Tumor marker for pancreatic cancer

This application is a U.S. national stage of International Application No. PCT/JP2008/063235 filed Jul. 24, 2008.

CROSS-REFERENCE OF RELATED APPLICATION

This patent application claims a priority based on a prior Japanese Patent Application, Japanese Patent Application No. 193328/2007 (filing date: Jul. 25, 2007). The whole disclosure of Japanese Patent Application No. 193328/2007 is incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel protein and fragment thereof which can be used as a tumor marker in the diagnosis of pancreatic cancer as well as a process for diagnosing pancreatic cancer with use of the marker.

2. Background Art

It is known that pancreatic cancer is a cancer which originates in pancreas, and 90% or more of the cancer is pancreatic duct adenocarcinoma originating in the exocrine cells, particularly the cells of the pancreatic duct, through which pancreatic juice is transferred. It is very difficult to find pancreatic cancer, because pancreas is surrounded by many organs such as stomach, duodenum, spleen, small intestine, large intestine, liver and gall bladder. On the other hand, pancreatic cancer tends to begin spreading to other organs at its initial stage and thus has an inclination of easy metastasis. Thus, it is essential for the therapy of pancreatic cancer to detect it at its early stage.

In general, tumor markers which enable the diagnosis of cancers by blood test are useful for detection of cancer at its early stage. The tumor markers of pancreatic cancer include, for example, CA19-9, CEA, Dupan-2, and the like. However, it is often difficult to detect pancreatic cancer at its early stage even with these tumor markers. Therefore, there is a demand on the development of novel tumor markers of pancreatic cancer.

Fibrinogen is a glycoprotein which is transferred by blood and consists of three different polypeptide chains. If blood vessel is damaged, fibrinogen is cleaved by thrombin to form fibrin as the main ingredient of clot. In addition, it is known that the cleaved products such as fibrinogen and fibrin are involved with cell adhesion and cell dispersion, exhibit blood vessel contracting activities and chemotactic activities, and also work as mitogenic factors for several cell types. Furthermore, it is known that the plasma concentration of fibrinogen is involved with the risk of coronary diseases (J. Thromb. Haemost. 4(10), 2204-2209, 2006). It is also known that the genetic mutation of .alpha. chain of fibrinogen (.alpha.-fibrinogen) is involved with disorders such as abnormal fibrinogenemia, fibrinogenopenia, afibrinogenemia and renal amyloidosis (Thromb. Haemost. 96(2), 231-232, 2006; Blood 80(8), 1972-1979, 1992).

SUMMARY OF THE INVENTION

The present inventors have detected a novel .alpha.-fibrinogen protein of which a specific amino acid residue is oxidized in a plasma sample of a pancreatic cancer patient, and have found that the concentration of the protein is significantly different between pancreatic cancer patients and normal subjects and thus the protein is useful as a tumor marker of pancreatic cancer. The present invention is based on the above findings.

Thus, the object of the present invention is to provide a novel protein and fragments thereof which are useful as a tumor marker for pancreatic cancer.

The protein and fragments thereof according to the present invention is a modified .alpha.-fibrinogen protein containing an oxidized amino acid residue(s) or a fragment thereof containing said oxidized amino acid residue(s), wherein the amino acid residue(s) which is oxidized is one or more amino acid residues selected from the group consisting of (a) a proline residue corresponding to the proline residue at the position of 530 in SEQ ID NO: 2, and (b) a proline residue corresponding to the proline residue at the position of 565 in SEQ ID NO: 2.

According to the present invention, it is possible to detect pancreatic cancer at earlier stages, which has been believed unfeasible, and to develop diagnostic reagents for detecting pancreatic cancer at earlier stages.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a histogram in which intensities of M/Z (mass-to-charge ratio) 552 of a glycoprotein fraction derived from a modified peptide in plasma samples and having a retention time (RT) of 8.3 minutes are compared among a plurality of the LC/MS data.

FIG. 1B is a histogram in which intensities of M/Z (mass-to-charge ratio) 827 of a glycoprotein fraction derived from a modified peptide in plasma samples and having a retention time (RT) of 8.3 minutes are compared among a plurality of the LC/MS data.

FIG. 1C is a histogram in which intensities of M/Z (mass-to-charge ratio) 1141 of a glycoprotein fraction derived from a modified peptide in plasma samples and having a retention time (RT) of 29.0 minutes are compared among a plurality of the LC/MS data.

FIG. 2A is a histogram in which intensities of M/Z (mass-to-charge ratio) 547 of a glycoprotein fraction derived from an unmodified peptide in plasma samples and having a retention time (RT) of 8.5 minutes are compared among a plurality of the LC/MS data.

FIG. 2B is a histogram in which intensities of M/Z (mass-to-charge ratio) 819 of a glycoprotein fraction derived from a modified peptide in plasma samples and having a retention time (RT) of 8.5 minutes are compared among a plurality of the LC/MS data.

FIG. 2C is a histogram in which intensities of M/Z (mass-to-charge ratio) 1133 of a glycoprotein fraction derived from a modified peptide in plasma samples and having a retention time (RT) of 30.0 minutes are compared among a plurality of the LC/MS data.

FIG. 3 illustrates the mass spectrograms in which the mass numbers of the modified peptide (827 m/z, 1141 m/z) and unmodified peptide (819 m/z, 1133 m/z) were calculated down to the third decimal place with Orbitrap.

FIG. 4 illustrates the mass spectrograms which show the results of the determination by tandem mass spectrometry for a modified peptide (827 m/z, 1141 m/z) and an unmodified peptide (819 m/z, 1133 m/z).

FIG. 5 illustrates the mass spectrograms which show the results of the determination of tandem mass spectrometry for a modified peptide (827 m/z) and an unmodified peptide (819 m/z).

DETAILED DESCRIPTION OF THE INVENTION

The term ".alpha.-fibrinogen protein" as used herein refers to a chain among the three chains which constitute fibrinogen. .alpha.-fibrinogen protein include a variety of .alpha.-fibrinogen proteins derived from a variety of animals and is not limited to any one of them, and is preferably a human .alpha.-fibrinogen protein. The human .alpha.-fibrinogen protein includes two isoforms obtained by selective splicing, of which the amino acid sequences are illustrated in SEQ ID NO: 2 (NCBI ACCESS NO: NP.sub.--068657) and SEQ ID NO: 4 (NCBI ACCESS NO: NP.sub.--000499), respectively. In these amino acid sequences, 19 residues at the N terminal is a signal peptide.

In the protein according to the present invention, one or both of (a) the proline residue corresponding to the proline residue at the 530 position in SEQ ID NO: 2 and (b) the proline residue corresponding to the proline residue at the 565 position in SEQ ID NO: 2 are oxidized. The positions of proline residues to be oxidized in a sequence other than SEQ ID NO: 2 may be readily determined by a person skilled in the art, for example, by comparing the sequence with that of SEQ ID NO: 2.

The specific structure of the oxidized amino acid residue may be any of the structures which are known for the partial oxidation of proteins in vivo. Preferred examples of the structures include the ones having an additional oxygen atom as compared with the corresponding natural amino acid residue, more preferably the ones having an additional hydroxy group as compared with the corresponding natural amino acid residue.

In the protein according to the present invention, it is sufficient that either of the amino acid residues described in (a) or (b) may be oxidized, and preferably both of these amino acid residues are oxidized.

In a preferred embodiment of the present invention, the .alpha.-fibrinogen protein comprises the residues at 20-644 positions in the amino acid sequence represented by SEQ ID NO: 2, in which either one or both of the proline residues at 530 and 565 positions are oxidized. In a more preferred embodiment, both of the proline residues at 530 and 565 positions are oxidized. In this embodiment, the .alpha.-fibrinogen protein may further contain the signal peptide represented by the residues at 1-19 positions in the amino acid sequence of SEQ ID NO: 2.

In another preferred embodiment of the present invention, the .alpha.-fibrinogen protein comprises the residues at 20-866 positions in the amino acid sequence represented by SEQ ID NO: 4, and either one or both of the proline residues at positions 530 and 565 in the amino acid sequence are oxidized. In a more preferred embodiment, both of the proline residues at positions 530 and 565 are oxidized. In this embodiment, the .alpha.-fibrinogen protein may further contain the signal peptide represented by the residues at 1-19 positions in the amino acid sequence represented by SEQ ID NO: 4.

The protein according to the present invention can be prepared by the conventional methods which are known as the method for preparing proteins. For instance, the cDNA sequence coding for the amino acid sequence represented by SEQ ID NO: 2 is shown in SEQ ID NO: 1 (NCBI ACCESS NO: NM.sub.--021871), and the cDNA sequence coding for the amino acid sequence represented by SEQ ID NO: 4 is shown in SEQ ID NO: 3 (NCBI ACCESS NO: NM.sub.--000508). A person skilled in the art can construct an appropriate expression vector with reference to these sequences to prepare the protein according to the present invention in an appropriate host cell. The oxidation reaction of the specific amino acid residue can also be carried out by the conventional methods known in the art. Alternatively, the protein according to the present invention may be isolated from plasma samples of pancreatic cancer patients.

The present invention also comprises the fragments of the protein described above. Such fragments contain oxidized amino acid residues described in either one or both of (a) and (b). The fragment of the protein according to the present invention is particularly useful for the development of diagnostic reagents of pancreatic cancer. For example, there may be contemplated as the diagnostic reagent of pancreatic cancer a reagent which is specifically linked to the protein according to the present invention. In order to use the fragment of the protein according to the present invention for developing such reagents, the fragment of the protein according to the present invention is preferably a specific fragment which is specific to the protein according to the present invention. The term "specific" as used herein means that the structure of the fragment is present only in the protein according to the present invention in the reaction system used for the detection of the protein according to the present invention. The sequence and structure of such specific fragments can be determined with a database available in the art. Furthermore, the reagents which are specifically linked to the protein according to the present invention include antibodies, and particularly monoclonal antibodies. In order to use the fragment of the protein according to the present invention for the development of such antibodies, it is preferably an immunogenic fragment which can be used for the preparation of antibodies. The fragment of the protein according to the present invention may be prepared by the methods described above on full-length proteins, or may be prepared by the conventional methods known in the art as the synthetic method of peptides.

The protein according to the present invention and a fragment thereof can be used for the development of diagnostic reagents of pancreatic cancer. Such reagents include those specifically linked to the protein according to the present invention and a fragment thereof, and particularly the reagents are preferably specific antibodies used for ELISA, and the like. Such specific antibodies may be a monoclonal antibody or its binding fragment, ScFv (single stranded Fv fragment), dAb (single domain antibody), or a minimal recognition unit of antibody.

According to one embodiment, said specific antibody may be a monoclonal antibody. The monoclonal antibody can be produced by the standard technique known in the art. By way of example, the methods for producing monoclonal antibodies include the ones described in "Monoclonal Antibodies: A manual of techniques", H. Zola (CRC Press, 1988) and "Monoclonal Hybridoma Antibodies: Techniques and Applications", J. G. R. Hurrell (CRC Press, 1982). Furthermore, non-human antibodies appropriately produced may also be "humanized" by inserting the CDR region of a mouse antibody into the framework of a human antibody. The protein according to the present invention in samples can be correctly detected by using the monoclonal antibody thus produced, and thus pancreatic cancer can be diagnosed rapidly.

EXAMPLE

The present invention is now described in more detail with reference to Example, but is not limited thereto.

Example 1

Identification of a Protein as a Pancreatic Cancer Marker

A 20 .mu.l portion of plasma samples from 43 patients with pancreatic cancer and 43 normal subjects was used for the extraction of glycoprotein fractions adsorbing on concanavalin A. Each of the glycoprotein fractions was analyzed by the 2DICAL method which enables the comparison of the LC/MS data of plural samples (Ono et al., Mol. Cell Proteomics, 5, 1338, 2006). The result of comparison between patients with pancreatic cancer and normal subjects on three peaks derived from a peptide having a modified sequence is shown in FIG. 1.

FIG. 1A is a histogram in which the intensities of M/Z (mass-to-charge ratio) 552 at the retention time (RT) of 8.3 minutes were compared. FIG. 1B is a histogram in which the intensities of M/Z (mass-to-charge ratio) 827 at the retention time (RT) of 8.3 minutes were compared. FIG. 1C is a histogram in which the intensities of M/Z (mass-to-charge ratio) 1141 at the retention time (RT) of 29.0 minutes were compared. These peaks showed significant difference between patients with pancreatic cancer and normal subjects, as illustrated by the P value of U test shown under the histogram.

In addition, the discrimination ratio and the area under the ROC curve with these peaks were 83% and 0.85, 83% and 0.83, 76% and 0.82 in the order of M/Z 552, M/Z 827 and M/Z 1141, respectively, but in the same period having small dispersion of mass spectrometry 81% and 0.83, 89% and 0.92, 86% and 0.91, respectively.

Tandem mass spectrometry data were obtained on the three peaks described above, and the assay of peptide sequence including post-translational modification was carried out with the protein identification software (MASCOT). As a result, it has been found that both M/Z 552 and M/Z 827 at RT 8.3 minutes are derived from the sequence of ESSSHHPGIAEFPSR (SEQ ID NO: 5). It has also been found that M/Z 1141 at RT 29.0 minutes is derived from the sequence of TFPGFFSPMLGEFVSETESR (SEQ ID NO: 6). These amino acid sequences were both derived from fibrinogen. In addition, these peptides were post-translationally modified peptides 16 dalton higher than the molecular weight of the expected sequence.

With respect to an unmodified peptide corresponding to the post-translational modification, the difference of its expression was compared between pancreatic cancer patients and normal subjects by the 2DICAL method as described above. The result is illustrated in FIG. 2.

FIG. 2A is a histogram in which the intensities of M/Z (mass-to-charge ratio) 547 at a retention time (RT) of 8.5 minutes were compared. FIG. 2B is a histogram in which the intensities of M/Z (mass-to-charge ratio) 819 at a retention time (RT) of 8.5 minutes were compared. FIG. 2C is a histogram in which the intensities of M/Z (mass-to-charge ratio) 1133 at a retention time (RT) of 30.0 minutes were compared. The intensities of these peaks derived from the unmodified peptides showed no difference between pancreatic cancer patients and normal subjects.

Next, the modification form of the two modified peptides described above was identified with an exact mass spectrometer Orbitrap (Thermo Fisher, San Jose, Calif.).

The mass numbers of the modified peptide (827 m/z, 1141 m/z) and unmodified peptide (819 m/z, 1133 m/z) were calculated down to the third decimal place with the exact mass spectrometer Orbitrap. It has been confirmed that these peptides have a difference of mass numbers of 15.995 Da which corresponds to one oxygen atom (FIG. 3).

The modified peptide (827 m/z, 1141 m/z) and the unmodified peptide (819 m/z, 1133 m/z) were subjected to tandem mass spectrometry analysis. The result is shown in FIG. 4. It has been confirmed from FIG. 4 that one oxygen atom difference between the fragments of these peptides is observed at the position of proline shown in the figure and thus the proline residue is oxidized.

Furthermore, tandem mass spectrometry analysis was performed with the exact mass spectrometer Orbitrap to confirm that the peptide showing 827 m/z is modified on the proline residue described above. As a result, it has been confirmed that the peptide residue 171.0762 m/z derived from the modified peptide and the peptide residue 155.0808 m/z derived from the unmodified peptide, of which the difference of the molecular weight is 15.995 Da, are unambiguously represented by the chemical formulas C.sub.7H.sub.11O.sub.3N.sub.2 and C.sub.7H.sub.11O.sub.2N.sub.2, respectively (FIG. 6). Peptide sequences having such structural formulas as described above are only represented by P(O)G and PG, and it has thus been confirmed that the peptide sequence ESSSHHP*GIAEFPSR is oxidized at the position of P*.

SEQUENCE LISTINGS

1

612210DNAHomo sapiensCDS(59)..(1990) 1agcaatcctt tctttcagct ggagtgctcc tcaggagcca gccccaccct tagaaaag 58atg ttt tcc atg agg atc gtc tgc ctg gtc cta agt gtg gtg ggc aca 106Met Phe Ser Met Arg Ile Val Cys Leu Val Leu Ser Val Val Gly Thr1 5 10 15gca tgg act gca gat agt ggt gaa ggt gac ttt cta gct gaa gga gga 154Ala Trp Thr Ala Asp Ser Gly Glu Gly Asp Phe Leu Ala Glu Gly Gly 20 25 30ggc gtg cgt ggc cca agg gtt gtg gaa aga cat caa tct gcc tgc aaa 202Gly Val Arg Gly Pro Arg Val Val Glu Arg His Gln Ser Ala Cys Lys 35 40 45gat tca gac tgg ccc ttc tgc tct gat gaa gac tgg aac tac aaa tgc 250Asp Ser Asp Trp Pro Phe Cys Ser Asp Glu Asp Trp Asn Tyr Lys Cys 50 55 60cct tct ggc tgc agg atg aaa ggg ttg att gat gaa gtc aat caa gat 298Pro Ser Gly Cys Arg Met Lys Gly Leu Ile Asp Glu Val Asn Gln Asp65 70 75 80ttt aca aac aga ata aat aag ctc aaa aat tca cta ttt gaa tat cag 346Phe Thr Asn Arg Ile Asn Lys Leu Lys Asn Ser Leu Phe Glu Tyr Gln 85 90 95aag aac aat aag gat tct cat tcg ttg acc act aat ata atg gaa att 394Lys Asn Asn Lys Asp Ser His Ser Leu Thr Thr Asn Ile Met Glu Ile 100 105 110ttg aga ggc gat ttt tcc tca gcc aat aac cgt gat aat acc tac aac 442Leu Arg Gly Asp Phe Ser Ser Ala Asn Asn Arg Asp Asn Thr Tyr Asn 115 120 125cga gtg tca gag gat ctg aga agc aga att gaa gtc ctg aag cgc aaa 490Arg Val Ser Glu Asp Leu Arg Ser Arg Ile Glu Val Leu Lys Arg Lys 130 135 140gtc ata gaa aaa gta cag cat atc cag ctt ctg cag aaa aat gtt aga 538Val Ile Glu Lys Val Gln His Ile Gln Leu Leu Gln Lys Asn Val Arg145 150 155 160gct cag ttg gtt gat atg aaa cga ctg gag gtg gac att gat att aag 586Ala Gln Leu Val Asp Met Lys Arg Leu Glu Val Asp Ile Asp Ile Lys 165 170 175atc cga tct tgt cga ggg tca tgc agt agg gct tta gct cgt gaa gta 634Ile Arg Ser Cys Arg Gly Ser Cys Ser Arg Ala Leu Ala Arg Glu Val 180 185 190gat ctg aag gac tat gaa gat cag cag aag caa ctt gaa cag gtc att 682Asp Leu Lys Asp Tyr Glu Asp Gln Gln Lys Gln Leu Glu Gln Val Ile 195 200 205gcc aaa gac tta ctt ccc tct aga gat agg caa cac tta cca ctg ata 730Ala Lys Asp Leu Leu Pro Ser Arg Asp Arg Gln His Leu Pro Leu Ile 210 215 220aaa atg aaa cca gtt cca gac ttg gtt ccc gga aat ttt aag agc cag 778Lys Met Lys Pro Val Pro Asp Leu Val Pro Gly Asn Phe Lys Ser Gln225 230 235 240ctt cag aag gta ccc cca gag tgg aag gca tta aca gac atg ccg cag 826Leu Gln Lys Val Pro Pro Glu Trp Lys Ala Leu Thr Asp Met Pro Gln 245 250 255atg aga atg gag tta gag aga cct ggt gga aat gag att act cga gga 874Met Arg Met Glu Leu Glu Arg Pro Gly Gly Asn Glu Ile Thr Arg Gly 260 265 270ggc tcc acc tct tat gga acc gga tca gag acg gaa agc ccc agg aac 922Gly Ser Thr Ser Tyr Gly Thr Gly Ser Glu Thr Glu Ser Pro Arg Asn 275 280 285cct agc agt gct gga agc tgg aac tct ggg agc tct gga cct gga agt 970Pro Ser Ser Ala Gly Ser Trp Asn Ser Gly Ser Ser Gly Pro Gly Ser 290 295 300act gga aac cga aac cct ggg agc tct ggg act gga ggg act gca acc 1018Thr Gly Asn Arg Asn Pro Gly Ser Ser Gly Thr Gly Gly Thr Ala Thr305 310 315 320tgg aaa cct ggg agc tct gga cct gga agt act gga agc tgg aac tct 1066Trp Lys Pro Gly Ser Ser Gly Pro Gly Ser Thr Gly Ser Trp Asn Ser 325 330 335ggg agc tct gga act gga agt act gga aac caa aac cct ggg agc cct 1114Gly Ser Ser Gly Thr Gly Ser Thr Gly Asn Gln Asn Pro Gly Ser Pro 340 345 350aga cct ggt agt acc gga acc tgg aat cct ggc agc tct gaa cgc gga 1162Arg Pro Gly Ser Thr Gly Thr Trp Asn Pro Gly Ser Ser Glu Arg Gly 355 360 365agt gct ggg cac tgg acc tct gag agc tct gta tct ggt agt act gga 1210Ser Ala Gly His Trp Thr Ser Glu Ser Ser Val Ser Gly Ser Thr Gly 370 375 380caa tgg cac tct gaa tct gga agt ttt agg cca gat agc cca ggc tct 1258Gln Trp His Ser Glu Ser Gly Ser Phe Arg Pro Asp Ser Pro Gly Ser385 390 395 400ggg aac gcg agg cct aac aac cca gac tgg ggc aca ttt gaa gag gtg 1306Gly Asn Ala Arg Pro Asn Asn Pro Asp Trp Gly Thr Phe Glu Glu Val 405 410 415tca gga aat gta agt cca ggg aca agg aga gag tac cac aca gaa aaa 1354Ser Gly Asn Val Ser Pro Gly Thr Arg Arg Glu Tyr His Thr Glu Lys 420 425 430ctg gtc act tct aaa gga gat aaa gag ctc agg act ggt aaa gag aag 1402Leu Val Thr Ser Lys Gly Asp Lys Glu Leu Arg Thr Gly Lys Glu Lys 435 440 445gtc acc tct ggt agc aca acc acc acg cgt cgt tca tgc tct aaa acc 1450Val Thr Ser Gly Ser Thr Thr Thr Thr Arg Arg Ser Cys Ser Lys Thr 450 455 460gtt act aag act gtt att ggt cct gat ggt cac aaa gaa gtt acc aaa 1498Val Thr Lys Thr Val Ile Gly Pro Asp Gly His Lys Glu Val Thr Lys465 470 475 480gaa gtg gtg acc tcc gaa gat ggt tct gac tgt ccc gag gca atg gat 1546Glu Val Val Thr Ser Glu Asp Gly Ser Asp Cys Pro Glu Ala Met Asp 485 490 495tta ggc aca ttg tct ggc ata ggt act ctg gat ggg ttc cgc cat agg 1594Leu Gly Thr Leu Ser Gly Ile Gly Thr Leu Asp Gly Phe Arg His Arg 500 505 510cac cct gat gaa gct gcc ttc ttc gac act gcc tca act gga aaa aca 1642His Pro Asp Glu Ala Ala Phe Phe Asp Thr Ala Ser Thr Gly Lys Thr 515 520 525ttc cca ggt ttc ttc tca cct atg tta gga gag ttt gtc agt gag act 1690Phe Pro Gly Phe Phe Ser Pro Met Leu Gly Glu Phe Val Ser Glu Thr 530 535 540gag tct agg ggc tca gaa tct ggc atc ttc aca aat aca aag gaa tcc 1738Glu Ser Arg Gly Ser Glu Ser Gly Ile Phe Thr Asn Thr Lys Glu Ser545 550 555 560agt tct cat cac cct ggg ata gct gaa ttc cct tcc cgt ggt aaa tct 1786Ser Ser His His Pro Gly Ile Ala Glu Phe Pro Ser Arg Gly Lys Ser 565 570 575tca agt tac agc aaa caa ttt act agt agc acg agt tac aac aga gga 1834Ser Ser Tyr Ser Lys Gln Phe Thr Ser Ser Thr Ser Tyr Asn Arg Gly 580 585 590gac tcc aca ttt gaa agc aag agc tat aaa atg gca gat gag gcc gga 1882Asp Ser Thr Phe Glu Ser Lys Ser Tyr Lys Met Ala Asp Glu Ala Gly 595 600 605agt gaa gcc gat cat gaa gga aca cat agc acc aag aga ggc cat gct 1930Ser Glu Ala Asp His Glu Gly Thr His Ser Thr Lys Arg Gly His Ala 610 615 620aaa tct cgc cct gtc aga ggt atc cac act tct cct ttg ggg aag cct 1978Lys Ser Arg Pro Val Arg Gly Ile His Thr Ser Pro Leu Gly Lys Pro625 630 635 640tcc ctg tcc ccc tagactaagt taaatatttc tgcacagtgt tcccatggcc 2030Ser Leu Ser Proccttgcattt ccttcttaac tctctgttac acgtcattga aactacactt ttttggtctg 2090tttttgtgct agactgtaag ttccttgggg gcagggcctt tgtctgtctc atctctgtat 2150tcccaaatgc ctaacagtac agagccatga ctcaataaat acatgttaaa tggatgaatg 22102644PRTHomo sapiens 2Met Phe Ser Met Arg Ile Val Cys Leu Val Leu Ser Val Val Gly Thr1 5 10 15Ala Trp Thr Ala Asp Ser Gly Glu Gly Asp Phe Leu Ala Glu Gly Gly 20 25 30Gly Val Arg Gly Pro Arg Val Val Glu Arg His Gln Ser Ala Cys Lys 35 40 45Asp Ser Asp Trp Pro Phe Cys Ser Asp Glu Asp Trp Asn Tyr Lys Cys 50 55 60Pro Ser Gly Cys Arg Met Lys Gly Leu Ile Asp Glu Val Asn Gln Asp65 70 75 80Phe Thr Asn Arg Ile Asn Lys Leu Lys Asn Ser Leu Phe Glu Tyr Gln 85 90 95Lys Asn Asn Lys Asp Ser His Ser Leu Thr Thr Asn Ile Met Glu Ile 100 105 110Leu Arg Gly Asp Phe Ser Ser Ala Asn Asn Arg Asp Asn Thr Tyr Asn 115 120 125Arg Val Ser Glu Asp Leu Arg Ser Arg Ile Glu Val Leu Lys Arg Lys 130 135 140Val Ile Glu Lys Val Gln His Ile Gln Leu Leu Gln Lys Asn Val Arg145 150 155 160Ala Gln Leu Val Asp Met Lys Arg Leu Glu Val Asp Ile Asp Ile Lys 165 170 175Ile Arg Ser Cys Arg Gly Ser Cys Ser Arg Ala Leu Ala Arg Glu Val 180 185 190Asp Leu Lys Asp Tyr Glu Asp Gln Gln Lys Gln Leu Glu Gln Val Ile 195 200 205Ala Lys Asp Leu Leu Pro Ser Arg Asp Arg Gln His Leu Pro Leu Ile 210 215 220Lys Met Lys Pro Val Pro Asp Leu Val Pro Gly Asn Phe Lys Ser Gln225 230 235 240Leu Gln Lys Val Pro Pro Glu Trp Lys Ala Leu Thr Asp Met Pro Gln 245 250 255Met Arg Met Glu Leu Glu Arg Pro Gly Gly Asn Glu Ile Thr Arg Gly 260 265 270Gly Ser Thr Ser Tyr Gly Thr Gly Ser Glu Thr Glu Ser Pro Arg Asn 275 280 285Pro Ser Ser Ala Gly Ser Trp Asn Ser Gly Ser Ser Gly Pro Gly Ser 290 295 300Thr Gly Asn Arg Asn Pro Gly Ser Ser Gly Thr Gly Gly Thr Ala Thr305 310 315 320Trp Lys Pro Gly Ser Ser Gly Pro Gly Ser Thr Gly Ser Trp Asn Ser 325 330 335Gly Ser Ser Gly Thr Gly Ser Thr Gly Asn Gln Asn Pro Gly Ser Pro 340 345 350Arg Pro Gly Ser Thr Gly Thr Trp Asn Pro Gly Ser Ser Glu Arg Gly 355 360 365Ser Ala Gly His Trp Thr Ser Glu Ser Ser Val Ser Gly Ser Thr Gly 370 375 380Gln Trp His Ser Glu Ser Gly Ser Phe Arg Pro Asp Ser Pro Gly Ser385 390 395 400Gly Asn Ala Arg Pro Asn Asn Pro Asp Trp Gly Thr Phe Glu Glu Val 405 410 415Ser Gly Asn Val Ser Pro Gly Thr Arg Arg Glu Tyr His Thr Glu Lys 420 425 430Leu Val Thr Ser Lys Gly Asp Lys Glu Leu Arg Thr Gly Lys Glu Lys 435 440 445Val Thr Ser Gly Ser Thr Thr Thr Thr Arg Arg Ser Cys Ser Lys Thr 450 455 460Val Thr Lys Thr Val Ile Gly Pro Asp Gly His Lys Glu Val Thr Lys465 470 475 480Glu Val Val Thr Ser Glu Asp Gly Ser Asp Cys Pro Glu Ala Met Asp 485 490 495Leu Gly Thr Leu Ser Gly Ile Gly Thr Leu Asp Gly Phe Arg His Arg 500 505 510His Pro Asp Glu Ala Ala Phe Phe Asp Thr Ala Ser Thr Gly Lys Thr 515 520 525Phe Pro Gly Phe Phe Ser Pro Met Leu Gly Glu Phe Val Ser Glu Thr 530 535 540Glu Ser Arg Gly Ser Glu Ser Gly Ile Phe Thr Asn Thr Lys Glu Ser545 550 555 560Ser Ser His His Pro Gly Ile Ala Glu Phe Pro Ser Arg Gly Lys Ser 565 570 575Ser Ser Tyr Ser Lys Gln Phe Thr Ser Ser Thr Ser Tyr Asn Arg Gly 580 585 590Asp Ser Thr Phe Glu Ser Lys Ser Tyr Lys Met Ala Asp Glu Ala Gly 595 600 605Ser Glu Ala Asp His Glu Gly Thr His Ser Thr Lys Arg Gly His Ala 610 615 620Lys Ser Arg Pro Val Arg Gly Ile His Thr Ser Pro Leu Gly Lys Pro625 630 635 640Ser Leu Ser Pro33655DNAHomo sapiensCDS(59)..(2656) 3agcaatcctt tctttcagct ggagtgctcc tcaggagcca gccccaccct tagaaaag 58atg ttt tcc atg agg atc gtc tgc ctg gtc cta agt gtg gtg ggc aca 106Met Phe Ser Met Arg Ile Val Cys Leu Val Leu Ser Val Val Gly Thr1 5 10 15gca tgg act gca gat agt ggt gaa ggt gac ttt cta gct gaa gga gga 154Ala Trp Thr Ala Asp Ser Gly Glu Gly Asp Phe Leu Ala Glu Gly Gly 20 25 30ggc gtg cgt ggc cca agg gtt gtg gaa aga cat caa tct gcc tgc aaa 202Gly Val Arg Gly Pro Arg Val Val Glu Arg His Gln Ser Ala Cys Lys 35 40 45gat tca gac tgg ccc ttc tgc tct gat gaa gac tgg aac tac aaa tgc 250Asp Ser Asp Trp Pro Phe Cys Ser Asp Glu Asp Trp Asn Tyr Lys Cys 50 55 60cct tct ggc tgc agg atg aaa ggg ttg att gat gaa gtc aat caa gat 298Pro Ser Gly Cys Arg Met Lys Gly Leu Ile Asp Glu Val Asn Gln Asp65 70 75 80ttt aca aac aga ata aat aag ctc aaa aat tca cta ttt gaa tat cag 346Phe Thr Asn Arg Ile Asn Lys Leu Lys Asn Ser Leu Phe Glu Tyr Gln 85 90 95aag aac aat aag gat tct cat tcg ttg acc act aat ata atg gaa att 394Lys Asn Asn Lys Asp Ser His Ser Leu Thr Thr Asn Ile Met Glu Ile 100 105 110ttg aga ggc gat ttt tcc tca gcc aat aac cgt gat aat acc tac aac 442Leu Arg Gly Asp Phe Ser Ser Ala Asn Asn Arg Asp Asn Thr Tyr Asn 115 120 125cga gtg tca gag gat ctg aga agc aga att gaa gtc ctg aag cgc aaa 490Arg Val Ser Glu Asp Leu Arg Ser Arg Ile Glu Val Leu Lys Arg Lys 130 135 140gtc ata gaa aaa gta cag cat atc cag ctt ctg cag aaa aat gtt aga 538Val Ile Glu Lys Val Gln His Ile Gln Leu Leu Gln Lys Asn Val Arg145 150 155 160gct cag ttg gtt gat atg aaa cga ctg gag gtg gac att gat att aag 586Ala Gln Leu Val Asp Met Lys Arg Leu Glu Val Asp Ile Asp Ile Lys 165 170 175atc cga tct tgt cga ggg tca tgc agt agg gct tta gct cgt gaa gta 634Ile Arg Ser Cys Arg Gly Ser Cys Ser Arg Ala Leu Ala Arg Glu Val 180 185 190gat ctg aag gac tat gaa gat cag cag aag caa ctt gaa cag gtc att 682Asp Leu Lys Asp Tyr Glu Asp Gln Gln Lys Gln Leu Glu Gln Val Ile 195 200 205gcc aaa gac tta ctt ccc tct aga gat agg caa cac tta cca ctg ata 730Ala Lys Asp Leu Leu Pro Ser Arg Asp Arg Gln His Leu Pro Leu Ile 210 215 220aaa atg aaa cca gtt cca gac ttg gtt ccc gga aat ttt aag agc cag 778Lys Met Lys Pro Val Pro Asp Leu Val Pro Gly Asn Phe Lys Ser Gln225 230 235 240ctt cag aag gta ccc cca gag tgg aag gca tta aca gac atg ccg cag 826Leu Gln Lys Val Pro Pro Glu Trp Lys Ala Leu Thr Asp Met Pro Gln 245 250 255atg aga atg gag tta gag aga cct ggt gga aat gag att act cga gga 874Met Arg Met Glu Leu Glu Arg Pro Gly Gly Asn Glu Ile Thr Arg Gly 260 265 270ggc tcc acc tct tat gga acc gga tca gag acg gaa agc ccc agg aac 922Gly Ser Thr Ser Tyr Gly Thr Gly Ser Glu Thr Glu Ser Pro Arg Asn 275 280 285cct agc agt gct gga agc tgg aac tct ggg agc tct gga cct gga agt 970Pro Ser Ser Ala Gly Ser Trp Asn Ser Gly Ser Ser Gly Pro Gly Ser 290 295 300act gga aac cga aac cct ggg agc tct ggg act gga ggg act gca acc 1018Thr Gly Asn Arg Asn Pro Gly Ser Ser Gly Thr Gly Gly Thr Ala Thr305 310 315 320tgg aaa cct ggg agc tct gga cct gga agt act gga agc tgg aac tct 1066Trp Lys Pro Gly Ser Ser Gly Pro Gly Ser Thr Gly Ser Trp Asn Ser 325 330 335ggg agc tct gga act gga agt act gga aac caa aac cct ggg agc cct 1114Gly Ser Ser Gly Thr Gly Ser Thr Gly Asn Gln Asn Pro Gly Ser Pro 340 345 350aga cct ggt agt acc gga acc tgg aat cct ggc agc tct gaa cgc gga 1162Arg Pro Gly Ser Thr Gly Thr Trp Asn Pro Gly Ser Ser Glu Arg Gly 355 360 365agt gct ggg cac tgg acc tct gag agc tct gta tct ggt agt act gga 1210Ser Ala Gly His Trp Thr Ser Glu Ser Ser Val Ser Gly Ser Thr Gly 370 375 380caa tgg cac tct gaa tct gga agt ttt agg cca gat agc cca ggc tct 1258Gln Trp His Ser Glu Ser Gly Ser Phe Arg Pro Asp Ser Pro Gly Ser385 390 395 400ggg aac gcg agg cct aac aac cca gac tgg ggc aca ttt gaa gag gtg 1306Gly Asn Ala Arg Pro Asn Asn Pro Asp Trp Gly Thr Phe Glu Glu Val 405 410 415tca gga aat gta agt cca ggg aca agg aga gag tac cac aca gaa aaa 1354Ser Gly Asn Val Ser Pro Gly Thr Arg Arg Glu Tyr His Thr Glu Lys 420 425 430ctg gtc act tct aaa gga gat aaa gag ctc agg act ggt aaa gag aag 1402Leu Val Thr Ser Lys Gly Asp Lys Glu Leu Arg Thr Gly Lys Glu Lys 435 440 445gtc acc tct ggt agc aca acc acc acg cgt cgt tca tgc tct aaa acc 1450Val Thr

Ser Gly Ser Thr Thr Thr Thr Arg Arg Ser Cys Ser Lys Thr 450 455 460gtt act aag act gtt att ggt cct gat ggt cac aaa gaa gtt acc aaa 1498Val Thr Lys Thr Val Ile Gly Pro Asp Gly His Lys Glu Val Thr Lys465 470 475 480gaa gtg gtg acc tcc gaa gat ggt tct gac tgt ccc gag gca atg gat 1546Glu Val Val Thr Ser Glu Asp Gly Ser Asp Cys Pro Glu Ala Met Asp 485 490 495tta ggc aca ttg tct ggc ata ggt act ctg gat ggg ttc cgc cat agg 1594Leu Gly Thr Leu Ser Gly Ile Gly Thr Leu Asp Gly Phe Arg His Arg 500 505 510cac cct gat gaa gct gcc ttc ttc gac act gcc tca act gga aaa aca 1642His Pro Asp Glu Ala Ala Phe Phe Asp Thr Ala Ser Thr Gly Lys Thr 515 520 525ttc cca ggt ttc ttc tca cct atg tta gga gag ttt gtc agt gag act 1690Phe Pro Gly Phe Phe Ser Pro Met Leu Gly Glu Phe Val Ser Glu Thr 530 535 540gag tct agg ggc tca gaa tct ggc atc ttc aca aat aca aag gaa tcc 1738Glu Ser Arg Gly Ser Glu Ser Gly Ile Phe Thr Asn Thr Lys Glu Ser545 550 555 560agt tct cat cac cct ggg ata gct gaa ttc cct tcc cgt ggt aaa tct 1786Ser Ser His His Pro Gly Ile Ala Glu Phe Pro Ser Arg Gly Lys Ser 565 570 575tca agt tac agc aaa caa ttt act agt agc acg agt tac aac aga gga 1834Ser Ser Tyr Ser Lys Gln Phe Thr Ser Ser Thr Ser Tyr Asn Arg Gly 580 585 590gac tcc aca ttt gaa agc aag agc tat aaa atg gca gat gag gcc gga 1882Asp Ser Thr Phe Glu Ser Lys Ser Tyr Lys Met Ala Asp Glu Ala Gly 595 600 605agt gaa gcc gat cat gaa gga aca cat agc acc aag aga ggc cat gct 1930Ser Glu Ala Asp His Glu Gly Thr His Ser Thr Lys Arg Gly His Ala 610 615 620aaa tct cgc cct gtc aga gac tgt gat gat gtc ctc caa aca cat cct 1978Lys Ser Arg Pro Val Arg Asp Cys Asp Asp Val Leu Gln Thr His Pro625 630 635 640tca ggt acc caa agt ggc att ttc aat atc aag cta ccg gga tcc agt 2026Ser Gly Thr Gln Ser Gly Ile Phe Asn Ile Lys Leu Pro Gly Ser Ser 645 650 655aag att ttt tct gtt tat tgc gat caa gag acc agt ttg gga gga tgg 2074Lys Ile Phe Ser Val Tyr Cys Asp Gln Glu Thr Ser Leu Gly Gly Trp 660 665 670ctt ttg atc cag caa aga atg gat gga tca ctg aat ttt aac cgg acc 2122Leu Leu Ile Gln Gln Arg Met Asp Gly Ser Leu Asn Phe Asn Arg Thr 675 680 685tgg caa gac tac aag aga ggt ttc ggc agc ctg aat gac gag ggg gaa 2170Trp Gln Asp Tyr Lys Arg Gly Phe Gly Ser Leu Asn Asp Glu Gly Glu 690 695 700gga gaa ttc tgg cta ggc aat gac tac ctc cac tta cta acc caa agg 2218Gly Glu Phe Trp Leu Gly Asn Asp Tyr Leu His Leu Leu Thr Gln Arg705 710 715 720ggc tct gtt ctt agg gtt gaa tta gag gac tgg gct ggg aat gaa gct 2266Gly Ser Val Leu Arg Val Glu Leu Glu Asp Trp Ala Gly Asn Glu Ala 725 730 735tat gca gaa tat cac ttc cgg gta ggc tct gag gct gaa ggc tat gcc 2314Tyr Ala Glu Tyr His Phe Arg Val Gly Ser Glu Ala Glu Gly Tyr Ala 740 745 750ctc caa gtc tcc tcc tat gaa ggc act gcg ggt gat gct ctg att gag 2362Leu Gln Val Ser Ser Tyr Glu Gly Thr Ala Gly Asp Ala Leu Ile Glu 755 760 765ggt tcc gta gag gaa ggg gca gag tac acc tct cac aac aac atg cag 2410Gly Ser Val Glu Glu Gly Ala Glu Tyr Thr Ser His Asn Asn Met Gln 770 775 780ttc agc acc ttt gac agg gat gca gac cag tgg gaa gag aac tgt gca 2458Phe Ser Thr Phe Asp Arg Asp Ala Asp Gln Trp Glu Glu Asn Cys Ala785 790 795 800gaa gtc tat ggg gga ggc tgg tgg tat aat aac tgc caa gca gcc aat 2506Glu Val Tyr Gly Gly Gly Trp Trp Tyr Asn Asn Cys Gln Ala Ala Asn 805 810 815ctc aat gga atc tac tac cct ggg ggc tcc tat gac cca agg aat aac 2554Leu Asn Gly Ile Tyr Tyr Pro Gly Gly Ser Tyr Asp Pro Arg Asn Asn 820 825 830agt cct tat gag att gag aat gga gtg gtc tgg gtt tcc ttt aga ggg 2602Ser Pro Tyr Glu Ile Glu Asn Gly Val Val Trp Val Ser Phe Arg Gly 835 840 845gca gat tat tcc ctc agg gct gtt cgc atg aaa att agg ccc ctt gtg 2650Ala Asp Tyr Ser Leu Arg Ala Val Arg Met Lys Ile Arg Pro Leu Val 850 855 860acc caa taggctgaag aagtgggaat gggagcactc tgtcttcttt gctagagaag 2706Thr Gln865tggagagaaa atacaaaagg taaagcagtt gagattctct acaacctaaa aaattcctag 2766gtgctatttt cttatccttt gtactgtagc taaatgtacc tgagacatat tagtctttga 2826aaaataaagt tatgtaaggt tttttttatc tttaaatagc tctgtgggtt ttaacatttt 2886tataaagata taccaagggc cattcagtac atcaggaaag tggcagacag aagcttctct 2946ctgcaacctt gaagactatt ggtttgagaa cttctcttcc cataccaccc aaaatcataa 3006tgccattgga aagcaaaaag ttgttttatc catttgattt gaattgtttt aagccaatat 3066tttaaggtaa aactcactga atctaaccat agctgacctt tgtagtagaa tttacaactt 3126ataattacaa tgcacaattt ataattacaa tatgtattta tgtcttttgc tatggagcaa 3186atccaggaag gcaagagaaa cattctttcc taaatataaa tgaaaatcta tcctttaaac 3246tcttccacta gacgttgtaa tgcacactta tttttttccc aaggagtaac caatttcttt 3306ctaaaacaca tttaaaattt taaaactatt tatgaatatt aaaaaaagac ataattcaca 3366cattaataaa caatctccca agtattgatt taacttcatt tttctaataa tcataaacta 3426tattctgtga catgctaatt attattaaat gtaagtcgtt agttcgaaag cctctcacta 3486agtatgatct atgctatatt caaaattcaa cccatttact ttggtcaata tttgatctaa 3546gttgcatctt taatcctggt ggtcttgcct tctgattttt aatttgtatc cttttctatt 3606aagatatatt tgtcattttc tcttgaatat gtattaaaat atcccaagc 36554866PRTHomo sapiens 4Met Phe Ser Met Arg Ile Val Cys Leu Val Leu Ser Val Val Gly Thr1 5 10 15Ala Trp Thr Ala Asp Ser Gly Glu Gly Asp Phe Leu Ala Glu Gly Gly 20 25 30Gly Val Arg Gly Pro Arg Val Val Glu Arg His Gln Ser Ala Cys Lys 35 40 45Asp Ser Asp Trp Pro Phe Cys Ser Asp Glu Asp Trp Asn Tyr Lys Cys 50 55 60Pro Ser Gly Cys Arg Met Lys Gly Leu Ile Asp Glu Val Asn Gln Asp65 70 75 80Phe Thr Asn Arg Ile Asn Lys Leu Lys Asn Ser Leu Phe Glu Tyr Gln 85 90 95Lys Asn Asn Lys Asp Ser His Ser Leu Thr Thr Asn Ile Met Glu Ile 100 105 110Leu Arg Gly Asp Phe Ser Ser Ala Asn Asn Arg Asp Asn Thr Tyr Asn 115 120 125Arg Val Ser Glu Asp Leu Arg Ser Arg Ile Glu Val Leu Lys Arg Lys 130 135 140Val Ile Glu Lys Val Gln His Ile Gln Leu Leu Gln Lys Asn Val Arg145 150 155 160Ala Gln Leu Val Asp Met Lys Arg Leu Glu Val Asp Ile Asp Ile Lys 165 170 175Ile Arg Ser Cys Arg Gly Ser Cys Ser Arg Ala Leu Ala Arg Glu Val 180 185 190Asp Leu Lys Asp Tyr Glu Asp Gln Gln Lys Gln Leu Glu Gln Val Ile 195 200 205Ala Lys Asp Leu Leu Pro Ser Arg Asp Arg Gln His Leu Pro Leu Ile 210 215 220Lys Met Lys Pro Val Pro Asp Leu Val Pro Gly Asn Phe Lys Ser Gln225 230 235 240Leu Gln Lys Val Pro Pro Glu Trp Lys Ala Leu Thr Asp Met Pro Gln 245 250 255Met Arg Met Glu Leu Glu Arg Pro Gly Gly Asn Glu Ile Thr Arg Gly 260 265 270Gly Ser Thr Ser Tyr Gly Thr Gly Ser Glu Thr Glu Ser Pro Arg Asn 275 280 285Pro Ser Ser Ala Gly Ser Trp Asn Ser Gly Ser Ser Gly Pro Gly Ser 290 295 300Thr Gly Asn Arg Asn Pro Gly Ser Ser Gly Thr Gly Gly Thr Ala Thr305 310 315 320Trp Lys Pro Gly Ser Ser Gly Pro Gly Ser Thr Gly Ser Trp Asn Ser 325 330 335Gly Ser Ser Gly Thr Gly Ser Thr Gly Asn Gln Asn Pro Gly Ser Pro 340 345 350Arg Pro Gly Ser Thr Gly Thr Trp Asn Pro Gly Ser Ser Glu Arg Gly 355 360 365Ser Ala Gly His Trp Thr Ser Glu Ser Ser Val Ser Gly Ser Thr Gly 370 375 380Gln Trp His Ser Glu Ser Gly Ser Phe Arg Pro Asp Ser Pro Gly Ser385 390 395 400Gly Asn Ala Arg Pro Asn Asn Pro Asp Trp Gly Thr Phe Glu Glu Val 405 410 415Ser Gly Asn Val Ser Pro Gly Thr Arg Arg Glu Tyr His Thr Glu Lys 420 425 430Leu Val Thr Ser Lys Gly Asp Lys Glu Leu Arg Thr Gly Lys Glu Lys 435 440 445Val Thr Ser Gly Ser Thr Thr Thr Thr Arg Arg Ser Cys Ser Lys Thr 450 455 460Val Thr Lys Thr Val Ile Gly Pro Asp Gly His Lys Glu Val Thr Lys465 470 475 480Glu Val Val Thr Ser Glu Asp Gly Ser Asp Cys Pro Glu Ala Met Asp 485 490 495Leu Gly Thr Leu Ser Gly Ile Gly Thr Leu Asp Gly Phe Arg His Arg 500 505 510His Pro Asp Glu Ala Ala Phe Phe Asp Thr Ala Ser Thr Gly Lys Thr 515 520 525Phe Pro Gly Phe Phe Ser Pro Met Leu Gly Glu Phe Val Ser Glu Thr 530 535 540Glu Ser Arg Gly Ser Glu Ser Gly Ile Phe Thr Asn Thr Lys Glu Ser545 550 555 560Ser Ser His His Pro Gly Ile Ala Glu Phe Pro Ser Arg Gly Lys Ser 565 570 575Ser Ser Tyr Ser Lys Gln Phe Thr Ser Ser Thr Ser Tyr Asn Arg Gly 580 585 590Asp Ser Thr Phe Glu Ser Lys Ser Tyr Lys Met Ala Asp Glu Ala Gly 595 600 605Ser Glu Ala Asp His Glu Gly Thr His Ser Thr Lys Arg Gly His Ala 610 615 620Lys Ser Arg Pro Val Arg Asp Cys Asp Asp Val Leu Gln Thr His Pro625 630 635 640Ser Gly Thr Gln Ser Gly Ile Phe Asn Ile Lys Leu Pro Gly Ser Ser 645 650 655Lys Ile Phe Ser Val Tyr Cys Asp Gln Glu Thr Ser Leu Gly Gly Trp 660 665 670Leu Leu Ile Gln Gln Arg Met Asp Gly Ser Leu Asn Phe Asn Arg Thr 675 680 685Trp Gln Asp Tyr Lys Arg Gly Phe Gly Ser Leu Asn Asp Glu Gly Glu 690 695 700Gly Glu Phe Trp Leu Gly Asn Asp Tyr Leu His Leu Leu Thr Gln Arg705 710 715 720Gly Ser Val Leu Arg Val Glu Leu Glu Asp Trp Ala Gly Asn Glu Ala 725 730 735Tyr Ala Glu Tyr His Phe Arg Val Gly Ser Glu Ala Glu Gly Tyr Ala 740 745 750Leu Gln Val Ser Ser Tyr Glu Gly Thr Ala Gly Asp Ala Leu Ile Glu 755 760 765Gly Ser Val Glu Glu Gly Ala Glu Tyr Thr Ser His Asn Asn Met Gln 770 775 780Phe Ser Thr Phe Asp Arg Asp Ala Asp Gln Trp Glu Glu Asn Cys Ala785 790 795 800Glu Val Tyr Gly Gly Gly Trp Trp Tyr Asn Asn Cys Gln Ala Ala Asn 805 810 815Leu Asn Gly Ile Tyr Tyr Pro Gly Gly Ser Tyr Asp Pro Arg Asn Asn 820 825 830Ser Pro Tyr Glu Ile Glu Asn Gly Val Val Trp Val Ser Phe Arg Gly 835 840 845Ala Asp Tyr Ser Leu Arg Ala Val Arg Met Lys Ile Arg Pro Leu Val 850 855 860Thr Gln865515PRTHomo sapiens 5Glu Ser Ser Ser His His Pro Gly Ile Ala Glu Phe Pro Ser Arg1 5 10 15620PRTHomo sapiens 6Thr Phe Pro Gly Phe Phe Ser Pro Met Leu Gly Glu Phe Val Ser Glu1 5 10 15Thr Glu Ser Arg 20