dark at room temperature to induce pigment aggregation. Initial absorbance at 600 nM was measured using a Bio-Tek Elx800 Microplate reader (ESBE Scientific) prior to addition of ligand. Human galanin (Peninsula) was added in duplicate wells, samples were mixed and incubated in the dark at room temperature for 1 hour, after which the final absorbance at 600 nm was determined. For Gi coupled responses, cell monolayers were incubated in the presence of 100 μl of 70% L-15 containing 2% fibroblast-conditioned growth medium, 2 mM glutamine, 100 ug/ml streptomycin, 100 units/ml penicillin and 15 mM HEPES for 15 minutes in the dark at room temperature to preset the cells to dispersion. After initial absorbance at 600 nM was determined, human galanin was added to cell monolayers, samples were mixed, incubated in the dark for 1.5 hour at room temperature and then final absorbances were determined. Absorbance readings were converted to transmission values in order to quantitate pigment dispersion using the following formula: 1−Tf/Ti, where Ti=the initial transmission at 600 nm and Tf=the final transmission at 600 nm. Pigment aggregation was quantitated using the following formula: Af/Ai−1, where Af=final absorbance at 600 nm and Ai is initial absorbance at 600 nm. 
     To determine whether the human GALR2 could be functionally expressed in melanophores, the expression plasmid pcIneo:hGALR2 was transiently transfected by electroporation into melanophores followed by stimulation of the transfected cells with human galanin. Increasing doses of galanin resulted in a dose-dependent dispersion of pigment in human GALR2-transfected melanophores, in contrast to control vector-transfected cells (FIG.  11 ). The apparent EC 50  for human galanin in pcIneo:hGALR2-transfected melanophores was 20 nM, in general agreement with specific  125 human galanin binding in pcIneo:hGALR2-transfected COS-7 cells (IC 50 ˜4 nM). The dispersion of pigment in the melanophore has been previously shown to occur either through Gαs coupling and stimulation of adenylyl cyclase or through Gαq coupling and mobilization of calcium. 
     There was no detectable aggregation of the pigment in either the pcIneo:hGALR2- or mock-transfected melanophores following incubation in the presence of 0.001-1000 nM human galanin. This result suggests that the hGALR2 does not couple to Gαi-mediated signaling pathways. 
     EXAMPLE 10 
     Aequorin Bioluminescence Assay 
     Measurement of GALR2 expression in the aequorin-expressing stable reporter cell line 293-AEQ17 (Button, D et al, 1993 “Aequorin-expressing mammalian cell lines used to report Ca 2+  mobilization”  Cell Calcium  14:663-671) was performed using a Luminoskan RT luminometer (Labsystems Inc., Gaithersburg, Md.) controlled by custom software written for a Macintosh PowerPC 6100. 293-AEQ17 cells (8×10 5  cells plated 18 hrs. before transfection in a T75 flask) were transfected with 22 μg of rat or human GALR2 plasmid DNA: 264 μg lipofectamine. Following approximately 40 hours of expression the apo-aequorin in the cells was charged for 4 hours with coelenterazine (10 μM) under reducing conditions (300 μM reduced glutathione) in ECB buffer (140 mM NaCl, 20 mM KCl, 20 mM HEPES-NaOH [pH=7.4], 5 mM glucose, 1 mM MgCl 2 , 1 mM CaCl 2 , 0.1 mg/ml bovine serum albumin). The cells were harvested, washed once in ECB medium and resuspended to 500,000 cells/ml. 100 μl of cell suspension (corresponding to 5×10 4  cells) was then injected into the test plate, and the integrated light emission was recorded over 30 seconds, in 0.5 second units. 20 mL of lysis buffer (0.1% final Triton X-100 concentration) was then injected and the integrated light emission recorded over 10 seconds, in 0.5 second units. The “fractional response” values for each well were calculated by taking the ratio of the integrated response to the initial challenge to the total integrated luminescence including the Triton-X100 lysis response. 
     The aequorin bioluminescence assay is a reliable test for identifying G protein-coupled receptors which couple through the Ga protein subunit family consisting of Gq and G11 which leads to the activation of phospholipase C, mobilization of intracellular calcium and activation of protein kinase C. Based on the above melanophore data for GALR2, utilization of the aequorin bioluminescence assay permitted the discrimination between the two possibilities for the primary intracellular signaling mechanism for GALR2, namely Gas coupling and stimulation of adenylyl cyclase or Gαq coupling and mobilization of calcium. Expression of human or rat GALR2 in the aequorin-expressing 293 cell line (293-AEQ17) gave a dose-dependant increase in aequorin bioluminescence in response to challenge by galanin and several related peptides. Transfection of human GALR1, which signals through Gi and the inhibition of adenylyl cyclase, gave no galanin-dependant increase in aequorin bioluminescence. Responses observed for human or rat GALR2 activation were saturable and the rank order of potency was similar to that observed for competition studies for  125 -human galanin binding. EC 50 &#39;s, given in nM for the human GALR2 (results were similar for the rat GALR2 ortholog) were: human galanin, 32; rat galanin, 12; rat galanin (2-29), 31; rat galanin (3-29)&gt;10,000; M35, 44; M40, 8.8. Of interest to note is that the galanin chimeric peptide antagonists (M35 and M40), thought by some to be pure antagonists on the GALR1 receptor, appear to be partial agonists on the GALR2 receptor. These data indicate that the primary signaling mechanism for GALR2 is through the phopholipase C/protein kinase C pathway, in contrast to GALR1, which communicates its intracellular signal by inhibition of adenylyl cyclase through Gi. In addition, while binding and activation of the rat and human GALR2 receptor by galanin is of high affinity and potency, rat or human GALR1 binds and is activated by galanin at a 10-30 fold lower concentration. This observation points to the existence of other undiscovered naturally-occurring ligand systems that may be agonists at the GALR2 receptor. 
     EXAMPLE 11 
     RNA Expression Profile of Human GalR2 
     Northern blotting analysis was utilized to assess the tissue specificity of human GALR2 mRNA expression. As shown in FIG. 15, modest expression (indicated by one “+”) is seen in a variey of brain regions and peripheral tissues, as observed for the rat ortholog of GALR2. The most prevalent transcript size is ˜2.2 kb with a band of ˜1.5 kb observed in spleen, thymus and prostate. Tissues with significantly higher expression levels (indicated by two or three “+”) were placenta, thymus and prostate. 
     EXAMPLE 12 
     Chromosome Localization of Human GalR2 Gene 
     Fluorescence in situ hybridization (FISH) of metaphase spread chromosomes derived from human lymphocytes together with DAPI banding patterns was used to map hGalR2 to its chromosome, as described (Heng, H. H. Q. and Tsui, L.-C.  Modes of DAPI banding and simultaneous in situ hybridization.  Chromosoma 102:325-332). FISH data localize the receptor gene to human chromosome 17q25. 
     EXAMPLE 13 
     Mouse GALR2: Clone Isolation: Cloning of Mouse GalR2 Genomic Clone 
     DNA fragments from the Human GalR2 gene were radiolabelled with [32P]dCTP by random octomer labeling (Gibco BRL) and used as a probe to screen a mouse 129sv genomic library (Stratagene). Positive phage clones were plaque purified, DNA was prepared, restriction enzyme digested, electrophoresed on an agarose gel, transferred to nylon membrane, and hybridized with the same probe used to screen the library. A positive NotI fragment was subcloned into pBluescript (Stratagene). 
     EXAMPLE 14 
     Gene Sequence and Structure 
     DNA sequence encoding the complete ORF for mouse GALR2 (SEQ ID NO:12) is shown in FIG. 12. A single intron of 1060 bp divides the ORF into two exons. Removal of the intron allows for conceptual translation to give the predicted GALR2 polypeptide of 371 amino acids (SEQ ID NO:13) as shown in FIG.  13 . Compared to both the human and rat orthologs, the mouse protein sequence bears strong identity (85% and 96% respectively). 
     
       
         
           
             20 
           
           
             
               2200 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
             
               not provided 
             
             1
CGCTCCCTCC ACACCTCCAG GGGCAGTGAG CCACTCAAGT CTAAAGCAGA GCGAGTCCCA     60
GGACTTGAGC GCGGGAAGCG AATGGAGTCA GGGTCATTCG ATTGCACCTC TCTCGGCTGC    120
GGGCCGGAGC GGGGTACCAT CCTACACTCT GGGTGCTCCC TCCTCCTCCC GTCCCCCGCG    180
CACCCCTGCC CTGGCTCCTG GAGCTCGGCA GTCTCGCTGG GGCGCTGCAG CGAGGGAGCA    240
GCGTGCTCAC CAAGACCCGG ACAGCTGCGG GAGCGGCGTC CACTTTGGTG ATACCATGAA    300
TGGCTCCGGC AGCCAGGGCG CGGAGAACAC GAGCCAGGAA GGCGGTAGCG GCGGCTGGCA    360
GCCTGAGGCG GTCCTTGTAC CCCTATTTTT CGCGCTCATC TTCCTCGTGG GCACCGTGGG    420
CAACGCGCTG GTGCTGGCGG TGCTGCTGCG CGGCGGCCAG GCGGTCAGCA CCACCAACCT    480
GTTCATCCTC AACCTGGGCG TGGCCGACCT GTGTTTCATC CTGTGCTGCG TGCCTTTCCA    540
GGCCACCATC TACACCCTGG ACGACTGGGT GTTCGGCTCG CTGCTCTGCA AGGCTGTTCA    600
TTTCCTCATC TTTCTCACTA TGCACGCCAG CAGCTTCACG CTGGCCGCCG TCTCCCTGGA    660
CAGGTAAAGG ACCCAGAAAG AAACATCCAG TATGCCCGGA GGGATCTTGA CTGGAAAAGA    720
CTGAATCCTG GTCTGGTGAC CTTAGTTCCC TGCCCTTTCA CATCACTTGG ACATTCCCAC    780
AGAAGAGCGG TGAAGAGGCG GTGGTCCTTA TTCTCCTCTG GTTTCCACTG AGTGCAACAT    840
GTGCGTCCTG AGTACGCTGG AGGGACTCAC AAAATTTCAG CTTTCTTTAG GAGTTTCCTT    900
GCTGTAGTTT GACCCAAGTC TTCTCCAGGT TTCTGTCAGA ACCTCAGGCA TGAGGGATCT    960
GCCTCCCCTG GTTGTCACCA GAGGATAACA ATCACTGCCC CCAGAAATCC AGACAGATTC   1020
TACAACTTTT AGTCTTCGGT GTTTTGGGGG TGCCCCTTCA CGTGGAGTAG GTCGGTGGCC   1080
ACATTCCCAG GAGTGACAAT AGCCTAGCAG TGAATCCTCT CGCTTAGCTG ATGCCCCCCC   1140
ACTGTCCCCA CAGGTATCTG GCCATCCGCT ACCCGCTGCA CTCCCGAGAG TTGCGCACAC   1200
CTCGAAACGC GCTGGCCGCC ATCGGGCTCA TCTGGGGGCT AGCACTGCTC TTCTCCGGGC   1260
CCTACCTGAG CTACTACCGT CAGTCGCAGC TGGCCAACCT GACAGTATGC CACCCAGCAT   1320
GGAGCGCACC TCGACGTCGA GCCATGGACC TCTGCACCTT CGTCTTTAGC TACCTGCTGC   1380
CAGTGCTAGT CCTCAGTCTG ACCTATGCGC GTACCCTGCG CTACCTCTGG CGCACAGTCG   1440
ACCCGGTGAC TGCAGGCTCA GGTTCCCAGC GCGCCAAACG CAAGGTGACA CGGATGATCA   1500
TCATCGTGGC GGTGCTTTTC TGCCTCTGTT GGATGCCCCA CCACGCGCTT ATCCTCTGCG   1560
TGTGGTTTGG TCGCTTCCCG CTCACGCGTG CCACTTACGC GTTGCGCATC CTTTCACACC   1620
TAGTTTCCTA TGCCAACTCC TGTGTCAACC CCATCGTTTA CGCTCTGGTC TCCAAGCATT   1680
TCCGTAAAGG TTTCCGCAAA ATCTGCGCGG GCCTGCTGCG CCCTGCCCCG AGGCGAGCTT   1740
CGGGCCGAGT GAGCATCCTG GCGCCTGGGA ACCATAGTGG CAGCATGCTG GAACAGGAAT   1800
CCACAGACCT GACACAGGTG AGCGAGGCAG CCGGGCCCCT TGTCCCACCA CCCGCACTTC   1860
CCAACTGCAC AGCCTCGAGT AGAACCCTGG ATCCGGCTTG TTAAAGGACC AAAGGGCATC   1920
TAACAGCTTC TAGACAGTGT GGCCCGAGGA TCCCTGGGGG TTATGCTTGA ACGTTACAGG   1980
GTTGAGGCTA AAGACTGARG ATTGATTGTA GGGAACCTCC AGTTATTAAA CGGTGCGGAT   2040
TGCTAGAGGG TGGCATAGTC CTTCAATCCT GGCACCCGAA AAGCAGATGC AGGAGCAGGA   2100
GCAGGAGCAA AGCCAGCCAT GGAGTTTGAG GCCTGCTTGA ACTACCTGAG ATCCAATAAT   2160
AAAACATTTC ATATGCTGTG AAAAAAAAAA AAAAAAAAAA                         2200 
           
           
             
               372 amino acids 
               amino acid 
               single 
               linear 
             
             
               protein 
             
             
               not provided 
             
             2
Met Asn Gly Ser Gly Ser Gln Gly Ala Glu Asn Thr Ser Gln Glu Gly
 1               5                  10                  15
Gly Ser Gly Gly Trp Gln Pro Glu Ala Val Leu Val Pro Leu Phe Phe
            20                  25                  30
Ala Leu Ile Phe Leu Val Gly Thr Val Gly Asn Ala Leu Val Leu Ala
        35                  40                  45
Val Leu Leu Arg Gly Gly Gln Ala Val Ser Thr Thr Asn Leu Phe Ile
    50                  55                  60
Leu Asn Leu Gly Val Ala Asp Leu Cys Phe Ile Leu Cys Cys Val Pro
65                  70                  75                  80
Phe Gln Ala Thr Ile Tyr Thr Leu Asp Asp Trp Val Phe Gly Ser Leu
                85                  90                  95
Leu Cys Lys Ala Val His Phe Leu Ile Phe Leu Thr Met His Ala Ser
            100                 105                 110
Ser Phe Thr Leu Ala Ala Val Ser Leu Asp Arg Tyr Leu Ala Ile Arg
        115                 120                 125
Tyr Pro Leu His Ser Arg Glu Leu Arg Thr Pro Arg Asn Ala Leu Ala
    130                 135                 140
Ala Ile Gly Leu Ile Trp Gly Leu Ala Leu Leu Phe Ser Gly Pro Tyr
145                 150                 155                 160
Leu Ser Tyr Tyr Arg Gln Ser Gln Leu Ala Asn Leu Thr Val Cys His
                165                 170                 175
Pro Ala Trp Ser Ala Pro Arg Arg Arg Ala Met Asp Leu Cys Thr Phe
            180                 185                 190
Val Phe Ser Tyr Leu Leu Pro Val Leu Val Leu Ser Leu Thr Tyr Ala
        195                 200                 205
Arg Thr Leu Arg Tyr Leu Trp Arg Thr Val Asp Pro Val Thr Ala Gly
    210                 215                 220
Ser Gly Ser Gln Arg Ala Lys Arg Lys Val Thr Arg Met Ile Ile Ile
225                 230                 235                 240
Val Ala Val Leu Phe Cys Leu Cys Trp Met Pro His His Ala Leu Ile
                245                 250                 255
Leu Cys Val Trp Phe Gly Arg Phe Pro Leu Thr Arg Ala Thr Tyr Ala
            260                 265                 270
Leu Arg Ile Leu Ser His Leu Val Ser Tyr Ala Asn Ser Cys Val Asn
        275                 280                 285
Pro Ile Val Tyr Ala Leu Val Ser Lys His Phe Arg Lys Gly Phe Arg
    290                 295                 300
Lys Ile Cys Ala Gly Leu Leu Arg Pro Ala Pro Arg Arg Ala Ser Gly
305                 310                 315                 320
Arg Val Ser Ile Leu Ala Pro Gly Asn His Ser Gly Ser Met Leu Glu
                325                 330                 335
Gln Glu Ser Thr Asp Leu Thr Gln Val Ser Glu Ala Ala Gly Pro Leu
            340                 345                 350
Val Pro Pro Pro Ala Leu Pro Asn Cys Thr Ala Ser Ser Arg Thr Leu
        355                 360                 365
Asp Pro Ala Cys
    370 
           
           
             
               346 amino acids 
               amino acid 
               single 
               linear 
             
             
               protein 
             
             
               not provided 
             
             3
Met Glu Leu Ala Pro Val Asn Leu Ser Glu Gly Asn Gly Ser Asp Pro
 1               5                  10                  15
Glu Pro Pro Ala Glu Pro Arg Pro Leu Phe Gly Ile Gly Val Glu Asn
            20                  25                  30
Phe Ile Thr Leu Val Val Phe Gly Leu Ile Phe Ala Met Gly Val Leu
        35                  40                  45
Gly Asn Ser Leu Val Ile Thr Val Leu Ala Arg Ser Lys Pro Gly Lys
    50                  55                  60
Pro Arg Ser Thr Thr Asn Leu Phe Ile Leu Asn Leu Ser Ile Ala Asp
65                  70                  75                  80
Leu Ala Tyr Leu Leu Phe Cys Ile Pro Phe Gln Ala Thr Val Tyr Ala
                85                  90                  95
Leu Pro Thr Trp Val Leu Gly Ala Phe Ile Cys Lys Phe Ile His Tyr
            100                 105                 110
Phe Phe Thr Val Ser Met Leu Val Ser Ile Phe Thr Leu Ala Ala Met
        115                 120                 125
Ser Val Asp Arg Tyr Val Ala Ile Val His Ser Arg Arg Ser Ser Ser
    130                 135                 140
Leu Arg Val Ser Arg Asn Ala Leu Leu Gly Val Gly Phe Ile Trp Ala
145                 150                 155                 160
Leu Ser Ile Ala Met Ala Ser Pro Val Ala Tyr Tyr Gln Arg Leu Phe
                165                 170                 175
His Arg Asp Ser Asn Gln Thr Phe Cys Trp Glu His Trp Pro Asn Gln
            180                 185                 190
Leu His Lys Lys Ala Tyr Val Val Cys Thr Phe Val Phe Gly Tyr Leu
        195                 200                 205
Leu Pro Leu Leu Leu Ile Cys Phe Cys Tyr Ala Lys Val Leu Asn His
    210                 215                 220
Leu His Lys Lys Leu Lys Asn Met Ser Lys Lys Ser Glu Ala Ser Lys
225                 230                 235                 240
Lys Lys Thr Ala Gln Thr Val Leu Val Val Val Val Val Phe Gly Ile
                245                 250                 255
Ser Trp Leu Pro His His Val Ile His Leu Trp Ala Glu Phe Gly Ala
            260                 265                 270
Phe Pro Leu Thr Pro Ala Ser Phe Phe Phe Arg Ile Thr Ala His Cys
        275                 280                 285
Leu Ala Tyr Ser Asn Ser Ser Val Asn Pro Ile Ile Tyr Ala Phe Leu
    290                 295                 300
Ser Glu Asn Phe Arg Lys Ala Tyr Lys Gln Val Phe Lys Cys Arg Val
305                 310                 315                 320
Cys Asn Glu Ser Pro His Gly Asp Ala Lys Glu Lys Asn Arg Ile Asp
                325                 330                 335
Thr Pro Pro Ser Thr Asn Cys Thr His Val
            340                 345 
           
           
             
               283 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               Other 
             
             
               not provided 
             
             
               Other 
                1...283 
                cDNA probe 
             
             4
TGCGGACCAC CACCAACTTG TACCTGGGCA GCATGGCCGT GTCCGACCTA CTCATCCTGC     60
TCGGGCTGCC GTTCGACCTG TACCGCCTCT GGCGCTCGCG GCCCTGGGTG TTCGGGCCGC    120
TGCTCTGCCG CCTGTCCCTC TACGTGGGCG AGGGCTGCAC CTACGCCACG CTGCTGCACA    180
TGACCGCGCT CAGCGTCGAG CGCTACCTGG CCATCTGCCG CCCGCTCCGC GCCCGCGTCT    240
TGGTCACCCG GCGCCGCGTC CGCGCGCTCA TCGCTGTGCT CTG                      283 
           
           
             
               3390 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
             
               not provided 
             
             
               Other 
                63...63 
                N = A, C, T or G
          (A) NAME/KEY Other
          (B) LOCATION 122...122
          (D) OTHER INFORMATION N = A, C, T or G 
             
             5
GAGCTCGGAA GCAGGTACAA GCGCCACTCT CCGCCTGCGC CGTGGAATGC GCGCCGGGAC     60
CANTCCGCAG CCCTTCCCCC AGCGCCGCCG GCCGCTGCTG GGGACAACCT CGCCCTCCTG    120
TNTCTTGCTC CTCCTCCTGA CCCCAGCGCA CCCCCATCCC CGCCCCAGAT GAGGCAAGGC    180
TCCCTCCGCC TTCAGCCCGG CAGAGTCGCA CTAGGAGTTG CAGCGGCCGC AGCCCCGGGA    240
GCTTCCCGCT CGCGGAGACC CAGACGGCTG CAGGAGCCCG GGCAGCCTCG GGGTCAGCGG    300
CACCATGAAC GTCTCGGGCT GCCCAGGGGC CGGGAACGCG AGCCAGGCGG GCGGCGGGGG    360
AGGCTGGCAC CCCGAGGCGG TCATCGTGCC CCTGCTCTTC GCGCTCATCT TCCTCGTGGG    420
CACCGTGGGC AACACGCTGG TGCTGGCGGT GCTGCTGCGC GGCGGCCAGG CGGTCAGCAC    480
TACCAACCTG TTCATCCTTA ACCTGGGCGT GGCCGACCTG TGTTTCATCC TGTGCTGCGT    540
GCCCTTCCAG GCCACCATCT ACACCCTGGA CGGCTGGGTG TTCGGCTCGC TGCTGTGCAA    600
GGCGGTGCAC TTCCTCATCT TCCTCACCAT GCACGCCAGC AGCTTCACGC TGGCCGCCGT    660
CTCCCTGGAC AGGTGAGCCA GCGCCTTGGC CTCCCTGGGA GATGGGCATC CACGCGGGGG    720
ATGGAGCGGG AGGCGGGACT GGGGACCAAG AAGGGACGCG CAGAGTGGGA CAGGACACTA    780
AGAAGGCAGT GGAAGACAAG CGGGCGCGGA GGAGGAAAAA GAGGAATAAG AATGGGGGAC    840
CGTGGTGTCC CTCGGTTAGA TGCGTCCTGG GGCCTGGAAG CCTGGAGAAT GTGGCTCTCC    900
AGCGCCGCCC GTGCCTGACA ACGCGCAGCG TTTCCCAGTA CGACGCGTTT GTGCGCGTTC    960
ATCTCGCTTG AGCTTAATGC CCTCCGTGAG GGTGGGATAG GACAAAGTGC CCAATATACA   1020
GAAGAGTTGA GTTCCTAAGT AACTCGCTCA GAGTCGCCAG CCAAGGGATC GGGTGCGTTG   1080
AAGTGACCGT CTGTCTCCTG CAGCCAACTT CAGGCGCCTC CACTGCGCTC GCCTCCAAGC   1140
CACGGTTTGG TTGGTTGGTG CAGCTGGCTC AGGTCCAGGC TGTGGATCTT GGGTCCTTTG   1200
CAAGGATCCA CTCCGGAGTC CCAGCGAGCG TGCCTAAAGG TCCCTAGCTC AGTCCCAGCC   1260
CACTCTGCCT CTCGCCTCCA AACAAAACAA AAACAAAATA AAATCCAAAA CAAGTGGGGC   1320
GGGAGAGGAA GCGTTGCCCT GGGGTTCTTC CTCCCAGCCA GAGGAGAGCG AAGAGACGCA   1380
CATTCGGGAG AGCCGCCGGG ACTCAGGTGG AGCTTGAAAG GACACTGGGA TGGTTTCCCT   1440
GGGGAGGAAA TCCGGGTATT TCCCCTCTCC ATCCTCTGGA AAAACAGAGA GGCGAGGCCA   1500
GACTGCCCCC ACACCTCCTG TAGCCACTGA GCGCGAAGTG CGTTGGTTCC GAGCGCGCTG   1560
GTGGGATCCA CAAAGCTCGC ATTCTCTCAG GAATCCCCTG AGAAATTAAC TGTCCCTTGC   1620
CCAACATGTC TTCTCCAGGC TGTCTGCTAG AGCCTCAGGC GCCTCCGCCC TCCCTCCCGC   1680
GGCACCGTCA CCAGTGGGTA GTCACAGCCT CCCGGAGCCC ATAGCCGGTT CTCCAACCTT   1740
TAGTCTTCAG TGGCTTTGGG GTGCCCTCTC AGTGGAGACT GTGGTTGCAG TCCCCGGGGG   1800
CAGCGGGAGA ATGGCTTGAA GGCACACCTT TCCTGCTGCC GGCCCGCCCC ATTTCCAGCG   1860
TCCGCTGAGT GTCTGGGACA CGCTGGGAGG CCCCCACCTC CGCCCTCACG CCGAGCCTCA   1920
CCCCCACCTC CTCTGTGTGC GGTGTAACCA TGCGCTAAGG ACCTTCCTTG AGAGCAGCCT   1980
TGGGACCGAG GTGCAGGGGT CGCGGCCCTC CAGCATGAAT GTGCCCGCTC AGCCGACGTC   2040
TCCCTTCCCG GTCTGACCGC AGGTATCTGG CCATCCGCTA CCCGCTGCAC TCCCGCGAGC   2100
TGCGCACGCC TCGAAACGCG CTGGCAGCCA TCGGGCTCAT CTGGGGGCTG TCGCTGCTCT   2160
TCTCCGGGCC CTACCTGAGC TACTACCGCC AGTCGCAGCT GGCCAACCTG ACCGTGTGCC   2220
ATCCCGCGTG GAGCGCCCCT CGCCGCCGCG CCATGGACAT CTGCACCTTC GTCTTCAGCT   2280
ACCTGCTTCC TGTGCTGGTT CTCGGCCTGA CCTACGCGCG CACCTTGCGC TACCTCTGGC   2340
GCGCCGTCGA CCCGGTGGCC GCGGGCTCGG GTGCCCGGCG CGCCAAGCGC AAGGTGACAC   2400
GCATGATCCT CATCGTGGCC GCGCTCTTCT GCCTCTGCTG GATGCCCCAC CACGCGCTCA   2460
TCCTCTGCGT GTGGTTCGGC CAGTTCCCGC TCACGCGCGC CACTTATGCG CTTCGCATCC   2520
TCTCGCACCT GGTCTCCTAC GCCAACTCCT GCGTCAACCC CATCGTTTAC GCGCTGGTCT   2580
CCAAGCACTT CCGCAAAGGC TTCCGCACGA TCTGCGCGGG CCTGCTGGGC CGTGCCCCAG   2640
GCCGAGCCTC GGGCCGTGTG TGCGCTGCCG CGCGGGGCAC CCACAGTGGC AGCGTGTTGG   2700
AGCGCGAGTC CAGCGACCTG TTGCACATGA GCGAGGCGGC GGGGGCCCTT CGTCCCTGCC   2760
CCGGCGCTTC CCAGCCATGC ATCCTCGAGC CCTGTCCTGG CCCGTCCTGG CAGGGCCCAA   2820
AGGCAGGCGA CAGCATCCTG ACGGTTGATG TGGCCTGAAA GCACTTAGCG GGCGCGCTGG   2880
GATGTCACAG AGTTGGAGTC ATTGTTGGGG GACCGTGGGG AGAGCTTTGC CTGTTAATAA   2940
AACGCACAAA CCATTTCACA CACAGTGACA GCGCTGTTTC GCGTTTCTCA TTGTCTTGAG   3000
ATTCTGGGAG GAAGCCTCTG GGGCTTCACA GAGGGGCTCC CTAGGGGTAA GTGCAGGACC   3060
CTTTGCAGAG CTACCAGGAA AGAGGGCTGA TCACACCTCA GGCAGCCGGG TTACAATCCG   3120
CATAAAAATC TGAGTCTGGG GAGCGTGCGA CAGAGGCAGG CAGATTGTTT AAGGCGTTCG   3180
ATAAAGTCGG TTGATGACAG ACACAGATGT GTGTTCCCAG CCGCATTTGT GCTCTGGTGT   3240
GTGACAGGTC TGTCCTTGCC TGCTTTCAGC TCCCAGGGCC CCTTTGAGTC TGGGCAGCCC   3300
AGTCAGTCCC CGTCCATTTT TGGCCTTAGC TTTTCCTTCC CTGGCTACAT CTGGGCCAGG   3360
ATCAAGTCTC CAGCAGCTGT TTCACTCCCC                                    3390 
           
           
             
               1164 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
             
               not provided 
             
             6
ATGAACGTCT CGGGCTGCCC AGGGGCCGGG AACGCGAGCC AGGCGGGCGG CGGGGGAGGC     60
TGGCACCCCG AGGCGGTCAT CGTGCCCCTG CTCTTCGCGC TCATCTTCCT CGTGGGCACC    120
GTGGGCAACA CGCTGGTGCT GGCGGTGCTG CTGCGCGGCG GCCAGGCGGT CAGCACTACC    180
AACCTGTTCA TCCTTAACCT GGGCGTGGCC GACCTGTGTT TCATCCTGTG CTGCGTGCCC    240
TTCCAGGCCA CCATCTACAC CCTGGACGGC TGGGTGTTCG GCTCGCTGCT GTGCAAGGCG    300
GTGCACTTCC TCATCTTCCT CACCATGCAC GCCAGCAGCT TCACGCTGGC CGCCGTCTCC    360
CTGGACAGGT ATCTGGCCAT CCGCTACCCG CTGCACTCCC GCGAGCTGCG CACGCCTCGA    420
AACGCGCTGG CAGCCATCGG GCTCATCTGG GGGCTGTCGC TGCTCTTCTC CGGGCCCTAC    480
CTGAGCTACT ACCGCCAGTC GCAGCTGGCC AACCTGACCG TGTGCCATCC CGCGTGGAGC    540
GCCCCTCGCC GCCGCGCCAT GGACATCTGC ACCTTCGTCT TCAGCTACCT GCTTCCTGTG    600
CTGGTTCTCG GCCTGACCTA CGCGCGCACC TTGCGCTACC TCTGGCGCGC CGTCGACCCG    660
GTGGCCGCGG GCTCGGGTGC CCGGCGCGCC AAGCGCAAGG TGACACGCAT GATCCTCATC    720
GTGGCCGCGC TCTTCTGCCT CTGCTGGATG CCCCACCACG CGCTCATCCT CTGCGTGTGG    780
TTCGGCCAGT TCCCGCTCAC GCGCGCCACT TATGCGCTTC GCATCCTCTC GCACCTGGTC    840
TCCTACGCCA ACTCCTGCGT CAACCCCATC GTTTACGCGC TGGTCTCCAA GCACTTCCGC    900
AAAGGCTTCC GCACGATCTG CGCGGGCCTG CTGGGCCGTG CCCCAGGCCG AGCCTCGGGC    960
CGTGTGTGCG CTGCCGCGCG GGGCACCCAC AGTGGCAGCG TGTTGGAGCG CGAGTCCAGC   1020
GACCTGTTGC ACATGAGCGA GGCGGCGGGG GCCCTTCGTC CCTGCCCCGG CGCTTCCCAG   1080
CCATGCATCC TCGAGCCCTG TCCTGGCCCG TCCTGGCAGG GCCCAAAGGC AGGCGACAGC   1140
ATCCTGACGG TTGATGTGGC CTGA                                          1164 
           
           
             
               387 amino acids 
               amino acid 
               single 
               linear 
             
             
               protein 
             
             
               not provided 
             
             7
Met Asn Val Ser Gly Cys Pro Gly Ala Gly Asn Ala Ser Gln Ala Gly
 1               5                  10                  15
Gly Gly Gly Gly Trp His Pro Glu Ala Val Ile Val Pro Leu Leu Phe
            20                  25                  30
Ala Leu Ile Phe Leu Val Gly Thr Val Gly Asn Thr Leu Val Leu Ala
        35                  40                  45
Val Leu Leu Arg Gly Gly Gln Ala Val Ser Thr Thr Asn Leu Phe Ile
    50                  55                  60
Leu Asn Leu Gly Val Ala Asp Leu Cys Phe Ile Leu Cys Cys Val Pro
65                  70                  75                  80
Phe Gln Ala Thr Ile Tyr Thr Leu Asp Gly Trp Val Phe Gly Ser Leu
                85                  90                  95
Leu Cys Lys Ala Val His Phe Leu Ile Phe Leu Thr Met His Ala Ser
            100                 105                 110
Ser Phe Thr Leu Ala Ala Val Ser Leu Asp Arg Tyr Leu Ala Ile Arg
        115                 120                 125
Tyr Pro Leu His Ser Arg Glu Leu Arg Thr Pro Arg Asn Ala Leu Ala
    130                 135                 140
Ala Ile Gly Leu Ile Trp Gly Leu Ser Leu Leu Phe Ser Gly Pro Tyr
145                 150                 155                 160
Leu Ser Tyr Tyr Arg Gln Ser Gln Leu Ala Asn Leu Thr Val Cys His
                165                 170                 175
Pro Ala Trp Ser Ala Pro Arg Arg Arg Ala Met Asp Ile Cys Thr Phe
            180                 185                 190
Val Phe Ser Tyr Leu Leu Pro Val Leu Val Leu Gly Leu Thr Tyr Ala
        195                 200                 205
Arg Thr Leu Arg Tyr Leu Trp Arg Ala Val Asp Pro Val Ala Ala Gly
    210                 215                 220
Ser Gly Ala Arg Arg Ala Lys Arg Lys Val Thr Arg Met Ile Leu Ile
225                 230                 235                 240
Val Ala Ala Leu Phe Cys Leu Cys Trp Met Pro His His Ala Leu Ile
                245                 250                 255
Leu Cys Val Trp Phe Gly Gln Phe Pro Leu Thr Arg Ala Thr Tyr Ala
            260                 265                 270
Leu Arg Ile Leu Ser His Leu Val Ser Tyr Ala Asn Ser Cys Val Asn
        275                 280                 285
Pro Ile Val Tyr Ala Leu Val Ser Lys His Phe Arg Lys Gly Phe Arg
    290                 295                 300
Thr Ile Cys Ala Gly Leu Leu Gly Arg Ala Pro Gly Arg Ala Ser Gly
305                 310                 315                 320
Arg Val Cys Ala Ala Ala Arg Gly Thr His Ser Gly Ser Val Leu Glu
                325                 330                 335
Arg Glu Ser Ser Asp Leu Leu His Met Ser Glu Ala Ala Gly Ala Leu
            340                 345                 350
Arg Pro Cys Pro Gly Ala Ser Gln Pro Cys Ile Leu Glu Pro Cys Pro
        355                 360                 365
Gly Pro Ser Trp Gln Gly Pro Lys Ala Gly Asp Ser Ile Leu Thr Val
    370                 375                 380
Asp Val Ala
385 
           
           
             
               2234 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
             
               not provided 
             
             8
GCCCTTTCCA CTTTGGTGAT ACCATGAATG GCTCGGACAG CCAGGGGGCG GAGGACTCGA     60
GCCAGGAAGG TGGCGGCGGC TGGCAGCCCG AGGCGGTCCT CGTACCCCTA TTTTTCGCGC    120
TCATCTTCCT CGTGGGCGCT GTGGGCAACG CGCTGGTGCT GGCGGTGCTG CTGCGCGGCG    180
GCCAGGCGGT CAGCACCACG AACCTATTCA TCCTCAACCT GGGTGTGGCC GACCTGTGTT    240
TCATCCTGTG CTGCGTGCCT TTCCAGGCCA CCATCTATAC CCTGGACGAT TGGGTGTTTG    300
GCTCACTGCT CTGCAAGGCC GTTCATTTCC TCATCTTCCT CACTATGCAC GCCAGCAGCT    360
TCACGCTGGC CGCTGTCTCG CTGGACAGGT GAGTGAACAT TCTGTGGTGT CTGAGAACTG    420
GGTACCCAGG TAGGAGCTTG CACTGGAGTC GCCACGCAAG GATCCAGAAG GGATGCGTAG    480
TCGGGGAGAA CACTAAAATT ACAAAGTGGC CCGAGGCCGT GAAACGCAAG GGGAAAGGGG    540
ACTAAGACTC CGTGACTAAG AGTGTCCCTT GATTAAGTCG GTCCTCAGAC CTCGAAGGCT    600
GGAGAAATCG GATTTCTGGG GTCTTTACGT TATTGTTGCT TGAGCTAAAA GTCTCTCAGA    660
AACATTGCAG TACTCAGACC AGAGTTGGCT TGCAAAGTAA CTTGCCAGTA TTCAAATGCT    720
AATTGAGAGC TGCAGAGAGG CATTTGCTTC TTGGCCCCAA GCTCAGCACC TGGAGCGTTG    780
TCCGGCTTTA GGCTTAGGAC TGAGCTGTAC TTTGGATAGA CCCATGCTGA AGTCCAAGGC    840
AGCGGGAGTG AGGGCTCCTA GCGGACGTCT AAAGCCTTCC AGGCCAAGGC TCCCCGCCCG    900
GAGACGCCTG CGGTTTGATG TTCCTTCCCT AGCTAAAGGA CCCAGAAAGA GAAACTTCCA    960
GAATGCTCTG AAGGACTCGT GACTGGAAAA GACACTAGAA ACAGGTCCTG GGAAGGATGT   1020
CATTAGTTCC CTGCCCCTTC GCATCACTTG GCCCTTCCCA CAGTAGAGCG GTGAAGAGAG   1080
GCGGAGATCC TCATTCTCTG CTTTCCACTG AGTGCAACAT GTGGGTTCTG AGTCCGCTGG   1140
TGGGACGCAC AAAACTTCAG CTTTCTTCAG GGATTTCCTT GCTCTACCCA AGTCTTCTCC   1200
GGGTTGTCTG TCAGAGAGCC TCAGGCATTA GAGATTTGTC TCCCTCGGTT GTCACAAGAG   1260
GATAATAATC ACTGCCCCCA GAAGTCCTGG CATATTCTAC AACTTTTAGT TTTCGGTGGT   1320
TTGGGGATGC CCTTTCGCGT GGTAGGTCAG TGGCCACATT CTCAGGGTTG GTAATGGTCT   1380
AGCAGTGAAT TAGTGAATCC TTTCGCTTAC CTGTCGTCGT CGTCCCCCCC GCCCCACTGT   1440
CCACTCAGGT ATCTGGCCAT CCGCTACCCG ATGCACTCCC GAGAGTTGCG CACACCTCGA   1500
AACGCGCTGG CGGCCATCGG GCTCATCTGG GGGCTAGCAC TGCTCTTCTC CGGGCCCTAC   1560
CTGAGCTACT ACAGTCAGTC GCAGCTGGCC AATCTGACGG TGTGCCACCC AGCGTGGAGC   1620
GCACCACGAC GTCGCGCCAT GGACCTCTGC ACTTTTGTCT TTAGCTACCT GTTGCCAGTG   1680
CTGGTGCTCA GCCTGACCTA TGCGCGCACC CTGCACTACC TCTGGCGCAC AGTTGACCCA   1740
GTAGCTGCAG GCTCAGGTTC CCAGCGCGCC AAGCGCAAGG TGACACGGAT GATCGTCATC   1800
GTGGCGGTAC TCTTCTGCCT CTGTTGGATG CCCCACCACG CGCTTATCCT CTGCGTGTGG   1860
TTTGGTCGCT TTCCGCTCAC GCGTGCCACT TACGCCCTGC GCATCCTTTC ACATCTAGTA   1920
TCTTATGCCA ACTCGTGTGT CAACCCCATC GTTTATGCTC TGGTCTCCAA GCATTTCCGC   1980
AAAGGTTTCC GCAAAATCTG CGCGGGCCTG CTACGCCGTG CCCCGAGGAG AGCTTCAGGC   2040
CGAGTGTGCA TCCTGGCGCC TGGAAACCAT AGTGGTGGCA TGCTGGAACC TGAGTCCACA   2100
GACCTGACAC AGGTGAGCGA GGCAGCCGGG CCCCTCGTCC CCGCACCCGC ACTTCCCAAC   2160
TGCACAACCT TGAGTAGAAC CCTCGATCCA GCCTGTTAAA GGACCAAAGG GCATCTAACA   2220
GCTTCTAAGG GCGA                                                     2234 
           
           
             
               371 amino acids 
               amino acid 
               single 
               linear 
             
             
               protein 
             
             
               not provided 
             
             9
Met Asn Gly Ser Asp Ser Gln Gly Ala Glu Asp Ser Ser Gln Glu Gly
 1               5                  10                  15
Gly Gly Gly Trp Gln Pro Glu Ala Val Leu Val Pro Leu Phe Phe Ala
            20                  25                  30
Leu Ile Phe Leu Val Gly Ala Val Gly Asn Ala Leu Val Leu Ala Val
        35                  40                  45
Leu Leu Arg Gly Gly Gln Ala Val Ser Thr Thr Asn Leu Phe Ile Leu
    50                  55                  60
Asn Leu Gly Val Ala Asp Leu Cys Phe Ile Leu Cys Cys Val Pro Phe
65                  70                  75                  80
Gln Ala Thr Ile Tyr Thr Leu Asp Asp Trp Val Phe Gly Ser Leu Leu
                85                  90                  95
Cys Lys Ala Val His Phe Leu Ile Phe Leu Thr Met His Ala Ser Ser
            100                 105                 110
Phe Thr Leu Ala Ala Val Ser Leu Asp Arg Tyr Leu Ala Ile Arg Tyr
        115                 120                 125
Pro Met His Ser Arg Glu Leu Arg Thr Pro Arg Asn Ala Leu Ala Ala
    130                 135                 140
Ile Gly Leu Ile Trp Gly Leu Ala Leu Leu Phe Ser Gly Pro Tyr Leu
145                 150                 155                 160
Ser Tyr Tyr Ser Gln Ser Gln Leu Ala Asn Leu Thr Val Cys His Pro
                165                 170                 175
Ala Trp Ser Ala Pro Arg Arg Arg Ala Met Asp Leu Cys Thr Phe Val
            180                 185                 190
Phe Ser Tyr Leu Leu Pro Val Leu Val Leu Ser Leu Thr Tyr Ala Arg
        195                 200                 205
Thr Leu His Tyr Leu Trp Arg Thr Val Asp Pro Val Ala Ala Gly Ser
    210                 215                 220
Gly Ser Gln Arg Ala Lys Arg Lys Val Thr Arg Met Ile Val Ile Val
225                 230                 235                 240
Ala Val Leu Phe Cys Leu Cys Trp Met Pro His His Ala Leu Ile Leu
                245                 250                 255
Cys Val Trp Phe Gly Arg Phe Pro Leu Thr Arg Ala Thr Tyr Ala Leu
            260                 265                 270
Arg Ile Leu Ser His Leu Val Ser Tyr Ala Asn Ser Cys Val Asn Pro
        275                 280                 285
Ile Val Tyr Ala Leu Val Ser Lys His Phe Arg Lys Gly Phe Arg Lys
    290                 295                 300
Ile Cys Ala Gly Leu Leu Arg Arg Ala Pro Arg Arg Ala Ser Gly Arg
305                 310                 315                 320
Val Cys Ile Leu Ala Pro Gly Asn His Ser Gly Gly Met Leu Glu Pro
                325                 330                 335
Glu Ser Thr Asp Leu Thr Gln Val Ser Glu Ala Ala Gly Pro Leu Val
            340                 345                 350
Pro Ala Pro Ala Leu Pro Asn Cys Thr Thr Leu Ser Arg Thr Leu Asp
        355                 360                 365
Pro Ala Cys
    370 
           
           
             
               348 amino acids 
               amino acid 
               single 
               linear 
             
             
               protein 
             
             
               not provided 
             
             10
Met Glu Leu Ala Met Val Asn Leu Ser Glu Gly Asn Gly Ser Asp Pro
 1               5                  10                  15
Glu Pro Pro Ala Pro Glu Ser Arg Pro Leu Phe Gly Ile Gly Val Glu
            20                  25                  30
Asn Phe Ile Thr Leu Val Val Phe Gly Leu Ile Phe Ala Met Gly Val
        35                  40                  45
Leu Gly Asn Ser Leu Val Ile Thr Val Leu Ala Arg Ser Lys Pro Gly
    50                  55                  60
Lys Pro Arg Ser Thr Thr Asn Leu Phe Ile Leu Asn Leu Ser Ile Ala
65                  70                  75                  80
Asp Leu Ala Tyr Leu Leu Phe Cys Ile Pro Phe Gln Ala Thr Val Tyr
                85                  90                  95
Ala Leu Pro Thr Trp Val Leu Gly Ala Phe Ile Cys Lys Phe Ile His
            100                 105                 110
Tyr Phe Phe Thr Val Ser Met Leu Val Ser Ile Phe Thr Leu Ala Ala
        115                 120                 125
Met Ser Val Asp Arg Tyr Val Ala Ile Val His Ser Arg Arg Ser Ser
    130                 135                 140
Ser Leu Arg Val Ser Arg Asn Ala Leu Leu Gly Val Gly Phe Ile Trp
145                 150                 155                 160
Ala Leu Ser Ile Ala Met Ala Ser Pro Val Ala Tyr His Gln Arg Leu
                165                 170                 175
Phe His Arg Asp Ser Asn Gln Thr Phe Cys Trp Glu Gln Trp Pro Asn
            180                 185                 190
Lys Leu His Lys Lys Ala Tyr Val Val Cys Thr Phe Val Phe Gly Tyr
        195                 200                 205
Leu Leu Pro Leu Leu Leu Ile Cys Phe Cys Tyr Ala Lys Val Leu Asn
    210                 215                 220
His Leu His Lys Lys Leu Lys Asn Met Ser Lys Lys Ser Glu Ala Ser
225                 230                 235                 240
Lys Lys Lys Thr Ala Gln Thr Val Leu Val Val Val Val Val Phe Gly
                245                 250                 255
Ile Ser Trp Leu Pro His His Val Val His Leu Trp Ala Glu Phe Gly
            260                 265                 270
Ala Phe Pro Leu Thr Pro Ala Ser Phe Phe Phe Arg Ile Thr Ala His
        275                 280                 285
Cys Leu Ala Tyr Ser Asn Ser Ser Val Asn Pro Ile Ile Tyr Ala Phe
    290                 295                 300
Leu Ser Glu Asn Phe Arg Lys Ala Tyr Lys Gln Val Phe Lys Cys His
305                 310                 315                 320
Val Cys Asp Glu Ser Pro Arg Ser Glu Thr Lys Glu Asn Lys Ser Arg
                325                 330                 335
Met Asp Thr Pro Pro Ser Thr Asn Cys Thr His Val
            340                 345 
           
           
             
               349 amino acids 
               amino acid 
               single 
               linear 
             
             
               protein 
             
             
               not provided 
             
             11
Met Glu Leu Ala Val Gly Asn Leu Ser Glu Gly Asn Ala Ser Cys Pro
 1               5                  10                  15
Glu Pro Pro Ala Pro Glu Pro Gly Pro Leu Phe Gly Ile Gly Val Glu
            20                  25                  30
Asn Phe Val Thr Leu Val Val Phe Gly Leu Ile Phe Ala Leu Gly Val
        35                  40                  45
Leu Gly Asn Ser Leu Val Ile Thr Val Leu Ala Arg Ser Lys Pro Gly
    50                  55                  60
Lys Pro Arg Ser Thr Thr Asn Leu Phe Ile Leu Asn Leu Ser Ile Ala
65                  70                  75                  80
Asp Leu Ala Tyr Leu Leu Phe Cys Ile Pro Phe Gln Ala Thr Val Tyr
                85                  90                  95
Ala Leu Pro Thr Trp Val Leu Gly Ala Phe Ile Cys Lys Phe Ile His
            100                 105                 110
Tyr Phe Phe Thr Val Ser Met Leu Val Ser Ile Phe Thr Leu Ala Ala
        115                 120                 125
Met Ser Val Asp Arg Tyr Val Ala Ile Val His Ser Arg Arg Ser Ser
    130                 135                 140
Ser Leu Arg Val Ser Arg Asn Ala Leu Leu Gly Val Gly Cys Ile Trp
145                 150                 155                 160
Ala Leu Ser Ile Ala Met Ala Ser Pro Val Ala Tyr His Gln Gly Leu
                165                 170                 175
Phe His Pro Arg Ala Ser Asn Gln Thr Phe Cys Trp Glu Gln Trp Pro
            180                 185                 190
Asp Pro Arg His Lys Lys Ala Tyr Val Val Cys Thr Phe Val Phe Gly
        195                 200                 205
Tyr Leu Leu Pro Leu Leu Leu Ile Cys Phe Cys Tyr Ala Lys Val Leu
    210                 215                 220
Asn His Leu His Lys Lys Leu Lys Asn Met Ser Lys Lys Ser Glu Ala
225                 230                 235                 240
Ser Lys Lys Lys Thr Ala Gln Thr Val Leu Val Val Val Val Val Phe
                245                 250                 255
Gly Ile Ser Trp Leu Pro His His Ile Ile His Leu Trp Ala Glu Phe
            260                 265                 270
Gly Val Phe Pro Leu Thr Pro Ala Ser Phe Leu Phe Arg Ile Thr Ala
        275                 280                 285
His Cys Leu Ala Tyr Ser Asn Ser Ser Val Asn Pro Ile Ile Tyr Ala
    290                 295                 300
Phe Leu Ser Glu Asn Phe Arg Lys Ala Tyr Lys Gln Val Phe Lys Cys
305                 310                 315                 320
His Ile Arg Lys Asp Ser His Leu Ser Asp Thr Lys Glu Asn Lys Ser
                325                 330                 335
Arg Ile Asp Thr Pro Pro Ser Thr Asn Cys Thr His Val
            340                 345 
           
           
             
               35 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               Other 
             
             
               not provided 
             
             
               Other 
                1...35 
                PCR primer 
             
             12
CCGGAATTCG GTACCATGAA CGTCTCGGGC TGCCC                                35 
           
           
             
               41 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               Other 
             
             
               not provided 
             
             
               Other 
                1...41 
                PCR primer 
             
             13
GGTAGCGGAT GGCCAGATAC CTGTCTAGAG AGACGGCGGC C                         41 
           
           
             
               41 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               Other 
             
             
               not provided 
             
             
               Other 
                1...41 
                PCR primer 
             
             14
GGCCGCCGTC TCTCTAGACA GGTATCTGGC CATCCGCTAC C                         41 
           
           
             
               41 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               Other 
             
             
               not provided 
             
             
               Other 
                1...41 
                PCR primer 
             
             15
GGCCGCCGTC TCTCTAGACA GGTATCTGGC CATCCGCTAC C                         41 
           
           
             
               27 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               Other 
             
             
               not provided 
             
             
               Other 
                1...27 
                PCR primer 
             
             16
CTGACCGYCA TGRSCATTGA CSGCTAC                                         27 
           
           
             
               24 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               Other 
             
             
               not provided 
             
             
               Other 
                1...24 
                PCR primer 
             
             17
GGGGTTGRSG CAGCTGTTGG CRTA                                            24 
           
           
             
               1116 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
             
               not provided 
             
             18
ATGAATGGCT CCGGCAGCCA GGGCGCGGAG AACACGAGCC AGGAAGGCGG TAGCGGCGGC     60
TGGCAGCCTG AGGCGGTCCT TGTACCCCTA TTTTTCGCGC TCATCTTCCT CGTGGGCACC    120
GTGGGCAACG CGCTGGTGCT GGCGGTGCTG CTGCGCGGCG GCCAGGCGGT CAGCACCACC    180
AACCTGTTCA TCCTCAACCT GGGCGTGGCC GACCTGTGTT TCATCCTGTG CTGCGTGCCT    240
TTCCAGGCCA CCATCTACAC CCTGGACGAC TGGGTGTTCG GCTCGCTGCT CTGCAAGGCT    300
GTTCATTTCC TCATCTTTCT CACTATGCAC GCCAGCAGCT TCACGCTGGC CGCCGTCTCC    360
CTGGACAGGT ATCTGGCCAT CCGCTACCCG CTGCACTCCC GAGAGTTGCG CACACCTCGA    420
AACGCGCTGG CCGCCATCGG GCTCATCTGG GGGCTAGCAC TGCTCTTCTC CGGGCCCTAC    480
CTGAGCTACT ACCGTCAGTC GCAGCTGGCC AACCTGACAG TATGCCACCC AGCATGGAGC    540
GCACCTCGAC GTCGAGCCAT GGACCTCTGC ACCTTCGTCT TTAGCTACCT GCTGCCAGTG    600
CTAGTCCTCA GTCTGACCTA TGCGCGTACC CTGCGCTACC TCTGGCGCAC AGTCGACCCG    660
GTGACTGCAG GCTCAGGTTC CCAGCGCGCC AAACGCAAGG TGACACGGAT GATCATCATC    720
GTGGCGGTGC TTTTCTGCCT CTGTTGGATG CCCCACCACG CGCTTATCCT CTGCGTGTGG    780
TTTGGTCGCT TCCCGCTCAC GCGTGCCACT TACGCGTTGC GCATCCTTTC ACACCTAGTT    840
TCCTATGCCA ACTCCTGTGT CAACCCCATC GTTTACGCTC TGGTCTCCAA GCATTTCCGT    900
AAAGGTTTCC GCAAAATCTG CGCGGGCCTG CTGCGCCCTG CCCCGAGGCG AGCTTCGGGC    960
CGAGTGAGCA TCCTGGCGCC TGGGAACCAT AGTGGCAGCA TGCTGGAACA GGAATCCACA   1020
GACCTGACAC AGGTGAGCGA GGCAGCCGGG CCCCTTGTCC CACCACCCGC ACTTCCCAAC   1080
TGCACAGCCT CGAGTAGAAC CCTGGATCCG GCTTGT                             1116 
           
           
             
               1116 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
             
               not provided 
             
             19
ATGAATGGCT CCGGCAGCCA GGGCGCGGAG AACACGAGCC AGGAAGGCGG TAGCGGCGGC     60
TGGCAGCCTG AGGCGGTCCT TGTACCCCTA TTTTTCGCGC TCATCTTCTT CGTGGGCACC    120
GTGGGCAACG CGCTGGTGCT GGCGGTGCTG CTGCGCGGCG GCCAGGCGGT CAGCACCACC    180
AACCTGTTCA TCCTCAACCT GGGCGTGGCC GACCTGTGTT TCATCCTGTG CTGCGTGCCT    240
TTCCAGGCCA CCATCTACAC CCTGGACGAC TGGGTGTTCG GCTCGCTGCT CTGCAAGGCT    300
GTTCATTTCC TCATCTTTCT CACTATGCAC GCCAGCAGCT TCACGCTGGC CGCCGTCTCC    360
CTGGACAGGT ATCTGGCCAT CCGCTACCCG CTGCACTCCC GAGAGTTGCG CACACCTCGA    420
AACGCGCTGG CCGCCATCGG GCTCATCTGG GGGCTAGCAC TGCTCTTCTC CGGGCCCTAC    480
CTGAGCTACT ACCGTCAGTC GCAGCTGGCC AACCTGACAG TATGCCACCC AGCATGGAGC    540
GCACCTCGAC GTCGAGCCAT GGACCTCTGC ACCTTCGTCT TTAGCTACCT GCTGCCAGTG    600
CTAGTCCTCA GTCTGACCTA TGCGCGTACC CTGCGCTACC TCTGGCGCAC AGTCGACCCG    660
GTGACTGCAG GCTCAGGTTC CCAGCGCGCC AAACGCAAGG TGACACGGAT GATCATCATC    720
GTGGCGGTGC TTTTCTGCCT CTGTTGGATG CCCCACCACG CGCTTATCCT CTGCGTGTGG    780
TTTGGTCGCT TCCCGCTCAC GCGTGCCACT TACGCGTTGC GCATCCTTTC ACACCTAGTT    840
TCCTATGCCA ACTCCTGTGT CAACCCCATC GTTTACGCTC TGGTCTCCAA GCATTTCCGT    900
AAAGGTTTCC GCAAAATCTG CGCGGGCCTG CTGCGCCCTG CCCCGAGGCG AGCTTCGGGC    960
CGAGTGAGCA TCCTGGCGCC TGGGAACCAT AGTGGCAGCA TGCTGGAACA GGAATCCACA   1020
GACCTGACAC AGGTGAGCGA GGCAGCCGGG CCCCTTGTCC CACCACCCGC ACTTCCCAAC   1080
TGCACAGCCT CGAGTAGAAC CCTGGATCCG GCTTGT                             1116 
           
           
             
               372 amino acids 
               amino acid 
               single 
               linear 
             
             
               protein 
             
             
               not provided 
             
             20
Met Asn Gly Ser Gly Ser Gln Gly Ala Glu Asn Thr Ser Gln Glu Gly
 1               5                  10                  15
Gly Ser Gly Gly Trp Gln Pro Glu Ala Val Leu Val Pro Leu Phe Phe
            20                  25                  30
Ala Leu Ile Phe Phe Val Gly Thr Val Gly Asn Ala Leu Val Leu Ala
        35                  40                  45
Val Leu Leu Arg Gly Gly Gln Ala Val Ser Thr Thr Asn Leu Phe Ile
    50                  55                  60
Leu Asn Leu Gly Val Ala Asp Leu Cys Phe Ile Leu Cys Cys Val Pro
65                  70                  75                  80
Phe Gln Ala Thr Ile Tyr Thr Leu Asp Asp Trp Val Phe Gly Ser Leu
                85                  90                  95
Leu Cys Lys Ala Val His Phe Leu Ile Phe Leu Thr Met His Ala Ser
            100                 105                 110
Ser Phe Thr Leu Ala Ala Val Ser Leu Asp Arg Tyr Leu Ala Ile Arg
        115                 120                 125
Tyr Pro Leu His Ser Arg Glu Leu Arg Thr Pro Arg Asn Ala Leu Ala
    130                 135                 140
Ala Ile Gly Leu Ile Trp Gly Leu Ala Leu Leu Phe Ser Gly Pro Tyr
145                 150                 155                 160
Leu Ser Tyr Tyr Arg Gln Ser Gln Leu Ala Asn Leu Thr Val Cys His
                165                 170                 175
Pro Ala Trp Ser Ala Pro Arg Arg Arg Ala Met Asp Leu Cys Thr Phe
            180                 185                 190
Val Phe Ser Tyr Leu Leu Pro Val Leu Val Leu Ser Leu Thr Tyr Ala
        195                 200                 205
Arg Thr Leu Arg Tyr Leu Trp Arg Thr Val Asp Pro Val Thr Ala Gly
    210                 215                 220
Ser Gly Ser Gln Arg Ala Lys Arg Lys Val Thr Arg Met Ile Ile Ile
225                 230                 235                 240
Val Ala Val Leu Phe Cys Leu Cys Trp Met Pro His His Ala Leu Ile
                245                 250                 255
Leu Cys Val Trp Phe Gly Arg Phe Pro Leu Thr Arg Ala Thr Tyr Ala
            260                 265                 270
Leu Arg Ile Leu Ser His Leu Val Ser Tyr Ala Asn Ser Cys Val Asn
        275                 280                 285
Pro Ile Val Tyr Ala Leu Val Ser Lys His Phe Arg Lys Gly Phe Arg
    290                 295                 300
Lys Ile Cys Ala Gly Leu Leu Arg Pro Ala Pro Arg Arg Ala Ser Gly
305                 310                 315                 320
Arg Val Ser Ile Leu Ala Pro Gly Asn His Ser Gly Ser Met Leu Glu
                325                 330                 335
Gln Glu Ser Thr Asp Leu Thr Gln Val Ser Glu Ala Ala Gly Pro Leu
            340                 345                 350
Val Pro Pro Pro Ala Leu Pro Asn Cys Thr Ala Ser Ser Arg Thr Leu
        355                 360                 365
Asp Pro Ala Cys
    370