Gαq protein variants and their use in the analysis and discovery of agonists and antagonists of chemosensory receptors

This application claims priority to U.S. Provisional Application No. 60/243,770, filed on Oct. 30, 2000, and is incorporated herein by reference in its entirety.

This invention relates to Gαq protein variants and their use in the analysis and discovery of agonists and antagonsists of chemosensory receptors, such as G protein coupled receptors involved in sensing of tastants, olfactants, and pheromones.

Heterotrimeric G proteins, consisting of alpha, beta and gamma subunits, couple ligand-bound seven transmembrane domain receptors (GPCRs or G-protein coupled receptors) to the regulation of effector proteins and production of intracellular second messengers such as cAMP, cGMP, and Ca 2+ . G protein signaling mediates the perception of environmental cues in all higher eukaryotic organisms, including yeast, Dictyostelium, plants, and animals. Agonist-bound sensory receptors catalyze the exchange of GTP for GDP on the surface of the Gx subunit to initiate intracellular responses to extracellular signals. Intracellular signaling is mediated through various effector enzymes, including cGMP phosphodiesterase, phospholipase C, adenylate cyclase, etc. (see Kinnamon & Margolskee, 1996, Curr. Opinion Neurobiol. 6: 506-513). Most effector proteins interact with the Gα, although Gβγ subunits also contribute to the specificity of receptor-G protein coupling (Xu et al., 1998, J. Biol. Chem. 273(42): 27275-79).

The G protein α subunits are grouped into four families, Gα s , Gα i , Gα q , and Gα 12 according to their sequence homologies and functional similarities. The Gα q family members couple a large group of GPCRs to phospholipase C. Activation of Gα q coupled GPCRs induces intracellular calcium release and the capacitative calcium entry from extracellular space. The consequential increase of cytosolic calcium concentration can be effectively detected by using synthetic or genetically-engineered fluorescent calcium indicators, bioluminescent calcium indicators, calcium-activated ion currents, and by monitoring calcium-regulated gene transcription. Assays based on such calcium readout are available in high-throughput screening (HTS) format.

Signaling specificity among a subunits of the same class having similar biochemical functions is not well understood in vivo. For instance, the Gα q (G q ) class includes four proteins expressed in mammals, called Gα q , Gα 11 , Gα 14 , and Gα 15 (in mice, Gα 16 in humans). Whereas orthologs of these subunits are highly conserved across species (99, 97, 96 and 85% identity, respectively), paralogs of these subunits (expressed in the same species) are not as conserved. This suggests that each type of subunit in the G q class has a distinct function, however, when transfected into Sf9 cells, the subunits stimulated phospholipase C with similar potency and showed similar activities (Nakamura et al., 1995, J. Biol. Chem. 270: 6246-6253). Xu and colleagues subsequently showed by gene knockouts in mice that Gq α subunits promiscuously couple to several different receptors in various cell types (1998, J. Biol. Chem. 273(42): 27275).

The promiscuity of the Gα q subclass of G protein subunits provides a valuable tool for analyzing the role of G protein complexes and GPCRs in chemosensory transduction. For instance, the ability of Gα q proteins to bypass the selectivity of the receptor G-protein interaction can be used to study the molecular mechanism of receptor-induced G-protein activation. In addition, the promiscuity toward receptors may be helpful in identifying ligands corresponding to orphan receptors whose signaling properties are unknown. Promiscuous G protein subunits play a particularly useful role in generating screening assays for high affinity GPCR agonists, antagonists, and modulators of chemosensory activity, in that using a single G protein coupler removes the variability of the G protein from the equation, thereby simplifying interpretation of results gleaned from various modulating compounds and GPCRs. Chemosensory modulating compounds involved in taste and/or smell, for instance, could then be used in the pharmaceutical and food industries to customize taste or aroma. In addition, such chemosensory molecules could be used to generate topographic maps that elucidate the relationship between the taste cells of the tongue or olfactory receptors (Ors) and sensory neurons leading to the brain.

Despite their promiscuity, however, Gα q class subunits do not mediate all GPCR—effector interactions. For instance, human Gα 16 and its murine counterpart Gα 15 are promiscuous G proteins in that they couple to GPCRs of different G protein families (Offermanns and Simon, 1995; Negulescu et al., 1997). However, they are not true universal adapters for GPCRs in that there are at least 11 GPCRs reported to be incapable of activating Gα15/Gα16 (Wu et al., 1992; Arai et al., 1996; Kuang et al., 1996; Lee et al., 1998; Parmentier et al., 1998; Mody et al., 2000). Similar problems arise when using Gα 15 /α 16 to identify ligands of ORs and T2Rs (bitter taste receptors) in that (1) calcium responses to odorants are small and quickly desensitized for ORs in Gα 15 /α 16 transiently transfected cells (Krautwurst et al., 1998); (2) most T2Rs remain orphan using cell lines stably transfected with Gα 15 (Adler et al., 2000; Chandrashekar et al., 2000); and (3) threshold concentration of denatonium measured is at least one order higher than expected for bitter receptors, hT2R4 and mT2R8 expressed in cells stably transfected with Gα 15 (Adler et al., 2000; Chandrashekar et al., 2000). These problems suggest that the coupling efficiency between ORs/T2Rs and Gα 15 /α 16 is weak and may vary within the family of ORs and T2Rs.

Given the partial promiscuity of Gα q class proteins, it would be desirable to identify or create Gα protein subunits that are more promiscuous than their native counterparts, and which are capable of interacting with a wider variety GPCRs.

The present invention addresses the above described problems associated with using Gα 15 /α 16 , as well as other problems known in the art relating to the use of weakly promiscuous Gα proteins. Generally, the invention provides a series of Gα q (G q class) protein variants that functionally couple sensory cell receptors such as taste GPCRs (TRs) and olfactory GPCRs (ORs). According to the invention, the functional coupling can be determined, for example, by measuring changes in intracellular IP3 or calcium. In a particular embodiment, the G q protein variants can be expressed in mammalian cell lines or Xenopus oocytes, and then evaluated using calcium fluorescence imaging and electrophysiological recording.

In one aspect of the invention, G alpha class q (G q ) variants that are capable of widely promiscuous functional coupling to chemosensory receptors, such as taste and olfactory receptors, and isolated nucleic acid sequences encoding the same are provided. Another aspect of the invention is directed to chimeric G q variants and the isolated nucleic acids encoding the same. In one embodiment, the chimeric G q protein variants comprise C-terminal sequences from transducin or Gα olf , which exhibit improved functional coupling to taste and olfactory receptors, respectively.

In yet another aspect of the invention, a method for the analysis and discovery of agonists and/or antagonists of chemosensory receptors using the G q protein variants is provided. One embodiment is directed to a mammalian cell-based assay using a transiently transfected gene or cDNA encoding a G q protein variant. Another embodiment is directed to a mammalian cell-based assay using a stably expressed gene or cDNAs encoding G q protein variants. In yet another embodiment, a method for analysis and discovery of agonists and/or antagonists of chemosensory receptors in Xenopus oocytes using genes, RNAs or DNAs encoding G q protein variants is provided. The agonists and/or antagonists discovered using the disclosed assays are also encompassed, as are antibodies which bind specifically to the G q variants described herein, but not those which also bind to known G q proteins.

Other aspects of the invention relate to expression vectors comprising nucleic acid sequences encoding the G q protein variants of the invention, as well as host cells comprising such expression vectors. Further aspects of the invention will become apparent to one of skill in the art from the following detailed description and examples.

BRIEF DESCRIPTION OF THE FIGS.

FIG. 1 illustrates the alignment of amino acid sequences of human Gα q , Gα s and Gα 16 (SEQ ID NOs:37-39, respectively) by the Clustal method.

FIG. 2 illustrates the amino acid sequences of mouse (SEQ ID NO:1) and human Gα q (SEQ ID NO:37). Significant amino acids described herein are boxed and differences between human and mouse are underlined.

FIGS. 3A, 3 B, and 3 C illustrates the amino acid sequences of mouse and human Gα q proteins according to the invention. The variations of the amino acids of Gα q are depicted in parenthesis. The sequence numbers of amino acid H or Q, V or L are 28 and 29 respectively. The sequence number of amino acid G or D is 66. Truncation of N-terminal six amino acids (MTLESI) are shown as ΔN. Hemaglutinin (HA) epitope tag (DVPDYA) spans from 125 to 130. C-terminal five amino acids (-t5) or 44 amino acids (-t44) of transducin and five amino acids of Gctα olf (-olf5) are used respectively to replace those of Gα q .

FIGS. 4A and 4B illustrates additional amino acid sequences according to the invention.

As described above, there are known problems with the use of Gα 15 /Gα 16 to couple chemosensory receptors in that the coupling efficiency between ORs/T2Rs and Gα 15 /α 16 is weak and may vary within the family of ORs and T2Rs (bitter taste receptors). As such, the invention provides a series of G q protein variants that functionally couple sensory cell receptors such as taste GPCRs (TRs) and olfactory GPCRs (ORs) in a promiscuous manner. According to the invention, “promiscuous” or “promiscuity” refers to the ability to functionally couple to more than one taste GCPRs and/or olfactory GPCRs. “Increased promiscuity” or “widely” promiscuous refers to the ability to functionally couple to more taste GCPRs and/or olfactory GPCRs than would be demonstrated by the native G q protein.

The term “G q ” as used herein encompasses all the Gα q subclasses, including Gα q , Gα 11 , Gα 14 , and Gα 15 (in mice, Gα 16 in humans). However, the chimeric promiscuous or widely promiscuous G q proteins described herein may have sequences incorporated from other Gα class proteins, for instance, from Gα s , Gα i and Gα 12 . The existing variation between members of the G q class could be utilized in combination with the characteristic of promiscuity to generate promiscuous G q proteins having altered or new receptor specificities. Protein sequence similarity between Gα q and Gα15/Gα q 16 is less than 57% (FIG. 1 ). Accordingly, such high divergence should result in significant differences in efficiency and selectivity of receptor coupling. The identification of functionally active Gq protein variants could allow for the pharmacological and genetic modulation of sensory transduction pathways.

For example, Gq protein variants could enable screening for high affinity agonists, antagonists, inverse agonists, and other modulators of sensory cell transduction and activity. Such sensory cell modulators could then be used in the pharmaceutical and food industries to customize sensory perceptions. In addition Gq protein variants could serve as tools in the generation of sensory topographic maps.

According to the invention, Gq protein variants include variants having point mutations that increase promiscuity with regard to GPCR coupling. For instance, the inventors have found that mouse Gα q variants comprising a Gly to Asp change at position 66 (G66D) demonstrate increased promiscuity. Similar mutations are predicted to have a similar effect on the activity of the corresponding human Gα 16 subunit given the level of homology and similar activity demonstrated between the two proteins. The mutation G66D is localized at linker 1 region between helices α1 and αA of Gα q (Lambright et al., 1996). For reference, the amino acid sequences for mouse and human Gα q are listed in FIG. 2 .

It was found by functional analysis using single-cell calcium imaging that activation of multi-family GPCRs evoked increases in cytosolic calcium in the presence of the Gα q variants with the G66D mutation. These GPCRs include Gα s -coupled β-adrenergic receptor, Gα olf -coupled mouse I7 olfactory receptor, Gα i -coupled m2 muscarinic receptor, and gustducin-coupled bitter receptor mT2R5. No significant change in cytosolic calcium could be detected by activation of the above GPCRs in the absence of the Gα q variants. Additional GPCRs can include those disclosed in U.S. patent application Ser. No. 09/510,332 filed Feb. 22, 2000; and U.S. Provisional Application No. 60/213,849 filed Jun. 23, 2000; No. 60/209,840 filed Jun. 6, 2000; No. 60/195,536 filed Apr. 7, 2000; No. 60/195,534 filed Apr. 7, 2000; No. 60/195,532 filed Apr. 7, 2000; which are herein incorporated by references for all purposes in a manner consistent with this disclosure.

Thus, Gα q variants according to the invention can comprise amino acid substitutions at or near position 66, or at any other position that results in an increase of promiscuity by the variant Gα protein. Other G q subclass variants can be designed having similar mutations. Mutations can be identified and isolated using site directed or random mutagenesis according to techniques that are known in the art, including random saturation mutagenesis around the mutation sites described herein. The variants may comprise these one or more of these mutations alone or in combination with C-terminal substitutions. In another embodiment of the invention, Gα q and other G q subclass variants comprise C-terminal sequences derived from other G proteins.

For instance, the present inventors have also discovered that the Gly to Asp mutation is synergistic with the replacement of the C-terminus of Gα q by that of transducin or Gα olf . Gα q proteins containing C-terminal amino acids from transducin or Gα olf in combination with a Gly66 to Asp alteration show increased activity compared to individual chimeras alone. A preferred embodiment is a variant G q proteins having at least about five amino acids in the C terminus of said G q protein replaced by at least about five amino acids from the C terminus of Gα olf or transducin, wherein said C-terminal substitution increases promiscuity of said variant G q protein as compared to the corresponding native G q protein. Up to 44 amino acids of the C terminus of transducin or Gα olf may be incorporated. Other possible variants are shown in FIGS. 3 and 4.

Other mutations and substitutions are envisioned to be within the scope of the invention. For instance, it would be within the level of skill in the art to perform additional amino acid substitutions at other amino acid positions using known protocols of recombinant gene technology including PCR, gene cloning, site-directed mutagenesis of cDNA, transfection of host cells, and in-vitro transcription. The variants could then be screened for functional coupling to chemosensory receptors as described herein. Further, additional C-terminal substitutions could be made from other G-protein molecules known in the art.

The present invention also includes isolated Gα q subunit polypeptide variants comprising polypeptides with greater than 80% amino acid sequence identity to a sequence selected from the group consisting of SEQ ID Nos 1-26. More preferably, variants comprising polypeptides with greater than 90% amino acid sequence identity are included, with the most preferable homologs being at least about 95% identical to the variants described herein.

The invention also includes isolated nucleic acid sequences encoding the G q protein variant polypeptides of the invention. Included are isolated nucleic acid sequences comprising a nucleic acid encoding a polypeptide with greater than 80% amino acid sequence identity to a sequence selected from the group consisting of SEQ ID Nos 1-26. More preferably, the isolated nucleic acid sequence encoding a Gα q protein variant comprises a nucleic acid encoding a polypeptide with greater than 90% amino acid sequence identity to a sequence selected from the group consisting of SEQ ID Nos 1-26. Most preferred are isolated nucleic acid sequences encoding Gα q protein variants which comprise a nucleic acid encoding a polypeptide with greater than about 95% amino acid sequence identity to a sequence selected from the group consisting of SEQ ID Nos 1-26.

The terms “identical” or “percent identity” in the context of two or more protein or nucleic acid sequences refers to sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same when compared and aligned for maximum correspondence over a comparison window or designated region, using either a sequence comparison algorithm that is known in the art or by manual inspection. Sequences with over 80% sequence identity are said to be “substantially identical.” Optionally, the identity, exists over a region that is at least about 25-30 amino acids or nucleotides in length, or optionally over a region that is 75-100 amino acids or nucleotides in length.

For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. A “comparison window” as used herein includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 25 to 500, usually about 50 to about 200, more usually about 100 to 150 in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences are well known in the art (see, e.g., Smith and Waterman, 1981, Adv. Appl. Math. 2: 482, Needleman and Wunsch, 1970, J. Mol. Biol. 48: 443, Pearson and Lipman, 1988, Proc. Natl. Acad. Sci. USA 85: 2444, and Current Protocols in Molecular Biology, Ausubel et al., 1995 Suppl.).

One example of a useful algorithm is PILEUP. PILEUP creates a multiple sequence alignment from a group of related sequences using progressive, pairwise alignments to show relationship and percent sequence identity, and can be obtained from the GOG sequence analysis software package, e.g., version 7.0 (Devereaux et al., 1984, Nuc. Acids Res. 12:387-395). Another example of an algorithm that is suitable for determining percent sequence identity is the BLAST or BLAST 2.0 algorithm described in Altschul et al., 1977, Nuc. Acids Res. 25:3389-3402 (1977) and Altschul et al., 1990, J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center Biotechnology Information.

Also included in the present invention are antibodies that selectively bind to the variant G q alpha proteins described herein, but not to the corresponding native G q alpha protein. Such antibodies include whole, chimeric, humanized, tetramer, single chain, domain-deleted and other recombinant antibodies of any immunglobulin class, as well as antibody fragments, Fv, Fab′, (Fab)′ 2 , etc. Preparation of such antibodies may be performed using any method known in the art (see, e.g., Kohler and Milstein, 1975, Nature 256: 495-97; Kozbar et al., 1983, Immunology Today 4: 72; Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, 1985). Mice or other animals may be immunized with the G q protein variants of the invention in order to generate antibodies, which may be screened to identify those specific for the G q variants of the invention which also do not recognize the corresponding native G q protein.

The present invention also encompasses expression vectors comprising the nucleic acid sequences of the present invention operably linked to a promoter that functions in mammalian cells or Xenopus oocytes. A “promoter” is defined as an array of nucleic acid control sequences that direct transcription of a nucleic acid. A “promoter” includes all the necessary sequences near the start site of transcription, i.e., including a polymerase binding site. A promoter optionally includes distal enhancer or repressor elements which can be located as much as thousands base pairs away from the start site of transcription. Promoters may be either constitutive, i.e. active under most environmental and developmental conditions, or inducible, i.e., under specific environmental or developmental control. The term “operably linked” refers to a functional linkage between a nucleic acid expression control sequence (such as a promoter) and a second nucleic acid sequence, such as one encoding a variant G q protein as described in the present invention, wherein the expression control sequence directs transcription of the nucleic acid corresponding to the second sequence. An “expression vector” is a nucleic acid construct comprising a coding nucleic acid sequence according to the invention operably linked to a promoter, which allows for recombinant production of the variant Gq proteins described herein. Expression vectors encompassed by the invention can be either incorporated into the genome of a host cell after transfection, or replicate extrachromosomally. Expression vectors can be either plasmids, viruses or nucleic acid fragments. Alternatively, coding sequences can be incorporated into the genome behind a native promoter, thereby creating an operable expression linkage following transfection. Host cells transfected with the expression vectors of the invention are also encompassed.

The present invention also includes methods for identifying a compound that modulates sensory signaling in sensory cells, the method comprising the steps of: (1) contacting the compound with a cell expressing the G q variant protein according to claim 1 ; and (2) determining the functional effect of said compound upon the G q protein variant. Typically, a cell expressing said G q variant protein is a transfected sensory cell, or other transfected cell suitable for making functional measurements of G protein activity, i.e., Xenopus oocyte. Functional effects of possible modulatory compounds may be determined by measuring changes in intracellular IP3 or Ca 2+ . Functional effects may also be determined by measuring changes in the electrical activity of the cells expressing said G q variant protein or by observing modification of an intracellular effector enzyme. Possible modulatory compounds include agonists, antagonists, antibodies, small molecules and proteins.

Also included in the invention are methods for identifying a compound that interacts with the G q variant protein of claim 1 , comprising the steps of (1) contacting said G q variant protein with a test compound; and (2) detecting a binding interaction between said compound and said G q protein variant. Methods of detecting the binding of G q protein variants to compounds can be performed wherein said G q variant protein is linked to solid phase, either covalently or noncovalently.

The present invention also includes an artificial array of GPCRs functionally coupled to the G q variant of claim 1 , wherein said array is a model of a native arrangement of GPCRs. For instance, the native arrangement can be an arrangement of olfactory receptors (ORs) typically seen in a mammalian nose, or an arrangement of taste receptors typically seen on a mammalian tongue. Said taste receptors typically include at least one type of taste receptor selected from the group consisting of bitter, sweet, salty, unami and sour taste receptors, in light of the observations that such taste receptors are typically arranged in spatially organized manner. The artificial arrays of the present invention are useful for analyzing the response to different sensory compounds in relation to brain activity. Such arrays will be improved by the promiscuous variant G q proteins of the present invention, which will simplify interpretation of results that might normally be complicated by the requirement for different G protein subunits for every GPCR in such an array.

It is also envisioned that the G q protein variants of the invention could be used in other types of functional assays such as biochemical binding assays, enzymatic assays, other cell-based assay, as well as with in vivo systems such as transgenic mice.

The following examples serve merely to illustrate the invention, and should not be construed as limiting the scope of the invention in any way.

Initially, the Gα q variant protein termed mGq(ON-HVD-HA) of Seq ID#5, described in Kostenis et al. (1998), was shown to functionally couple to taste receptor mT2R5 and olfactory OR I7. Previously, it had not been known whether this protein would allow functional expression of chemosensory receptors such as taste and olfactory receptors. The response using the Kostenis et al G protein was weak. Therefore, in order to improve functional coupling a series of variants was created. The variants were chimeras between the variants of the Kostenis G protein which contained the C terminal sequences from Gα olf or transducin. Variants containing the C-terminal changes exhibited improved function. The use of C-terminal replacements in G proteins had previously been reported by Conklin (Conklin et al., 1993; Conklin et al., 1996; Coward et al., 1999) but the sequences from Gα olf or transducin had not previously been shown to function with taste or olfactory receptors.

A series of Gα q protein variants having the sequences listed in FIG. 3 were constructed and tested in mammalian cell-based systems and in Xenopus oocytes for functional coupling efficiency with bitter receptor mT2R5 and mouse olfactory receptor I7. As shown in Table I below, one set of G proteins function with a taste receptor and another set of G proteins function with an olfactory receptor. All active G proteins consisted of mouse sequences, however given the similarities between human and mouse Gα q proteins, it is anticipated that the human variants will also functionally couple with human chemosensory receptors.

References

Adler et al., 2000, “A novel family of taste receptors,” Cell 100: 693-702.

Ari et al., 1996, “Differential regulation of G-protein-mediated signaling by chemokine receptors,” J. Biol. Chem. 271: 21814-21819.

Bertin et al., 1994, “Cellular signaling by an antagonist-activated receptor/Gsα fusion protein,” Proc. Nati. Acad. Sci. USA 91: 8827-8831.

Chandrashekar et al., 2000, “T2Rs function as bitter taste receptors,” Cell 100: 703-711.

Conklin et al., 1996, “Carboxyl-terminal mutations of Gpα and Gsα that alter the fidelity of receptor activation,” Mol. Pharm. 50: 885-90.

Coward et al., 1999, “Chimeric G proteins allow a high-throughput signaling assay of Gi-coupled receptors,” Anal. Biochem. 270: 242-248.

Kostenis et al., 1998, “Functional characterization of a series of mutant G protein alphaq subunits displaying promiscuous receptor coupling properties,” J. Biol. Chem. 273:17886-17892.

Krautwurst et al., “Identification of ligands for olfactory receptors by functional expression of a receptor library,” Cell 95: 917-26.

Kuang et al., 1996, Selective G Protein Coupling to C—C Chemokine Receptors,” J. Biol. Chem. 271:3975-3978.

Lambright et al., 1996, “The 2.0 Å Crystal Structure of a Heterotrimeric G Protein,” Nature, 379: 311-319.

Lee et al., 1998, “Differential Coupling of μ, δ and κ Opioid Receptors to G α16 -mediated Stimulation of Phospholipase C,” J. Neurochem. 70:2203-2211.

Mody et al., 2000, “Incorporation of G αz -Specific Sequence at the Carboxyl Terminus Increases the Promiscuity of G α16 toward G i -coupled Receptors,” Mol. Pharm., 57:13-23.

Negulescu et al., 1997, “Promiscuous G-protein Compositions and Their Use,” U.S. Pat. No. 6,004,808.

Offermanns & Simon, 1995, Gα15 and Gα16 couple a wide variety of receptors to phospholipase C,” J. Biol. Chem. 270:15175-15180.

Parmentier et al., 1998, The G protein-coupling Profile of Metabotropic Glutamate Receptors, as Determined with Exogenous G Proteins, is Independent of Their Ligand Recognition Domain,” Mol. Pharmacol. 53:778-786.

Seifert et al., 1999, “GPCR-Gα Fusion Proteins: Molecular Analysis of Receptor-G-Protein Coupling,” TiPS 20:383-389.

Wu et al., 1992, “Activation of Phospholipase C by α1-adrenergic Receptors is Mediated by the α Subunits of the Gq Family,” J. Biol. Chem. 267:25798-25802.

42

1

359

Mus sp.

1

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg Gln Leu Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Gly Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Glu Asn Pro Tyr

115 120 125

Val Asp Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ser Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Ile Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Glu Tyr Asn Leu Val

355

2

353

Mus sp.

2

Met Ala Cys Cys Leu Ser Glu Glu Ala Lys Glu Ala Arg Arg Ile Asn

1 5 10 15

Asp Glu Ile Glu Arg Gln Leu Arg Arg Asp Lys Arg Asp Ala Arg Arg

20 25 30

Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly Glu Ser Gly Lys Ser Thr

35 40 45

Phe Ile Lys Gln Met Arg Ile Ile His Gly Ser Gly Tyr Ser Asp Glu

50 55 60

Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr Gln Asn Ile Phe Thr Ala

65 70 75 80

Met Gln Ala Met Ile Arg Ala Met Asp Thr Leu Lys Ile Pro Tyr Lys

85 90 95

Tyr Glu His Asn Lys Ala His Ala Gln Leu Val Arg Glu Val Asp Val

100 105 110

Glu Lys Val Ser Ala Phe Glu Asn Pro Tyr Val Asp Ala Ile Lys Ser

115 120 125

Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys Tyr Asp Arg Arg Arg Glu

130 135 140

Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr Leu Asn Asp Leu Asp Arg

145 150 155 160

Val Ala Asp Pro Ser Tyr Leu Pro Thr Gln Gln Asp Val Leu Arg Val

165 170 175

Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr Pro Phe Asp Leu Gln Ser

180 185 190

Val Ile Phe Arg Met Val Asp Val Gly Gly Gln Arg Ser Glu Arg Arg

195 200 205

Lys Trp Ile His Cys Phe Glu Asn Val Thr Ser Ile Met Phe Leu Val

210 215 220

Ala Leu Ser Glu Tyr Asp Gln Val Leu Val Glu Ser Asp Asn Glu Asn

225 230 235 240

Arg Met Glu Glu Ser Lys Ala Leu Phe Arg Thr Ile Ile Thr Tyr Pro

245 250 255

Trp Phe Gln Asn Ser Ser Val Ile Leu Phe Leu Asn Lys Lys Asp Leu

260 265 270

Leu Glu Glu Lys Ile Met Tyr Ser His Leu Val Asp Tyr Phe Pro Glu

275 280 285

Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala Ala Arg Glu Phe Ile Leu

290 295 300

Lys Met Phe Val Asp Leu Asn Pro Asp Ser Asp Lys Ile Ile Tyr Ser

305 310 315 320

His Phe Thr Cys Ala Thr Asp Thr Glu Asn Ile Arg Phe Val Phe Ala

325 330 335

Ala Val Lys Asp Thr Ile Leu Gln Leu Asn Leu Lys Glu Tyr Asn Leu

340 345 350

Val

3

359

Mus sp.

3

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg Gln Leu Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Gly Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Asp Val Pro Asp

115 120 125

Tyr Ala Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ser Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Ile Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Glu Tyr Asn Leu Val

355

4

353

Mus sp.

4

Met Ala Cys Cys Leu Ser Glu Glu Ala Lys Glu Ala Arg Arg Ile Asn

1 5 10 15

Asp Glu Ile Glu Arg Gln Leu Arg Arg Asp Lys Arg Asp Ala Arg Arg

20 25 30

Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly Glu Ser Gly Lys Ser Thr

35 40 45

Phe Ile Lys Gln Met Arg Ile Ile His Gly Ser Gly Tyr Ser Asp Glu

50 55 60

Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr Gln Asn Ile Phe Thr Ala

65 70 75 80

Met Gln Ala Met Ile Arg Ala Met Asp Thr Leu Lys Ile Pro Tyr Lys

85 90 95

Tyr Glu His Asn Lys Ala His Ala Gln Leu Val Arg Glu Val Asp Val

100 105 110

Glu Lys Val Ser Ala Phe Asp Val Pro Asp Tyr Ala Ala Ile Lys Ser

115 120 125

Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys Tyr Asp Arg Arg Arg Glu

130 135 140

Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr Leu Asn Asp Leu Asp Arg

145 150 155 160

Val Ala Asp Pro Ser Tyr Leu Pro Thr Gln Gln Asp Val Leu Arg Val

165 170 175

Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr Pro Phe Asp Leu Gln Ser

180 185 190

Val Ile Phe Arg Met Val Asp Val Gly Gly Gln Arg Ser Glu Arg Arg

195 200 205

Lys Trp Ile His Cys Phe Glu Asn Val Thr Ser Ile Met Phe Leu Val

210 215 220

Ala Leu Ser Glu Tyr Asp Gln Val Leu Val Glu Ser Asp Asn Glu Asn

225 230 235 240

Arg Met Glu Glu Ser Lys Ala Leu Phe Arg Thr Ile Ile Thr Tyr Pro

245 250 255

Trp Phe Gln Asn Ser Ser Val Ile Leu Phe Leu Asn Lys Lys Asp Leu

260 265 270

Leu Glu Glu Lys Ile Met Tyr Ser His Leu Val Asp Tyr Phe Pro Glu

275 280 285

Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala Ala Arg Glu Phe Ile Leu

290 295 300

Lys Met Phe Val Asp Leu Asn Pro Asp Ser Asp Lys Ile Ile Tyr Ser

305 310 315 320

His Phe Thr Cys Ala Thr Asp Thr Glu Asn Ile Arg Phe Val Phe Ala

325 330 335

Ala Val Lys Asp Thr Ile Leu Gln Leu Asn Leu Lys Glu Tyr Asn Leu

340 345 350

Val

5

353

Mus sp.

5

Met Ala Cys Cys Leu Ser Glu Glu Ala Lys Glu Ala Arg Arg Ile Asn

1 5 10 15

Asp Glu Ile Glu Arg Gln Leu Arg Arg Asp Lys Arg Asp Ala Arg Arg

20 25 30

Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly Glu Ser Gly Lys Ser Thr

35 40 45

Phe Ile Lys Gln Met Arg Ile Ile His Gly Ser Gly Tyr Ser Asp Glu

50 55 60

Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr Gln Asn Ile Phe Thr Ala

65 70 75 80

Met Gln Ala Met Ile Arg Ala Met Asp Thr Leu Lys Ile Pro Tyr Lys

85 90 95

Tyr Glu His Asn Lys Ala His Ala Gln Leu Val Arg Glu Val Asp Val

100 105 110

Glu Lys Val Ser Ala Phe Asp Val Pro Asp Tyr Ala Ala Ile Lys Ser

115 120 125

Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys Tyr Asp Arg Arg Arg Glu

130 135 140

Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr Leu Asn Asp Leu Asp Arg

145 150 155 160

Val Ala Asp Pro Ser Tyr Leu Pro Thr Gln Gln Asp Val Leu Arg Val

165 170 175

Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr Pro Phe Asp Leu Gln Ser

180 185 190

Val Ile Phe Arg Met Val Asp Val Gly Gly Gln Arg Ser Glu Arg Arg

195 200 205

Lys Trp Ile His Cys Phe Glu Asn Val Thr Ser Ile Met Phe Leu Val

210 215 220

Ala Leu Ser Glu Tyr Asp Gln Val Leu Val Glu Ser Asp Asn Glu Asn

225 230 235 240

Arg Met Glu Glu Ser Lys Ala Leu Phe Arg Thr Ile Ile Thr Tyr Pro

245 250 255

Trp Phe Gln Asn Ser Ser Val Ile Leu Phe Leu Asn Lys Lys Asp Leu

260 265 270

Leu Glu Glu Lys Ile Met Tyr Ser His Leu Val Asp Tyr Phe Pro Glu

275 280 285

Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala Ala Arg Glu Phe Ile Leu

290 295 300

Lys Met Phe Val Asp Leu Asn Pro Asp Ser Asp Lys Ile Ile Tyr Ser

305 310 315 320

His Phe Thr Cys Ala Thr Asp Thr Glu Asn Ile Arg Phe Val Phe Ala

325 330 335

Ala Val Lys Asp Thr Ile Leu Gln Leu Asn Leu Lys Glu Tyr Asn Leu

340 345 350

Val

6

353

Mus sp.

6

Met Ala Cys Cys Leu Ser Glu Glu Ala Lys Glu Ala Arg Arg Ile Asn

1 5 10 15

Asp Glu Ile Glu Arg His Val Arg Arg Asp Lys Arg Asp Ala Arg Arg

20 25 30

Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly Glu Ser Gly Lys Ser Thr

35 40 45

Phe Ile Lys Gln Met Arg Ile Ile His Gly Ser Gly Tyr Ser Asp Glu

50 55 60

Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr Gln Asn Ile Phe Thr Ala

65 70 75 80

Met Gln Ala Met Ile Arg Ala Met Asp Thr Leu Lys Ile Pro Tyr Lys

85 90 95

Tyr Glu His Asn Lys Ala His Ala Gln Leu Val Arg Glu Val Asp Val

100 105 110

Glu Lys Val Ser Ala Phe Asp Val Pro Asp Tyr Ala Ala Ile Lys Ser

115 120 125

Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys Tyr Asp Arg Arg Arg Glu

130 135 140

Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr Leu Asn Asp Leu Asp Arg

145 150 155 160

Val Ala Asp Pro Ser Tyr Leu Pro Thr Gln Gln Asp Val Leu Arg Val

165 170 175

Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr Pro Phe Asp Leu Gln Ser

180 185 190

Val Ile Phe Arg Met Val Asp Val Gly Gly Gln Arg Ser Glu Arg Arg

195 200 205

Lys Trp Ile His Cys Phe Glu Asn Val Thr Ser Ile Met Phe Leu Val

210 215 220

Ala Leu Ser Glu Tyr Asp Gln Val Leu Val Glu Ser Asp Asn Glu Asn

225 230 235 240

Arg Met Glu Glu Ser Lys Ala Leu Phe Arg Thr Ile Ile Thr Tyr Pro

245 250 255

Trp Phe Gln Asn Ser Ser Val Ile Leu Phe Leu Asn Lys Lys Asp Leu

260 265 270

Leu Glu Glu Lys Ile Met Tyr Ser His Leu Val Asp Tyr Phe Pro Glu

275 280 285

Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala Ala Arg Glu Phe Ile Leu

290 295 300

Lys Met Phe Val Asp Leu Asn Pro Asp Ser Asp Lys Ile Ile Tyr Ser

305 310 315 320

His Phe Thr Cys Ala Thr Asp Thr Glu Asn Ile Arg Phe Val Phe Ala

325 330 335

Ala Val Lys Asp Thr Ile Leu Gln Leu Asn Leu Lys Asp Cys Gly Leu

340 345 350

Phe

7

357

Mus sp.

7

Met Ala Cys Cys Leu Ser Glu Glu Ala Lys Glu Ala Arg Arg Ile Asn

1 5 10 15

Asp Glu Ile Glu Arg His Val Arg Arg Asp Lys Arg Asp Ala Arg Arg

20 25 30

Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly Glu Ser Gly Lys Ser Thr

35 40 45

Phe Ile Lys Gln Met Arg Ile Ile His Gly Ser Gly Tyr Ser Asp Glu

50 55 60

Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr Gln Asn Ile Phe Thr Ala

65 70 75 80

Met Gln Ala Met Ile Arg Ala Met Asp Thr Leu Lys Ile Pro Tyr Lys

85 90 95

Tyr Glu His Asn Lys Ala His Ala Gln Leu Val Arg Glu Val Asp Val

100 105 110

Glu Lys Val Ser Ala Phe Asp Val Pro Asp Tyr Ala Ala Ile Lys Ser

115 120 125

Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys Tyr Asp Arg Arg Arg Glu

130 135 140

Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr Leu Asn Asp Leu Asp Arg

145 150 155 160

Val Ala Asp Pro Ser Tyr Leu Pro Thr Gln Gln Asp Val Leu Arg Val

165 170 175

Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr Pro Phe Asp Leu Gln Ser

180 185 190

Val Ile Phe Arg Met Val Asp Val Gly Gly Gln Arg Ser Glu Arg Arg

195 200 205

Lys Trp Ile His Cys Phe Glu Asn Val Thr Ser Ile Met Phe Leu Val

210 215 220

Ala Leu Ser Glu Tyr Asp Gln Val Leu Val Glu Ser Asp Asn Glu Asn

225 230 235 240

Arg Met Glu Glu Ser Lys Ala Leu Phe Arg Thr Ile Ile Thr Tyr Pro

245 250 255

Trp Phe Gln Asn Ser Ser Val Ile Leu Phe Leu Asn Lys Lys Asp Leu

260 265 270

Leu Glu Glu Lys Ile Met Tyr Ser His Leu Val Asp Tyr Phe Pro Glu

275 280 285

Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala Ala Arg Glu Phe Ile Leu

290 295 300

Lys Met Phe Val Asp Leu Asn Pro Asp Asn Met Arg Arg Asp Val Lys

305 310 315 320

Glu Ile Tyr Ser His Met Thr Cys Ala Thr Asp Thr Gln Asn Val Lys

325 330 335

Phe Val Phe Asp Ala Val Thr Asp Ile Ile Ile Lys Glu Asn Leu Lys

340 345 350

Asp Cys Gly Leu Phe

355

8

353

Mus sp.

8

Met Ala Cys Cys Leu Ser Glu Glu Ala Lys Glu Ala Arg Arg Ile Asn

1 5 10 15

Asp Glu Ile Glu Arg His Val Arg Arg Asp Lys Arg Asp Ala Arg Arg

20 25 30

Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly Glu Ser Gly Lys Ser Thr

35 40 45

Phe Ile Lys Gln Met Arg Ile Ile His Gly Ser Gly Tyr Ser Asp Glu

50 55 60

Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr Gln Asn Ile Phe Thr Ala

65 70 75 80

Met Gln Ala Met Ile Arg Ala Met Asp Thr Leu Lys Ile Pro Tyr Lys

85 90 95

Tyr Glu His Asn Lys Ala His Ala Gln Leu Val Arg Glu Val Asp Val

100 105 110

Glu Lys Val Ser Ala Phe Asp Val Pro Asp Tyr Ala Ala Ile Lys Ser

115 120 125

Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys Tyr Asp Arg Arg Arg Glu

130 135 140

Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr Leu Asn Asp Leu Asp Arg

145 150 155 160

Val Ala Asp Pro Ser Tyr Leu Pro Thr Gln Gln Asp Val Leu Arg Val

165 170 175

Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr Pro Phe Asp Leu Gln Ser

180 185 190

Val Ile Phe Arg Met Val Asp Val Gly Gly Gln Arg Ser Glu Arg Arg

195 200 205

Lys Trp Ile His Cys Phe Glu Asn Val Thr Ser Ile Met Phe Leu Val

210 215 220

Ala Leu Ser Glu Tyr Asp Gln Val Leu Val Glu Ser Asp Asn Glu Asn

225 230 235 240

Arg Met Glu Glu Ser Lys Ala Leu Phe Arg Thr Ile Ile Thr Tyr Pro

245 250 255

Trp Phe Gln Asn Ser Ser Val Ile Leu Phe Leu Asn Lys Lys Asp Leu

260 265 270

Leu Glu Glu Lys Ile Met Tyr Ser His Leu Val Asp Tyr Phe Pro Glu

275 280 285

Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala Ala Arg Glu Phe Ile Leu

290 295 300

Lys Met Phe Val Asp Leu Asn Pro Asp Ser Asp Lys Ile Ile Tyr Ser

305 310 315 320

His Phe Thr Cys Ala Thr Asp Thr Glu Asn Ile Arg Phe Val Phe Ala

325 330 335

Ala Val Lys Asp Thr Ile Leu Gln Leu Asn Leu Lys Glu Tyr Asn Leu

340 345 350

Val

9

359

Mus sp.

9

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg His Val Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Gly Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Asp Val Pro Asp

115 120 125

Tyr Ala Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ser Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Ile Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Glu Tyr Asn Leu Val

355

10

359

Mus sp.

10

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg Gln Leu Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Asp Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Asp Val Pro Asp

115 120 125

Tyr Ala Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ser Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Ile Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Glu Tyr Asn Leu Val

355

11

359

Mus sp.

11

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg His Val Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Asp Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Asp Val Pro Asp

115 120 125

Tyr Ala Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ser Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Ile Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Glu Tyr Asn Leu Val

355

12

359

Mus sp.

12

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg His Val Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Gly Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Asp Val Pro Asp

115 120 125

Tyr Ala Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ser Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Ile Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Asp Cys Gly Leu Phe

355

13

359

Mus sp.

13

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg His Val Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Asp Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Asp Val Pro Asp

115 120 125

Tyr Ala Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ser Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Ile Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Asp Cys Gly Leu Phe

355

14

353

Mus sp.

14

Met Ala Cys Cys Leu Ser Glu Glu Ala Lys Glu Ala Arg Arg Ile Asn

1 5 10 15

Asp Glu Ile Glu Arg His Val Arg Arg Asp Lys Arg Asp Ala Arg Arg

20 25 30

Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly Glu Ser Gly Lys Ser Thr

35 40 45

Phe Ile Lys Gln Met Arg Ile Ile His Gly Ser Asp Tyr Ser Asp Glu

50 55 60

Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr Gln Asn Ile Phe Thr Ala

65 70 75 80

Met Gln Ala Met Ile Arg Ala Met Asp Thr Leu Lys Ile Pro Tyr Lys

85 90 95

Tyr Glu His Asn Lys Ala His Ala Gln Leu Val Arg Glu Val Asp Val

100 105 110

Glu Lys Val Ser Ala Phe Asp Val Pro Asp Tyr Ala Ala Ile Lys Ser

115 120 125

Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys Tyr Asp Arg Arg Arg Glu

130 135 140

Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr Leu Asn Asp Leu Asp Arg

145 150 155 160

Val Ala Asp Pro Ser Tyr Leu Pro Thr Gln Gln Asp Val Leu Arg Val

165 170 175

Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr Pro Phe Asp Leu Gln Ser

180 185 190

Val Ile Phe Arg Met Val Asp Val Gly Gly Gln Arg Ser Glu Arg Arg

195 200 205

Lys Trp Ile His Cys Phe Glu Asn Val Thr Ser Ile Met Phe Leu Val

210 215 220

Ala Leu Ser Glu Tyr Asp Gln Val Leu Val Glu Ser Asp Asn Glu Asn

225 230 235 240

Arg Met Glu Glu Ser Lys Ala Leu Phe Arg Thr Ile Ile Thr Tyr Pro

245 250 255

Trp Phe Gln Asn Ser Ser Val Ile Leu Phe Leu Asn Lys Lys Asp Leu

260 265 270

Leu Glu Glu Lys Ile Met Tyr Ser His Leu Val Asp Tyr Phe Pro Glu

275 280 285

Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala Ala Arg Glu Phe Ile Leu

290 295 300

Lys Met Phe Val Asp Leu Asn Pro Asp Ser Asp Lys Ile Ile Tyr Ser

305 310 315 320

His Phe Thr Cys Ala Thr Asp Thr Glu Asn Ile Arg Phe Val Phe Ala

325 330 335

Ala Val Lys Asp Thr Ile Leu Gln Leu Asn Leu Lys Gln Tyr Glu Leu

340 345 350

Leu

15

359

Homo sapiens

15

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg Gln Leu Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Gly Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Glu Asn Pro Tyr

115 120 125

Val Asp Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ala Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Asn Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Glu Tyr Asn Ala Val

355

16

353

Homo sapiens

16

Met Ala Cys Cys Leu Ser Glu Glu Ala Lys Glu Ala Arg Arg Ile Asn

1 5 10 15

Asp Glu Ile Glu Arg Gln Leu Arg Arg Asp Lys Arg Asp Ala Arg Arg

20 25 30

Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly Glu Ser Gly Lys Ser Thr

35 40 45

Phe Ile Lys Gln Met Arg Ile Ile His Gly Ser Gly Tyr Ser Asp Glu

50 55 60

Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr Gln Asn Ile Phe Thr Ala

65 70 75 80

Met Gln Ala Met Ile Arg Ala Met Asp Thr Leu Lys Ile Pro Tyr Lys

85 90 95

Tyr Glu His Asn Lys Ala His Ala Gln Leu Val Arg Glu Val Asp Val

100 105 110

Glu Lys Val Ser Ala Phe Glu Asn Pro Tyr Val Asp Ala Ile Lys Ser

115 120 125

Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys Tyr Asp Arg Arg Arg Glu

130 135 140

Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr Leu Asn Asp Leu Asp Arg

145 150 155 160

Val Ala Asp Pro Ala Tyr Leu Pro Thr Gln Gln Asp Val Leu Arg Val

165 170 175

Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr Pro Phe Asp Leu Gln Ser

180 185 190

Val Ile Phe Arg Met Val Asp Val Gly Gly Gln Arg Ser Glu Arg Arg

195 200 205

Lys Trp Ile His Cys Phe Glu Asn Val Thr Ser Ile Met Phe Leu Val

210 215 220

Ala Leu Ser Glu Tyr Asp Gln Val Leu Val Glu Ser Asp Asn Glu Asn

225 230 235 240

Arg Met Glu Glu Ser Lys Ala Leu Phe Arg Thr Ile Ile Thr Tyr Pro

245 250 255

Trp Phe Gln Asn Ser Ser Val Ile Leu Phe Leu Asn Lys Lys Asp Leu

260 265 270

Leu Glu Glu Lys Ile Met Tyr Ser His Leu Val Asp Tyr Phe Pro Glu

275 280 285

Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala Ala Arg Glu Phe Ile Leu

290 295 300

Lys Met Phe Val Asp Leu Asn Pro Asp Ser Asp Lys Ile Ile Tyr Ser

305 310 315 320

His Phe Thr Cys Ala Thr Asp Thr Glu Asn Ile Arg Phe Val Phe Ala

325 330 335

Ala Val Lys Asp Thr Ile Leu Gln Leu Asn Leu Lys Glu Tyr Asn Ala

340 345 350

Val

17

353

Homo sapiens

17

Met Ala Cys Cys Leu Ser Glu Glu Ala Lys Glu Ala Arg Arg Ile Asn

1 5 10 15

Asp Glu Ile Glu Arg His Val Arg Arg Asp Lys Arg Asp Ala Arg Arg

20 25 30

Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly Glu Ser Gly Lys Ser Thr

35 40 45

Phe Ile Lys Gln Met Arg Ile Ile His Gly Ser Asp Tyr Ser Asp Glu

50 55 60

Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr Gln Asn Ile Phe Thr Ala

65 70 75 80

Met Gln Ala Met Ile Arg Ala Met Asp Thr Leu Lys Ile Pro Tyr Lys

85 90 95

Tyr Glu His Asn Lys Ala His Ala Gln Leu Val Arg Glu Val Asp Val

100 105 110

Glu Lys Val Ser Ala Phe Asp Val Pro Asp Tyr Ala Ala Ile Lys Ser

115 120 125

Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys Tyr Asp Arg Arg Arg Glu

130 135 140

Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr Leu Asn Asp Leu Asp Arg

145 150 155 160

Val Ala Asp Pro Ala Tyr Leu Pro Thr Gln Gln Asp Val Leu Arg Val

165 170 175

Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr Pro Phe Asp Leu Gln Ser

180 185 190

Val Ile Phe Arg Met Val Asp Val Gly Gly Gln Arg Ser Glu Arg Arg

195 200 205

Lys Trp Ile His Cys Phe Glu Asn Val Thr Ser Ile Met Phe Leu Val

210 215 220

Ala Leu Ser Glu Tyr Asp Gln Val Leu Val Glu Ser Asp Asn Glu Asn

225 230 235 240

Arg Met Glu Glu Ser Lys Ala Leu Phe Arg Thr Ile Ile Thr Tyr Pro

245 250 255

Trp Phe Gln Asn Ser Ser Val Ile Leu Phe Leu Asn Lys Lys Asp Leu

260 265 270

Leu Glu Glu Lys Ile Met Tyr Ser His Leu Val Asp Tyr Phe Pro Glu

275 280 285

Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala Ala Arg Glu Phe Ile Leu

290 295 300

Lys Met Phe Val Asp Leu Asn Pro Asp Ser Asp Lys Ile Ile Tyr Ser

305 310 315 320

His Phe Thr Cys Ala Thr Asp Thr Glu Asn Ile Arg Phe Val Phe Ala

325 330 335

Ala Val Lys Asp Thr Ile Leu Gln Leu Asn Leu Lys Glu Tyr Asn Leu

340 345 350

Val

18

353

Homo sapiens

18

Met Ala Cys Cys Leu Ser Glu Glu Ala Lys Glu Ala Arg Arg Ile Asn

1 5 10 15

Asp Glu Ile Glu Arg His Val Arg Arg Asp Lys Arg Asp Ala Arg Arg

20 25 30

Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly Glu Ser Gly Lys Ser Thr

35 40 45

Phe Ile Lys Gln Met Arg Ile Ile His Gly Ser Asp Tyr Ser Asp Glu

50 55 60

Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr Gln Asn Ile Phe Thr Ala

65 70 75 80

Met Gln Ala Met Ile Arg Ala Met Asp Thr Leu Lys Ile Pro Tyr Lys

85 90 95

Tyr Glu His Asn Lys Ala His Ala Gln Leu Val Arg Glu Val Asp Val

100 105 110

Glu Lys Val Ser Ala Phe Asp Val Pro Asp Tyr Ala Ala Ile Lys Ser

115 120 125

Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys Tyr Asp Arg Arg Arg Glu

130 135 140

Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr Leu Asn Asp Leu Asp Arg

145 150 155 160

Val Ala Asp Pro Ala Tyr Leu Pro Thr Gln Gln Asp Val Leu Arg Val

165 170 175

Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr Pro Phe Asp Leu Gln Ser

180 185 190

Val Ile Phe Arg Met Val Asp Val Gly Gly Gln Arg Ser Glu Arg Arg

195 200 205

Lys Trp Ile His Cys Phe Glu Asn Val Thr Ser Ile Met Phe Leu Val

210 215 220

Ala Leu Ser Glu Tyr Asp Gln Val Leu Val Glu Ser Asp Asn Glu Asn

225 230 235 240

Arg Met Glu Glu Ser Lys Ala Leu Phe Arg Thr Ile Ile Thr Tyr Pro

245 250 255

Trp Phe Gln Asn Ser Ser Val Ile Leu Phe Leu Asn Lys Lys Asp Leu

260 265 270

Leu Glu Glu Lys Ile Met Tyr Ser His Leu Val Asp Tyr Phe Pro Glu

275 280 285

Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala Ala Arg Glu Phe Ile Leu

290 295 300

Lys Met Phe Val Asp Leu Asn Pro Asp Ser Asp Lys Ile Ile Tyr Ser

305 310 315 320

His Phe Thr Cys Ala Thr Asp Thr Glu Asn Ile Arg Phe Val Phe Ala

325 330 335

Ala Val Lys Asp Thr Ile Leu Gln Leu Asn Leu Lys Asp Cys Gly Leu

340 345 350

Phe

19

353

Homo sapiens

19

Met Ala Cys Cys Leu Ser Glu Glu Ala Lys Glu Ala Arg Arg Ile Asn

1 5 10 15

Asp Glu Ile Glu Arg His Val Arg Arg Asp Lys Arg Asp Ala Arg Arg

20 25 30

Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly Glu Ser Gly Lys Ser Thr

35 40 45

Phe Ile Lys Gln Met Arg Ile Ile His Gly Ser Asp Tyr Ser Asp Glu

50 55 60

Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr Gln Asn Ile Phe Thr Ala

65 70 75 80

Met Gln Ala Met Ile Arg Ala Met Asp Thr Leu Lys Ile Pro Tyr Lys

85 90 95

Tyr Glu His Asn Lys Ala His Ala Gln Leu Val Arg Glu Val Asp Val

100 105 110

Glu Lys Val Ser Ala Phe Asp Val Pro Asp Tyr Ala Ala Ile Lys Ser

115 120 125

Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys Tyr Asp Arg Arg Arg Glu

130 135 140

Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr Leu Asn Asp Leu Asp Arg

145 150 155 160

Val Ala Asp Pro Ala Tyr Leu Pro Thr Gln Gln Asp Val Leu Arg Val

165 170 175

Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr Pro Phe Asp Leu Gln Ser

180 185 190

Val Ile Phe Arg Met Val Asp Val Gly Gly Gln Arg Ser Glu Arg Arg

195 200 205

Lys Trp Ile His Cys Phe Glu Asn Val Thr Ser Ile Met Phe Leu Val

210 215 220

Ala Leu Ser Glu Tyr Asp Gln Val Leu Val Glu Ser Asp Asn Glu Asn

225 230 235 240

Arg Met Glu Glu Ser Lys Ala Leu Phe Arg Thr Ile Ile Thr Tyr Pro

245 250 255

Trp Phe Gln Asn Ser Ser Val Ile Leu Phe Leu Asn Lys Lys Asp Leu

260 265 270

Leu Glu Glu Lys Ile Met Tyr Ser His Leu Val Asp Tyr Phe Pro Glu

275 280 285

Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala Ala Arg Glu Phe Ile Leu

290 295 300

Lys Met Phe Val Asp Leu Asn Pro Asp Ser Asp Lys Ile Ile Tyr Ser

305 310 315 320

His Phe Thr Cys Ala Thr Asp Thr Glu Asn Ile Arg Phe Val Phe Ala

325 330 335

Ala Val Lys Asp Thr Ile Leu Gln Leu Asn Leu Lys Asp Cys Gly Leu

340 345 350

Phe

20

359

Homo sapiens

20

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg Gln Leu Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Asp Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Asp Val Pro Asp

115 120 125

Tyr Ala Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ala Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Ile Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Glu Tyr Asn Leu Val

355

21

359

Homo sapiens

21

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg His Val Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Asp Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Asp Val Pro Asp

115 120 125

Tyr Ala Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ala Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Ile Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Glu Tyr Asn Leu Val

355

22

359

Homo sapiens

22

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg His Val Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Gly Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Asp Val Pro Asp

115 120 125

Tyr Ala Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ala Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Ile Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Asp Cys Gly Leu Phe

355

23

359

Homo sapiens

23

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg His Val Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Asp Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Asp Val Pro Asp

115 120 125

Tyr Ala Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ala Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Asn Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Asp Cys Gly Leu Phe

355

24

353

Homo sapiens

24

Met Ala Cys Cys Leu Ser Glu Glu Ala Lys Glu Ala Arg Arg Ile Asn

1 5 10 15

Asp Glu Ile Glu Arg His Val Arg Arg Asp Lys Arg Asp Ala Arg Arg

20 25 30

Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly Glu Ser Gly Lys Ser Thr

35 40 45

Phe Ile Lys Gln Met Arg Ile Ile His Gly Ser Asp Tyr Ser Asp Glu

50 55 60

Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr Gln Asn Ile Phe Thr Ala

65 70 75 80

Met Gln Ala Met Ile Arg Ala Met Asp Thr Leu Lys Ile Pro Tyr Lys

85 90 95

Tyr Glu His Asn Lys Ala His Ala Gln Leu Val Arg Glu Val Asp Val

100 105 110

Glu Lys Val Ser Ala Phe Asp Val Pro Asp Tyr Ala Ala Ile Lys Ser

115 120 125

Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys Tyr Asp Arg Arg Arg Glu

130 135 140

Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr Leu Asn Asp Leu Asp Arg

145 150 155 160

Val Ala Asp Pro Ala Tyr Leu Pro Thr Gln Gln Asp Val Leu Arg Val

165 170 175

Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr Pro Phe Asp Leu Gln Ser

180 185 190

Val Ile Phe Arg Met Val Asp Val Gly Gly Gln Arg Ser Glu Arg Arg

195 200 205

Lys Trp Ile His Cys Phe Glu Asn Val Thr Ser Ile Met Phe Leu Val

210 215 220

Ala Leu Ser Glu Tyr Asp Gln Val Leu Val Glu Ser Asp Asn Glu Asn

225 230 235 240

Arg Met Glu Glu Ser Lys Ala Leu Phe Arg Thr Ile Ile Thr Tyr Pro

245 250 255

Trp Phe Gln Asn Ser Ser Val Ile Leu Phe Leu Asn Lys Lys Asp Leu

260 265 270

Leu Glu Glu Lys Ile Met Tyr Ser His Leu Val Asp Tyr Phe Pro Glu

275 280 285

Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala Ala Arg Glu Phe Ile Leu

290 295 300

Lys Met Phe Val Asp Leu Asn Pro Asp Ser Asp Lys Ile Ile Tyr Ser

305 310 315 320

His Phe Thr Cys Ala Thr Asp Thr Glu Asn Ile Arg Phe Val Phe Ala

325 330 335

Ala Val Lys Asp Thr Ile Leu Gln Leu Asn Leu Lys Gln Tyr Glu Leu

340 345 350

Leu

25

359

Homo sapiens

25

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg His Val Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Asp Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Asp Val Pro Asp

115 120 125

Tyr Ala Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ala Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Ile Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Gln Tyr Glu Leu Leu

355

26

359

Homo sapiens

26

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg His Val Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Gly Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Asp Val Pro Asp

115 120 125

Tyr Ala Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ala Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Ile Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Gln Tyr Glu Leu Leu

355

27

983

Artificial Sequence

Description of Artificial Sequence Synthetic

nucleotide sequence

27

atggcccggt ccctgacttg gggctgctgt ccctggtgcc tgacagagga ggagaagact 60

gccgccagaa tcgaccagga gatcaacagg attttgttgg aacagaaaaa acaagagcgc 120

gaggaattga aactcctgct gttggggcct ggtgagagcg ggaagagtac gttcatcaag 180

cagatgcgca tcattcacgg tgtgggctac tcggaggagg accgcagagc cttccggctg 240

ctcatctacc agaacatctt cgtctccatg caggccatga tagatgcgat ggaccggctg 300

cagatcccct tcagcaggcc tgacagcaag cagcacgcca gcctagtgat gacccaggac 360

ccctataaag tgagcacatt cgagaagcca tatgcagtgg ccatgcagta cctgtggcgg 420

gacgcgggca tccgtgcatg ctacgagcga aggcgtgaat tccaccttct ggactccgcg 480

gtgtattacc tgtcacacct gggcgtagga aatggattca ctgttttgag aacgtgattg 540

ccctcatcta cctggcctcc ctgagcgagt atgaccagtg cctagaggag aacgatcagg 600

agaaccgcat ggaggagagt ctcgctctgt tcagcacgat cctagagctg ccctggttca 660

agagcacctc ggtcatcctc ttcctcaaca agacggacat cctggaagat aagattcaca 720

cctcccacct ggccacatac ttccccagct tccagggacc ccggcgagac gcagaggccg 780

ccaagagctt catcttggac atgtatgcgc gcgtgtacgc gagctgcgca gagccccagg 840

acggtggcag gaaaggctcc cgcgcgcgcc gcttcttcgc acacttcacc tgtgccacgg 900

acacgcaaag cgtccgcagc gtgttcaagg acgtgcggga ctcggtgctg gcccggtacc 960

tggacgagat caacctgctg tga 983

28

18

Artificial Sequence

Description of Artificial Sequence Synthetic

oligonucleotide

28

gactgtggcc tcttctga 18

29

18

Artificial Sequence

Description of Artificial Sequence Synthetic

oligonucleotide

29

gagtacaatc tggtctga 18

30

18

Artificial Sequence

Description of Artificial Sequence Synthetic

oligonucleotide

30

cagtatgagc tcttgtga 18

31

18

Artificial Sequence

Description of Artificial Sequence Synthetic

oligonucleotide

31

gagtgcggcc tctactga 18

32

18

Artificial Sequence

Description of Artificial Sequence Synthetic

oligonucleotide

32

ggatgcggac tctactga 18

33

18

Artificial Sequence

Description of Artificial Sequence Synthetic

oligonucleotide

33

tacatcggcc tctgctga 18

34

18

Artificial Sequence

Description of Artificial Sequence Synthetic

oligonucleotide

34

gacatcatgc tccaatga 18

35

18

Artificial Sequence

Description of Artificial Sequence Synthetic

oligonucleotide

35

caactaatgc tccaatga 18

36

18

Artificial Sequence

Description of Artificial Sequence Synthetic

oligonucleotide

36

caccaggttg aactctga 18

37

359

Homo sapiens

37

Met Thr Leu Glu Ser Ile Met Ala Cys Cys Leu Ser Glu Glu Ala Lys

1 5 10 15

Glu Ala Arg Arg Ile Asn Asp Glu Ile Glu Arg Gln Leu Arg Arg Asp

20 25 30

Lys Arg Asp Ala Arg Arg Glu Leu Lys Leu Leu Leu Leu Gly Thr Gly

35 40 45

Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile Ile His Gly

50 55 60

Ser Gly Tyr Ser Asp Glu Asp Lys Arg Gly Phe Thr Lys Leu Val Tyr

65 70 75 80

Gln Asn Ile Phe Thr Ala Met Gln Ala Met Ile Arg Ala Met Asp Thr

85 90 95

Leu Lys Ile Pro Tyr Lys Tyr Glu His Asn Lys Ala His Ala Gln Leu

100 105 110

Val Arg Glu Val Asp Val Glu Lys Val Ser Ala Phe Glu Asn Pro Tyr

115 120 125

Val Asp Ala Ile Lys Ser Leu Trp Asn Asp Pro Gly Ile Gln Glu Cys

130 135 140

Tyr Asp Arg Arg Arg Glu Tyr Gln Leu Ser Asp Ser Thr Lys Tyr Tyr

145 150 155 160

Leu Asn Asp Leu Asp Arg Val Ala Asp Pro Ala Tyr Leu Pro Thr Gln

165 170 175

Gln Asp Val Leu Arg Val Arg Val Pro Thr Thr Gly Ile Ile Glu Tyr

180 185 190

Pro Phe Asp Leu Gln Ser Val Ile Phe Arg Met Val Asp Val Gly Gly

195 200 205

Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu Asn Val Thr

210 215 220

Ser Ile Met Phe Leu Val Ala Leu Ser Glu Tyr Asp Gln Val Leu Val

225 230 235 240

Glu Ser Asp Asn Glu Asn Arg Met Glu Glu Ser Lys Ala Leu Phe Arg

245 250 255

Thr Ile Ile Thr Tyr Pro Trp Phe Gln Asn Ser Ser Val Ile Leu Phe

260 265 270

Leu Asn Lys Lys Asp Leu Leu Glu Glu Lys Ile Met Tyr Ser His Leu

275 280 285

Val Asp Tyr Phe Pro Glu Tyr Asp Gly Pro Gln Arg Asp Ala Gln Ala

290 295 300

Ala Arg Glu Phe Ile Leu Lys Met Phe Val Asp Leu Asn Pro Asp Ser

305 310 315 320

Asp Lys Ile Asn Tyr Ser His Phe Thr Cys Ala Thr Asp Thr Glu Asn

325 330 335

Ile Arg Phe Val Phe Ala Ala Val Lys Asp Thr Ile Leu Gln Leu Asn

340 345 350

Leu Lys Glu Tyr Asn Leu Val

355

38

374

Homo sapiens

38

Met Ala Arg Ser Leu Thr Trp Gly Cys Cys Pro Trp Cys Leu Thr Glu

1 5 10 15

Glu Glu Lys Thr Ala Ala Arg Ile Asp Gln Glu Ile Asn Arg Ile Leu

20 25 30

Leu Glu Gln Lys Lys Gln Glu Arg Glu Glu Leu Lys Leu Leu Leu Leu

35 40 45

Gly Pro Gly Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile

50 55 60

Ile His Gly Val Gly Tyr Ser Glu Glu Asp Arg Arg Ala Phe Arg Leu

65 70 75 80

Leu Ile Tyr Gln Asn Ile Phe Val Ser Met Gln Ala Met Ile Asp Ala

85 90 95

Met Asp Arg Leu Gln Ile Pro Phe Ser Arg Pro Asp Ser Lys Gln His

100 105 110

Ala Ser Leu Val Met Thr Gln Asp Pro Tyr Lys Val Ser Thr Phe Glu

115 120 125

Lys Pro Tyr Ala Val Ala Met Gln Tyr Leu Trp Arg Asp Ala Gly Ile

130 135 140

Arg Ala Cys Tyr Glu Arg Arg Arg Glu Phe His Leu Leu Asp Ser Ala

145 150 155 160

Val Tyr Tyr Leu Ser His Leu Glu Arg Ile Ser Glu Asp Ser Tyr Ile

165 170 175

Pro Thr Ala Gln Asp Val Leu Arg Ser Arg Met Pro Thr Thr Gly Ile

180 185 190

Asn Glu Tyr Cys Phe Ser Val Lys Lys Thr Lys Leu Arg Ile Val Asp

195 200 205

Val Gly Gly Gln Arg Ser Glu Arg Arg Lys Trp Ile His Cys Phe Glu

210 215 220

Asn Val Ile Ala Leu Ile Tyr Leu Ala Ser Leu Ser Glu Tyr Asp Gln

225 230 235 240

Cys Leu Glu Glu Asn Asp Gln Glu Asn Arg Met Glu Glu Ser Leu Ala

245 250 255

Leu Phe Ser Thr Ile Leu Glu Leu Pro Trp Phe Lys Ser Thr Ser Val

260 265 270

Ile Leu Phe Leu Asn Lys Thr Asp Ile Leu Glu Asp Lys Ile His Thr

275 280 285

Ser His Leu Ala Thr Tyr Phe Pro Ser Phe Gln Gly Pro Arg Arg Asp

290 295 300

Ala Glu Ala Ala Lys Ser Phe Ile Leu Asp Met Tyr Ala Arg Val Tyr

305 310 315 320

Ala Ser Cys Ala Glu Pro Gln Asp Gly Gly Arg Lys Gly Ser Arg Ala

325 330 335

Arg Arg Phe Phe Ala His Phe Thr Cys Ala Thr Asp Thr Gln Ser Val

340 345 350

Arg Ser Val Phe Lys Asp Val Arg Asp Ser Val Leu Ala Arg Tyr Leu

355 360 365

Asp Glu Ile Asn Leu Leu

370

39

374

Homo sapiens

39

Met Ala Arg Ser Leu Thr Trp Arg Cys Cys Pro Trp Cys Leu Thr Glu

1 5 10 15

Asp Glu Lys Ala Ala Ala Arg Val Asp Gln Glu Ile Asn Arg Ile Leu

20 25 30

Leu Glu Gln Lys Lys Gln Asp Arg Gly Glu Leu Lys Leu Leu Leu Leu

35 40 45

Gly Pro Gly Glu Ser Gly Lys Ser Thr Phe Ile Lys Gln Met Arg Ile

50 55 60

Ile His Gly Ala Gly Tyr Ser Glu Glu Glu Arg Lys Gly Phe Arg Pro

65 70 75 80

Leu Val Tyr Gln Asn Ile Phe Val Ser Met Arg Ala Met Ile Glu Ala

85 90 95

Met Glu Arg Leu Gln Ile Pro Phe Ser Arg Pro Glu Ser Lys His His

100 105 110

Ala Ser Leu Val Met Ser Gln Asp Pro Tyr Lys Val Thr Thr Phe Glu

115 120 125

Lys Arg Tyr Ala Ala Ala Met Gln Trp Leu Trp Arg Asp Ala Gly Ile

130 135 140

Arg Ala Cys Tyr Glu Arg Arg Arg Glu Phe His Leu Leu Asp Ser Ala

145 150 155 160

Val Tyr Tyr Leu Ser His Leu Glu Arg Ile Thr Glu Glu Gly Tyr Val

165 170 175

Pro Thr Ala Gln Asp Val Leu Arg Ser Arg Met Pro Thr Thr Gly Ile

180 185 190

Asn Glu Tyr Cys Phe Ser Val Gln Lys Thr Asn Leu Arg Ile Val Asp

195 200 205

Val Gly Gly Gln Lys Ser Glu Arg Lys Lys Trp Ile His Cys Phe Glu

210 215 220

Asn Val Ile Ala Leu Ile Tyr Leu Ala Ser Leu Ser Glu Tyr Asp Gln

225 230 235 240

Cys Leu Glu Glu Asn Asn Gln Glu Asn Arg Met Lys Glu Ser Leu Ala

245 250 255

Leu Phe Gly Thr Ile Leu Glu Leu Pro Trp Phe Lys Ser Thr Ser Val

260 265 270

Ile Leu Phe Leu Asn Lys Thr Asp Ile Leu Glu Glu Lys Ile Pro Thr

275 280 285

Ser His Leu Ala Thr Tyr Phe Pro Ser Phe Gln Gly Pro Lys Gln Asp

290 295 300

Ala Glu Ala Ala Lys Arg Phe Ile Leu Asp Met Tyr Thr Arg Met Tyr

305 310 315 320

Thr Gly Cys Val Asp Gly Pro Glu Gly Ser Lys Lys Gly Ala Arg Ser

325 330 335

Arg Arg Leu Phe Ser His Tyr Thr Cys Ala Thr Asp Thr Gln Asn Ile

340 345 350

Arg Lys Val Phe Lys Asp Val Arg Asp Ser Val Leu Ala Arg Tyr Leu

355 360 365

Asp Glu Ile Asn Leu Leu

370

40

6

Artificial Sequence

Description of Artificial Sequence Illustra-

tive N-terminal peptide sequence

40

Met Thr Leu Glu Ser Ile

1 5

41

6

Artificial Sequence

Description of Artificial Sequence Synthetic

hemaglutinin epitope tag

41

Asp Val Pro Asp Tyr Ala

1 5

42

11

Artificial Sequence

Description of Artificial Sequence Illustra-

tive oligonucleotide

42

ggcgcgccgc c 11