RECOMBINANT FILAGGRIN POLYPEPTIDES FOR CELL IMPORTATION

Abstract

Disclosed are recombinant polypeptides that include (a) a filaggrin amino acid sequence and (b) a cell importation signal sequence that includes a motif of two to fifteen amino acids, wherein the motif includes at least one arginine residue and at least one methionine residue. Also disclosed are nucleic acids encoding the recombinant polypeptides of the present invention, and compositions that include the recombinant polypeptides and nucleic acids of the present invention. Methods of treating or preventing a skin disease or skin disorder using the compositions of the present invention are also included, as well as kits that include a sealed containing that includes a recombinant polypeptide of the present invention.

Description

[0001] The present application is a continuation of U.S. application Ser. No. 16/242,487, filed Jan. 8, 2019, which is a continuation of U.S. application Ser. No. 13/511,267, filed Oct. 5, 2012, now U.S. Pat. No. 10,336,797, which is a national phase application under 35 U.S.C. .sctn. 371 of International Application No. PCT/US2010/057592, filed Nov. 22, 2010, which claims benefit of priority to U.S. Provisional Application Ser. No. 61/263,604, filed Nov. 23, 2009, the entire contents of each of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

[0002] The present invention relates generally to the fields of protein chemistry, intracellular protein transport, skin care, and the treatment and prevention of skin disease. More particularly, it concerns methods, compositions, and kits employing recombinant filaggrin polypeptides that include an attached cell importation signal sequence, or nucleic acids encoding a filaggrin polypeptide with an attached cell importation signal sequence.

2. Description of Related Art

[0003] Skin diseases are a common cause of morbidity in the U.S. For example, ichthyosis vulgaris and atopic dermatitis have a combined incidence of 1 in 250. They are the most common disorders of keratinization. These diseases are characterized by hyperlinearity, keratosis pilaris and itchy, scaly, often inflamed skin. Ichthyosis vulgaris and atopic dermatitis are also associated with one of the most common single-gene disorders in humans, a disorder of the filaggren (FLG) gene.

[0004] FLG is a 3-exon gene located in the Epidermal Differentiation Complex (EDC) on chromosome 1q21. In healthy patients, the FLG gene codes for the (pro) filaggrin protein, a protein essential for proper keratinization and squamification of epithelial cells, formation of epidermal barrier, and hydration. In almost fifty percent of patients with these diseases, however, one of two nonsense mutations have been present in exon 3 (R501X and 2282de14) (Hoffjan, 2007). These mutations disable the profilaggrin polyprotein from being proteolytically cleaved to the functioning FLG protein. FLG protein is expressed in the cytoplasm of epithelial cells; it is absent from the nucleus in vivo. A correlation between the number of filaggrin repeats and the predisposition to dry skin has also been shown (see U.S. Patent App. Publ. No. 2003/0124553). Administration of a polypeptide comprising a profilaggrin has been proposed as a treatment for dry skin (U.S. Patent Appl. Pub. No. 2003/0124553).

[0005] Despite the information available concerning FLG and its role in skin disease, there is a need for more effective methods of treating diseases or disorders of the skin.

SUMMARY OF THE INVENTION

[0006] The present invention is in part based on the finding that the uptake of a filaggrin polypeptide into a cell can be surprisingly and effectively enhanced by attaching a cell importation signal sequence to the filaggrin polypeptide. The cell importation sequence, for example, may be a sequence comprising a motif of two to fifteen amino acids, wherein the motif includes at least one arginine residue and at least one methionine residue. Compositions that include the polypeptides of the present invention have improved therapeutic efficacy compared to polypeptides that do not include the cell importation signal sequence.

[0007] Some embodiments of the present invention include a recombinant polypeptide that includes (a) a filaggrin amino acid sequence; and (b) a cell importation signal sequence including a motif of two to fifteen amino acids, wherein the motif includes at least one arginine residue and at least one methionine residue. The filaggrin amino acid sequence may include any number of amino acids of a native filaggrin protein. In some embodiments, for example, the filaggrin amino acid sequence includes 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 130, 150, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340 or more consecutive amino acids of any of the amino acid sequences set forth in Table 2 below, or any range of amino acids derivable therein, so long as the filaggrin amino acid sequence when conjugated to a cell importation signal sequence retains at least some of the function of a native filaggrin amino acid sequence conjugated to the same cell importation sequence. Non-limiting functions of a native filaggrin amino acid sequence include reduction in peeling of skin, reduction of skin redness, reduction of itching of skin, reduction of crusting of skin, reduction in dryness of skin, reduction in scaling of skin, reduction of skin inflammation, reducing of skin cracking, reduction of blistering of skin, reduction of scarring of skin, reduction of oozing of skin, and reduction of bleeding of skin.

[0008] In some embodiments, the filaggrin amino acid sequence includes any of the amino acid sequences set forth in Table 2. In particular embodiments, the filaggrin amino acid sequence includes SEQ ID NO:1.

[0009] In some embodiments, the filaggrin amino acid sequence has at least about 80%, 81%, 82%, 83, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with a native filaggrin amino acid sequence, or any range of percent sequence identify derivable therein. Examples of filaggrin sequences are set forth in Table 2 below. In particular embodiments, the filaggrin amino acid sequence has at least about 80%, 81%, 82%, 83, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO:1. "Sequence identity" is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues at corresponding positions in a native polypeptide sequence, after aligning the sequences and introducing gaps if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. The % sequence identity values may be generated by the NCBI BLAST2.0 software as defined by Altschul et al. (1997). The parameters are set to default values, with the exception of Penalty for mismatch, which is set to -1.

[0010] Regarding the cell importation sequence, in some embodiments, the amino acid sequence includes an arginine residue covalently attached to a methionine residue. In some embodiments, the arginine residue and the methionine residue are separated by 1, 2, 3, 4, 5, 6, 7, or 8 intervening amino acid residues. In a particular embodiment, the cell importation sequence comprises SEQ ID NO:23.

[0011] In some embodiments, the polypeptide includes a linker between the filaggrin amino acid sequence and the cell importation amino acid sequence. The linker may be any linker known to those of ordinary skill in the art. Some non-limiting examples of linkers are discussed in the specification below.

[0012] In some embodiments, the polypeptide includes SEQ ID NO:21 or SEQ ID NO:22. In a specific embodiment, the polypeptide is SEQ ID NO:21.

[0013] The polypeptide may be further defined as a fusion protein of the filaggrin amino acid sequence and the cell importation amino acid sequence. The filaggrin amino acid sequence may be attached to the N-terminus of the cell importation signal sequence, or it may be attached to the C-terminus of the cell importation signal sequence.

[0014] Other embodiments of the present invention include a nucleic acid that includes a nucleic acid sequence that encodes a chimeric polypeptide as set forth above. Further embodiments include a nucleic acid that encodes a filaggrin amino acid sequence. The filaggrin amino acid sequence is any filaggrin amino acid sequence as set forth herein. In some embodiments, the nucleic acid is comprised in a viral vector. Non-limiting examples of viral vectors include lentiviral vectors, adeno-associated viral vectors, and adenoviral vectors.

[0015] Other embodiments of the present invention concern a skin-care composition that includes an effective amount of a polypeptide that includes a filaggrin amino acid sequence and a cell importation signal sequence, or a nucleic acid encoding a polypeptide of the present invention as set forth above. The polypeptide may be any of the aforementioned polypeptide chimeras. The nucleic acid may be any of the aforementioned nucleic acids.

[0016] In some embodiments, the composition further includes a lipid component. The lipid component may have a net neutral charge. It may be include only neutral lipids, or it may optionally include cationic and anionic lipids such that the net charge of the lipids in the lipid component is neutral.

[0017] The lipid component may include a neutral lipid. For example, the neutral lipid may be a neutral phospholipid. Non-limiting examples of neutral phospholipids include phosphatidylcholine or phosphatidylethanolamine. Other examples of neutral phospholipids include 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), egg phosphatidylcholine ("EPC"), dilauryloylphosphatidylcholine ("DLPC"), dimyristoylphosphatidylcholine ("DMPC"), dipalmitoylphosphatidylcholine ("DPPC"), distearoylphosphatidylcholine ("DSPC"), 1-myristoyl-2-palmitoyl phosphatidylcholine ("MPPC"), 1-palmitoyl-2-myristoyl phosphatidylcholine ("PMPC"), 1-palmitoyl-2-stearoyl phosphatidylcholine ("PSPC"), 1-stearoyl-2-palmitoyl phosphatidylcholine ("SPPC"), dimyristyl phosphatidylcholine ("DMPC"), 1,2-distearoyl-sn-glycero-3-phosphocholine ("DAPC"), 1,2-diarachidoyl-sn-glycero-3-phosphocholine ("DBPC"), 1,2-dieicosenoyl-sn-glycero-3-phosphocholine ("DEPC"), palmitoyloeoyl phosphatidylcholine ("POPC"), lysophosphatidylcholine, dilinoleoylphosphatidylcholine distearoylphophatidylethanolamine ("DSPE"), dimyristoyl phosphatidylethanolamine ("DMPE"), dipalmitoyl phosphatidylethanolamine ("DPPE"), palmitoyloeoyl phosphatidylethanolamine ("POPE"), and lysophosphatidylethanolamine

[0018] The lipid component may include a negatively charged lipid. For example, the negatively charged lipid may be a negatively charged phospholipid. Non-limiting examples of negatively charged phospholipids include phosphatidylserine and phosphatidylglycerol. Other examples include dimyristoyl phosphatidylserine ("DMPS"), dipalmitoyl phosphatidylserine ("DPPS"), brain phosphatidylserine ("BPS"), dilauryloylphosphatidylglycerol ("DLPG"), dimyristoylphosphatidylglycerol ("DMPG"), dipalmitoylphosphatidylglycerol ("DPPG"), distearoylphosphatidylglycerol ("DSPG"), and dioleoylphosphatidylglycerol ("DOPG").

[0019] The lipid component may optionally include cholesterol of polyethyleneglycol (PEG).

[0020] Other possible lipid components include cationic lipids. Non-limiting examples of cationic lipids include 1,2-dioleyl-3-trymethylammoniumpropane (DOTAP), 1,2-dioleoyl-3-dimethylammonium-propane (DODAP), dimethyldioctadecylammonium bromide (DDAB), N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), and DC-cholesterol.

[0021] The lipid component may include a single type of lipid, or it may include two or more distinct types of lipids. In some embodiments, the composition includes liposomes. Liposomes are discussed in detail elsewhere in this specification.

[0022] In some embodiments, the composition is a solution, an emulsion, a cream, a lotion, a gel, or an ointment. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.

[0023] The composition may include any amount of chimeric polypeptide or nucleic acid encoding a chimeric polypeptide as set forth herein. For example, in some embodiments, the composition includes from about 0.001% to about 5.0% by weight of polypeptide.

[0024] The present invention also generally concerns methods of delivering a filaggrin polypeptide into a cell, comprising contacting a cell with any of the aforementioned chimeric polypeptides, wherein the filaggrin polypeptide is delivered into the cell. The cell may be any type of cell. In particular embodiments, the cell is a skin cell. For example, the skin cell may be a basal cell, a squamous cell, a melanocyte, or a keratinocyte.

[0025] The invention also in part concerns methods of treating or preventing a skin disease or skin disorder in a subject, involving administering to a subject an effective amount of a composition that includes (a) a recombinant chimeric polypeptide as set forth above or (b) a nucleic acid encoding any of the aforementioned chimeric polypeptides. The subject may be any subject, but in particular embodiments the subject is a mammal. Non-limiting examples of mammals include mice, rats, rabbits, cats, dogs, sheep, goats, pigs, horses, cows, primates, and humans. In particular embodiments, the subject is a human. For example, the human may have or be at risk of developing a skin disease or disorder. In some embodiments, the human is a patient with a skin disease. Non-limiting examples of skin diseases are set forth elsewhere in this specification. In particular embodiments, the skin disease is ichthyosis vulgaris or atopic dermatitis.

[0026] The composition may be administered to the subject using any method known to those of ordinary skill in the art. In particular embodiments, administering involves topically applying the composition to a skin surface of the subject. The skin surface may be a mucosal surface, or it may be a skin surface that does not include mucosa. The mucosa may include oral mucosa, vaginal mucosa, cervical mucosa, or anal mucosa.

[0027] The compositions set forth herein may optionally include one or more additional agents that can be applied in the treatment or prevention of a skin disease or disorder in a subject. Non-limiting examples of additional agents include a moisturizer, an exfoliating agent, an anti-inflammatory agent, or an antimicrobial agent. Others are detailed elsewhere in this specification. In some embodiments, the composition includes a lipid component, including any of the lipid components as set forth above. The composition may optionally include liposomes.

[0028] The composition may be formulated in any manner known to those of ordinary skill in the art. In some embodiments, the composition is a solution, an emulsion, a cream, a lotion, a gel, or an ointment. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. The composition may include any amount of active ingredient(s). For example, the composition may include from about 0.001% to about 5.0% by weight of chimeric polypeptide or other ingredient.

[0029] Other aspects of the present invention concern kits. The kit may include a sealed container that includes a recombinant polypeptide as set forth above, or a nucleic acid encoding a recombinant polypeptide as set forth above. The sealed container may be any type of sealed container. Non-limiting examples of sealed containers include a vial, a bottle, a dispenser, or a package. The kit may optionally include an applicator. The kit may include a sealed container that includes any of the compositions as set forth herein.

[0030] It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention. Furthermore, any composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any composition of the invention.

[0031] The use of the term "or" in the claims is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and/or."

[0032] Throughout this application, the term "about" is used to indicate that a value includes the standard deviation of error for the device and/or method being employed to determine the value.

[0033] As used herein the specification, "a" or "an" may mean one or more, unless clearly indicated otherwise. As used herein in the claim(s), when used in conjunction with the word "comprising," the words "a" or "an" may mean one or more than one. As used herein "another" may mean at least a second or more.

[0034] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0035] The present invention is in part based on the finding that the therapeutic efficacy of filaggrin as an agent to treat or prevent skin disease can be significantly improved by attaching a cell importation signal sequence to the filaggrin polypeptide. The cell importation sequence may include, for example, a motif of two to fifteen amino acids that include at least one arginine residue and at least one methionine residue. These polypeptides, and nucleic acids encoding these polypeptides, have application in the treatment or prevention of a wide variety of conditions, including skin diseases or disorders associated with abnormal keratinization or abnormal epidermal differentiation.

A. POLYPEPTIDES

[0036] 1. Polypeptides in General

[0037] The present invention concerns polypeptides that includes a filaggrin amino acid sequence and a cell importation signal sequence. As used herein, a "polypeptide" generally is defined herein to refer to a peptide sequence of about 2 to about 10,000 or more amino acid residues.

[0038] The term "amino acid" not only encompasses the 20 common amino acids in naturally synthesized proteins, but also includes any modified, unusual, or synthetic amino acid. One of ordinary skill in the art would be familiar with modified, unusual, or synthetic amino acids. Examples of modified and unusual amino acids are shown on Table 1 below.

TABLE-US-00001 TABLE 1 Modified and Unusual Amino Acids Abbr. Amino Acid Abbr. Amino Acid Aad 2-Aminoadipic acid EtAsn N-Ethylasparagine Baad 3-Aminoadipic acid Hyl Hydroxylysine Bala .beta.-alanine, .beta.-Amino-propionic AHyl allo-Hydroxylysine acid Abu 2-Aminobutyric acid 3Hyp 3-Hydroxyproline 4Abu 4-Aminobutyric acid, piperidinic 4Hyp 4-Hydroxyproline acid Acp 6-Aminocaproic acid Ide Isodesmosine Ahe 2-Aminoheptanoic acid AIle allo-Isoleucine Aib 2-Aminoisobutyric acid MeGly N-Methylglycine, sarcosine Abbr. Amino Acid Abbr. Amino Acid Baib 3-Aminoisobutyric acid MeIle N-Methylisoleucine Apm 2-Aminopimelic acid MeLys 6-N-Methyllysine Dbu 2,4-Diaminobutyric acid MeVal N-Methylvaline Des Desmosine Nva Norvaline Dpm 2,2'-Diaminopimelic acid Nle Norleucine Dpr 2,3-Diaminopropionic acid Orn Ornithine EtGly N-Ethylglycine

[0039] The polypeptides that are included in the methods set forth herein are chimeric in that they comprise a filaggrin amino acid sequence and a cell importation signal sequence. The polypeptides set forth herein may comprise one or more cell importation signal sequences, which may or may not be identical. Similarly, the polypeptides set forth herein may comprise one or more filaggrin amino acid sequences, which may or may not be identical.

[0040] In certain embodiments of the present invention, the polypeptide is a fusion polypeptide that includes a filaggrin amino acid sequence linked at the N- or C-terminus to a cell importation signal sequence. In other embodiments, the polypeptide comprises a linker interposed between the filaggrin amino acid sequence and the cell importation signal sequence. Linkers are discussed in greater detail in the specification below.

[0041] Furthermore, the polypeptides set forth herein may comprises a sequence of any number of additional amino acid residues at either the N-terminus or C-terminus of the amino acid sequence that includes the filaggrin amino acid sequence and the cell importation signal sequence. For example, there may be an amino acid sequence of about 3 to about 10,000 or more amino acid residues at either the N-terminus, the C-terminus, or both the N-terminus and C-terminus of the amino acid sequence that includes the filaggrin amino acid sequence and the cell importation signal sequence.

[0042] The polypeptide may include the addition of an immunologically active domain, such as an antibody epitope or other tag, to facilitate targeting or purification of the polypeptide. The use of 6.times. His and GST (glutathione S transferase) as tags is well known. Inclusion of a cleavage site at or near the fusion junction will facilitate removal of the extraneous polypeptide after purification. Other amino acid sequences that may be included in the polypeptide include functional domains, such as active sites from enzymes such as a hydrolase, glycosylation domains, cellular targeting signals or transmembrane regions. The polypeptide may further include one or more additional tissue-targeting moieties.

[0043] The polypeptides of the present invention may possess deletions and/or substitutions of amino acids relative to the native sequence; thus, sequences with a deletion, sequences with a substitution, and sequences with a deletion and a substitution are contemplated for inclusion in the polypeptides of the present invention. In some embodiments, these polypeptides may further include insertions or added amino acids, such as linkers.

[0044] Substitutional or replacement variants typically contain the exchange of one amino acid for another at one or more sites within the protein and may be designed to modulate one or more properties of the polypeptide, particularly to increase its efficacy or specificity. Substitutions of this kind preferably are conservative, that is, one amino acid is replaced with one of similar shape and charge. Conservative substitutions are well known in the art and include, for example, the changes of: alanine to serine; arginine to lysine; asparagine to glutamine or histidine; aspartate to glutamate; cysteine to serine; glutamine to asparagine; glutamate to aspartate; glycine to proline; histidine to asparagine or glutamine; isoleucine to leucine or valine; leucine to valine or isoleucine; lysine to arginine; methionine to leucine or isoleucine; phenylalanine to tyrosine, leucine or methionine; serine to threonine; threonine to serine; tryptophan to tyrosine; tyrosine to tryptophan or phenylalanine; and valine to isoleucine or leucine.

[0045] In addition to a deletion or substitution, the polypeptides may possess an insertion one or more residues. This may include the addition of one or more amino acid residues.

[0046] The term "biologically functional equivalent" is well understood in the art and is further defined in detail herein. Accordingly, sequences that have between about 70% and about 80%, or between about 81% and about 90%, or even between about 91% and about 99% of amino acids that are identical or functionally equivalent to the amino acids of the native filaggrin amino acid sequence or cell importation signal sequence are included, provided the biological activity of the native sequence is maintained.

[0047] Thus, the filaggrin amino acid sequence may be a biologically functionally equivalent to the native counterparts. For example, the filaggrin amino acid sequence may be functionally equivalent in terms of ability to maintain epidermal health. In some embodiments, the filaggrin amino acid sequence may have greater biological activity than their native counterparts.

[0048] The following is a discussion based upon changing of the amino acids of a polypeptide to create an equivalent, or even an improved, second-generation molecule. For example, certain amino acids may be substituted for other amino acids in a polypeptide without appreciable loss of function, such as ability to interact with an endothelial cell of a blood vessel. Since it is the interactive capacity and nature of a polypeptide that defines that polypeptide's biological functional activity, certain amino acid substitutions can be made in a polypeptide sequence and nevertheless produce a polypeptide with like properties.

[0049] In making such changes, the hydropathic index of amino acids may be considered. The importance of the hydropathic amino acid index in conferring interactive biologic function on a protein is generally understood in the art (Kyte and Doolittle, 1982). It is accepted that the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which in turn defines the interaction of the protein with other molecules, for example, enzymes, substrates, receptors, DNA, antibodies, antigens, and the like.

[0050] It also is understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity. U.S. Pat. No. 4,554,101, incorporated herein by reference, states that the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with a biological property of the protein. As detailed in U.S. Pat. No. 4,554,101, the following hydrophilicity values have been assigned to amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0.+-.1); glutamate (+3.0.+-.1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5.+-.1); alanine (-0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5); tryptophan (-3.4).

[0051] It is understood that an amino acid can be substituted for another having a similar hydrophilicity value and still produce a biologically equivalent and immunologically equivalent protein. In such changes, the substitution of amino acids whose hydrophilicity values are within .+-.2 is preferred, those that are within .+-.1 are particularly preferred, and those within .+-.0.5 are even more particularly preferred.

[0052] As outlined above, amino acid substitutions generally are based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. Exemplary substitutions that take into consideration the various foregoing characteristics are well known to those of skill in the art and include: arginine and lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine and isoleucine.

[0053] 2. Filaggrin Amino Acid Sequences

[0054] The filaggrin amino acid sequences contemplated for inclusion in the polypeptides, compositions, and methods of the present invention may be obtained from any source. For example, the filaggrin amino acid may be obtained from a natural source or may be chemically synthesized. The filaggrin amino acid sequence may be from any species. For example, it may be a mammalian filaggrin amino acid sequence. Non-limiting examples include mouse, rat, rabbit, goat, sheep, horse, cow, dog, cat, primate, or human amino acid sequence. In preferred embodiments, the filaggrin amino acid sequence is a human amino acid sequence. Non-limiting examples of filaggrin proteins are set forth in Table 2.

TABLE-US-00002 TABLE 2 Examples of Filaggrin Protein Sequences Sequence GenBank Accession No. SEQ ID NO: Filaggrin, Homo sapiens 1 Filaggrin, Homo sapiens NP_002007 2 Filaggrin, Homo sapiens AAA52454 3 Filaggrin, Homo sapiens CAI19595 4 Filaggrin, Homo sapiens P20930 5 Filaggrin, Mus musculus 6 Filaggrin, Mus musculus AAM23016 7 Filaggrin, Mus musculus AAA75559 8 Filaggrin, Mus musculus AAA37626 9 Filaggrin, Mus musculus AAA37625 10 Filaggrin, Mus musculus XP_485270 11 Filaggrin, Mus musculus P11088 12 Filaggrin, Mus musculus EDL00668.1 13 Filaggrin, Rattus norvegicus EDL87862 14 Filaggrin, Pan troglodytes XP_001134714 15 Filaggrin, Pan troglodytes XP_513808 16 Filaggrin, Bos taurus XP_001255583 17 Filaggrin, Macaca mulatta XP_001101725.1 18 Filaggrin, Macaca mulatta XP_001109011.1 19

[0055] 3. Cell Importation Signal Sequences

[0056] Any cell importation signal sequence that facilitates entry of a filaggrin amino acid sequence into a cell is contemplated as a cell importation signal sequence of the present invention. In some embodiments, the signal sequence includes a motif of two to fifteen amino acids, wherein the motif includes at least one arginine amino acid residue and at least one methionine amino acid residue. The arginine amino acid residue and the methionine amino acid residue may be consecutive residues within the motif, or they may be separated by one or more intervening amino acids. In some embodiments of the recombinant polypeptides of the present invention, the polypeptide includes more than one motif of two to fifteen amino acids, where each motif includes at least one arginine amino acid residue and at least one methionine amino acid residue. The motifs may include identical amino acid sequences or may have distinct amino acid sequences. Methionine/arginine-rich repeat motifs are discussed in Datar et al. (1993). Non-limiting examples of filaggrin proteins are set forth in Table 3.

TABLE-US-00003 TABLE 3 Examples of Cell Importation Signal Sequences Sequence SEQ ID NO: RMRRMRRMRR 23 RGRRGRRGRR 24 RRRRRRRRRR 25 RARRARRARR 26 RTRRTRRTRR 27 RSRRSRRSRR 28 RVRRVRRVRR 29 RKRRKRRKRR 30 RRRRRRR 31 RRRRRRRR 32 RRRRRRRRR 33 RRRRRRRRRRR 34 RRRRRRRRRRRR 35 RRRRRRRRRRRRR 36 RRRRRRRRRRRRRR 37 RRRRRRRRRRRRRRR 38

[0057] 4. Methods of Polypeptide Synthesis

[0058] In certain embodiments of the present invention, the polypeptide is encoded by a single recombinant nucleic acid sequence using recombinant techniques. In other embodiments, the filaggrin amino acid sequence and the cell importation signal sequence are encoded by separate nucleic acid sequences, and subsequently joined by chemical conjugation. In further embodiments, the polypeptide has been synthesized de novo.

[0059] a. Recombinant Techniques

[0060] In certain embodiments of the present invention, the chimeric polypeptide is encoded by a single recombinant polynucleotide using recombinant techniques well-known to those of ordinary skill in the art. The polynucleotide may include a sequence of additional nucleic acids that direct the expression of the chimeric polypeptide in appropriate host cells.

[0061] Due to the inherent degeneracy of the genetic code, other DNA sequences that encode substantially the same or a functionally equivalent amino acid sequence, may be used in the practice of the invention of the cloning and expression of the chimeric protein. Such DNA sequences include those capable of hybridizing to the chimeric sequences or their complementary sequences under stringent conditions. In one embodiment, the phrase "stringent conditions" as used herein refers to those hybridizing conditions that (1) employ low ionic strength and high temperature for washing, for example, 0.015 M NaCl/0.0015 M sodium citrate/0.1% SDS at 50.degree. C.; (2) employ during hybridization a denaturing agent such as formamide, for example, 50% (vol/vol) formamide with a 0.1% bovine serum albumin/0 1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM NaCl, 75 mM sodium citrate at 42.degree. C.; or (3) employ 50% formamide, 5.times.SSC (0.75 M NaCl, 0.075 M Sodium pyrophosphate, 5.times. Denhardt's solution, sonicated salmon sperm DNA (50 .mu.g/ml), 0.1% SDS, and 10% dextran sulfate at 42.degree. C., with washes at 42.degree. C. in 0.2.times.SSC and 0.1% SDS.

[0062] Altered DNA sequences that may be used in accordance with the invention include deletions, additions or substitutions of different nucleotide residues resulting in a sequence that encodes the same or a functionally equivalent polynucleotide. The polynucleotide may contain deletions, additions or substitutions of amino acid residues within a chimeric sequence, which result in a silent change thus producing a functionally equivalent chimeric polynucleotide. Such amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved, as discussed above.

[0063] The DNA sequences of the invention may be engineered in order to alter a chimeric coding sequence for a variety of ends, including but not limited to, alterations that modify processing and expression of the gene product. For example, mutations may be introduced using techniques that are well known in the art, e.g., site-directed mutagenesis, to insert new restriction sites, to alter glycosylation patterns, phosphorylation, etc.

[0064] In order to express a biologically active chimeric polypeptide, the nucleotide sequence coding for a chimeric polypeptide, or a functional equivalent, is inserted into an appropriate expression vector, i.e., a vector that contains the necessary elements for the transcription and translation of the inserted coding sequence. The chimeric gene products as well as host cells or cell lines transfected or transformed with recombinant chimeric expression vectors can be used for a variety of purposes. These include, but are not limited to, generating antibodies (i.e., monoclonal or polyclonal) that bind to epitopes of the proteins to facilitate their purification.

[0065] Methods that are well known to those skilled in the art can be used to construct expression vectors containing the chimeric coding sequence and appropriate transcriptional/translational control signals. These methods include in vitro recombinant DNA techniques, synthetic techniques and in vivo recombination/genetic recombination. See, for example, the techniques described in Sambrook et al., 2001.

[0066] A variety of host-expression vector systems may be utilized to express the chimeric polypeptide coding sequence. These include but are not limited to microorganisms such as bacteria transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing the chimeric protein coding sequence; yeast transformed with recombinant yeast expression vectors containing the chimeric protein coding sequence; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing the chimeric protein coding sequence; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing the chimeric protein coding sequence; or animal cell systems. It should be noted that since most apoptosis-inducing proteins cause programmed cell death in mammalian cells, it is preferred that the chimeric protein of the invention be expressed in prokaryotic or lower eukaryotic cells. Section 6 illustrates that IL2-Bax may be efficiently expressed in E. coli.

[0067] The expression elements of each system vary in their strength and specificities. Depending on the host/vector system utilized, any of a number of suitable transcription and translation elements, including constitutive and inducible promoters, may be used in the expression vector. For example, when cloning in bacterial systems, inducible promoters such as pL of bacteriophage .lamda., plac, ptrp, ptac (ptrp-lac hybrid promoter; cytomegalovirus promoter) and the like may be used; when cloning in insect cell systems, promoters such as the baculovirus polyhedrin promoter may be used; when cloning in plant cell systems, promoters derived from the genome of plant cells (e.g., heat shock promoters; the promoter for the small subunit of RUBISCO; the promoter for the chlorophyll .alpha./.beta. binding protein) or from plant viruses (e.g., the 35S RNA promoter of CaMV; the coat protein promoter of TMV) may be used; when cloning in mammalian cell systems, promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter) may be used; when generating cell lines that contain multiple copies of the chimeric DNA, SV40-, BPV- and EBV-based vectors may be used with an appropriate selectable marker.

[0068] In bacterial systems a number of expression vectors may be advantageously selected depending upon the use intended for the chimeric polypeptide expressed. For example, when large quantities of chimeric polypeptide are to be produced, vectors that direct the expression of high levels of protein products that are readily purified may be desirable. Such vectors include but are not limited to the E. coli expression vector pUR278 (Ruther et al., 1983), in which the chimeric protein coding sequence may be ligated into the vector in frame with the lacZ coding region so that a hybrid AS-lacZ protein is produced; pIN vectors (Van Heeke and Schuster, 1989); and the like.

[0069] An alternative expression system that could be used to express chimeric polypeptide is an insect system. In one such system, Autographa californica nuclear polyhidrosis virus (AcNPV) is used as a vector to express foreign genes. The virus grows in Spodoptera frugiperda cells. The chimeric protein coding sequence may be cloned into non-essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter). Successful insertion of the chimeric polypeptide coding sequence will result in inactivation of the polyhedrin gene and production of non-occluded recombinant virus (i.e., virus lacking the proteinaceous coat coded for by the polyhedrin gene). These recombinant viruses are then used to infect Spodoptera frugiperda cells in which the inserted gene is expressed. (e.g., see Smith et al., 1983; U.S. Pat. No. 4,215,051).

[0070] Specific initiation signals may also be required for efficient translation of the inserted chimeric protein coding sequence. These signals include the ATG initiation codon and adjacent sequences. In cases where the entire chimeric gene, including its own initiation codon and adjacent sequences, is inserted into the appropriate expression vector, no additional translational control signals may be needed. However, in cases where the chimeric protein coding sequence does not include its own initiation codon, exogenous translational control signals, including the ATG initiation codon, must be provided. Furthermore, the initiation codon must be in phase with the reading frame of the chimeric protein coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see Bittner et al., 1987).

[0071] In addition, a host cell strain may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may be important for the function of the protein. The presence of consensus N-glycosylation sites in a chimeric protein may require proper modification for optimal chimeric protein function. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the chimeric protein. To this end, eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the chimeric protein may be used. Such mammalian host cells include but are not limited to CHO, VERO, BHK, HeLa, COS, MDCK, 293, W138, and the like.

[0072] For long-term, high-yield production of recombinant chimeric polypeptides, stable expression is preferred. For example, cell lines that stably express the chimeric polypeptide may be engineered. Rather than using expression vectors that contain viral originals of replication, host cells can be transformed with a chimeric coding sequence controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of foreign DNA, engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media. The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines.

[0073] A number of selection systems may be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler et al., 1977), hypoxanthine-guanine phosphoribosyltransferase (Szybalski and Szybalski, 1962), and adenine phosphoribosyltransferase (Lowy et al., 1980) genes can be employed in tk-, hgprt- or aprt-cells, respectively. Also, antimetabolite resistance can be used as the basis of selection for dhfr, which confers resistance to methotrexate (Wigler et al., 1980; O'Hare et al., 1981); gpt, which confers resistance to mycophenolic acid (Mulligan and Berg, 1981); neo, which confers resistance to the aminoglycoside G-418 (Colbere-Garapin et al., 1981); and hygro, which confers resistance to hygromycin (Santerre et al., 1984) genes. Additional selectable genes have been described, namely trpB, which allows cells to utilize indole in place of tryptophan; hisD, which allows cells to utilize histinol in place of histidine (Hartman and Mulligan, 1988); and ODC (ornithine decarboxylase) which confers resistance to the ornithine decarboxylase inhibitor, 2-(difluoromethyl)-DL-ornithine, DFMO (see McConlogue, 1986).

[0074] b. De Novo Synthesis

[0075] In an alternate embodiment of the invention, the chimeric polypeptide could be synthesized de novo in whole or in part, using chemical methods well known in the art (see, for example, Caruthers et al., 1980; Crea and Horn, 1980; and Chow and Kempe, 1981). For example, the component amino acid sequences can be synthesized by solid phase techniques, cleaved from the resin, and purified by preparative high performance liquid chromatography followed by chemical linkage to form a chimeric protein. (e.g., see Creighton, 1983). The composition of the synthetic peptides may be confirmed by amino acid analysis or sequencing (e.g., the Edman degradation procedure; see Creighton, 1983).

[0076] Polypeptide synthesis techniques are well known to those of skill in the art (see, e.g., Bodanszky et al., 1976). These synthetic methods involve the sequential addition of one or more amino acid residues or suitable protected amino acid residues to a growing peptide chain. Normally, either the amino or carboxyl group of the first amino acid residue is protected by a suitable, selectively removable protecting group. A different, selectively removable protecting group is utilized for amino acids containing a reactive side group, such as lysine.

[0077] Using solid phase synthesis as an example, the protected or derivatized amino acid is attached to an inert solid support through its unprotected carboxyl or amino group. The protecting group of the amino or carboxyl group is then selectively removed and the next amino acid in the sequence having the complementary (amino or carboxyl) group suitably protected is admixed and reacted with the residue already attached to the solid support. The protecting group of the amino or carboxyl group is then removed from this newly added amino acid residue, and the next amino acid (suitably protected) is then added, and so forth. After all the desired amino acids have been linked in the proper sequence, any remaining terminal and side group protecting groups (and solid support) are removed sequentially or concurrently, to provide the final peptide. Such protecting group moieties may be used in the course of synthesis, but they are removed before the peptides are used. Additional reactions may be necessary, as described elsewhere, to form intramolecular linkages to restrain conformation.

[0078] c. Linkers

[0079] Alternatively, the two moieties of the chimeric polypeptide produced by synthetic or recombinant methods may be conjugated by linkers according to methods well known in the art (Brinkmann and Pastan, 1994). As used herein, a "linker" is a chemical or peptide or polypeptide that links an endothelial targeting amino acid sequence with a cytotoxic amino acid squence.

[0080] The two coding sequences can be fused directly without any linker or by using a flexible polylinker, such as one composed of the pentamer Gly-Gly-Gly-Gly-Ser (SEQ ID NO:39) repeated 1 to 3 times. Such linker has been used in constructing single chain antibodies (scFv) by being inserted between V.sub.H and V.sub.L (Bird et al., 1988; Huston et al., 1988). The linker is designed to enable the correct interaction between two beta-sheets forming the variable region of the single chain antibody. Other linkers which may be used include Glu-Gly-Lys-Ser-Ser-Gly-Ser-Gly-Ser-Glu-Ser-Lys-Val-Asp (SEQ ID NO:40) (Chaudhary et al., 1990) and Lys-Glu-Ser-Gly-Ser-Val-Ser-Ser-Glu-Gln-Leu-Ala-Gln-Phe-Arg-Ser-Leu-Asp (SEQ ID NO:41) (Bird et al., 1988).

[0081] Multiple peptides or polypeptides may also be joined via a biologically-releasable bond, such as a selectively-cleavable linker or amino acid sequence. For example, peptide linkers that include a cleavage site for an enzyme preferentially located or active within a tumor environment are contemplated. Exemplary forms of such peptide linkers are those that are cleaved by urokinase, plasmin, thrombin, Factor IXa, Factor Xa, or a metallaproteinase, such as collagenase, gelatinase, or stromelysin. Alternatively, polypeptides may be joined to an adjuvant. It can be considered as a general guideline that any linker known to those of ordinary skill in the art is contemplated for use as a linker in the present invention.

[0082] It is contemplated that cross-linkers may be implemented with the polypeptide molecules of the present invention. Cross-linking reagents are used to form molecular bridges that tie together functional groups of two different molecules, e.g., a stablizing and coagulating agent. To link two different polypeptides in a step-wise manner, hetero-bifunctional cross-linkers can be used that eliminate unwanted homopolymer formation. Bifunctional cross-linking reagents have been extensively used for a variety of purposes including preparation of affinity matrices, modification and stabilization of diverse structures, identification of binding sites, and structural studies. In the context of the invention, such cross-linker may be used to stabilize the polypeptide or to render it more useful as a therapeutic, for example, by improving the polypeptide's targeting capability or overall efficacy. Cross-linkers may also be cleavable, such as disulfides, acid-sensitive linkers, and others. Homobifunctional reagents that carry two identical functional groups proved to be highly efficient in inducing cross-linking between identical and different macromolecules or subunits of a macromolecule, and linking of polypeptides to specific binding sites on binding partners. Heterobifunctional reagents contain two different functional groups. By taking advantage of the differential reactivities of the two different functional groups, cross-linking can be controlled both selectively and sequentially. The bifunctional cross-linking reagents can be divided according to the specificity of their functional groups, e.g., amino, sulfhydryl, guanidino, indole, carboxyl specific groups. Of these, reagents directed to free amino groups have become especially popular because of their commercial availability, ease of synthesis and the mild reaction conditions under which they can be applied. A majority of heterobifunctional cross-linking reagents contains a primary amine-reactive group and a thiol-reactive group.

[0083] In another example, heterobifunctional cross-linking reagents and methods of using the cross-linking reagents are described (U.S. Pat. No. 5,889,155, specifically incorporated herein by reference in its entirety). The cross-linking reagents combine a nucleophilic hydrazide residue with an electrophilic maleimide residue, allowing coupling in one example, of aldehydes to free thiols. The cross-linking reagent can be modified to cross-link various functional groups and is thus useful for cross-linking polypeptides and sugars. In instances where a particular polypeptide, such as gelonin, does not contain a residue amenable for a given cross-linking reagent in its native sequence, conservative genetic or synthetic amino acid changes in the primary sequence can be utilized. Table 4 details certain exemplary hetero-bifunctional cross-linkers considered useful in the present invention.

TABLE-US-00004 TABLE 4 HETERO-BIFUNCTIONAL CROSS-LINKERS Spacer Arm Advantages and Length\after Linker Reactive Toward Applications cross-linking SMPT Primary amines Greater stability 11.2 A Sulfhydryls SPDP Primary amines Thiolation 6.8 A Sulfhydryls Cleavable cross-linking LC-SPDP Primary amines Extended spacer arm 15.6 A Sulfhydryls Sulfo-LC- Primary amines Extended spacer arm 15.6 A SPDP Sulfhydryls Water-soluble SMCC Primary amines Stable maleimide 11.6 A Sulfhydryls reactive group Enzyme-antibody conjugation Hapten-carrier protein conjugation Sulfo- Primary amines Stable maleimide 11.6 A reactive group SMCC Sulfhydryls Water-soluble Enzyme-antibody conjugation MBS Primary amines Enzyme-antibody 9.9 A Sulfhydryls conjugation Hapten-carrier protein conjugation Sulfo- Primary amines Water-soluble 9.9 A MBS Sulfhydryls SIAB Primary amines Enzyme-antibody 10.6 A Sulfhydryls conjugation Sulfo- Primary amines Water-soluble 10.6 A SIAB Sulfhydryls SMPB Primary amines Extended spacer arm 14.5 A Sulfhydryls Enzyme-antibody conjugation Sulfo- Primary amines Extended spacer arm 14.5 A SMPB Sulfhydryls Water-soluble EDC/Sulfo- Primary amines Hapten-Carrier 0 NHS Carboxyl groups conjugation ABH Carbohydrates Reacts with sugar groups 11.9 A Nonselective

[0084] d. Protein Purification

[0085] In certain embodiments of the present invention, the polypeptide has been purified. Generally, "purified" will refer to a polypeptide composition that has been subjected to fractionation to remove various other components, and which composition substantially retains its expressed biological activity. Where the term "substantially purified" is used, this designation will refer to a composition in which the polypeptide or peptide forms the major component of the composition, such as constituting about 50% to about 99.9% or more of the proteins in the composition.

[0086] Various methods for quantifying the degree of purification of the polypeptide will be known to those of skill in the art in light of the present disclosure. Exemplary techniques include high performance liquid chromatography, ion exchange chromatography, gel electrophoresis, affinity chromatography and the like. The actual conditions used to purify a particular polypeptide will depend, in part, on factors such as net charge, hydrophobicity, hydrophilicity, etc., and will be apparent to those having skill in the art.

[0087] For affinity chromatography purification, any antibody that specifically binds the polypeptide may be used. For the production of antibodies, various host animals, including but not limited to rabbits, mice, rats, etc., may be immunized by injection with a chimeric protein or a fragment thereof. The protein may be attached to a suitable carrier, such as bovine serum albumin (BSA), by means of a side chain functional group or linkers attached to a side chain functional group. Various adjuvants may be used to increase the immunological response, depending on the host species, including but not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhold limpet hemocyanin, dinitrophenol, and potentially useful human adjuvants such as BCG (bacilli Calmetter-Guerin) and Corynebacterium parvum.

[0088] Monoclonal antibodies to a chimeric polypeptide may be prepared using any technique that provides for the production of antibody molecules by continuous cell lines in culture. These include but are not limited to the hybridoma technique originally described by Kohler and Milstein (1975), the human B-cell hybridoma technique (Cote et al., 1983), and the EBV-hybridoma technique (Cole et al., 1985). In addition, techniques developed for the production of "chimeric antibodies" (Morrison et al., 1984; Neuberger et al., 1984; Takeda et al., 1985) by splicing the genes from a mouse antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity can be used. Alternatively, techniques described for the production of single chain antibodies (U.S. Pat. No. 4,946,778) can be adapted to produce chimeric protein-specific single chain antibodies for chimeric protein purification and detection.

B. NUCLEIC ACIDS

[0089] The present invention includes nucleic acids that include a nucleic acid sequence that encodes a recombinant polypeptide of the present invention.

[0090] The term "nucleic acid" is well known in the art. A "nucleic acid" as used herein will generally refer to a molecule (i.e., a strand) of DNA, RNA or a derivative or analog thereof, comprising a nucleobase. A nucleobase includes, for example, a naturally occurring purine or pyrimidine base found in DNA (e.g., an adenine "A," a guanine "G," a thymine "T" or a cytosine "C") or RNA (e.g., an A, a G, an uracil "U" or a C). The term "nucleic acid" encompass the terms "oligonucleotide" and "polynucleotide," each as a subgenus of the term "nucleic acid." The term "oligonucleotide" refers to a molecule of between 3 and about 100 nucleobases in length. The term "polynucleotide" refers to at least one molecule of greater than about 100 nucleobases in length.

[0091] These definitions refer to a single-stranded or double-stranded nucleic acid molecule. Double stranded nucleic acids are formed by fully complementary binding, although in some embodiments a double stranded nucleic acid may formed by partial or substantial complementary binding. Thus, a nucleic acid may encompass a double-stranded molecule that comprises one or more complementary strand(s) or "complement(s)" of a particular sequence, typically comprising a molecule. As used herein, a single stranded nucleic acid may be denoted by the prefix "ss" and a double stranded nucleic acid by the prefix "ds".

[0092] 1. Nucleobases

[0093] As used herein a "nucleobase" refers to a heterocyclic base, such as for example a naturally occurring nucleobase (i.e., an A, T, G, C or U) found in at least one naturally occurring nucleic acid (i.e., DNA and RNA), and naturally or non-naturally occurring derivative(s) and analogs of such a nucleobase. A nucleobase generally can form one or more hydrogen bonds ("anneal" or "hybridize") with at least one naturally occurring nucleobase in manner that may substitute for naturally occurring nucleobase pairing (e.g., the hydrogen bonding between A and T, G and C, and A and U).

[0094] "Purine" and/or "pyrimidine" nucleobase(s) encompass naturally occurring purine and/or pyrimidine nucleobases and also derivative(s) and analog(s) thereof, including but not limited to, those a purine or pyrimidine substituted by one or more of an alkyl, caboxyalkyl, amino, hydroxyl, halogen (i.e., fluoro, chloro, bromo, or iodo), thiol or alkylthiol moeity. Preferred alkyl (e.g., alkyl, caboxyalkyl, etc.) moeities comprise of from about 1, about 2, about 3, about 4, about 5, to about 6 carbon atoms. A nucleobase may be comprised in a nucleside or nucleotide, using any chemical or natural synthesis method described herein or known to one of ordinary skill in the art.

[0095] 2. Nucleosides

[0096] As used herein, a "nucleoside" refers to an individual chemical unit comprising a nucleobase covalently attached to a nucleobase linker moiety. A non-limiting example of a "nucleobase linker moiety" is a sugar comprising 5-carbon atoms (i.e., a "5-carbon sugar"), including but not limited to a deoxyribose, a ribose, an arabinose, or a derivative or an analog of a 5-carbon sugar. Non-limiting examples of a derivative or an analog of a 5-carbon sugar include a 2'-fluoro-2'-deoxyribose or a carbocyclic sugar where a carbon is substituted for an oxygen atom in the sugar ring.

[0097] Different types of covalent attachment(s) of a nucleobase to a nucleobase linker moiety are known in the art. By way of non-limiting example, a nucleoside comprising a purine (i.e., A or G) or a 7-deazapurine nucleobase typically covalently attaches the 9 position of a purine or a 7-deazapurine to the 1'-position of a 5-carbon sugar. In another non-limiting example, a nucleoside comprising a pyrimidine nucleobase (i.e., C, T or U) typically covalently attaches a 1 position of a pyrimidine to a 1'-position of a 5-carbon sugar (Kornberg and Baker, 1992).

[0098] 3. Nucleotides

[0099] As used herein, a "nucleotide" refers to a nucleoside further comprising a "backbone moiety". A backbone moiety generally covalently attaches a nucleotide to another molecule comprising a nucleotide, or to another nucleotide to form a nucleic acid. The "backbone moiety" in naturally occurring nucleotides typically comprises a phosphorus moiety, which is covalently attached to a 5-carbon sugar. The attachment of the backbone moiety typically occurs at either the 3'- or 5'-position of the 5-carbon sugar. However, other types of attachments are known in the art, particularly when a nucleotide comprises derivatives or analogs of a naturally occurring 5-carbon sugar or phosphorus moiety.

[0100] 4. Nucleic Acid Analogs

[0101] A nucleic acid may comprise, or be composed entirely of, a derivative or analog of a nucleobase, a nucleobase linker moiety and/or backbone moiety that may be present in a naturally occurring nucleic acid. As used herein a "derivative" refers to a chemically modified or altered form of a naturally occurring molecule, while the terms "mimic" or "analog" refer to a molecule that may or may not structurally resemble a naturally occurring molecule or moiety, but possesses similar functions. As used herein, a "moiety" generally refers to a smaller chemical or molecular component of a larger chemical or molecular structure. Nucleobase, nucleoside and nucleotide analogs or derivatives are well known in the art, and have been described (see for example, Scheit, 1980, incorporated herein by reference).

[0102] Additional non-limiting examples of nucleosides, nucleotides, or nucleic acids comprising 5-carbon sugar and/or backbone moiety derivatives or analogs, include those in U.S. Pat. No. 5,681,947 which describes oligonucleotides comprising purine derivatives that form triple helixes with and/or prevent expression of dsDNA; U.S. Pat. Nos. 5,652,099 and 5,763,167 which describe nucleic acids incorporating fluorescent analogs of nucleosides found in DNA or RNA, particularly for use as flourescent nucleic acids probes; U.S. Pat. No. 5,614,617 which describes oligonucleotide analogs with substitutions on pyrimidine rings that possess enhanced nuclease stability; U.S. Pat. Nos. 5,670,663, 5,872,232 and 5,859,221 which describe oligonucleotide analogs with modified 5-carbon sugars (i.e., modified 2'-deoxyfuranosyl moieties) used in nucleic acid detection; U.S. Patent 5,446,137 which describes oligonucleotides comprising at least one 5-carbon sugar moiety substituted at the 4' position with a substituent other than hydrogen that can be used in hybridization assays; U.S. Pat. No. 5,886,165 which describes oligonucleotides with both deoxyribonucleotides with 3'-5' internucleotide linkages and ribonucleotides with 2'-5' internucleotide linkages; U.S. Pat. No. 5,714,606 which describes a modified internucleotide linkage wherein a 3'-position oxygen of the internucleotide linkage is replaced by a carbon to enhance the nuclease resistance of nucleic acids; U.S. Pat. No. 5,672,697 which describes oligonucleotides containing one or more 5' methylene phosphonate internucleotide linkages that enhance nuclease resistance; U.S. Pat. Nos. 5,466,786 and 5,792,847 which describe the linkage of a substituent moeity which may comprise a drug or label to the 2' carbon of an oligonucleotide to provide enhanced nuclease stability and ability to deliver drugs or detection moieties; U.S. Pat. No. 5,223,618 which describes oligonucleotide analogs with a 2 or 3 carbon backbone linkage attaching the 4' position and 3' position of adjacent 5-carbon sugar moiety to enhanced cellular uptake, resistance to nucleases and hybridization to target RNA; U.S. Pat. No. 5,470,967 which describes oligonucleotides comprising at least one sulfamate or sulfamide internucleotide linkage that are useful as nucleic acid hybridization probe; U.S. Pat. Nos. 5,378,825, 5,777,092, 5,623,070, 5,610,289 and 5,602,240 which describe oligonucleotides with three or four atom linker moeity replacing phosphodiester backbone moeity used for improved nuclease resistance, cellular uptake and regulating RNA expression; U.S. Pat. No. 5,858,988 which describes hydrophobic carrier agent attached to the 2'-O position of oligonuceotides to enhanced their membrane permeability and stability; U.S. Pat. No. 5,214,136 which describes olignucleotides conjugated to anthraquinone at the 5' terminus that possess enhanced hybridization to DNA or RNA; enhanced stability to nucleases; U.S. Pat. No. 5,700,922 which describes PNA-DNA-PNA chimeras wherein the DNA comprises 2'-deoxy-erythro-pentofuranosyl nucleotides for enhanced nuclease resistance, binding affinity, and ability to activate RNase H; and U.S. Pat. No. 5,708,154 which describes RNA linked to a DNA to form a DNA-RNA hybrid.

[0103] 5. Polyether Nucleic Acids

[0104] In certain embodiments, it is contemplated that a nucleic acid comprising a derivative or analog of a nucleoside or nucleotide may be used in the methods and compositions of the invention. A non-limiting example is a "polyether nucleic acid", described in U.S. Pat. No. 5,908,845, incorporated herein by reference. In a polyether nucleic acid, one or more nucleobases are linked to chiral carbon atoms in a polyether backbone.

[0105] 6. Preparation of Nucleic Acids

[0106] A nucleic acid may be made by any technique known to one of ordinary skill in the art, such as chemical synthesis, enzymatic production or biological production. Non-limiting examples of a synthetic nucleic acid (e.g., a synthetic oligonucleotide), include a nucleic acid made by in vitro chemically synthesis using phosphotriester, phosphite or phosphoramidite chemistry and solid phase techniques such as described in EP 266,032, incorporated herein by reference, or via deoxynucleoside H-phosphonate intermediates as described by Froehler et al., 1986 and U.S. Pat. No. 5,705,629, each incorporated herein by reference. In the methods of the present invention, one or more oligonucleotide may be used. Various different mechanisms of oligonucleotide synthesis have been disclosed in for example, U.S. Pat. Nos. 4,659,774, 4,816,571, 5,141,813, 5,264,566, 4,959,463, 5,428,148, 5,554,744, 5,574,146, 5,602,244, each of which is incorporated herein by reference.

[0107] A non-limiting example of an enzymatically produced nucleic acid include one produced by enzymes in amplification reactions such as PCR.TM. (see for example, U.S. Pat. Nos. 4,683,202 and 4,682,195, each incorporated herein by reference), or the synthesis of an oligonucleotide described in U.S. Pat. No. 5,645,897, incorporated herein by reference. A non-limiting example of a biologically produced nucleic acid includes a recombinant nucleic acid produced (i.e., replicated) in a living cell, such as a recombinant DNA vector replicated in bacteria (see for example, Sambrook et al. 2001, incorporated herein by reference).

[0108] 7. Purification of Nucleic Acids

[0109] A nucleic acid may be purified on polyacrylamide gels, cesium chloride centrifugation gradients, or by any other means known to one of ordinary skill in the art (see for example, Sambrook et al., 2001, incorporated herein by reference).

[0110] In certain embodiments, the present invention concerns a nucleic acid that is an isolated nucleic acid. As used herein, the term "isolated nucleic acid" refers to a nucleic acid molecule (e.g., an RNA or DNA molecule) that has been isolated free of, or is otherwise free of, the bulk of the total genomic and transcribed nucleic acids of one or more cells. In certain embodiments, "isolated nucleic acid" refers to a nucleic acid that has been isolated free of, or is otherwise free of, bulk of cellular components or in vitro reaction components such as for example, macromolecules such as lipids or proteins, small biological molecules, and the like.

C. LIPID PREPARATIONS

[0111] Some embodiments of the present invention concern polypeptide- or nucleic acid-containing compositions that include a lipid component. A lipid component may include one type of lipid, or more than one type of lipid.

[0112] Lipids are fatty substances which may be naturally occurring or synthetic lipids. For example, lipids include the fatty droplets that naturally occur in the cytoplasm as well as the class of compounds which are well known to those of skill in the art which contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes.

[0113] Some embodiments of the compositions of the present invention include liposomes. "Liposome" is a generic term encompassing a variety of unilamellar, multilamellar, and multivesicular lipid vehicles formed by the generation of enclosed lipid bilayers or aggregates. Liposomes may be characterized as having vesicular structures with a phospholipid bilayer membrane and an inner aqueous medium. Multilamellar liposomes have multiple lipid layers separated by aqueous medium. They form spontaneously when phospholipids are suspended in an excess of aqueous solution. The lipid components undergo self-rearrangement before the formation of closed structures and entrap water and dissolved solutes between the lipid bilayers (Ghosh and Bachhawat, 1991). However, the present invention also encompasses compositions that have different structures in solution than the normal vesicular structure. For example, the lipids may assume a micellar structure or merely exist as non-uniform aggregates of lipid molecules. Also contemplated are lipofectamine-nucleic acid complexes.

[0114] 1. Neutral Liposomes

[0115] "Neutral liposomes or lipid composition" or "non-charged liposomes or lipid composition," as used herein, are defined as liposomes or lipid compositions having one or more lipids that yield an essentially-neutral, net charge (substantially non-charged). By "essentially neutral" or "essentially non-charged", it is meant that few, if any, lipids within a given population (e.g., a population of liposomes) include a charge that is not canceled by an opposite charge of another component (e.g., fewer than 10% of components include a non-canceled charge, more preferably fewer than 5%, and most preferably fewer than 1%). In certain embodiments of the present invention, a composition may be prepared wherein the lipid component of the composition is essentially neutral but is not in the form of liposomes.

[0116] In certain embodiments, neutral liposomes or lipid compositions may include mostly lipids and/or phospholipids that are themselves neutral. In certain embodiments, amphipathic lipids may be incorporated into or used to generate neutral liposomes or lipid compositions. For example, a neutral liposome may be generated by combining positively and negatively charged lipids so that those charges substantially cancel one another. For such a liposome, few, if any, charged lipids are present whose charge is not canceled by an oppositely-charged lipid (e.g., fewer than 10% of charged lipids have a charge that is not canceled, more preferably fewer than 5%, and most preferably fewer than 1%). It is also recognized that the above approach may be used to generate a neutral lipid composition wherein the lipid component of the composition is not in the form of liposomes.

[0117] 2. Phospholipids

[0118] Lipid-containing compositions of the present invention may comprise phospholipids. In certain embodiments, a single kind or type of phospholipid may be used in the creation of lipid compositions such as liposomes (e.g., DOPC used to generate neutral liposomes). In other embodiments, more than one kind or type of phospholipid may be used.

[0119] Phospholipids include glycerophospholipids and certain sphingolipids. Phospholipids include, but are not limited to, dioleoylphosphatidylycholine ("DOPC"), egg phosphatidylcholine ("EPC"), dilauryloylphosphatidylcholine ("DLPC"), dimyristoylphosphatidylcholine ("DMPC"), dipalmitoylphosphatidylcholine ("DPPC"), distearoylphosphatidylcholine ("DSPC"), 1-myristoyl-2-palmitoyl phosphatidylcholine ("MPPC"), 1-palmitoyl-2-myristoyl phosphatidylcholine ("PMPC"), 1-palmitoyl-2-stearoyl phosphatidylcholine ("PSPC"), 1-stearoyl-2-palmitoyl phosphatidylcholine ("SPPC"), dilauryloylphosphatidylglycerol ("DLPG"), dimyristoylphosphatidylglycerol ("DMPG"), dipalmitoylphosphatidylglycerol ("DPPG"), distearoylphosphatidylglycerol ("DSPG"), distearoyl sphingomyelin ("DSSP"), distearoylphophatidylethanolamine ("DSPE"), dioleoylphosphatidylglycerol ("DOPG"), dimyristoyl phosphatidic acid ("DMPA"), dipalmitoyl phosphatidic acid ("DPPA"), dimyristoyl phosphatidylethanolamine ("DMPE"), dipalmitoyl phosphatidylethanolamine ("DPPE"), dimyristoyl phosphatidylserine ("DMPS"), dipalmitoyl phosphatidylserine ("DPPS"), brain phosphatidylserine ("BPS"), brain sphingomyelin ("BSP"), dipalmitoyl sphingomyelin ("DPSP"), dimyristyl phosphatidylcholine ("DMPC"), 1,2-distearoyl-sn-glycero-3-phosphocholine ("DAPC"), 1,2-diarachidoyl-sn-glycero-3-phosphocholine ("DBPC"), 1,2-dieicosenoyl-sn-glycero-3-phosphocholine ("DEPC"), dioleoylphosphatidylethanolamine ("DOPE"), palmitoyloeoyl phosphatidylcholine ("POPC"), palmitoyloeoyl phosphatidylethanolamine ("POPE"), lysophosphatidylcholine, lysophosphatidylethanolamine, and dilinoleoylphosphatidylcholine.

[0120] Phospholipids include, for example, phosphatidylcholines, phosphatidylglycerols, and phosphatidylethanolamines; because phosphatidylethanolamines and phosphatidyl cholines are non-charged under physiological conditions (i.e., at about pH 7), these compounds may be particularly useful for generating neutral liposomes. In certain embodiments, the phospholipid DOPC is used to produce non-charged liposomes or lipid compositions. In certain embodiments, a lipid that is not a phospholipid (e.g., a cholesterol) can also be used

[0121] Phospholipids may be from natural or synthetic sources. However, phospholipids from natural sources, such as egg or soybean phosphatidylcholine, brain phosphatidic acid, brain or plant phosphatidylinositol, heart cardiolipin and plant or bacterial phosphatidylethanolamine are not used in certain embodiments as the primary phosphatide (i.e., constituting 50% or more of the total phosphatide composition) because this may result in instability and leakiness of the resulting liposomes.

[0122] 3. Production of Liposomes

[0123] Liposomes and lipid compositions of the present invention can be made by different methods. For example, a nucleotide (e.g., siRNA) may be encapsulated in a neutral liposome using a method involving ethanol and calcium (Bailey and Sullivan, 2000). The size of the liposomes varies depending on the method of synthesis. A liposome suspended in an aqueous solution is generally in the shape of a spherical vesicle, and may have one or more concentric layers of lipid bilayer molecules. Each layer consists of a parallel array of molecules represented by the formula XY, wherein X is a hydrophilic moiety and Y is a hydrophobic moiety. In aqueous suspension, the concentric layers are arranged such that the hydrophilic moieties tend to remain in contact with an aqueous phase and the hydrophobic regions tend to self-associate. For example, when aqueous phases are present both within and without the liposome, the lipid molecules may form a bilayer, known as a lamella, of the arrangement XY-YX. Aggregates of lipids may form when the hydrophilic and hydrophobic parts of more than one lipid molecule become associated with each other. The size and shape of these aggregates will depend upon many different variables, such as the nature of the solvent and the presence of other compounds in the solution.

[0124] Lipids suitable for use according to the present invention can be obtained from commercial sources. For example, dimyristyl phosphatidylcholine ("DMPC") can be obtained from Sigma Chemical Co., dicetyl phosphate ("DCP") can be obtained from K & K Laboratories (Plainview, N.Y.); cholesterol ("Chol") can be obtained from Calbiochem-Behring; dimyristyl phosphatidylglycerol ("DMPG") and other lipids may be obtained from Avanti Polar Lipids, Inc. (Birmingham, Ala.). Stock solutions of lipids in chloroform or chloroform/methanol can be stored at about -20.degree. C. Chloroform may be used as the only solvent since it is more readily evaporated than methanol.

[0125] Liposomes within the scope of the present invention can be prepared in accordance with known laboratory techniques. In certain embodiments, liposomes are prepared by mixing liposomal lipids, in a solvent in a container (e.g., a glass, pear-shaped flask). The container will typically have a volume ten-times greater than the volume of the expected suspension of liposomes. Using a rotary evaporator, the solvent may be removed at approximately 40.degree. C. under negative pressure. The solvent may be removed within about 5 minutes to 2 hours, depending on the desired volume of the liposomes. The composition can be dried further in a desiccator under vacuum. Dried lipids can be hydrated at approximately 25-50 mM phospholipid in sterile, pyrogen-free water by shaking until all the lipid film is resuspended. The aqueous liposomes can be then separated into aliquots, each placed in a vial, lyophilized and sealed under vacuum. Liposomes can also be prepared in accordance with other known laboratory procedures.

D. COMPOSITIONS

[0126] 1. Combinations and Amounts of Ingredients

[0127] It is contemplated that the compositions of the present invention may include number of combinations of the polypeptides and nucleic acids disclosed throughout this specification. Additionally, the compositions can include any number of combinations of additional ingredients described throughout this specification. The concentrations of the polypeptides, nucleic acids, and additional ingredients can vary. In non-limiting embodiments, for example, the compositions can include in their final form, for example, at least about 0.0001%, 0.0002%, 0.0003%, 0.0004%, 0.0005%, 0.0006%, 0.0007%, 0.0008%, 0.0009%, 0.0010%, 0.0011%, 0.0012%, 0.0013%, 0.0014%, 0.0015%, 0.0016%, 0.0017%, 0.0018%, 0.0019%, 0.0020%, 0.0021%, 0.0022%, 0.0023%, 0.0024%, 0.0025%, 0.0026%, 0.0027%, 0.0028%, 0.0029%, 0.0030%, 0.0031%, 0.0032%, 0.0033%, 0.0034%, 0.0035%, 0.0036%, 0.0037%, 0.0038%, 0.0039%, 0.0040%, 0.0041%, 0.0042%, 0.0043%, 0.0044%, 0.0045%, 0.0046%, 0.0047%, 0.0048%, 0.0049%, 0.0050%, 0.0051%, 0.0052%, 0.0053%, 0.0054%, 0.0055%, 0.0056%, 0.0057%, 0.0058%, 0.0059%, 0.0060%, 0.0061%, 0.0062%, 0.0063%, 0.0064%, 0.0065%, 0.0066%, 0.0067%, 0.0068%, 0.0069%, 0.0070%, 0.0071%, 0.0072%, 0.0073%, 0.0074%, 0.0075%, 0.0076%, 0.0077%, 0.0078%, 0.0079%, 0.0080%, 0.0081%, 0.0082%, 0.0083%, 0.0084%, 0.0085%, 0.0086%, 0.0087%, 0.0088%, 0.0089%, 0.0090%, 0.0091%, 0.0092%, 0.0093%, 0.0094%, 0.0095%, 0.0096%, 0.0097%, 0.0098%, 0.0099%, 0.0100%, 0.0200%, 0.0250%, 0.0275%, 0.0300%, 0.0325%, 0.0350%, 0.0375%, 0.0400%, 0.0425%, 0.0450%, 0.0475%, 0.0500%, 0.0525%, 0.0550%, 0.0575%, 0.0600%, 0.0625%, 0.0650%, 0.0675%, 0.0700%, 0.0725%, 0.0750%, 0.0775%, 0.0800%, 0.0825%, 0.0850%, 0.0875%, 0.0900%, 0.0925%, 0.0950%, 0.0975%, 0.1000%, 0.1250%, 0.1500%, 0.1750%, 0.2000%, 0.2250%, 0.2500%, 0.2750%, 0.3000%, 0.3250%, 0.3500%, 0.3750%, 0.4000%, 0.4250%, 0.4500%, 0.4750%, 0.5000%, 0.5250%, 0.550%, 0.5750%, 0.6000%, 0.6250%, 0.6500%, 0.6750%, 0.7000%, 0.7250%, 0.7500%, 0.7750%, 0.8000%, 0.8250%, 0.8500%, 0.8750%, 0.9000%, 0.9250%, 0.9500%, 0.9750%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% or more, or any range or integer derivable therein, of at least one of the polypeptides, nucleic acids, or other ingredients. In non-limiting aspects, the percentage of such ingredients can be calculated by weight or volume of the total weight of the compositions. The concentrations can vary depending on the desired effect of the compositions or on the product into which the compositions are incorporated.

[0128] 2. Composition Vehicles

[0129] The compositions of the present invention can be formulated into all types of vehicles. Non-limiting examples of suitable vehicles include emulsions (e.g., water-in-oil, water-in-oil-in-water, oil-in-water, oil-in-water-in-oil, oil-in-water-in-silicone emulsions), creams, lotions, solutions (both aqueous and hydro-alcoholic), anhydrous bases (such as lip sticks, powders), gels, and ointments or by other method or any combination of the forgoing as would be known to one of ordinary skill in the art. Variations and other appropriate vehicles will be apparent to the skilled artisan and are appropriate for use in the present invention. In certain aspects, the concentrations and combinations of the ingredients be selected in such a way that the combinations are chemically compatible and do not form complexes which precipitate from the finished product.

[0130] It is also contemplated that the polypeptides and polynucleotides of the present invention and additional ingredients identified throughout this specification can be encapsulated for delivery to a target area such as skin. Non-limiting examples of encapsulation techniques include the use of liposomes, vesicles, and/or nanoparticles (e.g., biodegradable and non-biodegradable colloidal particles comprising polymeric materials in which the ingredient is trapped, encapsulated, and/or absorbed-examples include nanospheres, nanocapsules, and liposomes) that can be used as delivery vehicles to deliver such ingredients to skin (see, e.g., U.S. Pat. Nos. 6,387,398; 6,203,802; 5,411,744).

[0131] Also contemplated are pharmaceutically-acceptable or pharmacologically-acceptable compositions. The phrase "pharmaceutically-acceptable" or "pharmacologically-acceptable" includes compositions that do not produce an allergic or similar untoward reaction when administered to a human Typically, such compositions are prepared either as topical compositions, liquid solutions or suspensions, solid forms suitable for solution in, or suspension in, liquid prior to use can also be prepared. Routes of administration can vary with the location and nature of the condition to be treated, and include, e.g., topical, inhalation, intradermal, transdermal, parenteral, intravenous, intramuscular, intranasal, subcutaneous, percutaneous, intratracheal, intraperitoneal, intratumoral, perfusion, lavage, direct injection, and oral administration and formulation.

[0132] 3. Products

[0133] The compositions of the present invention can be incorporated into products. Non-limiting examples of products include skin care products, cosmetic products, food-based products, pharmaceutical products, etc. By way of example only, non-limiting skin care products include sunscreen products, sunless skin tanning products, hair products, fingernail products, moisturizing creams, moisturizing lotions, skin benefit creams and lotions, softeners, day lotions, gels, ointments, lipsticks, or other known skin care products or applications. Additionally, the cosmetic products can be formulated as leave-on or rinse-off products.

[0134] 4. Additional Ingredients

[0135] Compositions of the present invention can optionally include additional ingredients. Non-limiting examples of additional ingredients include pharmaceutical ingredients and cosmetic ingredients (both active and non-active).

[0136] a. Pharmaceutical Ingredients

[0137] Pharmaceutical ingredients are also contemplated as being useful with the compositions of the present invention. Non-limiting examples of pharmaceutical ingredients include analgesics, anesthetics, antihistamines, anti-inflammatory agents including non-steroidal anti-inflammatory drugs, antibiotics, antifungals, antivirals, antimicrobials, anti-cancer actives, scabicides, pediculicides, antineoplastics, antiperspirants, antipruritics, antipsoriatic agents, antiseborrheic agents, biologically active proteins and peptides, burn treatment agents, cauterizing agents, depigmenting agents, depilatories, diaper rash treatment agents, enzymes, hair growth stimulants, hair growth retardants including DFMO and its salts and analogs, hemostatics, kerotolytics, canker sore treatment agents, cold sore treatment agents, dental and periodontal treatment agents, photosensitizing actives, skin protectant/barrier agents, steroids including hormones and corticosteroids, sunburn treatment agents, sunscreens, transdermal actives, nasal actives, vaginal actives, wart treatment agents, wound treatment agents, wound healing agents, etc.

[0138] Other pharmaceutical agents contemplated for inclusion in the compositions of the present invention include agents that can be applied in the treatment of ichthyosis vulgaris and atopic dermatitis. Examples include alpha hydroxy acids such as lactic and glycolic acid, retinoids, other vitamin A derivatives, calcineurin inhibitors, cyclosporine, interferon gamma-lb, or a topical or oral corticosteroid.

[0139] b. Cosmetic Ingredients

[0140] The CTFA International Cosmetic Ingredient Dictionary and Handbook (2004) describes a wide variety of non-limiting cosmetic ingredients that can be used in the context of the present invention. Examples of these ingredient classes include: fragrances (artificial and natural), dyes and color ingredients (e.g., Blue 1, Blue 1 Lake, Red 40, titanium dioxide, D&C blue no. 4, D&C green no. 5, D&C orange no. 4, D&C red no. 17, D&C red no. 33, D&C violet no. 2, D&C yellow no. 10, and D&C yellow no. 11), adsorbents, emulsifiers, stabilizers, lubricants, solvents, moisturizers (including, e.g., emollients, humectants, film formers, occlusive agents, and agents that affect the natural moisturization mechanisms of the skin), exfoliating agents, water-repellants, UV absorbers (physical and chemical absorbers such as paraaminobenzoic acid ("PABA") and corresponding PABA derivatives, titanium dioxide, zinc oxide, etc.), essential oils, vitamins (e.g., A, B, C, D, E, and K), trace metals (e.g., zinc, calcium and selenium), anti-irritants (e.g., steroids and non-steroidal anti-inflammatories), botanical extracts (e.g., aloe vera, chamomile, cucumber extract, ginkgo biloba, ginseng, and rosemary), anti-microbial agents, antioxidants (e.g., BHT and tocopherol), chelating agents (e.g., disodium EDTA and tetrasodium EDTA), preservatives (e.g., methylparaben and propylparaben), pH adjusters (e.g., sodium hydroxide and citric acid), absorbents (e.g., aluminum starch octenylsuccinate, kaolin, corn starch, oat starch, cyclodextrin, talc, and zeolite), skin bleaching and lightening agents (e.g., hydroquinone and niacinamide lactate), humectants (e.g., glycerin, propylene glycol, butylene glycol, pentylene glycol, sorbitol, urea, and manitol), exfoliants (e.g., alpha-hydroxyacids, and beta-hydroxyacids such as lactic acid, glycolic acid, and salicylic acid; and salts thereof) waterproofing agents (e.g., magnesium/aluminum hydroxide stearate), skin conditioning agents (e.g., aloe extracts, allantoin, bisabolol, ceramides, dimethicone, hyaluronic acid, and dipotassium glycyrrhizate), thickening agents (e.g., substances which that can increase the viscosity of a composition such as carboxylic acid polymers, crosslinked polyacrylate polymers, polyacrylamide polymers, polysaccharides, and gums), and silicone containing compounds (e.g., silicone oils and polyorganosiloxanes).

E. DISEASES TO BE TREATED OR PREVENTED

[0141] The diseases or disorders contemplated for treatment or prevention using the polynucleotides and polypeptides of the present invention include any disease or disorder where increase in intracellular filaggrin is known or suspected to be of benefit. Non-limiting examples of such diseases include diseases or disorders of the skin. The disease or disorder may be dry skin, peeling skin, scaling skin, inflamed skin, cracked skin, chapped skin, acne, calluses, corns, canker sores, carbuncles, cellulitis, cold sores, dandruff, dermatitis, eczema, atopic dermatitis, contact dermatitis, seborrhoeic dermatitis, cradle cap, nummular dermatitis, stasis dermatitis, perioral dermatitis, dermatitis herpetiformis, epidermolysis bullosa, erythrasma, erysipelas, folliculitis, herpes infection, impetigo, ichthyosis, hyperhidrosis, jock itch, keloid, keratoacanthoma, actinic keratosis, keratosis pilaris, seborrheic keratosis, hyperkeratosis, lichen planus, pemphigus, photosensitivity, pityriasis rosea, psoriasis, rosacea, scabies, scleroderma, sebacious cyst, shingles, basal cell carcinoma, squamous cell carcinoma, and warts.

F. KITS

[0142] Kits are also contemplated as being used in certain aspects of the present invention. For instance, a polypeptide or nucleic acid of the present invention can be included in a kit. A kit can include a sealed container. Non-limiting examples of containers include a bottle, a metal tube, a laminate tube, a plastic tube, a dispenser, a pressurized container, a barrier container, a package, a compartment, a lipstick container, a compact container, cosmetic pans that can hold cosmetic compositions, or other types of containers such as injection or blow-molded plastic containers into which the dispersions or compositions or desired bottles, dispensers, or packages are retained. Other examples of containers include glass or plastic vials or bottles. The kit and/or container can include indicia on its surface. The indicia, for example, can be a word, a phrase, an abbreviation, a picture, or a symbol.

[0143] The containers can dispense a pre-determined amount of a composition of the present invention. In other embodiments, the container can be squeezed (e.g., metal, laminate, or plastic tube) to dispense a desired amount of the composition. The composition can be dispensed as a spray, an aerosol, a liquid, a fluid, or a semi-solid. The containers can have spray, pump, or squeeze mechanisms. A kit can also include instructions for using the kit and/or compositions. Instructions can include an explanation of how to apply, administer, use, and maintain the compositions.

G. COMBINATION TREATMENTS

[0144] In order to increase the effectiveness of polypeptide of the present invention, or expression construct coding therefor, it may be desirable to combine these compositions with other agents effective in the treatment or prevention of a disease or disorder where a filaggrin polypeptide may be of benefit. For example, the chimeric polypeptides of the present invention can be administered in conjunction with other treatment of a skin disease such as atopic dermatitis or ichthyosis vulgaris. Non-limiting examples of these diseases or conditions are as set forth above.

[0145] The therapy may precede or follow the other agent treatment by intervals ranging from minutes to weeks. The therapies may be administered concurrently. In embodiments where the second therapy is applied separately, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the two therapies would still be able to exert an advantageously combined effect on the cell. In such instances, it is contemplated that one may administer both therapies within about 12-24 h of each other and, more preferably, within about 6-12 h of each other. In some situations, it may be desirable to extend the time period for treatment significantly, however, where several d (2, 3, 4, 5, 6 or 7) to several wk (1, 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations.

[0146] Various combinations may be employed, the polypeptide or polynucleotide of the present invention is "A" and the secondary agent is "B":

TABLE-US-00005 A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A

[0147] Administration of therapeutic agents and compositions of the present invention to a subject will follow general protocols for the administration of therapeutic agents, taking into account the toxicity, if any. It is expected that the treatment cycles would be repeated as necessary. It also is contemplated that various standard therapies may be applied in combination with the polypeptides and polynucleotides of the present invention. Non-limiting examples include the pharmaceutical agents set forth above. Other examples include procedures such as dermabrasion, laser therapy, laser resurfacing, ultraviolet treatment, and skin grafting.

H. EXAMPLES

[0148] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1

Treatment of Mouse Skin with Recombinant Filaggrin

[0149] The FLG protein was isolated, and several FLG peptides, consisting of partial or complete repeat regions, were created. These proteins were modified to contain a cell importation signal (made up of arginine methionine repeats--the "RMR" tag) that has been successfully employed to drive protein internalization by cells. The proteins that were synthesized include (1) human FLG with RMR tag; (2) mouse FLG with RMR tag; and (3) mouse FLG without RMR tag.

[0150] Multiple immunohistochemistry (IHC) experiments were performed to determine whether FLG with the RMR tag can be taken up by HEK 293 cells, a cell line derived from embryonic kidney cells. In these experiments, mouse FLG protein both with and without RMR importation signal were applied to HEK 293 cells at varying concentrations over varying time points. The FLG proteins were then stained with a FITC fluorescence stain and photographed under an Olympus IX81 confocal microscope. Preliminary staining experiments showed that FLG with the RMR tag are internalized into HEK 293 cells to a greater extent than FLG without the tag. In particular, MuFLG with RMR was shown to enter the cell at a higher rate than MuFLG without RMR after 4.5 hours observed and documented by imaging using an Olympus IX81 camera at 40.times.. While FLG without RMR are still taken up by the cells to a certain extent, possibly due to passive importation, higher fluorescence was found with the RMR tag than without it Immunohistochemical staining showed that while FLG plus RMR is internalized, it remains in the cytoplasm. HEK 293 cells stained with FITC (green for FLG) and DAPI (blue for nucleus) staining showed that FLG+RMR enters the cell but is absent in the nucleus after 1 hour, thus documenting the robust internalization of FLG-RMR and its localization in the cytoplasm. It is worth noting that active FLG protein (RMR.sup.-) is expressed in the cytoplasm yet absence from the nucleus in vivo.

[0151] Further studies are being conducted to examine the proteins on mouse and human keratinocyte cell lines. Cell lines being prepared include reconstructed human epidermis (RHE), a human derived keratinocyte polymer and mouse CL-177 keratinocytes. By techniques such as protein immunoblotting and immunohistochemistry, we will determine the amount and localization of FLG. To certify that FLG importation and expression can be duplicated in vivo testing of these proteins on mice is necessary.

[0152] To date, the FLG-RMR protein, mixed with a carrier solution (in this case, ABSORBASE cream), were tested on a flaky tail (ft) mouse model, a mouse model lacking the normal high molecular profilaggrin and cleaved filaggrin proteins resulting in dry, flaky skin. Initial experiments tested the efficiency of delivery and importation of the produced FLG-RMR peptides on flaky tail and normal C57B1 mice. The hair was shaved from the side of each mouse and FLG-RMR protein with carrier cream was applied. Twenty four hours after application of protein-carrier cream mixture, the treated skin area was biopsied and analyzed for changes in dermal layer phenotype and presence of FLG-RMR protein. Frozen sections from treated skin indicate that clear differences exist between the treated and untreated skin with the FLG-RMR protein as compared to the control.

[0153] Future experiments will include testing other carrier solutions and various concentrations of FLG-RMR at multiple time points to determine optimal conditions, and an experimental trial will be conducted. In this trial, flaky tail mice will be divided into four cohorts: (1) carrier with FLG protein and RMR tag; (2) carrier with FLG protein without RMR tag; (3) carrier only; (4) carrier with denatured protein and RMR tag. There will be five mice per cohort and the respective treatments will be applied on the tail, a shaved area of skin, and an unshaved area of skin after the mice have reached P60-P90. Various time points after the treatments have been applied, mice will be euthanized and dermal punch biopsies will be taken from each mouse. Immunoblotting experiments will be conducted to determine the amount of protein intake. By showing that FLG protein can be delivered via a carrier vehicle in a mouse model, clinical trials in humans are contemplated.

[0154] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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Sequence CWU 1

1

411344PRTHomo sapiens 1Arg Ser Gly Glu Thr Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val1 5 10 15Ser Thr His Glu Gln Ser Glu Ser Thr His Gly Gln Thr Ala Pro Ser 20 25 30Thr Gly Gly Arg Gln Gly Ser Arg His Glu Gln Ala Arg Asn Ser Ser 35 40 45Arg His Ser Ala Ser Gln Asp Gly Gln Asp Thr Ile Arg Gly His Pro 50 55 60Gly Ser Ser Arg Gly Gly Arg Gln Gly Ser Tyr His Glu Gln Ser Val65 70 75 80Asp Arg Ser Gly His Ser Gly Tyr His His Ser His Thr Thr Pro Gln 85 90 95Gly Arg Ser Asp Ala Ser His Gly Gln Ser Gly Pro Arg Ser Ala Ser 100 105 110Arg Gln Thr Arg Asn Glu Glu Gln Ser Gly Asp Gly Ser Arg His Ser 115 120 125Gly Ser Arg His His Glu Pro Ser Thr Arg Ala Gly Ser Ser Arg His 130 135 140Ser Gln Val Gly Gln Gly Glu Ser Ala Gly Ser Lys Thr Ser Arg Arg145 150 155 160Gln Gly Ser Ser Val Ser Gln Asp Arg Asp Ser Glu Gly His Ser Glu 165 170 175Asp Ser Glu Arg Arg Ser Glu Ser Ala Ser Arg Asn His Tyr Gly Ser 180 185 190Ala Arg Glu Gln Ser Arg His Gly Ser Arg Asn Pro Arg Ser His Gln 195 200 205Glu Asp Arg Ala Ser His Gly His Ser Ala Glu Ser Ser Arg Gln Ser 210 215 220Gly Thr Arg His Ala Glu Thr Ser Ser Gly Gly Gln Ala Ala Ser Ser225 230 235 240Gln Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His Gly Ser Arg His 245 250 255Gln Gln Ser Ala Asp Ser Ser Thr Asp Ser Gly Thr Gly Arg Arg Gln 260 265 270Asp Ser Ser Val Val Gly Asp Ser Gly Asn Arg Gly Ser Ser Gly Ser 275 280 285Gln Ala Ser Asp Ser Glu Gly His Ser Glu Glu Ser Asp Thr Gln Ser 290 295 300Val Ser Ala His Gly Gln Ala Gly Pro His Gln Gln Ser His Gln Glu305 310 315 320Ser Thr Arg Gly Gln Ser Gly Glu Arg Ser Gly Arg Ser Gly Ser Phe 325 330 335Tyr Gln Val Ser Thr His Glu Gln 34024061PRTHomo sapiens 2Met Ser Thr Leu Leu Glu Asn Ile Phe Ala Ile Ile Asn Leu Phe Lys1 5 10 15Gln Tyr Ser Lys Lys Asp Lys Asn Thr Asp Thr Leu Ser Lys Lys Glu 20 25 30Leu Lys Glu Leu Leu Glu Lys Glu Phe Arg Gln Ile Leu Lys Asn Pro 35 40 45Asp Asp Pro Asp Met Val Asp Val Phe Met Asp His Leu Asp Ile Asp 50 55 60His Asn Lys Lys Ile Asp Phe Thr Glu Phe Leu Leu Met Val Phe Lys65 70 75 80Leu Ala Gln Ala Tyr Tyr Glu Ser Thr Arg Lys Glu Asn Leu Pro Ile 85 90 95Ser Gly His Lys His Arg Lys His Ser His His Asp Lys His Glu Asp 100 105 110Asn Lys Gln Glu Glu Asn Lys Glu Asn Arg Lys Arg Pro Ser Ser Leu 115 120 125Glu Arg Arg Asn Asn Arg Lys Gly Asn Lys Gly Arg Ser Lys Ser Pro 130 135 140Arg Glu Thr Gly Gly Lys Arg His Glu Ser Ser Ser Glu Lys Lys Glu145 150 155 160Arg Lys Gly Tyr Ser Pro Thr His Arg Glu Glu Glu Tyr Gly Lys Asn 165 170 175His His Asn Ser Ser Lys Lys Glu Lys Asn Lys Thr Glu Asn Thr Arg 180 185 190Leu Gly Asp Asn Arg Lys Arg Leu Ser Glu Arg Leu Glu Glu Lys Glu 195 200 205Asp Asn Glu Glu Gly Val Tyr Asp Tyr Glu Asn Thr Gly Arg Met Thr 210 215 220Gln Lys Trp Ile Gln Ser Gly His Ile Ala Thr Tyr Tyr Thr Ile Gln225 230 235 240Asp Glu Ala Tyr Asp Thr Thr Asp Ser Leu Leu Glu Glu Asn Lys Ile 245 250 255Tyr Glu Arg Ser Arg Ser Ser Asp Gly Lys Ser Ser Ser Gln Val Asn 260 265 270Arg Ser Arg His Glu Asn Thr Ser Gln Val Pro Leu Gln Glu Ser Arg 275 280 285Thr Arg Lys Arg Arg Gly Ser Arg Val Ser Gln Asp Arg Asp Ser Glu 290 295 300Gly His Ser Glu Asp Ser Glu Arg His Ser Gly Ser Ala Ser Arg Asn305 310 315 320His His Gly Ser Ala Trp Glu Gln Ser Arg Asp Gly Ser Arg His Pro 325 330 335Arg Ser His Asp Glu Asp Arg Ala Ser His Gly His Ser Ala Asp Ser 340 345 350Ser Arg Gln Ser Gly Thr Arg His Ala Glu Thr Ser Ser Arg Gly Gln 355 360 365Thr Ala Ser Ser His Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His 370 375 380Gly Ser Gly His Gln Gln Ser Ala Asp Ser Ser Arg His Ser Ala Thr385 390 395 400Gly Arg Gly Gln Ala Ser Ser Ala Val Ser Asp Arg Gly His Arg Gly 405 410 415Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Asn Ser 420 425 430Asp Thr Gln Ser Val Ser Gly His Gly Lys Ala Gly Leu Arg Gln Gln 435 440 445Ser His Gln Glu Ser Thr Arg Gly Arg Ser Gly Glu Arg Ser Gly Arg 450 455 460Ser Gly Ser Ser Leu Tyr Gln Val Ser Thr His Glu Gln Pro Asp Ser465 470 475 480Ala His Gly Arg Thr Gly Thr Ser Thr Gly Gly Arg Gln Gly Ser His 485 490 495His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser Gln Glu Gly 500 505 510Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg Gln 515 520 525Gly Ser His His Glu Gln Ser Val Asn Arg Ser Gly His Ser Gly Ser 530 535 540His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser His Gly545 550 555 560Gln Ser Gly Ser Arg Ser Ala Ser Arg Gln Thr Arg Asn Glu Glu Gln 565 570 575Ser Gly Asp Gly Thr Arg His Ser Gly Ser Arg His His Glu Ala Ser 580 585 590Ser Gln Ala Asp Ser Ser Arg His Ser Gln Val Gly Gln Gly Gln Ser 595 600 605Ser Gly Pro Arg Thr Ser Arg Asn Gln Gly Ser Ser Val Ser Gln Asp 610 615 620Ser Asp Ser Gln Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser625 630 635 640Ala Ser Arg Asn His His Gly Ser Ala Gln Glu Gln Ser Arg Asp Gly 645 650 655Ser Arg His Pro Arg Ser His His Glu Asp Arg Ala Gly His Gly His 660 665 670Ser Ala Asp Ser Ser Arg Lys Ser Gly Thr Arg His Thr Gln Asn Ser 675 680 685Ser Ser Gly Gln Ala Ala Ser Ser His Glu Gln Ala Arg Ser Ser Ala 690 695 700Gly Glu Arg His Gly Ser Arg His Gln Leu Gln Ser Ala Asp Ser Ser705 710 715 720Arg His Ser Gly Thr Gly His Gly Gln Ala Ser Ser Ala Val Arg Asp 725 730 735Ser Gly His Arg Gly Ser Ser Gly Ser Gln Ala Thr Asp Ser Glu Gly 740 745 750His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Gly His Gly Gln Ala 755 760 765Gly His His Gln Gln Ser His Gln Glu Ser Ala Arg Asp Arg Ser Gly 770 775 780Glu Arg Ser Arg Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His785 790 795 800Lys Gln Ser Glu Ser Ser His Gly Trp Thr Gly Pro Ser Thr Gly Val 805 810 815Arg Gln Gly Ser His His Glu Gln Ala Arg Asp Asn Ser Arg His Ser 820 825 830Ala Ser Gln Asp Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser 835 840 845Arg Arg Gly Arg Gln Gly Ser His His Glu Gln Ser Val Asp Arg Ser 850 855 860Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg Ser865 870 875 880Asp Ala Ser Arg Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Thr Thr 885 890 895Arg Asn Glu Glu Gln Ser Arg Asp Gly Ser Arg His Ser Gly Ser Arg 900 905 910His His Glu Ala Ser Ser His Ala Asp Ile Ser Arg His Ser Gln Ala 915 920 925Gly Gln Gly Gln Ser Glu Gly Ser Arg Thr Ser Arg Arg Gln Gly Ser 930 935 940Ser Val Ser Gln Asp Ser Asp Ser Glu Gly His Ser Glu Asp Ser Glu945 950 955 960Arg Trp Ser Gly Ser Ala Ser Arg Asn His Arg Gly Ser Ala Gln Glu 965 970 975Gln Ser Arg His Gly Ser Arg His Pro Arg Ser His His Glu Asp Arg 980 985 990Ala Gly His Gly His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr Pro 995 1000 1005His Ala Glu Thr Ser Ser Gly Gly Gln Ala Ala Ser Ser His Glu 1010 1015 1020Gln Ala Arg Ser Ser Pro Gly Glu Arg His Gly Ser Arg His Gln 1025 1030 1035Gln Ser Ala Asp Ser Ser Arg His Ser Gly Ile Pro Arg Arg Gln 1040 1045 1050Ala Ser Ser Ala Val Arg Asp Ser Gly His Trp Gly Ser Ser Gly 1055 1060 1065Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Glu Ser Asp Thr 1070 1075 1080Gln Ser Val Ser Gly His Gly Gln Asp Gly Pro His Gln Gln Ser 1085 1090 1095His Gln Glu Ser Ala Arg Asp Trp Ser Gly Gly Arg Ser Gly Arg 1100 1105 1110Ser Gly Ser Phe Ile Tyr Gln Val Ser Thr His Glu Gln Ser Glu 1115 1120 1125Ser Ala His Gly Arg Thr Arg Thr Ser Thr Gly Arg Arg Gln Gly 1130 1135 1140Ser His His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser 1145 1150 1155Gln Glu Gly Gln Asp Thr Ile Arg Ala His Pro Gly Ser Arg Arg 1160 1165 1170Gly Gly Arg Gln Gly Ser His His Glu Gln Ser Val Asp Arg Ser 1175 1180 1185Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg 1190 1195 1200Ser Asp Ala Ser His Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg 1205 1210 1215Gln Thr Arg Lys Asp Lys Gln Ser Gly Asp Gly Ser Arg His Ser 1220 1225 1230Gly Ser Arg His His Glu Ala Ala Ser Trp Ala Asp Ser Ser Arg 1235 1240 1245His Ser Gln Val Gly Gln Glu Gln Ser Ser Gly Ser Arg Thr Ser 1250 1255 1260Arg His Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu Arg 1265 1270 1275His Ser Asp Asp Ser Glu Arg Leu Ser Gly Ser Ala Ser Arg Asn 1280 1285 1290His His Gly Ser Ser Arg Glu Gln Ser Arg Asp Gly Ser Arg His 1295 1300 1305Pro Gly Phe His Gln Glu Asp Arg Ala Ser His Gly His Ser Ala 1310 1315 1320Asp Ser Ser Arg Gln Ser Gly Thr His His Thr Glu Ser Ser Ser 1325 1330 1335His Gly Gln Ala Val Ser Ser His Glu Gln Ala Arg Ser Ser Pro 1340 1345 1350Gly Glu Arg His Gly Ser Arg His Gln Gln Ser Ala Asp Ser Ser 1355 1360 1365Arg His Ser Gly Ile Gly His Arg Gln Ala Ser Ser Ala Val Arg 1370 1375 1380Asp Ser Gly His Arg Gly Ser Ser Gly Ser Gln Val Thr Asn Ser 1385 1390 1395Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ala His 1400 1405 1410Gly Gln Ala Gly Pro His Gln Gln Ser His Lys Glu Ser Ala Arg 1415 1420 1425Gly Gln Ser Gly Glu Ser Ser Gly Arg Ser Arg Ser Phe Leu Tyr 1430 1435 1440Gln Val Ser Ser His Glu Gln Ser Glu Ser Thr His Gly Gln Thr 1445 1450 1455Ala Pro Ser Thr Gly Gly Arg Gln Gly Ser Arg His Glu Gln Ala 1460 1465 1470Arg Asn Ser Ser Arg His Ser Ala Ser Gln Asp Gly Gln Asp Thr 1475 1480 1485Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg Gln Gly Ser 1490 1495 1500Tyr His Glu Gln Ser Val Asp Arg Ser Gly His Ser Gly Tyr His 1505 1510 1515His Ser His Thr Thr Pro Gln Gly Arg Ser Asp Ala Ser His Gly 1520 1525 1530Gln Ser Gly Pro Arg Ser Ala Ser Arg Gln Thr Arg Asn Glu Glu 1535 1540 1545Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser Arg His His Glu 1550 1555 1560Pro Ser Thr Arg Ala Gly Ser Ser Arg His Ser Gln Val Gly Gln 1565 1570 1575Gly Glu Ser Ala Gly Ser Lys Thr Ser Arg Arg Gln Gly Ser Ser 1580 1585 1590Val Ser Gln Asp Arg Asp Ser Glu Gly His Ser Glu Asp Ser Glu 1595 1600 1605Arg Arg Ser Glu Ser Ala Ser Arg Asn His Tyr Gly Ser Ala Arg 1610 1615 1620Glu Gln Ser Arg His Gly Ser Arg Asn Pro Arg Ser His Gln Glu 1625 1630 1635Asp Arg Ala Ser His Gly His Ser Ala Glu Ser Ser Arg Gln Ser 1640 1645 1650Gly Thr Arg His Ala Glu Thr Ser Ser Gly Gly Gln Ala Ala Ser 1655 1660 1665Ser Gln Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His Gly Ser 1670 1675 1680Arg His Gln Gln Ser Ala Asp Ser Ser Thr Asp Ser Gly Thr Gly 1685 1690 1695Arg Arg Gln Asp Ser Ser Val Val Gly Asp Ser Gly Asn Arg Gly 1700 1705 1710Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Glu 1715 1720 1725Ser Asp Thr Gln Ser Val Ser Ala His Gly Gln Ala Gly Pro His 1730 1735 1740Gln Gln Ser His Gln Glu Ser Thr Arg Gly Gln Ser Gly Glu Arg 1745 1750 1755Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu 1760 1765 1770Gln Ser Glu Ser Ala His Gly Arg Thr Gly Pro Ser Thr Gly Gly 1775 1780 1785Arg Gln Arg Ser Arg His Glu Gln Ala Arg Asp Ser Ser Arg His 1790 1795 1800Ser Ala Ser Gln Glu Gly Gln Asp Thr Ile Arg Gly His Pro Gly 1805 1810 1815Ser Ser Arg Gly Gly Arg Gln Gly Ser His Tyr Glu Gln Ser Val 1820 1825 1830Asp Ser Ser Gly His Ser Gly Ser His His Ser His Thr Thr Ser 1835 1840 1845Gln Glu Arg Ser Asp Val Ser Arg Gly Gln Ser Gly Ser Arg Ser 1850 1855 1860Val Ser Arg Gln Thr Arg Asn Glu Lys Gln Ser Gly Asp Gly Ser 1865 1870 1875Arg His Ser Gly Ser Arg His His Glu Ala Ser Ser Arg Ala Asp 1880 1885 1890Ser Ser Arg His Ser Gln Val Gly Gln Gly Gln Ser Ser Gly Pro 1895 1900 1905Arg Thr Ser Arg Asn Gln Gly Ser Ser Val Ser Gln Asp Ser Asp 1910 1915 1920Ser Gln Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser Ala 1925 1930 1935Ser Arg Asn His Leu Gly Ser Ala Trp Glu Gln Ser Arg Asp Gly 1940 1945 1950Ser Arg His Pro Gly Ser His His Glu Asp Arg Ala Gly His Gly 1955 1960 1965His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr Arg His Thr Glu 1970 1975 1980Ser Ser Ser Arg Gly Gln Ala Ala Ser Ser His Glu Gln Ala Arg 1985 1990 1995Ser Ser Ala Gly Glu Arg His Gly Ser His His Gln Leu Gln Ser 2000 2005 2010Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Gly Gln Ala Ser 2015 2020 2025Ser Ala Val Arg Asp Ser Gly His Arg Gly Tyr Ser Gly Ser Gln 2030 2035 2040Ala Ser Asp Ser Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser 2045 2050 2055Val Ser Ala Gln Gly Lys Ala Gly Pro His Gln Gln Ser His Lys 2060 2065 2070Glu Ser Ala Arg Gly Gln Ser Gly Glu Ser Ser Gly Arg Ser Gly 2075 2080 2085Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser Thr 2090 2095 2100His Gly Gln Ser Ala Pro Ser Thr Gly Gly

Arg Gln Gly Ser His 2105 2110 2115Tyr Asp Gln Ala Gln Asp Ser Ser Arg His Ser Ala Ser Gln Glu 2120 2125 2130Gly Gln Asp Thr Ile Arg Gly His Pro Gly Pro Ser Arg Gly Gly 2135 2140 2145Arg Gln Gly Ser His Gln Glu Gln Ser Val Asp Arg Ser Gly His 2150 2155 2160Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp 2165 2170 2175Ala Ser Arg Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Lys Thr 2180 2185 2190Tyr Asp Lys Glu Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser 2195 2200 2205His His His Glu Ala Ser Ser Trp Ala Asp Ser Ser Arg His Ser 2210 2215 2220Leu Val Gly Gln Gly Gln Ser Ser Gly Pro Arg Thr Ser Arg Pro 2225 2230 2235Arg Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu Gly His Ser 2240 2245 2250Glu Asp Ser Glu Arg Arg Ser Gly Ser Ala Ser Arg Asn His His 2255 2260 2265Gly Ser Ala Gln Glu Gln Ser Arg Asp Gly Ser Arg His Pro Arg 2270 2275 2280Ser His His Glu Asp Arg Ala Gly His Gly His Ser Ala Glu Ser 2285 2290 2295Ser Arg Gln Ser Gly Thr His His Ala Glu Asn Ser Ser Gly Gly 2300 2305 2310Gln Ala Ala Ser Ser His Glu Gln Ala Arg Ser Ser Ala Gly Glu 2315 2320 2325Arg His Gly Ser His His Gln Gln Ser Ala Asp Ser Ser Arg His 2330 2335 2340Ser Gly Ile Gly His Gly Gln Ala Ser Ser Ala Val Arg Asp Ser 2345 2350 2355Gly His Arg Gly Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly 2360 2365 2370His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ala His Gly Gln 2375 2380 2385Ala Gly Pro His Gln Gln Ser His Gln Glu Ser Thr Arg Gly Arg 2390 2395 2400Ser Ala Gly Arg Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val 2405 2410 2415Ser Thr His Glu Gln Ser Glu Ser Ala His Gly Arg Thr Gly Thr 2420 2425 2430Ser Thr Gly Gly Arg Gln Gly Ser His His Lys Gln Ala Arg Asp 2435 2440 2445Ser Ser Arg His Ser Thr Ser Gln Glu Gly Gln Asp Thr Ile His 2450 2455 2460Gly His Pro Gly Ser Ser Ser Gly Gly Arg Gln Gly Ser His Tyr 2465 2470 2475Glu Gln Leu Val Asp Arg Ser Gly His Ser Gly Ser His His Ser 2480 2485 2490His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser His Gly His Ser 2495 2500 2505Gly Ser Arg Ser Ala Ser Arg Gln Thr Arg Asn Asp Glu Gln Ser 2510 2515 2520Gly Asp Gly Ser Arg His Ser Gly Ser Arg His His Glu Ala Ser 2525 2530 2535Ser Arg Ala Asp Ser Ser Gly His Ser Gln Val Gly Gln Gly Gln 2540 2545 2550Ser Glu Gly Pro Arg Thr Ser Arg Asn Trp Gly Ser Ser Phe Ser 2555 2560 2565Gln Asp Ser Asp Ser Gln Gly His Ser Glu Asp Ser Glu Arg Trp 2570 2575 2580Ser Gly Ser Ala Ser Arg Asn His His Gly Ser Ala Gln Glu Gln 2585 2590 2595Leu Arg Asp Gly Ser Arg His Pro Arg Ser His Gln Glu Asp Arg 2600 2605 2610Ala Gly His Gly His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr 2615 2620 2625Arg His Thr Gln Thr Ser Ser Gly Gly Gln Ala Ala Ser Ser His 2630 2635 2640Glu Gln Ala Arg Ser Ser Ala Gly Glu Arg His Gly Ser His His 2645 2650 2655Gln Gln Ser Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Gly 2660 2665 2670Gln Ala Ser Ser Ala Val Arg Asp Ser Gly His Arg Gly Tyr Ser 2675 2680 2685Gly Ser Gln Ala Ser Asp Asn Glu Gly His Ser Glu Asp Ser Asp 2690 2695 2700Thr Gln Ser Val Ser Ala His Gly Gln Ala Gly Ser His Gln Gln 2705 2710 2715Ser His Gln Glu Ser Ala Arg Gly Arg Ser Gly Glu Thr Ser Gly 2720 2725 2730His Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser 2735 2740 2745Glu Ser Ser His Gly Trp Thr Gly Pro Ser Thr Arg Gly Arg Gln 2750 2755 2760Gly Ser Arg His Glu Gln Ala Gln Asp Ser Ser Arg His Ser Ala 2765 2770 2775Ser Gln Asp Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser 2780 2785 2790Arg Gly Gly Arg Gln Gly Tyr His His Glu His Ser Val Asp Ser 2795 2800 2805Ser Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly 2810 2815 2820Arg Ser Asp Ala Ser Arg Gly Gln Ser Gly Ser Arg Ser Ala Ser 2825 2830 2835Arg Thr Thr Arg Asn Glu Glu Gln Ser Gly Asp Gly Ser Arg His 2840 2845 2850Ser Gly Ser Arg His His Glu Ala Ser Thr His Ala Asp Ile Ser 2855 2860 2865Arg His Ser Gln Ala Val Gln Gly Gln Ser Glu Gly Ser Arg Arg 2870 2875 2880Ser Arg Arg Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu 2885 2890 2895Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser Ala Ser Arg 2900 2905 2910Asn His His Gly Ser Ala Gln Glu Gln Leu Arg Asp Gly Ser Arg 2915 2920 2925His Pro Arg Ser His Gln Glu Asp Arg Ala Gly His Gly His Ser 2930 2935 2940Ala Asp Ser Ser Arg Gln Ser Gly Thr Arg His Thr Gln Thr Ser 2945 2950 2955Ser Gly Gly Gln Ala Ala Ser Ser His Glu Gln Ala Arg Ser Ser 2960 2965 2970Ala Gly Glu Arg His Gly Ser His His Gln Gln Ser Ala Asp Ser 2975 2980 2985Ser Arg His Ser Gly Ile Gly His Gly Gln Ala Ser Ser Ala Val 2990 2995 3000Arg Asp Ser Gly His Arg Gly Tyr Ser Gly Ser Gln Ala Ser Asp 3005 3010 3015Asn Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ala 3020 3025 3030His Gly Gln Ala Gly Ser His Gln Gln Ser His Gln Glu Ser Ala 3035 3040 3045Arg Gly Arg Ser Gly Glu Thr Ser Gly His Ser Gly Ser Phe Leu 3050 3055 3060Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser Ser His Gly Trp 3065 3070 3075Thr Gly Pro Ser Thr Arg Gly Arg Gln Gly Ser Arg His Glu Gln 3080 3085 3090Ala Gln Asp Ser Ser Arg His Ser Ala Ser Gln Tyr Gly Gln Asp 3095 3100 3105Thr Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg Gln Gly 3110 3115 3120Tyr His His Glu His Ser Val Asp Ser Ser Gly His Ser Gly Ser 3125 3130 3135His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser Arg 3140 3145 3150Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Thr Thr Arg Asn Glu 3155 3160 3165Glu Gln Ser Gly Asp Ser Ser Arg His Ser Val Ser Arg His His 3170 3175 3180Glu Ala Ser Thr His Ala Asp Ile Ser Arg His Ser Gln Ala Val 3185 3190 3195Gln Gly Gln Ser Glu Gly Ser Arg Arg Ser Arg Arg Gln Gly Ser 3200 3205 3210Ser Val Ser Gln Asp Ser Asp Ser Glu Gly His Ser Glu Asp Ser 3215 3220 3225Glu Arg Trp Ser Gly Ser Ala Ser Arg Asn His Arg Gly Ser Val 3230 3235 3240Gln Glu Gln Ser Arg His Gly Ser Arg His Pro Arg Ser His His 3245 3250 3255Glu Asp Arg Ala Gly His Gly His Ser Ala Asp Arg Ser Arg Gln 3260 3265 3270Ser Gly Thr Arg His Ala Glu Thr Ser Ser Gly Gly Gln Ala Ala 3275 3280 3285Ser Ser His Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His Gly 3290 3295 3300Ser Arg His Gln Gln Ser Ala Asp Ser Ser Arg His Ser Gly Ile 3305 3310 3315Pro Arg Gly Gln Ala Ser Ser Ala Val Arg Asp Ser Arg His Trp 3320 3325 3330Gly Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu 3335 3340 3345Glu Ser Asp Thr Gln Ser Val Ser Gly His Gly Gln Ala Gly Pro 3350 3355 3360His Gln Gln Ser His Gln Glu Ser Ala Arg Asp Arg Ser Gly Gly 3365 3370 3375Arg Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His 3380 3385 3390Glu Gln Ser Glu Ser Ala His Gly Arg Thr Arg Thr Ser Thr Gly 3395 3400 3405Arg Arg Gln Gly Ser His His Glu Gln Ala Arg Asp Ser Ser Arg 3410 3415 3420His Ser Ala Ser Gln Glu Gly Gln Asp Thr Ile Arg Gly His Pro 3425 3430 3435Gly Ser Ser Arg Arg Gly Arg Gln Gly Ser His Tyr Glu Gln Ser 3440 3445 3450Val Asp Arg Ser Gly His Ser Gly Ser His His Ser His Thr Thr 3455 3460 3465Ser Gln Gly Arg Ser Asp Ala Ser Arg Gly Gln Ser Gly Ser Arg 3470 3475 3480Ser Ala Ser Arg Gln Thr Arg Asn Asp Glu Gln Ser Gly Asp Gly 3485 3490 3495Ser Arg His Ser Trp Ser His His His Glu Ala Ser Thr Gln Ala 3500 3505 3510Asp Ser Ser Arg His Ser Gln Ser Gly Gln Gly Gln Ser Ala Gly 3515 3520 3525Pro Arg Thr Ser Arg Asn Gln Gly Ser Ser Val Ser Gln Asp Ser 3530 3535 3540Asp Ser Gln Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser 3545 3550 3555Ala Ser Arg Asn His Arg Gly Ser Ala Gln Glu Gln Ser Arg Asp 3560 3565 3570Gly Ser Arg His Pro Thr Ser His His Glu Asp Arg Ala Gly His 3575 3580 3585Gly His Ser Ala Glu Ser Ser Arg Gln Ser Gly Thr His His Ala 3590 3595 3600Glu Asn Ser Ser Gly Gly Gln Ala Ala Ser Ser His Glu Gln Ala 3605 3610 3615Arg Ser Ser Ala Gly Glu Arg His Gly Ser His His Gln Gln Ser 3620 3625 3630Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Gly Gln Ala Ser 3635 3640 3645Ser Ala Val Arg Asp Ser Gly His Arg Gly Ser Ser Gly Ser Gln 3650 3655 3660Ala Ser Asp Ser Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser 3665 3670 3675Val Ser Ala His Gly Gln Ala Gly Pro His Gln Gln Ser His Gln 3680 3685 3690Glu Ser Thr Arg Gly Arg Ser Ala Gly Arg Ser Gly Arg Ser Gly 3695 3700 3705Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser Ala 3710 3715 3720His Gly Arg Ala Gly Pro Ser Thr Gly Gly Arg Gln Gly Ser Arg 3725 3730 3735His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser Gln Glu 3740 3745 3750Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser Arg Arg Gly Gly 3755 3760 3765Arg Gln Gly Ser Tyr His Glu Gln Ser Val Asp Arg Ser Gly His 3770 3775 3780Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp 3785 3790 3795Ala Ser His Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Glu Thr 3800 3805 3810Arg Asn Glu Glu Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser 3815 3820 3825Arg His His Glu Ala Ser Thr Gln Ala Asp Ser Ser Arg His Ser 3830 3835 3840Gln Ser Gly Gln Gly Glu Ser Ala Gly Ser Arg Arg Ser Arg Arg 3845 3850 3855Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu Ala Tyr Pro 3860 3865 3870Glu Asp Ser Glu Arg Arg Ser Glu Ser Ala Ser Arg Asn His His 3875 3880 3885Gly Ser Ser Arg Glu Gln Ser Arg Asp Gly Ser Arg His Pro Gly 3890 3895 3900Ser Ser His Arg Asp Thr Ala Ser His Val Gln Ser Ser Pro Val 3905 3910 3915Gln Ser Asp Ser Ser Thr Ala Lys Glu His Gly His Phe Ser Ser 3920 3925 3930Leu Ser Gln Asp Ser Ala Tyr His Ser Gly Ile Gln Ser Arg Gly 3935 3940 3945Ser Pro His Ser Ser Ser Ser Tyr His Tyr Gln Ser Glu Gly Thr 3950 3955 3960Glu Arg Gln Lys Gly Gln Ser Gly Leu Val Trp Arg His Gly Ser 3965 3970 3975Tyr Gly Ser Ala Asp Tyr Asp Tyr Gly Glu Ser Gly Phe Arg His 3980 3985 3990Ser Gln His Gly Ser Val Ser Tyr Asn Ser Asn Pro Val Val Phe 3995 4000 4005Lys Glu Arg Ser Asp Ile Cys Lys Ala Ser Ala Phe Gly Lys Asp 4010 4015 4020His Pro Arg Tyr Tyr Ala Thr Tyr Ile Asn Lys Asp Pro Gly Leu 4025 4030 4035Cys Gly His Ser Ser Asp Ile Ser Lys Gln Leu Gly Phe Ser Gln 4040 4045 4050Ser Gln Arg Tyr Tyr Tyr Tyr Glu 4055 40603416PRTHomo sapiens 3Ala Gly Pro His Gln Gln Ser His Gln Glu Ser Thr Arg Gly Arg Ser1 5 10 15Ala Gly Arg Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr 20 25 30His Glu Gln Ser Glu Ser Ala His Gly Arg Thr Gly Thr Ser Thr Gly 35 40 45Gly Arg Gln Gly Ser His His Gln Gln Ala Arg Asp Ser Ser Arg His 50 55 60Ser Thr Ser Gln Glu Gly Gln Asp Thr Ile His Gly His Arg Gly Ser65 70 75 80Ser Ser Gly Gly Arg Gln Gly Ser His Tyr Glu Gln Leu Val Asp Arg 85 90 95Ser Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg 100 105 110Ser Asp Ala Ser His Gly His Ser Gly Ser Arg Ser Ala Ser Arg Gln 115 120 125Thr Arg Asn Asp Glu Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser 130 135 140Arg His His Glu Ala Ser Ser Arg Ala Asp Ser Ser Gly His Ser Gln145 150 155 160Val Gly Gln Gly Gln Ser Glu Gly Pro Arg Thr Ser Arg Asn Trp Gly 165 170 175Ser Ser Phe Ser Gln Asp Ser Asp Ser Gln Gly His Ser Glu Asp Ser 180 185 190Glu Arg Trp Ser Gly Ser Ala Ser Arg Asn His His Gly Ser Ala Gln 195 200 205Glu Gln Leu Arg Asp Gly Ser Arg His Pro Arg Ser His Gln Glu Asp 210 215 220Arg Ala Gly His Gly His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr225 230 235 240Arg His Thr Gln Thr Ser Ser Gly Gly Gln Ala Ala Ser Ser His Glu 245 250 255Gln Ala Arg Ser Ser Ala Gly Asp Arg His Gly Ser His His Gln Gln 260 265 270Ser Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Gly Gln Ala Ser 275 280 285Ser Ala Val Arg Asp Ser Gly His Arg Gly Tyr Ser Gly Ser Gln Ala 290 295 300Ser Asp Asn Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser305 310 315 320Ala His Gly Gln Ala Gly Ser His Gln Gln Ser His Gln Glu Ser Ala 325 330 335Arg Gly Arg Ser Gly Glu Thr Ser Gly His Ser Gly Ser Phe Leu Tyr 340 345 350Gln Val Ser Thr His Glu Gln Ser Glu Ser Ser His Gly Trp Thr Gly 355 360 365Pro Ser Thr Arg Gly Arg Gln Gly Ser Arg His Glu Gln Ala Gln Asp 370 375 380Ser Ser Arg His Ser Ala Ser Gln Asp Gly Gln Asp Thr Ile Arg Gly385 390 395 400His Pro Gly Ser Ser Arg Gly Gly Arg Gln Gly Tyr His His Glu Gln 405 410 41544061PRTHomo sapiens 4Met Ser Thr Leu Leu Glu Asn Ile Phe Ala Ile Ile Asn Leu Phe Lys1 5 10 15Gln Tyr Ser Lys Lys Asp Lys Asn Thr Asp Thr Leu Ser Lys Lys Glu 20 25 30Leu Lys Glu Leu Leu Glu Lys Glu Phe Arg Gln Ile Leu Lys Asn Pro 35 40 45Asp Asp Pro Asp Met Val Asp Val Phe Met Asp His Leu Asp Ile Asp 50 55 60His Asn Lys Lys Ile Asp Phe Thr Glu Phe Leu Leu

Met Val Phe Lys65 70 75 80Leu Ala Gln Ala Tyr Tyr Glu Ser Thr Arg Lys Glu Asn Leu Pro Ile 85 90 95Ser Gly His Lys His Arg Lys His Ser His His Asp Lys His Glu Asp 100 105 110Asn Lys Gln Glu Glu Asn Lys Glu Asn Arg Lys Arg Pro Ser Ser Leu 115 120 125Glu Arg Arg Asn Asn Arg Lys Gly Asn Lys Gly Arg Ser Lys Ser Pro 130 135 140Arg Glu Thr Gly Gly Lys Arg His Glu Ser Ser Ser Glu Lys Lys Glu145 150 155 160Arg Lys Gly Tyr Ser Pro Thr His Arg Glu Glu Glu Tyr Gly Lys Asn 165 170 175His His Asn Ser Ser Lys Lys Glu Lys Asn Lys Thr Glu Asn Thr Arg 180 185 190Leu Gly Asp Asn Arg Lys Arg Leu Ser Glu Arg Leu Glu Glu Lys Glu 195 200 205Asp Asn Glu Glu Gly Val Tyr Asp Tyr Glu Asn Thr Gly Arg Met Thr 210 215 220Gln Lys Trp Ile Gln Ser Gly His Ile Ala Thr Tyr Tyr Thr Ile Gln225 230 235 240Asp Glu Ala Tyr Asp Thr Thr Asp Ser Leu Leu Glu Glu Asn Lys Ile 245 250 255Tyr Glu Arg Ser Arg Ser Ser Asp Gly Lys Ser Ser Ser Gln Val Asn 260 265 270Arg Ser Arg His Glu Asn Thr Ser Gln Val Pro Leu Gln Glu Ser Arg 275 280 285Thr Arg Lys Arg Arg Gly Ser Arg Val Ser Gln Asp Arg Asp Ser Glu 290 295 300Gly His Ser Glu Asp Ser Glu Arg His Ser Gly Ser Ala Ser Arg Asn305 310 315 320His His Gly Ser Ala Trp Glu Gln Ser Arg Asp Gly Ser Arg His Pro 325 330 335Arg Ser His Asp Glu Asp Arg Ala Ser His Gly His Ser Ala Asp Ser 340 345 350Ser Arg Gln Ser Gly Thr Arg His Ala Glu Thr Ser Ser Arg Gly Gln 355 360 365Thr Ala Ser Ser His Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His 370 375 380Gly Ser Gly His Gln Gln Ser Ala Asp Ser Ser Arg His Ser Ala Thr385 390 395 400Gly Arg Gly Gln Ala Ser Ser Ala Val Ser Asp Arg Gly His Arg Gly 405 410 415Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Asn Ser 420 425 430Asp Thr Gln Ser Val Ser Gly His Gly Lys Ala Gly Leu Arg Gln Gln 435 440 445Ser His Gln Glu Ser Thr Arg Gly Arg Ser Gly Glu Arg Ser Gly Arg 450 455 460Ser Gly Ser Ser Leu Tyr Gln Val Ser Thr His Glu Gln Pro Asp Ser465 470 475 480Ala His Gly Arg Thr Gly Thr Ser Thr Gly Gly Arg Gln Gly Ser His 485 490 495His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser Gln Glu Gly 500 505 510Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg Gln 515 520 525Gly Ser His His Glu Gln Ser Val Asn Arg Ser Gly His Ser Gly Ser 530 535 540His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser His Gly545 550 555 560Gln Ser Gly Ser Arg Ser Ala Ser Arg Gln Thr Arg Asn Glu Glu Gln 565 570 575Ser Gly Asp Gly Thr Arg His Ser Gly Ser Arg His His Glu Ala Ser 580 585 590Ser Gln Ala Asp Ser Ser Arg His Ser Gln Val Gly Gln Gly Gln Ser 595 600 605Ser Gly Pro Arg Thr Ser Arg Asn Gln Gly Ser Ser Val Ser Gln Asp 610 615 620Ser Asp Ser Gln Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser625 630 635 640Ala Ser Arg Asn His His Gly Ser Ala Gln Glu Gln Ser Arg Asp Gly 645 650 655Ser Arg His Pro Arg Ser His His Glu Asp Arg Ala Gly His Gly His 660 665 670Ser Ala Asp Ser Ser Arg Lys Ser Gly Thr Arg His Thr Gln Asn Ser 675 680 685Ser Ser Gly Gln Ala Ala Ser Ser His Glu Gln Ala Arg Ser Ser Ala 690 695 700Gly Glu Arg His Gly Ser Arg His Gln Leu Gln Ser Ala Asp Ser Ser705 710 715 720Arg His Ser Gly Thr Gly His Gly Gln Ala Ser Ser Ala Val Arg Asp 725 730 735Ser Gly His Arg Gly Ser Ser Gly Ser Gln Ala Thr Asp Ser Glu Gly 740 745 750His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Gly His Gly Gln Ala 755 760 765Gly His His Gln Gln Ser His Gln Glu Ser Ala Arg Asp Arg Ser Gly 770 775 780Glu Arg Ser Arg Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His785 790 795 800Lys Gln Ser Glu Ser Ser His Gly Trp Thr Gly Pro Ser Thr Gly Val 805 810 815Arg Gln Gly Ser His His Glu Gln Ala Arg Asp Asn Ser Arg His Ser 820 825 830Ala Ser Gln Asp Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser 835 840 845Arg Arg Gly Arg Gln Gly Ser His His Glu Gln Ser Val Asp Arg Ser 850 855 860Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg Ser865 870 875 880Asp Ala Ser Arg Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Thr Thr 885 890 895Arg Asn Glu Glu Gln Ser Arg Asp Gly Ser Arg His Ser Gly Ser Arg 900 905 910His His Glu Ala Ser Ser His Ala Asp Ile Ser Arg His Ser Gln Ala 915 920 925Gly Gln Gly Gln Ser Glu Gly Ser Arg Thr Ser Arg Arg Gln Gly Ser 930 935 940Ser Val Ser Gln Asp Ser Asp Ser Glu Gly His Ser Glu Asp Ser Glu945 950 955 960Arg Trp Ser Gly Ser Ala Ser Arg Asn His Arg Gly Ser Ala Gln Glu 965 970 975Gln Ser Arg His Gly Ser Arg His Pro Arg Ser His His Glu Asp Arg 980 985 990Ala Gly His Gly His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr Pro 995 1000 1005His Ala Glu Thr Ser Ser Gly Gly Gln Ala Ala Ser Ser His Glu 1010 1015 1020Gln Ala Arg Ser Ser Pro Gly Glu Arg His Gly Ser Arg His Gln 1025 1030 1035Gln Ser Ala Asp Ser Ser Arg His Ser Gly Ile Pro Arg Arg Gln 1040 1045 1050Ala Ser Ser Ala Val Arg Asp Ser Gly His Trp Gly Ser Ser Gly 1055 1060 1065Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Glu Ser Asp Thr 1070 1075 1080Gln Ser Val Ser Gly His Gly Gln Asp Gly Pro His Gln Gln Ser 1085 1090 1095His Gln Glu Ser Ala Arg Asp Trp Ser Gly Gly Arg Ser Gly Arg 1100 1105 1110Ser Gly Ser Phe Ile Tyr Gln Val Ser Thr His Glu Gln Ser Glu 1115 1120 1125Ser Ala His Gly Arg Thr Arg Thr Ser Thr Gly Arg Arg Gln Gly 1130 1135 1140Ser His His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser 1145 1150 1155Gln Glu Gly Gln Asp Thr Ile Arg Ala His Pro Gly Ser Arg Arg 1160 1165 1170Gly Gly Arg Gln Gly Ser His His Glu Gln Ser Val Asp Arg Ser 1175 1180 1185Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg 1190 1195 1200Ser Asp Ala Ser His Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg 1205 1210 1215Gln Thr Arg Lys Asp Lys Gln Ser Gly Asp Gly Ser Arg His Ser 1220 1225 1230Gly Ser Arg His His Glu Ala Ala Ser Trp Ala Asp Ser Ser Arg 1235 1240 1245His Ser Gln Val Gly Gln Glu Gln Ser Ser Gly Ser Arg Thr Ser 1250 1255 1260Arg His Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu Arg 1265 1270 1275His Ser Asp Asp Ser Glu Arg Leu Ser Gly Ser Ala Ser Arg Asn 1280 1285 1290His His Gly Ser Ser Arg Glu Gln Ser Arg Asp Gly Ser Arg His 1295 1300 1305Pro Gly Phe His Gln Glu Asp Arg Ala Ser His Gly His Ser Ala 1310 1315 1320Asp Ser Ser Arg Gln Ser Gly Thr His His Thr Glu Ser Ser Ser 1325 1330 1335His Gly Gln Ala Val Ser Ser His Glu Gln Ala Arg Ser Ser Pro 1340 1345 1350Gly Glu Arg His Gly Ser Arg His Gln Gln Ser Ala Asp Ser Ser 1355 1360 1365Arg His Ser Gly Ile Gly His Arg Gln Ala Ser Ser Ala Val Arg 1370 1375 1380Asp Ser Gly His Arg Gly Ser Ser Gly Ser Gln Val Thr Asn Ser 1385 1390 1395Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ala His 1400 1405 1410Gly Gln Ala Gly Pro His Gln Gln Ser His Lys Glu Ser Ala Arg 1415 1420 1425Gly Gln Ser Gly Glu Ser Ser Gly Arg Ser Arg Ser Phe Leu Tyr 1430 1435 1440Gln Val Ser Ser His Glu Gln Ser Glu Ser Thr His Gly Gln Thr 1445 1450 1455Ala Pro Ser Thr Gly Gly Arg Gln Gly Ser Arg His Glu Gln Ala 1460 1465 1470Arg Asn Ser Ser Arg His Ser Ala Ser Gln Asp Gly Gln Asp Thr 1475 1480 1485Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg Gln Gly Ser 1490 1495 1500Tyr His Glu Gln Ser Val Asp Arg Ser Gly His Ser Gly Tyr His 1505 1510 1515His Ser His Thr Thr Pro Gln Gly Arg Ser Asp Ala Ser His Gly 1520 1525 1530Gln Ser Gly Pro Arg Ser Ala Ser Arg Gln Thr Arg Asn Glu Glu 1535 1540 1545Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser Arg His His Glu 1550 1555 1560Pro Ser Thr Arg Ala Gly Ser Ser Arg His Ser Gln Val Gly Gln 1565 1570 1575Gly Glu Ser Ala Gly Ser Lys Thr Ser Arg Arg Gln Gly Ser Ser 1580 1585 1590Val Ser Gln Asp Arg Asp Ser Glu Gly His Ser Glu Asp Ser Glu 1595 1600 1605Arg Arg Ser Glu Ser Ala Ser Arg Asn His Tyr Gly Ser Ala Arg 1610 1615 1620Glu Gln Ser Arg His Gly Ser Arg Asn Pro Arg Ser His Gln Glu 1625 1630 1635Asp Arg Ala Ser His Gly His Ser Ala Glu Ser Ser Arg Gln Ser 1640 1645 1650Gly Thr Arg His Ala Glu Thr Ser Ser Gly Gly Gln Ala Ala Ser 1655 1660 1665Ser Gln Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His Gly Ser 1670 1675 1680Arg His Gln Gln Ser Ala Asp Ser Ser Thr Asp Ser Gly Thr Gly 1685 1690 1695Arg Arg Gln Asp Ser Ser Val Val Gly Asp Ser Gly Asn Arg Gly 1700 1705 1710Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Glu 1715 1720 1725Ser Asp Thr Gln Ser Val Ser Ala His Gly Gln Ala Gly Pro His 1730 1735 1740Gln Gln Ser His Gln Glu Ser Thr Arg Gly Gln Ser Gly Glu Arg 1745 1750 1755Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu 1760 1765 1770Gln Ser Glu Ser Ala His Gly Arg Thr Gly Pro Ser Thr Gly Gly 1775 1780 1785Arg Gln Arg Ser Arg His Glu Gln Ala Arg Asp Ser Ser Arg His 1790 1795 1800Ser Ala Ser Gln Glu Gly Gln Asp Thr Ile Arg Gly His Pro Gly 1805 1810 1815Ser Ser Arg Gly Gly Arg Gln Gly Ser His Tyr Glu Gln Ser Val 1820 1825 1830Asp Ser Ser Gly His Ser Gly Ser His His Ser His Thr Thr Ser 1835 1840 1845Gln Glu Arg Ser Asp Val Ser Arg Gly Gln Ser Gly Ser Arg Ser 1850 1855 1860Val Ser Arg Gln Thr Arg Asn Glu Lys Gln Ser Gly Asp Gly Ser 1865 1870 1875Arg His Ser Gly Ser Arg His His Glu Ala Ser Ser Arg Ala Asp 1880 1885 1890Ser Ser Arg His Ser Gln Val Gly Gln Gly Gln Ser Ser Gly Pro 1895 1900 1905Arg Thr Ser Arg Asn Gln Gly Ser Ser Val Ser Gln Asp Ser Asp 1910 1915 1920Ser Gln Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser Ala 1925 1930 1935Ser Arg Asn His Leu Gly Ser Ala Trp Glu Gln Ser Arg Asp Gly 1940 1945 1950Ser Arg His Pro Gly Ser His His Glu Asp Arg Ala Gly His Gly 1955 1960 1965His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr Arg His Thr Glu 1970 1975 1980Ser Ser Ser Arg Gly Gln Ala Ala Ser Ser His Glu Gln Ala Arg 1985 1990 1995Ser Ser Ala Gly Glu Arg His Gly Ser His His Gln Leu Gln Ser 2000 2005 2010Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Gly Gln Ala Ser 2015 2020 2025Ser Ala Val Arg Asp Ser Gly His Arg Gly Tyr Ser Gly Ser Gln 2030 2035 2040Ala Ser Asp Ser Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser 2045 2050 2055Val Ser Ala Gln Gly Lys Ala Gly Pro His Gln Gln Ser His Lys 2060 2065 2070Glu Ser Ala Arg Gly Gln Ser Gly Glu Ser Ser Gly Arg Ser Gly 2075 2080 2085Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser Thr 2090 2095 2100His Gly Gln Ser Ala Pro Ser Thr Gly Gly Arg Gln Gly Ser His 2105 2110 2115Tyr Asp Gln Ala Gln Asp Ser Ser Arg His Ser Ala Ser Gln Glu 2120 2125 2130Gly Gln Asp Thr Ile Arg Gly His Pro Gly Pro Ser Arg Gly Gly 2135 2140 2145Arg Gln Gly Ser His Gln Glu Gln Ser Val Asp Arg Ser Gly His 2150 2155 2160Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp 2165 2170 2175Ala Ser Arg Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Lys Thr 2180 2185 2190Tyr Asp Lys Glu Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser 2195 2200 2205His His His Glu Ala Ser Ser Trp Ala Asp Ser Ser Arg His Ser 2210 2215 2220Leu Val Gly Gln Gly Gln Ser Ser Gly Pro Arg Thr Ser Arg Pro 2225 2230 2235Arg Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu Gly His Ser 2240 2245 2250Glu Asp Ser Glu Arg Arg Ser Gly Ser Ala Ser Arg Asn His His 2255 2260 2265Gly Ser Ala Gln Glu Gln Ser Arg Asp Gly Ser Arg His Pro Arg 2270 2275 2280Ser His His Glu Asp Arg Ala Gly His Gly His Ser Ala Glu Ser 2285 2290 2295Ser Arg Gln Ser Gly Thr His His Ala Glu Asn Ser Ser Gly Gly 2300 2305 2310Gln Ala Ala Ser Ser His Glu Gln Ala Arg Ser Ser Ala Gly Glu 2315 2320 2325Arg His Gly Ser His His Gln Gln Ser Ala Asp Ser Ser Arg His 2330 2335 2340Ser Gly Ile Gly His Gly Gln Ala Ser Ser Ala Val Arg Asp Ser 2345 2350 2355Gly His Arg Gly Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly 2360 2365 2370His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ala His Gly Gln 2375 2380 2385Ala Gly Pro His Gln Gln Ser His Gln Glu Ser Thr Arg Gly Arg 2390 2395 2400Ser Ala Gly Arg Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val 2405 2410 2415Ser Thr His Glu Gln Ser Glu Ser Ala His Gly Arg Thr Gly Thr 2420 2425 2430Ser Thr Gly Gly Arg Gln Gly Ser His His Lys Gln Ala Arg Asp 2435 2440 2445Ser Ser Arg His Ser Thr Ser Gln Glu Gly Gln Asp Thr Ile His 2450 2455 2460Gly His Pro Gly Ser Ser Ser Gly Gly Arg Gln Gly Ser His Tyr 2465 2470 2475Glu Gln Leu Val Asp Arg Ser Gly His Ser Gly Ser His His Ser 2480 2485 2490His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser His Gly His Ser 2495 2500 2505Gly Ser Arg Ser Ala Ser Arg Gln Thr Arg Asn Asp Glu Gln Ser 2510

2515 2520Gly Asp Gly Ser Arg His Ser Gly Ser Arg His His Glu Ala Ser 2525 2530 2535Ser Arg Ala Asp Ser Ser Gly His Ser Gln Val Gly Gln Gly Gln 2540 2545 2550Ser Glu Gly Pro Arg Thr Ser Arg Asn Trp Gly Ser Ser Phe Ser 2555 2560 2565Gln Asp Ser Asp Ser Gln Gly His Ser Glu Asp Ser Glu Arg Trp 2570 2575 2580Ser Gly Ser Ala Ser Arg Asn His His Gly Ser Ala Gln Glu Gln 2585 2590 2595Leu Arg Asp Gly Ser Arg His Pro Arg Ser His Gln Glu Asp Arg 2600 2605 2610Ala Gly His Gly His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr 2615 2620 2625Arg His Thr Gln Thr Ser Ser Gly Gly Gln Ala Ala Ser Ser His 2630 2635 2640Glu Gln Ala Arg Ser Ser Ala Gly Glu Arg His Gly Ser His His 2645 2650 2655Gln Gln Ser Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Gly 2660 2665 2670Gln Ala Ser Ser Ala Val Arg Asp Ser Gly His Arg Gly Tyr Ser 2675 2680 2685Gly Ser Gln Ala Ser Asp Asn Glu Gly His Ser Glu Asp Ser Asp 2690 2695 2700Thr Gln Ser Val Ser Ala His Gly Gln Ala Gly Ser His Gln Gln 2705 2710 2715Ser His Gln Glu Ser Ala Arg Gly Arg Ser Gly Glu Thr Ser Gly 2720 2725 2730His Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser 2735 2740 2745Glu Ser Ser His Gly Trp Thr Gly Pro Ser Thr Arg Gly Arg Gln 2750 2755 2760Gly Ser Arg His Glu Gln Ala Gln Asp Ser Ser Arg His Ser Ala 2765 2770 2775Ser Gln Asp Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser 2780 2785 2790Arg Gly Gly Arg Gln Gly Tyr His His Glu His Ser Val Asp Ser 2795 2800 2805Ser Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly 2810 2815 2820Arg Ser Asp Ala Ser Arg Gly Gln Ser Gly Ser Arg Ser Ala Ser 2825 2830 2835Arg Thr Thr Arg Asn Glu Glu Gln Ser Gly Asp Gly Ser Arg His 2840 2845 2850Ser Gly Ser Arg His His Glu Ala Ser Thr His Ala Asp Ile Ser 2855 2860 2865Arg His Ser Gln Ala Val Gln Gly Gln Ser Glu Gly Ser Arg Arg 2870 2875 2880Ser Arg Arg Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu 2885 2890 2895Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser Ala Ser Arg 2900 2905 2910Asn His His Gly Ser Ala Gln Glu Gln Leu Arg Asp Gly Ser Arg 2915 2920 2925His Pro Arg Ser His Gln Glu Asp Arg Ala Gly His Gly His Ser 2930 2935 2940Ala Asp Ser Ser Arg Gln Ser Gly Thr Arg His Thr Gln Thr Ser 2945 2950 2955Ser Gly Gly Gln Ala Ala Ser Ser His Glu Gln Ala Arg Ser Ser 2960 2965 2970Ala Gly Glu Arg His Gly Ser His His Gln Gln Ser Ala Asp Ser 2975 2980 2985Ser Arg His Ser Gly Ile Gly His Gly Gln Ala Ser Ser Ala Val 2990 2995 3000Arg Asp Ser Gly His Arg Gly Tyr Ser Gly Ser Gln Ala Ser Asp 3005 3010 3015Asn Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ala 3020 3025 3030His Gly Gln Ala Gly Ser His Gln Gln Ser His Gln Glu Ser Ala 3035 3040 3045Arg Gly Arg Ser Gly Glu Thr Ser Gly His Ser Gly Ser Phe Leu 3050 3055 3060Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser Ser His Gly Trp 3065 3070 3075Thr Gly Pro Ser Thr Arg Gly Arg Gln Gly Ser Arg His Glu Gln 3080 3085 3090Ala Gln Asp Ser Ser Arg His Ser Ala Ser Gln Tyr Gly Gln Asp 3095 3100 3105Thr Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg Gln Gly 3110 3115 3120Tyr His His Glu His Ser Val Asp Ser Ser Gly His Ser Gly Ser 3125 3130 3135His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser Arg 3140 3145 3150Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Thr Thr Arg Asn Glu 3155 3160 3165Glu Gln Ser Gly Asp Ser Ser Arg His Ser Val Ser Arg His His 3170 3175 3180Glu Ala Ser Thr His Ala Asp Ile Ser Arg His Ser Gln Ala Val 3185 3190 3195Gln Gly Gln Ser Glu Gly Ser Arg Arg Ser Arg Arg Gln Gly Ser 3200 3205 3210Ser Val Ser Gln Asp Ser Asp Ser Glu Gly His Ser Glu Asp Ser 3215 3220 3225Glu Arg Trp Ser Gly Ser Ala Ser Arg Asn His Arg Gly Ser Val 3230 3235 3240Gln Glu Gln Ser Arg His Gly Ser Arg His Pro Arg Ser His His 3245 3250 3255Glu Asp Arg Ala Gly His Gly His Ser Ala Asp Arg Ser Arg Gln 3260 3265 3270Ser Gly Thr Arg His Ala Glu Thr Ser Ser Gly Gly Gln Ala Ala 3275 3280 3285Ser Ser His Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His Gly 3290 3295 3300Ser Arg His Gln Gln Ser Ala Asp Ser Ser Arg His Ser Gly Ile 3305 3310 3315Pro Arg Gly Gln Ala Ser Ser Ala Val Arg Asp Ser Arg His Trp 3320 3325 3330Gly Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu 3335 3340 3345Glu Ser Asp Thr Gln Ser Val Ser Gly His Gly Gln Ala Gly Pro 3350 3355 3360His Gln Gln Ser His Gln Glu Ser Ala Arg Asp Arg Ser Gly Gly 3365 3370 3375Arg Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His 3380 3385 3390Glu Gln Ser Glu Ser Ala His Gly Arg Thr Arg Thr Ser Thr Gly 3395 3400 3405Arg Arg Gln Gly Ser His His Glu Gln Ala Arg Asp Ser Ser Arg 3410 3415 3420His Ser Ala Ser Gln Glu Gly Gln Asp Thr Ile Arg Gly His Pro 3425 3430 3435Gly Ser Ser Arg Arg Gly Arg Gln Gly Ser His Tyr Glu Gln Ser 3440 3445 3450Val Asp Arg Ser Gly His Ser Gly Ser His His Ser His Thr Thr 3455 3460 3465Ser Gln Gly Arg Ser Asp Ala Ser Arg Gly Gln Ser Gly Ser Arg 3470 3475 3480Ser Ala Ser Arg Gln Thr Arg Asn Asp Glu Gln Ser Gly Asp Gly 3485 3490 3495Ser Arg His Ser Trp Ser His His His Glu Ala Ser Thr Gln Ala 3500 3505 3510Asp Ser Ser Arg His Ser Gln Ser Gly Gln Gly Gln Ser Ala Gly 3515 3520 3525Pro Arg Thr Ser Arg Asn Gln Gly Ser Ser Val Ser Gln Asp Ser 3530 3535 3540Asp Ser Gln Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser 3545 3550 3555Ala Ser Arg Asn His Arg Gly Ser Ala Gln Glu Gln Ser Arg Asp 3560 3565 3570Gly Ser Arg His Pro Thr Ser His His Glu Asp Arg Ala Gly His 3575 3580 3585Gly His Ser Ala Glu Ser Ser Arg Gln Ser Gly Thr His His Ala 3590 3595 3600Glu Asn Ser Ser Gly Gly Gln Ala Ala Ser Ser His Glu Gln Ala 3605 3610 3615Arg Ser Ser Ala Gly Glu Arg His Gly Ser His His Gln Gln Ser 3620 3625 3630Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Gly Gln Ala Ser 3635 3640 3645Ser Ala Val Arg Asp Ser Gly His Arg Gly Ser Ser Gly Ser Gln 3650 3655 3660Ala Ser Asp Ser Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser 3665 3670 3675Val Ser Ala His Gly Gln Ala Gly Pro His Gln Gln Ser His Gln 3680 3685 3690Glu Ser Thr Arg Gly Arg Ser Ala Gly Arg Ser Gly Arg Ser Gly 3695 3700 3705Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser Ala 3710 3715 3720His Gly Arg Ala Gly Pro Ser Thr Gly Gly Arg Gln Gly Ser Arg 3725 3730 3735His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser Gln Glu 3740 3745 3750Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser Arg Arg Gly Gly 3755 3760 3765Arg Gln Gly Ser Tyr His Glu Gln Ser Val Asp Arg Ser Gly His 3770 3775 3780Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp 3785 3790 3795Ala Ser His Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Glu Thr 3800 3805 3810Arg Asn Glu Glu Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser 3815 3820 3825Arg His His Glu Ala Ser Thr Gln Ala Asp Ser Ser Arg His Ser 3830 3835 3840Gln Ser Gly Gln Gly Glu Ser Ala Gly Ser Arg Arg Ser Arg Arg 3845 3850 3855Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu Ala Tyr Pro 3860 3865 3870Glu Asp Ser Glu Arg Arg Ser Glu Ser Ala Ser Arg Asn His His 3875 3880 3885Gly Ser Ser Arg Glu Gln Ser Arg Asp Gly Ser Arg His Pro Gly 3890 3895 3900Ser Ser His Arg Asp Thr Ala Ser His Val Gln Ser Ser Pro Val 3905 3910 3915Gln Ser Asp Ser Ser Thr Ala Lys Glu His Gly His Phe Ser Ser 3920 3925 3930Leu Ser Gln Asp Ser Ala Tyr His Ser Gly Ile Gln Ser Arg Gly 3935 3940 3945Ser Pro His Ser Ser Ser Ser Tyr His Tyr Gln Ser Glu Gly Thr 3950 3955 3960Glu Arg Gln Lys Gly Gln Ser Gly Leu Val Trp Arg His Gly Ser 3965 3970 3975Tyr Gly Ser Ala Asp Tyr Asp Tyr Gly Glu Ser Gly Phe Arg His 3980 3985 3990Ser Gln His Gly Ser Val Ser Tyr Asn Ser Asn Pro Val Val Phe 3995 4000 4005Lys Glu Arg Ser Asp Ile Cys Lys Ala Ser Ala Phe Gly Lys Asp 4010 4015 4020His Pro Arg Tyr Tyr Ala Thr Tyr Ile Asn Lys Asp Pro Gly Leu 4025 4030 4035Cys Gly His Ser Ser Asp Ile Ser Lys Gln Leu Gly Phe Ser Gln 4040 4045 4050Ser Gln Arg Tyr Tyr Tyr Tyr Glu 4055 406054061PRTHomo sapiens 5Met Ser Thr Leu Leu Glu Asn Ile Phe Ala Ile Ile Asn Leu Phe Lys1 5 10 15Gln Tyr Ser Lys Lys Asp Lys Asn Thr Asp Thr Leu Ser Lys Lys Glu 20 25 30Leu Lys Glu Leu Leu Glu Lys Glu Phe Arg Gln Ile Leu Lys Asn Pro 35 40 45Asp Asp Pro Asp Met Val Asp Val Phe Met Asp His Leu Asp Ile Asp 50 55 60His Asn Lys Lys Ile Asp Phe Thr Glu Phe Leu Leu Met Val Phe Lys65 70 75 80Leu Ala Gln Ala Tyr Tyr Glu Ser Thr Arg Lys Glu Asn Leu Pro Ile 85 90 95Ser Gly His Lys His Arg Lys His Ser His His Asp Lys His Glu Asp 100 105 110Asn Lys Gln Glu Glu Asn Lys Glu Asn Arg Lys Arg Pro Ser Ser Leu 115 120 125Glu Arg Arg Asn Asn Arg Lys Gly Asn Lys Gly Arg Ser Lys Ser Pro 130 135 140Arg Glu Thr Gly Gly Lys Arg His Glu Ser Ser Ser Glu Lys Lys Glu145 150 155 160Arg Lys Gly Tyr Ser Pro Thr His Arg Glu Glu Glu Tyr Gly Lys Asn 165 170 175His His Asn Ser Ser Lys Lys Glu Lys Asn Lys Thr Glu Asn Thr Arg 180 185 190Leu Gly Asp Asn Arg Lys Arg Leu Ser Glu Arg Leu Glu Glu Lys Glu 195 200 205Asp Asn Glu Glu Gly Val Tyr Asp Tyr Glu Asn Thr Gly Arg Met Thr 210 215 220Gln Lys Trp Ile Gln Ser Gly His Ile Ala Thr Tyr Tyr Thr Ile Gln225 230 235 240Asp Glu Ala Tyr Asp Thr Thr Asp Ser Leu Leu Glu Glu Asn Lys Ile 245 250 255Tyr Glu Arg Ser Arg Ser Ser Asp Gly Lys Ser Ser Ser Gln Val Asn 260 265 270Arg Ser Arg His Glu Asn Thr Ser Gln Val Pro Leu Gln Glu Ser Arg 275 280 285Thr Arg Lys Arg Arg Gly Ser Arg Val Ser Gln Asp Arg Asp Ser Glu 290 295 300Gly His Ser Glu Asp Ser Glu Arg His Ser Gly Ser Ala Ser Arg Asn305 310 315 320His His Gly Ser Ala Trp Glu Gln Ser Arg Asp Gly Ser Arg His Pro 325 330 335Arg Ser His Asp Glu Asp Arg Ala Ser His Gly His Ser Ala Asp Ser 340 345 350Ser Arg Gln Ser Gly Thr Arg His Ala Glu Thr Ser Ser Arg Gly Gln 355 360 365Thr Ala Ser Ser His Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His 370 375 380Gly Ser Gly His Gln Gln Ser Ala Asp Ser Ser Arg His Ser Ala Thr385 390 395 400Gly Arg Gly Gln Ala Ser Ser Ala Val Ser Asp Arg Gly His Arg Gly 405 410 415Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Asn Ser 420 425 430Asp Thr Gln Ser Val Ser Gly His Gly Lys Ala Gly Leu Arg Gln Gln 435 440 445Ser His Gln Glu Ser Thr Arg Gly Arg Ser Gly Glu Arg Ser Gly Arg 450 455 460Ser Gly Ser Ser Leu Tyr Gln Val Ser Thr His Glu Gln Pro Asp Ser465 470 475 480Ala His Gly Arg Thr Gly Thr Ser Thr Gly Gly Arg Gln Gly Ser His 485 490 495His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser Gln Glu Gly 500 505 510Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg Gln 515 520 525Gly Ser His His Glu Gln Ser Val Asn Arg Ser Gly His Ser Gly Ser 530 535 540His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser His Gly545 550 555 560Gln Ser Gly Ser Arg Ser Ala Ser Arg Gln Thr Arg Asn Glu Glu Gln 565 570 575Ser Gly Asp Gly Thr Arg His Ser Gly Ser Arg His His Glu Ala Ser 580 585 590Ser Gln Ala Asp Ser Ser Arg His Ser Gln Val Gly Gln Gly Gln Ser 595 600 605Ser Gly Pro Arg Thr Ser Arg Asn Gln Gly Ser Ser Val Ser Gln Asp 610 615 620Ser Asp Ser Gln Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser625 630 635 640Ala Ser Arg Asn His His Gly Ser Ala Gln Glu Gln Ser Arg Asp Gly 645 650 655Ser Arg His Pro Arg Ser His His Glu Asp Arg Ala Gly His Gly His 660 665 670Ser Ala Asp Ser Ser Arg Lys Ser Gly Thr Arg His Thr Gln Asn Ser 675 680 685Ser Ser Gly Gln Ala Ala Ser Ser His Glu Gln Ala Arg Ser Ser Ala 690 695 700Gly Glu Arg His Gly Ser Arg His Gln Leu Gln Ser Ala Asp Ser Ser705 710 715 720Arg His Ser Gly Thr Gly His Gly Gln Ala Ser Ser Ala Val Arg Asp 725 730 735Ser Gly His Arg Gly Ser Ser Gly Ser Gln Ala Thr Asp Ser Glu Gly 740 745 750His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Gly His Gly Gln Ala 755 760 765Gly His His Gln Gln Ser His Gln Glu Ser Ala Arg Asp Arg Ser Gly 770 775 780Glu Arg Ser Arg Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His785 790 795 800Lys Gln Ser Glu Ser Ser His Gly Trp Thr Gly Pro Ser Thr Gly Val 805 810 815Arg Gln Gly Ser His His Glu Gln Ala Arg Asp Asn Ser Arg His Ser 820 825 830Ala Ser Gln Asp Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser 835 840 845Arg Arg Gly Arg Gln Gly Ser His His Glu Gln Ser Val Asp Arg Ser 850 855 860Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg Ser865 870 875 880Asp Ala Ser Arg Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Thr Thr 885 890 895Arg Asn Glu Glu Gln Ser Arg Asp Gly Ser Arg His Ser Gly Ser Arg

900 905 910His His Glu Ala Ser Ser His Ala Asp Ile Ser Arg His Ser Gln Ala 915 920 925Gly Gln Gly Gln Ser Glu Gly Ser Arg Thr Ser Arg Arg Gln Gly Ser 930 935 940Ser Val Ser Gln Asp Ser Asp Ser Glu Gly His Ser Glu Asp Ser Glu945 950 955 960Arg Trp Ser Gly Ser Ala Ser Arg Asn His Arg Gly Ser Ala Gln Glu 965 970 975Gln Ser Arg His Gly Ser Arg His Pro Arg Ser His His Glu Asp Arg 980 985 990Ala Gly His Gly His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr Pro 995 1000 1005His Ala Glu Thr Ser Ser Gly Gly Gln Ala Ala Ser Ser His Glu 1010 1015 1020Gln Ala Arg Ser Ser Pro Gly Glu Arg His Gly Ser Arg His Gln 1025 1030 1035Gln Ser Ala Asp Ser Ser Arg His Ser Gly Ile Pro Arg Arg Gln 1040 1045 1050Ala Ser Ser Ala Val Arg Asp Ser Gly His Trp Gly Ser Ser Gly 1055 1060 1065Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Glu Ser Asp Thr 1070 1075 1080Gln Ser Val Ser Gly His Gly Gln Asp Gly Pro His Gln Gln Ser 1085 1090 1095His Gln Glu Ser Ala Arg Asp Trp Ser Gly Gly Arg Ser Gly Arg 1100 1105 1110Ser Gly Ser Phe Ile Tyr Gln Val Ser Thr His Glu Gln Ser Glu 1115 1120 1125Ser Ala His Gly Arg Thr Arg Thr Ser Thr Gly Arg Arg Gln Gly 1130 1135 1140Ser His His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser 1145 1150 1155Gln Glu Gly Gln Asp Thr Ile Arg Ala His Pro Gly Ser Arg Arg 1160 1165 1170Gly Gly Arg Gln Gly Ser His His Glu Gln Ser Val Asp Arg Ser 1175 1180 1185Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg 1190 1195 1200Ser Asp Ala Ser His Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg 1205 1210 1215Gln Thr Arg Lys Asp Lys Gln Ser Gly Asp Gly Ser Arg His Ser 1220 1225 1230Gly Ser Arg His His Glu Ala Ala Ser Trp Ala Asp Ser Ser Arg 1235 1240 1245His Ser Gln Val Gly Gln Glu Gln Ser Ser Gly Ser Arg Thr Ser 1250 1255 1260Arg His Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu Arg 1265 1270 1275His Ser Asp Asp Ser Glu Arg Leu Ser Gly Ser Ala Ser Arg Asn 1280 1285 1290His His Gly Ser Ser Arg Glu Gln Ser Arg Asp Gly Ser Arg His 1295 1300 1305Pro Gly Phe His Gln Glu Asp Arg Ala Ser His Gly His Ser Ala 1310 1315 1320Asp Ser Ser Arg Gln Ser Gly Thr His His Thr Glu Ser Ser Ser 1325 1330 1335His Gly Gln Ala Val Ser Ser His Glu Gln Ala Arg Ser Ser Pro 1340 1345 1350Gly Glu Arg His Gly Ser Arg His Gln Gln Ser Ala Asp Ser Ser 1355 1360 1365Arg His Ser Gly Ile Gly His Arg Gln Ala Ser Ser Ala Val Arg 1370 1375 1380Asp Ser Gly His Arg Gly Ser Ser Gly Ser Gln Val Thr Asn Ser 1385 1390 1395Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ala His 1400 1405 1410Gly Gln Ala Gly Pro His Gln Gln Ser His Lys Glu Ser Ala Arg 1415 1420 1425Gly Gln Ser Gly Glu Ser Ser Gly Arg Ser Arg Ser Phe Leu Tyr 1430 1435 1440Gln Val Ser Ser His Glu Gln Ser Glu Ser Thr His Gly Gln Thr 1445 1450 1455Ala Pro Ser Thr Gly Gly Arg Gln Gly Ser Arg His Glu Gln Ala 1460 1465 1470Arg Asn Ser Ser Arg His Ser Ala Ser Gln Asp Gly Gln Asp Thr 1475 1480 1485Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg Gln Gly Ser 1490 1495 1500Tyr His Glu Gln Ser Val Asp Arg Ser Gly His Ser Gly Tyr His 1505 1510 1515His Ser His Thr Thr Pro Gln Gly Arg Ser Asp Ala Ser His Gly 1520 1525 1530Gln Ser Gly Pro Arg Ser Ala Ser Arg Gln Thr Arg Asn Glu Glu 1535 1540 1545Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser Arg His His Glu 1550 1555 1560Pro Ser Thr Arg Ala Gly Ser Ser Arg His Ser Gln Val Gly Gln 1565 1570 1575Gly Glu Ser Ala Gly Ser Lys Thr Ser Arg Arg Gln Gly Ser Ser 1580 1585 1590Val Ser Gln Asp Arg Asp Ser Glu Gly His Ser Glu Asp Ser Glu 1595 1600 1605Arg Arg Ser Glu Ser Ala Ser Arg Asn His Tyr Gly Ser Ala Arg 1610 1615 1620Glu Gln Ser Arg His Gly Ser Arg Asn Pro Arg Ser His Gln Glu 1625 1630 1635Asp Arg Ala Ser His Gly His Ser Ala Glu Ser Ser Arg Gln Ser 1640 1645 1650Gly Thr Arg His Ala Glu Thr Ser Ser Gly Gly Gln Ala Ala Ser 1655 1660 1665Ser Gln Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His Gly Ser 1670 1675 1680Arg His Gln Gln Ser Ala Asp Ser Ser Thr Asp Ser Gly Thr Gly 1685 1690 1695Arg Arg Gln Asp Ser Ser Val Val Gly Asp Ser Gly Asn Arg Gly 1700 1705 1710Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Glu 1715 1720 1725Ser Asp Thr Gln Ser Val Ser Ala His Gly Gln Ala Gly Pro His 1730 1735 1740Gln Gln Ser His Gln Glu Ser Thr Arg Gly Gln Ser Gly Glu Arg 1745 1750 1755Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu 1760 1765 1770Gln Ser Glu Ser Ala His Gly Arg Thr Gly Pro Ser Thr Gly Gly 1775 1780 1785Arg Gln Arg Ser Arg His Glu Gln Ala Arg Asp Ser Ser Arg His 1790 1795 1800Ser Ala Ser Gln Glu Gly Gln Asp Thr Ile Arg Gly His Pro Gly 1805 1810 1815Ser Ser Arg Gly Gly Arg Gln Gly Ser His Tyr Glu Gln Ser Val 1820 1825 1830Asp Ser Ser Gly His Ser Gly Ser His His Ser His Thr Thr Ser 1835 1840 1845Gln Glu Arg Ser Asp Val Ser Arg Gly Gln Ser Gly Ser Arg Ser 1850 1855 1860Val Ser Arg Gln Thr Arg Asn Glu Lys Gln Ser Gly Asp Gly Ser 1865 1870 1875Arg His Ser Gly Ser Arg His His Glu Ala Ser Ser Arg Ala Asp 1880 1885 1890Ser Ser Arg His Ser Gln Val Gly Gln Gly Gln Ser Ser Gly Pro 1895 1900 1905Arg Thr Ser Arg Asn Gln Gly Ser Ser Val Ser Gln Asp Ser Asp 1910 1915 1920Ser Gln Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser Ala 1925 1930 1935Ser Arg Asn His Leu Gly Ser Ala Trp Glu Gln Ser Arg Asp Gly 1940 1945 1950Ser Arg His Pro Gly Ser His His Glu Asp Arg Ala Gly His Gly 1955 1960 1965His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr Arg His Thr Glu 1970 1975 1980Ser Ser Ser Arg Gly Gln Ala Ala Ser Ser His Glu Gln Ala Arg 1985 1990 1995Ser Ser Ala Gly Glu Arg His Gly Ser His His Gln Leu Gln Ser 2000 2005 2010Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Gly Gln Ala Ser 2015 2020 2025Ser Ala Val Arg Asp Ser Gly His Arg Gly Tyr Ser Gly Ser Gln 2030 2035 2040Ala Ser Asp Ser Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser 2045 2050 2055Val Ser Ala Gln Gly Lys Ala Gly Pro His Gln Gln Ser His Lys 2060 2065 2070Glu Ser Ala Arg Gly Gln Ser Gly Glu Ser Ser Gly Arg Ser Gly 2075 2080 2085Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser Thr 2090 2095 2100His Gly Gln Ser Ala Pro Ser Thr Gly Gly Arg Gln Gly Ser His 2105 2110 2115Tyr Asp Gln Ala Gln Asp Ser Ser Arg His Ser Ala Ser Gln Glu 2120 2125 2130Gly Gln Asp Thr Ile Arg Gly His Pro Gly Pro Ser Arg Gly Gly 2135 2140 2145Arg Gln Gly Ser His Gln Glu Gln Ser Val Asp Arg Ser Gly His 2150 2155 2160Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp 2165 2170 2175Ala Ser Arg Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Lys Thr 2180 2185 2190Tyr Asp Lys Glu Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser 2195 2200 2205His His His Glu Ala Ser Ser Trp Ala Asp Ser Ser Arg His Ser 2210 2215 2220Leu Val Gly Gln Gly Gln Ser Ser Gly Pro Arg Thr Ser Arg Pro 2225 2230 2235Arg Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu Gly His Ser 2240 2245 2250Glu Asp Ser Glu Arg Arg Ser Gly Ser Ala Ser Arg Asn His His 2255 2260 2265Gly Ser Ala Gln Glu Gln Ser Arg Asp Gly Ser Arg His Pro Arg 2270 2275 2280Ser His His Glu Asp Arg Ala Gly His Gly His Ser Ala Glu Ser 2285 2290 2295Ser Arg Gln Ser Gly Thr His His Ala Glu Asn Ser Ser Gly Gly 2300 2305 2310Gln Ala Ala Ser Ser His Glu Gln Ala Arg Ser Ser Ala Gly Glu 2315 2320 2325Arg His Gly Ser His His Gln Gln Ser Ala Asp Ser Ser Arg His 2330 2335 2340Ser Gly Ile Gly His Gly Gln Ala Ser Ser Ala Val Arg Asp Ser 2345 2350 2355Gly His Arg Gly Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly 2360 2365 2370His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ala His Gly Gln 2375 2380 2385Ala Gly Pro His Gln Gln Ser His Gln Glu Ser Thr Arg Gly Arg 2390 2395 2400Ser Ala Gly Arg Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val 2405 2410 2415Ser Thr His Glu Gln Ser Glu Ser Ala His Gly Arg Thr Gly Thr 2420 2425 2430Ser Thr Gly Gly Arg Gln Gly Ser His His Lys Gln Ala Arg Asp 2435 2440 2445Ser Ser Arg His Ser Thr Ser Gln Glu Gly Gln Asp Thr Ile His 2450 2455 2460Gly His Pro Gly Ser Ser Ser Gly Gly Arg Gln Gly Ser His Tyr 2465 2470 2475Glu Gln Leu Val Asp Arg Ser Gly His Ser Gly Ser His His Ser 2480 2485 2490His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser His Gly His Ser 2495 2500 2505Gly Ser Arg Ser Ala Ser Arg Gln Thr Arg Asn Asp Glu Gln Ser 2510 2515 2520Gly Asp Gly Ser Arg His Ser Gly Ser Arg His His Glu Ala Ser 2525 2530 2535Ser Arg Ala Asp Ser Ser Gly His Ser Gln Val Gly Gln Gly Gln 2540 2545 2550Ser Glu Gly Pro Arg Thr Ser Arg Asn Trp Gly Ser Ser Phe Ser 2555 2560 2565Gln Asp Ser Asp Ser Gln Gly His Ser Glu Asp Ser Glu Arg Trp 2570 2575 2580Ser Gly Ser Ala Ser Arg Asn His His Gly Ser Ala Gln Glu Gln 2585 2590 2595Leu Arg Asp Gly Ser Arg His Pro Arg Ser His Gln Glu Asp Arg 2600 2605 2610Ala Gly His Gly His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr 2615 2620 2625Arg His Thr Gln Thr Ser Ser Gly Gly Gln Ala Ala Ser Ser His 2630 2635 2640Glu Gln Ala Arg Ser Ser Ala Gly Glu Arg His Gly Ser His His 2645 2650 2655Gln Gln Ser Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Gly 2660 2665 2670Gln Ala Ser Ser Ala Val Arg Asp Ser Gly His Arg Gly Tyr Ser 2675 2680 2685Gly Ser Gln Ala Ser Asp Asn Glu Gly His Ser Glu Asp Ser Asp 2690 2695 2700Thr Gln Ser Val Ser Ala His Gly Gln Ala Gly Ser His Gln Gln 2705 2710 2715Ser His Gln Glu Ser Ala Arg Gly Arg Ser Gly Glu Thr Ser Gly 2720 2725 2730His Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser 2735 2740 2745Glu Ser Ser His Gly Trp Thr Gly Pro Ser Thr Arg Gly Arg Gln 2750 2755 2760Gly Ser Arg His Glu Gln Ala Gln Asp Ser Ser Arg His Ser Ala 2765 2770 2775Ser Gln Asp Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser 2780 2785 2790Arg Gly Gly Arg Gln Gly Tyr His His Glu His Ser Val Asp Ser 2795 2800 2805Ser Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly 2810 2815 2820Arg Ser Asp Ala Ser Arg Gly Gln Ser Gly Ser Arg Ser Ala Ser 2825 2830 2835Arg Thr Thr Arg Asn Glu Glu Gln Ser Gly Asp Gly Ser Arg His 2840 2845 2850Ser Gly Ser Arg His His Glu Ala Ser Thr His Ala Asp Ile Ser 2855 2860 2865Arg His Ser Gln Ala Val Gln Gly Gln Ser Glu Gly Ser Arg Arg 2870 2875 2880Ser Arg Arg Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu 2885 2890 2895Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser Ala Ser Arg 2900 2905 2910Asn His His Gly Ser Ala Gln Glu Gln Leu Arg Asp Gly Ser Arg 2915 2920 2925His Pro Arg Ser His Gln Glu Asp Arg Ala Gly His Gly His Ser 2930 2935 2940Ala Asp Ser Ser Arg Gln Ser Gly Thr Arg His Thr Gln Thr Ser 2945 2950 2955Ser Gly Gly Gln Ala Ala Ser Ser His Glu Gln Ala Arg Ser Ser 2960 2965 2970Ala Gly Glu Arg His Gly Ser His His Gln Gln Ser Ala Asp Ser 2975 2980 2985Ser Arg His Ser Gly Ile Gly His Gly Gln Ala Ser Ser Ala Val 2990 2995 3000Arg Asp Ser Gly His Arg Gly Tyr Ser Gly Ser Gln Ala Ser Asp 3005 3010 3015Asn Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ala 3020 3025 3030His Gly Gln Ala Gly Ser His Gln Gln Ser His Gln Glu Ser Ala 3035 3040 3045Arg Gly Arg Ser Gly Glu Thr Ser Gly His Ser Gly Ser Phe Leu 3050 3055 3060Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser Ser His Gly Trp 3065 3070 3075Thr Gly Pro Ser Thr Arg Gly Arg Gln Gly Ser Arg His Glu Gln 3080 3085 3090Ala Gln Asp Ser Ser Arg His Ser Ala Ser Gln Tyr Gly Gln Asp 3095 3100 3105Thr Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg Gln Gly 3110 3115 3120Tyr His His Glu His Ser Val Asp Ser Ser Gly His Ser Gly Ser 3125 3130 3135His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser Arg 3140 3145 3150Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Thr Thr Arg Asn Glu 3155 3160 3165Glu Gln Ser Gly Asp Ser Ser Arg His Ser Val Ser Arg His His 3170 3175 3180Glu Ala Ser Thr His Ala Asp Ile Ser Arg His Ser Gln Ala Val 3185 3190 3195Gln Gly Gln Ser Glu Gly Ser Arg Arg Ser Arg Arg Gln Gly Ser 3200 3205 3210Ser Val Ser Gln Asp Ser Asp Ser Glu Gly His Ser Glu Asp Ser 3215 3220 3225Glu Arg Trp Ser Gly Ser Ala Ser Arg Asn His Arg Gly Ser Val 3230 3235 3240Gln Glu Gln Ser Arg His Gly Ser Arg His Pro Arg Ser His His 3245 3250 3255Glu Asp Arg Ala Gly His Gly His Ser Ala Asp Arg Ser Arg Gln 3260 3265 3270Ser Gly Thr Arg His Ala Glu Thr Ser Ser Gly Gly Gln Ala Ala 3275 3280 3285Ser Ser His Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His Gly 3290 3295 3300Ser Arg His Gln Gln Ser Ala Asp Ser Ser Arg His Ser Gly Ile 3305 3310 3315Pro Arg Gly Gln Ala Ser Ser Ala Val Arg Asp Ser Arg His Trp 3320 3325 3330Gly Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu

3335 3340 3345Glu Ser Asp Thr Gln Ser Val Ser Gly His Gly Gln Ala Gly Pro 3350 3355 3360His Gln Gln Ser His Gln Glu Ser Ala Arg Asp Arg Ser Gly Gly 3365 3370 3375Arg Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His 3380 3385 3390Glu Gln Ser Glu Ser Ala His Gly Arg Thr Arg Thr Ser Thr Gly 3395 3400 3405Arg Arg Gln Gly Ser His His Glu Gln Ala Arg Asp Ser Ser Arg 3410 3415 3420His Ser Ala Ser Gln Glu Gly Gln Asp Thr Ile Arg Gly His Pro 3425 3430 3435Gly Ser Ser Arg Arg Gly Arg Gln Gly Ser His Tyr Glu Gln Ser 3440 3445 3450Val Asp Arg Ser Gly His Ser Gly Ser His His Ser His Thr Thr 3455 3460 3465Ser Gln Gly Arg Ser Asp Ala Ser Arg Gly Gln Ser Gly Ser Arg 3470 3475 3480Ser Ala Ser Arg Gln Thr Arg Asn Asp Glu Gln Ser Gly Asp Gly 3485 3490 3495Ser Arg His Ser Trp Ser His His His Glu Ala Ser Thr Gln Ala 3500 3505 3510Asp Ser Ser Arg His Ser Gln Ser Gly Gln Gly Gln Ser Ala Gly 3515 3520 3525Pro Arg Thr Ser Arg Asn Gln Gly Ser Ser Val Ser Gln Asp Ser 3530 3535 3540Asp Ser Gln Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser 3545 3550 3555Ala Ser Arg Asn His Arg Gly Ser Ala Gln Glu Gln Ser Arg Asp 3560 3565 3570Gly Ser Arg His Pro Thr Ser His His Glu Asp Arg Ala Gly His 3575 3580 3585Gly His Ser Ala Glu Ser Ser Arg Gln Ser Gly Thr His His Ala 3590 3595 3600Glu Asn Ser Ser Gly Gly Gln Ala Ala Ser Ser His Glu Gln Ala 3605 3610 3615Arg Ser Ser Ala Gly Glu Arg His Gly Ser His His Gln Gln Ser 3620 3625 3630Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Gly Gln Ala Ser 3635 3640 3645Ser Ala Val Arg Asp Ser Gly His Arg Gly Ser Ser Gly Ser Gln 3650 3655 3660Ala Ser Asp Ser Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser 3665 3670 3675Val Ser Ala His Gly Gln Ala Gly Pro His Gln Gln Ser His Gln 3680 3685 3690Glu Ser Thr Arg Gly Arg Ser Ala Gly Arg Ser Gly Arg Ser Gly 3695 3700 3705Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser Ala 3710 3715 3720His Gly Arg Ala Gly Pro Ser Thr Gly Gly Arg Gln Gly Ser Arg 3725 3730 3735His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser Gln Glu 3740 3745 3750Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser Arg Arg Gly Gly 3755 3760 3765Arg Gln Gly Ser Tyr His Glu Gln Ser Val Asp Arg Ser Gly His 3770 3775 3780Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp 3785 3790 3795Ala Ser His Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Glu Thr 3800 3805 3810Arg Asn Glu Glu Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser 3815 3820 3825Arg His His Glu Ala Ser Thr Gln Ala Asp Ser Ser Arg His Ser 3830 3835 3840Gln Ser Gly Gln Gly Glu Ser Ala Gly Ser Arg Arg Ser Arg Arg 3845 3850 3855Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu Ala Tyr Pro 3860 3865 3870Glu Asp Ser Glu Arg Arg Ser Glu Ser Ala Ser Arg Asn His His 3875 3880 3885Gly Ser Ser Arg Glu Gln Ser Arg Asp Gly Ser Arg His Pro Gly 3890 3895 3900Ser Ser His Arg Asp Thr Ala Ser His Val Gln Ser Ser Pro Val 3905 3910 3915Gln Ser Asp Ser Ser Thr Ala Lys Glu His Gly His Phe Ser Ser 3920 3925 3930Leu Ser Gln Asp Ser Ala Tyr His Ser Gly Ile Gln Ser Arg Gly 3935 3940 3945Ser Pro His Ser Ser Ser Ser Tyr His Tyr Gln Ser Glu Gly Thr 3950 3955 3960Glu Arg Gln Lys Gly Gln Ser Gly Leu Val Trp Arg His Gly Ser 3965 3970 3975Tyr Gly Ser Ala Asp Tyr Asp Tyr Gly Glu Ser Gly Phe Arg His 3980 3985 3990Ser Gln His Gly Ser Val Ser Tyr Asn Ser Asn Pro Val Val Phe 3995 4000 4005Lys Glu Arg Ser Asp Ile Cys Lys Ala Ser Ala Phe Gly Lys Asp 4010 4015 4020His Pro Arg Tyr Tyr Ala Thr Tyr Ile Asn Lys Asp Pro Gly Leu 4025 4030 4035Cys Gly His Ser Ser Asp Ile Ser Lys Gln Leu Gly Phe Ser Gln 4040 4045 4050Ser Gln Arg Tyr Tyr Tyr Tyr Glu 4055 40606269PRTMus musculus 6Gly Ser Gly Phe Tyr Pro Val Tyr Tyr Tyr Tyr Glu Gln Glu His Ser1 5 10 15Glu Glu Glu Ser Asp Ser Gln His Gly His Gln His Glu Gln Gln Arg 20 25 30Gly His Gln His Gln His Gln His Glu His Glu Gln Pro Glu Ser Gly 35 40 45His Arg Gln Gln Gln Ser Ser Gly Arg Gly His Gln Gly Ala His Gln 50 55 60Glu Gln Gly Arg Asp Ser Ala Arg Ser Arg Gly Ser Asn Gln Gly His65 70 75 80Ser Ser Ser Arg His Gln Ala Asp Ser Pro Arg Val Ser Ala Arg Ser 85 90 95Gly Ser Gly Gly Arg Gly Gln Ser Pro Asp Ala Ser Gly Arg Ser Ser 100 105 110Asn Arg Arg Asp Arg Pro Arg Gln Pro Asn Pro Ser Gln Ser Ser Asp 115 120 125Ser Gln Val His Ser Gly Val Gln Val Glu Gly Arg Arg Gly Gln Ser 130 135 140Ser Ser Ala Asn Arg Arg Ala Gly Ser Ser Ser Gly Ser Gly Val Gln145 150 155 160Gly Ala Ser Ala Gly Gly Leu Ala Ala Asp Ala Ser Arg Arg Ser Gly 165 170 175Ala Arg Gln Gly Gln Ala Ser Ala Gln Gly Arg Ala Gly Ser Gln Gly 180 185 190Gln Ala Gln Gly Arg Val Gly Ser Ser Ala Asp Arg Gln Gly Arg Arg 195 200 205Gly Val Ser Glu Ser Gln Ala Ser Asp Ser Glu Gly His Ser Asp Phe 210 215 220Ser Glu Gly Gln Ala Val Gly Ala His Arg Gln Ser Gly Ala Gly Gln225 230 235 240Arg His Glu Gln Arg Ser Ser Arg Gly Gln His Gly Ser Gly Tyr Tyr 245 250 255Tyr Glu Gln Glu His Ser Glu Glu Glu Ser Asp Ser Gln 260 2657554PRTMus musculus 7Met Ser Ala Leu Leu Glu Ser Ile Thr Ser Met Ile Glu Ile Phe Gln1 5 10 15Gln Tyr Ser Thr Ser Asp Lys Glu Glu Glu Thr Leu Ser Lys Glu Glu 20 25 30Leu Lys Glu Leu Leu Glu Gly Gln Leu Gln Ala Val Leu Lys Asn Pro 35 40 45Asp Asp Gln Asp Ile Ala Glu Val Phe Met Gln Met Leu Asp Val Asp 50 55 60His Asp Asp Lys Leu Asp Phe Ala Glu Tyr Leu Leu Leu Val Leu Lys65 70 75 80Leu Ala Lys Ala Tyr Tyr Glu Ala Ser Lys Asn Glu Ser Phe Gln Thr 85 90 95His Gly Ser Asn Gly Arg Ser Lys Thr Asp Tyr Lys Gly Leu Glu Glu 100 105 110Glu Gly Glu Glu Gly Asn Glu Gln Asn Leu Arg Arg Arg His Gly Gly 115 120 125Thr Asp Gly Lys Arg Lys Ser Asp Arg Thr Arg Ser Pro Asn Gly Lys 130 135 140Arg Gly Lys Arg Gln Glu Ser Arg Cys Arg Ser Glu Gly Lys Asp Lys145 150 155 160His Arg Arg Glu Pro Glu Lys His Arg His Gln Gln Asp Ser Lys Arg 165 170 175Lys Gln Arg His Gly Ser Gly Ser Thr Glu Arg Lys Asp Asn Arg Asn 180 185 190Lys Lys Asn Arg Gln Ser Lys Glu Arg Asn Tyr Asp Glu Ile Tyr Asp 195 200 205Asn Gly Lys Tyr Asn Glu Asp Trp Glu Ala Ser Tyr Asn Asn Cys Tyr 210 215 220Tyr Lys Thr Gln Asn Thr Thr Leu Asp Gln Arg Glu Gly Asn Arg Arg225 230 235 240Pro Arg Ala Asp Ser Gln Lys Glu Pro Gln Ser Phe His Gly Gln Ala 245 250 255Asp Asn Ser Asp Ser Glu Gly Gly Arg Gln Gln Ser His Ser Lys Pro 260 265 270Ser Pro Val Arg Ala Asp Gln Arg Arg Ser Arg Ala Gly Gln Ala Gly 275 280 285Ser Ser Lys Val Ser Ala Arg Ser Gly Ser Gly Gly Arg Gly Gln Ser 290 295 300Pro Asp Gly Ser Gly Arg Ser Ser Asn Arg Arg Asp Arg Pro Arg Gln305 310 315 320Pro Ser Pro Ser Gln Ser Ser Asp Ser Gln Val His Ser Gly Val Gln 325 330 335Val Glu Gly Arg Arg Gly Gln Ser Ser Ser Ala Asn Arg Arg Ala Gly 340 345 350Ser Ser Ser Gly Ser Gly Val Gln Gly Ala Ser Ala Gly Gly Leu Ala 355 360 365Ala Asp Ala Ser Arg Arg Thr Gly Ala Leu Gln Gly Gln Ala Ser Ala 370 375 380Gln Gly Arg Ala Gly Ser Gln Gly Gln Ala Gln Gly Arg Val Gly Ser385 390 395 400Ser Ala Asp Arg Gln Gly Arg Arg Gly Val Ser Glu Ser Gln Ala Ser 405 410 415Asp Ser Glu Gly Gln Ser Asp Phe Ser Glu Gly Gln Ala Val Gly Ala 420 425 430His Arg Gln Ser Gly Ala Gly Gln Arg His Glu Gln Arg Ser Ser Arg 435 440 445Gly Gln Tyr Gly Ser Gly Phe Tyr Pro Val Tyr Tyr Tyr Tyr Glu Gln 450 455 460Glu His Ser Glu Glu Glu Ser Asp Ser Gln His Gly His Gln His Glu465 470 475 480Gln Gln Arg Gly His Gln His Gln His Gln His Glu His Glu Gln Pro 485 490 495Glu Ser Gly His Arg Gln Gln Gln Ser Ser Gly Arg Gly His Gln Gly 500 505 510Ala His Gln Glu Gln Gly Arg Asp Ser Ala Arg Ser Arg Gly Ser Asn 515 520 525Gln Gly His Ser Ser Ser Arg His Gln Ala Asp Ser Pro Arg Val Ser 530 535 540Val Arg Ser Gly Ser Gly Gly Arg Gly Gln545 5508336PRTMus musculus 8Pro Asp Gly Ser Gly Arg Ser Ser Asn Arg Arg Asp Arg Pro Arg Gln1 5 10 15Leu Ser Pro Ser Gln Ser Ser Asp Ser Gln Val His Ser Gly Val Gln 20 25 30Val Glu Gly Arg Arg Gly His Ser Ser Ser Ala Asn Arg Arg Ala Gly 35 40 45Ser Ser Ser Gly Ser Gly Val Gln Gly Ala Ser Ala Gly Gly Leu Ala 50 55 60Ala Asp Ala Ser Arg Arg Ser Gly Ala Arg Gln Gly Gln Ala Ser Ala65 70 75 80Gln Gly Arg Ala Gly Ser Gln Gly Gln Ala Gln Gly Arg Val Ser Ser 85 90 95Ser Ala Asp Arg Gln Gly Arg Arg Gly Val Ser Glu Ser Arg Ala Ser 100 105 110Asp Ser Glu Gly His Ser Asp Phe Ser Glu Gly Gln Ala Val Gly Ala 115 120 125His Arg Gln Ser Gly Ala Gly Gln Arg His Glu Gln Arg Ser Ser Arg 130 135 140Gly Gln His Gly Ser Gly Tyr Tyr Tyr Glu Gln Glu His Ser Glu Glu145 150 155 160Glu Ser Asp Ser Gln His Gln His Gly His Gln His Glu Gln Gln Arg 165 170 175Gly His Gln His Gln His Gln His Gln His Glu His Glu Gln Pro Glu 180 185 190Ser Gly His Arg Gln Gln Gln Ser Ser Gly Arg Gly His Gln Gly Ala 195 200 205His Gln Glu Gln Gly Arg Asp Ser Ala Arg Pro Arg Gly Ser Asn Gln 210 215 220Gly His Ser Ser Ser Arg His Gln Ala Asp Ser Pro Arg Val Ser Ala225 230 235 240Arg Ser Gly Ser Gly Gly Arg Gly Gln Ser Pro Asp Ala Ser Gly Arg 245 250 255Ser Ser Asn Arg Arg Asp Arg Pro Arg Gln Pro Ser Pro Ser Gln Ser 260 265 270Ser Asp Ser Gln Val His Ser Gly Val Gln Val Glu Ala Gln Arg Gly 275 280 285Gln Ser Ser Ser Ala Asn Arg Arg Ala Gly Ser Ser Ser Gly Ser Gly 290 295 300Val Gln Gly Ala Ala Ala Ser Gly Gln Gly Gly Tyr Glu Ser Ile Phe305 310 315 320Thr Ala Lys His Leu Asp Phe Asn Gln Ser His Ser Tyr Tyr Tyr Tyr 325 330 3359250PRTMus musculus 9Gly Gly Leu Ala Ala Asp Ala Ser Arg Arg Ser Gly Ala Leu Gln Gly1 5 10 15Gln Ala Ser Ala Gln Gly Arg Ala Gly Ser Gln Gly Gln Ala Gln Gly 20 25 30Arg Val Gly Ser Ser Ala Asp Arg Gln Gly Arg Arg Gly Val Ser Glu 35 40 45Ser Gln Ala Ser Asp Ser Glu Gly His Ser Asp Phe Ser Glu Gly Gln 50 55 60Ala Val Gly Ala His Arg Gln Ser Gly Ala Gly Gln Arg His Glu Gln65 70 75 80Arg Ser Ser Arg Gly Gln His Gly Ser Gly Tyr Tyr Tyr Glu Gln Glu 85 90 95His Ser Glu Glu Glu Ser Asp Ser Gln His Gln His Gly His Gln His 100 105 110Glu Gln Gln Arg Gly His Gln His Gln His Gln His Gln His Glu His 115 120 125Glu Gln Pro Glu Ser Gly His Arg Gln Gln Gln Ser Ser Gly Arg Gly 130 135 140His Gln Gly Ala His Gln Glu Gln Gly Arg Asp Ser Ala Arg Ser Arg145 150 155 160Gly Ser Asn Gln Gly His Ser Ser Ser Arg His Gln Ala Asp Ser Pro 165 170 175Arg Val Ser Ala Arg Ser Gly Ser Gly Gly Arg Gly Gln Ser Pro Asp 180 185 190Ala Ser Gly Arg Ser Ser Asn Arg Arg Asp Arg Pro Arg Gln Pro Ser 195 200 205Pro Ser Gln Ser Ser Asp Ser Gln Val His Ser Gly Val Gln Val Glu 210 215 220Gly Arg Arg Gly Gln Ser Ser Ser Ala Asn Arg Arg Ala Gly Ser Ser225 230 235 240Ser Ser Ser Gly Val Gln Gly Ala Ser Ala 245 25010255PRTMus musculus 10Gly Gly Leu Ala Ala Asp Ala Ser Arg Arg Ser Gly Ala Arg Gln Gly1 5 10 15Gln Ala Ser Ala Gln Gly Arg Ala Gly Ser Gln Gly Gln Ala Gln Gly 20 25 30Arg Val Gly Ser Ser Ala Asp Arg Gln Gly Arg Arg Gly Val Ser Glu 35 40 45Ser Gln Ala Ser Asp Ser Glu Gly His Ser Asp Phe Ser Glu Gly Gln 50 55 60Ala Val Gly Ala His Arg Gln Ser Gly Ala Gly Gln Arg His Glu Gln65 70 75 80Arg Ser Ser Arg Gly Gln His Gly Ser Gly Phe Tyr Pro Val Tyr Tyr 85 90 95Tyr Tyr Glu Gln Glu His Ser Glu Glu Glu Ser Asp Ser Gln His Gln 100 105 110His Gly His Gln His Glu Gln Gln Arg Gly His Gln His Gln His Gln 115 120 125His Gln His Glu His Glu Gln Pro Glu Ser Gly His Arg Gln Gln Gln 130 135 140Ser Ser Gly Arg Gly His Gln Gly Ala His Gln Glu Gln Gly Arg Asp145 150 155 160Ser Ala Arg Ser Arg Gly Ser Asn Gln Gly His Ser Ser Ser Arg His 165 170 175Gln Ala Asp Ser Pro Arg Val Ser Ala Arg Ser Gly Ser Gly Gly Arg 180 185 190Gly Gln Ser Pro Asp Ala Ser Gly Arg Ser Ser Asn Arg Arg Asp Arg 195 200 205Pro Arg Gln Pro Ser Pro Ser Gln Ser Ser Asp Ser Gln Val His Ser 210 215 220Gly Val Gln Val Glu Gly Arg Arg Gly Gln Ser Ser Ser Ala Asn Arg225 230 235 240Arg Ala Gly Ser Ser Ser Gly Ser Gly Val Gln Gly Ala Ser Ala 245 250 255113541PRTMus musculus 11Met Ser Ile Leu Glu Pro Arg Thr Lys Ala Arg Pro Arg Asp Ala Leu1 5 10 15Ile Cys Gly Leu Ala Ala Asp Ala Ser Arg Arg Ser Gly Ala Arg Gln 20 25 30Gly Gln Ala Ser Ala Gln Gly Arg Ala Gly Ser Gln Gly Gln Ala Gln 35 40 45Gly Arg Val Gly Ser Ser Ala Asp Arg Gln Gly Arg Arg Gly Val Ser 50 55 60Glu Ser Gln Ala Ser Asp Ser Glu Gly His Ser Asp

Phe Ser Glu Gly65 70 75 80Gln Ala Val Gly Ala His Arg Gln Ser Gly Ala Gly Gln Arg His Glu 85 90 95Gln Arg Ser Ser Arg Gly Gln His Gly Ser Arg Tyr Tyr Tyr Glu Gln 100 105 110Glu His Ser Glu Glu Glu Ser Asp Ser Gln His Gln His Gly His Gln 115 120 125His Glu Gln Gln Arg Gly His Gln His Gln His Glu His Glu Gln Pro 130 135 140Glu Ser Gly His Arg Gln Gln Gln Ser Ser Gly Arg Gly His Gln Gly145 150 155 160Ala His Gln Glu Gln Gly Arg Asp Ser Ala Arg Ser Arg Gly Ser Asn 165 170 175Gln Gly His Ser Ser Ser Arg His Gln Ala Asp Ser Pro Arg Val Ser 180 185 190Ala Arg Ser Gly Ser Gly Gly Arg Gly Gln Ser Pro Asp Ala Ser Gly 195 200 205Arg Ser Ser Asn Arg Arg Asp Arg Pro Arg Gln Pro Ser Pro Ser Gln 210 215 220Ser Ser Asp Ser Gln Val His Ser Gly Val Gln Val Glu Gly Arg Arg225 230 235 240Gly Gln Ser Ser Ser Ala Asn Arg Arg Ala Gly Ser Ser Ser Gly Ser 245 250 255Gly Val Gln Gly Ala Ser Ala Gly Gly Leu Ala Ala Asp Ala Ser Arg 260 265 270Arg Ser Gly Ala Arg Gln Gly Gln Ala Ser Ala Gln Gly Arg Ala Gly 275 280 285Ser Gln Gly Gln Ala Gln Gly Arg Ile Gly Ser Ser Ala Asp Arg Gln 290 295 300Gly Arg Arg Gly Val Ser Glu Ser Gln Ala Ser Asp Ser Glu Gly His305 310 315 320Ser Asp Phe Ser Glu Gly Gln Ala Val Gly Ala His Arg Gln Ser Glu 325 330 335Ala Gly Gln Arg His Glu Gln Arg Ser Ser Arg Gly Gln His Gly Ser 340 345 350Gly Tyr Tyr Tyr Glu Gln Glu His Ser Glu Glu Glu Ser Asp Ser Gln 355 360 365His Gln His Gly His Gln His Glu Gln Gln Arg Gly Thr Gln His Gln 370 375 380His Glu His Gln Gln Pro Glu Ser Gly His Arg Gln Gln Gln Ser Ser385 390 395 400Gly Arg Gly His Gln Gly Thr His Gln Glu Gln Gly Arg Asp Ser Ala 405 410 415Arg Ser Arg Gly Ser Asn Gln Gly His Ser Ser Ser Arg His Gln Ala 420 425 430Asp Ser Pro Arg Val Ser Ala Arg Ser Gly Ser Gly Gly Arg Gly Gln 435 440 445Ser Pro Asp Ala Ser Gly Arg Ser Ser Asn Arg Arg Asp Arg Pro Arg 450 455 460Gln Pro Ser Pro Ser Gln Ser Ser Asp Ser Gln Val His Ser Gly Val465 470 475 480Gln Val Glu Gly Arg Arg Arg Gln Ser Ser Ser Ala Asn Arg Arg Ala 485 490 495Gly Ser Ser Ser Gly Ser Gly Val Gln Gly Ala Ser Ala Gly Gly Leu 500 505 510Ala Ala Asp Ala Ser Arg Arg Ser Gly Ala Arg Gln Gly Gln Ala Ser 515 520 525Ala Gln Gly Arg Ala Gly Ser Gln Gly Gln Ala Gln Gly Arg Val Gly 530 535 540Ser Ser Ala Asp Arg Gln Gly Arg Arg Gly Val Ser Glu Ser Gln Ala545 550 555 560Ser Asp Ser Glu Gly His Ser Asp Phe Ser Glu Gly Gln Ala Val Gly 565 570 575Ala His Arg Gln Ser Gly Ala Gly Gln Arg His Glu Gln Arg Ser Ser 580 585 590Arg Gly Gln His Gly Ser Gly Phe Tyr Pro Val Tyr Tyr Tyr Tyr Glu 595 600 605Gln Glu His Ser Glu Glu Glu Ser Asp Ser Gln His Gln His Gly His 610 615 620Gln His Glu Gln Gln Arg Gly His Gln His Gln His Gln His Glu His625 630 635 640Glu Gln Pro Glu Ser Gly His Arg Gln Gln Gln Ser Ser Gly Arg Gly 645 650 655His Gln Gly Ala His Gln Glu Gln Gly Arg Asp Ser Ala Arg Ser Arg 660 665 670Gly Ser Asn Gln Gly His Ser Ser Ser Arg His Gln Ala Asp Ser Pro 675 680 685Arg Val Ser Ala Arg Ser Gly Ser Gly Gly Arg Gly Gln Ser Pro Asp 690 695 700Ala Ser Gly Arg Ser Ser Asn Arg Arg Asp Arg Pro Arg Gln Pro Ser705 710 715 720Pro Ser Gln Ser Ser Asp Ser Gln Val His Ser Gly Val Gln Val Glu 725 730 735Gly Arg Arg Gly Gln Ser Ser Ser Ala Asn Arg Arg Ala Gly Ser Ser 740 745 750Ser Gly Ser Gly Val Gln Gly Ala Ser Ala Gly Gly Leu Ala Ala Asp 755 760 765Ala Ser Arg Arg Ser Gly Ala Leu Gln Gly Gln Ala Ser Ala Gln Gly 770 775 780Arg Ala Gly Ser Gln Gly Gln Ala Gln Gly Arg Val Gly Ser Ser Ala785 790 795 800Asp Arg Gln Gly Arg Arg Gly Val Ser Gly Ser Gln Ala Ser Asp Ser 805 810 815Glu Gly His Ser Asp Phe Ser Glu Gly Gln Ala Val Gly Ala His Arg 820 825 830Gln Ser Gly Ala Gly Gln Arg His Glu Gln Arg Ser Ser Arg Gly Gln 835 840 845His Gly Ser Gly Tyr Tyr Tyr Glu Gln Glu His Ser Glu Glu Glu Ser 850 855 860Asp Ser Gln His Gln His Gly Pro Pro Ala Arg Thr Ala Thr Gln Gln865 870 875 880Gln Phe Ser Gly Arg Gly His Gln Gly Ala His Gln Glu Gln Gly Arg 885 890 895Asp Ser Ala Arg Ser Arg Gly Ser Asn Gln Gly His Ser Ser Ser Arg 900 905 910His Gln Ala Asp Ser Pro Arg Val Ser Ala Arg Ser Gly Ser Gly Gly 915 920 925Arg Gly Gln Ser Pro Asp Ala Ser Gly Arg Ser Ser Asn Arg Arg Asp 930 935 940Arg Pro Arg Gln Pro Ser Pro Ser Gln Ser Ser Asp Ser Gln Val His945 950 955 960Ser Gly Val Gln Val Glu Gly Arg Arg Gly Gln Ser Ser Ser Ala Asn 965 970 975Arg Arg Ala Gly Ser Ser Ser Gly Ser Gly Val Gln Gly Ala Ser Ala 980 985 990Gly Gly Leu Ala Ala Asp Ala Ser Arg Arg Ser Gly Ala Arg Gln Gly 995 1000 1005Gln Ala Ser Ala Gln Gly Arg Ala Gly Ser Gln Gly Gln Ala Gln 1010 1015 1020Gly Arg Val Gly Ser Ser Ala Asp Arg Gln Gly Arg Arg Gly Val 1025 1030 1035Ser Glu Ser Gln Ala Ser Asp Ser Glu Gly His Ser Asp Phe Ser 1040 1045 1050Glu Gly Gln Ala Val Gly Ala His Arg Gln Ser Gly Ala Gly Gln 1055 1060 1065Arg His Glu Gln Arg Ser Ser Arg Gly Gln His Gly Ser Gly Phe 1070 1075 1080Tyr Pro Val Tyr Tyr Tyr Tyr Glu Gln Glu His Ser Glu Glu Glu 1085 1090 1095Ser Asp Ser Gln His Gln His Gly His Gln His Glu Gln Gln Arg 1100 1105 1110Gly His Gln His Gln His Gln His Gln His Glu His Glu Gln Pro 1115 1120 1125Glu Ser Gly His Arg Gln Gln Gln Ser Ser Gly Arg Gly His Gln 1130 1135 1140Gly Ala His Gln Glu Gln Gly Arg Asp Ser Ala Arg Ser Arg Gly 1145 1150 1155Ser Asn Gln Gly His Ser Ser Ser Arg His Gln Ala Asp Ser Pro 1160 1165 1170Arg Val Ser Ala Arg Ser Gly Ser Gly Gly Arg Gly Gln Ser Pro 1175 1180 1185Asp Ala Ser Gly Arg Ser Ser Asn Arg Arg Asp Arg Pro Arg Gln 1190 1195 1200Pro Ser Pro Ser Gln Ser Ser Asp Ser Gln Val His Ser Gly Val 1205 1210 1215Gln Val Glu Gly Arg Arg Gly Gln Ser Ser Ser Ala Asn Arg Arg 1220 1225 1230Ala Gly Ser Ser Ser Gly Ser Gly Val Gln Gly Ala Ser Ala Gly 1235 1240 1245Gly Leu Ala Ala Asp Ala Ser Arg Arg Ser Gly Ala Arg Gln Gly 1250 1255 1260Gln Ala Ser Ala Gln Gly Arg Ala Gly Ser Gln Gly Gln Ala Gln 1265 1270 1275Gly Arg Val Gly Ser Ser Ala Asp Arg Gln Gly Arg Arg Gly Val 1280 1285 1290Ser Glu Ser Gln Ala Ser Asp Ser Glu Gly His Ser Asp Phe Ser 1295 1300 1305Glu Gly Gln Ala Val Gly Ala His Arg Gln Ser Gly Ala Gly Gln 1310 1315 1320Arg His Glu Gln Arg Ser Ser Arg Gly Gln His Gly Ser Gly Tyr 1325 1330 1335Tyr Tyr Glu Gln Glu His Ser Glu Glu Glu Ser Asp Ser Gln His 1340 1345 1350Gln His Ser His Gln His Glu Gln Gln Arg Gly His Gln His Gln 1355 1360 1365His Gln His Gln His Glu His Glu Gln Pro Glu Ser Gly His Arg 1370 1375 1380Gln Gln Gln Phe Ser Gly Arg Gly His Gln Gly Ala His Gln Glu 1385 1390 1395Gln Gly Arg Asp Ser Ala Arg Ser Arg Gly Ser Asn Gln Gly His 1400 1405 1410Ser Ser Ser Arg His Gln Ala Asp Ser Pro Arg Val Ser Ala Arg 1415 1420 1425Ser Gly Ser Gly Gly Arg Gly Gln Ser Pro Asp Ala Ser Gly Arg 1430 1435 1440Ser Ser Asn Arg Arg Asp Arg Pro Arg Gln Pro Ser Pro Ser Gln 1445 1450 1455Ser Ser Asp Ser Gln Val His Ser Gly Val Gln Val Glu Gly Arg 1460 1465 1470Arg Gly Gln Ser Ser Ser Ala Asn Arg Arg Ala Gly Ser Ser Ser 1475 1480 1485Gly Ser Gly Val Gln Gly Ala Ser Ala Gly Gly Leu Ala Ala Asp 1490 1495 1500Ala Ser Arg Arg Ser Gly Ala Arg Gln Gly Gln Ala Ser Ala Gln 1505 1510 1515Gly Arg Ala Gly Ser Gln Gly Gln Ala Gln Gly Arg Val Gly Ser 1520 1525 1530Ser Ala Asp Arg Gln Gly Arg Arg Gly Val Ser Glu Ser Gln Ala 1535 1540 1545Ser Asp Ser Glu Gly His Ser Asp Phe Ser Glu Gly Gln Ala Val 1550 1555 1560Gly Ala His Arg Gln Ser Gly Ala Gly Gln Arg His Glu Gln Arg 1565 1570 1575Ser Ser Arg Gly Gln His Gly Ser Gly Phe Tyr Pro Val Tyr Tyr 1580 1585 1590Tyr Tyr Glu Gln Glu His Ser Glu Glu Glu Ser Asp Ser Gln His 1595 1600 1605Gln His Gly His Gln His Glu Gln Gln Arg Gly His Gln His Gln 1610 1615 1620His Gln His Gln His Glu His Glu Gln Pro Glu Ser Gly His Arg 1625 1630 1635Gln Gln Gln Ser Ser Gly Arg Gly His Gln Gly Ala His Gln Glu 1640 1645 1650Gln Gly Arg Asp Ser Ala Arg Ser Arg Gly Ser Asn Gln Gly His 1655 1660 1665Ser Ser Ser Arg His Gln Ala Asp Ser Pro Arg Val Ser Ala Arg 1670 1675 1680Ser Gly Ser Gly Gly Arg Gly Gln Ser Pro Asp Ala Ser Gly Arg 1685 1690 1695Ser Ser Asn Arg Arg Asp Arg Pro Arg Gln Pro Ser Pro Ser Gln 1700 1705 1710Ser Ser Asp Ser Gln Val His Ser Gly Val Gln Val Glu Gly Arg 1715 1720 1725Arg Gly Gln Ser Ser Ser Ala Asn Arg Arg Ala Gly Ser Ser Ser 1730 1735 1740Gly Ser Gly Val Gln Gly Ala Ser Ala Gly Gly Leu Ala Ala Asp 1745 1750 1755Ala Ser Arg Arg Ser Gly Ala Arg Gln Gly Gln Ala Ser Ala Gln 1760 1765 1770Gly Arg Ala Gly Ser Gln Gly Gln Ala Gln Gly Arg Val Gly Ser 1775 1780 1785Ser Ala Asp Arg Gln Gly Arg Arg Gly Val Ser Glu Ser Gln Ala 1790 1795 1800Ser Asp Ser Glu Gly His Ser Asp Phe Ser Glu Gly Gln Ala Val 1805 1810 1815Gly Ala His Arg Gln Ser Gly Ala Gly Gln Arg His Glu Gln Arg 1820 1825 1830Ser Ser Arg Ser Gln His Gly Ser Gly Tyr Tyr Tyr Glu Gln Glu 1835 1840 1845His Ser Glu Glu Glu Ser Asp Ser Gln His Gln His Ser His Gln 1850 1855 1860His Glu Gln Gln Arg Gly His Gln His Gln His Gln His Gln His 1865 1870 1875Glu His Glu Gln Pro Glu Ser Gly His Arg Gln Gln Gln Ser Ser 1880 1885 1890Gly Arg Gly Asn Gln Gly Ala His Gln Glu Gln Gly Arg Asp Ser 1895 1900 1905Ala Arg Ser Arg Gly Ser Asn Gln Gly His Ser Ser Ser Arg His 1910 1915 1920Gln Ala Asp Ser Pro Arg Val Ser Ala Arg Ser Gly Ser Gly Gly 1925 1930 1935Arg Gly Gln Ser Pro Asp Ala Ser Gly Arg Ser Ser Asn Arg Arg 1940 1945 1950Asp Arg Pro Arg Gln Pro Ser Pro Ser Gln Ser Ser Asp Ser His 1955 1960 1965Val His Ser Gly Val Gln Val Glu Gly Arg Arg Gly Gln Ser Ser 1970 1975 1980Ser Ala Asn Arg Arg Ala Gly Ser Ser Ser Gly Ser Gly Val Gln 1985 1990 1995Gly Ala Ser Ala Gly Gly Leu Ala Ala Asp Ala Ser Arg Arg Ser 2000 2005 2010Gly Ala Arg Gln Gly Gln Ala Ser Ala Gln Gly Arg Ala Gly Ser 2015 2020 2025Gln Gly Gln Ala Gln Gly Arg Val Gly Ser Ser Ala Asp Arg Gln 2030 2035 2040Gly Arg Arg Gly Val Ser Glu Ser Gln Ala Ser Asp Ser Glu Gly 2045 2050 2055His Ser Asp Phe Ser Glu Gly Gln Ala Val Gly Ala His Arg Gln 2060 2065 2070Ser Gly Ala Gly Gln Arg His Glu Gln Arg Ser Ser Arg Gly Gln 2075 2080 2085His Gly Ser Gly Phe Tyr Pro Val Tyr Tyr Tyr Tyr Glu Gln Glu 2090 2095 2100His Ser Glu Glu Glu Ser Asp Ser Gln His Gln His Gly His Gln 2105 2110 2115His Glu Gln Gln Arg Gly His Gln His Gln His Gln His Gln His 2120 2125 2130Glu His Glu Gln Pro Glu Ser Gly His Arg Gln Gln Gln Ser Ser 2135 2140 2145Gly Arg Gly His Gln Gly Ala His Gln Glu Gln Gly Arg Asp Ser 2150 2155 2160Ala Arg Ser Arg Gly Ser Asn Gln Gly His Ser Ser Ser Arg His 2165 2170 2175Gln Ala Asp Ser Pro Arg Val Ser Ala Arg Ser Gly Ser Gly Gly 2180 2185 2190Arg Gly Gln Ser Pro Asp Ala Ser Gly Arg Ser Ser Asn Arg Arg 2195 2200 2205Asp Arg Ser Arg Gln Pro Ser Pro Ser Gln Ser Ser Asp Ser Gln 2210 2215 2220Val His Ser Gly Val Gln Val Glu Gly Arg Arg Gly Gln Ser Ser 2225 2230 2235Ser Ala Asn Arg Arg Ala Gly Ser Ser Ser Gly Ser Gly Val Gln 2240 2245 2250Gly Ala Ser Ala Gly Gly Leu Ala Ala Asp Ala Ser Arg Arg Ser 2255 2260 2265Gly Ala Arg Gln Gly Gln Ala Ser Ala Gln Gly Arg Ala Gly Ser 2270 2275 2280Gln Gly Gln Ala Gln Gly Arg Val Gly Ser Ser Ala Asp Arg Gln 2285 2290 2295Gly Arg Arg Gly Val Ser Glu Ser Gln Ala Ser Asp Ser Glu Gly 2300 2305 2310His Ser Asp Phe Ser Glu Gly Gln Ala Val Gly Ala His Arg Gln 2315 2320 2325Ser Gly Ala Gly Gln Arg His Glu Gln Arg Ser Ser Arg Gly Gln 2330 2335 2340His Gly Ser Gly Phe Tyr Pro Val Tyr Tyr Tyr Tyr Glu Gln Glu 2345 2350 2355His Ser Glu Glu Glu Ser Asp Ser Gln His Gln His Gly His Gln 2360 2365 2370His Glu Gln Gln Arg Gly His Gln His Gln His Gln His Glu His 2375 2380 2385Glu Gln Pro Glu Ser Gly His Arg Gln Gln Gln Ser Ser Gly Arg 2390 2395 2400Gly His Gln Gly Ala His Gln Glu Gln Gly Arg Asp Ser Ala Arg 2405 2410 2415Ser Arg Gly Ser Asn Gln Gly His Ser Ser Ser Arg His Gln Ala 2420 2425 2430Asp Ser Pro Arg Val Ser Ala Arg Ser Gly Ser Gly Gly Arg Gly 2435 2440 2445Gln Ser Pro Asp Ala Ser Gly Arg Ser Ser Asn Arg Arg Asp Arg 2450 2455 2460Pro Arg Gln Pro Ser Pro Ser Gln Ser Ser Asp Ser Gln Val His 2465 2470 2475Ser Gly Val Gln Val Glu Gly Arg Arg Gly Gln Ser Ser Ser Ala 2480 2485 2490Asn Arg Arg Ala Gly Ser Ser Ser Gly Ser Gly Val Gln Gly Ala 2495 2500 2505Ser Ala Gly Gly Leu Ala Ala Asp Ala Ser Arg Arg Ser Gly Ala 2510

2515 2520Leu Gln Gly Gln Ala Ser Ala Gln Gly Arg Ala Gly Ser Gln Gly 2525 2530 2535Gln Ala Gln Gly Arg Val Gly Ser Ser Ala Asp Arg Gln Gly Arg 2540 2545 2550Arg Gly Val Ser Glu Ser Gln Ala Ser Asp Ser Glu Gly His Ser 2555 2560 2565Asp Phe Ser Glu Gly Gln Ala Val Gly Ala His Arg Gln Ser Gly 2570 2575 2580Ala Gly Gln Arg His Glu Gln Arg Ser Ser Arg Gly Gln His Gly 2585 2590 2595Ser Gly Tyr Tyr Tyr Glu Gln Glu His Ser Glu Glu Glu Ser Asp 2600 2605 2610Ser Gln His Gln His Gly His Gln His Glu Gln Gln Arg Gly His 2615 2620 2625Gln His Gln His Gln His Gln His Glu His Glu Gln Pro Glu Ser 2630 2635 2640Gly His Arg Gln Gln Gln Ser Ser Gly Arg Gly His Gln Gly Ala 2645 2650 2655His Gln Glu Gln Gly Arg Asp Ser Ala Arg Ser Arg Gly Ser Asn 2660 2665 2670Gln Gly His Ser Ser Ser Arg His Gln Ala Asp Ser Pro Arg Val 2675 2680 2685Ser Ala Arg Ser Gly Ser Gly Gly Arg Gly Gln Ser Pro Asp Ala 2690 2695 2700Ser Gly Arg Ser Ser Asn Arg Arg Asp Arg Pro Arg Gln Pro Ser 2705 2710 2715Pro Ser Gln Ser Ser Asp Ser Gln Val His Ser Gly Val Gln Val 2720 2725 2730Glu Gly Arg Arg Gly Gln Ser Ser Ser Ala Asn Arg Arg Ala Gly 2735 2740 2745Ser Ser Ser Gly Ser Gly Val Gln Gly Ala Ser Ala Gly Gly Leu 2750 2755 2760Ala Ala Asp Ala Ser Arg Arg Ser Gly Ala Arg Gln Gly Gln Ala 2765 2770 2775Ser Ala Gln Gly Arg Ala Gly Ser Gln Gly Gln Ala Gln Gly Arg 2780 2785 2790Val Gly Ser Ser Ala Asp Arg Gln Gly Arg Arg Gly Val Ser Gly 2795 2800 2805Ser Gln Ala Ser Asp Ser Glu Gly His Ser Asp Phe Ser Glu Gly 2810 2815 2820Gln Ala Val Gly Ala His Arg Gln Ser Gly Ala Gly Gln Arg His 2825 2830 2835Glu Gln Arg Ser Ser Arg Gly Gln His Gly Ser Gly Tyr Tyr Tyr 2840 2845 2850Glu Gln Glu His Ser Glu Glu Glu Ser Asp Ser Gln His Gln His 2855 2860 2865Gly His Gln His Glu Gln Gln Arg Gly His Gln His Gln His Gln 2870 2875 2880His Gln His Glu His Glu Gln Pro Glu Ser Gly His Arg Gln Gln 2885 2890 2895Gln Phe Ser Gly Arg Gly His Gln Gly Ala His Gln Glu Gln Gly 2900 2905 2910Arg Asp Ser Ala Arg Ser Arg Gly Ser Asn Gln Gly His Ser Ser 2915 2920 2925Ser Arg His Gln Ala Asp Ser Pro Arg Val Ser Ala Arg Ser Gly 2930 2935 2940Ser Gly Gly Arg Gly Gln Ser Pro Asp Ala Ser Gly Arg Ser Ser 2945 2950 2955Asn Arg Arg Asp Arg Pro Arg Gln Pro Ser Pro Ser Gln Ser Ser 2960 2965 2970Asp Ser Gln Val His Ser Gly Val Gln Val Glu Gly Arg Arg Gly 2975 2980 2985Gln Ser Ser Ser Ala Asn Arg Arg Ala Gly Ser Ser Ser Ser Ser 2990 2995 3000Gly Val Gln Gly Ala Ser Ala Gly Gly Leu Ala Ala Asp Ala Ser 3005 3010 3015Arg Arg Ser Gly Ala Arg Gln Gly Gln Ala Ser Ala Gln Gly Arg 3020 3025 3030Ala Gly Ser Gln Gly Gln Ala Gln Gly Arg Val Gly Ser Ser Ala 3035 3040 3045Asp Arg Gln Gly Arg Arg Gly Val Ser Glu Ser Gln Ala Ser Asp 3050 3055 3060Ser Glu Gly His Ser Asp Phe Ser Glu Gly Gln Ala Val Gly Ala 3065 3070 3075His Arg Gln Ser Gly Ala Gly Gln Arg His Glu Gln Arg Ser Ser 3080 3085 3090Arg Gly Gln His Gly Ser Gly Phe Tyr Pro Val Tyr Tyr Tyr Tyr 3095 3100 3105Glu Gln Glu His Ser Glu Glu Glu Ser Asp Ser Gln His Gln His 3110 3115 3120Gly His Gln His Glu Gln Gln Arg Gly His Gln His Gln His Gln 3125 3130 3135His Gln His Glu His Glu Gln Pro Glu Ser Gly His Arg Gln Gln 3140 3145 3150Gln Phe Ser Gly Arg Gly His Gln Gly Ala His Gln Glu Gln Gly 3155 3160 3165Arg Asp Ser Ala Arg Ser Arg Gly Ser Asn Gln Gly His Ser Ser 3170 3175 3180Ser Arg His Gln Ala Asp Ser Pro Arg Val Ser Ala Arg Ser Gly 3185 3190 3195Ser Gly Gly Arg Gly Gln Ser Pro Asp Ala Ser Gly Arg Ser Ser 3200 3205 3210Asn Arg Arg Asp Arg Pro Arg Gln Pro Ser Pro Ser Gln Ser Ser 3215 3220 3225Asp Ser Gln Val His Ser Gly Val Gln Val Glu Gly Arg Arg Gly 3230 3235 3240Gln Ser Ser Ser Ala Asn Arg Arg Ala Gly Ser Ser Ser Gly Ser 3245 3250 3255Gly Val Gln Gly Ala Ser Ala Gly Gly Leu Ala Ala Asp Ala Ser 3260 3265 3270Arg Arg Ser Gly Ala Arg Gln Gly Gln Ala Ser Ala Gln Gly Arg 3275 3280 3285Ala Gly Ser Gln Gly Gln Ala Gln Gly Arg Val Gly Ser Ser Ala 3290 3295 3300Asp Arg Gln Gly Arg Arg Gly Val Ser Glu Ser Gln Ala Ser Asp 3305 3310 3315Ser Glu Gly His Ser Asp Phe Ser Glu Gly Gln Ala Val Gly Ala 3320 3325 3330His Arg Gln Ser Gly Ala Gly Gln Arg His Glu Gln Arg Ser Ser 3335 3340 3345Arg Gly Gln His Gly Ser Gly Tyr Tyr Tyr Glu Gln Glu His Ser 3350 3355 3360Glu Glu Glu Ser Asp Ser Gln His Gln Gln Gly His Gln His Glu 3365 3370 3375Gln Gln Arg Gly His Gln His Gln His Gln His Gln His Glu His 3380 3385 3390Glu Gln Pro Glu Ser Gly His Arg Gln Gln Gln Ser Ser Gly Arg 3395 3400 3405Gly His Gln Gly Ala His Gln Glu Gln Gly Arg Asp Ser Ala Arg 3410 3415 3420Ser Arg Gly Ser Asn Gln Gly His Ser Ser Ser Arg His Gln Ala 3425 3430 3435Asp Ser Pro Arg Val Ser Ala Arg Ser Gly Ser Gly Gly Arg Gly 3440 3445 3450Gln Ser Pro Asp Gly Ser Gly Arg Ser Ser Asn Arg Arg Asp Arg 3455 3460 3465Pro Arg Gln Pro Ser Ala Ser Gln Ser Ser Asp Ser Gln Val His 3470 3475 3480Ser Gly Val Gln Val Glu Ala Gln Arg Gly Gln Ser Ser Ser Ala 3485 3490 3495Asn Arg Arg Ala Gly Ser Ser Ser Gly Ser Gly Val Gln Ser Ala 3500 3505 3510Ala Ala Ser Gly Gln Gly Gly Tyr Glu Ser Ile Phe Thr Ala Lys 3515 3520 3525His Leu Asp Phe Asn Gln Ser His Ser Tyr Tyr Tyr Tyr 3530 3535 354012336PRTMus musculus 12Pro Asp Gly Ser Gly Arg Ser Ser Asn Arg Arg Asp Arg Pro Arg Gln1 5 10 15Leu Ser Pro Ser Gln Ser Ser Asp Ser Gln Val His Ser Gly Val Gln 20 25 30Val Glu Gly Arg Arg Gly His Ser Ser Ser Ala Asn Arg Arg Ala Gly 35 40 45Ser Ser Ser Gly Ser Gly Val Gln Gly Ala Ser Ala Gly Gly Leu Ala 50 55 60Ala Asp Ala Ser Arg Arg Ser Gly Ala Arg Gln Gly Gln Ala Ser Ala65 70 75 80Gln Gly Arg Ala Gly Ser Gln Gly Gln Ala Gln Gly Arg Val Ser Ser 85 90 95Ser Ala Asp Arg Gln Gly Arg Arg Gly Val Ser Glu Ser Arg Ala Ser 100 105 110Asp Ser Glu Gly His Ser Asp Phe Ser Glu Gly Gln Ala Val Gly Ala 115 120 125His Arg Gln Ser Gly Ala Gly Gln Arg His Glu Gln Arg Ser Ser Arg 130 135 140Gly Gln His Gly Ser Gly Tyr Tyr Tyr Glu Gln Glu His Ser Glu Glu145 150 155 160Glu Ser Asp Ser Gln His Gln His Gly His Gln His Glu Gln Gln Arg 165 170 175Gly His Gln His Gln His Gln His Gln His Glu His Glu Gln Pro Glu 180 185 190Ser Gly His Arg Gln Gln Gln Ser Ser Gly Arg Gly His Gln Gly Ala 195 200 205His Gln Glu Gln Gly Arg Asp Ser Ala Arg Pro Arg Gly Ser Asn Gln 210 215 220Gly His Ser Ser Ser Arg His Gln Ala Asp Ser Pro Arg Val Ser Ala225 230 235 240Arg Ser Gly Ser Gly Gly Arg Gly Gln Ser Pro Asp Ala Ser Gly Arg 245 250 255Ser Ser Asn Arg Arg Asp Arg Pro Arg Gln Pro Ser Pro Ser Gln Ser 260 265 270Ser Asp Ser Gln Val His Ser Gly Val Gln Val Glu Ala Gln Arg Gly 275 280 285Gln Ser Ser Ser Ala Asn Arg Arg Ala Gly Ser Ser Ser Gly Ser Gly 290 295 300Val Gln Gly Ala Ala Ala Ser Gly Gln Gly Gly Tyr Glu Ser Ile Phe305 310 315 320Thr Ala Lys His Leu Asp Phe Asn Gln Ser His Ser Tyr Tyr Tyr Tyr 325 330 33513357PRTMus musculus 13Met Ser Ala Leu Leu Glu Ser Ile Thr Ser Met Ile Glu Ile Phe Gln1 5 10 15Gln Tyr Ser Thr Ser Asp Lys Glu Glu Glu Thr Leu Ser Lys Glu Glu 20 25 30Leu Lys Glu Leu Leu Glu Gly Gln Leu Gln Ala Val Leu Lys Asn Pro 35 40 45Asp Asp Gln Asp Ile Ala Glu Val Phe Met Gln Met Leu Asp Val Asp 50 55 60His Asp Asp Lys Leu Asp Phe Ala Glu Tyr Leu Leu Leu Val Leu Lys65 70 75 80Leu Ala Lys Ala Tyr Tyr Glu Ala Ser Lys Asn Glu Ser Phe Gln Thr 85 90 95His Gly Ser Asn Gly Arg Ser Lys Thr Asp Tyr Lys Gly Leu Glu Glu 100 105 110Glu Gly Glu Glu Gly Asn Lys Gln Asn Leu Arg Arg Arg His Gly Gly 115 120 125Thr Asp Gly Lys Arg Lys Ser Asp Arg Thr Arg Ser Pro Asn Gly Lys 130 135 140Arg Gly Lys Arg Gln Glu Ser Arg Cys Arg Ser Glu Gly Lys Asp Lys145 150 155 160His Arg Arg Glu Pro Glu Lys His Arg His Gln Gln Asp Ser Lys Arg 165 170 175Lys Gln Arg His Gly Ser Gly Ser Thr Glu Arg Lys Asp Asn Arg Asn 180 185 190Lys Lys Asn Arg Gln Ser Lys Glu Arg Asn Tyr Asp Glu Ile Tyr Asp 195 200 205Asn Gly Lys Tyr Asn Glu Asp Trp Glu Ala Ser Tyr Asn Asn Cys Tyr 210 215 220Tyr Lys Thr Gln Asn Thr Thr Leu Asp Gln Arg Glu Gly Asn Arg Arg225 230 235 240Pro Arg Ala Asp Ser Gln Lys Glu Pro Gln Ser Ser His Gly Gln Ala 245 250 255Asp Asn Ser Asp Ser Glu Gly Gly Arg Gln Gln Ser His Ser Lys Pro 260 265 270Ser Pro Val Arg Ala Asp Gln Arg Arg Ser Arg Ala Gly Gln Ala Gly 275 280 285Ser Ser Lys Val Ser Ala Arg Ser Gly Ser Gly Gly Arg Gly Gln Ser 290 295 300Pro Asp Gly Ser Gly Arg Ser Ser Asn Arg Arg Asp Arg Pro Arg Gln305 310 315 320Pro Ser Pro Ser Gln Ser Ser Asp Ser Gln Val His Ser Gly Val Gln 325 330 335Val Glu Gly Arg Arg Gly Gln Ser Ser Ser Ala Asn Arg Arg Ala Gly 340 345 350Ser Ser Ser Gly Ser 35514366PRTRattus norvegicus 14Met Ser Thr Leu Leu Glu Ser Ile Thr Ser Met Ile Asp Ile Phe Gln1 5 10 15Gln Tyr Ser Asn Asn Asp Lys Glu Glu Glu Thr Leu Ser Lys Glu Glu 20 25 30Leu Lys Glu Leu Leu Glu Gly Glu Leu Gln Ala Val Leu Lys Asn Pro 35 40 45Asn Asp Gln Asp Ile Ala Glu Val Phe Met Gln Met Leu Asp Val Asp 50 55 60His Asp Asp Lys Ile Asp Phe Thr Glu Tyr Leu Leu Met Val Leu Lys65 70 75 80Leu Ala Gln Ala Tyr Tyr Glu Thr Ser Lys Lys Arg Arg Ser Gln Thr 85 90 95Lys Glu Ser Gly Lys Arg Asn Glu His Asp Tyr Lys Gly Tyr Glu Glu 100 105 110Arg Arg Glu Lys Val Gln Arg Arg His Arg Arg Arg Asn Ser Gly Thr 115 120 125Asp Gly Lys Gln Glu Asn Glu Arg Ser Lys Ser Pro Arg Gly Arg Gly 130 135 140Asn Lys Arg Arg Gly Ser Ser Thr Ile Ser Glu Glu Ser Asp Thr Asn145 150 155 160Arg Asn Ser Asp Thr Glu Asn Lys Arg His His His Gly Ser Asn Arg 165 170 175Arg Gln Arg Arg Gly Ser Asn Ser Ser Asp Arg Lys Glu Thr Arg Ser 180 185 190Lys Lys His Arg Glu Val Lys Glu Arg Asn Ala Gly Ile Tyr Asn Asp 195 200 205Gly Lys Asp Gly Gln Asp Trp Glu Val Asn Tyr Glu Asn Cys Tyr Tyr 210 215 220Lys Thr Glu Glu Ser Asn Arg Glu Gln Arg Glu Gly Arg Asn His Lys225 230 235 240Thr Lys Glu Ser His Ser Glu Ser Glu Ala Ser Gly Gly Gln Ala Gly 245 250 255Arg Arg Gly Thr Ala Ala Thr Arg His Thr Ser Arg Pro Glu Gln Ser 260 265 270Pro Asp Thr Ala Gly Arg Thr Gly Ser Ser Arg Gly Gln Gln Ser Ala 275 280 285Gln Arg His Ala Asp Ser Thr Pro Gly Ser Thr Arg Thr Gly Ser Arg 290 295 300Gly Arg Gly Glu Ser Pro Ala Gly Gln Gln Ser Pro Asp Arg Ala Arg305 310 315 320His Ile Glu Ser Arg Arg Gly Arg Thr Arg Glu Ala Ser Ala Ser Gln 325 330 335Ser Ser Asp Ser Glu Gly His Ser Gly Ala His Ala Gly Ile Gly Gln 340 345 350Gly Gln Thr Ser Thr Thr His Arg Arg Ala Gly Ser Ser Ser 355 360 365153088PRTPan troglodytes 15Met Ser Thr Leu Leu Glu Asn Ile Phe Ala Ile Ile Asn Leu Phe Lys1 5 10 15Gln Tyr Ser Lys Lys Asp Lys Asn Thr Asp Thr Leu Ser Lys Lys Glu 20 25 30Leu Lys Glu Leu Leu Glu Lys Glu Phe Arg Gln Ile Leu Lys Asn Pro 35 40 45Asp Asp Pro Asp Met Val Asp Val Phe Met Asp His Leu Asp Ile Asp 50 55 60His Asn Lys Lys Ile Asp Phe Thr Glu Phe Leu Leu Met Val Phe Lys65 70 75 80Leu Ala Gln Ala Tyr Tyr Glu Ser Thr Arg Lys Glu Asn Leu Pro Ile 85 90 95Ser Gly His Lys His Arg Lys His Ser His His Asp Lys His Glu Asp 100 105 110Asn Lys Gln Glu Glu Asn Lys Glu Asn Arg Lys Arg Pro Ser Ser Leu 115 120 125Glu Arg Arg Asn Asn Arg Lys Gly Asn Lys Gly Arg Ser Lys Ser Pro 130 135 140Arg Glu Thr Gly Gly Lys Arg His Glu Ser Ser Ser Glu Lys Lys Glu145 150 155 160Arg Lys Gly Tyr Ser Pro Thr His Arg Glu Glu Glu Tyr Gly Lys Asn 165 170 175His His Asn Ser Ser Lys Lys Gln Lys Asn Lys Thr Glu Asn Thr Arg 180 185 190Leu Glu Asp Asn Arg Lys Arg Leu Ser Glu Arg Leu Glu Glu Lys Glu 195 200 205Asp Asn Glu Glu Gly Gly Tyr Asp Tyr Glu Asn Thr Gly Arg Met Thr 210 215 220Gln Lys Trp Ile Gln Ser Gly His Ile Ala Thr Tyr Tyr Thr Ile Gln225 230 235 240Asp Glu Ala Tyr Asp Thr Thr Asp Asn Leu Leu Glu Glu Asn Lys Ile 245 250 255Tyr Glu Arg Ser Arg Ser Ser Asp Asp Lys Ser Ser Ser Gln Val Asn 260 265 270Arg Ser Arg His Glu Asn Thr Ser Gln Val Pro Leu Gln Glu Ser Arg 275 280 285Thr Arg Lys Arg Arg Gly Ser Arg Val Ser Gln Asp Arg Asp Ser Glu 290 295 300Gly His Ser Glu Asp Ser Glu Arg His Ser Gly Ser Ala Ser Arg Asn305 310 315 320His Pro Gly Ser Ala Arg Gln Gln Ser Arg Asp Gly Ser Arg His Pro 325 330 335Arg Ser His Asp Glu Asp Arg Ala Ser His Gly His Ser Ala Asp Ser 340 345 350Ser Arg Gln Ser Gly Thr Arg His Ala Glu Thr Ser Ser Arg Gly Gln

355 360 365Thr Ala Ser Ser His Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His 370 375 380Gly Ser Arg His Gln Gln Ser Ala Asp Ser Ser Arg His Ser Ala Thr385 390 395 400Gly Arg Gly Gln Ala Ser Ser Ala Val Ser Asp Arg Gly Pro Arg Gly 405 410 415Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Asn Ser 420 425 430Asp Thr Gln Ser Val Ser Gly His Gly Lys Ala Gly Pro Arg Gln Gln 435 440 445Ser His Gln Glu Ser Ala Arg Gly Arg Ser Gly Glu Arg Ser Gly His 450 455 460Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Asp Ser465 470 475 480Ala His Gly Arg Thr Gly Thr Ser Thr Gly Gly Arg Gln Gly Ser His 485 490 495His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser Gln Glu Gly 500 505 510Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg Gln 515 520 525Gly Ser His His Glu Gln Leu Val Asn Arg Ser Gly His Ser Gly Ser 530 535 540His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser His Gly545 550 555 560Gln Ser Gly Ser Arg Ser Ala Ser Arg Gln Thr Arg Asn Glu Glu Gln 565 570 575Ser Gly Asp Gly Ser Arg His Ser Gly Ser Arg His His Glu Ala Ser 580 585 590Ser Gln Ala Asp Ser Ser Arg His Ser Gln Val Gly Gln Gly Gln Ser 595 600 605Ser Gly Pro Arg Thr Ser Ser His Gln Gly Ser Ser Val Ser Gln Asp 610 615 620Ser Asp Ser Glu Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser625 630 635 640Ala Ser Arg Asn His His Gly Ser Ala Arg Glu Gln Ser Arg Asp Gly 645 650 655Ser Arg His Pro Arg Ser His His Glu Asp Arg Ala Gly His Gly His 660 665 670Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr Arg His Thr Glu Ser Ser 675 680 685Ser Arg Gly Gln Ala Val Ser Ser His Glu Gln Ala Arg Ser Ser Pro 690 695 700Gly Glu Arg His Gly Ser Arg His Gln Gln Ser Ala Asp Ser Ser Arg705 710 715 720His Ser Gly Ile Gly His Gly Gln Ala Ser Ser Ala Val Arg Asp Ser 725 730 735Gly His Arg Gly Ser Ser Gly Ser Gln Ala Ile Asp Ser Glu Gly His 740 745 750Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ser His Gly Gln Ala Gly 755 760 765Pro His Gln Gln Ser His Lys Glu Ser Ala Arg Gly Gln Ser Gly Glu 770 775 780Ser Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Ser His Glu785 790 795 800Gln Ser Glu Ser Thr Tyr Gly Gln Thr Ala Pro Ser Thr Gly Gly Arg 805 810 815Gln Gly Ser Arg His Glu Gln Ala Arg Asn Ser Ser Arg His Ser Ala 820 825 830Ser Gln Asp Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser Arg 835 840 845Gly Gly Arg Gln Gly Ser Tyr His Glu Gln Ser Val Asp Arg Ser Gly 850 855 860His Ser Gly Tyr His His Ser His Thr Thr Pro Gln Gly Arg Ser Asp865 870 875 880Ala Ser His Gly Gln Ser Gly Pro Arg Ser Ala Ser Arg Gln Thr Arg 885 890 895Asn Glu Glu Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser Arg His 900 905 910His Glu Pro Ser Thr Arg Ala Ser Ser Ser Arg His Ser Gln Val Gly 915 920 925Gln Gly Glu Ser Ala Val Ser Lys Thr Ser Arg Arg Gln Gly Ser Ser 930 935 940Val Ser Gln Asp Arg Asp Ser Glu Gly His Ser Glu Asp Ser Glu Arg945 950 955 960Gln Ser Glu Ser Ala Ser Arg Asn His Tyr Gly Ser Ala Arg Glu Gln 965 970 975Ser Arg His Gly Ser Arg Asn Pro Arg Ser His Gln Glu Asp Arg Ala 980 985 990Ser His Gly His Ser Ala Glu Ser Ser Arg Gln Ser Gly Thr His His 995 1000 1005Ala Glu Thr Ser Ser His Gly Gln Ala Ala Ser Ser Gln Glu Gln 1010 1015 1020Ala Arg Ser Ser Arg Gly Glu Arg His Gly Ser Arg His Gln Gln 1025 1030 1035Ser Ala Asp Ser Ser Thr Asp Ser Gly Thr Gly Gly Arg Gln Ala 1040 1045 1050Ser Ser Val Val Gly Asp Ser Gly Asn Arg Gly Ser Ser Gly Ser 1055 1060 1065Gln Ala Ser Asp Ser Glu Gly His Ser Glu Asp Ser Asp Thr Gln 1070 1075 1080Ser Val Ser Ala His Gly Gln Ala Gly Pro Arg Gln Gln Ser His 1085 1090 1095Gln Glu Ser Thr Arg Gly Gln Ser Gly Glu Arg Ser Gly Arg Ser 1100 1105 1110Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser 1115 1120 1125Ala His Gly Arg Thr Gly Pro Ser Thr Gly Gly Arg Gln Arg Ser 1130 1135 1140Arg His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser Gln 1145 1150 1155Glu Ser Gln Asp Ile Ile His Ala His Pro Gly Ser Ser Arg Gly 1160 1165 1170Gly Arg Gln Gly Ser His Tyr Glu Gln Ser Val Asp Arg Ser Gly 1175 1180 1185His Ser Gly Ser His His Ser His Thr Thr Ser Gln Glu Arg Ser 1190 1195 1200Asn Ala Ser His Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Gln 1205 1210 1215Thr Arg Asn Glu Glu Gln Ser Gly Asp Gly Ser Arg His Ser Gly 1220 1225 1230Ser Arg His His Glu Ala Ser Ser Arg Ala Asp Ser Ser Arg His 1235 1240 1245Ser Gln Val Gly Gln Gly Gln Ser Ser Gly Pro Arg Thr Ser Arg 1250 1255 1260Asn Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Gln Gly His 1265 1270 1275Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser Ala Ser Arg Asn His 1280 1285 1290His Gly Ser Ala Trp Glu Gln Ser Arg Asp Gly Ser Arg His Pro 1295 1300 1305Gly Ser His Gln Glu Asp Arg Ala Gly His Gly His Ser Ala Asp 1310 1315 1320Ser Ser Arg Gln Ser Gly Thr His His Thr Glu Ser Ser Ser Arg 1325 1330 1335Gly Gln Ala Ala Ser Ser His Glu His Ala Arg Ser Ser Ala Gly 1340 1345 1350Glu Arg His Gly Ser His His Gln Gln Ser Ala Asp Ser Ser Arg 1355 1360 1365His Ser Gly Ile Gly His Gly Gln Ala Ser Ser Ala Val Arg Asp 1370 1375 1380Ser Gly His Arg Gly Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu 1385 1390 1395Gly His Ser Glu Asp Ser Asp Thr Gln Ser Leu Ser Ala His Gly 1400 1405 1410Gln Ala Gly Pro His Gln Gln Ser His Gln Glu Ser Thr Arg Gly 1415 1420 1425Arg Ser Ala Glu Arg Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln 1430 1435 1440Val Ser Thr His Glu Gln Ser Glu Ser Ala His Gly Arg Thr Gly 1445 1450 1455Thr Ser Thr Gly Gly Arg Lys Arg Ser Leu His Glu Gln Ala Arg 1460 1465 1470Asp Ser Ser Arg His Ser Val Ser Gln Glu Gly Gln Asp Thr Ile 1475 1480 1485His Gly His Ala Gly Ser Ser Ser Gly Gly Arg Gln Gly Ser His 1490 1495 1500Tyr Glu Gln Leu Val Asp Arg Ser Gly His Ser Gly Ser His His 1505 1510 1515Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala Tyr His Gly Gln 1520 1525 1530Ser Gly Ser Arg Ser Ala Ser Arg Gln Thr His Asn Asp Glu Gln 1535 1540 1545Ser Gly Asp Gly Phe Arg His Ser Gly Ser His His His Glu Ala 1550 1555 1560Ser Ser Arg Ala Asp Ser Ser Arg His Ser Gln Val Gly Gln Gly 1565 1570 1575Gln Ser Glu Gly Pro Arg Thr Ser Arg His Arg Glu Ser Ser Val 1580 1585 1590Ser Gln Asp Ser Asp Ser Glu Gly His Ser Glu Asp Ser Glu Arg 1595 1600 1605Trp Ser Gly Ser Ala Ser Arg Asn His His Gly Ser Ala Arg Glu 1610 1615 1620Gln Ser Arg Asp Gly Ser Arg His Pro Arg Ser His His Glu Asp 1625 1630 1635Arg Ala Gly His Gly His Ser Ala Asp Ser Ser Arg Gln Ser Gly 1640 1645 1650Thr Arg His Thr Gln Thr Ser Ser Gly Gly Gln Ala Ala Ser Ser 1655 1660 1665His Glu Gln Gly Arg Ser Ser Ala Gly Glu Arg His Gly Ser Arg 1670 1675 1680His Gln Gln Ser Ala Asp Ser Ser Arg His Ser Gly Ile Gly His 1685 1690 1695Gly Gln Ala Ser Ser Ala Val Arg Asp Ser Gly His Arg Gly Tyr 1700 1705 1710Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Asp Ser 1715 1720 1725Asp Thr Gln Ser Val Ser Ala His Gly Gln Ala Gly Ser His Gln 1730 1735 1740Gln Ser His Gln Glu Ser Ala Arg Gly Arg Ser Gly Glu Arg Ser 1745 1750 1755Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln 1760 1765 1770Ser Glu Ser Ser His Gly Trp Thr Gly Pro Ser Thr Arg Gly Arg 1775 1780 1785Gln Gly Ser Arg His Glu Gln Ala Gln Asp Ser Ser Arg His Ser 1790 1795 1800Ala Ser Gln Glu Gly Gln Asp Thr Ile Arg Gly His Pro Gly Pro 1805 1810 1815Ser Arg Gly Gly Arg Gln Gly Tyr His His Glu Gln Ser Val Asp 1820 1825 1830Ser Ser Gly His Ser Gly Ser His His Ser His Ile Thr Ser Gln 1835 1840 1845Gly Ser Ser His Ala Ser His Gly Gln Ser Gly Ser Arg Ser Ala 1850 1855 1860Ser Arg Thr Thr Arg Asn Asp Glu Gln Ser Val Asp Gly Ser Arg 1865 1870 1875His Ser Gly Ser Arg His His Glu Ala Ser Thr His Ala Asp Ile 1880 1885 1890Ser Arg His Ser Gln Ala Gly Gln Gly Gln Ser Glu Gly Ser Arg 1895 1900 1905Thr Ser Arg Arg Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser 1910 1915 1920Glu Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser Ala Ser 1925 1930 1935Arg Asn His Arg Gly Ser Ala Gln Glu Gln Ser Arg Asp Gly Ser 1940 1945 1950Arg His Pro Arg Ser His His Glu Asp Arg Ala Gly His Gly His 1955 1960 1965Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr His His Ala Glu Thr 1970 1975 1980Ser Ser Gly Gly Gln Ala Ala Ser Ser Arg Glu Gln Ala Arg Ser 1985 1990 1995Ser Pro Gly Glu Arg His Gly Ser Arg His Gln Gln Ser Ala Asp 2000 2005 2010Ser Ser Arg His Ser Gly Ile Arg Arg Gly Gln Ala Ser Ser Ala 2015 2020 2025Val Arg Asp Ser Gly His Trp Gly Ser Ser Gly Ser Gln Ala Ser 2030 2035 2040Asp Ser Glu Gly His Ser Glu Glu Ser Asp Thr Gln Ser Val Ser 2045 2050 2055Gly His Gly Gln Asp Gly Pro His Gln Gln Ser His Gln Glu Ser 2060 2065 2070Ala Arg Asp Arg Ser Gly Gly Arg Ser Gly Arg Ser Gly Ser Phe 2075 2080 2085Leu Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser Thr His Gly 2090 2095 2100Gln Thr Gly Thr Ser Thr Gly Gly Arg Gln Gly Ser His His Glu 2105 2110 2115Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser Gln Glu Gly Gln 2120 2125 2130Asp Thr Ile His Ala His Pro Gly Ser Ser Arg Gly Gly Arg Gln 2135 2140 2145Gly Ser His His Glu Gln Ser Val Asp Thr Ser Gly His Ser Gly 2150 2155 2160Ser His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser 2165 2170 2175His Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Gln Thr Arg Asn 2180 2185 2190Asp Glu Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser His His 2195 2200 2205His Glu Ala Phe Thr Gln Ala Asp Ser Ser Arg His Ser Gln Ser 2210 2215 2220Gly Gln Gly Glu Ser Ala Gly Ser Arg Arg Ser Arg Arg Gln Gly 2225 2230 2235Ser Ser Val Ser Gln Asp Ser Asp Ser Gln Gly His Ser Glu Asp 2240 2245 2250Ser Glu Arg Trp Ser Gly Ser Ala Ser Arg Asn Gln His Gly Ser 2255 2260 2265Ala Arg Glu Gln Ser Arg Asp Gly Ser Arg His Pro Gly Ser His 2270 2275 2280Gln Glu Asp Arg Ala Gly His Gly His Ser Ala Asp Ser Ser Arg 2285 2290 2295Gln Ser Gly Thr Arg His Thr Glu Ser Ser Ser Arg Gly Gln Ala 2300 2305 2310Ala Ser Ser His Glu Gln Ala Arg Ser Ser Ala Gly Glu Arg His 2315 2320 2325Gly Ser Arg His Gln Leu Gln Ser Ala Asp Ser Ser Arg His Ser 2330 2335 2340Gly Ile Gly His Gly Gln Ala Ser Ser Ala Val Arg Asp Ser Gly 2345 2350 2355His Arg Gly Ser Ser Gly Ser Gln Ala Ile Asp Ser Glu Gly His 2360 2365 2370Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ala Gln Gly Gln Ala 2375 2380 2385Gly Pro His Gln Arg Ser His Lys Glu Ser Ala Arg Gly Gln Ser 2390 2395 2400Gly Glu Ser Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser 2405 2410 2415Thr His Glu Gln Pro Glu Ser Thr His Gly Gln Ser Ala Pro Ser 2420 2425 2430Thr Gly Gly Arg Gln Gly Ser His His Asp Gln Ala Gln Asp Ser 2435 2440 2445Ser Arg His Ser Ala Ser Gln Glu Gly Gln Asp Thr Ile Arg Gly 2450 2455 2460His Pro Gly Pro Ser Arg Gly Gly Arg Gln Gly Ser His His Lys 2465 2470 2475Gln Ser Val Asp Arg Ser Gly His Ser Gly Ser His His Ser His 2480 2485 2490Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser Arg Gly Gln Ser Gly 2495 2500 2505Ser Arg Ser Ala Ser Arg Gln Thr His Asp Lys Glu Gln Ser Gly 2510 2515 2520Asp Gly Ser Arg His Ser Gly Ser Arg His His Glu Ala Ser Ser 2525 2530 2535Trp Ala Asp Ser Ser Arg His Ser Gln Ala Gly Gln Gly Gln Ser 2540 2545 2550Glu Gly Ser Arg Thr Ser Arg Arg Gln Gly Ser Ser Phe Ser Gln 2555 2560 2565Asp Ser Asp Ser Glu Gly His Ser Glu Asp Ser Glu Arg Arg Ser 2570 2575 2580Gly Ser Ala Ser Arg Asn His Arg Gly Ser Ala Gln Glu Gln Ser 2585 2590 2595Arg Asp Gly Ser Arg His Pro Arg Ser His His Glu Asp Arg Ala 2600 2605 2610Gly His Gly His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr His 2615 2620 2625His Ala Gln Asn Ser Ser Gly Gly Gln Ala Ala Ser Phe His Glu 2630 2635 2640Gln Ala Arg Ser Ser Ala Gly Glu Arg His Gly Ser His His Gln 2645 2650 2655Gln Ser Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Gly Gln 2660 2665 2670Ala Ser Ser Ala Val Arg Asp Ser Gly His Arg Gly Ser Ser Gly 2675 2680 2685Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Asp Ser Asp Thr 2690 2695 2700Gln Ser Val Ser Ala His Gly Gln Ala Gly Pro His Gln Gln Ser 2705 2710 2715His Gln Glu Ser Thr Arg Gly Arg Ser Ala Glu Arg Ser Gly Arg 2720 2725 2730Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Glu 2735 2740 2745Ser Ala His Gly Arg Thr Gly Pro Ser Thr Gly Gly Arg Gln Gly 2750 2755 2760Ser Arg His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser 2765 2770 2775Gln Glu Gly Gln Asp Thr Ile His Gly His Pro Gly Ser Arg Arg 2780 2785 2790Gly Gly Arg Gln Gly Ser Tyr His Glu Gln Ser Val Asp Arg Ser 2795 2800

2805Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg 2810 2815 2820Ser Asp Ala Ser His Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg 2825 2830 2835Gln Thr Arg Asn Glu Gln Gln Ser Gly Asp Gly Ser Arg His Ser 2840 2845 2850Gly Ser Ser His His Glu Ala Ser Thr Gln Ala Asp Ser Ser Arg 2855 2860 2865His Ser Gln Ser Gly Gln Gly Glu Ser Ala Gly Ser Arg Arg Ser 2870 2875 2880Arg Arg Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser Glu Ala 2885 2890 2895Tyr Pro Glu Asp Ser Glu Arg Arg Ser Glu Ser Ala Ser Arg Asn 2900 2905 2910Arg His Gly Ser Ser Arg Glu Gln Ser Arg Asp Gly Ser Arg His 2915 2920 2925Pro Gly Ser Ser His Arg Asp Thr Thr Arg His Val Gln Ser Ser 2930 2935 2940Pro Val Gln Ser Asp Ser Ser Thr Ala Lys Glu His Gly His Phe 2945 2950 2955Ser Ser Leu Ser Gln Asp Ser Ala Tyr Arg Ser Gly Ile Gln Ser 2960 2965 2970Arg Gly Ser Pro His Ser Ser Ser Ser Tyr His Tyr Gln Ser Glu 2975 2980 2985Gly Thr Glu Arg Gln Lys Gly Gln Ser Gly Leu Val Trp Arg His 2990 2995 3000Gly Ser Tyr Gly Ser Ala Asp Tyr Asp Tyr Gly Glu Ser Gly Phe 3005 3010 3015Arg His Ser Gln His Gly Ser Val Ser Tyr Asn Ser Asn Pro Val 3020 3025 3030Val Phe Lys Glu Arg Ser Asp Ile Cys Lys Ala Ser Ala Phe Gly 3035 3040 3045Lys Asp His Pro Arg Tyr Tyr Ala Thr Tyr Ile Asn Lys Asp Pro 3050 3055 3060Gly Leu Cys Gly His Ser Ser Asp Ile Ser Lys Gln Leu Gly Phe 3065 3070 3075Ser Gln Ser Gln Arg Tyr Tyr Tyr Tyr Glu 3080 3085162764PRTPan troglodytes 16Met Ser Thr Leu Leu Glu Asn Ile Phe Ala Ile Ile Asn Leu Phe Lys1 5 10 15Gln Tyr Ser Lys Lys Asp Lys Asn Thr Asp Thr Leu Ser Lys Lys Glu 20 25 30Leu Lys Glu Leu Leu Glu Lys Glu Phe Arg Gln Ile Leu Lys Asn Pro 35 40 45Asp Asp Pro Asp Met Val Asp Val Phe Met Asp His Leu Asp Ile Asp 50 55 60His Asn Lys Lys Ile Asp Phe Thr Glu Phe Leu Leu Met Val Phe Lys65 70 75 80Leu Ala Gln Ala Tyr Tyr Glu Ser Thr Arg Lys Glu Asn Leu Pro Ile 85 90 95Ser Gly His Lys His Arg Lys His Ser His His Asp Lys His Glu Asp 100 105 110Asn Lys Gln Glu Glu Asn Lys Glu Asn Arg Lys Arg Pro Ser Ser Leu 115 120 125Glu Arg Arg Asn Asn Arg Lys Gly Asn Lys Gly Arg Ser Lys Ser Pro 130 135 140Arg Glu Thr Gly Gly Lys Arg His Glu Ser Ser Ser Glu Lys Lys Glu145 150 155 160Arg Lys Gly Tyr Ser Pro Thr His Arg Glu Glu Glu Tyr Gly Lys Asn 165 170 175His His Asn Ser Ser Lys Lys Gln Lys Asn Lys Thr Glu Asn Thr Arg 180 185 190Leu Glu Asp Asn Arg Lys Arg Leu Ser Glu Arg Leu Glu Glu Lys Glu 195 200 205Asp Asn Glu Glu Gly Gly Tyr Asp Tyr Glu Asn Thr Gly Arg Met Thr 210 215 220Gln Lys Trp Ile Gln Ser Gly His Ile Ala Thr Tyr Tyr Thr Ile Gln225 230 235 240Asp Glu Ala Tyr Asp Thr Thr Asp Asn Leu Leu Glu Glu Asn Lys Ile 245 250 255Tyr Glu Arg Ser Arg Ser Ser Asp Asp Lys Ser Ser Ser Gln Val Asn 260 265 270Arg Ser Arg His Glu Asn Thr Ser Gln Val Pro Leu Gln Glu Ser Arg 275 280 285Thr Arg Lys Arg Arg Gly Ser Arg Val Ser Gln Asp Arg Asp Ser Glu 290 295 300Gly His Ser Glu Asp Ser Glu Arg His Ser Gly Ser Ala Ser Arg Asn305 310 315 320His Pro Gly Ser Ala Arg Gln Gln Ser Arg Asp Gly Ser Arg His Pro 325 330 335Arg Ser His Asp Glu Asp Arg Ala Ser His Gly His Ser Ala Asp Ser 340 345 350Ser Arg Gln Ser Gly Thr Arg His Ala Glu Thr Ser Ser Arg Gly Gln 355 360 365Thr Ala Ser Ser His Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His 370 375 380Gly Ser Arg His Gln Gln Ser Ala Asp Ser Ser Arg His Ser Ala Thr385 390 395 400Gly Arg Gly Gln Ala Ser Ser Ala Val Ser Asp Arg Gly Pro Arg Gly 405 410 415Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Asn Ser 420 425 430Asp Thr Gln Ser Val Ser Gly His Gly Lys Ala Gly Pro Arg Gln Gln 435 440 445Ser His Gln Glu Ser Ala Arg Gly Arg Ser Gly Glu Arg Ser Gly His 450 455 460Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Asp Ser465 470 475 480Ala His Gly Arg Thr Gly Thr Ser Thr Gly Gly Arg Gln Gly Ser His 485 490 495His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser Gln Glu Gly 500 505 510Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser Arg Gly Gly Arg Gln 515 520 525Gly Ser His His Glu Gln Leu Val Asn Arg Ser Gly His Ser Gly Ser 530 535 540His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser His Gly545 550 555 560Gln Ser Gly Ser Arg Ser Ala Ser Arg Gln Thr Arg Asn Glu Glu Gln 565 570 575Ser Gly Asp Gly Ser Arg His Ser Gly Ser Arg His His Glu Ala Ser 580 585 590Ser Gln Ala Asp Ser Ser Arg His Ser Gln Val Gly Gln Gly Gln Ser 595 600 605Ser Gly Pro Arg Thr Ser Ser His Gln Gly Ser Ser Val Ser Gln Asp 610 615 620Ser Asp Ser Glu Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser625 630 635 640Ala Ser Arg Asn His His Gly Ser Ala Arg Glu Gln Ser Arg Asp Gly 645 650 655Ser Arg His Pro Arg Ser His His Glu Asp Arg Ala Gly His Gly His 660 665 670Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr Arg His Thr Glu Ser Ser 675 680 685Ser Arg Gly Gln Ala Val Ser Ser His Glu Gln Ala Arg Ser Ser Pro 690 695 700Gly Glu Arg His Gly Ser Arg His Gln Gln Ser Ala Asp Ser Ser Arg705 710 715 720His Ser Gly Ile Gly His Gly Gln Ala Ser Ser Ala Val Arg Asp Ser 725 730 735Gly His Arg Gly Ser Ser Gly Ser Gln Ala Ile Asp Ser Glu Gly His 740 745 750Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ser His Gly Gln Ala Gly 755 760 765Pro His Gln Gln Ser His Lys Glu Ser Ala Arg Gly Gln Ser Gly Glu 770 775 780Ser Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Ser His Glu785 790 795 800Gln Ser Glu Ser Thr Tyr Gly Gln Thr Ala Pro Ser Thr Gly Gly Arg 805 810 815Gln Gly Ser Arg His Glu Gln Ala Arg Asn Ser Ser Arg His Ser Ala 820 825 830Ser Gln Asp Gly Gln Asp Thr Ile Arg Gly His Pro Gly Ser Ser Arg 835 840 845Gly Gly Arg Gln Gly Ser Tyr His Glu Gln Ser Val Asp Arg Ser Gly 850 855 860His Ser Gly Tyr His His Ser His Thr Thr Pro Gln Gly Arg Ser Asn865 870 875 880Ala Ser His Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Gln Thr Arg 885 890 895Asn Glu Glu Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser Arg His 900 905 910His Glu Ala Ser Ser Arg Ala Asp Ser Ser Arg His Ser Gln Val Gly 915 920 925Gln Gly Gln Ser Ser Gly Pro Arg Thr Ser Arg Asn Gln Gly Ser Ser 930 935 940Val Ser Gln Asp Ser Asp Ser Gln Gly His Ser Glu Asp Ser Glu Arg945 950 955 960Trp Ser Gly Ser Ala Ser Arg Asn His His Gly Ser Ala Trp Glu Gln 965 970 975Ser Arg Asp Gly Ser Arg His Pro Gly Ser His Gln Glu Asp Arg Ala 980 985 990Gly His Gly His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr His His 995 1000 1005Thr Glu Ser Ser Ser Arg Gly Gln Ala Ala Ser Ser His Glu His 1010 1015 1020Ala Arg Ser Ser Ala Gly Glu Arg His Gly Ser His His Gln Gln 1025 1030 1035Ser Ala Asp Ser Ser Arg His Ser Gly Ile Gly His Gly Gln Ala 1040 1045 1050Ser Ser Ala Val Arg Asp Ser Gly His Arg Gly Ser Ser Gly Ser 1055 1060 1065Gln Ala Ser Asp Ser Glu Gly His Ser Glu Asp Ser Asp Thr Gln 1070 1075 1080Ser Leu Ser Ala His Gly Gln Ala Gly Pro His Gln Gln Ser His 1085 1090 1095Gln Glu Ser Thr Arg Gly Arg Ser Ala Glu Arg Ser Gly Arg Ser 1100 1105 1110Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser 1115 1120 1125Ala His Gly Arg Thr Gly Thr Ser Thr Gly Gly Arg Lys Arg Ser 1130 1135 1140Leu His Glu Gln Ala Arg Asp Ser Ser Arg His Ser Val Ser Gln 1145 1150 1155Glu Gly Gln Asp Thr Ile His Gly His Ala Gly Ser Ser Ser Gly 1160 1165 1170Gly Arg Gln Gly Ser His Tyr Glu Gln Leu Val Asp Arg Ser Gly 1175 1180 1185His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg Ser 1190 1195 1200Asp Ala Tyr His Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Gln 1205 1210 1215Thr His Asn Asp Glu Gln Ser Gly Asp Gly Phe Arg His Ser Gly 1220 1225 1230Ser His His His Glu Ala Ser Ser Arg Ala Asp Ser Ser Arg His 1235 1240 1245Ser Gln Val Gly Gln Gly Gln Ser Glu Gly Pro Arg Thr Ser Arg 1250 1255 1260His Arg Glu Ser Ser Val Ser Gln Asp Ser Asp Ser Glu Gly His 1265 1270 1275Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser Ala Ser Arg Asn His 1280 1285 1290His Gly Ser Ala Arg Glu Gln Ser Arg Asp Gly Ser Arg His Pro 1295 1300 1305Arg Ser His His Glu Asp Arg Ala Gly His Gly His Ser Ala Asp 1310 1315 1320Ser Ser Arg Gln Ser Gly Thr Arg His Thr Gln Thr Ser Ser Gly 1325 1330 1335Gly Gln Ala Ala Ser Ser His Glu Gln Gly Arg Ser Ser Ala Gly 1340 1345 1350Glu Arg His Gly Ser Arg His Gln Gln Ser Ala Asp Ser Ser Arg 1355 1360 1365His Ser Gly Ile Gly His Gly Gln Ala Ser Ser Ala Val Arg Asp 1370 1375 1380Ser Gly His Arg Gly Tyr Ser Gly Ser Gln Ala Ser Asp Ser Glu 1385 1390 1395Gly His Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ala His Gly 1400 1405 1410Gln Ala Gly Ser His Gln Gln Ser His Gln Glu Ser Ala Arg Gly 1415 1420 1425Arg Ser Gly Glu Arg Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln 1430 1435 1440Val Ser Thr His Glu Gln Ser Glu Ser Ser His Gly Trp Thr Gly 1445 1450 1455Pro Ser Thr Arg Gly Arg Gln Gly Ser Arg His Glu Gln Ala Gln 1460 1465 1470Asp Ser Ser Arg His Ser Ala Ser Gln Glu Gly Gln Asp Thr Ile 1475 1480 1485Arg Gly His Pro Gly Pro Ser Arg Gly Gly Arg Gln Gly Tyr His 1490 1495 1500His Glu Gln Ser Val Asp Ser Ser Gly His Ser Gly Ser His His 1505 1510 1515Ser His Ile Thr Ser Gln Gly Ser Ser His Ala Ser His Gly Gln 1520 1525 1530Ser Gly Ser Arg Ser Ala Ser Arg Thr Thr Arg Asn Asp Glu Gln 1535 1540 1545Ser Val Asp Gly Ser Arg His Ser Gly Ser Arg His His Glu Ala 1550 1555 1560Ser Thr His Ala Asp Ile Ser Arg His Ser Gln Ala Gly Gln Gly 1565 1570 1575Gln Ser Glu Gly Ser Arg Thr Ser Arg Arg Gln Gly Ser Ser Val 1580 1585 1590Ser Gln Asp Ser Asp Ser Glu Gly His Ser Glu Asp Ser Glu Arg 1595 1600 1605Trp Ser Gly Ser Ala Ser Arg Asn His Arg Gly Ser Ala Gln Glu 1610 1615 1620Gln Ser Arg Asp Gly Ser Arg His Pro Arg Ser His His Glu Asp 1625 1630 1635Arg Ala Gly His Gly His Ser Ala Asp Ser Ser Arg Gln Ser Gly 1640 1645 1650Thr His His Ala Glu Thr Ser Ser Gly Gly Gln Ala Ala Ser Ser 1655 1660 1665Arg Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His Gly Ser Arg 1670 1675 1680His Gln Gln Ser Ala Asp Ser Ser Arg His Ser Gly Ile Arg Arg 1685 1690 1695Gly Gln Ala Ser Ser Ala Val Arg Asp Ser Gly His Trp Gly Ser 1700 1705 1710Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Glu Ser 1715 1720 1725Asp Thr Gln Ser Val Ser Gly His Gly Gln Asp Gly Pro His Gln 1730 1735 1740Gln Ser His Gln Glu Ser Ala Arg Asp Arg Ser Gly Gly Arg Ser 1745 1750 1755Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln 1760 1765 1770Ser Glu Ser Thr His Gly Gln Thr Gly Thr Ser Thr Gly Gly Arg 1775 1780 1785Gln Gly Ser His His Glu Gln Ala Arg Asp Ser Ser Arg His Ser 1790 1795 1800Ala Ser Gln Glu Gly Gln Asp Thr Ile His Ala His Pro Gly Ser 1805 1810 1815Ser Arg Gly Gly Arg Gln Gly Ser His His Glu Gln Ser Val Asp 1820 1825 1830Thr Ser Gly His Ser Gly Ser His His Ser His Thr Thr Ser Gln 1835 1840 1845Gly Arg Ser Asp Ala Ser His Gly Gln Ser Gly Ser Arg Ser Ala 1850 1855 1860Ser Arg Gln Thr Arg Asn Asp Glu Gln Ser Gly Asp Gly Ser Arg 1865 1870 1875His Ser Gly Ser His His His Glu Ala Phe Thr Gln Ala Asp Ser 1880 1885 1890Ser Arg His Ser Gln Ser Gly Gln Gly Glu Ser Ala Gly Ser Arg 1895 1900 1905Arg Ser Arg Arg Gln Gly Ser Ser Val Ser Gln Asp Ser Asp Ser 1910 1915 1920Gln Gly His Ser Glu Asp Ser Glu Arg Trp Ser Gly Ser Ala Ser 1925 1930 1935Arg Asn Gln His Gly Ser Ala Arg Glu Gln Ser Arg Asp Gly Ser 1940 1945 1950Arg His Pro Gly Ser His Gln Glu Asp Arg Ala Gly His Gly His 1955 1960 1965Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr Arg His Thr Glu Ser 1970 1975 1980Ser Ser Arg Gly Gln Ala Ala Ser Ser His Glu Gln Ala Arg Ser 1985 1990 1995Ser Ala Gly Glu Arg His Gly Ser Arg His Gln Leu Gln Ser Ala 2000 2005 2010Asp Ser Ser Arg His Ser Gly Ile Gly His Gly Gln Ala Ser Ser 2015 2020 2025Ala Val Arg Asp Ser Gly His Arg Gly Ser Ser Gly Ser Gln Ala 2030 2035 2040Ile Asp Ser Glu Gly His Ser Glu Asp Ser Asp Thr Gln Ser Val 2045 2050 2055Ser Ala Gln Gly Gln Ala Gly Pro His Gln Arg Ser His Lys Glu 2060 2065 2070Ser Ala Arg Gly Gln Ser Gly Glu Ser Ser Gly Arg Ser Gly Ser 2075 2080 2085Phe Leu Tyr Gln Val Ser Thr His Glu Gln Pro Glu Ser Thr His 2090 2095 2100Gly Gln Ser Ala Pro Ser Thr Gly Gly Arg Gln Gly Ser His His 2105 2110 2115Asp Gln Ala Gln Asp Ser Ser Arg His Ser Ala Ser Gln Glu Gly 2120 2125 2130Gln Asp Thr Ile Arg Gly His Pro Gly Pro Ser Arg Gly Gly Arg 2135 2140 2145Gln Gly Ser His His Lys Gln Ser Val Asp Arg Ser Gly His Ser 2150 2155 2160Gly Ser His His

Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala 2165 2170 2175Ser Arg Gly Gln Ser Gly Ser Arg Ser Ala Ser Arg Gln Thr His 2180 2185 2190Asp Lys Glu Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser Arg 2195 2200 2205His His Glu Ala Ser Ser Trp Ala Asp Ser Ser Arg His Ser Gln 2210 2215 2220Ala Gly Gln Gly Gln Ser Glu Gly Ser Arg Thr Ser Arg Arg Gln 2225 2230 2235Gly Ser Ser Phe Ser Gln Asp Ser Asp Ser Glu Gly His Ser Glu 2240 2245 2250Asp Ser Glu Arg Arg Ser Gly Ser Ala Ser Arg Asn His Arg Gly 2255 2260 2265Ser Ala Gln Glu Gln Ser Arg Asp Gly Ser Arg His Pro Arg Ser 2270 2275 2280His His Glu Asp Arg Ala Gly His Gly His Ser Ala Asp Ser Ser 2285 2290 2295Arg Gln Ser Gly Thr His His Ala Gln Asn Ser Ser Gly Gly Gln 2300 2305 2310Ala Ala Ser Phe His Glu Gln Ala Arg Ser Ser Ala Gly Glu Arg 2315 2320 2325His Gly Ser His His Gln Gln Ser Ala Asp Ser Ser Arg His Ser 2330 2335 2340Gly Ile Gly His Gly Gln Ala Ser Ser Ala Val Arg Asp Ser Gly 2345 2350 2355His Arg Gly Ser Ser Gly Ser Gln Ala Ser Asp Ser Glu Gly His 2360 2365 2370Ser Glu Asp Ser Asp Thr Gln Ser Val Ser Ala His Gly Gln Ala 2375 2380 2385Gly Pro His Gln Gln Ser His Gln Glu Ser Thr Arg Gly Arg Ser 2390 2395 2400Ala Glu Arg Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val Ser 2405 2410 2415Thr His Glu Gln Ser Glu Ser Ala His Gly Arg Thr Gly Pro Ser 2420 2425 2430Thr Gly Gly Arg Gln Gly Ser Arg His Glu Gln Ala Arg Asp Ser 2435 2440 2445Ser Arg His Ser Ala Ser Gln Glu Gly Gln Asp Thr Ile His Gly 2450 2455 2460His Pro Gly Ser Arg Arg Gly Gly Arg Gln Gly Ser Tyr His Glu 2465 2470 2475Gln Ser Val Asp Arg Ser Gly His Ser Gly Ser His His Ser His 2480 2485 2490Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser His Gly Gln Ser Gly 2495 2500 2505Ser Arg Ser Ala Ser Arg Gln Thr Arg Asn Glu Gln Gln Ser Gly 2510 2515 2520Asp Gly Ser Arg His Ser Gly Ser Ser His His Glu Ala Ser Thr 2525 2530 2535Gln Ala Asp Ser Ser Arg His Ser Gln Ser Gly Gln Gly Glu Ser 2540 2545 2550Ala Gly Ser Arg Arg Ser Arg Arg Gln Gly Ser Ser Val Ser Gln 2555 2560 2565Asp Ser Asp Ser Glu Ala Tyr Pro Glu Asp Ser Glu Arg Arg Ser 2570 2575 2580Glu Ser Ala Ser Arg Asn Arg His Gly Ser Ser Arg Glu Gln Ser 2585 2590 2595Arg Asp Gly Ser Arg His Pro Gly Ser Ser His Arg Asp Thr Thr 2600 2605 2610Arg His Val Gln Ser Ser Pro Val Gln Ser Asp Ser Ser Thr Ala 2615 2620 2625Lys Glu His Gly His Phe Ser Ser Leu Ser Gln Asp Ser Ala Tyr 2630 2635 2640Arg Ser Gly Ile Gln Ser Arg Gly Ser Pro His Ser Ser Ser Ser 2645 2650 2655Tyr His Tyr Gln Ser Glu Gly Thr Glu Arg Gln Lys Gly Gln Ser 2660 2665 2670Gly Leu Val Trp Arg His Gly Ser Tyr Gly Ser Ala Asp Tyr Asp 2675 2680 2685Tyr Gly Glu Ser Gly Phe Arg His Ser Gln His Gly Ser Val Ser 2690 2695 2700Tyr Asn Ser Asn Pro Val Val Phe Lys Glu Arg Ser Asp Ile Cys 2705 2710 2715Lys Ala Ser Ala Phe Gly Lys Asp His Pro Arg Tyr Tyr Ala Thr 2720 2725 2730Tyr Ile Asn Lys Asp Pro Gly Leu Cys Gly His Ser Ser Asp Ile 2735 2740 2745Ser Lys Gln Leu Gly Phe Ser Gln Ser Gln Arg Tyr Tyr Tyr Tyr 2750 2755 2760Glu171656PRTBos taurus 17Met Ser Thr Leu Leu Glu Asn Ile Asn Asp Ile Ile Lys Ile Phe His1 5 10 15Lys Tyr Ser Lys Thr Asp Lys Glu Thr Asp Thr Leu Ser Glu Lys Glu 20 25 30Leu Lys Glu Leu Val Glu Val Glu Phe Arg Pro Ile Leu Lys Asn Pro 35 40 45Gly Asp Pro Asp Thr Ala Glu Val Phe Met Tyr Asn Leu Asp Arg Asp 50 55 60His Asn Asn Lys Ile Asp Phe Thr Glu Phe Phe Leu Met Val Phe Lys65 70 75 80Val Ala Gln Val Tyr Tyr Ser Tyr Thr Gln Arg Gln Asn Leu Gln Arg 85 90 95Ala Gly Gln Lys Gln Lys Lys Cys Thr Tyr His Tyr Gly Asp Glu Glu 100 105 110Asp Asp Thr Glu Glu Asp Lys Glu Glu Thr Glu Arg Lys Tyr Ser His 115 120 125Ser Arg Ser Asp Gly Lys Thr Gln Asp Arg Ser Lys Ser Pro Arg Gly 130 135 140Arg Gly Lys Lys Arg His Gly Ser Lys Ser Gly Ser Lys Gln Arg Arg145 150 155 160Gly Asp Thr Pro Thr Ser Gly Leu Arg His Gly Cys Ser Lys Lys His 165 170 175Glu Ser Arg Arg Glu Lys Lys Arg Arg Pro Ser Ser Thr Glu Pro Lys 180 185 190Glu Arg Arg His Met Ser Ser Val Ser Pro Thr Arg Gly Tyr Glu Glu 195 200 205Lys Glu Glu Glu His Gly Tyr Glu Asn Lys Gly Lys Thr Ser Ala Lys 210 215 220Cys Ile Gly Ser Glu Tyr Asp Asp Ser Tyr Gln Val Cys Glu Asp Lys225 230 235 240Val Thr Thr Asn Phe Gln Pro Ser His Ser Lys Asn Tyr Gly Ser Asn 245 250 255Ile Thr Lys Gly Arg Asp Thr Glu Gly His Ser Arg Asp Thr Gly Arg 260 265 270Lys Ser Val Phe Thr His Ala Arg Ser Gly Ser Ser Ser Arg Asn Gln 275 280 285Asn Gly Ser Val Gln Thr His Thr Gly Asp Asn Ser Thr His Ser Glu 290 295 300Ser Gln Gln Glu Thr Asn Ser Glu Ser Val His Arg Arg Ser Arg Asn305 310 315 320Thr Gly Gln Arg Gln Gly Ser His His Glu Gln Ser Arg Asp Ser Ser 325 330 335Arg His Ser Gly Thr Arg His Gly Gln Pro Ser Thr Gly Ser Gly Gly 340 345 350Ser Arg His Arg Glu Ser Ser Val Ser Gln Ala Ser Asp Ser Glu Gly 355 360 365His Ser Glu Asp Ser Gly Arg Gln Ser Val Thr Thr His Gly Arg Pro 370 375 380Gly Ser Ser Ser Arg Asn Gln His Gly Ser Ser Gln Gly Gln Thr Gly385 390 395 400Asp Ser Ser Arg His Ser Glu Ser His Gln Gly Arg His Ser Asp Ser 405 410 415Leu Gln Arg Arg Ser Gly Thr Ser Thr Gly Gln Arg Gln Gly Ser His 420 425 430His Glu Gln Ser Arg Asp Ser Ser Arg His Ser Gly Thr Gln Gln Gly 435 440 445Gln Thr Ser Thr Gly Ser Gly Ser Ser Arg His Arg Asp Ser Ser Val 450 455 460Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Asp Ser Gly Arg Gln465 470 475 480Ser Val Thr Thr His Gly Arg Pro Gly Ser Ser Ser Arg Asn Gln His 485 490 495Gly Ser Ser His Gly Gln Thr Gly Asp Ser Ser Arg His Ser Glu Ser 500 505 510His Gln Arg Ser His Ser Glu Ala Val His Glu Arg Ser Gly Ser Ser 515 520 525Thr Gly Gln Arg Gln Arg Ser His His Glu Gln Ser Arg Asp Ser Ser 530 535 540Arg His Ser Gly Thr Gly His Gly Gln Ile Ser Ala Glu Ser Gly Asn545 550 555 560Gly Arg His Arg Glu Ser Ser Val Ser Gln Ala Ser Asp Ser Glu Gly 565 570 575His Ala Arg Asp Ser Gly Arg His Ser Glu Thr Thr His Gly Arg Tyr 580 585 590Gly Ser Ser Ser Arg Asn Gln His Gly Ser Ser His Gly Gln Thr Gly 595 600 605Asp Ser Tyr Arg His Ser Glu Thr Asn Gln Gly Arg His Asn Lys Arg 610 615 620His Thr Arg Asp Ser Gly Arg His Ser Glu Thr Thr His Gly Arg Pro625 630 635 640Gly Ser Ser Ser Arg Asn Gln His Gly Ser Ser His Gly Gln Ser Gly 645 650 655Asp Ser Ser Arg His Ser Glu Ser His Gln Glu Arg His Ser Glu Ser 660 665 670Val His Gly Arg Ser Gly Ser Ser Thr Gly Gln Arg Gln Gly Ser His 675 680 685His Glu Gln Ser Arg Asp Ser Ser Arg His Ser Gly Thr Arg His Gly 690 695 700Gln Thr Ser Ala Glu Ser Gly Asn Gly Arg His Arg Glu Ser Ser Val705 710 715 720Ser Gln Ala Ser Asp Ser Glu Gly His Thr Arg Asp Ser Gly Arg His 725 730 735Ser Glu Thr Thr His Gly Arg Pro Gly Ser Ser Ser Arg Asn Gln His 740 745 750Gly Ser Ser Gln Gly Gln Thr Gly Asp Ser Ser Arg Tyr Ser Ala Tyr 755 760 765His Gln Gly Arg His Ser Glu Ser Val His Glu Arg Ser Ala Ser Arg 770 775 780Thr Gly Gln Arg Gln Gly Ser His His Glu Gln Ser Arg Asp Ser Ser785 790 795 800Arg Gln Ser Gly Thr Gly His Gly His Thr Ser Ala Gly Ser Gly Asn 805 810 815Gly Arg His Arg Glu Ser Ser Val Ser Gln Ser Ser Asp Arg Glu Gly 820 825 830His Ala Arg Asp Ser Gly Arg Gln Ser Val Thr Thr His Gly Arg Pro 835 840 845Gly Ser Ser Ser Arg Asn Gln His Val Ser Ser His Gly Gln Ile Gly 850 855 860Asp Ser Ser Ser His Ser Glu Thr Asn Gln Gly Ser His Asn Glu Arg865 870 875 880His Thr Arg Asp Ser Gly Arg His Ser Glu Thr Thr His Gly Arg Leu 885 890 895Gly Ser Ser Ser Arg Asn Gln His Gly Ser Val His Gly Gln Thr Arg 900 905 910Asp Ser Pro Arg His Ser Glu Ser His Gln Glu Arg His Ser Glu Ser 915 920 925Val His Gly Arg Ser Gly Ser Ser Thr Gly Gln Arg Gln Glu Ser His 930 935 940His Glu Gln Ser Arg Asp Ser Ser Arg Gln Ser Gly Thr Gly His Gly945 950 955 960His Thr Ser Ala Gly Ser Gly Asn Ser Arg His Arg Glu Ser Ser Val 965 970 975Ser Gln Ala Ser Asp Ser Glu Gly His Ser Glu Asp Ser Gly Arg Gln 980 985 990Asn Val Thr Thr His Gly Arg Pro Gly Ser Ser Ser Arg Asn Gln His 995 1000 1005Gly Ser Ser Gln Gly Gln Thr Gly Asp Ser Ser Arg Tyr Ser Ala 1010 1015 1020Tyr His Gln Gly Arg His Ser Glu Ser Val His Glu Arg Ser Ala 1025 1030 1035Ser Arg Thr Gly Gln Arg Gln Gly Ser His His Glu Gln Ser Arg 1040 1045 1050Asp Ser Ser Arg Gln Ser Gly Thr Gly His Gly His Ala Ser Ala 1055 1060 1065Gly Ser Gly Ile Asn Arg His Arg Glu Ser Ser Val Ser Gln Ala 1070 1075 1080Ser Asp Arg Glu Gly His Ala Arg Asp Ser Gly Arg Gln Ser Val 1085 1090 1095Thr Thr His Gly Arg Pro Gly Ser Ser Ser Arg Asn Gln His Val 1100 1105 1110Ser Ser His Gly Gln Ile Gly Asp Ser Ser Ser His Ser Glu Thr 1115 1120 1125Asn Gln Gly Ser His Asn Glu Arg His Thr Arg Asp Ser Gly Arg 1130 1135 1140His Ser Glu Thr Thr His Gly Arg Leu Gly Ser Ser Ser Arg Asn 1145 1150 1155Gln His Gly Ser Val His Gly Gln Thr Arg Asp Ser Pro Arg His 1160 1165 1170Ser Glu Ser His Gln Glu Arg His Ser Glu Ser Val His Glu Arg 1175 1180 1185Ser Gly Ser Ser Thr Gly Gln Arg Gln Gly Ser His His Glu Gln 1190 1195 1200Ser Arg Asp Ser Ser Arg His Ser Gly Thr Arg His Gly Gln Thr 1205 1210 1215Ser Thr Val Ser Gly Gly Ser Arg His Arg Glu Pro Ser Val Ser 1220 1225 1230Gln Ala Ser Asp Ser Glu Gly His Ser Glu Asp Ser Gly Arg Gln 1235 1240 1245Ser Val Thr Thr His Gly Arg Pro Gly Ser Thr Ser Arg Asn Gln 1250 1255 1260His Gly Ser Val His Gly Gln Thr Arg Asp Ser Pro Arg His Ser 1265 1270 1275Glu Ser His Gln Glu Arg His Ser Glu Ser Val His Gln Arg Ser 1280 1285 1290Gly Ser Ser Thr Gly Gln Arg Gln Gly Ser His His Glu Gln Ser 1295 1300 1305Arg Asp Ser Ser Arg His Ser Gly Thr Gly His Gly Gln Thr Ser 1310 1315 1320Ala Gly Ser Gly Ser Ser Arg His Arg Glu Ser Ser Val Ser Gln 1325 1330 1335Ala Ser Asp Ser Glu Gly His Ser Glu Asp Ser Gly Arg Gln Asn 1340 1345 1350Val Thr Thr His Gly Arg Pro Gly Ser Ser Ser Arg Asn Gln His 1355 1360 1365Gly Ser Ser Gln Gly Gln Thr Gly Asp Ser Ser Arg Tyr Ser Ala 1370 1375 1380Ser His Gln Gly Arg His Ser Glu Ser Val His Glu Arg Ser Thr 1385 1390 1395Ser Arg Thr Gly Gln Arg Gln Gly Ser His His Glu Gln Ser Arg 1400 1405 1410Asp Ser Ser Arg Gln Ser Gly Thr Gly His Gly His Ala Ser Ala 1415 1420 1425Gly Ser Gly Ile Asn Arg His Arg Glu Ser Ser Val Ser Gln Ala 1430 1435 1440Ser Asp Ser Glu Gly His Ser Glu Asp Ser Gly Arg Gln Asn Val 1445 1450 1455Thr Thr His Gly Arg Pro Gly Ser Ser Ser Ser Asn Gln His Gly 1460 1465 1470Ser Ser His Gly Gln Thr Gly Asp Ser Ser Arg His Ser Glu Ser 1475 1480 1485His Gln Gly Ser His Gly Glu Ser Val His Gln Arg Ser Gly Ser 1490 1495 1500Ser Thr Gly Gln Arg Gln Gly Ser His His Glu Gln Ser Arg Asp 1505 1510 1515Ser Ser Arg His Ser Gly Thr Gly His Gly Glu Thr Ser Thr Gly 1520 1525 1530Ser Gly Ser Ser Arg His Arg Glu Ser Ser Val Ser Gln Ser Ser 1535 1540 1545Asp Ser Lys Gly His Ser Arg Gly Ser Gly Asn Gln Thr Val Thr 1550 1555 1560Asn Gln Arg Met Ser Ala Phe Tyr Ser Arg Phe Gln Asn His Gly 1565 1570 1575Ala Gly Gln Val Trp Arg His Gly Ser Tyr Gly Ser Ser Asn Tyr 1580 1585 1590Asp Tyr Gly Gln Leu Gly Thr Gly His Ser Pro Asp Glu Asn Phe 1595 1600 1605Ser His Asp Ser Ser His Val Glu Lys Arg Asp Lys Pro Glu Tyr 1610 1615 1620Arg Gly Glu Leu Met Arg Ser Asn Ile Thr Val Arg Asn Ile His 1625 1630 1635Pro Gly Thr Tyr Gly His Ser Asn Tyr Ile Ser Lys Gln Leu Gly 1640 1645 1650Phe Gly Gln 1655181183PRTMacaca mulatta 18Met Ser Thr Leu Leu Glu Asn Ile Phe Ala Ile Ile Asn Leu Phe Lys1 5 10 15Gln Tyr Ser Lys Lys Asp Lys Asn Thr Asp Thr Leu Ser Lys Lys Glu 20 25 30Leu Lys Glu Leu Leu Glu Lys Glu Phe Arg Pro Ile Leu Lys Asn Pro 35 40 45Asp Asp Pro Asp Thr Val Glu Val Phe Met Asp His Leu Asp Ile Asp 50 55 60His Asn Lys Lys Ile Asp Phe Thr Glu Phe Leu Leu Met Val Phe Lys65 70 75 80Leu Ala Gln Ala Tyr Tyr Glu Ser Thr Arg Lys Gln Asn Leu Pro Ile 85 90 95Ala Gly His Lys His Arg Lys His Ser His His Asp Lys His Glu Asp 100 105 110Asn Lys Glu Glu Glu Asn Lys Glu Lys Arg Lys Arg Pro Leu Ser Leu 115 120 125Glu Arg Arg Asn Asn Arg Lys Gly Asn Thr Gly Arg Ser Lys Ser Pro 130 135 140Arg Glu Arg Gly Gly Lys Arg His Glu Ser Ser Phe Glu Lys Lys Glu145 150 155 160Arg Lys Gly Tyr Ser Pro Thr Tyr Glu Glu Glu Glu Tyr Gly Gln Asn 165 170 175His His Lys Ser Ser Lys Lys Glu Lys Asn Lys Thr Glu Ile Thr Arg 180 185 190Leu Glu His Glu Gly

Lys Arg Ile Ser Glu Arg Pro Glu Lys Lys Glu 195 200 205Glu Lys Glu Asp Gly Gln Phe Asp Tyr Glu Asn Ala Gly Arg Met Asp 210 215 220Glu Lys Trp Thr Glu Ser Gly His Ile Ala Ile Tyr His Ala Ile Gln225 230 235 240Asp Glu Val Asp Asp Thr Thr Glu Asn Ile Leu Glu Glu Asn Arg Arg 245 250 255Tyr Glu Thr Ser Arg Ser Pro His Asp Lys Ser Ser Leu Arg Val Asn 260 265 270Arg Ser Pro Asn Ala Asn Thr Ser Gln Ile Pro Leu Val Glu Pro Arg 275 280 285Arg Arg Thr Arg Gln Arg Ser Ser Val Ser Gln Asp Ser Asp Ser Glu 290 295 300Gly His Ser Glu Asp Ser Glu Arg Gln Ser Glu Ser Ala Ser Arg Asn305 310 315 320His His Gly Ser Val Arg Glu Gln Ser Arg His Gly Ser Arg His Pro 325 330 335Gly Ser His His Glu Asp Arg Ala Gly His Gly His Ser Ala Asp Ser 340 345 350Ser Thr Gln Ser Gly Thr Arg His Thr Glu Thr Ser Ser Arg Gly Gln 355 360 365Ala Val Ser Ser His Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His 370 375 380Gly Ser Arg His Gln Gln Ser Ala Glu Ser Ser Arg His Ser Gly Ile385 390 395 400Gly Arg Gly Gln Ala Ser Ser Ala Val Ser Asp Arg Gly His Gln Gly 405 410 415Pro Ser Gly Ser His Phe Ser Asp Ser Glu Gly His Ser Glu His Ser 420 425 430Asp Thr Gln Ser Val Ser Gly His Gly Gln Ala Gly Pro His Pro His 435 440 445Ser His Gln Glu Ser Ala Arg Gly Arg Ser Arg Glu Arg Ser Gly Arg 450 455 460Ser Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser465 470 475 480Thr His Gly Arg Thr Gly Pro Ser Ser Ala Gly Arg Gln Gly Ser Arg 485 490 495Asn Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser His Glu Val 500 505 510Gln Asp Thr Val His Gly His His Gly Ser Ser Arg Gly Arg Arg Gln 515 520 525Gly Ser His His Glu Gln Leu Val Asp Ser Ser Gly His Ser Gly Ser 530 535 540His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp Ala Ser Arg Gly545 550 555 560Glu Ser Gly Ala Arg Ser Ala Ser Arg Gln Thr Arg His Glu Glu Gln 565 570 575Ser Gly Asp Gly Ser Arg His Ser Gly Ser Arg His His Glu Ser Ser 580 585 590Asn Arg Ala Asp Ser Ser Arg His Ala Gln Ser Ser Gln Gly Gln Ser 595 600 605Ala Gly Phe Arg Thr Ser Thr Arg Arg Gly Ser Ser Val Ser Gln Asp 610 615 620Ser Asp Ser Glu Gly His Ser Glu Asp Ser Glu Arg Gln Ser Glu Ser625 630 635 640Ala Ser Arg Asn His His Gly Ser Val Arg Glu Gln Ser Arg His Gly 645 650 655Ser Gly His Ser Gly Ser His His Gln Asp Lys Val Gly His Arg Tyr 660 665 670Ser Gly Asp Ser Ser Arg Gln Ser Gly Thr His His Val Glu Thr Ser 675 680 685Ser His Gly Gln Ala Ala Ser Ser His Glu Gln Thr Arg Ser Ser Pro 690 695 700Gly Glu Arg His Gly Ser His His Gln Gln Ser Ala Asp Ser Ser Arg705 710 715 720His Ser Gly Thr Gly Arg Gly Gln Ala Ser Ser Ala Val Ser Asp Arg 725 730 735Gly His Gln Gly Pro Ser Gly Ser His Phe Ser Asp Ser Glu Gly His 740 745 750Ser Glu His Ser Asp Thr Gln Ser Val Ser Gly Gln Gly Gln Ala Gly 755 760 765Arg His Pro His Ser His Gln Glu Ser Ala Arg Gly Arg Ser Gly Glu 770 775 780Arg Ser Gly Arg Ser Gly Ser Phe Val Tyr Gln Val Ser Thr His Glu785 790 795 800Gln Ser Glu Ser Thr His Gly Arg Thr Gly Pro Ser Thr Gly Gly Arg 805 810 815Gln Gly Ser Arg Asn Glu Gln Ala Arg Asp Ser Ser Arg His Ser Val 820 825 830Ser His Glu Gly Gln Asp Thr Ile His Gly His His Gly Ser Ser Arg 835 840 845Gly Gly Arg Gln Gly Ser His His Glu Gln Ser Val Asp Ser Ser Gly 850 855 860His Ser Gly Ser His His Ser His Thr Thr Ser Gln Gly Arg Ser Asp865 870 875 880Ala Ser Arg Gly Glu Ser Gly Ala Arg Ser Ala Ser Arg Gln Thr Arg 885 890 895His Glu Glu Gln Ser Gly Asp Gly Ser Arg His Ser Gly Ser Arg His 900 905 910His Glu Ala Ser Asn Arg Ala Asp Ser Ser Arg His Ala Gln Ser Gly 915 920 925Gln Gly Gln Ser Ala Gly Phe Arg Thr Ser Thr Arg Arg Gly Ser Ser 930 935 940Val Ser Gln Asp Ser Asp Ser Glu Gly His Ser Glu Asp Ser Glu Arg945 950 955 960Gln Ser Glu Ser Ala Ser Arg Asn His His Gly Ser Val Arg Glu Gln 965 970 975Ser Arg His Gly Ser Arg His Pro Gly Ser His His Glu Asp Arg Ala 980 985 990Gly His Gly His Ser Ala Asp Ser Ser Arg Gln Ser Gly Thr Arg His 995 1000 1005Thr Glu Thr Ser Ser Arg Gly Gln Ala Val Ser Ser His Glu Gln 1010 1015 1020Ala Arg Ser Ser Pro Gly Glu Arg His Gly Ser Arg His Gln Gln 1025 1030 1035Ser Ala Glu Ser Ser Arg His Ser Gly Ile Gly Arg Gly Gln Ala 1040 1045 1050Ser Ser Ala Val Ser Asp Arg Gly His Gln Gly Pro Ser Gly Ser 1055 1060 1065His Phe Ser Asp Ser Glu Gly His Ser Glu His Ser Asp Thr Gln 1070 1075 1080Ser Val Ser Gly His Gly Gln Ala Gly Pro His Pro His Ser His 1085 1090 1095Gln Glu Ser Ala Arg Gly Arg Ser Gly Glu Arg Ser Gly Arg Ser 1100 1105 1110Gly Ser Phe Leu Tyr Gln Val Ser Thr His Glu Gln Ser Glu Ser 1115 1120 1125Thr His Gly Arg Thr Gly Pro Ser Ser Ala Gly Arg Gln Gly Ser 1130 1135 1140Arg Asn Glu Gln Ala Arg Asp Ser Ser Arg His Ser Ala Ser His 1145 1150 1155Glu Val Gln Asp Thr Val His Gly His His Gly Ser Ser Arg Gly 1160 1165 1170Gly Arg Gln Gly Ser His His Glu Gln Ser 1175 1180192265PRTMacaca mulatta 19Met Thr Asp Leu Leu Arg Ser Val Val Thr Val Ile Asp Val Phe Tyr1 5 10 15Lys Tyr Thr Lys Gln Asp Gly Glu Cys Gly Thr Leu Ser Lys Asp Glu 20 25 30Leu Lys Glu Leu Leu Glu Lys Glu Phe His Pro Val Leu Lys Asn Pro 35 40 45Asp Asp Pro Asp Thr Val Asp Val Ile Met His Met Leu Asp Arg Asp 50 55 60His Asp Arg Arg Leu Asp Phe Thr Glu Phe Leu Leu Met Ile Phe Lys65 70 75 80Leu Thr Met Ala Cys Asn Lys Val Leu Ser Lys Glu Tyr Cys Lys Ala 85 90 95Ser Gly Ser Lys Lys His Arg Arg Gly His Arg His Gln Glu Glu Glu 100 105 110Ser Glu Thr Glu Glu Asp Glu Glu Asp Thr Pro Glu His Lys Ser Gly 115 120 125Tyr Arg His Ser Ser Trp Ser Glu Gly Glu Glu His Gly Tyr Ser Ser 130 135 140Gly His Ser Arg Gly Thr Val Lys Arg Arg His Gly Ser Asn Ser Arg145 150 155 160Arg Leu Gly Arg Gln Gly His Leu Ser Ser Ser Gly Asn Gln Glu Arg 165 170 175Ser Gln Lys Arg Tyr His Arg Ser Ser Ser Gly His Ser Trp Ser Ser 180 185 190Gly Lys Glu Arg His Gly Phe Ser Ser Gly Glu Leu Arg Glu Arg Ile 195 200 205Asn Lys Ser His Val Ser Pro Ser Arg Glu Phe Gly Glu Glu Tyr Glu 210 215 220Ser Gly Ser Gly Ser Lys Ser Trp Glu Arg Lys Gly His Gly Gly Leu225 230 235 240Ser Cys Gly Leu Glu Ile Ser Gly His Glu Ser Asn Ser Thr Gln Ser 245 250 255Arg Ser Ser Gly Gln Lys Leu Gly Ser Ser Arg Ser Cys Ser Gly Asp 260 265 270Ser Arg Arg Arg Ser His Ala Cys Gly Tyr Ser Asn Ser Ser Gly Cys 275 280 285Gly Arg Pro Gln Asn Ala Ser Asn Ser Cys Gln Ser His Arg Phe Gly 290 295 300Gly Gln Val Asn Gln Ser Ser Tyr Ile Gln Ser Gly Cys Gln Ser Gly305 310 315 320Ile Asn Gly Glu Gln Gly His Asp Cys Val Ser Gly Gly Gln Pro Ser 325 330 335Gly Cys Gly Gln Pro Glu Ser Asn Ser Cys Ser Gln Ser Tyr Ser Gln 340 345 350Arg Gly Tyr Gly Ala Arg Glu Asn Gly Gln Pro Gln Asn Cys Gly Gly 355 360 365Gln Gln Arg Thr Gly Ser Ser Gln Ser Ser Phe Cys Gly Gln Tyr Glu 370 375 380Ser Gly Gly Ser Gln Ser Cys Ser Asn Gly Gln His Glu His Gly Ser385 390 395 400Cys Gly Arg Phe Ser Asn Ser Ser Ser Ser Asn Glu Phe Ser Lys Cys 405 410 415Gly Lys His Arg Ser Gly Ser Gly Gln Phe Thr Ser Cys Glu Gln His 420 425 430Gly Thr Gly Leu Ser Gln Ser Ser Gly Phe Glu Gln Gln Val Ala Gly 435 440 445Ser Ser Gln Thr Cys Ser Gln Tyr Gly Ser Arg Ser Ser Gln Ser Ser 450 455 460Gly Tyr Asp Glu His Gly Ser Ser Ser Gly Lys Thr Ser Gly Phe Gly465 470 475 480Gln His Arg Ser Gly Ser Gly His Ser Ser Gly Phe Gly Gln His Gly 485 490 495Ser Gly Ser Gly Gln Ser Phe Gly Phe Gly Gln His Gly Ser Gly Ser 500 505 510Gly Gln Ser Ser Gly Phe Gly Gln His Glu Ser Arg Ser Cys Gln Ser 515 520 525Ser Tyr Gly Gln His Gly Ser Gly Ser Ser Gln Ser Ser Gly Tyr Gly 530 535 540Gln His Ala Ser Arg Gln Thr Ser Gly Phe Gly Gln His Gly Leu Gly545 550 555 560Ser Gly Gln Ser Thr Gly Phe Gly Gln Tyr Gly Ser Gly Ser Gly Gln 565 570 575Ser Ser Gly Phe Gly Gln His Gly Ser Gly Ser Gly Gln Ser Ser Gly 580 585 590Phe Gly Gln His Glu Ser Arg Ser Gly Gln Ser Ser Tyr Gly Gln His 595 600 605Ser Ser Ser Ser Ser Gln Ser Ser Gly Tyr Gly Gln His Gly Ser Arg 610 615 620Gln Thr Ser Gly Phe Gly Gln His Gly Ser Gly Ser Gly Gln Ser Thr625 630 635 640Gly Phe Gly Gln Tyr Gly Ser Ser Leu Gly Gln Ser Ser Gly Phe Gly 645 650 655Gln His Gly Ser Gly Ser Gly Gln Ser Ser Gly Phe Gly Gln His Glu 660 665 670Ser Thr Ser Gly Gln Ser Ser Tyr Gly Gln His Gly Phe Gly Ser Ser 675 680 685Gln Ser Ser Gly Cys Gly Gln His Gly Leu Ser Ser Gly Gln Thr Ser 690 695 700Gly Phe Gly Gln His Glu Leu Ser Ser Gly Gln Ser Ser Ser Phe Gly705 710 715 720Gln His Gly Ser Gly Ser Gly Gln Ser Ser Gly Phe Arg Gln His Glu 725 730 735Ser Gly Ser Gly Gln Ser Ser Gly Phe Gly Gln His Glu Ser Arg Ser 740 745 750His Gln Ser Ser Tyr Gly Pro His Gly Ser Gly Ser Gly Gln Ser Ser 755 760 765Gly Tyr Gly Gln His Gly Ser Ser Ser Gly Gln Thr Ser Gly Phe Gly 770 775 780Gln Gln Gly Ser Ser Ser Ser Gln Tyr Ser Gly Phe Gly Gln His Gly785 790 795 800Ser Gly Leu Gly Gln Ser Ser Gly Phe Gly Gln His Gly Thr Gly Ser 805 810 815Gly Gln Phe Ser Gly Phe Gly Gln His Glu Ser Arg Ser His Gln Ser 820 825 830Ser Tyr Gly Gln His Gly Ser Gly Ser Ser Gln Ser Ser Gly Tyr Gly 835 840 845Gln His Gly Ser Ser Ser Gly His Thr Thr Gly Phe Gly Gln His Arg 850 855 860Ser Ser Ser Gly Gln Tyr Ser Gly Phe Gly Gln His Gly Ser Gly Leu865 870 875 880Gly Gln Ser Ser Gly Phe Gly Gln His Gly Thr Gly Ser Gly Gln Ser 885 890 895Ser Gly Phe Gly Gln His Glu Ser Arg Ser His Gln Ser Ser Tyr Gly 900 905 910Gln His Gly Ser Gly Ser Ser Gln Ser Ser Ser Tyr Gly Gln His Gly 915 920 925Ser Ser Ser Gly Gln Thr Ser Gly Phe Gly Gln His Arg Ser Gly Ser 930 935 940Gly Gln Ser Ser Gly Phe Gly Gln Tyr Gly Leu Gly Ser Gly Gln Ser945 950 955 960Ser Gly Phe Gly Gln His Gly Ser Gly Thr Gly Gln Ser Ser Gly Phe 965 970 975Ala Arg His Glu Tyr Arg Ser Gly Gln Ser Ser Tyr Gly Gln His Gly 980 985 990Thr Gly Ser Ser Gln Ser Ser Gly Cys Gly Gln Arg Glu Ser Gly Ser 995 1000 1005Gly Pro Thr Thr Gly Phe Gly Gln His Val Ser Gly Ser Asp Asn 1010 1015 1020Phe Ser Ser Ser Gly Gln His Ile Ser Gly Ser Asp Gln Ser Thr 1025 1030 1035Gly Phe Gly Gln Tyr Gly Ser Gly Ser Gly Gln Ser Thr Gly Leu 1040 1045 1050Gly Gln Val Glu Ser Gln Gln Val Ala Ser Gly Ser Thr Val His 1055 1060 1065Gly Arg Gln Glu Thr Thr His Gly Gln Thr Ile Asn Thr Ala Arg 1070 1075 1080His Ser Gln Ser Gly Gln Gly Gln Ser Thr Gln Thr Gly Ser Arg 1085 1090 1095Val Ser Arg Arg Arg Arg Ser Ser Gln Ser Glu Asn Ile Asp Ser 1100 1105 1110Glu Val His Ser Arg Val Ser His Arg His Ser Glu His Ile Asp 1115 1120 1125Thr Gln Val Gly Ser His Tyr Pro Glu Ser Gly Ser Thr Val His 1130 1135 1140Arg Arg Gln Gly Thr Thr His Gly Gln Arg Gly Asp Thr Thr Arg 1145 1150 1155His Ser His Ser Gly His Gly Gln Ser Thr Gln Thr Gly Ser Arg 1160 1165 1170Thr Thr Gly Arg Gln Arg Phe Ser His Ser Asp Ala Thr Asp Ser 1175 1180 1185Glu Val His Ser Gly Val Ser His Arg Pro His Ser Gln Glu His 1190 1195 1200Thr His Gly Gln Asp Gly Ser Gln Leu Gly Glu Ser Gln Ser Thr 1205 1210 1215Val His Glu Arg His Glu Thr Thr Tyr Gly Gln Thr Gly Asp Ala 1220 1225 1230Thr Gly His Gly Tyr Ser Gly His Gly Gln Ser Thr Gln Ile Gly 1235 1240 1245Ser Arg Thr Ser Gly Arg Arg Gly Ser Gly His Ser Glu Ser Ser 1250 1255 1260Asp Thr Glu Val His Ser Gly Gly Ser His Arg Pro His Ser Gln 1265 1270 1275Glu Gln Thr His Gly Gln Ala Arg Ser Gln His Gly Glu Ser Arg 1280 1285 1290Ser Thr Val His Glu Arg His Gly Thr Thr His Gly Gln Thr Gly 1295 1300 1305Asp Thr Thr Arg Tyr Ala His Tyr His Asn Gly Gln Ser Ala Gln 1310 1315 1320Arg Gly Ser Arg Thr Thr Gly Arg Gly Ser Gly His Ser Glu Tyr 1325 1330 1335Ser Asp Ser Glu Leu Tyr Ser Gly Gly Ser His Thr Tyr Ser Gly 1340 1345 1350His Thr His Gly Gln Ala Gly Ser Gln His Gly Glu Ser Asp Ser 1355 1360 1365Ile Val His Glu Arg Tyr Gly Thr Thr His Gly Gln Thr Gly Asp 1370 1375 1380Thr Thr Arg His Ala His Tyr Ser His Gly Gln Ser Lys Gln Arg 1385 1390 1395Gly Ser Arg Thr Thr Gly Arg Arg Gly Ser Gly His Ser Glu Tyr 1400 1405 1410Ser Asp Ser Glu Gly His Ser Gly Gly Ser His Thr His Ser Gly 1415 1420 1425His Thr His Gly His Thr His Gly Gln Ala Gly Ser Gln His Gly 1430 1435 1440Glu Ser Gly Ser Ser Gly His Gly Gly Gln Gly Thr Thr His Gly 1445 1450 1455Gln Thr Gly Asp Thr Thr Arg His Ala His Tyr Gly His Gly Gln 1460 1465

1470Ser Thr Gln Arg Gly Ser Arg Thr Ala Gly Arg Arg Gly Ser Gly 1475 1480 1485His Ser Glu Tyr Ser Asp Ser Glu Gly His Ser Gly Val Ser His 1490 1495 1500Thr His Ser Gly His Thr His Gly Gln Ala Gly Ser Gln His Gly 1505 1510 1515Glu Ser Glu Ser Thr Val His Glu Arg Gln Gln Thr Thr His Gly 1520 1525 1530Gln Thr Gly Asp Thr Thr Arg His Ala His Tyr Gly His Gly Gln 1535 1540 1545Ser Thr Gln Thr Gly Ser Arg Thr Thr Gly Arg Arg Gly Ser Gly 1550 1555 1560His Ser Glu Tyr Ser Asp Ser Glu Gly His Ser Gly Val Ser His 1565 1570 1575Thr His Ser Gly His Thr His Gly Gln Ala Arg Ser Gln His Gly 1580 1585 1590Glu Ser Gly Ser Ala Ile His Gly Arg Gln Gly Thr Ile His Gly 1595 1600 1605Gln Thr Gly Asp Thr Thr Arg His Gly Gln Ser Gly His Gly Gln 1610 1615 1620Ser Thr Gln Thr Gly Ser Arg Thr Thr Gly Arg Arg Gly Ser Gly 1625 1630 1635His Ser Glu Tyr Ser Asp Ser Glu Gly His Ser Gly Gly Ser His 1640 1645 1650Thr His Ser Gly His Thr His Gly Gln Ala Gly Ser Gln His Gly 1655 1660 1665Glu Ser Gly Ser Thr Val His Gly Arg Gln Gly Thr Ile His Gly 1670 1675 1680Gln Thr Gly Asp Thr Thr Arg His Gly Gln Ser Gly His Gly Gln 1685 1690 1695Ser Ile Glu Thr Gly Ser Arg Thr Thr Gly Arg Arg Gly Ser Gly 1700 1705 1710His Ser Glu Tyr Ser Asp Ser Glu Gly His Ser Gly Val Ser His 1715 1720 1725Thr His Ser Gly His Thr His Gly Gln Ala Gly Ser Gln His Gly 1730 1735 1740Glu Ser Glu Ser Thr Val His Glu Arg Gln Gln Thr Thr His Gly 1745 1750 1755Gln Thr Gly Asp Ile Thr Glu His Gly His Ser Ser His Gly Gln 1760 1765 1770Thr Thr Gln Thr Gly Ser Arg Thr Thr Gly Arg Arg Gly Ser Gly 1775 1780 1785His Ser Glu Tyr Ser Asp Ser Glu Trp His Ser Gly Gly Ser His 1790 1795 1800Thr His Ser Gly His Thr His Gly Gln Ala Gly Phe Gln His Gly 1805 1810 1815Glu Ser Gly Ser Ala Val His Gly Arg Gln Gly Thr Ile His Gly 1820 1825 1830Gln Thr Gly Asp Thr Thr Arg His Gly Gln Ser Gly His Gly Glu 1835 1840 1845Ser Ile Gln Thr Gly Ser Arg Thr Ile Gly Arg Arg Gly Ser Gly 1850 1855 1860His Ser Glu Tyr Ser Asp Ser Glu Gly His Ser Gly Ile Ser His 1865 1870 1875Thr His Ser Gly His Thr His Gly Gln Ala Gly Ser Gln His Gly 1880 1885 1890Glu Ser Gly Ser Ser Gly His Gly Arg Gln Gly Thr Ala His Gly 1895 1900 1905Gln Thr Gly Asp Thr Thr Arg His Ala His Tyr Asp His Gly Gln 1910 1915 1920Ser Thr Gln Arg Gly Ser Arg Thr Ala Gly Arg Arg Gly Ser Gly 1925 1930 1935His Ser Glu Tyr Ser Asp Ser Glu Gly His Ser Gly Val Ser His 1940 1945 1950Thr His Ser Gly His Thr His Gly Gln Ala Gly Ser Gln His Gly 1955 1960 1965Glu Ser Gly Ala Ala Val His Gly Arg Gln Gly Ile Ile His Gly 1970 1975 1980Gln Thr Gly Asp Thr Thr Arg His Gly Gln Ser Gly Gln Gly Gln 1985 1990 1995Ser Thr Gln Arg Gly Ser Arg Thr Thr Gly Arg Arg Gly Ser Gly 2000 2005 2010His Ser Glu Tyr Ser Asp Ser Val Gly His Ser Gly Val Ser His 2015 2020 2025Thr His Ser Gly His Thr His Gly Leu Ala Gly Ser Gln His Gly 2030 2035 2040Glu Ser Gly Ser Ser Gly His Gly Arg Gln Gly Thr Leu His Gly 2045 2050 2055Gln Thr Gly Asp Thr Thr Arg His Ala His Tyr Gly His Gly Gln 2060 2065 2070Ser Thr Gln Arg Gly Ser Arg Thr Ala Gly Arg Arg Gly Ser Gly 2075 2080 2085His Ser Glu Tyr Ser Asp Ser Glu Trp His Ser Gly Gly Ser His 2090 2095 2100Thr His Ser Gly His Thr His Gly Gln Ala Gly Ser Gln His Gly 2105 2110 2115Glu Ser Gly Ser Ala Val His Gly Arg Gln Gly Thr Ile His Gly 2120 2125 2130Gln Thr Gly Asp Thr Thr Arg His Gly Gln Ser Gly His Gly Gln 2135 2140 2145Ser Thr Gln Ile Gly Pro His Ser Ser Ser Ser Tyr Asn Tyr His 2150 2155 2160Ser Glu Gly Thr Glu Arg Glu Arg Gly Gln Ser Gly Leu Val Trp 2165 2170 2175Arg His Gly Ser Tyr Gly Ser Ala Asp Tyr Asp Tyr Gly Glu Ser 2180 2185 2190Arg Phe Arg His Ser Gln His Gly Ser Val Ser Tyr Asn Ser Asn 2195 2200 2205Pro Val Val Phe Lys Glu Arg Ser Asp Ile Arg Lys Ala Ser Ala 2210 2215 2220Phe Gly Glu Asp His Pro Arg Tyr Tyr Ala Arg Tyr Val Asn Arg 2225 2230 2235Gln Pro Gly Leu Tyr Arg His Ser Ser Asp Ile Ser Lys Gln Leu 2240 2245 2250Gly Phe Ser Gln Ser Gln Arg Tyr Tyr Tyr Tyr Glu 2255 2260 22652010PRTArtificial SequenceSynthetic peptide 20Arg Met Arg Arg Met Arg Arg Met Arg Arg1 5 1021354PRTArtificial SequenceSynthetic peptide 21Arg Ser Gly Glu Thr Ser Gly Arg Ser Gly Ser Phe Leu Tyr Gln Val1 5 10 15Ser Thr His Glu Gln Ser Glu Ser Thr His Gly Gln Thr Ala Pro Ser 20 25 30Thr Gly Gly Arg Gln Gly Ser Arg His Glu Gln Ala Arg Asn Ser Ser 35 40 45Arg His Ser Ala Ser Gln Asp Gly Gln Asp Thr Ile Arg Gly His Pro 50 55 60Gly Ser Ser Arg Gly Gly Arg Gln Gly Ser Tyr His Glu Gln Ser Val65 70 75 80Asp Arg Ser Gly His Ser Gly Tyr His His Ser His Thr Thr Pro Gln 85 90 95Gly Arg Ser Asp Ala Ser His Gly Gln Ser Gly Pro Arg Ser Ala Ser 100 105 110Arg Gln Thr Arg Asn Glu Glu Gln Ser Gly Asp Gly Ser Arg His Ser 115 120 125Gly Ser Arg His His Glu Pro Ser Thr Arg Ala Gly Ser Ser Arg His 130 135 140Ser Gln Val Gly Gln Gly Glu Ser Ala Gly Ser Lys Thr Ser Arg Arg145 150 155 160Gln Gly Ser Ser Val Ser Gln Asp Arg Asp Ser Glu Gly His Ser Glu 165 170 175Asp Ser Glu Arg Arg Ser Glu Ser Ala Ser Arg Asn His Tyr Gly Ser 180 185 190Ala Arg Glu Gln Ser Arg His Gly Ser Arg Asn Pro Arg Ser His Gln 195 200 205Glu Asp Arg Ala Ser His Gly His Ser Ala Glu Ser Ser Arg Gln Ser 210 215 220Gly Thr Arg His Ala Glu Thr Ser Ser Gly Gly Gln Ala Ala Ser Ser225 230 235 240Gln Glu Gln Ala Arg Ser Ser Pro Gly Glu Arg His Gly Ser Arg His 245 250 255Gln Gln Ser Ala Asp Ser Ser Thr Asp Ser Gly Thr Gly Arg Arg Gln 260 265 270Asp Ser Ser Val Val Gly Asp Ser Gly Asn Arg Gly Ser Ser Gly Ser 275 280 285Gln Ala Ser Asp Ser Glu Gly His Ser Glu Glu Ser Asp Thr Gln Ser 290 295 300Val Ser Ala His Gly Gln Ala Gly Pro His Gln Gln Ser His Gln Glu305 310 315 320Ser Thr Arg Gly Gln Ser Gly Glu Arg Ser Gly Arg Ser Gly Ser Phe 325 330 335Tyr Gln Val Ser Thr His Glu Gln Arg Met Arg Arg Met Arg Arg Met 340 345 350Arg Arg22279PRTArtificial SequenceSynthetic peptide 22Gly Ser Gly Phe Tyr Pro Val Tyr Tyr Tyr Tyr Glu Gln Glu His Ser1 5 10 15Glu Glu Glu Ser Asp Ser Gln His Gly His Gln His Glu Gln Gln Arg 20 25 30Gly His Gln His Gln His Gln His Glu His Glu Gln Pro Glu Ser Gly 35 40 45His Arg Gln Gln Gln Ser Ser Gly Arg Gly His Gln Gly Ala His Gln 50 55 60Glu Gln Gly Arg Asp Ser Ala Arg Ser Arg Gly Ser Asn Gln Gly His65 70 75 80Ser Ser Ser Arg His Gln Ala Asp Ser Pro Arg Val Ser Ala Arg Ser 85 90 95Gly Ser Gly Gly Arg Gly Gln Ser Pro Asp Ala Ser Gly Arg Ser Ser 100 105 110Asn Arg Arg Asp Arg Pro Arg Gln Pro Asn Pro Ser Gln Ser Ser Asp 115 120 125Ser Gln Val His Ser Gly Val Gln Val Glu Gly Arg Arg Gly Gln Ser 130 135 140Ser Ser Ala Asn Arg Arg Ala Gly Ser Ser Ser Gly Ser Gly Val Gln145 150 155 160Gly Ala Ser Ala Gly Gly Leu Ala Ala Asp Ala Ser Arg Arg Ser Gly 165 170 175Ala Arg Gln Gly Gln Ala Ser Ala Gln Gly Arg Ala Gly Ser Gln Gly 180 185 190Gln Ala Gln Gly Arg Val Gly Ser Ser Ala Asp Arg Gln Gly Arg Arg 195 200 205Gly Val Ser Glu Ser Gln Ala Ser Asp Ser Glu Gly His Ser Asp Phe 210 215 220Ser Glu Gly Gln Ala Val Gly Ala His Arg Gln Ser Gly Ala Gly Gln225 230 235 240Arg His Glu Gln Arg Ser Ser Arg Gly Gln His Gly Ser Gly Tyr Tyr 245 250 255Tyr Glu Gln Glu His Ser Glu Glu Glu Ser Asp Ser Gln Arg Met Arg 260 265 270Arg Met Arg Arg Met Arg Arg 2752310PRTArtificial SequenceSynthetic peptide 23Arg Met Arg Arg Met Arg Arg Met Arg Arg1 5 102410PRTArtificial SequenceSynthetic peptide 24Arg Gly Arg Arg Gly Arg Arg Gly Arg Arg1 5 102510PRTArtificial SequenceSynthetic peptide 25Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg1 5 102610PRTArtificial SequenceSynthetic peptide 26Arg Ala Arg Arg Ala Arg Arg Ala Arg Arg1 5 102710PRTArtificial SequenceSynthetic peptide 27Arg Thr Arg Arg Thr Arg Arg Thr Arg Arg1 5 102810PRTArtificial SequenceSynthetic peptide 28Arg Ser Arg Arg Ser Arg Arg Ser Arg Arg1 5 102910PRTArtificial SequenceSynthetic peptide 29Arg Val Arg Arg Val Arg Arg Val Arg Arg1 5 103010PRTArtificial SequenceSynthetic peptide 30Arg Lys Arg Arg Lys Arg Arg Lys Arg Arg1 5 10317PRTArtificial SequenceSynthetic peptide 31Arg Arg Arg Arg Arg Arg Arg1 5328PRTArtificial SequenceSynthetic peptide 32Arg Arg Arg Arg Arg Arg Arg Arg1 5339PRTArtificial SequenceSynthetic peptide 33Arg Arg Arg Arg Arg Arg Arg Arg Arg1 53411PRTArtificial SequenceSynthetic peptide 34Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg1 5 103512PRTArtificial SequenceSynthetic peptide 35Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg1 5 103613PRTArtificial SequenceSynthetic peptide 36Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg1 5 103714PRTArtificial SequenceSynthetic peptide 37Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg1 5 103815PRTArtificial SequenceSynthetic peptide 38Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg1 5 10 15395PRTArtificial SequenceSynthetic peptide 39Gly Gly Gly Gly Ser1 54014PRTArtificial SequenceSynthetic Peptide 40Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Val Asp1 5 104118PRTArtificial SequenceSynthetic peptide 41Lys Glu Ser Gly Ser Val Ser Ser Glu Gln Leu Ala Gln Phe Arg Ser1 5 10 15Leu Asp

Claims

1. A recombinant polypeptide comprising a human filaggrin sequence and a cell importation sequence positioned on the N-terminus side or the C-terminus side of the filaggrin sequence.

2. The recombinant polypeptide of claim 1, further comprising a linker region positioned between the human filaggrin sequence and the cell importation sequence.

3. The recombinant polypeptide of claim 1, wherein the cell importation sequence comprises an RMR tag.

4. The recombinant polypeptide of claim 3, wherein the RMR tag comprises SEQ ID NO:23.

5. The recombinant polypeptide of claim 3, wherein the RMR tag consists of SEQ ID NO:23.

6. The recombinant polypeptide of claim 3, wherein the cell importation sequence is positioned on the C-terminus side of the filaggrin sequence.

7. The recombinant polypeptide of claim 1, comprised in a topical formulation.

8. The recombinant polypeptide of claim 7, wherein the topical formulation is an emulsion, a cream, a lotion, a gel, or an ointment.

9. A recombinant polypeptide comprising a human filaggrin sequence and an RMR sequence motif positioned on the N terminus side or the C-terminus side of the filaggrin sequence.

10. The recombinant polypeptide of claim 9, wherein the motif comprises repeating units of RMR.

11. The recombinant polypeptide of claim 10, wherein the RMR sequence motif comprises SEQ ID NO:23.

12. The recombinant polypeptide of claim 11, wherein the RMR sequence motif consists of SEQ ID NO:23.

13. The recombinant polypeptide of claim 10, wherein the RMR sequence motif is positioned on the C-terminus side of the filaggrin sequence.

14. The recombinant polypeptide of claim 9, further comprising a linker region positioned between the human filaggrin sequence and the RMR sequence motif.

15. The recombinant polypeptide of claim 9, comprised in a topical formulation.

16. The recombinant polypeptide of claim 15, wherein the topical formulation is an emulsion, a cream, a lotion, a gel, or an ointment.

17. A recombinant chimeric nucleic acid molecule comprising a human filaggrin coding region under the control of a eukaryotic or prokaryotic promoter.

18. The recombinant nucleic acid molecule of claim 17, wherein the promoter is a eukaryotic promoter.

19. The recombinant nucleic acid molecule of claim 17, wherein the promoter is a prokaryotic promoter.

20. The recombinant nucleic acid molecule of claim 17, further defined as an expression vector.

21. The recombinant nucleic acid molecule of claim 20, wherein the expression vector is a prokaryotic expression vector.

22. The recombinant nucleic acid molecule of claim 20, wherein the expression vector is a eukaryotic expression vector.

23. The recombinant nucleic acid molecule of claim 17, wherein the molecule further comprises a region encoding a cell importation sequence.

24. The recombinant chimeric nucleic acid molecule of claim 17, wherein the molecule further comprises a region encoding an RMR tag.

25. The recombinant polypeptide of claim 24, wherein the RMR tag comprises SEQ ID NO:23.

26. The recombinant polypeptide of claim 26, wherein the RMR tag consists of SEQ ID NO:23.

27. The recombinant nucleic acid molecule of claim 17, further comprising a region encoding a linker region positioned between the human filaggrin sequence and the cell importation sequence.

28. The recombinant chimeric nucleic acid molecule of claim 17, positioned in a host cell that expresses human filaggrin.

29. The recombinant chimeric nucleic acid molecule of claim 28, wherein the host cell is a prokaryote.

30. The recombinant chimeric nucleic acid molecule of claim 29, wherein the host cell is a bacteria.

31. The recombinant chimeric nucleic acid molecule of claim 28, wherein the host cell is a eukaryote. .