Abstract:
Disclosed are methods and compositions for identifying agents which modulate the interaction of Robo and a Robo ligand and for modulating the interaction of Robo and a Robo ligand. The methods for identifying Robo:ligand modulators find particular application in commercial drug screens. These methods generally comprise (1) combining a Robo polypeptide, a Slit polypeptide and a candidate agent under conditions whereby, but for the presence of the agent, the Robo and Slit polypeptides engage in a first interaction, and (2) determining a second interaction of the Robo and Slit polypeptides in the presence of the agent, wherein a difference between the first and second interactions indicates that the aget modulates the interaction of the Robo and Slit polypeptides. The subject methods of modulating the interaction of Robo and a Robo ligand involve combining a Robo polypeptide, a Slit polypeptide and a modulator under conditions whereby, but for the presence of the modulator, the Robo and Slit polypeptides engage in a first interaction, whereby the Robo and Slit polypeptides engage in a second interaction different from the first interaction. In a particular embodiment, the modulator is dominant negative form of the Robo or Slit polypeptide.

Description:
CROSS-REFERENCE TO RELATED APPLICATION  
       [0001]    This application claims the benefit of U.S. application Ser. No. 09/922,600, filed Aug. 3, 2001, which claims the benefit of U.S. application Ser. No. 09/540,245, filed Mar. 31, 2000, now U.S. Pat. No. 6,270,984, which claims the benefit of U.S. application Ser. No. 09/191,647, filed Nov. 13, 1998, which claims the benefit of U.S. Provisional Application No. 60/081,057 filed Apr. 7, 1998 and U.S. Provisional Application No. 60/065,544, filed Nov. 14, 1997, all of which are incorporated herein by reference. 
     
    
       [0002] The research carried out in the subject application was supported in part by NIH grant NS18366. The government may have rights in any patent issuing on this application. 
     
    
     
       INTRODUCTION  
         [0003]    1. Field of the Invention  
           [0004]    The field of this invention is methods for modulating nerve cell function.  
           [0005]    2. Background  
           [0006]    In the developing CNS, most growth cones confront the midline at one or multiple times during their journey and make the decision of whether to cross or not to cross. This decision is not a static one but rather changes according to the growth cone&#39;s history. For example, in the Drosophila ventral nerve cord, about 10% of the interneurons project their axons only on their own side, in some cases extending near the midline without crossing it. The other 90% of the interneurons first project their axons across the midline and then turn to project longitudinally on the other side, often extending near the midline. These growth cones, having crossed the midline once, never cross it again, in spite of their close proximity to the midline and the many commissural axons crossing it. This decision to cross or not to cross is not unique to Drosophila but is common to a variety of midline structures in all bilaterally symmetric nervous systems.  
           [0007]    What midline signals and growth cone receptors control whether growth cones do or do not cross the midline? After crossing once, what mechanism prevents these growth cones from crossing again? A related issue concerns the nature of the midline as an intermediate target. If so many growth cones find the midline such an attractive structure, why do they cross over it rather than linger? Why do they leave the midline? 
           [0008]    One approach to find the genes encoding the components of such a system is to screen for mutations in which either too many or too few axons cross the midline. Such a large-scale mutant screen was previously conducted in Drosophila, and led to the identification of two key genes: commissureless (comm) and roundabout (robo) (Seeger et al., 1993; reviewed by Tear et al., 1993). In comm mutant embryos, commissural growth cones initially orient toward the midline but then fail to cross it and instead recoil and extend on their own side. robo mutant embryos, on the other hand, display the opposite phenotype in that too many axons cross the midline; many growth cones that normally extend only on their own side instead now project across the midline and axons that normally cross the midline only once instead appear to cross and recross multiple times (Seeger et al, 1993; present disclosure). Double mutants of comm and robo display a robo-like phenotype.  
           [0009]    How do comm and robo function to control midline crossing? Neither the initial paper on these genes (Seeger et al., 1993) nor the cloning of comm (Tear et al., 1996) resolved this question. comm encodes a novel surface protein expressed on midline cells. In fact, the comm paper (Tear et al., 1996) ended with the hope that future work would “ . . . help shed some light on the enigmatic function of Comm.” 
           [0010]    U.S. Ser. No. 08/971,172 (Robo, A Novel Family of Polypeptides and Nucleic Acids, by inventors: Corey S. Goodman, Thomas Kidd, Kevin J. Mitchell and Guy Tear) discloses the cloning and characterization of robo in various species including Drosophila; Robo polypeptides and polypeptide-encoding nucleic acids are also disclosed and their genbank accession numbers referenced in Kidd et al. (1998) Cell 92, 205-215. robo encodes a new class of guidance receptor with 5 immunoglobulin (Ig) domains, 3 fibronectin type HI domains, a transmembrane domain, and a long cytoplasmic domain. Robo defines a new subfamily of Ig superfamily proteins that is highly conserved from fruit flies to mammals. The Robo ectodomains, and in particular the first two Ig domains, are highly conserved from fruit fly to human, while the cytoplasmic domains are more divergent. Nevertheless, the cytoplasmic domains contain three highly conserved short proline-rich motifs which may represent binding sites for SH3 or other binding domains in linker or signaling molecules.  
           [0011]    For those axons that never cross the midline, Robo is expressed on their growth cones from the outset; for the majority of axons that do cross the midline, Robo is expressed at high levels on their growth cones only after they cross the midline. Transgenic rescue experiments in Drosophila reveal that Robo can function in a cell autonomous fashion, consistent with it functioning as a receptor. Thus, in Drosophila, Robo appears to function as the gatekeeper controlling midline crossing; growth cones expressing high levels of Robo are prevented from crossing the midline. Robo proteins in mammals function in a similar manner in controlling axon guidance.  
           [0012]    U.S. Ser. No. 60/065,54 (Methods for Modulating Nerve Cell Function, by inventors: Corey S. Goodman, Thomas Kidd, Guy Tear, Claire Russell and Kevin Mitchell) discloses ectopic and overexpression studies revealing that Comm down-regulates Robo expression, demonstrating that Comm functions to suppress the Robo-mediated midline repulsion. These results show that the levels of Comm at the midline and Robo on growth cones are tightly intertwined and dynamically regulated to assure that only certain growth cones cross the midline, that those growth cones that cross do not linger at the midline, and that once they cross they never do so again.  
         RELEVANT LITERATURE  
         [0013]    Seeger, M., Tear, G., Ferres-Marco, D. and Goodman C.S. (1993) Neuron 10, 409-426; Tear G., et al. (1996) Neuron 16, 501-514; Rothberg et al. (1990) Genes Dev 4, 2169-2187; Kidd et al. (1998) Cell 92, 205-215.  
         SUMMARY OF THE INVENTION  
         [0014]    The invention provides methods and compositions relating to vertebrate Slit1 and Slit2, collectively vertebrate Slit) polypeptides, related nucleic acids, polypeptide domains thereof having vertebrate Slit-specific structure and activity, and modulators of vertebrate Slit function. Vertebrate Slit polypeptides can regulate cell, especially nerve cell, function and morphology. The polypeptides may be produced recombinantly from transformed host cells from the subject vertebrate Slit polypeptide encoding nucleic acids or purified from mammalian cells. The invention provides isolated vertebrate Slit hybridization probes and primers capable of specifically hybridizing with natural vertebrate Slit genes, vertebrate Slit-specific binding agents such as specific antibodies, and methods of making and using the subject compositions in diagnosis (e.g. genetic hybridization screens for vertebrate Slit transcripts), therapy (e.g. to modulate nerve cell growth) and in the biopharmaceutical industry (e.g. as immunogens, reagents for isolating vertebrate Slit genes and polypeptides, reagents for screening chemical libraries for lead pharmacological agents, etc.).  
           [0015]    The invention also provides methods and compositions for identifying agents which modulate the interaction of Robo and a Robo ligand and for modulating the interaction of Robo and a Robo ligand. The methods for identifying Robo:ligand modulators find particular application in commercial drug screens. These methods generally comprise (1) combining a Robo polypeptide, a Slit polypeptide and a candidate agent under conditions whereby, but for the presence of the agent, the Robo and Slit polypeptides engage in a first interaction, and (2) determining a second interaction of the Robo and Slit polypeptides in the presence of the agent, wherein a difference between the first and second interactions indicates that the aget modulates the interaction of the Robo and Slit polypeptides. The subject methods of modulating the interaction of Robo and a Robo ligand involve combining a Robo polypeptide, a Slit polypeptide and a modulator under conditions whereby, but for the presence of the modulator, the Robo and Slit polypeptides engage in a first interaction, whereby the Robo and Slit polypeptides engage in a second interaction different from the first interaction. In a particular embodiment, the modulator is dominant negative form of the Robo or Slit polypeptide.  
         DETAILED DESCRIPTION OF THE INVENTION  
         [0016]    The subject methods include screens for agents which modulate Robo:ligand interactions and methods for modulating Robo:ligand interactions. Robo activation is found to regulate a wide variety of cell functions, including cell-cell interactions, cell mobility, morphology, etc. Slit polypeptides are disclosed as specific activators and inactivators of Robo polypeptides. Accordingly, the invention provides methods for modulating targeted cell function comprising the step of modulating Robo activation by contacting the cell with a modulator of a Robo:Slit interaction.  
           [0017]    The targeted Robo polypeptide is generally naturally expressed on the targeted cells. The nucleotide sequences of exemplary natural cDNAs encoding drosophila 1, drosophila 2, C. elegans, human 1, human 2 and mouse 1 Robo polypeptides and their translates are described in Kidd et al. (1998) Cell 92, 205-215 and U.S. Ser. No. 08/971,172. The targeted Robo polypeptides comprise at least a functional Robo domain, which domain has Robo-specific amino acid sequence and binding specificity or function. Preferred Robo domains comprise at least 8, preferably at least 16, more preferably at least 32, most preferably at least 64 consecutive residues of a natural full length Robo. In a particular embodiment, the domains comprise one or more structural/functional Robo immunoglobulin, fibronectin or cytoplasmic motif domains described herein. The subject domains provide Robo-specific antigens and/or immunogens, especially when coupled to carrier proteins. For example, peptides corresponding to Robo- and human Robo-specific domains are covalently coupled to keyhole limpet antigen (KLH) and the conjugate is emulsified in Freunds complete adjuvant. Laboratory rabbits are immunized according to conventional protocol and bled. The presence of Robo-specific antibodies is assayed by solid phase immunosorbant assays using immobilized Robo polypeptides. Generic Robo-specific peptides are readily apparent as conserved regions in aligned Robo polypeptide sequences. In addition, species-specific antigenic and/or immunogenic peptides are readily apparent as diverged extracellular or cytosolic regions in alignments Human Robo-specific antibodies are characterized as uncross-reactive with non-human Robo polypeptides.  
           [0018]    The subject domains provide Robo domain specific activity or function, such as Robo-specific cell, especially neuron modulating or modulating inhibitory activity, Robo-ligand-binding or binding inhibitory activity. Robo-specific activity or function may be determined by convenient in vitro, cell-based, or in vivo assays: e.g. in vitro binding assays, cell culture assays, in animals (e.g. gene therapy, transgenics, etc.), etc. The binding target may be a natural intracellular binding target, a Robo regulating protein or other regulator that directly modulates Robo activity or its localization; or non-natural binding target such as a specific immune protein such as an antibody, or a Robo specific agent such as those identified in screening assays such as described below. Robo-binding specificity may be assayed by binding equilibrium constants (usually at least about 10 7  M −1 , preferably at least about 10 8  M −1 , more preferably at least about 10 9  M −1 ), by the ability of the subject polypeptide to function as negative mutants in Robo-expressing cells, to elicit Robo specific antibody in a heterologous host (e.g a rodent or rabbit), etc.  
           [0019]    Similarly, the Slit polypeptide is conveniently selected from Slit polypeptides which specifically activate or inhibit the activation of the Robo polypeptide. Exemplary suitable Slit polypeptides (a) comprises a vertebrate Slit sequence disclosed herein, especially human Slit-1 (SEQ ID NO:02), or a deletion mutant thereof which specifically modulates Robo expression or a sequence about 60-70%, preferably about 70-80%, more preferably about 80-90%, more preferably about 90-95%, most preferably about 95-99% similar to a vertebrate Slit sequence disclosed herein as determined by Best Fit analysis using default settings and is other than a natural drosophila Slit sequence, preferably other than a natural invertebrate Slit sequence, and/or (b) is encoded by a nucleic acid comprising a natural Slit encoding sequence (such as a natural human Slit-1 encoding sequence, SEQ ID NO:01) or a fragment thereof at least 36, preferably at least 72, more preferably at least 144, most preferably at least 288 nucleotides in length which specifically hybridizes thereto. Suitable deletion mutants are readily screened in Robo binding or activation assays as described herein. Preferred Slit domains/deletion mutants/fragments comprise at least 8, preferably at least 16, more preferably at least 32, most preferably at least 64 consecutive residues of a disclosed vertebrate Slit sequences and provide a Slit specific activity, such as Slit-specific antigenicity and/or immunogenicity, especially when coupled to carrier proteins as described above for Robo above. Suitable natural Slit encoding sequence fragments are of length sufficient to encode such Slit domains. In a particular embodiment, the Slit fragments comprise species specific fragments; such fragments are readily discerned from alignments of the disclosed sequences, see, e.g. shown as unboxed sequences in Tables 1 and 2. Exemplary such human Slit-1 immunogenic and/or antigenic peptides are shown in Table 3.  
                             TABLE 3                           Immunogenic human Slit-1 polypeptides eliciting Slit-1 specific       rabbit polyclonal antibody: Slit polypeptide-KLH conjugates       immunized per protocol described above.                Slit Polypeptide   Immunogenicity                       SEQ ID NO:02, res. 1-10   +++           SEQ ID NO:02, res. 29-41   +++           SEQ ID NO:02, res. 75-87   +++           SEQ ID NO:02, res. 92-109   +++           SEQ ID NO:02, res. 132-141   +++           SEQ ID NO:02, res. 192-205   +++           SEQ ID NO:02, res. 258-269   +++           SEQ ID NO:02, res. 295-311   +++           SEQ ID NO:02, res. 316-330   +++           SEQ ID NO:02, res. 373-382   +++           SEQ ID NO:02, res. 403-422   +++           SEQ ID NO:02, res. 474-485   +++           SEQ ID NO:02, res. 561-576   +++           SEQ ID NO:02, res. 683-697   +++           SEQ ID NO:02, res. 768-777   +++           SEQ ID NO:02, res. 798-813   +++           SEQ ID NO:02, res. 882-894   +++           SEQ ID NO:02, res. 934-946   +++           SEQ ID NO:02, res. 1054-1067   +++           SEQ ID NO:02, res. 1181-1192   +++           SEQ ID NO:02, res. 1273-1299   +++           SEQ ID NO:02, res. 1383-1397   +++           SEQ ID NO:02, res. 1468-1477   +++           SEQ ID NO:02, res. 1508-1517   +++                      
 
           [0020]    The subject domains provide Slit domain specific activity or function, such as Slit-specific cell, especially neuron modulating or modulating inhibitory activity, Slit-ligand-binding or binding inhibitory activity. Slit-specific activity or function may be determined by convenient in vitro, cell-based, or in vivo assays: e.g. in vitro binding assays, cell culture assays, in animals (e.g. gene therapy, transgenics, etc.), etc. The binding target may be a natural intracellular binding target, a Slit regulating protein or other regulator that directly modulates Slit activity or its localization; or non-natural binding target such as a specific immune protein such as an antibody, or a Slit specific agent such as those identified in screening assays such as described below. Slit-binding specificity may be assayed by binding equilibrium constants (usually at least about 10 7 M −1 , preferably at least about 10 8  M −1 , more preferably at least about 10 9  M −1 ), by the ability of the subject polypeptide to function as negative mutants in Slit-expressing cells, to elicit Slit specific antibody in a heterologous host (e.g a rodent or rabbit), etc.  
           [0021]    In one embodiment, the Slit polypeptides are encoded by a nucleic acid comprising SEQ ID NO:01 or a fragment thereof which hybridizes with a full-length strand thereof, preferably under stringent conditions. Such nucleic acids comprise at least 36, preferably at least 72, more preferably at least 144 and most preferably at least 288 nucleotides of SEQ ID NO:01. Demonstrating specific hybridization generally requires stringent conditions, for example, hybridizing in a buffer comprising 30% formamide in 5×SSPE (0.18 M NaCl, 0.01 M NaPO 4 , pH 7.7, 0.001 M EDTA) buffer at a temperature of 42° C. and remaining bound when subject to washing at 42° C. with 0.2×SSPE (Conditions I); preferably hybridizing in a buffer comprising 50% formamide in 5×SSPE buffer at a temperature of 42° C. and remaining bound when subject to washing at 42° C. with 0.2×SSPE buffer at 42° C. (Conditions II). Exemplary nucleic acids which hybridize with a strand of SEQ ID NO:01 are shown in Table 4.  
                             TABLE 4                           Exemplary nucleic acids which hybridize with a strand of       SEQ ID NO:01 under Conditions I and/or II.                Slit Nucleic Acid   Hybridization                       SEQ ID NO:01, nucl. 1-47   +           SEQ ID NO:01, nucl. 58-99   +           SEQ ID NO:01, nucl. 95-138   +           SEQ ID NO:01, nucl. 181-220   +           SEQ ID NO:01, nucl. 261-299   +           SEQ ID NO:01, nucl. 274-315   +           SEQ ID NO:01, nucl. 351-389   +           SEQ ID NO:01, nucl. 450-593   +           SEQ ID NO:01, nucl. 524-546   +           SEQ ID NO:01, nucl. 561-608   +           SEQ ID NO:01, nucl. 689-727   +           SEQ ID NO:01, nucl. 708-737   +           SEQ ID NO:01, nucl. 738-801   +           SEQ ID NO:01, nucl. 805-854   +           SEQ ID NO:01, nucl. 855-907   +           SEQ ID NO:01, nucl. 910-953   +           SEQ ID NO:01, nucl. 1007-1059   +           SEQ ID NO:01, nucl. 1147-1163   +           SEQ ID NO:01, nucl. 1258-1279   +           SEQ ID NO:01, nucl. 1375-1389   +           SEQ ID NO:01, nucl. 1581-1595   +           SEQ ID NO:01, nucl. 1621-1639   +           SEQ ID NO:01, nucl. 1744-1755   +           SEQ ID NO:01, nucl. 1951-1969   +           SEQ ID NO:01, nucl. 2150-2163   +           SEQ ID NO:01, nucl. 2524-2546   +           SEQ ID NO:01, nucl. 2761-2780   +           SEQ ID NO:01, nucl. 2989-2999   +           SEQ ID NO:01, nucl. 3108-3117   +           SEQ ID NO:01, nucl. 3338-3351   +           SEQ ID NO:01, nucl. 3505-3514   +           SEQ ID NO:01, nucl. 3855-3867   +           SEQ ID NO:01, nucl. 4010-4025   +           SEQ ID NO:01, nucl. 4207-4219   +           SEQ ID NO:01, nucl. 4333-4345   +           SEQ ID NO:01, nucl. 4521-4529   +                      
 
           [0022]    A wide variety of cell types express Robo polypeptides subject to regulation by the disclosed methods, including many neuronal cells, transformed cells, infected (e.g. virus) cells, etc. Ascertaining Robo binding or activation is readily effected by binding assays or cells function assays as disclosed herein or in the cited copending applications. Accordingly, indications for the subject methods encompass a wide variety of cell types and function, including axon outgrowth, tumor cell invasion or migration, etc. The target cell may reside in culture or in situ, i.e. within the natural host. For in situ applications, the compositions are added to a retained physiological fluid such as blood or synovial fluid. For CNS administration, a variety of techniques are available for promoting transfer of the therapeutic across the blood brain barrier including disruption by surgery or injection, drugs which transiently open adhesion contact between CNS vasculature endothelial cells, and compounds which facilitate translocation through such cells. Slit polypeptides may also be amenable to direct injection or infusion, topical, intratracheal/nasal administration e.g. through aerosol, intraocularly, or within/on implants e.g. fibers e.g. collagen, osmotic pumps, grafts comprising appropriately transformed cells, etc. A particular method of administration involves coating, embedding or derivatizing fibers, such as collagen fibers, protein polymers, etc. with therapeutic polypeptides. Other useful approaches are described in Otto et al. (1989) J Neuroscience Research 22, 83-91 and Otto and Unsicker (1990) J Neuroscience 10, 1912-1921. Generally, the amount administered will be empirically determined, typically in the range of about 10 to 1000 μg/kg of the recipient and the concentration will generally be in the range of about 50 to 500 μg/ml in the dose administered. Other additives may be included, such as stabilizers, bactericides, etc. will be present in conventional amounts.  
           [0023]    In one embodiment, the invention provides administering the subject Slit polypeptides in combination with a pharmaceutically acceptable excipient such as sterile saline or other medium, gelatin, an oil, etc. to form pharmaceutically acceptable compositions. The compositions and/or compounds may be administered alone or in combination with any convenient carrier, diluent, etc. and such administration may be provided in single or multiple dosages. Useful carriers include solid, semi-solid or liquid media including water and non-toxic organic solvents. In another embodiment, the invention provides the subject compounds in the form of a pro-drug, which can be metabolically converted to the subject compound by the recipient host. A wide variety of pro-drug formulations for polypeptide-based therapeutics are known in the art. The compositions may be provided in any convenient form including tablets, capsules, troches, powders, sprays, creams, etc. As such the compositions, in pharmaceutically acceptable dosage units or in bulk, may be incorporated into a wide variety of containers. For example, dosage units may be included in a variety of containers including capsules, pills, etc. The compositions may be advantageously combined and/or used in combination with other therapeutic or prophylactic agents, different from the subject compounds. In many instances, administration in conjunction with the subject compositions enhances the efficacy of such agents, see e.g.  Goodman  &amp;  Gilman &#39;s The Pharmacological Basis of Therapeutics,  9 th  Ed., 1996, McGraw-Hill.  
           [0024]    In another aspect, the invention provides methods of screening for agents which modulate Robo-Slit interactions. These methods generally involve forming a mixture of a Robo-expressing cell, a Slit polypeptide and a candidate agent, and determining the effect of the agent on the amount of Robo expressed by the cell. The methods are amenable to automated, cost-effective high throughput screening of chemical libraries for lead compounds. Identified reagents find use in the pharmaceutical industries for animal and human trials; for example, the reagents may be derivatized and rescreened in in vitro and in vivo assays to optimize activity and minimize toxicity for pharmaceutical development. Cell and animal based neural guidance/repulsion assays are described in detail in the experimental section below.  
           [0025]    The amino acid sequences of the disclosed vertebrate Slit polypeptides are used to back-translate Slit polypeptide-encoding nucleic acids optimized for selected expression systems (Holler et al. (1993) Gene 136, 323-328; Martin et al. (1995) Gene 154, 150-166) or used to generate degenerate oligonucleotide primers and probes for use in the isolation of natural Slit-encoding nucleic acid sequences (“GCG” software, Genetics Computer Group, Inc, Madison Wis.). Slit-encoding nucleic acids used in Slit-expression vectors and incorporated into recombinant host cells, e.g. for expression and screening, transgenic animals, e.g. for functional studies such as the efficacy of candidate drugs for disease associated with Slit-modulated cell function, etc.  
           [0026]    The invention also provides nucleic acid hybridization probes and replication/amplification primers having a vertebrate Slit cDNA specific sequence comprising a fragment of a disclosed vertebrate cDNA sequence, and sufficient to effect specific hybridization thereto. Such primers or probes are at least 12, preferably at least 24, more preferably at least 36 and most preferably at least 96 nucleotides in length. Demonstrating specific hybridization generally requires stringent conditions, for example, hybridizing in a buffer comprising 30% formamide in 5×SSPE (0.18 M NaCl, 0.01 M NaPO 4 , pH 7.7, 0.001 M EDTA) buffer at a temperature of 42° C. and remaining bound when subject to washing at 42° C. with 0.2×SSPE; preferably hybridizing in a buffer comprising 50% formamide in 5×SSPE buffer at a temperature of 42° C. and remaining bound when subject to washing at 42° C. with 0.2×SSPE buffer at 42° C. Slit nucleic acids can also be distinguished using alignment algorithms, such as BLASTX (Altschul et al. (1990) Basic Local Alignment Search Tool, J Mol Biol 215, 403-410). In addition, the invention provides nucleic acids having a sequence about 60-70%, preferably about 70-80%, more preferably about 80-90%, more preferably about 90-95%, most preferably about 95-99% similar to a vertebrate Slit sequence disclosed herein as determined by Best Fit analysis using default settings and is other than a natural drosophila Slit sequence, preferably other than a natural invertebrate Slit sequence. In a particular embodiment, the Slit polynucleotide fragments comprise species specific fragments; such fragments are readily discerned from alignments of the disclosed sequences.  
           [0027]    The subject nucleic acids are of synthetic/non-natural sequences and/or are recombinant, meaning they comprise a non-natural sequence or a natural sequence joined to nucleotide(s) other than that which it is joined to on a natural chromosome. The subject recombinant nucleic acids comprising the nucleotide sequence of disclosed vertebrate Slit nucleic acids, or fragments thereof, contain such sequence or fragment at a terminus, immediately flanked by (i.e. contiguous with) a sequence other than that which it is joined to on a natural chromosome, or flanked by a native flanking region fewer than 10 kb, preferably fewer than 2 kb, more preferably fewer than 500 bp, which is at a terminus or is immediately flanked by a sequence other than that which it is joined to on a natural chromosome. While the nucleic acids are usually RNA or DNA, it is often advantageous to use nucleic acids comprising other bases or nucleotide analogs to provide modified stability, etc.  
           [0028]    The subject nucleic acids find a wide variety of applications including use as translatable transcripts, hybridization probes, PCR primers, diagnostic nucleic acids, etc.; use in detecting the presence of Slit genes and gene transcripts and in detecting or amplifying nucleic acids encoding additional Slit homologs and structural analogs. In diagnosis, Slit hybridization probes find use in identifying wild-type and mutant Slit alleles in clinical and laboratory samples. Mutant alleles are used to generate allele-specific oligonucleotide (ASO) probes for high-throughput clinical diagnoses. In therapy, therapeutic Slit nucleic acids are used to modulate cellular expression or intracellular concentration or availability of active Slit. Exemplary human Slit-1 probes and primers are shown in Table 5 and Table 6.  
                         TABLE 5                       Hybridization Probes for Regions of Human Slit-1.                                Hybridization probe for first   SEQ ID NO:01, nucleotides 82-828       leucine rich repeat region       Hybridization probe for second   SEQ ID NO:01, nucleotides 829-1503       leucine rich repeat region       Hybridization probe for third   SEQ ID NO:01, nucleotides 1504-2166       leucine rich repeat region       Hybridization probe for fourth   SEQ ID NO:01, nucleotides 2167-2751       leucine rich repeat region       Hybridization probe for EGF   SEQ ID NO:01, nucleotides 2752-3327       repeats one to five       Hybridization probe for the sixth   SEQ ID NO:01, nucleotides 3328-3461       EGF repeat and preceding spacer       region       Hybridization probe for the 99aa   SEQ ID NO:01, nucleotides 3462-3987       spacer/G-loop region       Hybridization probe for EGF   SEQ ID NO:01, nucleotides 3988-4341       repeats seven to nine       Hybridization probe for the   SEQ ID NO:01, nucleotides 4342-4575       cysteine knot region                  
 
           [0029]    [0029]                         TABLE 6                       PCR Primers for regions of Human Slit.                                PCR Primers for first   Forward: SEQ ID NO:01, nucleotides 82-111       leucine rich repeat   Reverse: reverse complement of SEQ ID NO:01,       region   nucleotides 799-828       PCR Primers for   Forward: SEQ ID NO:01, nucleotides 829-858       second leucine rich   Reverse: reverse complement of SEQ ID NO:01,       repeat region   nucleotides 1474-1503       PCR Primers for third   Forward: SEQ ID NO:01, nucleotides 1504-1533       leucine rich repeat   Reverse: reverse complement of SEQ ID NO:01,       region   nucleotides 2137-2166       PCR Primers for   Forward: SEQ ID NO:01, nucleotides 2167-2196       fourth leucine rich   Reverse: reverse complement of SEQ ID NO:01,       repeat region   nucleotides 2722-2751       PCR Primers for EGF   Forward: SEQ ID NO:01, nucleotides 2752-2781       repeats one to five   Reverse: reverse complement of SEQ ID NO:01,           nucleotides 3298-3327       PCR Primers for the   Forward: SEQ ID NO:01, nucleotides 3328-3357       sixth EGF repeat and   Reverse: reverse complement of SEQ ID NO:01,       preceding spacer   nucleotides 3432-3461       region       PCR Primers for the   Forward: SEQ I:01, nucleotides 3462-3491       99aa spacer/G-loop   Reverse: reverse complement of SEQ ID NO:01,       region   nucleotides 3958-3987       PCR Primers for EGF   Forward: SEQ ID NO:01, nucleotides 3988-4017       repeats seven to nine   Reverse: reverse complement of SEQ ID NO:01,           nucleotides 4312-4341       PCR Primers for the   Forward: SEQ ID NO:01, nucleotides 4342-4371       cysteine knot region   Reverse: reverse complement of SEQ ID NO:01,           nucleotides 4546-4575                    
           [0030]    Leucine rich repeats (LRRs) are predicted by comparison with known proteins and by the presence of a leucine rich core sequence. In slit proteins, the LRRs are flanked by conserved sequences referred to as the amino- and carboxy-flanking regions. These flanking regions are found in other known proteins, but only in a few instances are both the amino- and carboxy-flank regions present in a single protein. The so called “99aa spacer” is actually ˜200 amino acids in the Drosophila protein and 174 amino acids in Human Slit-1. This region shows homology to the G-loops of laminin A chains.  
           [0031]    Cysteine knots are dimerisation domains defined by the presence of six cysteine residues between which disulphide bridges form. The only absolutely conserved residues are the six cysteines, and spacing between them is highly variable, apart from between cysteines 2 and 3, and 5 and 6. The glycine between cysteines 2 and 3 is only present in a subset of cysteine knots. Drosophila slit and Human slit-i both have an extra cysteine after cysteines 5 and 6: this may serve as an intermolecular bond. Human Slit-1 gene displays the overall structure of the Drosophila gene, and amino acid conservation is found along the entire length of the protein (48% homology at the amino acid sequence excluding the signal sequence; see below). The Human gene has an extra LRR between LRR2 and LRR3 of the first set of LRRs; in the third set, the Human gene has an extra LRR between LRR3 and LRR4. The Human gene has two extra EGF repeats, on either side of the seventh EGF repeat in Drosophila slit.  
           [0032]    Isolation of Human Slit-1  
           [0033]    Searching of the EST database revealed an EST, ab16g10.r1, with homology to the 99aa spacer region of Drosophila slit. This EST was used to probe a Human fetal brain library (Stratagene), and clones for Human slit-1 were isolated.  
           [0034]    Features of Human Slit Predicted Protein  
                                       Signal sequence   SEQ ID NO:02, residues 7-24       First amino-flanking sequence   SEQ ID NO:02, residues 28-59       First set of Leucine Rich Repeats   SEQ ID NO:02, residues 60-179           (6 repeats)       First carboxy-flanking sequence   SEQ ID NO:02, residues 180-276       Second amino-flanking sequence   SEQ ID NO:02, residues 277-308       Second set of Leucine Rich   SEQ ID NO:02, residues 309-434       Repeats   (5 repeats)       Second carboxy-flanking sequence   SEQ ID NO:02, residues 435-501       Third amino-flanking sequence   SEQ ID NO:02, residues 502-533       Third set of Leucine Rich Repeats   SEQ ID NO:02, residues 534-560           (5 repeats)       Third carboxy-flanking sequence   SEQ ID NO:02, residues 661-722       Fourth amino-flanking sequence   SEQ ID NO:02, residues 723-754       Fourth set of Leucine Rich Repeats   SEQ ID NO:02, residues 755-855           (4 repeats)       Fourth carboxy-flanking sequence   SEQ ID NO:02, residues 856-917       First EGF repeat   SEQ ID NO:02, residues 918-952       Second EGF repeat   SEQ ID NO:02, residues 953-993       Third EGF repeat   SEQ ID NO:02, residues 994-1031       Fourth EGF repeat   SEQ ID NO:02, residues 1032-1071       Fifth EGF repeat   SEQ ID NO:02, residues 1072-1109       Spacer   SEQ ID NO:02, residues 1110-1116       Sixth EGF repeat   SEQ ID NO:02, residues 1117-1153       “99aa spacer”   SEQ ID NO:02, residues 1155-1329       Seventh EGF repeat   SEQ ID NO:02, residues 1330-1366       Eighth EGF repeat   SEQ ID NO:02, residues 1367-1404       Ninth EGF repeat   SEQ ID NO:02, residues 1405-1447       Cysteine knot motif   SEQ ID NO:02, residues 1448-1525                  
 
           [0035]    Amino Acid Identity Between Drosophila and Human Slit-1  
                                       First amino-flanking sequence   53%       First set of Leucine Rich Repeats   52%           (54%, 67%, NA, 38%, 54%, 50%)       First carboxy-flanking sequence   42%       Second amino-flanking sequence   50%       Second set of Leucine Rich Repeats   60%           (54%, 58%, 67%, 71%, 50%)       Second carboxy-flanking sequence   62%       Third amino-flanking sequence   56%       Third set of Leucine Rich Repeats   49%           (46%, 46%, 42%, NA, 58%)       Third carboxy-flanking sequence   36%       Fourth amino-flanking sequence   53%       Fourth set of Leucine Rich Repeats   48%           (25%, 58%, 46%, 63%)       Fourth carboxy-flanking sequence   63%       First EGF repeat   34%       Second EGF repeat   46%       Third EGF repeat   46%       Fourth EGF repeat   35%       Fifth EGF repeat   47%       Spacer   22%       Sixth EGF repeat   40%       “99aa spacer”   38%       Seventh EGF repeat   11%/NA       Eighth EGF repeat   44%       Nineth EGF repeat   29%/NA       Cysteine knot motif   34%                          
 
           [0036]    Figures for Individual LLRs are Shown in Brackets.  
           [0037]    The following examplary assay is offered by way of illustration and not by way of limitation: 
       
    
    
     EXAMPLES  
       [0038]    Protocol for Ligand Screening of Transfected COS Cells.  
         [0039]    I. Prepare the Ligand  
         [0040]    Expression Construct: cDNAs encoding targeted Slit polypeptides are tagged with the Fc portion of human IgG and subcloned into a 293 expression vector (pCEP4: In Vitrogen).  
         [0041]    Transfection: 293 EBNA cells are transfected (CaPO 4  method) with the Slit expression constructs. After 24 h recovery, transfected cells are selected with G418 (geneticin, 250 ug/ml, Gibco) and hygromycin (200 ug/ml). Once the selection process is complete, cells are maintained in Dulbecco&#39;s Modified Eagles medium (DME)/10% FCS under selection.  
         [0042]    Preparation of Conditioned Medium: Serum-containing media is replaced with Optimem with glutamax-1 (Gibco) and 300 ng/ml heparin (Sigma), and the cells are conditioned for 3 days. The media is collected and spun at 3,000×g for 10 minutes. The supernatant is filtered (0.45 μm) and stored with 0.1% azide at 4° C. for no more than 2 weeks.  
         [0043]    II. Prepare Truncated Receptor (Positive Control)  
         [0044]    Expression Construct: cDNA encoding a corresponding Robo C-terminal deletion mutant comprising the extracellular domain (truncated immediately N-terminal to the transmembrane region) is subcloned into a 293 expression vector (pCEP4: In Vitrogen).  
         [0045]    Transfection: 293 EBNA cells are transfected (CaPO 4  method) with the receptor mutant expression construct. After 24 h recovery, transfected cells are selected with G418 (geneticin, 250 ug/ml, Gibco) and hygromycin (200 ug/ml). Once the selection process is complete, cells are maintained in Dulbecco&#39;s Modified Eagles medium (DME)/10% FCS under selection.  
         [0046]    Preparation of Conditioned Medium: Serum-containing media is replaced with Optimem with glutamax-1 (Gibco) and 300 ng/ml heparin (Sigma), and the cells are conditioned for 3 days. The media is collected and spun at 3,000×g for 10 minutes. The supernatant is filtered (0.45 μm) and stored with 0.1% azide at 4° C. for no more than 2 weeks.  
         [0047]    II. Transfect COS Cells  
         [0048]    Seed COS cells (250,000) on 35 mm dishes in 2 ml DME/10% FCS.  
         [0049]    18-24 h later, dilute 1 ug of Robo-encoding DNA (cDNA cloned into pMT21 expression vector) into 200 ul serum-free media and add 6 ul of Lipofectamine (Gibco). Incubate this solution at room temperature for 15-45 min.  
         [0050]    Wash the cells 2× with PBS. Add 800 ul serum-free media to the tube containing the lipid-DNA complexes. Overlay this solution onto the washed cells.  
         [0051]    Incubate for 6 h. Stop the reaction by adding 1 ml DMA/20% FCS. Refeed cells. Assay cells 12 hr later.  
         [0052]    III. Ligand Binding Assay  
         [0053]    Wash plates of transfected COS cells 1× with cold PBS (plus Ca/Mg)/1% goat serum. Add 1 ml conditioned media neat and incubate 90 min at room temp.  
         [0054]    Wash plates 3× with PBS (plus Ca/Mg). On the 4th wash, add 1 ml 50% methanol to 1 ml PBS. Then add 1 ml methanol. Evacuate and add 1 ml methanol.  
         [0055]    Wash 1× with PBS. Wash 1× PBS/1% goat serum.  
         [0056]    Add secondary antibody (1-to-2,000 anti-human Fc conjugated to alkaline phosphatase (Jackson Lab)) in PBS/1% goat serum. Incubate 30-40 min room temp.  
         [0057]    Wash 3× with PBS. Wash 1× alkaline phosphatase buffer (100 mM Tris-Cl, pH 9.5, 100 mM NaCl, 5 mM MgCl 2 ). Prepare alkaline phosphatase reagents: 4.5 ul/ml NBT and 3.5 ul/ml BCIP (Gibco) in alkaline phosphatase buffer.  
         [0058]    Incubate 10-30 min, quench with 20 mM EDTA in PBS. Cells that have bound Slit polypeptides are visible by the presence of a dark purple reaction product.  
         [0059]    In parallel incubations, positive controls are provided by titrating Slit binding with serial dilutions of the mutant receptor conditioned medium. IV. Results: Binding of Slit to Robo Cell expressing mammalian Slit polypeptides were shown to bind Robo. No reactivity was observed with control COS cells or with receptor-expressing COS cells in the presence of the secondary antibody but in the absence of the Slit-Fc fusion. Binding was observed to receptor-expression cells using a construct in which a Slit polypeptide is fused directly to alkaline phosphatase, for which a secondary antibody is not required. Receptor deletion mutants titrate the Slit-Robo binding, serving as a positive control for inhibition assays.  
         [0060]    Protocol for High Throughput Robo-Slit Binding Assay.  
         [0061]    A. Reagents:  
         [0062]    Neutralite Avidin: 20 μg/ml in PBS.  
         [0063]    Blocking buffer: 5% BSA, 0.5% Tween 20 in PBS; 1 hour at room temperature.  
         [0064]    Assay Buffer: 100 mM KCl, 20 mM HEPES pH 7.6, 1 mM MgCl 2 , 1% glycerol, 0.5% NP-40, 50 nmM β-mercaptoethanol, 1 mg/ml BSA, cocktail of protease inhibitors.  
         [0065]    [0065] 33 P Robo polypeptide 10× stock: 10 −8 -10 −6 M “cold” Robo polypeptide specific Robo domain supplemented with 200,000-250,000 cpm of labeled Robo (Beckman counter). Place in the 4° C. microfridge during screening.  
         [0066]    Protease inhibitor cocktail (1000×): 10 mg Trypsin Inhibitor (BMB # 109894), 10 mg Aprotinin (BMB # 236624), 25 mg Benzamidine (Sigma # B-6506), 25 mg Leupeptin (BMB # 1017128), 10 mg APMSF (BMB # 917575), and 2 mM NaVO 3 (Sigma # S-6508) in 10 ml of PBS.  
         [0067]    Slit: 10 −7 -10 −5  M biotinylated Slit in PBS.  
         [0068]    B. Preparation of Assay Plates:  
         [0069]    Coat with 120 μl of stock N-Avidin per well overnight at 4° C.  
         [0070]    Wash 2 times with 200 μl PBS.  
         [0071]    Block with 150 μl of blocking buffer.  
         [0072]    Wash 2 times with 200 μl PBS.  
         [0073]    C. Assay:  
         [0074]    Add 40 μl assay buffer/well.  
         [0075]    Add 10 μl compound or extract.  
         [0076]    Add 10 μl  33 P-Robo (20-25,000 cpm/0.1-10 pmoles/well=10 −9 -10 −7  M final conc).  
         [0077]    Shake at 25° C. for 15 minutes.  
         [0078]    Incubate additional 45 minutes at 25° C.  
         [0079]    Add 40 μM biotinylated Slit (0.1-10 pmoles/40 ul in assay buffer)  
         [0080]    Incubate 1 hour at room temperature.  
         [0081]    Stop the reaction by washing 4 times with 200 μM PBS.  
         [0082]    Add 150 μM scintillation cocktail.  
         [0083]    Count in Topcount.  
         [0084]    D. Controls for All Assays (Located on Each Plate):  
         [0085]    a. Non-specific binding  
         [0086]    b. Soluble (non-biotinylated Slit) at 80% inhibition.  
         [0087]    All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.  
                     TABLE 1                           Alignment of human Slit-1 (SEQ ID NO:02), human Slit-2 (SEQ ID NOS:03-06), Drosophila       Slit-1 (SEQ ID NO:07),  C. elegans  Slit-1 (SEQ ID NOS:08-09), mouse Slit-2 (SEQ ID NOS:10-       11) and mouse Slit-1 (SEQ ID NOS:12-14).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
 
         [0088]    [0088]                         TABLE 2                           Alignment of human Slit-1 (SEQ ID NO:02) and Drosophila Slit-1 (SEQ ID NO:07)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
         [0089]    [0089] 
     
       
       
         1 
         
           
             20  
           
           
             1  
             4758  
             DNA  
             human  
             
               CDS  
               (1)..(4575)  
             
           
            1 

atg cgc ggc gtt ggc tgg cag atg ctg tcc ctg tcg ctg ggg tta gtg       48 
Met Arg Gly Val Gly Trp Gln Met Leu Ser Leu Ser Leu Gly Leu Val 
  1               5                  10                  15 

ctg gcg atc ctg aac aag gtg gca ccg cag gcg tgc ccg gcg cag tgc       96 
Leu Ala Ile Leu Asn Lys Val Ala Pro Gln Ala Cys Pro Ala Gln Cys 
             20                  25                  30 

tct tgc tcg ggc agc aca gtg gac tgt cac ggg ctg gcg ctg cgc agc      144 
Ser Cys Ser Gly Ser Thr Val Asp Cys His Gly Leu Ala Leu Arg Ser 
         35                  40                  45 

gtg ccc agg aat atc ccc cgc aac acc gag aga ctg gat tta aat gga      192 
Val Pro Arg Asn Ile Pro Arg Asn Thr Glu Arg Leu Asp Leu Asn Gly 
     50                  55                  60 

aat aac atc aca aga att acg aag aca gat ttt gct ggt ctt aga cat      240 
Asn Asn Ile Thr Arg Ile Thr Lys Thr Asp Phe Ala Gly Leu Arg His 
 65                  70                  75                  80 

cta aga gtt ctt cag ctt atg gag aat aag att agc acc att gaa aga      288 
Leu Arg Val Leu Gln Leu Met Glu Asn Lys Ile Ser Thr Ile Glu Arg 
                 85                  90                  95 

gga gca ttc cag gat ctt aaa gaa cta gag aga ctg cgt tta aac aga      336 
Gly Ala Phe Gln Asp Leu Lys Glu Leu Glu Arg Leu Arg Leu Asn Arg 
            100                 105                 110 

aat cac ctt cag ctg ttt cct gag ttg ctg ttt ctt ggg act gcg aag      384 
Asn His Leu Gln Leu Phe Pro Glu Leu Leu Phe Leu Gly Thr Ala Lys 
        115                 120                 125 

cta tac agg ctt gat ctc agt gaa aac caa att cag gca atc cca agg      432 
Leu Tyr Arg Leu Asp Leu Ser Glu Asn Gln Ile Gln Ala Ile Pro Arg 
    130                 135                 140 

aaa gct ttc cgt ggg gca gtt gac ata aaa aat ttg caa ctg gat tac      480 
Lys Ala Phe Arg Gly Ala Val Asp Ile Lys Asn Leu Gln Leu Asp Tyr 
145                 150                 155                 160 

aac cag atc agc tgt att gaa gat ggg gca ttc agg gct ctc cgg gac      528 
Asn Gln Ile Ser Cys Ile Glu Asp Gly Ala Phe Arg Ala Leu Arg Asp 
                165                 170                 175 

ctg gaa gtg ctc act ctc aac aat aac aac att act aga ctt tct gtg      576 
Leu Glu Val Leu Thr Leu Asn Asn Asn Asn Ile Thr Arg Leu Ser Val 
            180                 185                 190 

gca agt ttc aac cat atg cct aaa ctt agg act ttt cga ctg cat tca      624 
Ala Ser Phe Asn His Met Pro Lys Leu Arg Thr Phe Arg Leu His Ser 
        195                 200                 205 

aac aac ctg tat tgt gac tgc cac ctg gcc tgg ctc tcc gac tgg ctt      672 
Asn Asn Leu Tyr Cys Asp Cys His Leu Ala Trp Leu Ser Asp Trp Leu 
    210                 215                 220 

cgc aaa agg cct cgg gtt ggt ctg tac act cag tgt atg ggc ccc tcc      720 
Arg Lys Arg Pro Arg Val Gly Leu Tyr Thr Gln Cys Met Gly Pro Ser 
225                 230                 235                 240 

cac ctg aga ggc cat aat gta gcc gag gtt caa aaa cga gaa ttt gtc      768 
His Leu Arg Gly His Asn Val Ala Glu Val Gln Lys Arg Glu Phe Val 
                245                 250                 255 

tgc agt gat gag gaa gaa ggt cac cag tca ttt atg gct cct tct tgt      816 
Cys Ser Asp Glu Glu Glu Gly His Gln Ser Phe Met Ala Pro Ser Cys 
            260                 265                 270 

agt gtt ttg cac tgc cct gcc gcc tgt acc tgt agc aac aat atc gta      864 
Ser Val Leu His Cys Pro Ala Ala Cys Thr Cys Ser Asn Asn Ile Val 
        275                 280                 285 

gac tgt cgt ggg aaa ggt ctc act gag atc ccc aca aat ctt cca gag      912 
Asp Cys Arg Gly Lys Gly Leu Thr Glu Ile Pro Thr Asn Leu Pro Glu 
    290                 295                 300 

acc atc aca gaa ata cgt ttg gaa cag aac aca atc aaa gtc atc cct      960 
Thr Ile Thr Glu Ile Arg Leu Glu Gln Asn Thr Ile Lys Val Ile Pro 
305                 310                 315                 320 

cct gga gct ttc tca cca tat aaa aag ctt aga cga att gac ctg agc     1008 
Pro Gly Ala Phe Ser Pro Tyr Lys Lys Leu Arg Arg Ile Asp Leu Ser 
                325                 330                 335 

aat aat cag atc tct gaa ctt gca cca gat gct ttc caa gga cta cgc     1056 
Asn Asn Gln Ile Ser Glu Leu Ala Pro Asp Ala Phe Gln Gly Leu Arg 
            340                 345                 350 

tct ctg aat tca ctt gtc ctc tat gga aat aaa atc aca gaa ctc ccc     1104 
Ser Leu Asn Ser Leu Val Leu Tyr Gly Asn Lys Ile Thr Glu Leu Pro 
        355                 360                 365 

aaa agt tta ttt gaa gga ctg ttt tcc tta cag ctc cta tta ttg aat     1152 
Lys Ser Leu Phe Glu Gly Leu Phe Ser Leu Gln Leu Leu Leu Leu Asn 
    370                 375                 380 

gcc aac aag ata aac tgc ctt cgg gta gat gct ttt cag gat ctc cac     1200 
Ala Asn Lys Ile Asn Cys Leu Arg Val Asp Ala Phe Gln Asp Leu His 
385                 390                 395                 400 

aac ttg aac ctt ctc tcc cta tat gac aac aag ctt cag acc atc gcc     1248 
Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys Leu Gln Thr Ile Ala 
                405                 410                 415 

aag ggg acc ttt tca cct ctt cgg gcc att caa act atg cat ttg gcc     1296 
Lys Gly Thr Phe Ser Pro Leu Arg Ala Ile Gln Thr Met His Leu Ala 
            420                 425                 430 

cag aac ccc ttt att tgt gac tgc cat ctc aag tgg cta gcg gat tat     1344 
Gln Asn Pro Phe Ile Cys Asp Cys His Leu Lys Trp Leu Ala Asp Tyr 
        435                 440                 445 

ctc cat acc aac ccg att gag acc agt ggt gcc cgt tgc acc agc ccc     1392 
Leu His Thr Asn Pro Ile Glu Thr Ser Gly Ala Arg Cys Thr Ser Pro 
    450                 455                 460 

cgc cgc ctg gca aac aaa aga att gga cag atc aaa agc aag aaa ttc     1440 
Arg Arg Leu Ala Asn Lys Arg Ile Gly Gln Ile Lys Ser Lys Lys Phe 
465                 470                 475                 480 

cgt tgt tca ggt aca gaa gat tat cga tca aaa tta agt gga gac tgc     1488 
Arg Cys Ser Gly Thr Glu Asp Tyr Arg Ser Lys Leu Ser Gly Asp Cys 
                485                 490                 495 

ttt gcg gat ctg gct tgc cct gaa aag tgt cgc tgt gaa gga acc aca     1536 
Phe Ala Asp Leu Ala Cys Pro Glu Lys Cys Arg Cys Glu Gly Thr Thr 
            500                 505                 510 

gta gat tgc tct aat caa aag ctc aac aaa atc ccg gag cac att ccc     1584 
Val Asp Cys Ser Asn Gln Lys Leu Asn Lys Ile Pro Glu His Ile Pro 
        515                 520                 525 

cag tac act gca gag ttg cgt ctc aat aat aat gaa ttt acc gtg ttg     1632 
Gln Tyr Thr Ala Glu Leu Arg Leu Asn Asn Asn Glu Phe Thr Val Leu 
    530                 535                 540 

gaa gcc aca gga atc ttt aag aaa ctt cct caa tta cgt aaa ata aac     1680 
Glu Ala Thr Gly Ile Phe Lys Lys Leu Pro Gln Leu Arg Lys Ile Asn 
545                 550                 555                 560 

ttt agc aac aat aag atc aca gat att gag gag gga gca ttt gaa gga     1728 
Phe Ser Asn Asn Lys Ile Thr Asp Ile Glu Glu Gly Ala Phe Glu Gly 
                565                 570                 575 

gca tct ggt gta aat gaa ata ctt ctt acg agt aat cgt ttg gaa aat     1776 
Ala Ser Gly Val Asn Glu Ile Leu Leu Thr Ser Asn Arg Leu Glu Asn 
            580                 585                 590 

gtg cag cat aag atg ttc aag gga ttg gaa agc ctc aaa act ttg atg     1824 
Val Gln His Lys Met Phe Lys Gly Leu Glu Ser Leu Lys Thr Leu Met 
        595                 600                 605 

ttg aga agc aat cga ata acc tgt gtg ggg aat gac agt ttc ata gga     1872 
Leu Arg Ser Asn Arg Ile Thr Cys Val Gly Asn Asp Ser Phe Ile Gly 
    610                 615                 620 

ctc agt tct gtg cgt ttg ctt tct ttg tat gat aat caa att act aca     1920 
Leu Ser Ser Val Arg Leu Leu Ser Leu Tyr Asp Asn Gln Ile Thr Thr 
625                 630                 635                 640 

gtt gca cca ggg gca ttt gat act ctc cat tct tta tct act cta aac     1968 
Val Ala Pro Gly Ala Phe Asp Thr Leu His Ser Leu Ser Thr Leu Asn 
                645                 650                 655 

ctc ttg gcc aat cct ttt aac tgt aac tgc tac ctg gct tgg ttg gga     2016 
Leu Leu Ala Asn Pro Phe Asn Cys Asn Cys Tyr Leu Ala Trp Leu Gly 
            660                 665                 670 

gag tgg ctg aga aag aag aga att gtc acg gga aat cct aga tgt caa     2064 
Glu Trp Leu Arg Lys Lys Arg Ile Val Thr Gly Asn Pro Arg Cys Gln 
        675                 680                 685 

aaa cca tac ttc ctg aaa gaa ata ccc atc cag gat gtg gcc att cag     2112 
Lys Pro Tyr Phe Leu Lys Glu Ile Pro Ile Gln Asp Val Ala Ile Gln 
    690                 695                 700 

gac ttc act tgt gat gac gga aat gat gac aat agt tgc tcc cca ctt     2160 
Asp Phe Thr Cys Asp Asp Gly Asn Asp Asp Asn Ser Cys Ser Pro Leu 
705                 710                 715                 720 

tct cgc tgt cct act gaa tgt act tgc ttg gat aca gtc gtc cga tgt     2208 
Ser Arg Cys Pro Thr Glu Cys Thr Cys Leu Asp Thr Val Val Arg Cys 
                725                 730                 735 

agc aac aag ggt ttg aag gtc ttg ccg aaa ggt att cca aga gat gtc     2256 
Ser Asn Lys Gly Leu Lys Val Leu Pro Lys Gly Ile Pro Arg Asp Val 
            740                 745                 750 

aca gag ttg tat ctg gat gga aac caa ttt aca ctg gtt ccc aag gaa     2304 
Thr Glu Leu Tyr Leu Asp Gly Asn Gln Phe Thr Leu Val Pro Lys Glu 
        755                 760                 765 

ctc tcc aac tac aaa cat tta aca ctt ata gac tta agt aac aac aga     2352 
Leu Ser Asn Tyr Lys His Leu Thr Leu Ile Asp Leu Ser Asn Asn Arg 
    770                 775                 780 

ata agc acg ctt tct aat cag agc ttc agc aac atg acc cag ctc ctc     2400 
Ile Ser Thr Leu Ser Asn Gln Ser Phe Ser Asn Met Thr Gln Leu Leu 
785                 790                 795                 800 

acc tta att ctt agt tac aac cgt ctg aga tgt att cct cct cgc acc     2448 
Thr Leu Ile Leu Ser Tyr Asn Arg Leu Arg Cys Ile Pro Pro Arg Thr 
                805                 810                 815 

ttt gat gga tta aag tct ctt cga tta ctt tct cta cat gga aat gac     2496 
Phe Asp Gly Leu Lys Ser Leu Arg Leu Leu Ser Leu His Gly Asn Asp 
            820                 825                 830 

att tct gtt gtg cct gaa ggt gct ttc aat gat ctt tct gca tta tca     2544 
Ile Ser Val Val Pro Glu Gly Ala Phe Asn Asp Leu Ser Ala Leu Ser 
        835                 840                 845 

cat cta gca att gga gcc aac cct ctt tac tgt gat tgt aac atg cag     2592 
His Leu Ala Ile Gly Ala Asn Pro Leu Tyr Cys Asp Cys Asn Met Gln 
    850                 855                 860 

tgg tta tcc gac tgg gtg aag tcg gaa tat aag gag cct gga att gct     2640 
Trp Leu Ser Asp Trp Val Lys Ser Glu Tyr Lys Glu Pro Gly Ile Ala 
865                 870                 875                 880 

cgt tgt gct ggt cct gga gaa atg gca gat aaa ctt tta ctc aca act     2688 
Arg Cys Ala Gly Pro Gly Glu Met Ala Asp Lys Leu Leu Leu Thr Thr 
                885                 890                 895 

ccc tcc aaa aaa ttt acc tgt caa ggt cct gtg gat gtc aat att cta     2736 
Pro Ser Lys Lys Phe Thr Cys Gln Gly Pro Val Asp Val Asn Ile Leu 
            900                 905                 910 

gct aag tgt aac ccc tgc cta tca aat ccg tgt aaa aat gat ggc aca     2784 
Ala Lys Cys Asn Pro Cys Leu Ser Asn Pro Cys Lys Asn Asp Gly Thr 
        915                 920                 925 

tgt aat agt gat cca gtt gac ttt tac cga tgc acc tgt cca tat ggt     2832 
Cys Asn Ser Asp Pro Val Asp Phe Tyr Arg Cys Thr Cys Pro Tyr Gly 
    930                 935                 940 

ttc aag ggg cag gac tgt gat gtc cca att cat gcc tgc atc agt aac     2880 
Phe Lys Gly Gln Asp Cys Asp Val Pro Ile His Ala Cys Ile Ser Asn 
945                 950                 955                 960 

cca tgt aaa cat gga gga act tgc cac tta aag gaa gga gaa gaa gat     2928 
Pro Cys Lys His Gly Gly Thr Cys His Leu Lys Glu Gly Glu Glu Asp 
                965                 970                 975 

gga ttc tgg tgt att tgt gct gat gga ttt gaa gga gaa aat tgt gaa     2976 
Gly Phe Trp Cys Ile Cys Ala Asp Gly Phe Glu Gly Glu Asn Cys Glu 
            980                 985                 990 

gtc aac gtt gat gat tgt gaa gat aat gac tgt gaa aat aat tct aca     3024 
Val Asn Val Asp Asp Cys Glu Asp Asn Asp Cys Glu Asn Asn Ser Thr 
        995                1000                1005 

tgt gtc gat ggc att aat aac tac aca tgc ctt tgc cca cct gag tat     3072 
Cys Val Asp Gly Ile Asn Asn Tyr Thr Cys Leu Cys Pro Pro Glu Tyr 
   1010                1015                1020 

aca ggt gag ttg tgt gag gag aag ctg gac ttc tgt gcc cag gac ctg     3120 
Thr Gly Glu Leu Cys Glu Glu Lys Leu Asp Phe Cys Ala Gln Asp Leu 
1025               1030                1035                1040 

aac ccc tgc cag cac gat tca aag tgc atc cta act cca aag gga ttc     3168 
Asn Pro Cys Gln His Asp Ser Lys Cys Ile Leu Thr Pro Lys Gly Phe 
               1045                1050                1055 

aaa tgt gac tgc aca cca ggg tac gta ggt gaa cac tgc gac atc gat     3216 
Lys Cys Asp Cys Thr Pro Gly Tyr Val Gly Glu His Cys Asp Ile Asp 
           1060                1065                1070 

ttt gac gac tgc caa gac aac aag tgt aaa aac gga gcc cac tgc aca     3264 
Phe Asp Asp Cys Gln Asp Asn Lys Cys Lys Asn Gly Ala His Cys Thr 
       1075                1080                1085 

gat gca gtg aac ggc tat acg tgc ata tgc ccc gaa ggt tac agt ggc     3312 
Asp Ala Val Asn Gly Tyr Thr Cys Ile Cys Pro Glu Gly Tyr Ser Gly 
   1090                1095                1100 

ttg ttc tgt gag ttt tct cca ccc atg gtc ctc cct cgt acc agc ccc     3360 
Leu Phe Cys Glu Phe Ser Pro Pro Met Val Leu Pro Arg Thr Ser Pro 
1105               1110                1115                1120 

tgt gat aat ttt gat tgt cag aat gga gct cag tgt atc gtc aga ata     3408 
Cys Asp Asn Phe Asp Cys Gln Asn Gly Ala Gln Cys Ile Val Arg Ile 
               1125                1130                1135 

aat gag cca ata tgt cag tgt ttg cct ggc tat cag gga gaa aag tgt     3456 
Asn Glu Pro Ile Cys Gln Cys Leu Pro Gly Tyr Gln Gly Glu Lys Cys 
           1140                1145                1150 

gaa aaa ttg gtt agt gtg aat ttt ata aac aaa gag tct tat ctt cag     3504 
Glu Lys Leu Val Ser Val Asn Phe Ile Asn Lys Glu Ser Tyr Leu Gln 
       1155                1160                1165 

att cct tca gcc aag gtt cgg cct cag acg aac ata aca ctt cag att     3552 
Ile Pro Ser Ala Lys Val Arg Pro Gln Thr Asn Ile Thr Leu Gln Ile 
   1170                1175                1180 

gcc aca gat gaa gac agc gga atc ctc ctg tat aag ggt gac aaa gac     3600 
Ala Thr Asp Glu Asp Ser Gly Ile Leu Leu Tyr Lys Gly Asp Lys Asp 
1185               1190                1195                1200 

cat atc gcg gta gaa ctc tat cgg ggg cgt gtt cgt gcc agc tat gac     3648 
His Ile Ala Val Glu Leu Tyr Arg Gly Arg Val Arg Ala Ser Tyr Asp 
               1205                1210                1215 

acc ggc tct cat cca gct tct gcc att tac agt gtg gag aca atc aat     3696 
Thr Gly Ser His Pro Ala Ser Ala Ile Tyr Ser Val Glu Thr Ile Asn 
           1220                1225                1230 

gat gga aac ttc cac att gtg gaa cta ctt gcc ttg gat cag agt ctc     3744 
Asp Gly Asn Phe His Ile Val Glu Leu Leu Ala Leu Asp Gln Ser Leu 
       1235                1240                1245 

tct ttg tcc gtg gat ggt ggg aac ccc aaa atc atc act aac ttg tca     3792 
Ser Leu Ser Val Asp Gly Gly Asn Pro Lys Ile Ile Thr Asn Leu Ser 
   1250                1255                1260 

aag cag tcc act ctg aat ttt gac tct cca ctc tat gta gga ggc atg     3840 
Lys Gln Ser Thr Leu Asn Phe Asp Ser Pro Leu Tyr Val Gly Gly Met 
1265               1270                1275                1280 

cca ggg aag agt aac gtg gca tct ctg cgc cag gcc cct ggg cag aac     3888 
Pro Gly Lys Ser Asn Val Ala Ser Leu Arg Gln Ala Pro Gly Gln Asn 
               1285                1290                1295 

gga acc agc ttc cac ggc tgc atc cgg aac ctt tac atc aac agt gag     3936 
Gly Thr Ser Phe His Gly Cys Ile Arg Asn Leu Tyr Ile Asn Ser Glu 
           1300                1305                1310 

ctg cag gac ttc cag aag gtg ccg atg caa aca ggc att ttg cct ggc     3984 
Leu Gln Asp Phe Gln Lys Val Pro Met Gln Thr Gly Ile Leu Pro Gly 
       1315                1320                1325 

tgt gag cca tgc cac aag aag gtg tgt gcc cat ggc aca tgc cag ccc     4032 
Cys Glu Pro Cys His Lys Lys Val Cys Ala His Gly Thr Cys Gln Pro 
   1330                1335                1340 

agc agc cag gca ggc ttc acc tgc gag tgc cag gaa gga tgg atg ggg     4080 
Ser Ser Gln Ala Gly Phe Thr Cys Glu Cys Gln Glu Gly Trp Met Gly 
1345               1350                1355                1360 

ccc ctc tgt gac caa cgg acc aat gac cct tgc ctt gga aat aaa tgc     4128 
Pro Leu Cys Asp Gln Arg Thr Asn Asp Pro Cys Leu Gly Asn Lys Cys 
               1365                1370                1375 

gta cat ggc acc tgc ttg ccc atc aat gcg ttc tcc tac agc tgt aag     4176 
Val His Gly Thr Cys Leu Pro Ile Asn Ala Phe Ser Tyr Ser Cys Lys 
           1380                1385                1390 

tgc ttg gag ggc cat gga ggt gtc ctc tgt gat gaa gag gag gat ctg     4224 
Cys Leu Glu Gly His Gly Gly Val Leu Cys Asp Glu Glu Glu Asp Leu 
       1395                1400                1405 

ttt aac cca tgc cag gcg atc aag tgc aag cat ggg aag tgc agg ctt     4272 
Phe Asn Pro Cys Gln Ala Ile Lys Cys Lys His Gly Lys Cys Arg Leu 
   1410                1415                1420 

tca ggt ctg ggg cag ccc tac tgt gaa tgc agc agt gga tac acg ggg     4320 
Ser Gly Leu Gly Gln Pro Tyr Cys Glu Cys Ser Ser Gly Tyr Thr Gly 
1425               1430                1435                1440 

gac agc tgt gat cga gaa atc tct tgt cga ggg gaa agg ata aga gat     4368 
Asp Ser Cys Asp Arg Glu Ile Ser Cys Arg Gly Glu Arg Ile Arg Asp 
               1445                1450                1455 

tat tac caa aag cag cag ggc tat gct gct tgc caa aca acc aag aag     4416 
Tyr Tyr Gln Lys Gln Gln Gly Tyr Ala Ala Cys Gln Thr Thr Lys Lys 
           1460                1465                1470 

gtg tcc cga tta gag tgc aga ggt ggg tgt gca gga ggg cag tgc tgt     4464 
Val Ser Arg Leu Glu Cys Arg Gly Gly Cys Ala Gly Gly Gln Cys Cys 
       1475                1480                1485 

gga ccg ctg agg agc aag cgg cgg aaa tac tct ttc gaa tgc act gac     4512 
Gly Pro Leu Arg Ser Lys Arg Arg Lys Tyr Ser Phe Glu Cys Thr Asp 
   1490                1495                1500 

ggc tcc tcc ttt gtg gac gag gtt gag aaa gtg gtg aag tgc ggc tgt     4560 
Gly Ser Ser Phe Val Asp Glu Val Glu Lys Val Val Lys Cys Gly Cys 
1505               1510                1515                1520 

acg agg tgt gtg tcc taaacacact cccggcagct ctgtctttgg aaaaggttgt     4615 
Thr Arg Cys Val Ser 
               1525 

atacttcttg accatgtggg actaatgaat gcttcatagt ggaaatattt gaaatatatt   4675 

gtaaaataca gaacagactt atttttatta tgagaataaa gacttttttt ctgcatttgg   4735 

aaaaaaaaaa aaaaaaaact cga                                           4758 

 
           
             2  
             1525  
             PRT  
             human  
           
            2 

Met Arg Gly Val Gly Trp Gln Met Leu Ser Leu Ser Leu Gly Leu Val 
  1               5                  10                  15 

Leu Ala Ile Leu Asn Lys Val Ala Pro Gln Ala Cys Pro Ala Gln Cys 
             20                  25                  30 

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

Val Pro Arg Asn Ile Pro Arg Asn Thr Glu Arg Leu Asp Leu Asn Gly 
     50                  55                  60 

Asn Asn Ile Thr Arg Ile Thr Lys Thr Asp Phe Ala Gly Leu Arg His 
 65                  70                  75                  80 

Leu Arg Val Leu Gln Leu Met Glu Asn Lys Ile Ser Thr Ile Glu Arg 
                 85                  90                  95 

Gly Ala Phe Gln Asp Leu Lys Glu Leu Glu Arg Leu Arg Leu Asn Arg 
            100                 105                 110 

Asn His Leu Gln Leu Phe Pro Glu Leu Leu Phe Leu Gly Thr Ala Lys 
        115                 120                 125 

Leu Tyr Arg Leu Asp Leu Ser Glu Asn Gln Ile Gln Ala Ile Pro Arg 
    130                 135                 140 

Lys Ala Phe Arg Gly Ala Val Asp Ile Lys Asn Leu Gln Leu Asp Tyr 
145                 150                 155                 160 

Asn Gln Ile Ser Cys Ile Glu Asp Gly Ala Phe Arg Ala Leu Arg Asp 
                165                 170                 175 

Leu Glu Val Leu Thr Leu Asn Asn Asn Asn Ile Thr Arg Leu Ser Val 
            180                 185                 190 

Ala Ser Phe Asn His Met Pro Lys Leu Arg Thr Phe Arg Leu His Ser 
        195                 200                 205 

Asn Asn Leu Tyr Cys Asp Cys His Leu Ala Trp Leu Ser Asp Trp Leu 
    210                 215                 220 

Arg Lys Arg Pro Arg Val Gly Leu Tyr Thr Gln Cys Met Gly Pro Ser 
225                 230                 235                 240 

His Leu Arg Gly His Asn Val Ala Glu Val Gln Lys Arg Glu Phe Val 
                245                 250                 255 

Cys Ser Asp Glu Glu Glu Gly His Gln Ser Phe Met Ala Pro Ser Cys 
            260                 265                 270 

Ser Val Leu His Cys Pro Ala Ala Cys Thr Cys Ser Asn Asn Ile Val 
        275                 280                 285 

Asp Cys Arg Gly Lys Gly Leu Thr Glu Ile Pro Thr Asn Leu Pro Glu 
    290                 295                 300 

Thr Ile Thr Glu Ile Arg Leu Glu Gln Asn Thr Ile Lys Val Ile Pro 
305                 310                 315                 320 

Pro Gly Ala Phe Ser Pro Tyr Lys Lys Leu Arg Arg Ile Asp Leu Ser 
                325                 330                 335 

Asn Asn Gln Ile Ser Glu Leu Ala Pro Asp Ala Phe Gln Gly Leu Arg 
            340                 345                 350 

Ser Leu Asn Ser Leu Val Leu Tyr Gly Asn Lys Ile Thr Glu Leu Pro 
        355                 360                 365 

Lys Ser Leu Phe Glu Gly Leu Phe Ser Leu Gln Leu Leu Leu Leu Asn 
    370                 375                 380 

Ala Asn Lys Ile Asn Cys Leu Arg Val Asp Ala Phe Gln Asp Leu His 
385                 390                 395                 400 

Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys Leu Gln Thr Ile Ala 
                405                 410                 415 

Lys Gly Thr Phe Ser Pro Leu Arg Ala Ile Gln Thr Met His Leu Ala 
            420                 425                 430 

Gln Asn Pro Phe Ile Cys Asp Cys His Leu Lys Trp Leu Ala Asp Tyr 
        435                 440                 445 

Leu His Thr Asn Pro Ile Glu Thr Ser Gly Ala Arg Cys Thr Ser Pro 
    450                 455                 460 

Arg Arg Leu Ala Asn Lys Arg Ile Gly Gln Ile Lys Ser Lys Lys Phe 
465                 470                 475                 480 

Arg Cys Ser Gly Thr Glu Asp Tyr Arg Ser Lys Leu Ser Gly Asp Cys 
                485                 490                 495 

Phe Ala Asp Leu Ala Cys Pro Glu Lys Cys Arg Cys Glu Gly Thr Thr 
            500                 505                 510 

Val Asp Cys Ser Asn Gln Lys Leu Asn Lys Ile Pro Glu His Ile Pro 
        515                 520                 525 

Gln Tyr Thr Ala Glu Leu Arg Leu Asn Asn Asn Glu Phe Thr Val Leu 
    530                 535                 540 

Glu Ala Thr Gly Ile Phe Lys Lys Leu Pro Gln Leu Arg Lys Ile Asn 
545                 550                 555                 560 

Phe Ser Asn Asn Lys Ile Thr Asp Ile Glu Glu Gly Ala Phe Glu Gly 
                565                 570                 575 

Ala Ser Gly Val Asn Glu Ile Leu Leu Thr Ser Asn Arg Leu Glu Asn 
            580                 585                 590 

Val Gln His Lys Met Phe Lys Gly Leu Glu Ser Leu Lys Thr Leu Met 
        595                 600                 605 

Leu Arg Ser Asn Arg Ile Thr Cys Val Gly Asn Asp Ser Phe Ile Gly 
    610                 615                 620 

Leu Ser Ser Val Arg Leu Leu Ser Leu Tyr Asp Asn Gln Ile Thr Thr 
625                 630                 635                 640 

Val Ala Pro Gly Ala Phe Asp Thr Leu His Ser Leu Ser Thr Leu Asn 
                645                 650                 655 

Leu Leu Ala Asn Pro Phe Asn Cys Asn Cys Tyr Leu Ala Trp Leu Gly 
            660                 665                 670 

Glu Trp Leu Arg Lys Lys Arg Ile Val Thr Gly Asn Pro Arg Cys Gln 
        675                 680                 685 

Lys Pro Tyr Phe Leu Lys Glu Ile Pro Ile Gln Asp Val Ala Ile Gln 
    690                 695                 700 

Asp Phe Thr Cys Asp Asp Gly Asn Asp Asp Asn Ser Cys Ser Pro Leu 
705                 710                 715                 720 

Ser Arg Cys Pro Thr Glu Cys Thr Cys Leu Asp Thr Val Val Arg Cys 
                725                 730                 735 

Ser Asn Lys Gly Leu Lys Val Leu Pro Lys Gly Ile Pro Arg Asp Val 
            740                 745                 750 

Thr Glu Leu Tyr Leu Asp Gly Asn Gln Phe Thr Leu Val Pro Lys Glu 
        755                 760                 765 

Leu Ser Asn Tyr Lys His Leu Thr Leu Ile Asp Leu Ser Asn Asn Arg 
    770                 775                 780 

Ile Ser Thr Leu Ser Asn Gln Ser Phe Ser Asn Met Thr Gln Leu Leu 
785                 790                 795                 800 

Thr Leu Ile Leu Ser Tyr Asn Arg Leu Arg Cys Ile Pro Pro Arg Thr 
                805                 810                 815 

Phe Asp Gly Leu Lys Ser Leu Arg Leu Leu Ser Leu His Gly Asn Asp 
            820                 825                 830 

Ile Ser Val Val Pro Glu Gly Ala Phe Asn Asp Leu Ser Ala Leu Ser 
        835                 840                 845 

His Leu Ala Ile Gly Ala Asn Pro Leu Tyr Cys Asp Cys Asn Met Gln 
    850                 855                 860 

Trp Leu Ser Asp Trp Val Lys Ser Glu Tyr Lys Glu Pro Gly Ile Ala 
865                 870                 875                 880 

Arg Cys Ala Gly Pro Gly Glu Met Ala Asp Lys Leu Leu Leu Thr Thr 
                885                 890                 895 

Pro Ser Lys Lys Phe Thr Cys Gln Gly Pro Val Asp Val Asn Ile Leu 
            900                 905                 910 

Ala Lys Cys Asn Pro Cys Leu Ser Asn Pro Cys Lys Asn Asp Gly Thr 
        915                 920                 925 

Cys Asn Ser Asp Pro Val Asp Phe Tyr Arg Cys Thr Cys Pro Tyr Gly 
    930                 935                 940 

Phe Lys Gly Gln Asp Cys Asp Val Pro Ile His Ala Cys Ile Ser Asn 
945                 950                 955                 960 

Pro Cys Lys His Gly Gly Thr Cys His Leu Lys Glu Gly Glu Glu Asp 
                965                 970                 975 

Gly Phe Trp Cys Ile Cys Ala Asp Gly Phe Glu Gly Glu Asn Cys Glu 
            980                 985                 990 

Val Asn Val Asp Asp Cys Glu Asp Asn Asp Cys Glu Asn Asn Ser Thr 
        995                1000                1005 

Cys Val Asp Gly Ile Asn Asn Tyr Thr Cys Leu Cys Pro Pro Glu Tyr 
   1010                1015                1020 

Thr Gly Glu Leu Cys Glu Glu Lys Leu Asp Phe Cys Ala Gln Asp Leu 
1025               1030                1035                1040 

Asn Pro Cys Gln His Asp Ser Lys Cys Ile Leu Thr Pro Lys Gly Phe 
               1045                1050                1055 

Lys Cys Asp Cys Thr Pro Gly Tyr Val Gly Glu His Cys Asp Ile Asp 
           1060                1065                1070 

Phe Asp Asp Cys Gln Asp Asn Lys Cys Lys Asn Gly Ala His Cys Thr 
       1075                1080                1085 

Asp Ala Val Asn Gly Tyr Thr Cys Ile Cys Pro Glu Gly Tyr Ser Gly 
   1090                1095                1100 

Leu Phe Cys Glu Phe Ser Pro Pro Met Val Leu Pro Arg Thr Ser Pro 
1105               1110                1115                1120 

Cys Asp Asn Phe Asp Cys Gln Asn Gly Ala Gln Cys Ile Val Arg Ile 
               1125                1130                1135 

Asn Glu Pro Ile Cys Gln Cys Leu Pro Gly Tyr Gln Gly Glu Lys Cys 
           1140                1145                1150 

Glu Lys Leu Val Ser Val Asn Phe Ile Asn Lys Glu Ser Tyr Leu Gln 
       1155                1160                1165 

Ile Pro Ser Ala Lys Val Arg Pro Gln Thr Asn Ile Thr Leu Gln Ile 
   1170                1175                1180 

Ala Thr Asp Glu Asp Ser Gly Ile Leu Leu Tyr Lys Gly Asp Lys Asp 
1185               1190                1195                1200 

His Ile Ala Val Glu Leu Tyr Arg Gly Arg Val Arg Ala Ser Tyr Asp 
               1205                1210                1215 

Thr Gly Ser His Pro Ala Ser Ala Ile Tyr Ser Val Glu Thr Ile Asn 
           1220                1225                1230 

Asp Gly Asn Phe His Ile Val Glu Leu Leu Ala Leu Asp Gln Ser Leu 
       1235                1240                1245 

Ser Leu Ser Val Asp Gly Gly Asn Pro Lys Ile Ile Thr Asn Leu Ser 
   1250                1255                1260 

Lys Gln Ser Thr Leu Asn Phe Asp Ser Pro Leu Tyr Val Gly Gly Met 
1265               1270                1275                1280 

Pro Gly Lys Ser Asn Val Ala Ser Leu Arg Gln Ala Pro Gly Gln Asn 
               1285                1290                1295 

Gly Thr Ser Phe His Gly Cys Ile Arg Asn Leu Tyr Ile Asn Ser Glu 
           1300                1305                1310 

Leu Gln Asp Phe Gln Lys Val Pro Met Gln Thr Gly Ile Leu Pro Gly 
       1315                1320                1325 

Cys Glu Pro Cys His Lys Lys Val Cys Ala His Gly Thr Cys Gln Pro 
   1330                1335                1340 

Ser Ser Gln Ala Gly Phe Thr Cys Glu Cys Gln Glu Gly Trp Met Gly 
1345               1350                1355                1360 

Pro Leu Cys Asp Gln Arg Thr Asn Asp Pro Cys Leu Gly Asn Lys Cys 
               1365                1370                1375 

Val His Gly Thr Cys Leu Pro Ile Asn Ala Phe Ser Tyr Ser Cys Lys 
           1380                1385                1390 

Cys Leu Glu Gly His Gly Gly Val Leu Cys Asp Glu Glu Glu Asp Leu 
       1395                1400                1405 

Phe Asn Pro Cys Gln Ala Ile Lys Cys Lys His Gly Lys Cys Arg Leu 
   1410                1415                1420 

Ser Gly Leu Gly Gln Pro Tyr Cys Glu Cys Ser Ser Gly Tyr Thr Gly 
1425               1430                1435                1440 

Asp Ser Cys Asp Arg Glu Ile Ser Cys Arg Gly Glu Arg Ile Arg Asp 
               1445                1450                1455 

Tyr Tyr Gln Lys Gln Gln Gly Tyr Ala Ala Cys Gln Thr Thr Lys Lys 
           1460                1465                1470 

Val Ser Arg Leu Glu Cys Arg Gly Gly Cys Ala Gly Gly Gln Cys Cys 
       1475                1480                1485 

Gly Pro Leu Arg Ser Lys Arg Arg Lys Tyr Ser Phe Glu Cys Thr Asp 
   1490                1495                1500 

Gly Ser Ser Phe Val Asp Glu Val Glu Lys Val Val Lys Cys Gly Cys 
1505               1510                1515                1520 

Thr Arg Cys Val Ser 
               1525 

 
           
             3  
             105  
             PRT  
             human  
           
            3 

Ser Pro Cys Thr Cys Ser Asn Asn Ile Val Asp Cys Arg Gly Lys Gly 
  1               5                  10                  15 

Leu Met Glu Ile Pro Ala Asn Leu Pro Glu Gly Ile Val Glu Ile Arg 
             20                  25                  30 

Leu Glu Gln Asn Ser Ile Lys Ala Ile Pro Ala Gly Ala Phe Thr Gln 
         35                  40                  45 

Tyr Lys Lys Leu Lys Arg Ile Asp Ile Ser Lys Asn Gln Ile Ser Asp 
     50                  55                  60 

Ile Ala Pro Asp Ala Phe Gln Gly Leu Lys Ser Leu Thr Ser Leu Val 
 65                  70                  75                  80 

Leu Tyr Gly Asn Lys Ile Thr Glu Ile Ala Lys Gly Leu Phe Asp Gly 
                 85                  90                  95 

Leu Val Ser Leu Gln Leu Leu Leu Leu 
            100                 105 

 
           
             4  
             138  
             PRT  
             human  
           
            4 

Glu Gly Ala Phe Asn Gly Ala Ala Ser Val Gln Glu Leu Met Leu Thr 
  1               5                  10                  15 

Gly Asn Gln Leu Glu Thr Val His Gly Arg Gly Phe Arg Gly Gly Leu 
             20                  25                  30 

Ser Gly Leu Lys Thr Leu Met Leu Arg Ser Asn Leu Ile Gly Cys Val 
         35                  40                  45 

Ser Asn Asp Thr Phe Ala Gly Leu Ser Ser Val Arg Leu Leu Ser Leu 
     50                  55                  60 

Tyr Asp Asn Arg Ile Thr Thr Ile Thr Pro Gly Ala Phe Thr Thr Leu 
 65                  70                  75                  80 

Val Ser Leu Ser Thr Ile Asn Leu Leu Ser Asn Pro Phe Asn Cys Asn 
                 85                  90                  95 

Cys His Leu Gly Ala Gly Leu Gly Lys Trp Leu Arg Lys Arg Arg Ile 
            100                 105                 110 

Val Ser Gly Asn Pro Arg Cys Gln Lys Pro Phe Phe Leu Lys Glu Ile 
        115                 120                 125 

Pro Ile Gln Gly Val Gly His Pro Gly Ile 
    130                 135 

 
           
             5  
             160  
             PRT  
             human  
             
               misc_feature  
               (121)..(150)  
               note=“Xaa signifies gap in sequence” 
             
           
            5 

Trp Pro Arg Cys Glu Cys Met Pro Gly Tyr Ala Gly Asp Asn Cys Ser 
  1               5                  10                  15 

Glu Asn Gln Asp Asp Cys Arg Asp His Arg Cys Gln Asn Gly Ala Gln 
             20                  25                  30 

Cys Met Asp Glu Val Asn Ser Tyr Ser Cys Leu Cys Ala Glu Gly Tyr 
         35                  40                  45 

Ser Gly Gln Leu Cys Glu Ile Pro Pro His Leu Pro Ala Pro Lys Ser 
     50                  55                  60 

Pro Cys Glu Gly Thr Glu Cys Gln Asn Gly Ala Asn Cys Val Asp Gln 
 65                  70                  75                  80 

Gly Asn Arg Pro Val Cys Gln Cys Leu Pro Gly Phe Gly Gly Pro Glu 
                 85                  90                  95 

Cys Glu Lys Leu Leu Ser Val Asn Phe Val Asp Arg Asp Thr Tyr Leu 
            100                 105                 110 

Gln Phe Thr Asp Leu Gln Asn Trp Xaa Arg Xaa Asn Ile Thr Leu Gln 
        115                 120                 125 

Val Phe Thr Ala Glu Asp Asn Gly Ile Leu Leu Tyr Asn Gly Gly Asn 
    130                 135                 140 

Asp His Ile Ala Val Xaa Leu Tyr Xaa Gly His Val Arg Phe Ser Tyr 
145                 150                 155                 160 

 
           
             6  
             103  
             PRT  
             human  
           
            6 

Gln Cys His Ile Ser Asp Gln Gly Glu Pro Tyr Cys Leu Cys Gln Pro 
  1               5                  10                  15 

Gly Phe Ser Gly Glu His Cys Gln Gln Glu Asn Pro Cys Leu Gly Gln 
             20                  25                  30 

Val Val Arg Glu Val Ile Arg Arg Gln Lys Gly Tyr Ala Ser Cys Ala 
         35                  40                  45 

Thr Ala Ser Lys Val Pro Ile Met Glu Cys Arg Gly Gly Cys Gly Pro 
     50                  55                  60 

Gln Cys Cys Gln Pro Thr Arg Ser Lys Arg Arg Lys Tyr Val Phe Gln 
 65                  70                  75                  80 

Cys Thr Asp Gly Ser Ser Phe Val Glu Glu Val Glu Arg His Leu Glu 
                 85                  90                  95 

Cys Gly Cys Leu Ala Cys Ser 
            100 

 
           
             7  
             1480  
             PRT  
             Drosophila melanogaster  
           
            7 

Met Ala Ala Pro Ser Arg Thr Thr Leu Met Pro Pro Pro Phe Arg Leu 
  1               5                  10                  15 

Gln Leu Arg Leu Leu Ile Leu Pro Ile Leu Leu Leu Leu Arg His Asp 
             20                  25                  30 

Ala Val His Ala Glu Pro Tyr Ser Gly Gly Phe Gly Ser Ser Ala Val 
         35                  40                  45 

Ser Ser Gly Gly Leu Gly Ser Val Gly Ile His Ile Pro Gly Gly Gly 
     50                  55                  60 

Val Gly Val Ile Thr Glu Ala Arg Cys Pro Arg Val Cys Ser Cys Thr 
 65                  70                  75                  80 

Gly Leu Asn Val Asp Cys Ser His Arg Gly Leu Thr Ser Val Pro Arg 
                 85                  90                  95 

Lys Ile Ser Ala Asp Val Glu Arg Leu Glu Leu Gln Gly Asn Asn Leu 
            100                 105                 110 

Thr Val Ile Tyr Glu Thr Asp Phe Gln Arg Leu Thr Lys Leu Arg Met 
        115                 120                 125 

Leu Gln Leu Thr Asp Asn Gln Ile His Thr Ile Glu Arg Asn Ser Phe 
    130                 135                 140 

Gln Asp Leu Val Ser Leu Glu Arg Leu Asp Ile Ser Asn Asn Val Ile 
145                 150                 155                 160 

Thr Thr Val Gly Arg Arg Val Phe Lys Gly Ala Gln Ser Leu Arg Ser 
                165                 170                 175 

Leu Gln Leu Asp Asn Asn Gln Ile Thr Cys Leu Asp Glu His Ala Phe 
            180                 185                 190 

Lys Gly Leu Val Glu Leu Glu Ile Leu Thr Leu Asn Asn Asn Asn Leu 
        195                 200                 205 

Thr Ser Leu Pro His Asn Ile Phe Gly Gly Leu Gly Arg Leu Arg Ala 
    210                 215                 220 

Leu Arg Leu Ser Asp Asn Pro Phe Ala Cys Asp Cys His Leu Ser Trp 
225                 230                 235                 240 

Leu Ser Arg Phe Leu Arg Ser Ala Thr Arg Leu Ala Pro Tyr Thr Arg 
                245                 250                 255 

Cys Gln Ser Pro Ser Gln Leu Lys Gly Gln Asn Val Ala Asp Leu His 
            260                 265                 270 

Asp Gln Glu Phe Lys Cys Ser Gly Leu Thr Glu His Ala Pro Met Glu 
        275                 280                 285 

Cys Gly Ala Glu Asn Ser Cys Pro His Pro Cys Arg Cys Ala Asp Gly 
    290                 295                 300 

Ile Val Asp Cys Arg Glu Lys Ser Leu Thr Ser Val Pro Val Thr Leu 
305                 310                 315                 320 

Pro Asp Asp Thr Thr Asp Val Arg Leu Glu Gln Asn Phe Ile Thr Glu 
                325                 330                 335 

Leu Pro Pro Lys Ser Phe Ser Ser Phe Arg Arg Leu Arg Arg Ile Asp 
            340                 345                 350 

Leu Ser Asn Asn Asn Ile Ser Arg Ile Ala His Asp Ala Leu Ser Gly 
        355                 360                 365 

Leu Lys Gln Leu Thr Thr Leu Val Leu Tyr Gly Asn Lys Ile Lys Asp 
    370                 375                 380 

Leu Pro Ser Gly Val Phe Lys Gly Leu Gly Ser Leu Arg Leu Leu Leu 
385                 390                 395                 400 

Leu Asn Ala Asn Glu Ile Ser Cys Ile Arg Lys Asp Ala Phe Arg Asp 
                405                 410                 415 

Leu His Ser Leu Ser Leu Leu Ser Leu Tyr Asp Asn Asn Ile Gln Ser 
            420                 425                 430 

Leu Ala Asn Gly Thr Phe Asp Ala Met Lys Ser Met Lys Thr Val His 
        435                 440                 445 

Leu Ala Lys Asn Pro Phe Ile Cys Asp Cys Asn Leu Arg Trp Leu Ala 
    450                 455                 460 

Asp Tyr Leu His Lys Asn Pro Ile Glu Thr Ser Gly Ala Arg Cys Glu 
465                 470                 475                 480 

Ser Pro Lys Arg Met His Arg Arg Arg Ile Glu Ser Leu Arg Glu Glu 
                485                 490                 495 

Lys Phe Lys Cys Ser Trp Gly Glu Leu Arg Met Lys Leu Ser Gly Glu 
            500                 505                 510 

Cys Arg Met Asp Ser Asp Cys Pro Ala Met Cys His Cys Glu Gly Thr 
        515                 520                 525 

Thr Val Asp Cys Thr Gly Arg Arg Leu Lys Glu Ile Pro Arg Asp Ile 
    530                 535                 540 

Pro Leu His Thr Thr Glu Leu Leu Leu Asn Asp Asn Glu Leu Gly Arg 
545                 550                 555                 560 

Ile Ser Ser Asp Gly Leu Phe Gly Arg Leu Pro His Leu Val Lys Leu 
                565                 570                 575 

Glu Leu Lys Arg Asn Gln Leu Thr Gly Ile Glu Pro Asn Ala Phe Glu 
            580                 585                 590 

Gly Ala Ser His Ile Gln Glu Leu Gln Leu Gly Glu Asn Lys Ile Lys 
        595                 600                 605 

Glu Ile Ser Asn Lys Met Phe Leu Gly Leu His Gln Leu Lys Thr Leu 
    610                 615                 620 

Asn Leu Tyr Asp Asn Gln Ile Ser Cys Val Met Pro Gly Ser Phe Glu 
625                 630                 635                 640 

His Leu Asn Ser Leu Thr Ser Leu Asn Leu Ala Ser Asn Pro Phe Asn 
                645                 650                 655 

Cys Asn Cys His Leu Ala Trp Phe Ala Glu Cys Val Arg Lys Lys Ser 
            660                 665                 670 

Leu Asn Gly Gly Ala Ala Arg Cys Gly Ala Pro Ser Lys Val Arg Asp 
        675                 680                 685 

Val Gln Ile Lys Asp Leu Pro His Ser Glu Phe Lys Cys Ser Ser Glu 
    690                 695                 700 

Asn Ser Glu Gly Cys Leu Gly Asp Gly Tyr Cys Pro Pro Ser Cys Thr 
705                 710                 715                 720 

Cys Thr Gly Thr Val Val Ala Cys Ser Arg Asn Gln Leu Lys Glu Ile 
                725                 730                 735 

Pro Arg Gly Ile Pro Ala Glu Thr Ser Glu Leu Tyr Leu Glu Ser Asn 
            740                 745                 750 

Glu Ile Glu Gln Ile His Tyr Glu Arg Ile Arg His Leu Arg Ser Leu 
        755                 760                 765 

Thr Arg Leu Asp Leu Ser Asn Asn Gln Ile Thr Ile Leu Ser Asn Tyr 
    770                 775                 780 

Thr Phe Ala Asn Leu Thr Lys Leu Ser Thr Leu Ile Ile Ser Tyr Asn 
785                 790                 795                 800 

Lys Leu Gln Cys Leu Gln Arg His Ala Leu Ser Gly Leu Asn Asn Leu 
                805                 810                 815 

Arg Val Val Ser Leu His Gly Asn Arg Ile Ser Met Leu Pro Glu Gly 
            820                 825                 830 

Ser Phe Glu Asp Leu Lys Ser Leu Thr His Ile Ala Leu Gly Ser Asn 
        835                 840                 845 

Pro Leu Tyr Cys Asp Cys Gly Leu Lys Trp Phe Ser Asp Trp Ile Lys 
    850                 855                 860 

Leu Asp Tyr Val Glu Pro Gly Ile Ala Arg Cys Ala Glu Pro Glu Gln 
865                 870                 875                 880 

Met Lys Asp Lys Leu Ile Leu Ser Thr Pro Ser Ser Ser Phe Val Cys 
                885                 890                 895 

Arg Gly Arg Val Arg Asn Asp Ile Leu Ala Lys Cys Asn Ala Cys Phe 
            900                 905                 910 

Glu Gln Pro Cys Gln Asn Gln Ala Gln Cys Val Ala Leu Pro Gln Arg 
        915                 920                 925 

Glu Tyr Gln Cys Leu Cys Gln Pro Gly Tyr His Gly Lys His Cys Glu 
    930                 935                 940 

Phe Met Ile Asp Ala Cys Tyr Gly Asn Pro Cys Arg Asn Asn Ala Thr 
945                 950                 955                 960 

Cys Thr Val Leu Glu Glu Gly Arg Phe Ser Cys Gln Cys Ala Pro Gly 
                965                 970                 975 

Tyr Thr Gly Ala Arg Cys Glu Thr Asn Ile Asp Asp Cys Leu Gly Glu 
            980                 985                 990 

Ile Lys Cys Gln Asn Asn Ala Thr Cys Ile Asp Gly Val Glu Ser Tyr 
        995                1000                1005 

Lys Cys Glu Cys Gln Pro Gly Phe Ser Gly Glu Phe Cys Asp Thr Lys 
   1010                1015                1020 

Ile Gln Phe Cys Ser Pro Glu Phe Asn Pro Cys Ala Asn Gly Ala Lys 
1025               1030                1035                1040 

Cys Met Asp His Phe Thr His Tyr Ser Cys Asp Cys Gln Ala Gly Phe 
               1045                1050                1055 

His Gly Thr Asn Cys Thr Asp Asn Ile Asp Asp Cys Gln Asn His Met 
           1060                1065                1070 

Cys Gln Asn Gly Gly Thr Cys Val Asp Gly Ile Asn Asp Tyr Gln Cys 
       1075                1080                1085 

Arg Cys Pro Asp Asp Tyr Thr Gly Lys Tyr Cys Glu Gly His Asn Met 
   1090                1095                1100 

Ile Ser Met Met Tyr Pro Gln Thr Ser Pro Cys Gln Asn His Glu Cys 
1105               1110                1115                1120 

Lys His Gly Val Cys Phe Gln Pro Asn Ala Gln Gly Ser Asp Tyr Leu 
               1125                1130                1135 

Cys Arg Cys His Pro Gly Tyr Thr Gly Lys Trp Cys Glu Tyr Leu Thr 
           1140                1145                1150 

Ser Ile Ser Phe Val His Asn Asn Ser Phe Val Glu Leu Glu Pro Leu 
       1155                1160                1165 

Arg Thr Arg Pro Glu Ala Asn Val Thr Ile Val Phe Ser Ser Ala Glu 
   1170                1175                1180 

Gln Asn Gly Ile Leu Met Tyr Asp Gly Gln Asp Ala His Leu Ala Val 
1185               1190                1195                1200 

Glu Leu Phe Asn Gly Arg Ile Arg Val Ser Tyr Asp Val Gly Asn His 
               1205                1210                1215 

Pro Val Ser Thr Met Tyr Ser Phe Glu Met Val Ala Asp Gly Lys Tyr 
           1220                1225                1230 

His Ala Val Glu Leu Leu Ala Ile Lys Lys Asn Phe Thr Leu Arg Val 
       1235                1240                1245 

Asp Arg Gly Leu Ala Arg Ser Ile Ile Asn Glu Gly Ser Asn Asp Tyr 
   1250                1255                1260 

Leu Lys Leu Thr Thr Pro Met Phe Leu Gly Gly Leu Pro Val Asp Pro 
1265               1270                1275                1280 

Ala Gln Gln Ala Tyr Lys Asn Trp Gln Ile Arg Asn Leu Thr Ser Phe 
               1285                1290                1295 

Lys Gly Cys Met Lys Glu Val Trp Ile Asn His Lys Leu Val Asp Phe 
           1300                1305                1310 

Gly Asn Ala Gln Arg Gln Gln Lys Ile Thr Pro Gly Cys Ala Leu Leu 
       1315                1320                1325 

Glu Gly Glu Gln Gln Glu Glu Glu Asp Asp Glu Gln Asp Phe Met Asp 
   1330                1335                1340 

Glu Thr Pro His Ile Lys Glu Glu Pro Val Asp Pro Cys Leu Glu Asn 
1345               1350                1355                1360 

Lys Cys Arg Arg Gly Ser Arg Cys Val Pro Asn Ser Asn Ala Arg Asp 
               1365                1370                1375 

Gly Tyr Gln Cys Lys Cys Lys His Gly Gln Arg Gly Arg Tyr Cys Asp 
           1380                1385                1390 

Gln Gly Glu Gly Ser Thr Glu Pro Pro Thr Val Thr Ala Ala Ser Thr 
       1395                1400                1405 

Cys Arg Lys Glu Gln Val Arg Glu Tyr Tyr Thr Glu Asn Asp Cys Arg 
   1410                1415                1420 

Ser Arg Gln Pro Leu Lys Tyr Ala Lys Cys Val Gly Gly Cys Gly Asn 
1425               1430                1435                1440 

Gln Cys Cys Ala Ala Lys Ile Val Arg Arg Arg Lys Val Arg Met Val 
               1445                1450                1455 

Cys Ser Asn Asn Arg Lys Tyr Ile Lys Asn Leu Asp Ile Val Arg Lys 
           1460                1465                1470 

Cys Gly Cys Thr Lys Lys Cys Tyr 
       1475                1480 

 
           
             8  
             155  
             PRT  
             Caenorhabditis elegans  
             
               misc_feature  
               (4)..(152)  
               note=“Xaa signifies gap in sequence” 
             
           
            8 

Arg Asn Pro Xaa Ile Cys Asp Cys Asn Leu Gln Trp Leu Ala Gln Ile 
  1               5                  10                  15 

Asn Leu Gln Lys Asn Ile Glu Thr Ser Gly Ala Arg Cys Glu Gln Pro 
             20                  25                  30 

Lys Arg Leu Arg Lys Lys Lys Phe Ala Thr Leu Pro Pro Asn Lys Phe 
         35                  40                  45 

Lys Cys Lys Gly Ser Glu Ser Phe Val Ser Met Tyr Ala Asp Ser Cys 
     50                  55                  60 

Phe Ile Asp Ser Ile Cys Pro Thr Gln Cys Asp Cys Tyr Gly Thr Thr 
 65                  70                  75                  80 

Val Asp Cys Asn Lys Arg Gly Leu Asn Thr Ile Pro Thr Ser Ile Pro 
                 85                  90                  95 

Arg Phe Ala Thr Gln Leu Leu Leu Ser Gly Asn Asn Ile Ser Thr Val 
            100                 105                 110 

Asp Leu Asn Ser Asn Ile His Val Leu Glu Asn Leu Glu Xaa Leu Asp 
        115                 120                 125 

Leu Ser Asn Asn His Ile Thr Phe Ile Asn Asp Lys Ser Phe Glu Lys 
    130                 135                 140 

Leu Ser Lys Leu Arg Glu Leu Xaa Leu Asn Asp 
145                 150                 155 

 
           
             9  
             735  
             PRT  
             Caenorhabditis elegans  
           
            9 

Ser Asn Lys Asn Leu Thr Ser Phe Pro Ser Arg Ile Pro Phe Asp Thr 
  1               5                  10                  15 

Thr Glu Leu Tyr Leu Asp Ala Asn Tyr Ile Asn Glu Ile Pro Ala His 
             20                  25                  30 

Asp Leu Asn Arg Leu Tyr Ser Leu Thr Lys Leu Asp Leu Ser His Asn 
         35                  40                  45 

Arg Leu Ile Ser Leu Glu Asn Asn Thr Phe Ser Asn Leu Thr Arg Leu 
     50                  55                  60 

Ser Thr Leu Ile Ile Ser Tyr Asn Lys Leu Arg Cys Leu Gln Pro Leu 
 65                  70                  75                  80 

Ala Phe Asn Gly Leu Asn Ala Leu Arg Ile Leu Ser Leu His Gly Asn 
                 85                  90                  95 

Asp Ile Ser Phe Leu Pro Gln Ser Ala Phe Ser Asn Leu Thr Ser Ile 
            100                 105                 110 

Thr His Ile Ala Val Gly Ser Asn Ser Leu Tyr Cys Asp Cys Asn Met 
        115                 120                 125 

Ala Trp Phe Ser Lys Trp Ile Lys Ser Lys Phe Ile Glu Ala Gly Ile 
    130                 135                 140 

Ala Arg Cys Glu Tyr Pro Asn Thr Val Ser Asn Gln Leu Leu Leu Thr 
145                 150                 155                 160 

Ala Gln Pro Tyr Gln Phe Thr Cys Asp Ser Lys Val Pro Thr Lys Leu 
                165                 170                 175 

Ala Thr Lys Cys Asp Leu Cys Leu Asn Ser Pro Cys Lys Asn Asn Ala 
            180                 185                 190 

Ile Cys Glu Thr Thr Ser Ser Arg Lys Tyr Thr Cys Asn Cys Thr Pro 
        195                 200                 205 

Gly Phe Tyr Gly Val His Cys Glu Asn Gln Ile Asp Ala Cys Tyr Gly 
    210                 215                 220 

Ser Pro Cys Leu Asn Asn Ala Thr Cys Lys Val Ala Gln Ala Gly Arg 
225                 230                 235                 240 

Phe Asn Cys Tyr Cys Asn Lys Gly Phe Glu Gly Asp Tyr Cys Glu Lys 
                245                 250                 255 

Asn Ile Asp Asp Cys Val Asn Ser Lys Cys Glu Asn Gly Gly Lys Cys 
            260                 265                 270 

Val Asp Leu Val Arg Phe Cys Ser Glu Glu Leu Lys Asn Phe Gln Ser 
        275                 280                 285 

Phe Gln Ile Asn Ser Tyr Arg Cys Asp Cys Pro Met Glu Tyr Glu Gly 
    290                 295                 300 

Lys His Cys Glu Asp Lys Leu Glu Tyr Cys Thr Lys Lys Leu Asn Pro 
305                 310                 315                 320 

Cys Glu Asn Asn Gly Lys Cys Ile Pro Ile Asn Gly Ser Tyr Ser Cys 
                325                 330                 335 

Met Cys Ser Pro Gly Phe Thr Gly Asn Asn Cys Glu Thr Asn Ile Asp 
            340                 345                 350 

Asp Cys Lys Asn Val Glu Cys Gln Asn Gly Gly Ser Cys Val Asp Gly 
        355                 360                 365 

Ile Leu Ser Tyr Asp Cys Leu Cys Arg Pro Gly Tyr Ala Gly Gln Tyr 
    370                 375                 380 

Cys Glu Ile Pro Pro Met Met Asp Met Glu Tyr Gln Lys Thr Asp Ala 
385                 390                 395                 400 

Cys Gln Gln Ser Ala Cys Gly Gln Gly Glu Cys Val Ala Ser Gln Asn 
                405                 410                 415 

Ser Ser Asp Phe Thr Cys Lys Cys His Glu Gly Phe Ser Gly Pro Ser 
            420                 425                 430 

Cys Asp Arg Gln Met Ser Val Gly Phe Lys Asn Pro Gly Ala Tyr Leu 
        435                 440                 445 

Ala Leu Asp Pro Leu Ala Ser Asp Gly Thr Ile Thr Met Thr Leu Arg 
    450                 455                 460 

Thr Thr Ser Lys Ile Gly Ile Leu Leu Tyr Tyr Gly Asp Asp His Phe 
465                 470                 475                 480 

Val Ser Ala Glu Leu Tyr Asp Gly Arg Val Lys Leu Val Tyr Tyr Ile 
                485                 490                 495 

Gly Asn Phe Pro Ala Ser His Met Tyr Ser Ser Val Lys Val Asn Asp 
            500                 505                 510 

Gly Leu Pro His Arg Ile Ser Ile Arg Thr Ser Glu Arg Lys Cys Phe 
        515                 520                 525 

Leu Gln Ile Asp Lys Asn Pro Val Gln Ile Val Glu Asn Ser Gly Lys 
    530                 535                 540 

Ser Asp Gln Leu Ile Thr Lys Gly Lys Glu Met Leu Tyr Ile Gly Gly 
545                 550                 555                 560 

Leu Pro Ile Glu Lys Ser Gln Asp Ala Lys Arg Arg Phe His Val Lys 
                565                 570                 575 

Asn Ser Glu Ser Leu Lys Gly Cys Ile Ser Ser Ile Thr Ile Asn Glu 
            580                 585                 590 

Val Pro Ile Asn Leu Gln Gln Ala Leu Glu Asn Val Asn Thr Glu Gln 
        595                 600                 605 

Ser Cys Ser Ala Thr Val Asn Phe Cys Ala Gly Ile Asp Cys Gly Asn 
    610                 615                 620 

Gly Lys Cys Thr Asn Asn Ala Leu Ser Pro Lys Gly Tyr Met Cys Gln 
625                 630                 635                 640 

Cys Asp Ser His Phe Ser Gly Glu His Cys Asp Glu Lys Arg Ile Lys 
                645                 650                 655 

Cys Asp Lys Gln Lys Phe Arg Arg His His Ile Glu Asn Glu Cys Arg 
            660                 665                 670 

Ser Val Asp Arg Ile Lys Ile Ala Glu Cys Asn Gly Tyr Cys Gly Gly 
        675                 680                 685 

Glu Gln Asn Cys Cys Thr Ala Val Lys Lys Lys Gln Arg Lys Val Lys 
    690                 695                 700 

Met Ile Cys Lys Asn Gly Thr Thr Lys Ile Ser Thr Val His Ile Ile 
705                 710                 715                 720 

Arg Gln Cys Gln Cys Glu Pro Thr Lys Ser Val Leu Ser Glu Lys 
                725                 730                 735 

 
           
             10  
             154  
             PRT  
             mouse  
           
            10 

Asp Pro Leu Pro Val His His Arg Cys Glu Cys Met Leu Gly Tyr Thr 
  1               5                  10                  15 

Gly Asp Asn Cys Ser Glu Asn Gln Asp Asp Cys Lys Asp His Lys Cys 
             20                  25                  30 

Gln Asn Gly Ala Gln Cys Val Asp Glu Val Asn Ser Tyr Ala Cys Leu 
         35                  40                  45 

Cys Val Glu Gly Tyr Ser Gly Gln Leu Cys Glu Ile Pro Pro Ala Pro 
     50                  55                  60 

Arg Ser Ser Cys Glu Gly Thr Glu Cys Gln Asn Gly Ala Asn Cys Val 
 65                  70                  75                  80 

Asp Gln Gly Ser Arg Pro Val Cys Gln Cys Leu Pro Gly Phe Gly Gly 
                 85                  90                  95 

Pro Glu Cys Glu Lys Leu Leu Ser Val Asn Phe Val Asp Arg Asp Thr 
            100                 105                 110 

Tyr Leu Gln Phe Thr Asp Leu Gln Asn Trp Pro Arg Ala Asn Ile Thr 
        115                 120                 125 

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

Asp Asn Asp His Ile Ala Val Glu Leu Tyr 
145                 150 

 
           
             11  
             110  
             PRT  
             mouse  
           
            11 

Ala Phe Lys Cys His His Gly Gln Cys His Ile Ser Asp Arg Gly Glu 
  1               5                  10                  15 

Pro Tyr Cys Leu Cys Gln Pro Gly Phe Ser Gly His His Cys Glu Gln 
             20                  25                  30 

Glu Asn Pro Cys Met Gly Glu Ile Val Arg Glu Ala Ile Arg Arg Gln 
         35                  40                  45 

Lys Asp Tyr Ala Ser Cys Ala Thr Ala Ser Lys Val Pro Ile Met Glu 
     50                  55                  60 

Cys Arg Gly Gly Cys Gly Thr Thr Cys Cys Gln Pro Ile Arg Ser Lys 
 65                  70                  75                  80 

Arg Arg Lys Tyr Val Phe Gln Cys Thr Asp Gly Ser Ser Phe Val Glu 
                 85                  90                  95 

Glu Val Glu Arg His Leu Glu Cys Gly Cys Arg Ala Cys Ser 
            100                 105                 110 

 
           
             12  
             134  
             PRT  
             mouse  
           
            12 

His Leu Arg Val Leu Gln Leu Met Glu Asn Arg Ile Ser Thr Ile Glu 
  1               5                  10                  15 

Arg Gly Ala Phe Gln Asp Leu Lys Glu Leu Glu Arg Leu Arg Leu Asn 
             20                  25                  30 

Arg Asn Asn Leu Gln Leu Phe Pro Glu Leu Leu Phe Leu Gly Thr Ala 
         35                  40                  45 

Arg Leu Tyr Arg Leu Asp Leu Ser Glu Asn Gln Ile Gln Ala Ile Pro 
     50                  55                  60 

Arg Lys Ala Phe Arg Gly Ala Val Asp Ile Lys Asn Leu Gln Leu Asp 
 65                  70                  75                  80 

Tyr Asn Gln Ile Ser Cys Ile Glu Asp Gly Ala Phe Arg Ala Leu Arg 
                 85                  90                  95 

Asp Leu Glu Val Leu Thr Leu Asn Asn Asn Asn Ile Thr Arg Leu Ser 
            100                 105                 110 

Val Ala Ser Phe Asn His Met Pro Lys Leu Arg Thr Phe Arg Leu His 
        115                 120                 125 

Ser Asn Asn Leu Tyr Cys 
    130 

 
           
             13  
             104  
             PRT  
             mouse  
           
            13 

Asn Asn Asp Asp Cys Val Gly His Lys Cys Arg His Gly Ala Gln Cys 
  1               5                  10                  15 

Val Asp Glu Val Asn Gly Tyr Thr Cys Ile Cys Pro Gln Gly Phe Ser 
             20                  25                  30 

Gly Leu Phe Cys Glu His Pro Pro Pro Met Val Leu Leu Gln Thr Ser 
         35                  40                  45 

Pro Cys Asp Gln Tyr Glu Cys Gln Asn Gly Ala Gln Cys Ile Val Val 
     50                  55                  60 

Gln Gln Glu Pro Thr Cys Arg Cys Pro Pro Gly Phe Ala Gly Pro Arg 
 65                  70                  75                  80 

Cys Glu Lys Leu Ile Thr Val Asn Phe Val Gly Lys Asp Ser Tyr Val 
                 85                  90                  95 

Glu Leu Ala Ser Ala Lys Val Arg 
            100 

 
           
             14  
             243  
             PRT  
             mouse  
           
            14 

Ile Leu Asp Val Ala Ser Leu Arg Gln Ala Pro Gly Glu Asn Gly Thr 
  1               5                  10                  15 

Ser Phe His Gly Cys Ile Arg Asn Leu Tyr Ile Asn Ser Glu Leu Gln 
             20                  25                  30 

Asp Phe Arg Lys Met Pro Met Gln Thr Gly Ile Leu Pro Gly Cys Glu 
         35                  40                  45 

Pro Cys His Lys Lys Val Cys Ala His Gly Cys Cys Gln Pro Ser Ser 
     50                  55                  60 

Gln Ser Gly Phe Thr Cys Glu Cys Glu Glu Gly Trp Met Gly Pro Leu 
 65                  70                  75                  80 

Cys Asp Gln Arg Thr Asn Asp Pro Cys Leu Gly Asn Lys Cys Val His 
                 85                  90                  95 

Gly Thr Cys Leu Pro Ile Asn Ala Phe Ser Tyr Ser Cys Lys Cys Leu 
            100                 105                 110 

Glu Gly His Gly Gly Val Leu Cys Asp Glu Glu Glu Asp Leu Phe Asn 
        115                 120                 125 

Pro Cys Gln Met Ile Lys Cys Lys His Gly Lys Cys Arg Leu Ser Gly 
    130                 135                 140 

Val Gly Gln Pro Tyr Cys Glu Cys Asn Ser Gly Phe Thr Gly Asp Ser 
145                 150                 155                 160 

Cys Asp Arg Glu Ile Ser Cys Arg Gly Glu Arg Ile Arg Asp Tyr Tyr 
                165                 170                 175 

Gln Lys Gln Gln Gly Tyr Ala Ala Cys Gln Thr Thr Lys Lys Val Ser 
            180                 185                 190 

Arg Leu Glu Cys Arg Gly Gly Cys Ala Gly Gly Gln Cys Cys Gly Pro 
        195                 200                 205 

Leu Arg Ser Lys Arg Arg Lys Tyr Ser Phe Glu Cys Thr Asp Gly Ser 
    210                 215                 220 

Ser Phe Val Asp Glu Val Glu Lys Val Val Lys Cys Gly Cys Ala Arg 
225                 230                 235                 240 

Cys Ala Ser 

 
           
             15  
             1395  
             PRT  
             Drosophila melanogaster  
           
            15 

Met His Pro Met His Pro Glu Asn His Ala Ile Ala Arg Ser Thr Ser 
1               5                   10                  15 

Thr Thr Asn Asn Pro Ser Arg Ser Arg Ser Ser Arg Met Trp Leu Leu 
            20                  25                  30 

Pro Ala Trp Leu Leu Leu Val Leu Val Ala Ser Asn Gly Leu Pro Ala 
        35                  40                  45 

Val Arg Gly Gln Tyr Gln Ser Pro Arg Ile Ile Glu His Pro Thr Asp 
    50                  55                  60 

Leu Val Val Lys Lys Asn Glu Pro Ala Thr Leu Asn Cys Lys Val Glu 
65                  70                  75                  80 

Gly Lys Pro Glu Pro Thr Ile Glu Trp Phe Lys Asp Gly Glu Pro Val 
                85                  90                  95 

Ser Thr Asn Glu Lys Lys Ser His Arg Val Gln Phe Lys Asp Gly Ala 
            100                 105                 110 

Leu Phe Phe Tyr Arg Thr Met Gln Gly Lys Lys Glu Gln Asp Gly Gly 
        115                 120                 125 

Glu Tyr Trp Cys Val Ala Lys Asn Arg Val Gly Gln Ala Val Ser Arg 
    130                 135                 140 

His Ala Ser Leu Gln Ile Ala Val Leu Arg Asp Asp Phe Arg Val Glu 
145                 150                 155                 160 

Pro Lys Asp Thr Arg Val Ala Lys Gly Glu Thr Ala Leu Leu Glu Cys 
                165                 170                 175 

Gly Pro Pro Lys Gly Ile Pro Glu Pro Thr Leu Ile Trp Ile Lys Asp 
            180                 185                 190 

Gly Val Pro Leu Asp Asp Leu Lys Ala Met Ser Phe Gly Ala Ser Ser 
        195                 200                 205 

Arg Val Arg Ile Val Asp Gly Gly Asn Leu Leu Ile Ser Asn Val Glu 
    210                 215                 220 

Pro Ile Asp Glu Gly Asn Tyr Lys Cys Ile Ala Gln Asn Leu Val Gly 
225                 230                 235                 240 

Thr Arg Glu Ser Ser Tyr Ala Lys Leu Ile Val Gln Val Lys Pro Tyr 
                245                 250                 255 

Phe Met Lys Glu Pro Lys Asp Gln Val Met Leu Tyr Gly Gln Thr Ala 
            260                 265                 270 

Thr Phe His Cys Ser Val Gly Gly Asp Pro Pro Pro Lys Val Leu Trp 
        275                 280                 285 

Lys Lys Glu Glu Gly Asn Ile Pro Val Ser Arg Ala Arg Ile Leu His 
    290                 295                 300 

Asp Glu Lys Ser Leu Glu Ile Ser Asn Ile Thr Pro Thr Asp Glu Gly 
305                 310                 315                 320 

Thr Tyr Val Cys Glu Ala His Asn Asn Val Gly Gln Ile Ser Ala Arg 
                325                 330                 335 

Ala Ser Leu Ile Val His Ala Pro Pro Asn Phe Thr Lys Arg Pro Ser 
            340                 345                 350 

Asn Lys Lys Val Gly Leu Asn Gly Val Val Gln Leu Pro Cys Met Ala 
        355                 360                 365 

Ser Gly Asn Pro Pro Pro Ser Val Phe Trp Thr Lys Glu Gly Val Ser 
    370                 375                 380 

Thr Leu Met Phe Pro Asn Ser Ser His Gly Arg Gln Tyr Val Ala Ala 
385                 390                 395                 400 

Asp Gly Thr Leu Gln Ile Thr Asp Val Arg Gln Glu Asp Glu Gly Tyr 
                405                 410                 415 

Tyr Val Cys Ser Ala Phe Ser Val Val Asp Ser Ser Thr Val Arg Val 
            420                 425                 430 

Phe Leu Gln Val Ser Ser Val Asp Glu Arg Pro Pro Pro Ile Ile Gln 
        435                 440                 445 

Ile Gly Pro Ala Asn Gln Thr Leu Pro Lys Gly Ser Val Ala Thr Leu 
    450                 455                 460 

Pro Cys Arg Ala Thr Gly Asn Pro Ser Pro Arg Ile Lys Trp Phe His 
465                 470                 475                 480 

Asp Gly His Ala Val Gln Ala Gly Asn Arg Tyr Ser Ile Ile Gln Gly 
                485                 490                 495 

Ser Ser Leu Arg Val Asp Asp Leu Gln Leu Ser Asp Ser Gly Thr Tyr 
            500                 505                 510 

Thr Cys Thr Ala Ser Gly Glu Arg Gly Glu Thr Ser Trp Ala Ala Thr 
        515                 520                 525 

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

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

Ser Arg Thr Ser Ile Ser Leu Arg Trp Ala Lys Ser Gln Glu Lys Pro 
                565                 570                 575 

Gly Ala Val Gly Pro Ile Ile Gly Tyr Thr Val Glu Tyr Phe Ser Pro 
            580                 585                 590 

Asp Leu Gln Thr Gly Trp Ile Val Ala Ala His Arg Val Gly Asp Thr 
        595                 600                 605 

Gln Val Thr Ile Ser Gly Leu Thr Pro Gly Thr Ser Tyr Val Phe Leu 
    610                 615                 620 

Val Arg Ala Glu Asn Thr Gln Gly Ile Ser Val Pro Ser Gly Leu Ser 
625                 630                 635                 640 

Asn Val Ile Lys Thr Ile Glu Ala Asp Phe Asp Ala Ala Ser Ala Asn 
                645                 650                 655 

Asp Leu Ser Ala Ala Arg Thr Leu Leu Thr Gly Lys Ser Val Glu Leu 
            660                 665                 670 

Ile Asp Ala Ser Ala Ile Asn Ala Ser Ala Val Arg Leu Glu Trp Met 
        675                 680                 685 

Leu His Val Ser Ala Asp Glu Lys Tyr Val Glu Gly Leu Arg Ile His 
    690                 695                 700 

Tyr Lys Asp Ala Ser Val Pro Ser Ala Gln Tyr His Ser Ile Thr Val 
705                 710                 715                 720 

Met Asp Ala Ser Ala Glu Ser Phe Val Val Gly Asn Leu Lys Lys Tyr 
                725                 730                 735 

Thr Lys Tyr Glu Phe Phe Leu Thr Pro Phe Phe Glu Thr Ile Glu Gly 
            740                 745                 750 

Gln Pro Ser Asn Ser Lys Thr Ala Leu Thr Tyr Glu Asp Val Pro Ser 
        755                 760                 765 

Ala Pro Pro Asp Asn Ile Gln Ile Gly Met Tyr Asn Gln Thr Ala Gly 
    770                 775                 780 

Trp Val Arg Trp Thr Pro Pro Pro Ser Gln His His Asn Gly Asn Leu 
785                 790                 795                 800 

Tyr Gly Tyr Lys Ile Glu Val Ser Ala Gly Asn Thr Met Lys Val Leu 
                805                 810                 815 

Ala Asn Met Thr Leu Asn Ala Thr Thr Thr Ser Val Leu Leu Asn Asn 
            820                 825                 830 

Leu Thr Thr Gly Ala Val Tyr Ser Val Arg Leu Asn Ser Phe Thr Lys 
        835                 840                 845 

Ala Gly Asp Gly Pro Tyr Ser Lys Pro Ile Ser Leu Phe Met Asp Pro 
    850                 855                 860 

Thr His His Val His Pro Pro Arg Ala His Pro Ser Gly Thr His Asp 
865                 870                 875                 880 

Gly Arg His Glu Gly Gln Asp Leu Thr Tyr His Asn Asn Gly Asn Ile 
                885                 890                 895 

Pro Pro Gly Asp Ile Asn Pro Thr Thr His Lys Lys Thr Thr Asp Tyr 
            900                 905                 910 

Leu Ser Gly Pro Trp Leu Met Val Leu Val Cys Ile Val Leu Leu Val 
        915                 920                 925 

Leu Val Ile Ser Ala Ala Ile Ser Met Val Tyr Phe Lys Arg Lys His 
    930                 935                 940 

Gln Met Thr Lys Glu Leu Gly His Leu Ser Val Val Ser Asp Asn Glu 
945                 950                 955                 960 

Ile Thr Ala Leu Asn Ile Asn Ser Lys Glu Ser Leu Trp Ile Asp His 
                965                 970                 975 

His Arg Gly Trp Arg Thr Ala Asp Thr Asp Lys Asp Ser Gly Leu Ser 
            980                 985                 990 

Glu Ser Lys Leu Leu Ser His Val Asn Ser Ser Gln Ser Asn Tyr Asn 
        995                 1000                1005 

Asn Ser Asp Gly Gly Thr Asp Tyr Ala Glu Val Asp Thr Arg Asn Leu 
    1010                1015                1020 

Thr Thr Phe Tyr Asn Cys Arg Lys Ser Pro Asp Asn Pro Thr Pro Tyr 
1025                1030                1035                1040 

Ala Thr Thr Met Ile Ile Gly Thr Ser Ser Ser Glu Thr Cys Thr Lys 
                1045                1050                1055 

Thr Thr Ser Ile Ser Ala Asp Lys Asp Ser Gly Thr His Ser Pro Tyr 
            1060                1065                1070 

Ser Asp Ala Phe Ala Gly Gln Val Pro Ala Val Pro Val Val Lys Ser 
        1075                1080                1085 

Asn Tyr Leu Gln Tyr Pro Val Glu Pro Ile Asn Trp Ser Glu Phe Leu 
    1090                1095                1100 

Pro Pro Pro Pro Glu His Pro Pro Pro Ser Ser Thr Tyr Gly Tyr Ala 
1105                1110                1115                1120 

Gln Gly Ser Pro Glu Ser Ser Arg Lys Ser Ser Lys Ser Ala Gly Ser 
                1125                1130                1135 

Gly Ile Ser Thr Asn Gln Ser Ile Leu Asn Ala Ser Ile His Ser Ser 
            1140                1145                1150 

Ser Ser Gly Gly Phe Ser Ala Trp Gly Val Ser Pro Gln Tyr Ala Val 
        1155                1160                1165 

Ala Cys Pro Pro Glu Asn Val Tyr Ser Asn Pro Leu Ser Ala Val Ala 
    1170                1175                1180 

Gly Gly Thr Gln Asn Arg Tyr Gln Ile Thr Pro Thr Asn Gln His Pro 
1185                1190                1195                1200 

Pro Gln Leu Pro Ala Tyr Phe Ala Thr Thr Gly Pro Gly Gly Ala Val 
                1205                1210                1215 

Pro Pro Asn His Leu Pro Phe Ala Thr Gln Arg His Ala Ala Ser Glu 
            1220                1225                1230 

Tyr Gln Ala Gly Leu Asn Ala Ala Arg Cys Ala Gln Ser Arg Ala Cys 
        1235                1240                1245 

Asn Ser Cys Asp Ala Leu Ala Thr Pro Ser Pro Met Gln Pro Pro Pro 
    1250                1255                1260 

Pro Val Pro Val Pro Glu Gly Trp Tyr Gln Pro Val His Pro Asn Ser 
1265                1270                1275                1280 

His Pro Met His Pro Thr Ser Ser Asn His Gln Ile Tyr Gln Cys Ser 
                1285                1290                1295 

Ser Glu Cys Ser Asp His Ser Arg Ser Ser Gln Ser His Lys Arg Gln 
            1300                1305                1310 

Leu Gln Leu Glu Glu His Gly Ser Ser Ala Lys Gln Arg Gly Gly His 
        1315                1320                1325 

His Arg Arg Arg Ala Pro Val Val Gln Pro Cys Met Glu Ser Glu Asn 
    1330                1335                1340 

Glu Asn Met Leu Ala Glu Tyr Glu Gln Arg Gln Tyr Thr Ser Asp Cys 
1345                1350                1355                1360 

Cys Asn Ser Ser Arg Glu Gly Asp Thr Cys Ser Cys Ser Glu Gly Ser 
                1365                1370                1375 

Cys Leu Tyr Ala Glu Ala Gly Glu Pro Ala Pro Arg Gln Met Thr Ala 
            1380                1385                1390 

Lys Asn Thr 
        1395 

 
           
             16  
             1381  
             PRT  
             Drosophila melanogaster  
           
            16 

Gly Glu Asn Pro Arg Ile Ile Glu His Pro Met Asp Thr Thr Val Pro 
1               5                   10                  15 

Lys Asn Asp Pro Phe Thr Phe Asn Cys Gln Ala Glu Gly Asn Pro Thr 
            20                  25                  30 

Pro Thr Ile Gln Trp Phe Lys Asp Gly Arg Glu Leu Lys Thr Asp Thr 
        35                  40                  45 

Gly Ser His Arg Ile Met Leu Pro Ala Gly Gly Leu Phe Phe Leu Lys 
    50                  55                  60 

Val Ile His Ser Arg Arg Glu Ser Asp Ala Gly Thr Tyr Trp Cys Glu 
65                  70                  75                  80 

Ala Lys Asn Glu Phe Gly Val Ala Arg Ser Arg Asn Ala Thr Leu Gln 
                85                  90                  95 

Val Ala Val Leu Arg Asp Glu Phe Arg Leu Glu Pro Ala Asn Thr Arg 
            100                 105                 110 

Val Ala Gln Gly Glu Val Ala Leu Met Glu Cys Gly Ala Pro Arg Gly 
        115                 120                 125 

Ser Pro Glu Pro Gln Ile Ser Trp Arg Lys Asn Gly Gln Thr Leu Asn 
    130                 135                 140 

Leu Val Gly Asn Lys Arg Ile Arg Ile Val Asp Gly Gly Asn Leu Ala 
145                 150                 155                 160 

Ile Gln Glu Ala Arg Gln Ser Asp Asp Gly Arg Tyr Gln Cys Val Val 
                165                 170                 175 

Lys Asn Val Val Gly Thr Arg Glu Ser Ala Thr Ala Phe Leu Lys Val 
            180                 185                 190 

His Val Arg Pro Phe Leu Ile Arg Gly Pro Gln Asn Gln Thr Ala Val 
        195                 200                 205 

Val Gly Ser Ser Val Val Phe Gln Cys Arg Ile Gly Gly Asp Pro Leu 
    210                 215                 220 

Pro Asp Val Leu Trp Arg Arg Thr Ala Ser Gly Gly Asn Met Pro Leu 
225                 230                 235                 240 

Arg Lys Phe Ser Trp Leu His Ser Ala Ser Gly Arg Val His Val Leu 
                245                 250                 255 

Glu Asp Arg Ser Leu Lys Leu Asp Asp Val Thr Leu Glu Asp Met Gly 
            260                 265                 270 

Glu Tyr Thr Cys Glu Ala Asp Asn Ala Val Gly Gly Ile Thr Ala Thr 
        275                 280                 285 

Gly Ile Leu Thr Val His Ala Pro Pro Lys Phe Val Ile Arg Pro Lys 
    290                 295                 300 

Asn Gln Leu Val Glu Ile Gly Asp Glu Val Leu Phe Glu Cys Gln Ala 
305                 310                 315                 320 

Asn Gly His Pro Arg Pro Thr Leu Tyr Trp Ser Val Glu Gly Asn Ser 
                325                 330                 335 

Ser Leu Leu Leu Pro Gly Tyr Arg Asp Gly Arg Met Glu Val Thr Leu 
            340                 345                 350 

Thr Pro Glu Gly Arg Ser Val Leu Ser Ile Ala Arg Phe Ala Arg Glu 
        355                 360                 365 

Asp Ser Gly Lys Val Val Thr Cys Asn Ala Leu Asn Ala Val Gly Ser 
    370                 375                 380 

Val Ser Ser Arg Thr Val Val Ser Val Asp Thr Gln Phe Glu Leu Pro 
385                 390                 395                 400 

Pro Pro Ile Ile Glu Gln Gly Pro Val Asn Gln Thr Leu Pro Val Lys 
                405                 410                 415 

Ser Ile Val Val Leu Pro Cys Arg Thr Leu Gly Thr Pro Val Pro Gln 
            420                 425                 430 

Val Ser Trp Tyr Leu Asp Gly Ile Pro Ile Asp Val Gln Glu His Glu 
        435                 440                 445 

Arg Arg Asn Leu Ser Asp Ala Gly Ala Leu Thr Ile Ser Asp Leu Gln 
    450                 455                 460 

Arg His Glu Asp Glu Gly Leu Tyr Thr Cys Val Ala Ser Asn Arg Asn 
465                 470                 475                 480 

Gly Lys Ser Ser Trp Ser Gly Tyr Leu Arg Leu Asp Thr Pro Thr Asn 
                485                 490                 495 

Pro Asn Ile Lys Phe Phe Arg Ala Pro Glu Leu Ser Thr Tyr Pro Gly 
            500                 505                 510 

Pro Pro Gly Lys Pro Gln Met Val Glu Lys Gly Glu Asn Ser Val Thr 
        515                 520                 525 

Leu Ser Trp Thr Arg Ser Asn Lys Val Gly Gly Ser Ser Leu Val Gly 
    530                 535                 540 

Tyr Val Ile Glu Met Phe Gly Lys Asn Glu Thr Asp Gly Trp Val Ala 
545                 550                 555                 560 

Val Gly Thr Arg Val Gln Asn Thr Thr Phe Thr Gln Thr Gly Leu Leu 
                565                 570                 575 

Pro Gly Val Asn Tyr Phe Phe Leu Ile Arg Ala Glu Asn Ser His Gly 
            580                 585                 590 

Leu Ser Leu Pro Ser Pro Met Ser Glu Pro Ile Thr Val Gly Thr Arg 
        595                 600                 605 

Tyr Phe Asn Ser Gly Leu Asp Leu Ser Glu Ala Arg Ala Ser Leu Leu 
    610                 615                 620 

Ser Gly Asp Val Val Glu Leu Ser Asn Ala Ser Val Val Asp Ser Thr 
625                 630                 635                 640 

Ser Met Lys Leu Thr Trp Gln Ile Ile Asn Gly Lys Tyr Val Glu Gly 
                645                 650                 655 

Phe Tyr Val Tyr Ala Arg Gln Leu Pro Asn Pro Ile Val Asn Asn Pro 
            660                 665                 670 

Ala Pro Val Thr Ser Asn Thr Asn Pro Leu Leu Gly Ser Thr Ser Thr 
        675                 680                 685 

Ser Ala Ser Ala Ser Ala Ser Ala Ser Ala Leu Ile Ser Thr Lys Pro 
    690                 695                 700 

Asn Ile Ala Ala Ala Gly Lys Arg Asp Gly Glu Thr Asn Gln Ser Gly 
705                 710                 715                 720 

Gly Gly Ala Pro Thr Pro Leu Asn Thr Lys Tyr Arg Met Leu Thr Ile 
                725                 730                 735 

Leu Asn Gly Gly Gly Ala Ser Ser Cys Thr Ile Thr Gly Leu Val Gln 
            740                 745                 750 

Tyr Thr Leu Tyr Glu Phe Phe Ile Val Pro Phe Tyr Lys Ser Val Glu 
        755                 760                 765 

Gly Lys Pro Ser Asn Ser Arg Ile Ala Arg Thr Leu Glu Asp Val Pro 
    770                 775                 780 

Ser Glu Ala Pro Tyr Gly Met Glu Ala Leu Leu Leu Asn Ser Ser Ala 
785                 790                 795                 800 

Val Phe Leu Lys Trp Lys Ala Pro Glu Leu Lys Asp Arg His Gly Val 
                805                 810                 815 

Leu Leu Asn Tyr His Val Ile Val Arg Gly Ile Asp Thr Ala His Asn 
            820                 825                 830 

Phe Ser Arg Ile Leu Thr Asn Val Thr Ile Asp Ala Ala Ser Pro Thr 
        835                 840                 845 

Leu Val Leu Ala Asn Leu Thr Glu Gly Val Met Tyr Thr Val Gly Val 
    850                 855                 860 

Ala Ala Gly Asn Asn Ala Gly Val Gly Pro Tyr Cys Val Pro Ala Thr 
865                 870                 875                 880 

Leu Arg Leu Asp Pro Ile Thr Lys Arg Leu Asp Pro Phe Ile Asn Gln 
                885                 890                 895 

Arg Asp His Val Asn Asp Val Leu Thr Gln Pro Trp Phe Ile Ile Leu 
            900                 905                 910 

Leu Gly Ala Ile Leu Ala Val Leu Met Leu Ser Phe Gly Ala Met Val 
        915                 920                 925 

Phe Val Lys Arg Lys His Met Met Met Lys Gln Ser Ala Leu Asn Thr 
    930                 935                 940 

Met Arg Gly Asn His Thr Ser Asp Val Leu Lys Met Pro Ser Leu Ser 
945                 950                 955                 960 

Ala Arg Asn Gly Asn Gly Tyr Trp Leu Asp Ser Ser Thr Gly Gly Met 
                965                 970                 975 

Val Trp Arg Pro Ser Pro Gly Gly Asp Ser Leu Glu Met Gln Lys Asp 
            980                 985                 990 

His Ile Ala Asp Tyr Ala Pro Val Cys Gly Ala Pro Gly Ser Pro Ala 
        995                 1000                1005 

Gly Gly Gly Thr Ser Ser Gly Gly Ser Gly Gly Ala Gly Ser Gly Ala 
    1010                1015                1020 

Ser Gly Gly Asp Asp Ile His Gly Gly His Gly Ser Glu Arg Asn Gln 
1025                1030                1035                1040 

Gln Arg Tyr Val Gly Glu Tyr Ser Asn Ile Pro Thr Asp Tyr Ala Glu 
                1045                1050                1055 

Val Ser Ser Phe Gly Lys Ala Pro Ser Glu Tyr Gly Arg His Gly Asn 
            1060                1065                1070 

Ala Ser Pro Ala Pro Tyr Ala Thr Ser Ser Ile Leu Ser Pro His Gln 
        1075                1080                1085 

Gln Gln Gln Gln Gln Gln Pro Arg Tyr Gln Gln Arg Pro Val Pro Gly 
    1090                1095                1100 

Tyr Gly Leu Gln Arg Pro Met His Pro His Tyr Gln Gln Gln Gln His 
1105                1110                1115                1120 

Gln Gln Gln Gln Ala Gln Gln Thr His Gln Gln His Gln Ala Leu Gln 
                1125                1130                1135 

Gln His Gln Gln Leu Pro Pro Ser Asn Ile Tyr Gln Gln Met Ser Thr 
            1140                1145                1150 

Thr Ser Glu Ile Tyr Pro Thr Asn Thr Gly Pro Ser Arg Ser Val Tyr 
        1155                1160                1165 

Ser Glu Gln Tyr Tyr Tyr Pro Lys Asp Lys Gln Arg His Ile His Ile 
    1170                1175                1180 

Thr Glu Asn Lys Leu Ser Asn Cys His Thr Tyr Glu Ala Ala Pro Gly 
1185                1190                1195                1200 

Ala Lys Gln Ser Ser Pro Ile Ser Ser Gln Phe Ala Ser Val Arg Arg 
                1205                1210                1215 

Gln Gln Leu Pro Pro Asn Cys Ser Ile Gly Arg Glu Ser Ala Arg Phe 
            1220                1225                1230 

Lys Val Leu Asn Thr Asp Gln Gly Lys Asn Gln Gln Asn Leu Leu Asp 
        1235                1240                1245 

Leu Asp Gly Ser Ser Met Cys Tyr Asn Gly Leu Ala Asp Ser Gly Cys 
    1250                1255                1260 

Gly Gly Ser Pro Ser Pro Met Ala Met Leu Met Ser His Glu Asp Glu 
1265                1270                1275                1280 

His Ala Leu Tyr His Thr Ala Asp Gly Asp Leu Asp Asp Met Glu Arg 
                1285                1290                1295 

Leu Tyr Val Lys Val Asp Glu Gln Gln Pro Pro Gln Gln Gln Gln Gln 
            1300                1305                1310 

Leu Ile Pro Leu Val Pro Gln His Pro Ala Glu Gly His Leu Gln Ser 
        1315                1320                1325 

Trp Arg Asn Gln Ser Thr Arg Ser Ser Arg Lys Asn Gly Gln Glu Cys 
    1330                1335                1340 

Ile Lys Glu Pro Ser Glu Leu Ile Tyr Ala Pro Gly Ser Val Ala Ser 
1345                1350                1355                1360 

Glu Arg Ser Leu Leu Ser Asn Ser Gly Ser Gly Thr Ser Ser Gln Pro 
                1365                1370                1375 

Ala Gly His Asn Val 
            1380 

 
           
             17  
             1297  
             PRT  
             Caenorhabditis elegans  
           
            17 

Met Tyr Tyr Leu Gly Phe Tyr His Thr His Thr His Thr His Thr Tyr 
1               5                   10                  15 

Ile Asn Phe Asp Lys Ile Pro Asn Ala Ser Asn Leu Ala Pro Val Ile 
            20                  25                  30 

Ile Glu His Pro Ile Asp Val Val Val Ser Arg Gly Ser Pro Ala Thr 
        35                  40                  45 

Leu Asn Cys Gly Ala Lys Pro Ser Thr Ala Lys Ile Thr Trp Tyr Lys 
    50                  55                  60 

Asp Gly Gln Pro Val Ile Thr Asn Lys Glu Gln Val Asn Ser His Arg 
65                  70                  75                  80 

Ile Val Leu Asp Thr Gly Ser Leu Phe Leu Leu Lys Val Asn Ser Gly 
                85                  90                  95 

Lys Asn Gly Lys Asp Ser Asp Ala Gly Ala Tyr Tyr Cys Val Ala Ser 
            100                 105                 110 

Asn Glu His Gly Glu Val Lys Ser Asn Glu Gly Ser Leu Lys Leu Ala 
        115                 120                 125 

Met Leu Arg Glu Asp Phe Arg Val Arg Pro Arg Thr Val Gln Ala Leu 
    130                 135                 140 

Gly Gly Glu Met Ala Val Leu Glu Cys Ser Pro Pro Arg Gly Phe Pro 
145                 150                 155                 160 

Glu Pro Val Val Ser Trp Arg Lys Asp Asp Lys Glu Leu Arg Ile Gln 
                165                 170                 175 

Asp Met Pro Arg Tyr Thr Leu His Ser Asp Gly Asn Leu Ile Ile Asp 
            180                 185                 190 

Pro Val Asp Arg Ser Asp Ser Gly Thr Tyr Gln Cys Val Ala Asn Asn 
        195                 200                 205 

Met Val Gly Glu Arg Val Ser Asn Pro Ala Arg Leu Ser Val Phe Glu 
    210                 215                 220 

Lys Pro Lys Phe Glu Gln Glu Pro Lys Asp Met Thr Val Asp Val Gly 
225                 230                 235                 240 

Ala Ala Val Leu Phe Asp Cys Arg Val Thr Gly Asp Pro Gln Pro Gln 
                245                 250                 255 

Ile Thr Trp Lys Arg Lys Asn Glu Pro Met Pro Val Thr Arg Ala Tyr 
            260                 265                 270 

Ile Ala Lys Asp Asn Arg Gly Leu Arg Ile Glu Arg Val Gln Pro Ser 
        275                 280                 285 

Asp Glu Gly Glu Tyr Val Cys Tyr Ala Arg Asn Pro Ala Gly Thr Leu 
    290                 295                 300 

Glu Ala Ser Ala His Leu Arg Val Gln Ala Pro Pro Ser Phe Gln Thr 
305                 310                 315                 320 

Lys Pro Ala Asp Gln Ser Val Pro Ala Gly Gly Thr Ala Thr Phe Glu 
                325                 330                 335 

Cys Thr Leu Val Gly Gln Pro Ser Pro Ala Tyr Phe Trp Ser Lys Glu 
            340                 345                 350 

Gly Gln Gln Asp Leu Leu Phe Pro Ser Tyr Val Ser Ala Asp Gly Arg 
        355                 360                 365 

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

Val Asp Glu Gly Ala Tyr Val Cys Ala Gly Met Asn Ser Ala Gly Ser 
385                 390                 395                 400 

Ser Leu Ser Lys Ala Ala Leu Lys Ala Thr Phe Glu Thr Lys Gly Arg 
                405                 410                 415 

Val Gln Lys Lys Lys Ser Lys Met Gly Lys Gln Lys Gln Lys Asn Val 
            420                 425                 430 

Gln Ser Ile Ile Lys Tyr Leu Ile Ser Ala Val Thr Gly Asn Thr Pro 
        435                 440                 445 

Ala Lys Pro Pro Pro Thr Ile Glu His Gly His Gln Asn Gln Thr Leu 
    450                 455                 460 

Met Val Gly Ser Ser Ala Ile Leu Pro Cys Gln Ala Ser Gly Lys Pro 
465                 470                 475                 480 

Thr Pro Gly Ile Ser Trp Leu Arg Asp Gly Leu Pro Ile Asp Ile Thr 
                485                 490                 495 

Asp Ser Arg Ile Ser Gln His Ser Thr Gly Ser Leu His Ile Ala Asp 
            500                 505                 510 

Leu Lys Lys Pro Asp Thr Gly Val Tyr Thr Cys Ile Ala Lys Asn Glu 
        515                 520                 525 

Asp Gly Glu Ser Thr Trp Ser Ala Ser Leu Thr Val Glu Asp His Thr 
    530                 535                 540 

Ser Asn Ala Gln Phe Val Arg Met Pro Asp Pro Ser Asn Phe Pro Ser 
545                 550                 555                 560 

Ser Pro Thr Gln Pro Ile Ile Val Asn Val Thr Asp Thr Glu Val Glu 
                565                 570                 575 

Leu His Trp Asn Ala Pro Ser Thr Ser Gly Ala Gly Pro Ile Thr Gly 
            580                 585                 590 

Tyr Ile Ile Gln Tyr Tyr Ser Pro Asp Leu Gly Gln Thr Trp Phe Asn 
        595                 600                 605 

Ile Pro Asp Tyr Val Ala Ser Thr Glu Tyr Arg Ile Lys Gly Leu Lys 
    610                 615                 620 

Pro Ser His Ser Tyr Met Phe Val Ile Arg Ala Glu Asn Glu Lys Gly 
625                 630                 635                 640 

Ile Gly Thr Pro Ser Val Ser Ser Ala Leu Val Thr Thr Ser Lys Pro 
                645                 650                 655 

Ala Ala Gln Val Ala Leu Ser Asp Lys Asn Lys Met Asp Met Ala Ile 
            660                 665                 670 

Ala Glu Lys Arg Leu Thr Ser Glu Gln Leu Ile Lys Leu Glu Glu Val 
        675                 680                 685 

Lys Thr Ile Asn Ser Thr Ala Val Arg Leu Phe Trp Lys Lys Arg Lys 
    690                 695                 700 

Leu Glu Glu Leu Ile Asp Gly Tyr Tyr Ile Lys Trp Arg Gly Pro Pro 
705                 710                 715                 720 

Arg Thr Asn Asp Asn Gln Tyr Val Asn Val Thr Ser Pro Ser Thr Glu 
                725                 730                 735 

Asn Tyr Val Val Ser Asn Leu Met Pro Phe Thr Asn Tyr Glu Phe Phe 
            740                 745                 750 

Val Ile Pro Tyr His Ser Gly Val His Ser Ile His Gly Ala Pro Ser 
        755                 760                 765 

Asn Ser Met Asp Val Leu Thr Ala Glu Ala Pro Pro Ser Leu Pro Pro 
    770                 775                 780 

Glu Asp Val Arg Ile Arg Met Leu Asn Leu Thr Thr Leu Arg Ile Ser 
785                 790                 795                 800 

Trp Lys Ala Pro Lys Ala Asp Gly Ile Asn Gly Ile Leu Lys Gly Phe 
                805                 810                 815 

Gln Ile Val Ile Val Gly Gln Ala Pro Asn Asn Asn Arg Asn Ile Thr 
            820                 825                 830 

Thr Asn Glu Arg Ala Ala Ser Val Thr Leu Phe His Leu Val Thr Gly 
        835                 840                 845 

Met Thr Tyr Lys Ile Arg Val Ala Ala Arg Ser Asn Gly Gly Val Gly 
    850                 855                 860 

Val Ser His Gly Thr Ser Glu Val Ile Met Asn Gln Asp Thr Leu Glu 
865                 870                 875                 880 

Lys His Leu Ala Ala Gln Gln Glu Asn Glu Ser Phe Leu Tyr Gly Leu 
                885                 890                 895 

Ile Asn Lys Ser His Val Pro Val Ile Val Ile Val Ala Ile Leu Ile 
            900                 905                 910 

Ile Phe Val Val Ile Ile Ile Ala Tyr Cys Tyr Trp Arg Asn Ser Arg 
        915                 920                 925 

Asn Ser Asp Gly Lys Asp Arg Ser Phe Ile Lys Ile Asn Asp Gly Ser 
    930                 935                 940 

Val His Met Ala Ser Asn Asn Leu Trp Asp Val Ala Gln Asn Pro Asn 
945                 950                 955                 960 

Gln Asn Pro Met Tyr Asn Thr Ala Gly Arg Met Thr Met Asn Asn Arg 
                965                 970                 975 

Asn Gly Gln Ala Leu Tyr Ser Leu Thr Pro Asn Ala Gln Asp Phe Phe 
            980                 985                 990 

Asn Asn Cys Asp Asp Tyr Ser Gly Thr Met His Arg Pro Gly Ser Glu 
        995                 1000                1005 

His His Tyr His Tyr Ala Gln Leu Thr Gly Gly Pro Gly Asn Ala Met 
    1010                1015                1020 

Ser Thr Phe Tyr Gly Asn Gln Tyr His Asp Asp Pro Ser Pro Tyr Ala 
1025                1030                1035                1040 

Thr Thr Thr Leu Val Leu Ser Asn Gln Gln Pro Ala Trp Leu Asn Asp 
                1045                1050                1055 

Lys Met Leu Arg Ala Pro Ala Met Pro Thr Asn Pro Val Pro Pro Glu 
            1060                1065                1070 

Pro Pro Ala Arg Tyr Ala Asp His Thr Ala Gly Arg Arg Ser Arg Ser 
        1075                1080                1085 

Ser Arg Ala Ser Asp Gly Arg Gly Thr Leu Asn Gly Gly Leu His His 
    1090                1095                1100 

Arg Thr Ser Gly Ser Gln Arg Ser Asp Ser Pro Pro His Thr Asp Val 
1105                1110                1115                1120 

Ser Tyr Val Gln Leu His Ser Ser Asp Gly Thr Gly Ser Ser Lys Glu 
                1125                1130                1135 

Arg Thr Gly Glu Arg Arg Thr Pro Pro Asn Lys Thr Leu Met Asp Phe 
            1140                1145                1150 

Ile Pro Pro Pro Pro Ser Asn Pro Pro Pro Pro Gly Gly His Val Tyr 
        1155                1160                1165 

Asp Thr Ala Thr Arg Arg Gln Leu Asn Arg Gly Ser Thr Pro Arg Glu 
    1170                1175                1180 

Asp Thr Tyr Asp Ser Val Ser Asp Gly Ala Phe Ala Arg Val Asp Val 
1185                1190                1195                1200 

Asn Ala Arg Pro Thr Ser Arg Asn Arg Asn Leu Gly Gly Arg Pro Leu 
                1205                1210                1215 

Lys Gly Lys Arg Asp Asp Asp Ser Gln Arg Ser Ser Leu Met Met Asp 
            1220                1225                1230 

Asp Asp Gly Gly Ser Ser Glu Ala Asp Gly Glu Asn Ser Glu Gly Asp 
        1235                1240                1245 

Val Pro Arg Gly Gly Val Arg Lys Ala Val Pro Arg Met Gly Ile Ser 
    1250                1255                1260 

Ala Ser Thr Leu Ala His Ser Cys Tyr Gly Thr Asn Gly Thr Ala Gln 
1265                1270                1275                1280 

Arg Phe Arg Ser Ile Pro Arg Asn Asn Gly Ile Val Thr Gln Glu Gln 
                1285                1290                1295 

Thr 

 
           
             18  
             1651  
             PRT  
             human  
           
            18 

Met Lys Trp Lys His Val Pro Phe Leu Val Met Ile Ser Leu Leu Ser 
1               5                   10                  15 

Leu Ser Pro Asn His Leu Phe Leu Ala Gln Leu Ile Pro Asp Pro Glu 
            20                  25                  30 

Asp Val Glu Arg Gly Asn Asp His Gly Thr Pro Ile Pro Thr Ser Asp 
        35                  40                  45 

Asn Asp Asp Asn Ser Leu Gly Tyr Thr Gly Ser Arg Leu Arg Gln Glu 
    50                  55                  60 

Asp Phe Pro Pro Arg Ile Val Glu His Pro Ser Asp Leu Ile Val Ser 
65                  70                  75                  80 

Lys Gly Glu Pro Ala Thr Leu Asn Cys Lys Ala Glu Gly Arg Pro Thr 
                85                  90                  95 

Pro Thr Ile Glu Trp Tyr Lys Gly Gly Glu Arg Val Glu Thr Asp Lys 
            100                 105                 110 

Asp Asp Pro Arg Ser His Arg Met Leu Leu Pro Ser Gly Ser Leu Phe 
        115                 120                 125 

Phe Leu Arg Ile Val His Gly Arg Lys Ser Arg Pro Asp Glu Gly Val 
    130                 135                 140 

Tyr Val Cys Val Ala Arg Asn Tyr Leu Gly Glu Ala Val Ser His Asn 
145                 150                 155                 160 

Ala Ser Leu Glu Val Ala Ile Leu Arg Asp Asp Phe Arg Gln Asn Pro 
                165                 170                 175 

Ser Asp Val Met Val Ala Val Gly Glu Pro Ala Val Met Glu Cys Gln 
            180                 185                 190 

Pro Pro Arg Gly His Pro Glu Pro Thr Ile Ser Trp Lys Lys Asp Gly 
        195                 200                 205 

Ser Pro Leu Asp Asp Lys Asp Glu Arg Ile Thr Ile Arg Gly Gly Lys 
    210                 215                 220 

Leu Met Ile Thr Tyr Thr Arg Lys Ser Asp Ala Gly Lys Tyr Val Cys 
225                 230                 235                 240 

Val Gly Thr Asn Met Val Gly Glu Arg Glu Ser Glu Val Ala Glu Leu 
                245                 250                 255 

Thr Val Leu Glu Arg Pro Ser Phe Val Lys Arg Pro Ser Asn Leu Ala 
            260                 265                 270 

Val Thr Val Asp Asp Ser Ala Glu Phe Lys Cys Glu Ala Arg Gly Asp 
        275                 280                 285 

Pro Val Pro Thr Val Arg Trp Arg Lys Asp Asp Gly Glu Leu Pro Lys 
    290                 295                 300 

Ser Arg Tyr Glu Ile Arg Asp Asp His Thr Leu Lys Ile Arg Lys Val 
305                 310                 315                 320 

Thr Ala Gly Asp Met Gly Ser Tyr Thr Cys Val Ala Glu Asn Met Val 
                325                 330                 335 

Gly Lys Ala Glu Ala Ser Ala Thr Leu Thr Val Gln Glu Pro Pro His 
            340                 345                 350 

Phe Val Val Lys Pro Arg Asp Gln Val Val Ala Leu Gly Arg Thr Val 
        355                 360                 365 

Thr Phe Gln Cys Glu Ala Thr Gly Asn Pro Gln Pro Ala Ile Phe Trp 
    370                 375                 380 

Arg Arg Glu Gly Ser Gln Asn Leu Leu Phe Ser Tyr Gln Pro Pro Gln 
385                 390                 395                 400 

Ser Ser Ser Arg Phe Ser Val Ser Gln Thr Gly Asp Leu Thr Ile Thr 
                405                 410                 415 

Asn Val Gln Arg Ser Asp Val Gly Tyr Tyr Ile Cys Gln Thr Leu Asn 
            420                 425                 430 

Val Ala Gly Ser Ile Ile Thr Lys Ala Tyr Leu Glu Val Thr Asp Val 
        435                 440                 445 

Ile Ala Asp Arg Pro Pro Pro Val Ile Arg Gln Gly Pro Val Asn Gln 
    450                 455                 460 

Thr Val Ala Val Asp Gly Thr Phe Val Leu Ser Cys Val Ala Thr Gly 
465                 470                 475                 480 

Ser Pro Val Pro Thr Ile Leu Trp Arg Lys Asp Gly Val Leu Val Ser 
                485                 490                 495 

Thr Gln Asp Ser Arg Ile Lys Gln Leu Glu Asn Gly Val Leu Gln Ile 
            500                 505                 510 

Arg Tyr Ala Lys Leu Gly Asp Thr Gly Arg Tyr Thr Cys Ile Ala Ser 
        515                 520                 525 

Thr Pro Ser Gly Glu Ala Thr Trp Ser Ala Tyr Ile Glu Val Gln Glu 
    530                 535                 540 

Phe Gly Val Pro Val Gln Pro Pro Arg Pro Thr Asp Pro Asn Leu Ile 
545                 550                 555                 560 

Pro Ser Ala Pro Ser Lys Pro Glu Val Thr Asp Val Ser Arg Asn Thr 
                565                 570                 575 

Val Thr Leu Ser Trp Gln Pro Asn Leu Asn Ser Gly Ala Thr Pro Thr 
            580                 585                 590 

Ser Tyr Ile Ile Glu Ala Phe Ser His Ala Ser Gly Ser Ser Trp Gln 
        595                 600                 605 

Thr Val Ala Glu Asn Val Lys Thr Glu Thr Ser Ala Ile Lys Gly Leu 
    610                 615                 620 

Lys Pro Asn Ala Ile Tyr Leu Phe Leu Val Arg Ala Ala Asn Ala Tyr 
625                 630                 635                 640 

Gly Ile Ser Asp Pro Ser Gln Ile Ser Asp Pro Val Lys Thr Gln Asp 
                645                 650                 655 

Val Leu Pro Thr Ser Gln Gly Val Asp His Lys Gln Val Gln Arg Glu 
            660                 665                 670 

Leu Gly Asn Ala Val Leu His Leu His Asn Pro Thr Val Leu Ser Ser 
        675                 680                 685 

Ser Ser Ile Glu Val His Trp Thr Val Asp Gln Gln Ser Gln Tyr Ile 
    690                 695                 700 

Gln Gly Tyr Lys Ile Leu Tyr Arg Pro Ser Gly Ala Asn His Gly Glu 
705                 710                 715                 720 

Ser Asp Trp Leu Val Phe Glu Val Arg Thr Pro Ala Lys Asn Ser Val 
                725                 730                 735 

Val Ile Pro Asp Leu Arg Lys Gly Val Asn Tyr Glu Ile Lys Ala Arg 
            740                 745                 750 

Pro Phe Phe Asn Glu Phe Gln Gly Ala Asp Ser Glu Ile Lys Phe Ala 
        755                 760                 765 

Lys Thr Leu Glu Glu Ala Pro Ser Ala Pro Pro Gln Gly Val Thr Val 
    770                 775                 780 

Ser Lys Asn Asp Gly Asn Gly Thr Ala Ile Leu Val Ser Trp Gln Pro 
785                 790                 795                 800 

Pro Pro Glu Asp Thr Gln Asn Gly Met Val Gln Glu Tyr Lys Val Trp 
                805                 810                 815 

Cys Leu Gly Asn Glu Thr Arg Tyr His Ile Asn Lys Thr Val Asp Gly 
            820                 825                 830 

Ser Thr Phe Ser Val Val Ile Pro Phe Leu Val Pro Gly Ile Arg Tyr 
        835                 840                 845 

Ser Val Glu Val Ala Ala Ser Thr Gly Ala Gly Ser Gly Val Lys Ser 
    850                 855                 860 

Glu Pro Gln Phe Ile Gln Leu Asp Ala His Gly Asn Pro Val Ser Pro 
865                 870                 875                 880 

Glu Asp Gln Val Ser Leu Ala Gln Gln Ile Ser Asp Val Val Lys Gln 
                885                 890                 895 

Pro Ala Phe Ile Ala Gly Ile Gly Ala Ala Cys Trp Ile Ile Leu Met 
            900                 905                 910 

Val Phe Ser Ile Trp Leu Tyr Arg His Arg Lys Lys Arg Asn Gly Leu 
        915                 920                 925 

Thr Ser Thr Tyr Ala Gly Ile Arg Lys Val Pro Ser Phe Thr Phe Thr 
    930                 935                 940 

Pro Thr Val Thr Tyr Gln Arg Gly Gly Glu Ala Val Ser Ser Gly Gly 
945                 950                 955                 960 

Arg Pro Gly Leu Leu Asn Ile Ser Glu Pro Ala Ala Gln Pro Trp Leu 
                965                 970                 975 

Ala Asp Thr Trp Pro Asn Thr Gly Asn Asn His Asn Asp Cys Ser Ile 
            980                 985                 990 

Ser Cys Cys Thr Ala Gly Asn Gly Asn Ser Asp Ser Asn Leu Thr Thr 
        995                 1000                1005 

Tyr Ser Arg Pro Ala Asp Cys Ile Ala Asn Tyr Asn Asn Gln Leu Asp 
    1010                1015                1020 

Asn Lys Gln Thr Asn Leu Met Leu Pro Glu Ser Thr Val Tyr Gly Asp 
1025                1030                1035                1040 

Val Asp Leu Ser Asn Lys Ile Asn Glu Met Lys Thr Phe Asn Ser Pro 
                1045                1050                1055 

Asn Leu Lys Asp Gly Arg Phe Val Asn Pro Ser Gly Gln Pro Thr Pro 
            1060                1065                1070 

Tyr Ala Thr Thr Gln Leu Ile Gln Ser Asn Leu Ser Asn Asn Met Asn 
        1075                1080                1085 

Asn Gly Ser Gly Asp Ser Gly Glu Lys His Trp Lys Pro Leu Gly Gln 
    1090                1095                1100 

Gln Lys Gln Glu Val Ala Pro Val Gln Tyr Asn Ile Val Glu Gln Asn 
1105                1110                1115                1120 

Lys Leu Asn Lys Asp Tyr Arg Ala Asn Asp Thr Val Pro Pro Thr Ile 
                1125                1130                1135 

Pro Tyr Asn Gln Ser Tyr Asp Gln Asn Thr Gly Gly Ser Tyr Asn Ser 
            1140                1145                1150 

Ser Asp Arg Gly Ser Ser Thr Ser Gly Ser Gln Gly His Lys Lys Gly 
        1155                1160                1165 

Ala Arg Thr Pro Lys Val Pro Lys Gln Gly Gly Met Asn Trp Ala Asp 
    1170                1175                1180 

Leu Leu Pro Pro Pro Pro Ala His Pro Pro Pro His Ser Asn Ser Glu 
1185                1190                1195                1200 

Glu Tyr Asn Ile Ser Val Asp Glu Ser Tyr Asp Gln Glu Met Pro Cys 
                1205                1210                1215 

Pro Val Pro Pro Ala Arg Met Tyr Leu Gln Gln Asp Glu Leu Glu Glu 
            1220                1225                1230 

Glu Glu Asp Glu Arg Gly Pro Thr Pro Pro Val Arg Gly Ala Ala Ser 
        1235                1240                1245 

Ser Pro Ala Ala Val Ser Tyr Ser His Gln Ser Thr Ala Thr Leu Thr 
    1250                1255                1260 

Pro Ser Pro Gln Glu Glu Leu Gln Pro Met Leu Gln Asp Cys Pro Glu 
1265                1270                1275                1280 

Glu Thr Gly His Met Gln His Gln Pro Asp Arg Arg Arg Gln Pro Val 
                1285                1290                1295 

Ser Pro Pro Pro Pro Pro Arg Pro Ile Ser Pro Pro His Thr Tyr Gly 
            1300                1305                1310 

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

Glu Glu Glu Asp Glu Ala Asp Met Glu Val Ala Lys Met Gln Thr Arg 
    1330                1335                1340 

Arg Leu Leu Leu Arg Gly Leu Glu Gln Thr Pro Ala Ser Ser Val Gly 
1345                1350                1355                1360 

Asp Leu Glu Ser Ser Val Thr Gly Ser Met Ile Asn Gly Trp Gly Ser 
                1365                1370                1375 

Ala Ser Glu Glu Asp Asn Ile Ser Ser Gly Arg Ser Ser Val Ser Ser 
            1380                1385                1390 

Ser Asp Gly Ser Phe Phe Thr Asp Ala Asp Phe Ala Gln Ala Val Ala 
        1395                1400                1405 

Ala Ala Ala Glu Tyr Ala Gly Leu Lys Val Ala Arg Arg Gln Met Gln 
    1410                1415                1420 

Asp Ala Ala Gly Arg Arg His Phe His Ala Ser Gln Cys Pro Arg Pro 
1425                1430                1435                1440 

Thr Ser Pro Val Ser Thr Asp Ser Asn Met Ser Ala Ala Val Met Gln 
                1445                1450                1455 

Lys Thr Arg Pro Ala Lys Lys Leu Lys His Gln Pro Gly His Leu Arg 
            1460                1465                1470 

Arg Glu Thr Tyr Thr Asp Asp Leu Pro Pro Pro Pro Val Pro Pro Pro 
        1475                1480                1485 

Ala Ile Lys Ser Pro Thr Ala Gln Ser Lys Thr Gln Leu Glu Val Arg 
    1490                1495                1500 

Pro Val Val Val Pro Lys Leu Pro Ser Met Asp Ala Arg Thr Asp Arg 
1505                1510                1515                1520 

Ser Ser Asp Arg Lys Gly Ser Ser Tyr Lys Gly Arg Glu Val Leu Asp 
                1525                1530                1535 

Gly Arg Gln Val Val Asp Met Arg Thr Asn Pro Gly Asp Pro Arg Glu 
            1540                1545                1550 

Ala Gln Glu Gln Gln Asn Asp Gly Lys Gly Arg Gly Asn Lys Ala Ala 
        1555                1560                1565 

Lys Arg Asp Leu Pro Pro Ala Lys Thr His Leu Ile Gln Glu Asp Ile 
    1570                1575                1580 

Leu Pro Tyr Cys Arg Pro Thr Phe Pro Thr Ser Asn Asn Pro Arg Asp 
1585                1590                1595                1600 

Pro Ser Ser Ser Ser Ser Met Ser Ser Arg Gly Ser Gly Ser Arg Gln 
                1605                1610                1615 

Arg Glu Gln Ala Asn Val Gly Arg Arg Asn Ile Ala Glu Met Gln Val 
            1620                1625                1630 

Leu Gly Gly Tyr Glu Arg Gly Glu Asp Asn Asn Glu Glu Leu Glu Glu 
        1635                1640                1645 

Thr Glu Ser 
    1650 

 
           
             19  
             434  
             PRT  
             human  
             
               misc_feature  
               (285)..(396)  
               note=“Xaa signifies gap in sequence” 
             
           
            19 

Gln Ile Val Ala Gln Gly Arg Thr Val Thr Phe Pro Cys Glu Thr Lys 
1               5                   10                  15 

Gly Asn Pro Gln Pro Ala Val Phe Trp Gln Lys Glu Gly Ser Gln Asn 
            20                  25                  30 

Leu Leu Phe Pro Asn Gln Pro Gln Gln Pro Asn Ser Arg Cys Ser Val 
        35                  40                  45 

Ser Pro Thr Gly Asp Leu Thr Ile Thr Asn Ile Gln Arg Ser Asp Ala 
    50                  55                  60 

Gly Tyr Tyr Ile Cys Gln Ala Leu Thr Val Ala Gly Ser Ile Leu Ala 
65                  70                  75                  80 

Lys Ala Gln Leu Glu Val Thr Asp Val Leu Thr Asp Arg Pro Pro Pro 
                85                  90                  95 

Ile Ile Leu Gln Gly Pro Ala Asn Gln Thr Leu Ala Val Asp Gly Thr 
            100                 105                 110 

Ala Leu Leu Lys Cys Lys Ala Thr Gly Asp Pro Leu Pro Val Ile Ser 
        115                 120                 125 

Trp Leu Lys Glu Gly Phe Thr Phe Pro Gly Arg Asp Pro Arg Ala Thr 
    130                 135                 140 

Ile Gln Glu Gln Gly Thr Leu Gln Ile Lys Asn Leu Arg Ile Ser Asp 
145                 150                 155                 160 

Thr Gly Thr Tyr Thr Cys Val Ala Thr Ser Ser Ser Gly Glu Ala Ser 
                165                 170                 175 

Trp Ser Ala Val Leu Asp Val Thr Glu Ser Gly Ala Thr Ile Ser Lys 
            180                 185                 190 

Asn Tyr Asp Leu Ser Asp Leu Pro Gly Pro Pro Ser Lys Pro Gln Val 
        195                 200                 205 

Thr Asp Val Thr Lys Asn Ser Val Thr Leu Ser Trp Gln Pro Gly Thr 
    210                 215                 220 

Pro Gly Thr Leu Pro Ala Ser Ala Tyr Ile Ile Glu Ala Phe Ser Gln 
225                 230                 235                 240 

Ser Val Ser Asn Ser Trp Gln Thr Val Ala Asn His Val Lys Thr Thr 
                245                 250                 255 

Leu Tyr Thr Val Arg Gly Leu Arg Pro Asn Thr Ile Tyr Leu Phe Met 
            260                 265                 270 

Val Arg Ala Ile Asn Pro Lys Val Ser Val Thr Gln Xaa Lys Pro Gln 
        275                 280                 285 

Lys Asn Asn Gly Ser Thr Trp Ala Asn Val Pro Leu Pro Pro Pro Pro 
    290                 295                 300 

Val Gln Pro Leu Pro Gly Thr Glu Leu Glu His Tyr Ala Val Glu Gln 
305                 310                 315                 320 

Gln Glu Asn Gly Tyr Asp Ser Asp Ser Trp Cys Pro Pro Leu Pro Val 
                325                 330                 335 

Gln Thr Tyr Leu His Gln Gly Leu Glu Asp Glu Leu Glu Glu Asp Asp 
            340                 345                 350 

Asp Arg Val Pro Thr Pro Pro Val Arg Gly Val Ala Ser Ser Pro Ala 
        355                 360                 365 

Ile Ser Phe Gly Gln Gln Ser Thr Ala Thr Leu Thr Pro Ser Pro Arg 
    370                 375                 380 

Glu Glu Met Gln Pro Met Leu Gln Ala Ser Pro Xaa Phe Thr Ser Ser 
385                 390                 395                 400 

Gln Arg Pro Arg Pro Thr Ser Pro Phe Ser Thr Asp Ser Asn Thr Ser 
                405                 410                 415 

Ala Ala Leu Ser Gln Ser Gln Arg Pro Arg Pro Thr Lys Lys His Lys 
            420                 425                 430 

Gly Gly 

 
           
             20  
             148  
             PRT  
             mouse  
           
            20 

Ala Gln Ala Val Ala Ala Ala Ala Glu Tyr Ala Gly Leu Lys Val Ala 
1               5                   10                  15 

Arg Arg Gln Met Gln Asp Ala Ala Gly Arg Arg His Phe His Ala Ser 
            20                  25                  30 

Gln Cys Pro Arg Pro Thr Ser Pro Val Ser Thr Asp Ser Asn Met Ser 
        35                  40                  45 

Ala Val Val Ile Gln Lys Ala Arg Pro Ala Lys Lys Gln Lys His Gln 
    50                  55                  60 

Pro Gly His Leu Arg Arg Glu Ala Tyr Ala Asp Asp Leu Pro Pro Pro 
65                  70                  75                  80 

Pro Val Pro Pro Pro Ala Ile Lys Ser Pro Thr Val Gln Ser Lys Ala 
                85                  90                  95 

Gln Leu Glu Val Arg Pro Val Met Val Pro Lys Leu Ala Ser Ile Glu 
            100                 105                 110 

Ala Arg Thr Asp Arg Ser Ser Asp Arg Lys Gly Gly Ser Tyr Lys Gly 
        115                 120                 125 

Arg Glu Ala Leu Asp Gly Arg Gln Val Thr Asp Leu Arg Thr Asn Pro 
    130                 135                 140 

Ser Asp Pro Arg 
145