CN100445300C

CN100445300C - GLP-1 fusion protein and its preparation method and medicinal uses

Info

Publication number: CN100445300C
Application number: CNB2005100171754A
Authority: CN
Inventors: 魏洋; 李玉新; 刘霞; 鲍永利; 单保红; 乌垠
Original assignee: Individual
Current assignee: Individual
Priority date: 2005-09-30
Filing date: 2005-09-30
Publication date: 2008-12-24
Anticipated expiration: 2025-09-30
Also published as: CN1765931A

Abstract

The present invention provides a GLP-1 fusion protein and a preparing method thereof. The fusion protein can be used for treating insulin non-independent type diabetes, obesity, etc.

Description

GLP-1 fusion protein, preparation method and medical application thereof

Technical Field

The invention discloses a GLP-1 fusion protein and a preparation method thereof, relates to the preparation of fusion proteins of GLP-1(7-37) and a plurality of polypeptides, also provides the medical application of the fusion proteins in the treatment of diseases such as insulin-independent diabetes mellitus, obesity and the like, and belongs to the technical field of biological genetic engineering.

Background

The GLP-1(glucagon-like peptide-1, hereinafter referred to as GLP-1) is mainly a polypeptide consisting of 37 amino acids secreted by L-cells of small intestine, and the active forms of the GLP-1(7-37) OH and the GLP-1(7-36) NH2(Mojsov S, J Clininvest.1987 Feb; 79 (2): 616-9).

GLP-1 analogs are a new class of drugs for the treatment of type II diabetes today. Exenatide was approved by the U.S. food and drug administration in 4.2005, a drug that can be injected, sold under the trade name Byetta, as an adjunctive therapeutic for type II diabetics, Byetta being a GLP-1 analog from lizard saliva, developed by Eli Lilly and Amylin pharmaceuticals. GLP-1 has the effects of obviously reducing blood sugar of a patient after meal, stimulating insulin production, having a certain weight-reducing effect and not causing hypoglycemia (Drucker DJ, diabetes, 1998 Feb; 47 (2): 159-69.). Recent studies have also shown that GLP-1 has a regenerative effect on the pancreas (Drucker DJ, Endocrinology.2003Dec; 144 (12): 5145-8.). As the 2 nd Ala at the N-end of the natural GLP-1 is quickly degraded by dipeptidyl peptidase IV (DPP-IV) in vivo, the clinical application of the natural GLP-1 is greatly limited. In order to extend the in vivo biological half-life of the GLP-1 peptide for better clinical use as a therapeutic agent, long-acting GLP-1 analogs or analogs with resistance to enzymatic degradation must be developed.

Glucagon is a29 amino acid polypeptide produced by pancreatic a-cells that, in contrast to insulin, increases blood glucose and inhibits insulin production. Studies have shown that blood glucagon is significantly elevated in type II diabetics and that blood glucose can be significantly reduced using glucagon antagonists or anti-glucagon antibodies (Shah P, J Clin EndocrinoloMetab.2000 Nov; 85 (11): 4053-9; and Johnson DG, science.1982Feb 26; 215 (4536): 1115-6). Thus, there is a potential for developing glucagon antagonists as new drugs for the treatment of type II diabetes (Djuric SW, Curr Opin investigdrugs, 2002 Nov; 3 (11): 1617-23).

Disclosure of Invention

The invention provides a GLP-1 fusion protein, which is a fusion protein of GLP-1, a human glucagon receptor or any polypeptide receptor in a glucagon family, a human immunoglobulin Fc part and an immunoglobulin Fc part fragment. The C-terminus of GLP-1 can be fused directly or through a peptide linker to the Fc portion of an immunoglobulin or to the N-terminus of a receptor of the human glucagon family.

The invention discloses a preparation method of GLP-1 fusion protein.

The invention also provides linkers that fuse GLP-1 to a glucagon family receptor or an Fc portion of an immunoglobulin, consisting of several freely extendible amino acids, allowing better folding of the fused proteins.

The GLP-1 fusion proteins of the present invention comprise two polypeptides, wherein the first polypeptide is a GLP-1 compound and the second is a glucagon family receptor selected from the group consisting of:

(1) the entire glucagon receptor sequence;

(2) glucagon receptor functional area-1, which is mainly composed of the outer ring of the first membrane of glucagon receptor and the transmembrane areas at the two ends;

(3) the functional region-1 of any polypeptide receptor in the glucagon family is mainly composed of the first membrane outer ring of the receptor and transmembrane regions at two ends of the first membrane outer ring;

(4) the functional region-2 of any polypeptide receptor in the glucagon family, which mainly consists of the outer ring of the 2 nd membrane of the receptor and transmembrane regions at the two ends of the receptor;

(5) the functional region-3 of any polypeptide receptor in the glucagon family, which mainly consists of the outer ring of the 3 rd membrane of the receptor and transmembrane regions at the two ends of the receptor;

(6) GLP-1, GLP-2 or glucose-dependent insulin-dependent nutritive polypeptides belong to the receptors for glucagon family polypeptides.

Wherein the C-terminus of the first polypeptide is fused to the N-terminus of the second polypeptide or is linked by a peptide linker.

The peptide linker is preferably selected from:

(1) a peptide having (Gly-Thr-Gly) n, wherein n is 1, 2, 3, 4, 5, 6;

(2) a peptide having (Gly-Ala-Pro) n, wherein n is 1, 2, 3, 4, 5, 6;

(3) a peptide having (Gly-Pro-Gly) n, wherein n is 1, 2, 3, 4, 5, 6;

(4) a peptide having (Gly-Gly-Gly-Gly-Ser) n. Wherein n is 1, 2, 3, 4, 5, 6.

The fusion protein of the invention may also be a fusion of a GLP-1 compound with a human immunoglobulin Fc-fragment, wherein the human immunoglobulin Fc-fragment is selected from the group consisting of:

(1) the Fc portion of a human immunoglobulin;

(2) analogs of the Fc portion of human immunoglobulins;

(3) fragments of the Fc portion of human immunoglobulins.

The fusion of the two polypeptides may be a fusion of the C-terminus of the first polypeptide and the N-terminus of the second polypeptide or by a peptide linker. The peptide linker is preferably selected from:

(1) a peptide having (Gly-Thr-Gly) n, wherein n is 1, 2, 3, 4, 5, 6;

(2) a peptide having (Gly-Ala-Pro) n, wherein n is 1, 2, 3, 4, 5, 6;

(3) a peptide having (Gly-Pro-Gly) n, wherein n is 1, 2, 3, 4, 5, 6;

(4) Gly-Gly-Gly-Gly-Ser) n. Wherein n is 1, 2, 3, 4, 5, 6.

The fusion protein of the invention may also be a fusion of three polypeptides, wherein the first polypeptide is a GLP-1 compound, the second polypeptide is a human immunoglobulin Fc segment or a fragment of an Fc segment, and the third polypeptide is a human glucagon receptor or a receptor for any polypeptide in the glucagon family.

Wherein the three polypeptides are linked directly or via an intermediate linker, preferably selected from:

(1) a peptide having (Gly-Thr-Gly) n, wherein n is 1, 2, 3, 4, 5, 6;

(2) a peptide having (Gly-Ala-Pro) n, wherein n is 1, 2, 3, 4, 5, 6;

(3) a peptide having (Gly-Pro-Gly) n, wherein n is 1, 2, 3, 4, 5, 6;

(4) a peptide having (Gly-Gly-Gly-Gly-Ser) n. Wherein n is 1, 2, 3, 4, 5, 6.

GLP-1 as part of a fusion protein generally preferably has no more than 6 amino acids different from the corresponding amino acids in GLP-1(7-37) OH, GLP-1(7-36) OH or Exendin-4. Even more preferably, GLP-1 compounds have no more than 5 amino acids other than the corresponding amino acid in GLP-1(7-37) OH, GLP-1(7-36) OH or Exendin-4. GLP-1 compounds most preferably have no more than 4, 3, or 2 amino acids other than the corresponding amino acid in GLP-1(7-37) OH, GLP-1(7-36) OH, or Exendin-4.

The GLP-1 fusion protein can be obtained by the following preparation method: gene recombination technology or solid phase protein synthesis technology.

The specific technical solution for producing the fusion protein of the invention by a recombinant method is as follows:

construction of recombinant vector encoding fusion protein of the present invention

(I) fishing of GLP-1

Designing PCR primer according to the disclosed GLP-1 sequence, and obtaining GLP-1cDNA sequence by PCR amplification with cDNA expressing human GLP-1, such as pancreas, small intestine and brain tissue cDNA as template.

(II) fishing of glucagon receptor and other receptors of its family

The glucagon receptor part in the fusion protein can be obtained by PCR amplification by using human liver tissue cDNA as a template and using a primer of a corresponding receptor, and then cloned into a TOPO TA vector (Invitrogen), and the recombinant vector is identified by Eco RI enzyme digestion and sequence analysis. The resulting plasmid is referred to herein as the TOPO TA-glucagon receptor.

A glucagon receptor N-terminal extramembranous functional region; functional region-1; functional region-2; the functional region-3 segment can be obtained by taking the TOPO TA-glucagon receptor as a template and performing PCR amplification by using corresponding primers.

Other receptors of the glucagon family can be targeted using the same methods as the glucagon receptor.

After the gene fragments are obtained, the corresponding genes can be ligated by using ligase, or fused together by using an overlap PCR method, and then cloned into an expression vector.

(III) fishing of human IgG1Fc fragment

The cDNA sequences encoding the CH2 and CH3 functional regions of human IgG1 subtype were cloned into pV05 vector (FIG. 6) by PCR using IgG-expressing human tissue cDNA as template, and the obtained plasmid was named pV 05-human IgG1 Fc.

(IV) construction of recombinant expression vectors

A gene encoding a fusion protein is constructed by in-frame ligation of a DNA encoding GLP-1 and a DNA encoding an immunoglobulin Fc portion or a receptor for glucagon and its analogs. The gene encoding GLP-1 can also be linked in-frame to a gene encoding the Fc portion of an immunoglobulin or the receptor for glucagon and its analogs by a gene encoding a linker peptide.

The DNA encoding wild-type GLP-1, glucagon and its analog receptors, Fc polypeptides and fragments may be mutated prior to ligation or within the cDNA encoding the entire fusion protein. Various mutagenesis techniques are known in the art. For example, a mutagenic PCR method using chain overlap extension to prepare a specific base mutation for changing a specific amino acid sequence in a corresponding protein.

When the fusion protein is expressed in mammalian cells, a signal peptide is required so that the expressed fusion protein can be secreted into the cytoplasm and the signal peptide is automatically cleaved off. The present invention uses the signal peptide of pre-glucagon, other signal peptides may also be used, such as: the signal peptide of parathyroid hormone (Wiren, KMetc. the J of Bio. chem.263 (36): 19771-19777(1988), or the signal peptide of human IgG1 Fc.

When bacteria are used for expressing the fusion protein, a bacterial fusion protein expression method can be adopted, a protease cutting point and an HA or 6HIS label are added at the N end for adsorption and purification, and the expressed fusion protein is subjected to protease enzyme digestion to obtain the fusion protein containing the correct cutting point. The latest IMPACT bacterial expression system (New England, BioLabs Inc.) can also be used. This IMPACT protein fusion and purification system utilizes the self-cleaving activity of inducible engineered protein cleavage elements for protein purification and processing. Protein purification by pH and temperature induced lysis: using the pTWIN vector, this intein tag was fused to the N-terminus of the protein of interest. This protein of interest is then released by pH and temperature induced lysis.

Once the gene encoding the complete fusion protein is produced, it can be cloned into an appropriate expression vector.

Second, general methods for expressing the fusion proteins of the invention

Host cells, which may be eukaryotic or prokaryotic host cells, are transfected or transformed with the expression vectors described herein for the production of fusion proteins. Techniques for transforming or transfecting cells with recombinant DNA vectors are well known in the art.

Thirdly, recovery and purification of the recombinantly produced protein

The expressed fusion protein can be purified by a corresponding column chromatography using a sequence tag added at the N-terminus or C-terminus or the characteristics of the fusion protein.

Fourth, detection of Activity of fusion protein

(I) determination of the binding Activity of fusion proteins in vitro

By using¹²⁵I-labeled commercial GLP-1(7-36) competes with the fusion protein of the invention for binding to the GLP-1 receptor and, as a result, shows that the fusion protein of the invention binds slightly more actively to the GLP-1 receptor than commercial human GLP-1 (7-36).

(II) Effect of fusion proteins on cAMP levels in vitro

The recombinant vector containing GLP-1 receptor cDNA was transfected into CHO cells for 48 hours before measuring cAMP as described in the literature (Wei and Mojsov, 1996), and the results showed that the fusion protein of the present invention had substantially the same effect on cAMP levels in vitro as that of commercial human GLP-1 (7-36).

(III) pharmacokinetic detection of fusion proteins

C57BL/6 mice were injected intravenously with fusion protein (50nM), and blood samples were taken from the tail vein at 0min, 1hr, 6hr, 12hr, 24hr, 36hr, 48hr, 60hr and 72hr after injection. Plasma was centrifuged at 4 ℃ and the fusion protein level was measured by ELISA. The result shows that the biological half-life period of the fusion protein is obviously prolonged compared with that of pure GLP-1.

(IV) Effect of fusion proteins on sugar tolerance in mice

Mice (C57BL/6) fasted overnight (16-18h) were injected subcutaneously with different doses of fusion protein (4. mu.g/kg, 16. mu.g/kg, 80. mu.g/kg and 1mg/kg) or saline, 30min and 24h later, i.p.with 1.5mg/g body weight of glucose, and blood samples were taken from the tail tips at 0, 10, 20, 30, 60, 90, and 120min after injection, respectively. The glucose level in blood was measured by the glucoenzyme method using a glucose meter. The result shows that the glucose tolerance of the mouse is obviously improved after the fusion protein is administered, the blood glucose reducing function is obviously achieved after the fusion protein is administered at 0.07nmol/kg, the blood glucose reducing function of the mouse is positively correlated with the concentration of the fusion protein, and the blood glucose reducing function of the mouse becomes more obvious when the concentration of the fusion protein is increased to 18 nmol/kg.

In conclusion, the results of in vitro and in vivo biological activity tests show that the fusion protein prepared by the invention not only has the normal biological activity of GLP-1, but also has the biological half-life period obviously prolonged compared with that of the independent GLP-1 polypeptide.

Fusion protein pharmaceutical composition and application

The fusion protein of the invention is useful for the treatment of insulin-independent diabetes, insulin-dependent diabetes, stroke, myocardial infarction, obesity, altered catabolism following surgery, functional dyspepsia and irritable bowel syndrome. Also included are patients in need of prophylactic treatment with GLP-1 compounds, such as patients at risk for developing insulin-independent diabetes: subjects with glucose intolerance or impaired fasting glucose, subjects weighing more than 25% of normal weight relative to the patient's height and size, subjects who have undergone a partial pancreatectomy, subjects with gestational diabetes mellitus, and subjects with acute or chronic pancreatitis. The fusion protein not only keeps the biological activity of GLP-1, but also prolongs the biological half-life of GLP-1 in vivo, so the fusion protein can be used for treating the diseases.

The invention also provides a pharmaceutical composition comprising an effective amount of the above fusion protein or a pharmaceutically acceptable carrier or diluent.

The dosage of the active ingredient in the composition of the invention may vary, but the amount of active ingredient must be such that a suitable dosage form is obtained. The selected dosage will vary depending upon the desired therapeutic effect, the route of administration, and the treatment period. In general, an effective amount of the active ingredient of the present invention is 1X 10^-7200 mg/kg/day, 1X 10^-4-100 mg/kg/day, which can be administered in a single dose or divided into multiple doses.

The fusion proteins of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, subcutaneous injection or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and may be formulated with a pharmaceutically acceptable carrier to provide a dosage form suitable for each route of administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert carrier, such as sucrose, lactose or starch. Such dosage forms may be used as is or may include, in addition to the inert diluent, other substances such as, for example, lubricating agents, e.g., magnesium stearate. In capsules, tablets and pills, these dosage forms may also comprise buffering agents. Tablets and pills may additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, containing inert diluents commonly used in the art, such as water. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, and perfuming agents.

Formulations of the invention for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions or emulsions. Non-aqueous solvents or vehicles, such as propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil and corn oil), gelatin, injectable organic esters (e.g., ethyl oleate). These dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Sterilization may be performed, for example, by filtration through a bacterial retaining filter, by adding a sterilizing agent to the composition, by irradiating the composition, or by heating the composition. They may also be formulated as sterile solid compositions which are dissolved in sterile water or other injectable sterile medium immediately prior to use.

Compositions for rectal or vaginal administration are preferably suppositories which, in addition to the active substance, may contain excipients, for example cocoa butter or a suppository wax.

Compositions for nasal or sublingual administration may also be prepared using standard excipients well known in the art. In addition, the compositions of the present invention may be administered in the form of sustained release compositions.

The invention has the positive effects that: GLP-1 in the fusion protein can keep the natural function, the half-life of GLP-1 can be prolonged by the glucagon family receptor part and the human IgG Fc fragment part, and the glucagon family receptor has the function of neutralizing glucagon and can play a role in dual hypoglycemic effect; the human IgG Fc fragment portion facilitates purification of the fusion protein.

The glucagon family receptor moiety of the present invention extends the half-life of GLP-1 for the following reasons:

the membrane 1 and 3 outer loops of the glucagon receptor bind to the N-terminus of glucagon. The N-terminus of GLP-1 is nearly identical to glucagon, so GLP-1 binds weakly to the glucagon receptor (or to a receptor for other polypeptides of the glucagon family), which weak binding protects GLP-1 to some extent from degradation by DPPIV, thus prolonging the half-life of GLP-1. Similarly, when GLP-1 and the GLP-1 receptor or partial domain are fused together, GLP-1 will bind weakly to the receptor moiety to which it is attached to protect GLP-1, and when the fusion protein encounters the native receptor, its binding force is stronger than that of the receptor moiety of the fusion protein, so GLP-1 in the fusion protein tends to bind to the native receptor and exert its biological effect.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Drawings

FIG. 1 shows the result of immunoblotting of fusion protein PPS601

FIG. 2a shows GLP-1 receptor sequences

FIG. 2b shows the result of the binding of the fusion protein PPS601 to the human GLP-1(7-37) receptor

FIG. 3 shows the effect of the fusion protein PPS601 on cAMP levels

FIG. 4 shows the in vivo pharmacokinetic results of the fusion protein PPS601

FIG. 5 shows the effect of the fusion protein PPS601 on the glucose tolerance of mice

FIG. 6 shows a map of the pV05 vector

FIG. 7 shows a map of the PPS601 recombinant vector

The specific implementation mode is as follows:

the following examples are intended to help describe how various embodiments of the invention may be practiced. These examples are intended to illustrate, but not to limit in any way the scope of the invention.

Example 1

Construction of fusion protein vectors

The GLP-1 part in the fusion protein can be obtained by taking any cDNA expressing human GLP-1, such as pancreas, small intestine and brain tissue cDNA as a template and performing PCR amplification. Mice have the same GLP-1 amino acid sequence as humans, and thus can be substituted for human cDNA.

The DNA encoding GLP-1 of the present invention can be prepared by various methods, including the cloning method described above and the method of chemically synthesizing DNA.

The glucagon receptor part in the fusion protein can be obtained by PCR amplification by using human liver tissue cDNA as a template and using primers 5'-ATGCCCCCCTGCCAGCCACAG-3' and 5'-TCAGAAGGGGCTCTCAGCCAATC-3'. The amplified glucagon receptor was 1431bp and cloned into TOPO TA vector (Invitrogen), and the recombinant vector was identified by EcoRI cleavage and sequence analysis. The resulting plasmid is referred to herein as the TOPO TA-glucagon receptor.

A glucagon receptor N-terminal extramembranous functional region; functional region-1; functional region-2; the functional region-3 segment can be obtained by taking the TOPO TA-glucagon receptor as a template and performing PCR amplification by using corresponding primers. After the gene fragments are obtained, the corresponding genes can be connected through a ligase to prepare fusion proteins, and the fusion proteins can also be fused together by an overlapping PCR method. And then cloned into an expression vector.

The GLP-1 receptor in the fusion protein can be obtained by taking human liver tissue cDNA as a template and performing PCR amplification by using primers 5'-ATGGCCGGCGCCCCCGGC-3' and 5'-TCAGCTGTAGGAGGCCTGGC-3'. The amplified GLP-1 receptor is 1392bp, and is cloned into TOPO TA vector (Invitrogen), and the recombinant vector is cut by EcoRI and identified by sequence analysis. The resulting plasmid is referred to herein as TOPO TA-GLP-1 receptor.

An N-terminal extramembranous functional region of the GLP-1 receptor; functional region-1; functional region-2; the functional region-3 segment can be obtained by taking the TOPO TA-GLP-1 receptor as a template and carrying out PCR amplification by using corresponding primers. After the gene fragments are obtained, the corresponding genes can be connected through a ligase to prepare fusion proteins, and the fusion proteins can also be fused together by an overlapping PCR method. And then cloned into an expression vector.

The GLP-2 receptor in the fusion protein can be obtained by taking human liver tissue cDNA as a template and performing PCR amplification by using primers 5'-ATGAAGCTGGGATCGAGCAG-3' and 5'-CTAGATCTCACTCTCTTCCAG-3'. The amplified GLP-2 receptor is 1162bp, which is cloned into TOPO TA vector (Invitrogen), and the recombinant vector is cut by EcoRI and identified by sequence analysis. The resulting plasmid is referred to herein as TOPO TA-GLP-2 receptor.

An N-terminal extramembranous functional region of the GLP-2 receptor; functional region-1; functional region-2; the functional region-3 fragment can be obtained by taking the TOPO TA-GLP-2 receptor as a template and carrying out PCR amplification by using corresponding primers. After the gene fragments are obtained, the corresponding genes can be connected through a ligase to prepare fusion proteins, and the fusion proteins can also be fused together by an overlapping PCR method. And then cloned into an expression vector.

The Fc region of human immunoglobulin G1 in the fusion protein can be obtained by PCR amplification using any expressed human tissue cDNA. The cDNA sequences of human cDNA library (GIBCO, BRL) encoding the CH2 and CH3 functional regions of IgG1 subtype were extracted. The primers used were:

5'-AAAAGGCCCGGGCGACAAAACTCACACATGC-3' (containing SrfI cleavage site)

And 5'-ATTTCGCCGGCGTTATTTACCCGGAGACAGGG-3' (containing NotI cleavage sites)

This pair of primers was used to amplify a 214-19 bp region of the IgG1 heavy chain coding region, which included the hinge region, CH2, and CH3 functional regions (Strausberg, R.L.etc. Proc.Natl.Acad.Sci.U.S.A.99(26), 16899-169903 (2002)). The Fc of the obtained human immunoglobulin G1 was 759bp, which contained a middle linker GGCCCGGGC (SrfI cleavage site) at its 5 '-end and a TAA stop codon and NotI cleavage site at its 3' -end, which was cloned into the pV05 vector (FIG. 6), and the obtained plasmid was named pV 05-human immune protein G1 Fc.

When bacteria are used for expressing the fusion protein, a bacterial fusion protein expression method can be adopted, a protease cutting point and HA or 6HIS TAG are added at the N end for adsorption and purification, and the expressed fusion protein is subjected to protease enzyme digestion to obtain the fusion protein containing the correct cutting point. The latest IMPACT bacterial expression system (New England, BioLabs Inc.) can also be used. This IMPACT protein fusion and purification system utilizes the self-cleaving activity of inducible engineered protein cleavage elements for protein purification and processing. Protein purification by pH and temperature induced lysis: using the pTWIN vector, this intein tag was fused to the N-terminus of the protein of interest. This protein of interest is then released by pH and temperature induced lysis.

Example 1a

Construction of recombinant vector of fusion protein (G at 2-position replaces A) GLP-1-intermediate connector-glucagon receptor N-end extramembranous functional region-human immune protein G1 Fc:

mouse brain tissue cDNA was used as a template, and the following primers were used:

(a)5’-CCCAAGCTT ATGAAGACCATTTACTTTGT-3’

(b)5’-GGTCCCTTCAGCATGCTGCCAGCTGCCTTGCAC-3’

(c)5’-CATGCTGAAGGGACCTTTAC-3’

(d)5’-AAAAGGCGCGCCTTCCTCGGCCTTTCACCAGCC-3’

the glucagon signal peptide and the GLP-1 coding sequence can be respectively obtained by PCR amplification. The 3 'end of the obtained signal peptide is inserted into 15bp GLP-15' end sequence through a primer, and then the signal peptide and GLP-1 are fused together through overlapping PCR by the primers (a) and (d). Ala was changed to Gly (GAA to GCT) in primers (b) and (c), and the 5 'and 3' ends of the obtained fragments were inserted with HindIII and AscI sites, respectively, for cloning.

Using TOPO TA-glucagon receptor as template, the following primers:

(e)5’-AAGGCGCGCCTGCTCAGGTGATGGACTTC-3’

(f)5’-AAAAGCCCGGGCCCTGGAAGCTGCTGTACATC-3’

the glucagon receptor N-terminal extramembranous functional region is obtained by PCR amplification, the 5 '-end of the glucagon receptor N-terminal extramembranous functional region contains GGCGCGCCT (AscI enzyme cutting site), and the 3' -end of the glucagon receptor N-terminal extramembranous functional region contains GCCCGGGCC (SrfI enzyme cutting site).

After obtaining the above two fragments, they were cloned into the Fc of the HindIII and SrfI digested vector pV 05-human immune protein G1 and then transformed into HB10D competent cells (invitrogen). The recombinant plasmid is completely correct after HindIII and NotI enzyme digestion and sequence analysis identification.

The expressed fusion protein sequence is [ sequence ID NO: 35]:

HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRG-GAP-AQVMDFLFEKWKLYGDQCHHNL

SLLPPPTELV

CNRTFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPW

RDASQCQMDGEEI EVQKEVAKMYSSFQ-GPG-DKTHTCPPCPAPELLGGPSVFLFPPK

PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS

VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ

VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG

NVFSCSVMHEALHNHYTQKSLSLSPGK

example 1b

Construction of recombinant vector of fusion protein (G at position 2 substituted with A) GLP-1-intermediate connector-glucagon receptor functional region-1-intermediate connector-human immune protein G1Fc

The preparation of the signal peptide- (G at position 2 instead of A) GLP-1 fragment is the same as in method 1 a.

Glucagon receptor functional region-1 can be obtained by PCR amplification using the following primers:

the primer for amplifying the glucagon receptor functional area-1 comprises the following components:

5'-CCGGCGCGCCTGTCATTGATGGGCTGCTCAG-3' (containing Asc I cleavage site) and 5'-AAAAGCCCGGGCCAGCCACCGCTCCATCACT-3' (containing Srf I cleavage site).

The fragment obtained by the above PCR was digested with HindIII and SrfI and cloned into Fc of the HindIII and SrfI digested vector pV 05-human immunoglobulin G1. The insertion sequence of the recombinant plasmid is verified to be completely correct by nucleotide sequencing.

Example 1c

Construction of recombinant vector of fusion protein (G at position 2 substituted with A) GLP-1-intermediate connector-glucagon receptor functional region-3-intermediate connector-human immune protein G1Fc

Glucagon receptor functional region-3 can be obtained by PCR amplification using the following primers:

the primer for amplifying the glucagon receptor functional area-3 comprises the following components:

5'-CCGGCGCGCCTGACGAGCACGCCCAGGGC-3' (containing Asc I cleavage site)

5'-AAAAGCCCGGGCCGAGGTCGAAGAAGAGCTT-3' (containing Srf I cleavage site)

Example 1d

Construction of recombinant vector of fusion protein (G at position 2 substituted A) GLP-1-intermediate connector-glucagon receptor functional region-3-intermediate connector-human immunity protein G1 Fc:

The glucagon receptor functional region-1 and the functional region-3 can be respectively obtained by PCR amplification by using the following primers:

5'-CCGGCGCGCCTGTC ATT GAT GGG CTG CTC AG-3' (containing Asc I cleavage site) and 5 'ACTTCCACCTCCGCCAGCCACCGCTCCATCACT-3' (containing ACTTCCACCTCCGCC intermediate linker).

5'-GGCGGAGGTGGAAGTGACGAGCACGCCCAGGGC-3' and 5'-AAAAGCCCGGGCCGAGGTCGAAGAAGAGCTT-3' (containing Srf I cleavage sites)

The two fragments obtained by the PCR are fused together by overlapping PCR, are cloned into Fc of a vector pV 05-human immunoglobulin G1 cut by HindIII and SrfI after being cut by HindIII and SrfI, and the sequence of the insertion sequence of the recombinant plasmid is identified to be completely correct by nucleotide sequencing.

The expressed fusion protein sequence is [ sequence ID NO: 36]:

HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRG-

GAP-VIDGLLRTRYSQKIGDDLSVSTWLSDGAVAG

-GGGS-DEHAQGTLRSAKLFFDL-GPG-DKTHTCPPCPAPELLGGPSVFLFPPKPK

DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST

YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT

LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG

SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

example 1e

Construction of fusion protein (G at position 2 substituted A) GLP-1-intermediate linker-human immunity protein G1 Fc:

the preparation of the signal peptide- (G8 instead of A) GLP-1 fragment was identical to example 1 a. Except that in primer (d) SrfI was used instead of AscI. After this was obtained it was cloned into the Fc of the HindIII and SrfI digested vector pV 05-human immune protein G1. The insertion sequence of the recombinant plasmid is verified to be completely correct by nucleotide sequencing.

The expressed fusion protein sequence is [ sequence ID NO: 37]:

HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRG-GAP-DKTHTCPPCPAPELLGGP

SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK

PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ

PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP

PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

example 1f

Construction of recombinant vector of fusion protein (G at position 2 substituted for A) GLP-1-intermediate linker-GLP-1 receptor-human immunoglobulin G1Fc

(a)5’-CCCAAGCTT ATGAAGACCATTTACTTTGT-3’

(b)5’-GGTCCCTTCAGCATGCTGCCAGCTGCCTTGCAC-3’

(c)5’-CATGCTGAAGGGACCTTTAC-3’

(d)5’-AAAAGGCGCGCCTTCCTCGGCCTTTCACCAGCC-3’

The TOPO TA-GLP-1 receptor was used as template with the following primers:

(e)5’-AAGGCGCGCCTCGCCCCCAGGGTGCCAC-3’

(f)5’-AAAAGCCCGGGCCGCTGCAGGAGGCCTG-3’

the GLP-1 receptor is obtained by PCR amplification, wherein the 5 '-end of the GLP-1 receptor contains GGCGCGCCT (Asc I enzyme cutting site) and the 3' -end of the GLP-1 receptor contains GCCCGGGCC (SrfI enzyme cutting site).

After obtaining the above two fragments, they were cloned into the Fc of the HindIII and SrfI digested vector pV 05-human immune protein G1 and then transformed into HB10D competent cells (invitrogen). The recombinant plasmid is completely correct in sequence through HindIII and NotI enzyme digestion and sequence analysis.

Example 1g

Construction of recombinant vector of fusion protein (G at position 2 substituted for A) GLP-1-intermediate linker-GLP-1 receptor N-terminal extramembranous functional region-human immunoglobulin G1Fc

(a)5’-CCCAAGCTT ATGAAGACCATTTACTTTGT-3’

(b)5’-GGTCCCTTCAGCATGCTGCCAGCTGCCTTGCAC-3’

(c)5’-CATGCTGAAGGGACCTTTAC-3’

(d)5’-AAAAGGCGCGCCTTCCTCGGCCTTTCACCAGCC-3’

The TOPO TA-GLP-1 receptor was used as template with the following primers:

(e)5’-AAGGCGCGCCTCGCCCCCAGGGTGCCAC-3’

(f)5’-AAAAGCCCGGGCCGTAGAGGAACAGGAGCTG-3’

obtaining a GLP-1 receptor N-end extramembranous functional region through PCR amplification, wherein the 5 '-end of the functional region contains GGCGCGCCT (AscI restriction enzyme cutting site), and the 3' -end of the functional region contains GCCCGGGCC (SrfI restriction enzyme cutting site). After obtaining the above two fragments, they were cloned into the Fc of the HindIII and SrfI digested vector pV 05-human immune protein G1 and then transformed into HB10D competent cells (invitrogen). The recombinant plasmid is completely correct in sequence through HindIII and NotI enzyme digestion and sequence analysis.

Example 1h

Construction of recombinant vector of fusion protein (G at position 2 substituted for A) GLP-1-intermediate linker-GLP-1 receptor functional region-1-intermediate linker-human immunoglobulin G1Fc

GLP-1 receptor functional region-1 can be obtained by PCR amplification using the following primers:

the primers for amplifying the GLP-1 receptor functional region-1 are as follows:

5'-CCGGCGCGCCTAACTACATCCACCTGAAC-3' (containing Asc I cleavage site) and 5'-AAAAGCCCGGGCCCAGGTACACGCCCTCCAC-3' (containing Srf I cleavage site).

The fragment obtained by the PCR is cut by HindIII and SrfI and then cloned into Fc of a vector pV 05-human immunoglobulin G1 cut by HindIII and SrfI, and the sequence of the insertion sequence of the recombinant plasmid is identified to be completely correct by nucleotide sequencing.

Example 1i

Construction of recombinant vector of fusion protein (G at position 2 substituted for A) GLP-1-intermediate linker-GLP-1 receptor functional region-2-intermediate linker human immunoglobulin G1Fc

The preparation of the signal peptide- (G at position 2 instead of A) GLP-1 fragment is the same as in method 1 a. GLP-1 receptor functional region-2 can be obtained by PCR amplification using the following primers:

the primers for amplifying the GLP-1 receptor functional region-2 are as follows:

5'-CCGGCGCGCCTTTCAGGCTCTACGTGAGC-3' (containing Asc I cleavage site) and 5'-AAAAGCCCGGGCCGCAGATGACCCGAACAAAG-3' (containing Srf I cleavage site).

The fragment obtained by the PCR was digested with HindIII and SrfI and cloned into Fc of vector pV 05-human immunoglobulin G1 digested with HindIII and SrfI. The insertion sequence of the recombinant plasmid is verified to be completely correct by nucleotide sequencing.

Example 1j

Construction of recombinant vector of fusion protein (G at position 2 substituted for A) GLP-1-intermediate linker-GLP-1 receptor functional region-3-intermediate linker-human immunoglobulin G1Fc

GLP-1 receptor functional region-3 can be obtained by PCR amplification by using the following primers:

the primers for amplifying the GLP-1 receptor functional region-3 are as follows:

5'-CCGGCGCGCCTTCCACGCTGACACTCATC-3' (containing Asc I cleavage site) and 5'-AAAAGCCCGGGCCCTCATTGTTGACAAAGC-3' (containing Srf I cleavage site)

Example 1k

Construction of recombinant vector of fusion protein (G at position 2 replaces A) GLP-1-intermediate joint-GLP-1 receptor functional region-3-intermediate joint-human immunoglobulin G1Fc

GLP-1 receptor functional region-1 and functional region-3 can be obtained by PCR amplification by using the following primers:

5'-CCGGCGCGCCTAACTACATCCACCTGAAC-3' (containing Asc I cleavage site) and 5 'ACTTCCACCTCCGCCCAGGTACACGCCCTCCAC-3' (containing ACTTCCACCTCCGCC intermediate linker).

5'-GGCGGAGGTGGAAGTTCCACGCTGACACTCATC-3' and 5'-AAAAGCCCGGGCCCTCATTGTTGACAAAGC-3' (containing Srf I cleavage sites)

The two fragments obtained by the above PCR were fused together by overlap PCR, digested with HindIII and SrfI, and cloned into Fc of HindIII and SrfI digested vector pV 05-human immunoglobulin G1. The insertion sequence of the recombinant plasmid is verified to be completely correct by nucleotide sequencing.

Example 2

Expression of fusion proteins

For expression of the fusion protein in the recombinant vector constructed in example 1, transient transfection CHO method can be used. CHO cells were seeded 10cm dishes⁶After 24 hours of culture, transfection was performed. Lipofectamine (Invitrogen), OptiMEM and plasmid were mixed, kept at room temperature for 30 minutes, and then addedCHO cells washed with serum-free OptiMEM were cultured for 5 hours, then CHO-S-SFMII media (Gibco cat # 31033-.

Example 3

Purification of fusion proteins

The above CHO supernatant containing the expressed protein was concentrated 10-fold by 10K filtration membrane, and then the Fc-containing fusion protein was captured by using protein G column, eluted with 50mM citric acid (pH 3.3), and the eluate (0.5ml) was collected and neutralized with acidity by adding 100. mu.l of 1M Tris pH 8.0. After determination of the protein content by OD280nm, all protein-containing collection tubes were pooled and dialyzed 2 times against a 10K dialysis membrane in PBS (pH 7.4).

Example 4

Immunoblot identification of fusion proteins

The purified material of PPS601 and serum samples under inducer-free induction conditions was diluted with PBS containing 1% SDS and 2mg bromophenol blue. After boiling denaturation, 20. mu.l of the sample was applied to SDS-PAGE and, after electrophoresis, the protein was transferred to nitrocellulose. The membrane was blocked with 5% nonfat dry milk at room temperature for 2hr, HRP-labeled goat anti-human IgG (Sigma, USA) was added, and then luminescence-color development was performed with ECL kit (Amersham Pharmacia Biotech, USA), resulting in better expression of the fusion protein of the present invention as shown in FIG. 1.

Example 5

In vitro binding Activity assay for fusion proteins

The GLP-1 receptor cDNA was obtained using PCR amplification (FIG. 2a) and cloned into pcDNA3.1(Invitrogen, USA). Competitive binding assays were performed 48 hours after transfection of GLP-1 receptor cDNA into CHO cells as described in the literature (Wei and Mojsov, 1996). Contacting CHO cells with¹²⁵I-GLP-1(7-36) (2200Ci/mmol, New England Nuclear, USA) in increasing concentrations (pM-uM) of hGLP-1(7-37) small peptide (anaSPEC, USA) or GLP-1 fusionIncubate at 4 ℃ for 15-18 hours in the presence of the complex protein. The reaction was carried out in Hank's balanced salt solution containing 20mM HEPES, pH7.4, 0.5% BSA and 0.1mM phenylmethylisolfonyl-fluoride (PMSF). After incubation, the cells were washed twice with ice-cold PBS, lysed with 1N NaOH, and radioactivity was measured using a gamma counter, resulting in a fusion protein of the invention that binds slightly more to the GLP-1 receptor than commercial human GLP-1(7-36) as shown in FIG. 2 b.

Example 6

Effect of fusion proteins on cAMP levels in vitro

The recombinant vector containing the GLP-1 receptor cDNA was transfected into CHO cells 48 hours before cAMP was measured as described in the literature (Wei and Mojsov, 1996). Cells were re-seeded in 24-well plates for 24 hours and then incubated with buffer (Macy's 5A pH7.4, 20mM HEPES, 0.5% BSA, 0.5mM IBMX). The cells were incubated at 37 ℃ for 45 minutes without any small peptide or with varying concentrations of hGLP-1 or GLP-1 fusion protein (pM to. mu.M). Forskolin (10 μ M, Sigma, USA) was used as a positive control in each experiment. The culture solution was discarded, the cells were washed twice with PBS, lysed with 95% ethanol, centrifuged at 13000rpm for 3 minutes, the supernatant was vacuum-dried and then dissolved in 0.05M acetate buffer (0.5ml), and cAMP levels were measured using the cAMPBiotrak SPA system (Amersham, USA), and as a result, the effect of the fusion protein of the present invention on cAMP levels in vitro was substantially the same as that of commercial human GLP-1(7-36) as shown in FIG. 3.

Example 7

In vivo pharmacokinetics of fusion proteins

In vivo pharmacokinetics of the fusion protein: c57BL/6 mice were injected intravenously with fusion protein (50nM), and blood samples were taken from the tail vein at 0min, 1hr, 6hr, 12hr, 24hr, 36hr, 48hr, 60hr and 72hr after injection. Plasma was centrifuged at 4 ℃ and PPS601 levels were measured by ELISA. The results of the pharmacokinetics in vivo of the fusion protein (G at the 2 nd position substituted A) GLP-1-intermediate linker-glucagon receptor functional region-3-intermediate linker-human IgG1Fc (PPS 601) are shown in FIG. 4, and the half-life in vivo of the fusion protein of the invention is obviously prolonged compared with that of GLP-1 alone.

Example 8

ELISA method for detecting concentration of fusion protein in mouse plasma

The concentration of total fusion protein in the mouse plasma was identified by ELISA. Mu.l (2. mu.g/ml) of anti-human IgG gamma chain specific affinity extracted antibody (Sigma, USA) diluted in PBS was coated on a 96-well microplate (Nunc-Immunoplate Maxisorp; Nalge Nunc International, Demark) at 4 ℃ overnight. After washing 4 times, blocking with 300. mu.l of 1% BSA-PBS at room temperature for 2 hr. Adding PPS601 standard diluted with 0.5% BSA-PBS and serum, and allowing to act at room temperature for 2 hr. After four washes, HRP-labeled goat anti-human IgG (jackson immunoresearch, USA) was added and allowed to react at room temperature for 1hr, followed by TMB at room temperature for 20 minutes. The 450-570nm values were determined after the reaction was stopped with sulfuric acid.

Example 9

Effect of fusion proteins on sugar tolerance in mice

Glucose tolerance experiments in mice given the fusion protein: mice (C57BL/6) fasted overnight (16-18h) were injected subcutaneously with different doses of fusion protein (4ug/kg, 16ug/kg, 80ug/kg and 1mg/kg) or saline, 30min and 24h later, i.p. with 1.5mg/g body weight of glucose, and blood samples were taken from the tail tips at 0, 10, 20, 30, 60, 90, and 120min after injection, respectively. The glucose level in blood was measured by the glucoenzyme method using a glucose meter. The results of the glucose tolerance experiment of mice given the fusion protein PPS601 are shown in FIG. 5, and the glucose tolerance of the mice is obviously enhanced after the fusion protein of the invention is given.

Sequence listing

<110> northeast university

<120> GLP-1 fusion protein, preparation method and medical application thereof

<130>GLP-1

<160>37

<170>PatentIn version 3.3

<210>1

<211>31

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(2)..(2)

<223> Xaa at position 2 is Ala, Gly, Ser or Thr;

<220>

<221>misc_feature

<222>(3)..(3)

<223> Xaa at position 3 is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(5)..(5)

<223> Xaa at position 5 is Thr, Arg or Ile;

<220>

<221>misc_feature

<222>(6)..(6)

<223> Xaa at position 6 is Phe, Tyr or Leu;

<220>

<221>misc_feature

<222>(8)..(8)

<223> Xaa at position 8 is Ser or Asn;

<220>

<221>misc_feature

<222>(9)..(9)

<223> Xaa at position 9 is Asp or Asn;

<220>

<221>misc_feature

<222>(10)..(10)

<223> Xaa at position 10 is Val, Ile, Met or Ala;

<220>

<221>misc_feature

<222>(11)..(11)

<223> Xaa at position 11 is Ser, Thr, Ala or Asp;

<220>

<221>misc_feature

<222>(12)..(12)

<223> Xaa at position 12 is Ser, Gln, Glu, Asn or Thr;

<220>

<221>misc_feature

<222>(13)..(13)

<223> Xaa at position 13 is Tyr, Phe, Gln, His, or Leu;

<220>

<221>misc_feature

<222>(14)..(14)

<223> Xaa at position 14 is Leu, Thr or Ser;

<220>

<221>misc_feature

<222>(15)..(15)

<223> Xaa at position 15 is Glu, Gln, Asn, Asp, Arg or Lys;

<220>

<221>misc_feature

<222>(16)..(16)

<223> Xaa at position 16 is Gly, Glu, Asp, Gln, Asn, Arg or Lys;

<220>

<221>misc_feature

<222>(17)..(17)

<223> Xaa at position 17 is Gln, Lys, Leu or Phe;

<220>

<221>misc_feature

<222>(18)..(18)

<223> Xaa at position 18 is Ala or Lys;

<220>

<221>misc_feature

<222>(19)..(19)

<223> Xaa at position 19 is Ala, Thr, Ile or Ser;

<220>

<221>misc_feature

<222>(20)..(20)

<223> Xaa at position 20 is Lys, Arg or Gln;

<220>

<221>misc_feature

<222>(21)..(21)

<223> Xaa at position 21 is Glu, Asp, Asn, Ala, Ser, Lys or Arg;

<220>

<221>misc_feature

<222>(23)..(23)

<223> Xaa at position 23 is Ile or Val;

<220>

<221>misc_feature

<222>(24)..(24)

<223> Xaa at position 24 is Ala, Ser, Asp, Glu, Gly or Thr;

<220>

<221>misc_feature

<222>(25)..(25)

<223> Xaa at position 25 is Trp, Arg, Lys or Ser;

<220>

<221>misc_feature

<222>(26)..(26)

<223> Xaa at position 26 is Val, Lys, Ile, Ser or Ala;

<220>

<221>misc_feature

<222>(28)..(28)

<223> Xaa at position 28 is Lys, Arg, Asn, Gln, Ser, Ala or Thr;

<220>

<221>misc_feature

<222>(29)..(29)

<223> Xaa at position 29 is Gly, Tyr or Ser;

<220>

<221>misc_feature

<222>(30)..(30)

<223> Xaa at position 30 is Arg, Lys, Gln, Asp, Asn, Gly, Ala or Pro;

<220>

<221>misc_feature

<222>(31)..(31)

<223> Xaa at position 31 is Gly, Pro, Val, Arg, Lys or Ala or deleted;

<400>1

His Xaa Xaa Gly Xaa Xaa Thr Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5 10 15

Xaa Xaa Xaa Xaa Xaa Phe Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa Xaa

20 25 30

<210>2

<211>452

<212>PRT

<213> human

<400>2

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Val Met Tyr Thr Val Gly Tyr Ser Leu Ser Leu

115 120 125

Gly Ala Leu Leu Leu Ala Leu Ala Ile Leu Gly Gly Leu Ser Lys Leu

130 135 140

His Cys Thr Arg Asn Ala Ile His Ala Asn Leu Phe Ala Ser Phe Val

145 150 155 160

Leu Lys Ala Ser Ser Val Leu Val Ile Asp Gly Leu Leu Arg Thr Arg

165 170 175

Tyr Ser Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Thr Trp Leu Ser

180 185 190

Asp Gly Ala Val Ala Gly Cys Arg Val Ala Ala Val Phe Met Gln Tyr

195 200 205

Gly Ile Val Ala Asn Tyr Cys Trp Leu Leu Val Glu Gly Leu Tyr Leu

210 215 220

His Asn Leu Leu Gly Leu Ala Thr Leu Pro Glu Arg Ser Phe Phe Ser

225 230 235 240

Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met Leu Phe Val Val Pro

245 250 255

Trp Ala Val Val Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser

260 265 270

Asn Asp Asn Met Gly Phe Trp Trp Ile Leu Arg Phe Pro Val Phe Leu

275 280 285

Ala Ile Leu Ile Asn Phe Phe Ile Phe Val Arg Ile Val Gln Leu Leu

290 295 300

Val Ala Lys Leu Arg Ala Arg Gln Met His His Thr Asp Tyr Lys Phe

305 310 315 320

Arg Leu Ala Lys Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Val His

325 330 335

Glu Val Val Phe Ala Phe Val Thr Asp Glu His Ala Gln Gly Thr Leu

340 345 350

Arg Ser Ala Lys Leu Phe Phe Asp Leu Phe Leu Ser Ser Phe Gln Gly

355 360 365

Leu Leu Val Ala Val Leu Tyr Cys Phe Leu Asn Lys Glu Val Gln Ser

370 375 380

Glu Leu Arg Arg Arg Trp His Arg Trp Arg Leu Gly Lys Val Leu Trp

385 390 395 400

Glu Glu Arg Asn Thr Ser Asn His Arg Ala Ser Ser Ser Pro Gly His

405 410 415

Gly Pro Pro Ser Lys Glu Leu Gln Phe Gly Arg Gly Gly Gly Ser Gln

420 425 430

Asp Ser Ser Ala Glu Thr Pro Leu Ala Gly Gly Leu Pro Arg Leu Ala

435 440 445

Glu Ser Pro Phe

450

<210>3

<211>117

<212>PRT

<213> human

<400>3

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp ValArg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln

115

<210>4

<211>32

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(1)..(1)

<223> Xaa at position 1 is Asn Ala Ile His Ala Asn Leu Phe Ala Ser Phe Val Leu LysAla Ser

Ser Val Leu Val, all amino acids can be removed one by one from the N-terminus;

<220>

<221>misc_feature

<222>(32)..(32)

<223> Xaa at position 32 is Cys Arg Val Ala Ala Val Phe Met Gln Tyr Gly Ile Val AlaAsn Tyr

Cys Trp Leu Leu Val Glu Gly Leu Tyr Leu, all amino acids can be removed one by one from the C-terminus;

<400>4

Xaa Ile Asp Gly Leu Leu Arg Thr Arg Tyr Ser Gln Lys Ile Gly Asp

1 5 10 15

Asp Leu Ser Val Ser Thr Trp Leu Ser Asp Gly Ala Val Ala Gly Xaa

20 25 30

<210>5

<211>20

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(1)..(1)

<223> Xaa at position 1 is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPheVal

Val Pro Trp Ala Val Val, all amino acids can be removed one by one from the N-terminus;

<220>

<221>misc_feature

<222>(20)..(20)

<223> Xaa at position 20 is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

Phe Ile Phe Val Arg Ile Val, all amino acids can be removed one by one from the C-terminus;

<400>5

Xaa Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser Asn Asp Asn

1 5 10 15

Met Gly Phe Xaa

20

<210>6

<211>20

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(1)..(1)

<223> Xaa at position 1 is Thr Leu Thr Leu Ile Pro Leu Leu Gly Val His Glu Val Val PheAla

Phe Val Thr, from the N-terminus all amino acids can be removed one by one;

<220>

<221>misc_feature

<222>(20)..(20)

<223> Xaa at position 20 is Leu Phe Leu Ser Ser Phe Gln Gly Leu Leu Val Ala Val LeuTyr Cys

Phe Leu Asn, from the C-terminus, all amino acids can be removed one by one;

<400>6

Xaa Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser Asn Asp Asn

1 5 10 15

Met Gly Phe Xaa

20

<210>7

<211>55

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(1)..(1)

<223> Xaa at position 1 is Asn Ala Ile His Ala Asn Leu Phe Ala Ser Phe Val Leu Lys AlaSier

Ser Val Leu Val, all amino acids can be removed one by one from the N-terminus;

<220>

<221>misc_feature

<222>(32)..(32)

<220>

<221>misc_feature

<222>(33)..(33)

<223> Xaa at position 33 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer

<220>

<221>misc_feature

<222>(34)..(34)

<223> Xaa at position 34 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted

<220>

<221>misc_feature

<222>(35)..(35)

<223> Xaa at position 35 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted

<220>

<221>misc_feature

<222>(36)..(36)

<223> Xaa at position 36 is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPheVal

<220>

<221>misc_feature

<222>(55)..(55)

<223> Xaa at position 55 is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>7

Xaa Ile Asp Gly Leu Leu Arg Thr Arg Tyr Ser Gln Lys Ile Gly Asp

1 5 10 15

Asp Leu Ser Val Ser Thr Trp Leu Ser Asp Gly Ala Val Ala Gly Xaa

20 25 30

Xaa Xaa Xaa Xaa Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser

35 40 45

Asn Asp Asn Met Gly Phe Xaa

50 55

<210>8

<211>53

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(1)..(1)

Ser Val Leu Val, all amino acids can be removed one by one from the N-terminus;

<220>

<221>misc_feature

<222>(32)..(32)

<220>

<221>misc_feature

<222>(33)..(33)

<220>

<221>misc_feature

<222>(34)..(34)

<220>

<221>misc_feature

<222>(35)..(35)

<220>

<221>misc_feature

<222>(36)..(36)

<220>

<221>misc_feature

<222>(53)..(53)

<223> Xaa at position 53 is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>8

Xaa Ile Asp Gly Leu Leu Arg Thr Arg Tyr Ser Gln Lys Ile Gly Asp

1 5 10 15

Asp Leu Ser Val Ser Thr Trp Leu Ser Asp Gly Ala Val Ala Gly Xaa

20 25 30

Xaa Xaa Xaa Xaa Asp Glu His Ala Gln Gly Thr Leu Arg Ser Ala Lys

35 40 45

Leu Phe Phe Asp Xaa

50

<210>9

<211>41

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(1)..(1)

<223> Xaa at position 1 is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met Leu PheVal

<220>

<221>misc_feature

<222>(20)..(20)

Phe Ile Phe Val Arg Ile Val, from the C-terminus, all amino acids can be removed one by one;

<220>

<221>misc_feature

<222>(21)..(21)

<223> Xaa at position 21 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(22)..(22)

<223> Xaa at position 22 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(23)..(23)

<223> Xaa at position 23 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(24)..(24)

<223> Xaa at position 24 is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPheVal

<220>

<221>misc_feature

<222>(41)..(41)

<223> Xaa at position 41 is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>9

Xaa Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser Asn Asp Asn

1 5 10 15

Met Gly Phe Xaa Xaa Xaa Xaa Xaa Asp Glu His Ala Gln Gly Thr Leu

20 25 30

Arg Ser Ala Lys Leu Phe Phe Asp Xaa

35 40

<210>10

<211>76

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(1)..(1)

Ser Val Leu Val, all amino acids can be removed one by one from the N-terminus;

<220>

<221>misc_feature

<222>(32)..(32)

<220>

<221>misc_feature

<222>(33)..(33)

<223> Xaa at position 33 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(34)..(34)

<223> Xaa at position 34 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(35)..(35)

<223> Xaa at position 35 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(36)..(36)

<220>

<221>misc_feature

<222>(55)..(55)

<220>

<221>misc_feature

<222>(56)..(56)

<223> Xaa at position 56 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(57)..(57)

<223> Xaa at position 57 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(58)..(58)

<223> Xaa at position 58 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(59)..(59)

<223> Xaa at position 59 is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPheVal

<220>

<221>misc_feature

<222>(76)..(76)

<223> Xaa at position 76 is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>10

Xaa Ile Asp Gly Leu Leu Arg Thr Arg Tyr Ser Gln Lys Ile Gly Asp

1 5 10 15

Asp Leu Ser Val Ser Thr Trp Leu Ser Asp Gly Ala Val Ala Gly Xaa

20 25 30

Xaa Xaa Xaa Xaa Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser

35 40 45

Asn Asp Asn Met Gly Phe Xaa Xaa Xaa Xaa Xaa Asp Glu His Ala Gln

50 55 60

Gly Thr Leu Arg Ser Ala Lys Leu Phe Phe Asp Xaa

65 70 75

<210>11

<211>152

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(118)..(118)

<223> Xaa at position 118 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(119)..(119)

<223> Xaa at position 119 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(120)..(120)

<223> Xaa at position 120 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(121)..(121)

<223> Xaa at position 121 is Asn Ala Ile His Ala Asn Leu Phe Ala Ser Phe Val Leu LysAla Ser

Ser Val Leu Val, all amino acids can be removed one by one from the N-terminus;

<220>

<221>misc_feature

<222>(152)..(152)

<223> Xaa at position 152 is Cys Arg Val Ala Ala Val Phe Met Gln Tyr Gly Ile Val AlaAsn Tyr

<400>11

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Xaa Xaa Xaa Xaa Ile Asp Gly Leu Leu Arg Thr

115 120 125

Arg Tyr Ser Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Thr Trp Leu

130 135 140

Ser Asp Gly Ala Val Ala Gly Xaa

145 150

<210>12

<211>140

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(118)..(118)

<220>

<221>misc_feature

<222>(119)..(119)

<220>

<221>misc_feature

<222>(120)..(120)

<220>

<221>misc_feature

<222>(121)..(121)

<223> Xaa at position 121 is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPheVal

<220>

<221>misc_feature

<222>(140)..(140)

<223> Xaa at position 140 is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>12

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Xaa Xaa Xaa Xaa Lys Cys Leu Phe Glu Asn Val

115 120 125

Gln Cys Trp Thr Ser Asn Asp Asn Met Gly Phe Xaa

130 135 140

<210>13

<211>138

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(118)..(118)

<220>

<221>misc_feature

<222>(119)..(119)

<220>

<221>misc_feature

<222>(120)..(120)

<220>

<221>misc_feature

<222>(121)..(121)

<220>

<221>misc_feature

<222>(138)..(138)

<223> Xaa at position 138 is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>13

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Xaa Xaa Xaa Xaa Asp Glu His Ala Gln Gly Thr

115 120 125

Leu Arg Ser Ala Lys Leu Phe Phe Asp Xaa

130 135

<210>14

<211>175

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(118)..(118)

<220>

<221>misc_feature

<222>(119)..(119)

<220>

<221>misc_feature

<222>(120)..(120)

<220>

<221>misc_feature

<222>(121)..(121)

Ser Val Leu Val, all amino acids can be removed one by one from the N-terminus;

<220>

<221>misc_feature

<222>(152)..(152)

<220>

<221>misc_feature

<222>(153)..(153)

<223> Xaa at position 153 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(154)..(154)

<223> Xaa at position 154 is Gly Thr Gly, Gly Ala Pro, Gly ProGly or Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(155)..(155)

<223> Xaa at position 155 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(156)..(156)

<223> Xaa at position 156 is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPheVal

<220>

<221>misc_feature

<222>(175)..(175)

<223> Xaa at position 175 is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>14

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Xaa Xaa Xaa Xaa Ile Asp Gly Leu Leu Arg Thr

115 120 125

Arg Tyr Ser Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Thr Trp Leu

130 135 140

Ser Asp Gly Ala Val Ala Gly Xaa Xaa Xaa Xaa Xaa Lys Cys Leu Phe

145 150 155 160

Glu Asn Val Gln Cys Trp Thr Ser Asn Asp Asn Met Gly Phe Xaa

165 170 175

<210>15

<211>173

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(118)..(118)

<220>

<221>misc_feature

<222>(119)..(119)

<220>

<221>misc_feature

<222>(120)..(120)

<220>

<221>misc_feature

<222>(121)..(121)

Ser Val Leu Val, all amino acids can be removed one by one from the N-terminus;

<220>

<221>misc_feature

<222>(152)..(152)

<220>

<221>misc_feature

<222>(153)..(153)

<220>

<221>misc_feature

<222>(154)..(154)

<223> Xaa at position 154 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or GlyGly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(155)..(155)

<220>

<221>misc_feature

<222>(156)..(156)

<220>

<221>misc_feature

<222>(173)..(173)

<223> Xaa at position 173 is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>15

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Xaa Xaa Xaa Xaa Ile Asp Gly Leu Leu Arg Thr

115 120 125

Arg Tyr Ser Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Thr Trp Leu

130 135 140

Ser Asp Gly Ala Val Ala Gly Xaa Xaa Xaa Xaa Xaa Asp Glu His Ala

145 150 155 160

Gln Gly Thr Leu Arg Ser Ala Lys Leu Phe Phe Asp Xaa

165 170

<210>16

<211>161

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(118)..(118)

<220>

<221>misc_feature

<222>(119)..(119)

<220>

<221>misc_feature

<222>(120)..(120)

<220>

<221>misc_feature

<222>(121)..(121)

<220>

<221>misc_feature

<222>(140)..(140)

<220>

<221>misc_feature

<222>(141)..(141)

<223> Xaa at position 141 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(142)..(142)

<223> Xaa at position 142 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(143)..(143)

<223> Xaa at position 143 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(144)..(144)

<223> Xaa at position 144 is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPhe Val

<220>

<221>misc_feature

<222>(161)..(161)

<223> Xaa at position 161 is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>16

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Xaa Xaa Xaa Xaa Lys Cys Leu Phe Glu Asn Val

115 120 125

Gln Cys Trp Thr Ser Asn Asp Asn Met Gly Phe Xaa Xaa Xaa Xaa Xaa

130 135 140

Asp Glu His Ala Gln Gly Thr Leu Arg Ser Ala Lys Leu Phe Phe Asp

145 150 155 160

Xaa

<210>17

<211>196

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(118)..(118)

<220>

<221>misc_feature

<222>(119)..(119)

<220>

<221>misc_feature

<222>(120)..(120)

<220>

<221>misc_feature

<222>(121)..(121)

Ser Val Leu Val, all amino acids can be removed one by one from the N-terminus;

<220>

<221>misc_feature

<222>(152)..(152)

<220>

<221>misc_feature

<222>(153)..(153)

<220>

<221>misc_feature

<222>(154)..(154)

<223> Xaa at position 154 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(155)..(155)

<220>

<221>misc_feature

<222>(156)..(156)

<220>

<221>misc_feature

<222>(175)..(175)

<220>

<221>misc_feature

<222>(176)..(176)

<223> Xaa at position 176 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(177)..(177)

<223> Xaa at position 177 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(178)..(178)

<223> Xaa at position 178 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(179)..(179)

<223> Xaa at position 179 is Phe Ser Leu Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met LeuPheVal

<220>

<221>misc_feature

<222>(196)..(196)

<223> Xaa at position 196 is Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu IleAsn Phe

<400>17

Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp

1 5 10 15

Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val

20 25 30

Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala

35 40 45

Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His

50 55 60

Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln

65 70 75 80

Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys

85 90 95

ln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met

100 105 110

Tyr Ser Ser Phe Gln Xaa Xaa Xaa Xaa Ile Asp Gly Leu Leu Arg Thr

115 120 125

Arg Tyr Ser Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Thr Trp Leu

130 135 140

Ser Asp Gly Ala Val Ala Gly Xaa Xaa Xaa Xaa Xaa Lys Cys Leu Phe

145 150 155 160

Glu Asn Val Gln Cys Trp Thr Ser Asn Asp Asn Met Gly Phe Xaa Xaa

165 170 175

Xaa Xaa Xaa Asp Glu His Ala Gln Gly Thr Leu Arg Ser Ala Lys Leu

180 185 190

Phe Phe Asp Xaa

195

<210>18

<211>440

<212>PRT

<213> human

<400>18

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

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

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

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

115 120 125

Tyr Ala Leu Ser Phe Ser Ala Leu Val Ile Ala Ser Ala Ile Leu Leu

130 135 140

Gly Phe Arg His Leu His Cys Thr Arg Asn Tyr Ile His Leu Asn Leu

145 150 155 160

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

165 170 175

Ala Leu Lys Trp Met Tyr Ser Thr Ala Ala Gln Gln His Gln Trp Asp

180 185 190

Gly Leu Leu Ser Tyr Gln Asp Ser Leu Ser Cys Arg Leu Val Phe Leu

195 200 205

Leu Met Gln Tyr Cys Val Ala Ala Asn Tyr Tyr Trp Leu Leu Val Glu

210 215 220

Gly Val Tyr Leu Tyr Thr Leu Leu Ala Phe Ser Val Phe Ser Glu Gln

225 230 235 240

Trp Ile Phe Arg Leu Tyr Val Ser Ile Gly Trp Gly Val Pro Leu Leu

245 250 255

Phe Val Val Pro Trp Gly Ile Val Lys Tyr Leu Tyr Glu Asp Glu Gly

260 265 270

Cys Trp Thr Arg Asn Ser Asn Met Asn Tyr Trp Leu Ile Ile Arg Leu

275 280 285

Pro Ile Leu Phe Ala Ile Gly Val Asn Phe Leu Ile Phe Val Arg Val

290 295 300

Ile Cys Ile Val Val Ser Lys Leu Lys Ala Asn Leu Met Cys Lys Thr

305 310 315 320

Asp Ile Lys Cys Arg Leu Ala Lys Ser Thr Leu Thr Leu Ile Pro Leu

325 330 335

Leu Gly Thr His Glu Val Ile Phe Ala Phe Val Met Asp Glu His Ala

340 345 350

Arg Gly Thr Leu Arg Phe Ile Lys Leu Phe Thr Glu Leu Ser Phe Thr

355 360 365

Ser Phe Gln Gly Leu Met Val Ala Ile Leu Tyr Cys Phe Val Asn Asn

370 375 380

Glu Val Gln Leu Glu Phe Arg Lys Ser Trp Glu Arg Trp Arg Leu Glu

385 390 395 400

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

405 410 415

Thr Ser Ser Leu Ser Ser Gly Ala Thr Ala Gly Ser Ser Met Tyr Thr

420 425 430

Ala Thr Cys Gln Ala Ser Cys Ser

435 440

<210>19

<211>122

<212>PRT

<213> human

<400>19

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

yr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

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

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr

115 120

<210>20

<211>78

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(2)..(2)

<223> Xaa at position 2 is Tyr, Ala or is deleted;

<220>

<221>misc_feature

<222>(5)..(5)

<223> Xaa at position 5 is Leu, Ala, Met or deleted;

<220>

<221>misc_feature

<222>(9)..(9)

<223> Xaa at position 9 is Ala, Gly or deleted;

<220>

<221>misc_feature

<222>(12)..(12)

<223> Xaa at position 12 is Ile, Val, Met or deleted;

<220>

<221>misc_feature

<222>(14)..(14)

<223> Xaa at position 14 is Leu, Val or deleted;

<220>

<221>misc_feature

<222>(15)..(15)

<223> Xaa at position 15 is Arg, Lys or deleted;

<220>

<221>misc_feature

<222>(16)..(16)

<223> Xaa at position 16 is Ala, Ser or deleted;

<220>

<221>misc_feature

<222>(17)..(17)

<223> Xaa at position 17 is Leu, Ser or deleted;

<220>

<221>misc_feature

<222>(19)..(19)

<223> Xaa at position 19 is Val, Leu or deleted;

<220>

<221>misc_feature

<222>(20)..(20)

<223> Xaa at position 20 is Phe, Leu or deleted;

<220>

<221>misc_feature

<222>(21)..(21)

<223> Xaa at position 21 is Ile, Val or deleted;

<220>

<221>misc_feature

<222>(22)..(22)

<223> Xaa at position 22 is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(24)..(24)

<223> Xaa at position 24 is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(25)..(25)

<223> Xaa at position 25 is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(27)..(27)

<223> Xaa at position 27 is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(28)..(28)

<223> Xaa at position 28 is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(29)..(29)

<223> Xaa at position 29 is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(30)..(30)

<223> Xaa at position 30 is Tyr or Asn;

<220>

<221>misc_feature

<222>(31)..(31)

<223> Xaa at position 31 is Ser or Arg;

<220>

<221>misc_feature

<222>(32)..(32)

<223> Xaa at position 32 is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(33)..(33)

<223> Xaa at position 33 is Lys, Arg or deleted;

<220>

<221>misc_feature

<222>(34)..(34)

<223> Xaa at position 34 is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(35)..(35)

<223> Xaa at position 35 is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(36)..(36)

<223> Xaa at position 36 is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(37)..(37)

<223> Xaa at position 37 is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(38)..(38)

<223> Xaa at position 38 is His or Leu;

<220>

<221>misc_feature

<222>(39)..(39)

<223> Xaa at position 39 is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(40)..(40)

<223> Xaa at position 40 is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(41)..(41)

<223> Xaa at position 41 is Asp or Ser;

<220>

<221>misc_feature

<222>(42)..(42)

<223> Xaa at position 42 is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(43)..(43)

<223> Xaa at position 43 is Arg or deleted;

<220>

<221>misc_feature

<222>(44)..(44)

<223> Xaa at position 44 is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(46)..(46)

<223> Xaa at position 46 is Ser or Asp;

<220>

<221>misc_feature

<222>(47)..(47)

<223> Xaa at position 47 is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(48)..(48)

<223> Xaa at position 48 is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(49)..(49)

<223> Xaa at position 49 is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(50)..(50)

<223> Xaa at position 50 is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(51)..(51)

<223> Xaa at position 51 is Leu, Ala, Thr, or Val;

<220>

<221>misc_feature

<222>(52)..(52)

<223> Xaa at position 52 is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(53)..(53)

<223> Xaa at position 53 is Cys or is deleted;

<220>

<221>misc_feature

<222>(54)..(54)

<223> Xaa at position 54 is Arg or deleted;

<220>

<221>misc_feature

<222>(55)..(55)

<223> Xaa at position 55 is Leu, Val, Ala, Ser or deleted;

<220>

<221>misc_feature

<222>(56)..(56)

<223> Xaa at position 56 is Val, Ala or deleted;

<220>

<221>misc_feature

<222>(57)..(57)

<223> Xaa at position 57 is Phe, Ala, Thr, Met or deleted;

<220>

<221>misc_feature

<222>(58)..(58)

<223> Xaa at position 58 is Leu, Val or deleted;

<220>

<221>misc_feature

<222>(59)..(59)

<223> Xaa at position 59 is Leu, Phe, Met or deleted;

<220>

<221>misc_feature

<222>(63)..(63)

<223> Xaa at position 63 is Cys, Gly, Ser or deleted;

<220>

<221>misc_feature

<222>(64)..(64)

<223> Xaa at position 64 is Val, Ile, Met or deleted;

<220>

<221>misc_feature

<222>(65)..(65)

<223> Xaa at position 65 is Ala, Val, Met, Ile or deleted;

<220>

<221>misc_feature

<222>(69)..(69)

<223> Xaa at position 69 is Tyr, Cys or is deleted;

<220>

<221>misc_feature

<222>(76)..(76)

<223> Xaa at position 76 is Val or Leu or deleted;

<400>20

Asn Xaa Ile His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa

1 5 10 15

Xaa Ser Xaa Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

20 25 30

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa

35 40 45

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa

50 55 60

Xaa Ala Asn Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu

65 70 75

<210>21

<211>64

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(2)..(2)

<223> Xaa at position 2 is Arg or Ser or deleted;

<220>

<221>misc_feature

<222>(5)..(5)

<223> Xaa at position 5 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(6)..(6)

<223> Xaa at position 6 is Ser, Gly or Cys or is deleted;

<220>

<221>misc_feature

<222>(11)..(11)

<223> Xaa at position 11 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(13)..(13)

<223> Xaa at position 13 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(17)..(17)

<223> Xaa at position 17 is Val, Leu or Ile or deleted;

<220>

<221>misc_feature

<222>(20)..(20)

<223> Xaa at position 20 is Gly, Ala, Met or Val or is deleted;

<220>

<221>misc_feature

<222>(21)..(21)

<223> Xaa at position 21 is Ile, Val, Thr or Ala or deleted;

<220>

<221>misc_feature

<222>(22)..(22)

<223> Xaa at position 22 is Val or is deleted;

<220>

<221>misc_feature

<222>(23)..(23)

<223> Xaa at position 23 is Lys or is deleted;

<220>

<221>misc_feature

<222>(24)..(24)

<222> Xaa at position 24 is Tyr or Cys;

<220>

<221>misc_feature

<222>(26)..(26)

<223> Xaa at position 26 is Tyr or Phe;

<220>

<221>misc_feature

<222>(28)..(28)

<223> Xaa at position 28 is Asp or Asn;

<220>

<221>misc_feature

<222>(29)..(29)

<223> Xaa at position 29 is Glu or Val;

<220>

<221>misc_feature

<222>(30)..(30)

<223> Xaa at position 30 is Gly, Gln, Glu or Asp;

<220>

<221>misc_feature

<222>(33)..(33)

<223> Xaa at position 33 is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(34)..(34)

<223> Xaa at position 34 is Arg or Ser;

<220>

<221>misc_feature

<222>(36)..(36)

<223> Xaa at position 36 is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(39)..(39)

<223> Xaa at position 39 is Asn or Gly or deleted;

<220>

<221>misc_feature

<222>(40)..(40)

<223> Xaa at position 40 is Tyr or Phe or is deleted;

<220>

<221>misc_feature

<222>(42)..(42)

<223> Xaa at position 42 is Leu or Trp or deleted;

<220>

<221>misc_feature

<222>(44)..(44)

<223> Xaa at position 44 is Ile or Leu or deleted;

<220>

<221>misc_feature

<222>(46)..(46)

<223> Xaa at position 46 is Leu, Phe, Ile or Ser or is deleted;

<220>

<221>misc_feature

<222>(48)..(48)

<223> Xaa at position 48 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(49)..(49)

<223> Xaa at position 49 is Leu or Phe or deleted;

<220>

<221>misc_feature

<222>(50)..(50)

<223> Xaa at position 50 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(53)..(53)

<223> Xaa at position 53 is Gly or Leu or deleted;

<220>

<221>misc_feature

<222>(54)..(54)

<223> Xaa at position 54 is Val or Ile or deleted;

<220>

<221>misc_feature

<222>(57)..(57)

<223> Xaa at position 57 is Leu, Phe or Ile or is deleted;

<220>

<221>misc_feature

<222>(62)..(62)

<223> Xaa at position 62 is Val or Ile or deleted;

<220>

<221>misc_feature

<222>(63)..(63)

<223> Xaa at position 63 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(64)..(64)

<223> Xaa at position 64 is Gln or Cys or is deleted;

<400>21

Phe Xaa Leu Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe Val

1 5 10 15

Xaa Pro Trp Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys Trp

20 25 30

Xaa Xaa Asn Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro Xaa

35 40 45

Xaa Xaa Ala Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa Xaa

50 55 60

<210>22

<211>57

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(11)..(11)

<223> Xaa at position 11 is Thr, Val or Ile or is deleted;

<220>

<221>misc_feature

<222>(15)..(15)

<223> Xaa at position 15 is Ile, Val, Leu or Ala or deleted;

<220>

<221>misc_feature

<222>(20)..(20)

<223> Xaa at position 20 is Met, Thr, Ile, Ala or deleted;

<220>

<221>misc_feature

<222>(23)..(23)

<223> Xaa at position 23 is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(24)..(24)

<223> Xaa at position 24 is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(25)..(25)

<223> Xaa at position 25 is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(26)..(26)

<223> Xaa at position 26 is Gly or Ser;

<220>

<221>misc_feature

<222>(27)..(27)

<223> Xaa at position 27 is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(30)..(30)

<223> Xaa at position 30 is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(31)..(31)

<223> Xaa at position 31 is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(32)..(32)

<223> Xaa at position 32 is Lys or Arg;

<220>

<221>misc_feature

<222>(35)..(35)

<223> Xaa at position 35 is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(36)..(36)

<223> Xaa at position 36 is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(38)..(38)

<223> Xaa at position 38 is Ser, Phe or Leu is deleted;

<220>

<221>misc_feature

<222>(39)..(39)

<223> Xaa at position 39 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(40)..(40)

<223> Xaa at position 40 is Thr, Ser or Gly or deleted;

<220>

<221>misc_feature

<222>(45)..(45)

<223> Xaa at position 45 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(46)..(46)

<223> Xaa at position 46 is Met or Leu or deleted;

<220>

<221>misc_feature

<222>(49)..(49)

<223> Xaa at position 49 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(54)..(54)

<223> Xaa at position 54 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(56)..(56)

<223> Xaa at position 56 is Asn or Lys or is deleted;

<400>22

Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Xaa His Glu Val Xaa Phe

1 5 10 15

Ala Phe Val Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu Arg Xaa Xaa Xaa

20 25 30

Leu Phe Xaa Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly Xaa Xaa Val Ala

35 40 45

Xaa Leu Tyr Cys Phe Xaa Asn Xaa Glu

50 55

<210>23

<211>145

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(2)..(2)

<223> Xaa at position 2 is Tyr or Ala or is removed;

<220>

<221>misc_feature

<222>(5)..(5)

<223> Xaa at position 5 is Leu, Ala or Met or deleted;

<220>

<221>misc_feature

<222>(9)..(9)

<223> Xaa at position 9 is Ala or Gly or deleted;

<220>

<221>misc_feature

<222>(12)..(12)

<223> Xaa at position 12 is Ile, Val or Met or deleted;

<220>

<221>misc_feature

<222>(14)..(14)

<223> Xaa at position 14 is Leu or Val or deleted;

<220>

<221>misc_feature

<222>(15)..(15)

<223> Xaa at position 15 is Arg or Lys or is deleted;

<220>

<221>misc_feature

<222>(16)..(16)

<223> Xaa at position 16 is Ala or Ser or deleted;

<220>

<221>misc_feature

<222>(17)..(17)

<223> Xaa at position 17 is Leu or Ser or deleted;

<220>

<221>misc_feature

<222>(19)..(19)

<223> Xaa at position 19 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(20)..(20)

<223> Xaa at position 20 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(21)..(21)

<223> Xaa at position 21 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(22)..(22)

<223> Xaa at position 22 is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(24)..(24)

<223> Xaa at position 24 is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(25)..(25)

<223> Xaa at position 25 is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(27)..(27)

<223> Xaa at position 27 is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(28)..(28)

<223> Xaa at position 28 is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(29)..(29)

<223> Xaa at position 29 is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(30)..(30)

<223> Xaa at position 30 is Tyr or Asn;

<220>

<221>misc_feature

<222>(31)..(31)

<223> Xaa at position 31 is Ser or Arg;

<220>

<221>misc_feature

<222>(32)..(32)

<223> Xaa at position 32 is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(33)..(33)

<223> Xaa at position 33 is Lys or Arg or skip;

<220>

<221>misc_feature

<222>(34)..(34)

<223> Xaa at position 34 is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(35)..(35)

<223> Xaa at position 35 is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(36)..(36)

<223> Xaa at position 36 is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(37)..(37)

<223> Xaa at position 37 is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(38)..(38)

<223> Xaa at position 38 is His or Leu;

<220>

<221>misc_feature

<222>(39)..(39)

<223> Xaa at position 39 is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(40)..(40)

<223> Xaa at position 40 is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(41)..(41)

<223> Xaa at position 41 is Asp or Ser;

<220>

<221>misc_feature

<222>(42)..(42)

<223> Xaa at position 42 is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(43)..(43)

<223> Xaa at position 43 is Arg or skip;

<220>

<221>misc_feature

<222>(44)..(44)

<223> Xaa at position 44 is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(46)..(46)

<223> Xaa at position 46 is Ser or Asp;

<220>

<221>misc_feature

<222>(47)..(47)

<223> Xaa at position 47 is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(48)..(48)

<223> Xaa at position 48 is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(49)..(49)

<223> Xaa at position 49 is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(50)..(50)

<223> Xaa at position 50 is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(51)..(51)

<223> Xaa at position 51 is Leu, Ala, Thr, or Val;

<220>

<221>misc_feature

<222>(52)..(52)

<223> Xaa at position 52 is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(53)..(53)

<223> Xaa at position 53 is Cys or is deleted;

<220>

<221>misc_feature

<222>(54)..(54)

<223> Xaa at position 54 is Arg or deleted;

<220>

<221>misc_feature

<222>(55)..(55)

<223> Xaa at position 55 is Leu, Val, Ala or Ser or deleted;

<220>

<221>misc_feature

<222>(56)..(56)

<223> Xaa at position 56 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(57)..(57)

<223> Xaa at position 57 is Phe, Ala, Thr or Met or is deleted;

<220>

<221>misc_feature

<222>(58)..(58)

<223> Xaa at position 58 is Leu or Val or deleted;

<220>

<221>misc_feature

<222>(59)..(59)

<223> Xaa at position 59 is Leu, Phe or Met or is deleted;

<220>

<221>misc_feature

<222>(63)..(63)

<223> Xaa at position 63 is Cys, Gly or Ser or is deleted;

<220>

<221>misc_feature

<222>(64)..(64)

<223> Xaa at position 64 is Val, Ile or Met or is deleted;

<220>

<221>misc_feature

<222>(65)..(65)

<223> Xaa at position 65 is Ala, Val, Met or Ile or is deleted;

<220>

<221>misc_feature

<222>(69)..(69)

<223> Xaa at position 69 is Tyr or Cys or is deleted;

<220>

<221>misc_feature

<222>(76)..(76)

<223> Xaa at position 76 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(79)..(79)

<223> Xaa at position 79 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(80)..(80)

<223> Xaa at position 80 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(81)..(81)

<223> Xaa at position 81 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(83)..(83)

<223> Xaa at position 83 is Arg or Ser or deleted;

<220>

<221>misc_feature

<222>(86)..(86)

<223> Xaa at position 86 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(87)..(87)

<223> Xaa at position 87 is Ser, Gly or Cys or is deleted;

<220>

<221>misc_feature

<222>(92)..(92)

<223> Xaa at position 92 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(94)..(94)

<223> Xaa at position 94 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(98)..(98)

<223> Xaa at position 98 is Val, Leu or Ile or deleted;

<220>

<221>misc_feature

<222>(101)..(101)

<223> Xaa at position 101 is Gly, Ala, Met or Val or is deleted;

<220>

<221>misc_feature

<222>(102)..(102)

<223> Xaa at position 102 is Ile, Val, Thr or Ala or deleted;

<220>

<221>misc_feature

<222>(103)..(103)

<223> Xaa at position 103 is Val or is deleted;

<220>

<221>misc_feature

<222>(104)..(104)

<223> Xaa at position 104 is Lys or is deleted;

<220>

<221>misc_feature

<222>(105)..(105)

<223> Xaa at position 105 is Tyr or Cys;

<220>

<221>misc_feature

<222>(107)..(107)

<223> Xaa at position 107 is Tyr or Phe;

<220>

<221>misc_feature

<222>(109)..(109)

<223> Xaa at position 109 is Asp or Asn;

<220>

<221>misc_feature

<222>(110)..(110)

<223> Xaa at position 110 is Glu or Val;

<220>

<221>misc_feature

<222>(111)..(111)

<223> Xaa at position 111 is Gly, Gln, Glu or Asp;

<220>

<221>misc_feature

<222>(114)..(114)

<223> Xaa at position 114 is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(115)..(115)

<223> Xaa at position 115 is Arg or Ser;

<220>

<221>misc_feature

<222>(117)..(117)

<223> Xaa at position 117 is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(120)..(120)

<223> Xaa at position 120 is Asn or Gly or deleted;

<220>

<221>misc_feature

<222>(121)..(121)

<223> Xaa at position 121 is Tyr or Phe or is deleted;

<220>

<221>misc_feature

<222>(123)..(123)

<223> Xaa at position 123 is Leu or Trp or deleted;

<220>

<221>misc_feature

<222>(125)..(125)

<223> Xaa at position 125 is Ile or Leu or deleted;

<220>

<221>misc_feature

<222>(127)..(127)

<223> Xaa at position 127 is Leu, Phe, Ile or Ser or is deleted;

<220>

<221>misc_feature

<222>(129)..(129)

<223> Xaa at position 129 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(130)..(130)

<223> Xaa at position 130 is Leu or Phe or deleted;

<220>

<221>misc_feature

<222>(131)..(131)

<223> Xaa at position 131 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(134)..(134)

<223> Xaa at position 134 is Gly or Leu or deleted;

<220>

<221>misc_feature

<222>(135)..(135)

<223> Xaa at position 135 is Val or Ile or deleted;

<220>

<221>misc_feature

<222>(138)..(138)

<223> Xaa at position 138 is Leu, Phe or Ile or is deleted;

<220>

<221>misc_feature

<222>(143)..(143)

<223> Xaa at position 143 is Val or Ile or deleted;

<220>

<221>misc_feature

<222>(144)..(144)

<223> Xaa at position 144 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(145)..(145)

<223> Xaa at position 145 is Gln or Cys or deleted;

<400>23

Asn Xaa Ile His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa

1 5 10 15

Xaa Ser Xaa Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

20 25 30

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa

35 40 45

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa

50 55 60

Xaa Ala Asn Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu Xaa Xaa

65 70 75 80

Xaa Phe Xaa Leu Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe

85 90 95

Val Xaa Pro Trp Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys

100 105 110

Trp Xaa Xaa Asn Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro

115 120 125

Xaa Xaa Xaa Ala Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa

130 135 140

Xaa

145

<210>24

<211>138

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(2)..(2)

<223> Xaa at position 2 is Tyr or Ala or is removed;

<220>

<221>misc_feature

<222>(5)..(5)

<223> Xaa at position 5 is Leu, Ala or Met or deleted;

<220>

<221>misc_feature

<222>(9)..(9)

<223> Xaa at position 9 is Ala or Gly or deleted;

<220>

<221>misc_feature

<222>(12)..(12)

<223> Xaa at position 12 is Ile, Val or Met or deleted;

<220>

<221>misc_feature

<222>(14)..(14)

<223> Xaa at position 14 is Leu or Val or deleted;

<220>

<221>misc_feature

<222>(15)..(15)

<223> Xaa at position 15 is Arg or Lys or is deleted;

<220>

<221>misc_feature

<222>(16)..(16)

<223> Xaa at position 16 is Ala or Ser or deleted;

<220>

<221>misc_feature

<222>(17)..(17)

<223> Xaa at position 17 is Leu or Ser or deleted;

<220>

<221>misc_feature

<222>(19)..(19)

<223> Xaa at position 19 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(20)..(20)

<223> Xaa at position 20 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(21)..(21)

<223> Xaa at position 21 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(22)..(22)

<223> Xaa at position 22 is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(24)..(24)

<223> Xaa at position 24 is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(25)..(25)

<223> Xaa at position 25 is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(27)..(27)

<223> Xaa at position 27 is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(28)..(28)

<223> Xaa at position 28 is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(29)..(29)

<223> Xaa at position 29 is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(30)..(30)

<223> Xaa at position 30 is Tyr or Asn;

<220>

<221>misc_feature

<222>(31)..(31)

<223> Xaa at position 31 is Ser or Arg;

<220>

<221>misc_feature

<222>(32)..(32)

<223> Xaa at position 32 is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(33)..(33)

<223> Xaa at position 33 is Lys or Arg or skip;

<220>

<221>misc_feature

<222>(34)..(34)

<223> Xaa at position 34 is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(35)..(35)

<223> Xaa at position 35 is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(36)..(36)

<223> Xaa at position 36 is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(37)..(37)

<223> Xaa at position 37 is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(38)..(38)

<223> Xaa at position 38 is His or Leu;

<220>

<221>misc_feature

<222>(39)..(39)

<223> Xaa at position 39 is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(40)..(40)

<223> Xaa at position 40 is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(41)..(41)

<223> Xaa at position 41 is Asp or Ser;

<220>

<221>misc_feature

<222>(42)..(42)

<223> Xaa at position 42 is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(43)..(43)

<223> Xaa at position 43 is Arg or skip;

<220>

<221>misc_feature

<222>(44)..(44)

<223> Xaa at position 44 is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(46)..(46)

<223> Xaa at position 46 is Ser or Asp;

<220>

<221>misc_feature

<222>(47)..(47)

<223> Xaa at position 47 is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(48)..(48)

<223> Xaa at position 48 is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(49)..(49)

<223> Xaa at position 49 is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(50)..(50)

<223> Xaa at position 50 is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(51)..(51)

<223> Xaa at position 51 is Leu, Ala, Thr, or Val;

<220>

<221>misc_feature

<222>(52)..(52)

<223> Xaa at position 52 is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(53)..(53)

<223> Xaa at position 53 is Cys or is deleted;

<220>

<221>misc_feature

<222>(54)..(54)

<223> Xaa at position 54 is Arg or deleted;

<220>

<221>misc_feature

<222>(55)..(55)

<223> Xaa at position 55 is Leu, Val, Ala or Ser or deleted;

<220>

<221>misc_feature

<222>(56)..(56)

<223> Xaa at position 56 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(57)..(57)

<223> Xaa at position 57 is Phe, Ala, Thr or Met or is deleted;

<220>

<221>misc_feature

<222>(58)..(58)

<223> Xaa at position 58 is Leu or Val or deleted;

<220>

<221>misc_feature

<222>(59)..(59)

<223> Xaa at position 59 is Leu, Phe or Met or is deleted;

<220>

<221>misc_feature

<222>(63)..(63)

<223> Xaa at position 63 is Cys, Gly or Ser or is deleted;

<220>

<221>misc_feature

<222>(64)..(64)

<223> Xaa at position 64 is Val, Ile or Met or is deleted;

<220>

<221>misc_feature

<222>(65)..(65)

<223> Xaa at position 65 is Ala, Val, Met or Ile or is deleted;

<220>

<221>misc_feature

<222>(69)..(69)

<223> Xaa at position 69 is Tyr or Cys or is deleted;

<220>

<221>misc_feature

<222>(76)..(76)

<223> Xaa at position 76 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(79)..(79)

<220>

<221>misc_feature

<222>(80)..(80)

<220>

<221>misc_feature

<222>(81)..(81)

<220>

<221>misc_feature

<222>(92)..(92)

<223> Xaa at position 92 is Thr, Val or Ile or deleted;

<220>

<221>misc_feature

<222>(96)..(96)

<223> Xaa at position 96 is Ile, Val, Leu or Ala or deleted;

<220>

<221>misc_feature

<222>(101)..(101)

<223> Xaa at position 101 is Met, Thr, Ile or Ala or is deleted;

<220>

<221>misc_feature

<222>(104)..(104)

<223> Xaa at position 104 is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(105)..(105)

<223> Xaa at position 105 is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(106)..(106)

<223> Xaa at position 106 is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(107)..(107)

<223> Xaa at position 107 is Gly or Ser;

<220>

<221>misc_feature

<222>(108)..(108)

<223> Xaa at position 108 is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(111)..(111)

<223> Xaa at position 11l is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(112)..(112)

<223> Xaa at position 112 is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(113)..(113)

<223> Xaa at position 113 is Lys or Arg;

<220>

<221>misc_feature

<222>(116)..(116)

<223> Xaa at position 116 is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(117)..(117)

<223> Xaa at position 117 is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(119)..(119)

<223> Xaa at position 119 is Ser, Phe or Leu is deleted;

<220>

<221>misc_feature

<222>(120)..(120)

<223> Xaa at position 120 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(121)..(121)

<223> Xaa at position 121 is Thr, Ser or Gly or deleted;

<220>

<221>misc_feature

<222>(126)..(126)

<223> Xaa at position 126 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(127)..(127)

<223> Xaa at position 127 is Met or Leu or deleted;

<220>

<221>misc_feature

<222>(130)..(130)

<223> Xaa at position 130 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(135)..(135)

<223> Xaa at position 135 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(137)..(137)

<223> Xaa at position 137 is Asn or Lys or is deleted;

<400>24

Asn Xaa Ile His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa

1 5 10 15

Xaa Ser Xaa Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

20 25 30

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa

35 40 45

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa

50 55 60

Xaa Ala Asn Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu Xaa Xaa

65 70 75 80

Xaa Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Xaa His Glu Val Xaa

85 90 95

Phe Ala Phe Val Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu Arg Xaa Xaa

100 105 110

Xaa Leu Phe Xaa Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly Xaa Xaa Val

115 120 125

Ala Xaa Leu Tyr Cys Phe Xaa Asn Xaa Glu

130 135

<210>25

<211>124

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(2)..(2)

<223> Xaa at position 2 is Arg or Ser or deleted;

<220>

<221>misc_feature

<222>(5)..(5)

<223> Xaa at position 5 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(6)..(6)

<223> Xaa at position 6 is Ser, Gly or Cys or is deleted;

<220>

<221>misc_feature

<222>(11)..(11)

<223> Xaa at position 11 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(13)..(13)

<223> Xaa at position 13 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(17)..(17)

<223> Xaa at position 17 is Val, Leu or Ile or deleted;

<220>

<221>misc_feature

<222>(20)..(20)

<223> Xaa at position 20 is Gly, Ala, Met or Val or is deleted;

<220>

<221>misc_feature

<222>(21)..(21)

<223> Xaa at position 21 is Ile, Val, Thr or Ala or deleted;

<220>

<221>misc_feature

<222>(22)..(22)

<223> Xaa at position 22 is Val or is deleted;

<220>

<221>misc_feature

<222>(23)..(23)

<223> Xaa at position 23 is Lys or is deleted;

<220>

<221>misc_feature

<222>(24)..(24)

<223> Xaa at position 24 is Tyr or Cys;

<220>

<221>misc_feature

<222>(26)..(26)

<223> Xaa at position 26 is Tyr or Phe;

<220>

<221>misc_feature

<222>(28)..(28)

<223> Xaa at position 28 is Asp or Asn;

<220>

<221>misc_feature

<222>(29)..(29)

<223> Xaa at position 29 is Glu or Val;

<220>

<221>misc_feature

<222>(30)..(30)

<223> Xaa at position 30 is Gly, Gln, Glu or Asp;

<220>

<221>misc_feature

<222>(33)..(33)

<223> Xaa at position 33 is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(34)..(34)

<223> Xaa at position 34 is Arg or Ser;

<220>

<221>misc_feature

<222>(36)..(36)

<223> Xaa at position 36 is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(39)..(39)

<223> Xaa at position 39 is Asn or Gly or deleted;

<220>

<221>misc_feature

<222>(40)..(40)

<223> Xaa at position 40 is Tyr or Phe or is deleted;

<220>

<221>misc_feature

<222>(42)..(42)

<223> Xaa at position 42 is Leu or Trp or deleted;

<220>

<221>misc_feature

<222>(44)..(44)

<223> Xaa at position 44 is Ile or Leu or deleted;

<220>

<221>misc_feature

<222>(46)..(46)

<223> Xaa at position 46 is Leu, Phe, Ile or Ser or is deleted;

<220>

<221>misc_feature

<222>(48)..(48)

<223> Xaa at position 48 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(49)..(49)

<223> Xaa at position 49 is Leu or Phe or deleted;

<220>

<221>misc_feature

<222>(50)..(50)

<223> Xaa at position 50 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(53)..(53)

<223> Xaa at position 53 is Gly or Leu or deleted;

<220>

<221>misc_feature

<222>(54)..(54)

<223> Xaa at position 54 is Val or Ile or deleted;

<220>

<221>misc_feature

<222>(57)..(57)

<223> Xaa at position 57 is Leu, Phe or Ile or is deleted;

<220>

<221>misc_feature

<222>(62)..(62)

<223> Xaa at position 62 is Val or Ile or deleted;

<220>

<221>misc_feature

<222>(63)..(63)

<223> Xaa at position 63 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(64)..(64)

<223> Xaa at position 64 is Gln or Cys or is deleted;

<220>

<221>misc_feature

<222>(65)..(65)

<223> Xaa at position 65 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(66)..(66)

<223> Xaa at position 66 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(67)..(67)

<223> Xaa at position 67 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(78)..(78)

<223> Xaa at position 78 is Thr, Val or Ile or deleted;

<220>

<221>misc_feature

<222>(82)..(82)

<223> Xaa at position 82 is Ile, Val, Leu or Ala or deleted;

<220>

<221>misc_feature

<222>(87)..(87)

<223> Xaa at position 87 is Met, Thr, Ile or Ala or is deleted;

<220>

<221>misc_feature

<222>(90)..(90)

<223> Xaa at position 90 is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(91)..(91)

<223> Xaa at position 91 is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(92)..(92)

<223> Xaa at position 92 is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(93)..(93)

<223> Xaa at position 93 is Gly or Ser;

<220>

<221>misc_feature

<222>(94)..(94)

<223> Xaa at position 94 is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(97)..(97)

<223> Xaa at position 97 is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(98)..(98)

<223> Xaa at position 98 is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(99)..(99)

<223> Xaa at position 99 is Lys or Arg;

<220>

<221>misc_feature

<222>(102)..(102)

<223> Xaa at position 102 is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(103)..(103)

<223> Xaa at position 103 is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(105)..(105)

<223> Xaa at position 105 is Ser, Phe or Leu is deleted;

<220>

<221>misc_feature

<222>(106)..(106)

<223> Xaa at position 106 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(107)..(107)

<223> Xaa at position 107 is Thr, Ser or Gly or deleted;

<220>

<221>misc_feature

<222>(112)..(112)

<223> Xaa at position 112 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(113)..(113)

<223> Xaa at position 113 is Met or Leu or deleted;

<220>

<221>misc_feature

<222>(116)..(116)

<223> Xaa at position 116 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(121)..(121)

<223> Xaa at position 121 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(123)..(123)

<223> Xaa at position 123 is Asn or Lys or is deleted;

<400>25

Phe Xaa Leu Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe Val

1 5 10 15

Xaa Pro Trp Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys Trp

20 25 30

Xaa Xaa Asn Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro Xaa

35 40 45

Xaa Xaa Ala Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa Xaa

50 55 60

Xaa Xaa Xaa Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Xaa His Glu

65 70 75 80

Val Xaa Phe Ala Phe Val Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu Arg

85 90 95

Xaa Xaa Xaa Leu Phe Xaa Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly Xaa

100 105 110

Xaa Val Ala Xaa Leu Tyr Cys Phe Xaa Asn Xaa Glu

115 120

<210>26

<211>205

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(2)..(2)

<223> Xaa at position 2 is Tyr or Ala or is removed;

<220>

<221>misc_feature

<222>(5)..(5)

<223> Xaa at position 5 is Leu, Ala or Met or deleted;

<220>

<221>misc_feature

<222>(9)..(9)

<223> Xaa at position 9 is Ala or Gly or deleted;

<220>

<221>misc_feature

<222>(12)..(12)

<223> Xaa at position 12 is Ile, Val or Met or deleted;

<220>

<221>misc_feature

<222>(14)..(14)

<223> Xaa at position 14 is Leu or Val or deleted;

<220>

<221>misc_feature

<222>(15)..(15)

<223> Xaa at position 15 is Arg or Lys or is deleted;

<220>

<221>misc_feature

<222>(16)..(16)

<223> Xaa at position 16 is Ala or Ser or deleted;

<220>

<221>misc_feature

<222>(17)..(17)

<223> Xaa at position 17 is Leu or Ser or deleted;

<220>

<221>misc_feature

<222>(19)..(19)

<223> Xaa at position 19 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(20)..(20)

<223> Xaa at position 20 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(21)..(21)

<223> Xaa at position 21 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(22)..(22)

<223> Xaa at position 22 is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(24)..(24)

<223> Xaa at position 24 is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(25)..(25)

<223> Xaa at position 25 is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(27)..(27)

<223> Xaa at position 27 is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(28)..(28)

<223> Xaa at position 28 is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(29)..(29)

<223> Xaa at position 29 is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(30)..(30)

<223> Xaa at position 30 is Tyr or Asn;

<220>

<221>misc_feature

<222>(31)..(31)

<223> Xaa at position 31 is Ser or Arg;

<220>

<221>misc_feature

<222>(32)..(32)

<223> Xaa at position 32 is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(33)..(33)

<223> Xaa at position 33 is Lys or Arg or skip;

<220>

<221>misc_feature

<222>(34)..(34)

<223> Xaa at position 34 is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(35)..(35)

<223> Xaa at position 35 is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(36)..(36)

<223> Xaa at position 36 is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(37)..(37)

<223> Xaa at position 37 is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(38)..(38)

<223> Xaa at position 38 is His or Leu;

<220>

<221>misc_feature

<222>(39)..(39)

<223> Xaa at position 39 is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(40)..(40)

<223> Xaa at position 40 is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(41)..(41)

<223> Xaa at position 41 is Asp or Ser;

<220>

<221>misc_feature

<222>(42)..(42)

<223> Xaa at position 42 is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(43)..(43)

<223> Xaa at position 43 is Arg or skip;

<220>

<221>misc_feature

<222>(44)..(44)

<223> Xaa at position 44 is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(46)..(46)

<223> Xaa at position 46 is Ser or Asp;

<220>

<221>misc_feature

<222>(47)..(47)

<223> Xaa at position 47 is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(48)..(48)

<223> Xaa at position 48 is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(49)..(49)

<223> Xaa at position 49 is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(50)..(50)

<223> Xaa at position 50 is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(51)..(51)

<223> Xaa at position 51 is Leu, Ala, Thr, or Val;

<220>

<221>misc_feature

<222>(52)..(52)

<223> Xaa at position 52 is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(53)..(53)

<223> Xaa at position 53 is Cys or is deleted;

<220>

<221>misc_feature

<222>(54)..(54)

<223> Xaa at position 54 is Arg or deleted;

<220>

<221>misc_feature

<222>(55)..(55)

<223> Xaa at position 55 is Leu, Val, Ala or Ser or deleted;

<220>

<221>misc_feature

<222>(56)..(56)

<223> Xaa at position 56 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(57)..(57)

<223> Xaa at position 57 is Phe, Ala, Thr or Met or is deleted;

<220>

<221>misc_feature

<222>(58)..(58)

<223> Xaa at position 58 is Leu or Val or deleted;

<220>

<221>misc_feature

<222>(59)..(59)

<223> Xaa at position 59 is Leu, Phe or Met or is deleted;

<220>

<221>misc_feature

<222>(63)..(63)

<223> Xaa at position 63 is Cys, Gly or Ser or is deleted;

<220>

<221>misc_feature

<222>(64)..(64)

<223> Xaa at position 64 is Val, Ile or Met or is deleted;

<220>

<221>misc_feature

<222>(65)..(65)

<223> Xaa at position 65 is Ala, Val, Met or Ile or is deleted;

<220>

<221>misc_feature

<222>(69)..(69)

<223> Xaa at position 69 is Tyr or Cys or is deleted;

<220>

<221>misc_feature

<222>(76)..(76)

<223> Xaa at position 76 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(79)..(79)

<220>

<221>misc_feature

<222>(80)..(80)

<220>

<221>misc_feature

<222>(81)..(81)

<220>

<221>misc_feature

<222>(83)..(83)

<223> Xaa at position 83 is Arg or Ser or deleted;

<220>

<221>misc_feature

<222>(86)..(86)

<223> Xaa at position 86 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(87)..(87)

<223> Xaa at position 87 is Ser, Gly or Cys or is deleted;

<220>

<221>misc_feature

<222>(92)..(92)

<223> Xaa at position 92 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(94)..(94)

<223> Xaa at position 94 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(98)..(98)

<223> Xaa at position 98 is Val, Leu or Ile or deleted;

<220>

<221>misc_feature

<222>(101)..(101)

<223> Xaa at position 101 is Gly, Ala, Met or Val or is deleted;

<220>

<221>misc_feature

<222>(102)..(102)

<223> Xaa at position 102 is Ile, Val, Thr or Ala or deleted;

<220>

<221>misc_feature

<222>(103)..(103)

<223> Xaa at position 103 is Val or is deleted;

<220>

<221>misc_feature

<222>(104)..(104)

<223> Xaa at position 104 is Lys or is deleted;

<220>

<221>misc_feature

<222>(105)..(105)

<223> Xaa at position 105 is Tyr or Cys;

<220>

<221>misc_feature

<222>(107)..(107)

<223> Xaa at position 107 is Tyr or Phe;

<220>

<221>misc_feature

<222>(109)..(109)

<223> Xaa at position 109 is Asp or Asn;

<220>

<221>misc_feature

<222>(110)..(110)

<223> Xaa at position 110 is Glu or Val;

<220>

<221>misc_feature

<222>(111)..(111)

<223> Xaa at position 111 is Gly, Gln, Glu or Asp;

<220>

<221>misc_feature

<222>(114)..(114)

<223> Xaa at position 114 is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(115)..(115)

<223> Xaa at position 115 is Arg or Ser;

<220>

<221>misc_feature

<222>(117)..(117)

<223> Xaa at position 117 is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(120)..(120)

<223> Xaa at position 120 is Asn or Gly or deleted;

<220>

<221>misc_feature

<222>(121)..(121)

<223> Xaa at position 121 is Tyr or Phe or is deleted;

<220>

<221>misc_feature

<222>(123)..(123)

<223> Xaa at position 123 is Leu or Trp or deleted;

<220>

<221>misc_feature

<222>(125)..(125)

<223> Xaa at position 125 is Ile or Leu or deleted;

<220>

<221>misc_feature

<222>(127)..(127)

<223> Xaa at position 127 is Leu, Phe, Ile or Ser or is deleted;

<220>

<221>misc_feature

<222>(129)..(129)

<223> Xaa at position 129 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(130)..(130)

<223> Xaa at position 130 is Leu or Phe or deleted;

<220>

<221>misc_feature

<222>(131)..(131)

<223> Xaa at position 131 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(134)..(134)

<223> Xaa at position 134 is Gly or Leu or deleted;

<220>

<221>misc_feature

<222>(135)..(135)

<223> Xaa at position 135 is Val or Ile or deleted;

<220>

<221>misc_feature

<222>(138)..(138)

<223> Xaa at position 138 is Leu, Phe or Ile or is deleted;

<220>

<221>misc_feature

<222>(143)..(143)

<223> Xaa at position 143 is Val or Ile or deleted;

<220>

<221>misc_feature

<222>(144)..(144)

<223> Xaa at position 144 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(145)..(145)

<223> Xaa at position 145 is Gln or Cys or deleted;

<220>

<221>misc_feature

<222>(146)..(146)

<223> Xaa at position 146 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(147)..(147)

<223> Xaa at position 147 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(148)..(148)

<223> Xaa at position 148 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(159)..(159)

<223> Xaa at position 159 is Thr, Val or Ile or deleted;

<220>

<221>misc_feature

<222>(163)..(163)

<223> Xaa at position 163 is Ile, Val, Leu or Ala or deleted;

<220>

<221>misc_feature

<222>(168)..(168)

<223> Xaa at position 168 is Met, Thr, Ile or Ala or is deleted;

<220>

<221>misc_feature

<222>(171)..(171)

<223> Xaa at position 171 is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(172)..(172)

<223> Xaa at position 172 is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(173)..(173)

<223> Xaa at position 173 is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(174)..(174)

<223> Xaa at position 174 is Gly or Ser;

<220>

<221>misc_feature

<222>(175)..(175)

<223> Xaa at position 175 is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(178)..(178)

<223> Xaa at position 178 is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(179)..(179)

<223> Xaa at position 179 is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(180)..(180)

<223> Xaa at position 180 is Lys or Arg;

<220>

<221>misc_feature

<222>(183)..(183)

<223> Xaa at position 183 is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(184)..(184)

<223> Xaa at position 184 is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(186)..(186)

<223> Xaa at position 186 is Ser, Phe or Leu is deleted;

<220>

<221>misc_feature

<222>(187)..(187)

<223> Xaa at position 187 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(188)..(188)

<223> Xaa at position 188 is Thr, Ser or Gly or is deleted;

<220>

<221>misc_feature

<222>(193)..(193)

<223> Xaa at position 193 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(194)..(194)

<223> Xaa at position 194 is Met or Leu or deleted;

<220>

<221>misc_feature

<222>(197)..(197)

<223> Xaa at position 197 is Ile or Val or is deleted;

<220>

<221>misc_feature

<222>(202)..(202)

<223> Xaa at position 202 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(204)..(204)

<223> Xaa at position 204 is Asn or Lys or is deleted;

<400>26

Asn Xaa Ile His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa

1 5 10 15

Xaa Ser Xaa Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

20 25 30

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa

35 40 45

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa

50 55 60

Xaa Ala Asn Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu Xaa Xaa

65 70 75 80

Xaa Phe Xaa Leu Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe

85 90 95

Val Xaa Pro Trp Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys

100 105 110

Trp Xaa Xaa Asn Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro

115 120 125

Xaa Xaa Xaa Ala Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa

130 135 140

Xaa Xaa Xaa Xaa Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Xaa His

145 150 155 160

Glu Val Xaa Phe Ala Phe Val Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu

165 170 175

Arg Xaa Xaa Xaa Leu Phe Xaa Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly

180 185 190

Xaa Xaa Val Ala Xaa Leu Tyr Cys Phe Xaa Asn Xaa Glu

195 200 205

<210>27

<211>203

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(123)..(123)

<223> Xaa at position 123 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(124)..(124)

<223> Xaa at position 124 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(125)..(125)

<223> Xaa at position 125 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(127)..(127)

<223> Xaa at position 127 is Tyr or Ala or is removed;

<220>

<221>misc_feature

<222>(130)..(130)

<223> Xaa at position 130 is Leu, Ala or Met or deleted;

<220>

<221>misc_feature

<222>(134)..(134)

<223> Xaa at position 134 is Ala or Gly or deleted;

<220>

<221>misc_feature

<222>(137)..(137)

<223> Xaa at position 137 is Ile, Val or Met or is deleted;

<220>

<221>misc_feature

<222>(139)..(139)

<223> Xaa at position 139 is Leu or Val or deleted;

<220>

<221>misc_feature

<222>(140)..(140)

<223> Xaa at position 140 is Arg or Lys or is deleted;

<220>

<221>misc_feature

<222>(141)..(141)

<223> Xaa at position 141 is Ala or Ser or deleted;

<220>

<221>misc_feature

<222>(142)..(142)

<223> Xaa at position 142 is Leu or Ser or deleted;

<220>

<221>misc_feature

<222>(144)..(144)

<223> Xaa at position 144 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(145)..(145)

<223> Xaa at position 145 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(146)..(146)

<223> Xaa at position 146 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(147)..(147)

<223> Xaa at position 147 is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(149)..(149)

<223> Xaa at position 149 is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(150)..(150)

<223> Xaa at position 150 is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(152)..(152)

<223> Xaa at position 152 is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(153)..(153)

<223> Xaa at position 153 is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(154)..(154)

<223> Xaa at position 154 is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(155)..(155)

<223> Xaa at position 155 is Tyr or Asn;

<220>

<221>misc_feature

<222>(156)..(156)

<223> Xaa at position 156 is Ser or Arg;

<220>

<221>misc_feature

<222>(157)..(157)

<223> Xaa at position 157 is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(158)..(158)

<223> Xaa at position 158 is Lys or Arg or skip;

<220>

<221>misc_feature

<222>(159)..(159)

<223> Xaa at position 159 is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(160)..(160)

<223> Xaa at position 160 is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(161)..(161)

<223> Xaa at position 161 is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(162)..(162)

<223> Xaa at position 162 is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(163)..(163)

<223> Xaa at position 163 is His or Leu;

<220>

<221>misc_feature

<222>(164)..(164)

<223> Xaa at position 164 is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(165)..(165)

<223> Xaa at position 165 is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(166)..(166)

<223> Xaa at position 166 is Asp or Ser;

<220>

<221>misc_feature

<222>(167)..(167)

<223> Xaa at position 167 is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(168)..(168)

<223> Xaa at position 168 is Arg or skip;

<220>

<221>misc_feature

<222>(169)..(169)

<223> Xaa at position 169 is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(171)..(171)

<223> Xaa at position 171 is Ser or Asp;

<220>

<221>misc_feature

<222>(172)..(172)

<223> Xaa at position 172 is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(173)..(173)

<223> Xaa at position 173 is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(174)..(174)

<223> Xaa at position 174 is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(175)..(175)

<223> Xaa at position 175 is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(176)..(176)

<223> Xaa at position 176 is Leu, Ala, Thr, or Val;

<220>

<221>misc_feature

<222>(177)..(177)

<223> Xaa at position 177 is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(178)..(178)

<223> Xaa at position 178 is Cys or is deleted;

<220>

<221>misc_feature

<222>(179)..(179)

<223> Xaa at position 179 is Arg or deleted;

<220>

<221>misc_feature

<222>(180)..(180)

<223> Xaa at position 180 is Leu, Val, Ala or Ser or deleted;

<220>

<221>misc_feature

<222>(181)..(181)

<223> Xaa at position 181 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(182)..(182)

<223> Xaa at position 182 is Phe, Ala, Thr or Met or is deleted;

<220>

<221>misc_feature

<222>(183)..(183)

<223> Xaa at position 183 is Leu or Val or deleted;

<220>

<221>misc_feature

<222>(184)..(184)

<223> Xaa at position 184 is Leu, Phe or Met or is deleted;

<220>

<221>misc_feature

<222>(188)..(188)

<223> Xaa at position 188 is Cys, Gly or Ser or is deleted;

<220>

<221>misc_feature

<222>(189)..(189)

<223> Xaa at position 189 is Val, Ile or Met or deleted;

<220>

<221>misc_feature

<222>(190)..(190)

<223> Xaa at position 190 is Ala, Val, Met or Ile or is deleted;

<220>

<221>misc_feature

<222>(194)..(194)

<223> Xaa at position 194 is Tyr or Cys or is deleted;

<220>

<221>misc_feature

<222>(201)..(201)

<223> Xaa at position 102 is Val or Leu or deleted;

<400>27

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

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

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Xaa Xaa Xaa Asn Xaa Ile

115 120 125

His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa Xaa Ser Xaa

130 135 140

Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

145 150 155 160

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

165 170 175

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa Xaa Ala Asn

180 185 190

Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu

195 200

<210>28

<211>189

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(123)..(123)

<220>

<221>misc_feature

<222>(124)..(124)

<220>

<221>misc_feature

<222>(125)..(125)

<220>

<221>misc_feature

<222>(127)..(127)

<223> Xaa at position 127 is Arg or Ser or deleted;

<220>

<221>misc_feature

<222>(130)..(130)

<223> Xaa at position 130 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(131)..(131)

<223> Xaa at position 131 is Ser, Gly or Cys or is deleted;

<220>

<221>misc_feature

<222>(136)..(136)

<223> Xaa at position 136 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(138)..(138)

<223> Xaa at position 138 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(142)..(142)

<223> Xaa at position 142 is Val, Leu or Ile or deleted;

<220>

<221>misc_feature

<222>(145)..(145)

<223> Xaa at position 145 is Gly, Ala, Met or Val or deleted;

<220>

<221>misc_feature

<222>(146)..(146)

<223> Xaa at position 146 is Ile, Val, Thr or Ala or deleted;

<220>

<221>misc_feature

<222>(147)..(147)

<223> Xaa at position 147 is Val or is deleted;

<220>

<221>misc_feature

<222>(148)..(148)

<223> Xaa at position 148 is Lys or is removed;

<220>

<221>misc_feature

<222>(149)..(149)

<223> Xaa at position 149 is Tyr or Cys;

<220>

<221>misc_feature

<222>(151)..(151)

<223> Xaa at position 151 is Tyr or Phe;

<220>

<221>misc_feature

<222>(153)..(153)

<223> Xaa at position 153 is Asp or Asn;

<220>

<221>misc_feature

<222>(154)..(154)

<223> Xaa at position 154 is Glu or Val;

<220>

<221>misc_feature

<222>(155)..(155)

<223> Xaa at position 155 is Gly, Gln, Glu or Asp;

<220>

<221>misc_feature

<222>(158)..(158)

<223> Xaa at position 158 is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(159)..(159)

<223> Xaa at position 159 is Arg or Ser;

<220>

<221>misc_feature

<222>(161)..(161)

<223> Xaa at position 161 is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(164)..(164)

<223> Xaa at position 164 is Asn or Gly or deleted;

<220>

<221>misc_feature

<222>(165)..(165)

<223> Xaa at position 165 is Tyr or Phe or is deleted;

<220>

<221>misc_feature

<222>(167)..(167)

<223> Xaa at position 167 is Leu or Trp or deleted;

<220>

<221>misc_feature

<222>(169)..(169)

<223> Xaa at position 169 is Ile or Leu or deleted;

<220>

<221>misc_feature

<222>(171)..(171)

<223> Xaa at position 171 is Leu, Phe, Ile or Ser or is deleted;

<220>

<221>misc_feature

<222>(173)..(173)

<223> Xaa at position 173 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(174)..(174)

<223> Xaa at position 174 is Leu or Phe or deleted;

<220>

<221>misc_feature

<222>(175)..(175)

<223> Xaa at position 175 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(178)..(178)

<223> Xaa at position 178 is Gly or Leu or deleted;

<220>

<221>misc_feature

<222>(179)..(179)

<223> Xaa at position 179 is Val or Ile or is deleted;

<220>

<221>misc_feature

<222>(182)..(182)

<223> Xaa at position 182 is Leu, Phe or Ile or is deleted;

<220>

<221>misc_feature

<222>(187)..(187)

<223> Xaa at position 187 is Val or Ile or deleted;

<220>

<221>misc_feature

<222>(188)..(188)

<223> Xaa at position 188 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(189)..(189)

<223> Xaa at position 189 is Gln or Cys or deleted;

<400>28

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

ro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

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

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Xaa Xaa Xaa Phe Xaa Leu

115 120 125

Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe Val Xaa Pro Trp

130 135 140

Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys Trp Xaa Xaa Asn

145 150 155 160

Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro Xaa Xaa Xaa Ala

165 170 175

Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa Xaa

180 185

<210>29

<211>182

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(123)..(123)

<220>

<221>misc_feature

<222>(124)..(124)

<220>

<221>misc_feature

<222>(125)..(125)

<220>

<221>misc_feature

<222>(136)..(136)

<223> Xaa at position 136 is Thr, Val or Ile or is deleted;

<220>

<221>misc_feature

<222>(140)..(140)

<223> Xaa at position 140 is Ile, Val, Leu or Ala or deleted;

<220>

<221>misc_feature

<222>(145)..(145)

<223> Xaa at position 145 is Met, Thr, Ile or Ala or deleted;

<220>

<221>misc_feature

<222>(148)..(148)

<223> Xaa at position 148 is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(149)..(149)

<223> Xaa at position 149 is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(150)..(150)

<223> Xaa at position 150 is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(151)..(151)

<223> Xaa at position 151 is Gly or Ser;

<220>

<221>misc_feature

<222>(152)..(152)

<223> Xaa at position 152 is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(155)..(155)

<223> Xaa at position 155 is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(156)..(156)

<223> Xaa at position 156 is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(157)..(157)

<223> Xaa at position 157 is Lys or Arg;

<220>

<221>misc_feature

<222>(160)..(160)

<223> Xaa at position 160 is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(161)..(161)

<223> Xaa at position 161 is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(163)..(163)

<223> Xaa at position 163 is Ser, Phe or Leu is deleted;

<220>

<221>misc_feature

<222>(164)..(164)

<223> Xaa at position 164 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(165)..(165)

<223> Xaa at position 165 is Thr, Ser or Gly or deleted;

<220>

<221>misc_feature

<222>(170)..(170)

<223> Xaa at position 170 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(171)..(171)

<223> Xaa at position 171 is Met or Leu or deleted;

<220>

<221>misc_feature

<222>(174)..(174)

<223> Xaa at position 174 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(179)..(179)

<223> Xaa at position 179 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(181)..(181)

<223> Xaa at position 181 is Asn or Lys or is deleted;

<400>29

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

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

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Xaa Xaa Xaa Ser Thr Leu

115 120 125

Thr Leu Ile Pro Leu Leu Gly Xaa His Glu Val Xaa Phe Ala Phe Val

130 135 140

Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu Arg Xaa Xaa Xaa Leu Phe Xaa

145 150 155 160

Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly Xaa Xaa Val Ala Xaa Leu Tyr

165 170 175

Cys Phe Xaa Asn Xaa Glu

180

<210>30

<211>270

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(123)..(123)

<220>

<221>misc_feature

<222>(124)..(124)

<220>

<221>misc_feature

<222>(125)..(125)

<220>

<221>misc_feature

<222>(127)..(127)

<223> Xaa at position 127 is Tyr or Ala or is removed;

<220>

<221>misc_feature

<222>(130)..(130)

<223> Xaa at position 130 is Leu, Ala or Met or deleted;

<220>

<221>misc_feature

<222>(134)..(134)

<223> Xaa at position 134 is Ala or Gly or deleted;

<220>

<221>misc_feature

<222>(137)..(137)

<223> Xaa at position 137 is Ile, Val or Met or is deleted;

<220>

<221>misc_feature

<222>(139)..(139)

<223> Xaa at position 139 is Leu or Val or deleted;

<220>

<221>misc_feature

<222>(140)..(140)

<223> Xaa at position 140 is Arg or Lys or is deleted;

<220>

<221>misc_feature

<222>(141)..(141)

<223> Xaa at position 141 is Ala or Ser or deleted;

<220>

<221>misc_feature

<222>(142)..(142)

<223> Xaa at position 142 is Leu or Ser or deleted;

<220>

<221>misc_feature

<222>(144)..(144)

<223> Xaa at position 144 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(145)..(145)

<223> Xaa at position 145 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(146)..(146)

<223> Xaa at position 146 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(147)..(147)

<223> Xaa at position 147 is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(149)..(149)

<223> Xaa at position 149 is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(150)..(150)

<223> Xaa at position 150 is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(152)..(152)

<223> Xaa at position 152 is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(153)..(153)

<223> Xaa at position 153 is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(154)..(154)

<223> Xaa at position 154 is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(155)..(155)

<223> Xaa at position 155 is Tyr or Asn;

<220>

<221>misc_feature

<222>(156)..(156)

<223> Xaa at position 156 is Ser or Arg;

<220>

<221>misc_feature

<222>(157)..(157)

<223> Xaa at position 157 is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(158)..(158)

<223> Xaa at position 158 is Lys or Arg or skip;

<220>

<221>misc_feature

<222>(159)..(159)

<223> Xaa at position 159 is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(160)..(160)

<223> Xaa at position 160 is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(161)..(161)

<223> Xaa at position 161 is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(162)..(162)

<223> Xaa at position 162 is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(163)..(163)

<223> Xaa at position 163 is His or Leu;

<220>

<221>misc_feature

<222>(164)..(164)

<223> Xaa at position 164 is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(165)..(165)

<223> Xaa at position 165 is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(166)..(166)

<223> Xaa at position 166 is Asp or Ser;

<220>

<221>misc_feature

<222>(167)..(167)

<223> Xaa at position 167 is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(168)..(168)

<223> Xaa at position 168 is Arg or skip;

<220>

<221>misc_feature

<222>(169)..(169)

<223> Xaa at position 169 is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(171)..(171)

<223> Xaa at position 171 is Ser or Asp;

<220>

<221>misc_feature

<222>(172)..(172)

<223> Xaa at position 172 is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(173)..(173)

<223> Xaa at position 173 is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(174)..(174)

<223> Xaa at position 174 is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(175)..(175)

<223> Xaa at position 175 is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(176)..(176)

<223> Xaa at position 176 is Leu, Ala, Thr, or Val;

<220>

<221>misc_feature

<222>(177)..(177)

<223> Xaa at position 177 is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(178)..(178)

<223> Xaa at position 178 is Cys or is deleted;

<220>

<221>misc_feature

<222>(179)..(179)

<223> Xaa at position 179 is Arg or deleted;

<220>

<221>misc_feature

<222>(180)..(180)

<223> Xaa at position 180 is Leu, Val, Ala or Ser or deleted;

<220>

<221>misc_feature

<222>(181)..(181)

<223> Xaa at position 181 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(182)..(182)

<223> Xaa at position 182 is Phe, Ala, Thr or Met or is deleted;

<220>

<221>misc_feature

<222>(183)..(183)

<223> Xaa at position 183 is Leu or Val or deleted;

<220>

<221>misc_feature

<222>(184)..(184)

<223> Xaa at position 184 is Leu, Phe or Met or is deleted;

<220>

<221>misc_feature

<222>(188)..(188)

<223> Xaa at position 188 is Cys, Gly or Ser or is deleted;

<220>

<221>misc_feature

<222>(189)..(189)

<223> Xaa at position 189 is Val, Ile or Met or deleted;

<220>

<221>misc_feature

<222>(190)..(190)

<223> Xaa at position 190 is Ala, Val, Met or Ile or is deleted;

<220>

<221>misc_feature

<222>(194)..(194)

<223> Xaa at position 194 is Tyr or Cys or is deleted;

<220>

<221>misc_feature

<222>(201)..(201)

<223> Xaa at position 201 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(204)..(204)

<223> Xaa at position 204 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(205)..(205)

<223> Xaa at position 205 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(206)..(206)

<223> Xaa at position 206 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(208)..(208)

<223> Xaa at position 208 is Arg or Ser or deleted;

<220>

<221>misc_feature

<222>(211)..(211)

<223> Xaa at position 211 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(212)..(212)

<223> Xaa at position 212 is Ser, Gly or Cys or is deleted;

<220>

<221>misc_feature

<222>(217)..(217)

<223> Xaa at position 217 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(219)..(219)

<223> Xaa at position 219 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(223)..(223)

<223> Xaa at position 223 is Val, Leu or Ile or deleted;

<220>

<221>misc_feature

<222>(226)..(226)

<223> Xaa at position 226 is Gly, Ala, Met or Val or deleted;

<220>

<221>misc_feature

<222>(227)..(227)

<223> Xaa at position 227 is Ile, Val, Thr or Ala or deleted;

<220>

<221>misc_feature

<222>(228)..(228)

<223> Xaa at position 228 is Val or is deleted;

<220>

<221>misc_feature

<222>(229)..(229)

<223> Xaa at position 229 is Lys or is removed;

<220>

<221>misc_feature

<222>(230)..(230)

<223> Xaa at position 230 is Tyr or Cys;

<220>

<221>misc_feature

<222>(232)..(232)

<223> Xaa at position 232 is Tyr or Phe;

<220>

<221>misc_feature

<222>(234)..(234)

<223> Xaa at position 234 is Asp or Asn;

<220>

<221>misc_feature

<222>(235)..(235)

<223> Xaa at position 235 is Glu or Val;

<220>

<221>misc_feature

<222>(236)..(236)

<223> Xaa at position 236 is Gly, Gln, Glu, or Asp;

<220>

<221>misc_feature

<222>(239)..(239)

<223> Xaa at position 239 is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(240)..(240)

<223> Xaa at position 240 is Arg or Ser;

<220>

<221>misc_feature

<222>(242)..(242)

<223> Xaa at position 242 is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(245)..(245)

<223> Xaa at position 245 is Asn or Gly or deleted;

<220>

<221>misc_feature

<222>(246)..(246)

<223> Xaa at position 246 is Tyr or Phe or is deleted;

<220>

<221>misc_feature

<222>(248)..(248)

<223> Xaa at position 248 is Leu or Trp or deleted;

<220>

<221>misc_feature

<222>(250)..(250)

<223> Xaa at position 250 is Ile or Leu or deleted;

<220>

<221>misc_feature

<222>(252)..(252)

<223> Xaa at position 252 is Leu, Phe, Ile or Ser or is deleted;

<220>

<221>misc_feature

<222>(254)..(254)

<223> Xaa at position 254 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(255)..(255)

<223> Xaa at position 255 is Leu or Phe or deleted;

<220>

<221>misc_feature

<222>(256)..(256)

<223> Xaa at position 256 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(259)..(259)

<223> Xaa at position 259 is Gly or Leu or deleted;

<220>

<221>misc_feature

<222>(260)..(260)

<223> Xaa at position 260 is Val or Ile or deleted;

<220>

<221>misc_feature

<222>(263)..(263)

<223> Xaa at position 263 is Leu, Phe or Ile or is deleted;

<220>

<221>misc_feature

<222>(268)..(268)

<223> Xaa at position 268 Val or Ile or deleted;

<220>

<221>misc_feature

<222>(269)..(269)

<223> Xaa at position 269 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(270)..(270)

<223> Xaa at position 270 is Gln or Cys or is deleted;

<400>30

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

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

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Xaa Xaa Xaa Asn Xaa Ile

115 120 125

His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa Xaa Ser Xaa

130 135 140

Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

145 150 155 160

aa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

165 170 175

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa Xaa Ala Asn

180 185 190

Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu Xaa Xaa Xaa Phe Xaa

195 200 205

Leu Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe Val Xaa Pro

210 215 220

Trp Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys Trp Xaa Xaa

225 230 235 240

Asn Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro Xaa Xaa Xaa

245 250 255

Ala Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa Xaa

260 265 270

<210>31

<211>263

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(123)..(123)

<220>

<221>misc_feature

<222>(124)..(124)

<220>

<221>misc_feature

<222>(125)..(125)

<220>

<221>misc_feature

<222>(127)..(127)

<223> Xaa at position 127 is Tyr or Ala or is removed;

<220>

<221>misc_feature

<222>(130)..(130)

<223> Xaa at position 130 is Leu, Ala or Met or deleted;

<220>

<221>misc_feature

<222>(134)..(134)

<223> Xaa at position 134 is Ala or Gly or deleted;

<220>

<221>misc_feature

<222>(137)..(137)

<223> Xaa at position 137 is Ile, Val or Met or is deleted;

<220>

<221>misc_feature

<222>(139)..(139)

<223> Xaa at position 139 is Leu or Val or deleted;

<220>

<221>misc_feature

<222>(140)..(140)

<223> Xaa at position 140 is Arg or Lys or is deleted;

<220>

<221>misc_feature

<222>(141)..(141)

<223> Xaa at position 141 is Ala or Ser or deleted;

<220>

<221>misc_feature

<222>(142)..(142)

<223> Xaa at position 142 is Leu or Ser or deleted;

<220>

<221>misc_feature

<222>(144)..(144)

<223> Xaa at position 144 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(145)..(145)

<223> Xaa at position 145 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(146)..(146)

<223> Xaa at position 146 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(147)..(147)

<223> Xaa at position 147 is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(149)..(149)

<223> Xaa at position 149 is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(150)..(150)

<223> Xaa at position 150 is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(152)..(152)

<223> Xaa at position 152 is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(153)..(153)

<223> Xaa at position 153 is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(154)..(154)

<223> Xaa at position 154 is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(155)..(155)

<223> Xaa at position 155 is Tyr or Asn;

<220>

<221>misc_feature

<222>(156)..(156)

<223> Xaa at position 156 is Ser or Arg;

<220>

<221>misc_feature

<222>(157)..(157)

<223> Xaa at position 157 is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(158)..(158)

<223> Xaa at position 158 is Lys or Arg or skip;

<220>

<221>misc_feature

<222>(159)..(159)

<223> Xaa at position 159 is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(160)..(160)

<223> Xaa at position 160 is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(161)..(161)

<223> Xaa at position 161 is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(162)..(162)

<223> Xaa at position 162 is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(163)..(163)

<223> Xaa at position 163 is His or Leu;

<220>

<221>misc_feature

<222>(164)..(164)

<223> Xaa at position 164 is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(165)..(165)

<223> Xaa at position 165 is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(166)..(166)

<223> Xaa at position 166 is Asp or Ser;

<220>

<221>misc_feature

<222>(167)..(167)

<223> Xaa at position 167 is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(168)..(168)

<223> Xaa at position 168 is Arg or skip;

<220>

<221>misc_feature

<222>(169)..(169)

<223> Xaa at position 169 is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(171)..(171)

<223> Xaa at position 171 is Ser or Asp;

<220>

<221>misc_feature

<222>(172)..(172)

<223> Xaa at position 172 is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(173)..(173)

<223> Xaa at position 173 is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(174)..(174)

<223> Xaa at position 174 is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(175)..(175)

<223> Xaa at position 175 is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(176)..(176)

<223> Xaa at position 176 is Leu, Ala, Thr, or Val;

<220>

<221>misc_feature

<222>(177)..(177)

<223> Xaa at position 177 is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(178)..(178)

<223> Xaa at position 178 is Cys or is deleted;

<220>

<221>misc_feature

<222>(179)..(179)

<223> Xaa at position 179 is Arg or deleted;

<220>

<221>misc_feature

<222>(180)..(180)

<223> Xaa at position 180 is Leu, Val, Ala or Ser or deleted;

<220>

<221>misc_feature

<222>(181)..(181)

<223> Xaa at position 181 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(182)..(182)

<223> Xaa at position 182 is Phe, Ala, Thr or Met or is deleted;

<220>

<221>misc_feature

<222>(183)..(183)

<223> Xaa at position 183 is Leu or Val or deleted;

<220>

<221>misc_feature

<222>(184)..(184)

<223> Xaa at position 184 is Leu, Phe or Met or is deleted;

<220>

<221>misc_feature

<222>(188)..(188)

<223> Xaa at position 188 is Cys, Gly or Ser or is deleted;

<220>

<221>misc_feature

<222>(189)..(189)

<223> Xaa at position 189 is Val, Ile or Met or deleted;

<220>

<221>misc_feature

<222>(190)..(190)

<223> Xaa at position 190 is Ala, Val, Met or Ile or is deleted;

<220>

<221>misc_feature

<222>(194)..(194)

<223> Xaa at position 194 is Tyr or Cys or is deleted;

<220>

<221>misc_feature

<222>(201)..(201)

<223> Xaa at position 201 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(204)..(204)

<220>

<221>misc_feature

<222>(205)..(205)

<220>

<221>misc_feature

<222>(206)..(206)

<220>

<221>misc_feature

<222>(217)..(217)

<223> Xaa at position 217 is Thr, Val or Ile or is deleted;

<220>

<221>misc_feature

<222>(221)..(221)

<223> Xaa at position 221 is Ile, Val, Leu or Ala or deleted;

<220>

<221>misc_feature

<222>(226)..(226)

<223> Xaa at position 226 is Met, Thr, Ile or Ala or is deleted;

<220>

<221>misc_feature

<222>(229)..(229)

<223> Xaa at position 229 is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(230)..(230)

<223> Xaa at position 230 is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(231)..(231)

<223> Xaa at position 231 is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(232)..(232)

<223> Xaa at position 232 is Gly or Ser;

<220>

<221>misc_feature

<222>(233)..(233)

<223> Xaa at position 233 is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(236)..(236)

<223> Xaa at position 236 is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(237)..(237)

<223> Xaa at position 237 is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(238)..(238)

<223> Xaa at position 238 is Lys or Arg;

<220>

<221>misc_feature

<222>(241)..(241)

<223> Xaa at position 241 is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(242)..(242)

<223> Xaa at position 242 is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(244)..(244)

<223> Xaa at position 244 is Ser, Phe or Leu is deleted;

<220>

<221>misc_feature

<222>(245)..(245)

<223> Xaa at position 245 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(246)..(246)

<223> Xaa at position 246 is Thr, Ser or Gly or deleted;

<220>

<221>misc_feature

<222>(251)..(251)

<223> Xaa at position 251 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(252)..(252)

<223> Xaa at position 252 is Met or Leu or deleted;

<220>

<221>misc_feature

<222>(255)..(255)

<223> Xaa at position 255 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(260)..(260)

<223> Xaa at position 260 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(262)..(262)

<223> Xaa at position 262 is Asn or Lys or is deleted;

<400>31

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

ys Thr Ala Glu Gly Leu Trp Leu Gln Lys Asp Asn Ser Ser Leu Pro

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Xaa Xaa Xaa Asn Xaa Ile

115 120 125

His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa Xaa Ser Xaa

130 135 140

Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

145 150 155 160

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

165 170 175

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa XaaAla Asn

180 185 190

Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu Xaa Xaa Xaa Ser Thr

195 200 205

Leu Thr Leu Ile Pro Leu Leu Gly Xaa His Glu Val Xaa Phe Ala Phe

210 215 220

Val Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu Arg Xaa Xaa Xaa Leu Phe

225 230 235 240

Xaa Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly Xaa Xaa Val Ala Xaa Leu

245 250 255

Tyr Cys Phe Xaa Asn Xaa Glu

260

<210>32

<211>249

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(123)..(123)

<220>

<221>misc_feature

<222>(124)..(124)

<220>

<221>misc_feature

<222>(125)..(125)

<220>

<221>misc_feature

<222>(127)..(127)

<223> Xaa at position 127 is Arg or Ser or deleted;

<220>

<221>misc_feature

<222>(130)..(130)

<223> Xaa at position 130 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(131)..(131)

<223> Xaa at position 131 is Ser, Gly or Cys or is deleted;

<220>

<221>misc_feature

<222>(136)..(136)

<223> Xaa at position 136 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(138)..(138)

<223> Xaa at position 138 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(142)..(142)

<223> Xaa at position 142 is Val, Leu or Ile or deleted;

<220>

<221>misc_feature

<222>(145)..(145)

<223> Xaa at position 145 is Gly, Ala, Met or Val or deleted;

<220>

<221>misc_feature

<222>(146)..(146)

<223> Xaa at position 146 is Ile, Val, Thr or Ala or deleted;

<220>

<221>misc_feature

<222>(147)..(147)

<223> Xaa at position 147 is Val or is deleted;

<220>

<221>misc_feature

<222>(148)..(148)

<223> Xaa at position 148 is Lys or is removed;

<220>

<221>misc_feature

<222>(149)..(149)

<223> Xaa at position 149 is Tyr or Cys;

<220>

<221>misc_feature

<222>(151)..(151)

<223> Xaa at position 151 is Tyr or Phe;

<220>

<221>misc_feature

<222>(153)..(153)

<223> Xaa at position 153 is Asp or Asn;

<220>

<221>misc_feature

<222>(154)..(154)

<223> Xaa at position 154 is Glu or Val;

<220>

<221>misc_feature

<222>(155)..(155)

<223> Xaa at position 155 is Gly, Gln, Glu or Asp;

<220>

<221>misc_feature

<222>(158)..(158)

<223> Xaa at position 158 is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(159)..(159)

<223> Xaa at position 159 is Arg or Ser;

<220>

<221>misc_feature

<222>(161)..(161)

<223> Xaa at position 161 is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(164)..(164)

<223> Xaa at position 164 is Asn or Gly or deleted;

<220>

<221>misc_feature

<222>(165)..(165)

<223> Xaa at position 165 is Tyr or Phe or is deleted;

<220>

<221>misc_feature

<222>(167)..(167)

<223> Xaa at position 167 is Leu or Trp or deleted;

<220>

<221>misc_feature

<222>(169)..(169)

<223> Xaa at position 169 is Ile or Leu or deleted;

<220>

<221>misc_feature

<222>(171)..(171)

<223> Xaa at position 171 is Leu, Phe, Ile or Ser or is deleted;

<220>

<221>misc_feature

<222>(173)..(173)

<223> Xaa at position 173 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(174)..(174)

<223> Xaa at position 174 is Leu or Phe or deleted;

<220>

<221>misc_feature

<222>(175)..(175)

<223> Xaa at position 175 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(178)..(178)

<223> Xaa at position 178 is Gly or Leu or deleted;

<220>

<221>misc_feature

<222>(179)..(179)

<223> Xaa at position 179 is Val or Ile or is deleted;

<220>

<221>misc_feature

<222>(182)..(182)

<223> Xaa at position 182 is Leu, Phe or Ile or is deleted;

<220>

<221>misc_feature

<222>(187)..(187)

<223> Xaa at position 187 is Val or Ile or deleted;

<220>

<221>misc_feature

<222>(188)..(188)

<223> Xaa at position 188 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(189)..(189)

<223> Xaa at position 189 is Gln or Cys or deleted;

<220>

<221>misc_feature

<222>(190)..(190)

<223> Xaa at position 190 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(191)..(191)

<223> Xaa at position 191 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(192)..(192)

<223> Xaa at position 192 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(203)..(203)

<223> Xaa at position 203 is Thr, Val or Ile or deleted;

<220>

<221>misc_feature

<222>(207)..(207)

<223> Xaa at position 207 is Ile, Val, Leu or Ala or deleted;

<220>

<221>misc_feature

<222>(212)..(212)

<223> Xaa at position 212 is Met, Thr, Ile or Ala or is deleted;

<220>

<221>misc_feature

<222>(215)..(215)

<223> Xaa at position 215 is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(216)..(216)

<223> Xaa at position 216 is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(217)..(217)

<223> Xaa at position 217 is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(218)..(218)

<223> Xaa at position 218 is Gly or Ser;

<220>

<221>misc_feature

<222>(219)..(219)

<223> Xaa at position 219 is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(222)..(222)

<223> Xaa at position 222 is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(223)..(223)

<223> Xaa at position 223 is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(224)..(224)

<223> Xaa at position 224 is Lys or Arg;

<220>

<221>misc_feature

<222>(227)..(227)

<223> Xaa at position 227 is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(228)..(228)

<223> Xaa at position 228 is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(230)..(230)

<223> Xaa at position 230 is Ser, Phe or Leu is deleted;

<220>

<221>misc_feature

<222>(231)..(231)

<223> Xaa at position 231 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(232)..(232)

<223> Xaa at position 232 is Thr, Ser or Gly or deleted;

<220>

<221>misc_feature

<222>(237)..(237)

<223> Xaa at position 237 is Leu or Met or is deleted;

<220>

<221>misc_feature

<222>(238)..(238)

<223> Xaa at position 238 is Met or Leu or deleted;

<220>

<221>misc_feature

<222>(241)..(241)

<223> Xaa at position 241 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(246)..(246)

<223> Xaa at position 246 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(248)..(248)

<223> Xaa at position 248 is Asn or Lys or is deleted;

<400>32

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

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

85 90 95

TrpArg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Xaa Xaa Xaa Phe Xaa Leu

115 120 125

Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe Val Xaa Pro Trp

130 135 140

Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys Trp Xaa Xaa Asn

145 150 155 160

Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro Xaa Xaa Xaa Ala

165 170 175

Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa Xaa Xaa Xaa Xaa

180 185 190

Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Xaa His Glu Val Xaa Phe

195 200 205

Ala Phe Val Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa LeuArg Xaa Xaa Xaa

210 215 220

Leu Phe Xaa Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly Xaa Xaa Val Ala

225 230 235 240

Xaa Leu Tyr Cys Phe Xaa Asn Xaa Glu

245

<210>33

<211>330

<212>PRT

<213> Artificial sequence

<220>

<221>misc_feature

<222>(123)..(123)

<220>

<221>misc_feature

<222>(124)..(124)

<220>

<221>misc_feature

<222>(125)..(125)

<220>

<221>misc_feature

<222>(127)..(127)

<223> Xaa at position 127 is Tyr or Ala or is removed;

<220>

<221>misc_feature

<222>(130)..(130)

<223> Xaa at position 130 is Leu, Ala or Met or deleted;

<220>

<221>misc_feature

<222>(134)..(134)

<223> Xaa at position 134 is Ala or Gly or deleted;

<220>

<221>misc_feature

<222>(137)..(137)

<223> Xaa at position 137 is Ile, Val or Met or is deleted;

<220>

<221>misc_feature

<222>(139)..(139)

<223> Xaa at position 139 is Leu or Val or deleted;

<220>

<221>misc_feature

<222>(140)..(140)

<223> Xaa at position 140 is Arg or Lys or is deleted;

<220>

<221>misc_feature

<222>(141)..(141)

<223> Xaa at position 141 is Ala or Ser or deleted;

<220>

<221>misc_feature

<222>(142)..(142)

<223> Xaa at position 142 is Leu or Ser or deleted;

<220>

<221>misc_feature

<222>(144)..(144)

<223> Xaa at position 144 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(145)..(145)

<223> Xaa at position 145 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(146)..(146)

<223> Xaa at position 146 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(147)..(147)

<223> Xaa at position 147 is Lys, Arg, Gln, Asp, Glu, Asn or Ile;

<220>

<221>misc_feature

<222>(149)..(149)

<223> Xaa at position 149 is Ala, Gly, Thr, Trp, Val, Arg or Ile;

<220>

<221>misc_feature

<222>(150)..(150)

<223> Xaa at position 150 is Ala, Leu or Val;

<220>

<221>misc_feature

<222>(152)..(152)

<223> Xaa at position 152 is Lys, Arg or Asp;

<220>

<221>misc_feature

<222>(153)..(153)

<223> Xaa at position 153 is Trp, Thr, Gln or Asn;

<220>

<221>misc_feature

<222>(154)..(154)

<223> Xaa at position 154 is Met, Arg or Ser;

<220>

<221>misc_feature

<222>(155)..(155)

<223> Xaa at position 155 is Tyr or Asn;

<220>

<221>misc_feature

<222>(156)..(156)

<223> Xaa at position 156 is Ser or Arg;

<220>

<221>misc_feature

<222>(157)..(157)

<223> Xaa at position 157 is Thr, Gln or Ala;

<220>

<221>misc_feature

<222>(158)..(158)

<223> Xaa at position 158 is Lys or Arg or skip;

<220>

<221>misc_feature

<222>(159)..(159)

<223> Xaa at position 159 is Ala, Ile or Ser;

<220>

<221>misc_feature

<222>(160)..(160)

<223> Xaa at position 160 is Ala, Gly or Ile;

<220>

<221>misc_feature

<222>(161)..(161)

<223> Xaa at position 161 is Gln, Asp, Pro, Glu or Ile;

<220>

<221>misc_feature

<222>(162)..(162)

<223> Xaa at position 162 is Gln, Asp, Glu, Ser or Asn;

<220>

<221>misc_feature

<222>(163)..(163)

<223> Xaa at position 163 is His or Leu;

<220>

<221>misc_feature

<222>(164)..(164)

<223> Xaa at position 164 is Gln, Ser, Tyr or Glu;

<220>

<221>misc_feature

<222>(165)..(165)

<223> Xaa at position 165 is Trp, Val or Gln;

<220>

<221>misc_feature

<222>(166)..(166)

<223> Xaa at position 166 is Asp or Ser;

<220>

<221>misc_feature

<222>(167)..(167)

<223> Xaa at position 167 is Gly, Thr, Val, Ser or Ala;

<220>

<221>misc_feature

<222>(168)..(168)

<223> Xaa at position 168 is Arg or skip;

<220>

<221>misc_feature

<222>(169)..(169)

<223> Xaa at position 169 is Leu, Trp, Arg, Thr or Tyr;

<220>

<221>misc_feature

<222>(171)..(171)

<223> Xaa at position 171 is Ser or Asp;

<220>

<221>misc_feature

<222>(172)..(172)

<223> Xaa at position 172 is Tyr, Asp or Thr;

<220>

<221>misc_feature

<222>(173)..(173)

<223> Xaa at position 173 is Gln, Glu or Gly;

<220>

<221>misc_feature

<222>(174)..(174)

<223> Xaa at position 174 is Asp, Ala or Thr;

<220>

<221>misc_feature

<222>(175)..(175)

<223> Xaa at position 175 is Ser, Val, Leu or Met;

<220>

<221>misc_feature

<222>(176)..(176)

<223> Xaa at position 176 is Leu, Ala, Thr, or Val;

<220>

<221>misc_feature

<222>(177)..(177)

<223> Xaa at position 177 is Ser, Gly or Ala;

<220>

<221>misc_feature

<222>(178)..(178)

<223> Xaa at position 178 is Cys or is deleted;

<220>

<221>misc_feature

<222>(179)..(179)

<223> Xaa at position 179 is Arg or deleted;

<220>

<221>misc_feature

<222>(180)..(180)

<223> Xaa at position 180 is Leu, Val, Ala or Ser or deleted;

<220>

<221>misc_feature

<222>(181)..(181)

<223> Xaa at position 181 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(182)..(182)

<223> Xaa at position 182 is Phe, Ala, Thr or Met or is deleted;

<220>

<221>misc_feature

<222>(183)..(183)

<223> Xaa at position 183 is Leu or Val or deleted;

<220>

<221>misc_feature

<222>(184)..(184)

<223> Xaa at position 184 is Leu, Phe or Met or is deleted;

<220>

<221>misc_feature

<222>(188)..(188)

<223> Xaa at position 188 is Cys, Gly or Ser or is deleted;

<220>

<221>misc_feature

<222>(189)..(189)

<223> Xaa at position 189 is Val, Ile or Met or deleted;

<220>

<221>misc_feature

<222>(190)..(190)

<223> Xaa at position 190 is Ala, Val, Met or Ile or is deleted;

<220>

<221>misc_feature

<222>(194)..(194)

<223> Xaa at position 194 is Tyr or Cys or is deleted;

<220>

<221>misc_feature

<222>(201)..(201)

<223> Xaa at position 201 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(204)..(204)

<220>

<221>misc_feature

<222>(205)..(205)

<220>

<221>misc_feature

<222>(206)..(206)

<220>

<221>misc_feature

<222>(208)..(208)

<223> Xaa at position 208 is Arg or Ser or deleted;

<220>

<221>misc_feature

<222>(211)..(211)

<223> Xaa at position 211 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(212)..(212)

<223> Xaa at position 212 is Ser, Gly or Cys or is deleted;

<220>

<221>misc_feature

<222>(217)..(217)

<223> Xaa at position 217 is Val or Ala or deleted;

<220>

<221>misc_feature

<222>(219)..(219)

<223> Xaa at position 219 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(223)..(223)

<223> Xaa at position 223 is Val, Leu or Ile or deleted;

<220>

<221>misc_feature

<222>(226)..(226)

<223> Xaa at position 226 is Gly, Ala, Met or Val or deleted;

<220>

<221>misc_feature

<222>(227)..(227)

<223> Xaa at position 227 is Ile, Val, Thr or Ala or deleted;

<220>

<221>misc_feature

<222>(228)..(228)

<223> Xaa at position 228 is Val or is deleted;

<220>

<221>misc_feature

<222>(229)..(229)

<223> Xaa at position 229 is Lys or is removed;

<220>

<221>misc_feature

<222>(230)..(230)

<223> Xaa at position 230 is Tyr or Cys;

<220>

<221>misc_feature

<222>(232)..(232)

<223> Xaa at position 232 is Tyr or Phe;

<220>

<221>misc_feature

<222>(234)..(234)

<223> Xaa at position 234 is Asp or Asn;

<220>

<221>misc_feature

<222>(235)..(235)

<223> Xaa at position 235 is Glu or Val;

<220>

<221>misc_feature

<222>(236)..(236)

<223> Xaa at position 236 is Gly, Gln, Glu, or Asp;

<220>

<221>misc_feature

<222>(239)..(239)

<223> Xaa at position 239 is Thr, Glu or Ser;

<220>

<221>misc_feature

<222>(240)..(240)

<223> Xaa at position 240 is Arg or Ser;

<220>

<221>misc_feature

<222>(242)..(242)

<223> Xaa at position 242 is Ser, Asp, Asn or Met;

<220>

<221>misc_feature

<222>(245)..(245)

<223> Xaa at position 245 is Asn or Gly or deleted;

<220>

<221>misc_feature

<222>(246)..(246)

<223> Xaa at position 246 is Tyr or Phe or is deleted;

<220>

<221>misc_feature

<222>(248)..(248)

<223> Xaa at position 248 is Leu or Trp or deleted;

<220>

<221>misc_feature

<222>(250)..(250)

<223> Xaa at position 250 is Ile or Leu or deleted;

<220>

<221>misc_feature

<222>(252)..(252)

<223> Xaa at position 252 is Leu, Phe, Ile or Ser or is deleted;

<220>

<221>misc_feature

<222>(254)..(254)

<223> Xaa at position 254 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(255)..(255)

<223> Xaa at position 255 is Leu or Phe or deleted;

<220>

<221>misc_feature

<222>(256)..(256)

<223> Xaa at position 256 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(259)..(259)

<223> Xaa at position 259 is Gly or Leu or deleted;

<220>

<221>misc_feature

<222>(260)..(260)

<223> Xaa at position 260 is Val or Ile or deleted;

<220>

<221>misc_feature

<222>(263)..(263)

<223> Xaa at position 263 is Leu, Phe or Ile or is deleted;

<220>

<221>misc_feature

<222>(268)..(268)

<223> Xaa at position 268 Val or Ile or deleted;

<220>

<221>misc_feature

<222>(269)..(269)

<223> Xaa at position 269 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(270)..(270)

<223> Xaa at position 270 is Gln, Cys or deleted;

<220>

<221>misc_feature

<222>(271)..(271)

<223> Xaa at position 271 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer;

<220>

<221>misc_feature

<222>(272)..(272)

<223> Xaa at position 272 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(273)..(273)

<223> Xaa at position 273 is Gly Thr Gly, Gly Ala Pro, Gly Pro Gly or Gly Gly Gly Gly GlySer or is deleted;

<220>

<221>misc_feature

<222>(284)..(284)

<223> Xaa at position 284 is Thr, Val or Ile or deleted;

<220>

<221>misc_feature

<222>(288)..(288)

<223> Xaa at position 288 is Ile, Val, Leu or Ala or deleted;

<220>

<221>misc_feature

<222>(293)..(293)

<223> Xaa at position 293 is Met, Thr, Ile or Ala or is deleted;

<220>

<221>misc_feature

<222>(296)..(296)

<223> Xaa at position 296 is His, Pro, Gln or Thr;

<220>

<221>misc_feature

<222>(297)..(297)

<223> Xaa at position 297 is Ala, Lys, Val or Thr;

<220>

<221>misc_feature

<222>(298)..(298)

<223> Xaa at position 298 is Arg, Lys, Gln or Glu;

<220>

<221>misc_feature

<222>(299)..(299)

<223> Xaa at position 299 is Gly or Ser;

<220>

<221>misc_feature

<222>(300)..(300)

<223> Xaa at position 300 is Thr, Leu, Phe or Ala;

<220>

<221>misc_feature

<222>(303)..(303)

<223> Xaa at position 303 is Phe, Ser or Leu;

<220>

<221>misc_feature

<222>(304)..(304)

<223> Xaa at position 304 is Ile, Ala, Val or Thr;

<220>

<221>misc_feature

<222>(305)..(305)

<223> Xaa at position 305 is Lys or Arg;

<220>

<221>misc_feature

<222>(308)..(308)

<223> Xaa at position 308 is Thr, Phe, Tyr or Ile;

<220>

<221>misc_feature

<222>(309)..(309)

<223> Xaa at position 309 is Glu, Asp, Gln or Asn;

<220>

<221>misc_feature

<222>(311)..(311)

<223> Xaa at position 311 is Ser, Phe or Leu is deleted;

<220>

<221>misc_feature

<222>(312)..(312)

<223> Xaa at position 312 is Phe or Leu or deleted;

<220>

<221>misc_feature

<222>(313)..(313)

<223> Xaa at position 313 is Thr, Ser or Gly or deleted;

<220>

<221>misc_feature

<222>(318)..(318)

<223> Xaa at position 318 is Leu or Met or deleted;

<220>

<221>misc_feature

<222>(319)..(319)

<223> Xaa at position 319 is Met or Leu or deleted;

<220>

<221>misc_feature

<222>(322)..(322)

<223> Xaa at position 322 is Ile or Val or deleted;

<220>

<221>misc_feature

<222>(327)..(327)

<223> Xaa at position 327 is Val or Leu or deleted;

<220>

<221>misc_feature

<222>(329)..(329)

<223> Xaa at position 329 is Asn or Lys or is deleted;

<400>33

Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln Lys Trp

1 5 10 15

Arg Glu Tyr Arg Arg Gln Cys Gln Arg Ser Leu Thr Glu Asp Pro Pro

20 25 30

Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr Ala Cys

35 40 45

Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys Pro Trp

50 55 60

Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr Arg Phe

65 70 75 80

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

85 90 95

Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu Arg Ser

100 105 110

Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Xaa Xaa Xaa Asn Xaa Ile

115 120 125

His Xaa Asn Leu Phe Xaa Ser Phe Xaa Leu Xaa Xaa Xaa Xaa Ser Xaa

130 135 140

Xaa Xaa Xaa Asp Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

145 150 155 160

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa

165 170 175

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Met Gln Tyr Xaa Xaa Xaa Ala Asn

180 185 190

Tyr Xaa Trp Leu Leu Val Glu Gly Xaa Tyr Leu Xaa Xaa Xaa Phe Xaa

195 200 205

Leu Tyr Xaa Xaa Ile Gly Trp Gly Xaa Pro Xaa Leu Phe Val Xaa Pro

210 215 220

Trp Xaa Xaa Xaa Xaa Xaa Leu Xaa Glu Xaa Xaa Xaa Cys Trp Xaa Xaa

225 230 235 240

Asn Xaa Asn Met Xaa Xaa Trp Xaa Ile Xaa Arg Xaa Pro Xaa Xaa Xaa

245 250 255

Ala Ile Xaa Xaa Asn Phe Xaa Ile Phe Val Arg Xaa Xaa Xaa Xaa Xaa

260 265 270

Xaa Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Xaa His Glu Val Xaa

275 280 285

Phe Ala Phe Val Xaa Asp Glu Xaa Xaa Xaa Xaa Xaa Leu Arg Xaa Xaa

290 295 300

Xaa Leu Phe Xaa Xaa Leu Xaa Xaa Xaa Ser Phe Gln Gly Xaa Xaa Val

305 310 315 320

Ala Xaa Leu Tyr Cys Phe Xaa Asn Xaa Glu

325 330

<210>34

<211>227

<212>PRT

<213> human

<400>34

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

1 5 10 15

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

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

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Lys

225

<210>35

<211>381

<212>PRT

<213> Artificial sequence

<400>35

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Ala Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr

35 40 45

Gly Asp Gln Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu

50 55 60

Leu Val Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr

65 70 75 80

Pro Ala Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp

85 90 95

His His Lys Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp

100 105 110

Gly Gln Trp Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser

115 120 125

Gln Cys Gln Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala

130 135 140

Lys Met Tyr Ser Ser Phe Gln Gly Pro Gly Asp Lys Thr His Thr Cys

145 150 155 160

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

165 170 175

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

180 185 190

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

195 200 205

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

210 215 220

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

225 230 235 240

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

245 250 255

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

260 265 270

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

275 280 285

Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

290 295 300

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

305 310 315 320

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

325 330 335

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

340 345 350

Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

355 360 365

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

370 375 380

<210>36

<211>340

<212>PRT

<213> Artificial sequence

<400>36

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Asn Ala Ile His Ala Asn Leu Phe Ala Ser Phe Val Leu Lys

35 40 45

Ala Ser Ser Val Leu Val Ile Asp Gly Leu Leu Arg Thr Arg Tyr Ser

50 55 60

Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Thr Trp Leu Ser Asp Gly

65 70 75 80

Ala Val Ala Gly Cys Arg Val Ala Ala Val Phe Met Gln Tyr Gly Ile

85 90 95

Val Ala Asn Tyr Cys Trp Leu Leu Val Glu Gly Leu Tyr Leu Gly Pro

100 105 110

Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu

115 120 125

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

130 135 140

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

145 150 155 160

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

165 170 175

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ash Ser Thr

180 185 190

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

195 200 205

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro

210 215 220

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

225 230 235 240

Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val

245 250 255

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

260 265 270

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

275 280 285

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr

290 295 300

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val

305 310 315 320

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

325 330 335

Ser Pro Gly Lys

340

<210>37

<211>318

<212>PRT

<213> Artificial sequence

<400>37

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Thr Leu Thr Leu Ile Pro Leu Leu Gly Val His Glu Val Val

35 40 45

Phe Ala Phe Val Thr Asp Glu His Ala Gln Gly Thr Leu Arg Ser Ala

50 55 60

Lys Leu Phe Phe Asp Leu Phe Leu Ser Ser Phe Gln Gly Leu Leu Val

65 70 75 80

Ala Val Leu Tyr Cys Phe Leu Asn Gly Pro Gly Asp Lys Thr His Thr

85 90 95

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

100 105 110

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

115 120 125

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

130 135 140

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

145 150 155 160

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

165 170 175

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

180 185 190

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

195 200 205

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

210 215 220

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

225 230 235 240

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

245 250 255

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

260 265 270

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

275 280 285

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

290 295 300

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

305 310 315

<210>38

<211>316

<212>PRT

<213> Artificial sequence

<400>38

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Val Ile Asp Gly Leu Leu Arg Thr Arg Tyr Ser Gln Lys Ile

35 40 45

Gly Asp Asp Leu Ser Val Ser Thr Trp Leu Ser Asp Gly Ala Val Ala

50 55 60

Gly Gly Gly Gly Ser Asp Glu His Ala Gln Gly Thr Leu Arg Ser Ala

65 70 75 80

Lys Leu Phe Phe Asp Leu Gly Pro Gly Asp Lys Thr His Thr Cys Pro

85 90 95

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe

100 105 110

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

115 120 125

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe

130 135 140

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

145 150 155 160

Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

165 170 175

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

180 185 190

Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala

195 200 205

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg

210 215 220

Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

225 230 235 240

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

245 250 255

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

260 265 270

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln

275 280 285

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

290 295 300

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

305 310 315

<210>39

<211>261

<212>PRT

<213> Artificial sequence

<400>39

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

35 40 45

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

50 55 60

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

65 70 75 80

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

85 90 95

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

100 105 110

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

115 120 125

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

130 135 140

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

145 150 155 160

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

165 170 175

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

180 185 190

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

195 200 205

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

210 215 220

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

225 230 235 240

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

245 250 255

Leu Ser Pro Gly Lys

260

<210>40

<211>704

<212>PRT

<213> Artificial sequence

<400>40

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln

35 40 45

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

50 55 60

Pro Pro Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr

65 70 75 80

Ala Cys Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys

85 90 95

Pro Trp Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr

100 105 110

Arg Phe Cys Thr Ala Glu Gly Leu Trp Leu Gln Lys Asp Asn Ser Ser

115 120 125

Leu Pro Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu

130 135 140

Arg Ser Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Ile Ile Tyr Thr

145 150 155 160

Val Gly Tyr Ala Leu Ser Phe Ser Ala Leu Val Ile Ala Ser Ala Ile

165 170 175

Leu Leu Gly Phe Arg His Leu His Cys Thr Arg Asn Tyr Ile His Leu

180 185 190

Asn Leu Phe Ala Ser Phe Ile Leu Arg Ala Leu Ser Val Phe Ile Lys

195 200 205

Asp Ala Ala Leu Lys Trp Met Tyr Ser Thr Ala Ala Gln Gln His Gln

210 215 220

Trp Asp Gly Leu Leu Ser Tyr Gln Asp Ser Leu Ser Cys Arg Leu Val

225 230 235 240

Phe Leu Leu Met Gln Tyr Cys Val Ala Ala Asn Tyr Tyr Trp Leu Leu

245 250 255

Val Glu Gly Val Tyr Leu Tyr Thr Leu Leu Ala Phe Ser Val Phe Ser

260 265 270

Glu Gln Trp Ile Phe Arg Leu Tyr Val Ser Ile Gly Trp Gly Val Pro

275 280 285

Leu Leu Phe Val Val Pro Trp Gly Ile Val Lys Tyr Leu Tyr Glu Asp

290 295 300

Glu Gly Cys Trp Thr Arg Asn Ser Asn Met Asn Tyr Trp Leu Ile Ile

305 310 315 320

Arg Leu Pro Ile Leu Phe Ala Ile Gly Val Asn Phe Leu Ile Phe Val

325 330 335

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

340 345 350

Lys Thr Asp Ile Lys Cys Arg Leu Ala Lys Ser Thr Leu Thr Leu Ile

355 360 365

Pro Leu Leu Gly Thr His Glu Val Ile Phe Ala Phe Val Met Asp Glu

370 375 380

His Ala Arg Gly Thr Leu Arg Phe Ile Lys Leu Phe Thr Glu Leu Ser

385 390 395 400

Phe Thr Ser Phe Gln Gly Leu Met Val Ala Ile Leu Tyr Cys Phe Val

405 410 415

Asn Asn Glu Val Gln Leu Glu Phe Arg Lys Ser Trp Glu Arg Trp Arg

420 425 430

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

435 440 445

Cys Pro Thr Ser Ser Leu Ser Ser Gly Ala Thr Ala Gly Ser Ser Met

450 455 460

Tyr Thr Ala Thr Cys Gln Ala Ser Cys Ser Gly Pro Gly Asp Lys Thr

465 470 475 480

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

485 490 495

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

500 505 510

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

515 520 525

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

530 535 540

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

545 550 555 560

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

565 570 575

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

580 585 590

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

595 600 605

Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys

610 615 620

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

625 630 635 640

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

645 650 655

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

660 665 670

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

675 680 685

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

690 695 700

<210>41

<211>386

<212>PRT

<213> Artificial sequence

<400>41

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Arg Pro Gln Gly Ala Thr Val Ser Leu Trp Glu Thr Val Gln

35 40 45

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

50 55 60

Pro Pro Pro Ala Thr Asp Leu Phe Cys Asn Arg Thr Phe Asp Glu Tyr

65 70 75 80

Ala Cys Trp Pro Asp Gly Glu Pro Gly Ser Phe Val Asn Val Ser Cys

85 90 95

Pro Trp Tyr Leu Pro Trp Ala Ser Ser Val Pro Gln Gly His Val Tyr

100 105 110

Arg Phe Cys Thr Ala Glu Gly Leu Trp Leu Gln Lys Asp Asn Ser Ser

115 120 125

Leu Pro Trp Arg Asp Leu Ser Glu Cys Glu Glu Ser Lys Arg Gly Glu

130 135 140

Arg Ser Ser Pro Glu Glu Gln Leu Leu Phe Leu Tyr Gly Pro Gly Asp

145 150 155 160

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

165 170 175

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

180 185 190

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

195 200 205

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

210 215 220

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

225 230 235 240

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

245 250 255

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

260 265 270

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

275 280 285

Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu

290 295 300

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

305 310 315 320

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

325 330 335

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

340 345 350

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

355 360 365

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

370 375 380

Gly Lys

385

<210>42

<211>339

<212>PRT

<213> Artificial sequence

<400>42

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Asn Tyr Ile His Leu Asn Leu Phe Ala Ser Phe Ile Leu Arg

35 40 45

Ala Leu Ser Val Phe Ile Lys Asp Ala Ala Leu Lys Trp Met Tyr Ser

50 55 60

Thr Ala Ala Gln Gln His Gln Trp Asp Gly Leu Leu Ser Tyr Gln Asp

65 70 75 80

Ser Leu Ser Cys Arg Leu Val Phe Leu Leu Met Gln Tyr Cys Val Ala

85 90 95

Ala Asn Tyr Tyr Trp Leu Leu Val Glu Gly Val Tyr Leu Gly Pro Gly

100 105 110

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

115 120 125

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

130 135 140

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

145 150 155 160

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

165 170 175

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

180 185 190

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

195 200 205

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

210 215 220

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

225 230 235 240

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

245 250 255

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

260 265 270

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

275 280 285

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

290 295 300

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

305 310 315 320

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

325 330 335

Pro Gly Lys

<210>43

<211>328

<212>PRT

<213> Artificial sequence

<400>43

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Phe Arg Leu Tyr Val Ser Ile Gly Trp Gly Val Pro Leu Leu

35 40 45

Phe Val Val Pro Trp Gly Ile Val Lys Tyr Leu Tyr Glu Asp Glu Gly

50 55 60

Cys Trp Thr Arg Asn Ser Asn Met Asn Tyr Trp Leu Ile Ile Arg Leu

65 70 75 80

Pro Ile Leu Phe Gly Ile Gly Val Asn Phe Leu Ile Phe Val Arg Val

85 90 95

Ile Cys Gly Pro Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

100 105 110

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

115 120 125

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

130 135 140

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

145 150 155 160

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

165 170 175

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

180 185 190

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

195 200 205

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

210 215 220

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

225 230 235 240

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

245 250 255

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

260 265 270

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

275 280 285

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

290 295 300

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

305 310 315 320

Ser Leu Ser Leu Ser Pro Gly Lys

325

<210>44

<211>321

<212>PRT

<213> Artificial sequence

<400>44

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Thr His Glu Val

35 40 45

Ile Phe Ala Phe Val Met Asp Glu His Ala Arg Gly Thr Leu Arg Phe

50 55 60

Ile Lys Leu Phe Thr Glu Leu Ser Phe Thr Ser Phe Gln Gly Leu Met

65 70 75 80

Val Ala Ile Leu Tyr Cys Phe Val Asn Asn Glu Gly Pro Gly Asp Lys

85 90 95

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

100 105 110

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

115 120 125

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

130 135 140

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

145 150 155 160

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

165 170 175

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

180 185 190

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

195 200 205

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

210 215 220

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

225 230 235 240

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

245 250 255

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

260 265 270

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

275 280 285

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

290 295 300

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

305 310 315 320

Lys

<210>45

<211>399

<212>PRT

<213> Artificial sequence

<400>45

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly

1 5 10 15

Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Gly

20 25 30

Ala Pro Asn Tyr Ile His Leu Asn Leu Phe Ala Ser Phe Ile Leu Arg

35 40 45

Ala Leu Ser Val Phe Ile Lys Asp Ala Ala Leu Lys Trp Met Tyr Ser

50 55 60

Thr Ala Ala Gln Gln His Gln Trp Asp Gly Leu Leu Ser Tyr Gln Asp

65 70 75 80

Ser Leu Ser Cys Arg Leu Val Phe Leu Leu Met Gln Tyr Cys Val Ala

85 90 95

Ala Asn Tyr Tyr Trp Leu Leu Val Glu Gly Val Tyr Leu Gly Pro Gly

100 105 110

Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Thr His Glu Val Ile Phe

115 120 125

Ala Phe Val Met Asp Glu His Ala Arg Gly Thr Leu Arg Phe Ile Lys

130 135 140

Leu Phe Thr Glu Leu Ser Phe Thr Ser Phe Gln Gly Leu Met Val Ala

145 150 155 160

Ile Leu Tyr Cys Phe Val Asn Asn Glu Gly Pro Gly Asp Lys Thr His

165 170 175

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

180 185 190

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

195 200 205

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

210 215 220

Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

225 230 235 240

Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser

245 250 255

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

260 265 270

Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile

275 280 285

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

290 295 300

Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

305 310 315 320

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

325 330 335

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

340 345 350

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

355 360 365

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

370 375 380

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

385 390 395

Claims

1. A glucagon-like peptide-1 (GLP-1) fusion protein, the amino acid sequence general formula of which is: polypeptide a-linker-polypeptide B, polypeptide a-linker-polypeptide B-linker-polypeptide C or polypeptide a-linker-polypeptide C-linker-polypeptide B; wherein,

the polypeptide A is GLP-1(7-37) [ sequence ID: n0: 1] having the sequence:

His-Xaa2-Xaa3-Gly-Xaa5-Xaa6-Thr-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Phe-Xaa23-Xaa24-Xaa25-Xaa26-Leu-Xaa28-Xaa29-Xaa30-Xaa31

xaa2 is: ala, Gly, Ser, Thr; xaa3 is: glu, Asp, Gln, Asn; xaa5 is: thr, Arg, Ile; xaa6 is: phe, Tyr, Leu; xaa8 is: ser, Asn; xaa9 is: asp, Asn; xaa10 is: val, Ile, Met, Ala; xaa11 is: ser, Thr, Ala, Asp; xaa12 is: ser, Gln, Glu, Asn, Thr; xaa13 is: tyr, Phe, Gln, His, Leu; xaa14 is: leu, Thr, Ser; xaa15 is: glu, Gln, Asn, Asp, Arg, Lys; xaa16 is: gly, Glu, Asp, Gln, Asn, Arg, Lys; xaa17 is: gln, Lys, Leu, Phe; xaa18 is: ala, Lys; xaa19 is: ala, Thr, Ile, Ser; xaa20 is: lys, Arg, Gln; xaa21 is: glu, Asp, Asn, Ala, Ser, Lys, Arg; xaa23 is: ile, Val; xaa24 is: ala, Ser, Asp, Glu, Gly, Thr; xaa25 is: trp, Arg, Lys, Ser; xaa27 is: val, Lys, Ile, Ser, Ala; xaa28 is: lys, Arg, Asn, Gln, Ser, Ala, Thr; xaa29 is: gly, Tyr, Ser; xaa30 is: arg, Lys, Gln, Asp, Asn, Gly, Ala, Pro; xaa31 is: gly, Pro, Val, Arg, Lys, Ala or deleted;

polypeptide B is the full-length sequence of human glucagon receptor, N-terminal extramembranous functional region, glucagon receptor functional region-1, glucagon receptor functional region-2, glucagon receptor functional region-3 or the combined sequence of the glucagon receptor functional regions;

the polypeptide C is a CH2-CH3 segment of human immunoglobulin G1 Fc.

2. The fusion protein according to claim 1, characterized in that: a linker between polypeptide a, polypeptide B and polypeptide C selected from the group consisting of:

(Gly-Thr-Gly) n, (Gly-Ala-Pro) n, (Gly-Pro-Gly) n, or (GIy-Gly-Gly-Gly-Ser) n;

wherein n is 1, 2, 3, 4, 5, 6.

3. The fusion protein of claim 1, characterized in that the glucagon receptor is any one of the following sequences:

(1) the entire glucagon receptor sequence [ sequence ID NO: 2] having the sequence:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQVMYTVGYSLSLGALLLALAILGGLSKLHCTRNAIHANLFASFVLKASSVLVIDGLLRTRYSQKIGDDLSVSTWLSDGAVAGCRVAAVFMQYGIVANYCWLLVEGLYLHNLLGLATLPERSFFSLYLGIGWGAPMLFVVPWAVVKCLFENVQCWTSNDNMGFWWILRFPVFLAILINFFIFVRIVQLLVAKLRARQMHHTDYKFRLAKSTLTLIPLLGVHEVVFAFVTDEHAQGTLRSAKLFFDLFLSSFQGLLVAVLYCFLNKEVQSELRRRWHRWRLGKVLWEERNTSNHRASSSPGHGPPSKELQFGRGGGSQDSSAETPLAGGLPRLAESPF

(2) the N-terminal extramembranous domain of the glucagon receptor [ sequence ID NO: 3] having the sequence:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQ

(3) glucagon receptor functional region-1, which is composed of the outer ring of the first membrane of glucagon receptor and the transmembrane regions at both ends [ sequence ID NO: 4] having the sequence:

Xaa1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa2

wherein Xaa1 is the following sequence: NAIHANLFASFVLKASSVLV

From the N-terminus of Xaa1, all amino acids can be removed one by one;

wherein Xaa2 is the following sequence: CRVAAVFMQYGIVANYCWLLVEGLYL

From the C-terminus of Xaa2, all amino acids can be removed one by one;

(4) glucagon receptor functional domain-2, which is composed of the membrane outer loop of glucagon receptor 2 and transmembrane domains at both ends thereof [ sequence ID NO: 5] having the sequence:

Xaa3-KCLFENVQCWTSNDNMGF-Xaa4

wherein Xaa3 is the following sequence: FSLYLGIGWGAPMLFVVPWAVV

From the N-terminus of Xaa3, all amino acids can be removed one by one;

wherein Xaa4 is the following sequence: WWILRFPVFLAILINFFIFVRIV

From the C-terminus of Xaa4, all amino acids can be removed one by one;

(5) glucagon receptor functional region-3, which is composed of glucagon receptor 3 rd membrane outer ring and transmembrane regions at two ends [ sequence ID NO: 6] having the sequence:

Xaa5-DEHAQGTLRSAKLFFD-Xaa6

wherein Xaa5 is the following sequence: TLTLIPLLGVHEVVFAFVT

From the N-terminus of Xaa5, all amino acids can be removed one by one;

wherein Xaa6 is the following sequence: LFLSSFQGLLVAVLYCFLN

From the C-terminus of Xaa6, all amino acids can be removed one by one;

(6) glucagon receptor domain 1-linker-glucagon receptor domain 2, having the sequence structure [ sequence ID NO: 7]:

xaa1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa 2-intermediate joint-Xaa 3-KCLFENVQCWTSNDNMGF-Xaa4

Wherein Xaa1 is the following sequence: NAIHANLFASFVLKASSVLV

From the N-terminus of Xaa1, all amino acids can be removed one by one;

wherein Xaa2 is the following sequence: CRVAAVFMQYGIVANYCWLLVEGLYL

From the C-terminus of Xaa2, all amino acids can be removed one by one;

wherein Xaa3 is the following sequence: FSLYLGIGWGAPMLFVVPWAVV

From the N-terminus of Xaa3, all amino acids can be removed one by one;

wherein Xaa4 is the following sequence: WWILRFPVFLAILINFFIFVRIV

From the C-terminus of Xaa4, all amino acids can be removed one by one;

(7) glucagon receptor domain 1-linker-glucagon receptor domain 3, having the sequence structure [ sequence ID NO: 8]:

xaa1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa 2-intermediate joint-Xaa 5-DEHAQGTLRSAKLFFD-Xaa6

Wherein Xaa1 is the following sequence: NAIHANLFASFVLKASSVLV

From the N-terminus of Xaa1, all amino acids can be removed one by one;

wherein Xaa2 is the following sequence: CRVAAVFMQYGIVANYCWLLVEGLYL

From the C-terminus of Xaa2, all amino acids can be removed one by one;

wherein Xaa5 is the following sequence: TLTLIPLLGVHEVVFAFVT

From the N-terminus of Xaa5, all amino acids can be removed one by one;

wherein Xaa6 is the following sequence: LFLSSFQGLLVAVLYCFLN

From the C-terminus of Xaa6, all amino acids can be removed one by one;

(8) glucagon receptor domain 2-linker-glucagon receptor domain 3, having the sequence structure [ sequence ID NO: 9]:

xaa3-KCLFENVQCWTSNDNMGF-Xaa 4-intermediate linker-Xaa 5-DEHAQGTLRSAKLFFD-Xaa 6.

Wherein Xaa3 is the following sequence: FSLYLGIGWGAPMLFVVPWAVV

From the N-terminus of Xaa3, all amino acids can be removed one by one;

wherein Xaa4 is the following sequence: WWILRFPVFLAILINFFIFVRIV

From the C-terminus of Xaa4, all amino acids can be removed one by one;

wherein Xaa5 is the following sequence: TLTLIPLLGVHEVVFAFVT

From the N-terminus of Xaa5, all amino acids can be removed one by one;

wherein Xaa6 is the following sequence: LFLSSFQGLLVAVLYCFLN

From the C-terminus of Xaa6, all amino acids can be removed one by one;

(9) glucagon receptor functional region 1-intermediate linker-glucagon receptor functional region 2-intermediate linker-glucagon receptor functional region 3, the sequence structure of which is as follows [ sequence ID NO: 10]:

xaa1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa 2-intermediate joint-Xaa 3-KCLFENVQCWTSNDNMGF-Xaa 4-intermediate joint-Xaa 5-DEHAQGTLRSAKLFFD-Xaa6

Wherein Xaa1 is the following sequence: NAIHANLFASFVLKASSVLV

From the N-terminus of Xaa1, all amino acids can be removed one by one;

wherein Xaa2 is the following sequence: CRVAAVFMQYGIVANYCWLLVEGLYL

From the C-terminus of Xaa2, all amino acids can be removed one by one;

wherein Xaa3 is the following sequence: FSLYLGIGWGAPMLFVVPWAVV

From the N-terminus of Xaa3, all amino acids can be removed one by one;

wherein Xaa4 is the following sequence: WWILRFPVFLAILINFFIFVRIV

From the C-terminus of Xaa4, all amino acids can be removed one by one;

wherein Xaa5 is the following sequence: TLTLIPLLGVHEVVFAFVT

From the N-terminus of Xaa5, all amino acids can be removed one by one;

wherein Xaa6 is the following sequence: LFLSSFQGLLVAVLYCFLN

From the C-terminus of Xaa6, all amino acids can be removed one by one;

(10) the glucagon receptor N-terminal extramembranous functional region-intermediate connector-glucagon receptor functional region 1 has the following sequence structure [ sequence ID NO: 11]:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQ-intermediate joint-Xaa 1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa2

Wherein Xaa1 is the following sequence: NAIHANLFASFVLKASSVLV

From the N-terminus of Xaa1, all amino acids can be removed one by one;

wherein Xaa2 is the following sequence: CRVAAVFMQYGIVANYCWLLVEGLYL

From the C-terminus of Xaa2, all amino acids can be removed one by one;

(11) the glucagon receptor N-terminal extramembranous functional region-intermediate connector-glucagon receptor functional region 2 has the following sequence structure [ sequence ID NO: 12]:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQ-intermediate joint-Xaa 3-KCLFENVQCWTSNDNMGF-Xaa4

Wherein Xaa3 is the following sequence: FSLYLGIGWGAPMLFVVPWAVV

From the N-terminus of Xaa3, all amino acids can be removed one by one;

wherein Xaa4 is the following sequence: WWILRFPVFLAILINFFIFVRIV

From the C-terminus of Xaa4, all amino acids can be removed one by one;

(12) the glucagon receptor N-terminal extramembranous functional region-intermediate linker-glucagon receptor functional region 3 has the following sequence structure [ sequence ID NO: 13]:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQ-intermediate joint-Xaa 5-DEHAQGTLRSAKLFFD-Xaa6

Wherein Xaa5 is the following sequence: TLTLIPLLGVHEVVFAFVT

From the N-terminus of Xaa5, all amino acids can be removed one by one;

wherein Xaa6 is the following sequence: LFLSSFQGLLVAVLYCFLN

From the C-terminus of Xaa6, all amino acids can be removed one by one;

(13) the glucagon receptor N-end extramembranous functional region-intermediate connector-glucagon receptor functional region 1-intermediate connector-glucagon receptor functional region 2 has the following sequence structure [ sequence ID NO: 14]:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTAN I SCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQ-intermediate joint-Xaa 1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa 2-intermediate joint-Xaa 3-KCLFENVQCWTSNDNMGF-Xaa4

Wherein Xaa1 is the following sequence: NAIHANLFASFVLKASSVLV

From the N-terminus of Xaa1, all amino acids can be removed one by one;

wherein Xaa2 is the following sequence: CRVAAVFMQYGIVANYCWLLVEGLYL

From the C-terminus of Xaa2, all amino acids can be removed one by one;

wherein Xaa3 is the following sequence: FSLYLGIGWGAPMLFVVPWAVV

From the N-terminus of Xaa3, all amino acids can be removed one by one;

wherein Xaa4 is the following sequence: WWILRFPVFLAILINFFIFVRIV

From the C-terminus of Xaa4, all amino acids can be removed one by one;

(14) the glucagon receptor N-end extramembranous functional region-intermediate connector-glucagon receptor functional region 1-intermediate connector-glucagon receptor functional region 3 has the following sequence structure [ sequence ID NO: 15]:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISCPWYLPWHHKQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQ-intermediate joint-Xaa 1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa 2-intermediate joint-Xaa 5-DEHAQGTLRSAKLFFD-Xaa 6.

Wherein Xaa1 is the following sequence: NAIHANLFASFVLKASSVLV

From the N-terminus of Xaa1, all amino acids can be removed one by one;

wherein Xaa2 is the following sequence: CRVAAVFMQYGIVANYCWLLVEGLYL

From the C-terminus of Xaa2, all amino acids can be removed one by one;

wherein Xaa5 is the following sequence: TLTLIPLLGVHEVVFAFVT

From the N-terminus of Xaa5, all amino acids can be removed one by one;

wherein Xaa6 is the following sequence: LFLSSFQGLLVAVLYCFLN

From the C-terminus of Xaa6, all amino acids can be removed one by one;

(15) the glucagon receptor N-end extramembranous functional region-intermediate connector-glucagon receptor functional region 2-intermediate connector-glucagon receptor functional region 3 has the following sequence structure [ sequence ID NO: 16]:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQ-intermediate joint-Xaa 3-KCLFENVQCWTSNDNMGF-Xaa 4-intermediate joint-Xaa 5-DEHAQGTLRSAKLFFD-Xaa6

Wherein Xaa3 is the following sequence: FSLYLGIGWGAPMLFVVPWAVV

From the N-terminus of Xaa3, all amino acids can be removed one by one;

wherein Xaa4 is the following sequence: WWILRFPVFLAILINFFIFVRIV

From the C-terminus of Xaa4, all amino acids can be removed one by one;

wherein Xaa5 is the following sequence: TLTLIPLLGVHEVVFAFVT

From the N-terminus of Xaa5, all amino acids can be removed one by one;

wherein Xaa6 is the following sequence: LFLSSFQGLLVAVLYCFLN

From the C-terminus of Xaa6, all amino acids can be removed one by one;

(16) the glucagon receptor N-terminal extramembranous functional region-intermediate connector-glucagon receptor functional region 1-intermediate connector-glucagon receptor functional region 2-intermediate connector-glucagon receptor functional region 3 has the following sequence structure [ sequence ID NO: 17]:

AQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQ-intermediate joint-Xaa 1-IDGLLRTRYSQKIGDDLSVSTWLSDGAVAG-Xaa 2-intermediate joint-Xaa 3-KCLFENVQCWTSNDNMGF-Xaa 4-intermediate joint-Xaa 5-DEHAQGTLRSAKLFFD-Xaa 6.

Wherein Xaa1 is the following sequence: NAIHANLFASFVLKASSVLV

From the N-terminus of Xaa1, all amino acids can be removed one by one;

wherein Xaa2 is the following sequence: CRVAAVFMQYGIVANYCWLLVEGLYL

From the C-terminus of Xaa2, all amino acids can be removed one by one;

wherein Xaa3 is the following sequence: FSLYLGIGWGAPMLFVVPWAVV

From the N-terminus of Xaa3, all amino acids can be removed one by one;

wherein Xaa4 is the following sequence: WWILRFPVFLAILINFFIFVRIV

From the C-terminus of Xaa4, all amino acids can be removed one by one;

wherein Xaa5 is the following sequence: TLTLIPLLGVHEVVFAFVT

From the N-terminus of Xaa5, all amino acids can be removed one by one;

wherein Xaa6 is the following sequence: LFLSSFQGLLVAVLYCFLN

From the C-terminus of Xaa6, all amino acids can be removed one by one;

4. the fusion protein of GLP-1 of claim 1, wherein polypeptide C is the CH2-CH3 segment of human immunoglobulin G1Fc, the sequence of which is [ SEQ ID NO: 34]:

DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK。

5. a pharmaceutical composition for treating non-insulin dependent diabetes mellitus or obesity, comprising the fusion protein of any one of claims 1 to 4.

6. Use of a fusion protein of GLP-1 as defined in claims 1-4 for the preparation of a medicament for the treatment of type I diabetes, type II diabetes, obesity, stroke.