CN112813049B - Fusion protein for live cell RNA marking and application - Google Patents

Abstract

The invention belongs to the field of research on RNA living cell markers, and particularly provides a fusion protein of dCas13 protein and fluorescent protein with RNA nuclease activity deletion or reduction, and a method and application of RNA markers in living cells. The RNA marking method has the characteristics of short experimental period, simple operation, high sensitivity, high specificity and the like. The rapid endogenous RNA labeling can be realized by using the labeling method.

Description

Fusion protein for RNA (ribonucleic acid) marking of living cells and application

Technical Field

The invention belongs to the field of nucleic acid labeling, and particularly relates to a fusion protein for labeling cell RNA and application thereof.

Background

RNA, one of important biological macromolecules, is widely involved in various cell life activities. Research on RNA has long previously focused primarily on the study of cellular biological functions and biophysical properties of RNA using biochemical and molecular biological means. However, it was reported in 1983 that transcripts were not randomly distributed in the egg cells of ascidians petioli and that the distribution of transcripts was constantly changing during embryonic development (Jeffery et al, 1983), suggesting that subcellular localization of mRNA under different spatiotemporal conditions plays an important role during development. Since noncoding RNA, especially long noncoding RNA (incrna), does not have the ability to encode functional protein, incrna functions by determining its own sequence properties to locate in a cell, and functions directly or by interacting with a related RNA binding protein to form a complex. Therefore, it is very important to study the function of RNA whether it is mRNA encoding protein or non-coding RNA and to understand its subcellular localization and spatiotemporal changes under different conditions.

For the research on the localization of RNA, RNA Fluorescence In Situ Hybridization (FISH) is mainly used, but since RNA FISH is hybridized in fixed cells, the use of a fixative may cause cell deformation or affect the original localization of molecules in cells, which may cause the observed phenomenon to be different from the real situation, and FISH may lose some important information because it cannot reflect the dynamic change of RNA in the state of living cells (Schnell et al, 2012). The method of fluorescence probe labeling of live cell RNA is similar to RNA FISH technology (Raj et al, 2008, santangelo et al, 2009, simon et al, 2010), and due to the integrity of the live cell membrane and the preservation of cell activity, fluorescence probe labeling of live cells inevitably creates several problems: (1) The fluorescent probe is difficult to deliver to living cells, and the current methods mainly comprise methods such as liposome transfection, electrotransformation and microinjection; microinjection can inject an accurate and quantitative probe into cells, but the operation is complex, the transfection and electrotransformation efficiency of liposome is low, and the toxicity to cells is high; (2) The probe can be degraded and unstable by nuclease after entering a living cell, and the existence time is short. When the probe is manufactured, the problem that the probe is degraded can be effectively solved by using 2' -O-methylation modified ribonucleotide to replace oligodeoxyribonucleotide or preparing the probe with a stable skeleton structure, but the corresponding preparation cost of the probe is also greatly increased (Molenaar et al, 2001, okabe et al, 2011); (3) A relatively high background signal is also a relatively large problem that needs to be faced with fluorescence labeling of live cell RNA. After the fluorescent probe enters into a living cell and is combined with target RNA, a large amount of free probes which are not combined with the target RNA still exist, and the free probes inevitably cause high background signals to influence the detection and observation of the target RNA. Although the fluorescent probe labeling method has been subjected to multiple modifications and improvements, so that there may be some advantages in labeling RNA, the higher manufacturing cost becomes a great limitation to its popularization and application. The RNA aptamer labeling method based on a specific structure can be classified into a fluorescent protein labeling method and a fluorescein labeling method. Although no RNA capable of automatically generating fluorescence can directly mark target RNA like labeled protein, a class of RNA with a special structure such as Spinach2 has been found to be capable of combining with fluorescein DFHBI and improving the quantum efficiency of DFHBI so as to be detected, so that Spinach2 is inserted into the target RNA and the target RNA can be detected by DFHBI staining, but the fluorescence intensity is very low, the signal is difficult to detect, and the application of the RNA is greatly limited (Strack and Jaffrey, 2015). In addition, based on the specific binding of some RNA binding proteins to some RNAs with stem-loop structures, fluorescently labeled RNA binding proteins can be recruited to label the RNA of interest after insertion of the RNA into the RNA of interest (Beach et al, 1999 horvatova et al, 2017. However, this RNA aptamer-based approach requires the insertion of a sequence into the RNA of interest, which may affect the structure and function of RNA, particularly lncRNA, which functions mainly depending on its structure, even if the marker is in the untranslated region of mRNA (Heinrich et al, 2017).

In summary, although many different methods have been developed for the labeling of live cells of RNA, these labeling methods are either too costly to be affordable in the laboratory or cannot label endogenous RNA that has not been modified by sequence insertions. Therefore, it is necessary to develop a simple and convenient RNA labeling technique that can realize the detection and observation of endogenous RNA in living cells.

Disclosure of Invention

In order to overcome the problems of the prior art, the present invention aims to provide a fusion protein for RNA labeling of living cells and application thereof.

One aspect of the invention provides a fusion protein comprising a dCas protein having a deleted or reduced RNA nuclease activity, one or more marker sequences and optionally one or more intracellular localization sequences.

In one or more embodiments, the dCas protein is N-terminal to the one or more marker sequences.

In one or more embodiments, the dCas protein is dCas13 protein. Preferably, the dCas13 protein is derived from the following species: lachnospiraceae bacteria, leptotrichia wadei, prevotella sp.P5-125, porphyromonas gulae, eubacterium siaeum DSM15702, anaerobic digesterter metagenome 15706, ruminococcus flavefaciens XPD3002.

In one or more embodiments, the dCas13 protein is selected from one or more of a deletion or a reduced mutant of RNA nuclease activity of: lbaCas13a, lwaCas13a, pspCas13b, pguCas13b, ranCas13b, admCas13d, esCas13d, rfxCas13d. In one or more embodiments, the mutation is located in one or both HEPN domains of the Cas13 protein.

In one or more embodiments, the dCas13 protein has one or more of the following sequences or a sequence having at least 70% identity thereto: position 18-1456 of SEQ ID NO.1, position 18-1171 of SEQ ID NO.2, position 9-1089 of SEQ ID NO.3, position 9-1183 of SEQ ID NO.4, position 9-1103 of SEQ ID NO. 5, position 18-966 of SEQ ID NO. 6, position 18-974 of SEQ ID NO. 7, position 18-986 of SEQ ID NO. 8, or a combination thereof. Preferably, the sequence of the dCas13 protein is shown in SEQ ID NO.3 at positions 9-1089 or SEQ ID NO.4 at positions 9-1183.

In one or more embodiments, the fusion protein comprises a plurality of tag sequences.

In one or more embodiments, the marker sequence is an optically active polypeptide, preferably a fluorescent protein.

In one or more embodiments, the marker sequence has one or more of the following sequences or a sequence having at least 70% identity thereto: 1, 1123-1360 of SEQ ID NO.9, 1111-1345 of SEQ ID NO.11, or a combination thereof.

In one or more embodiments, the fusion protein comprises a plurality of intracellular localization sequences.

In one or more embodiments, the intracellular localization sequence is a nuclear localization signal.

In one or more embodiments, the intracellular localization sequence has one or more of the following sequences or a sequence having at least 70% identity thereto: positions 2-17 of SEQ ID NO.1 or positions 1363-1369 of SEQ ID NO.9, or a combination thereof.

In one or more embodiments, the nuclear localization signal is located N-terminal to dCas and/or C-terminal to the marker sequence.

In one or more embodiments, the fusion protein has, from N-terminus to C-terminus, one or more nuclear localization signals, dCas protein, one or more marker sequences, and one or more nuclear localization signals.

In one or more embodiments, the fusion protein has or consists of a sequence set forth in any one of SEQ ID NOs 1-18 or a sequence having at least 70% identity thereto.

In another aspect, the invention provides a polynucleotide selected from: (1) a polynucleotide encoding a fusion protein described herein; (2) the complement of (1); and (3) a fragment of (1) or (2). Preferably, the polynucleotide sequence is shown in SEQ ID NO. 46.

The invention also provides a nucleic acid construct comprising a polynucleotide as described herein. In one or more embodiments, the nucleic acid construct is a cloning vector or an expression vector.

The invention also provides a host cell that (1) expresses a fusion protein described herein; (2) comprising a polynucleotide as described herein; (3) comprising a nucleic acid construct as described herein; (4) optionally comprising a gRNA directed against the target. In one or more embodiments, the target is a target RNA. The gRNA recognizes dCas13 in the target RNA and fusion protein.

Also provided herein is a detection composition containing a fusion protein, a polynucleotide, a nucleic acid construct, a gRNA for a target, and reagents for detecting a marker sequence as described herein. In one or more embodiments, the target is a target RNA. The gRNA recognizes dCas13 in the target RNA and the fusion protein.

Also provided herein is a detection kit comprising (1) the fusion protein described herein, or the coding sequence of said fusion protein or a complement thereof, or a nucleic acid construct comprising said coding sequence or a complement thereof, (2) reagents for detecting a marker sequence, and optionally (3) a gRNA directed against a target or a nucleic acid construct comprising the gRNA or a complement thereof. In one or more embodiments, the target is a target RNA. The gRNA recognizes dCas13 in the target RNA and fusion protein.

In one or more embodiments, the kit can further comprise various reagents suitable for transfecting the polynucleotide or nucleic acid construct into a cell, and optionally instructions directing a person of skill in the art to transfect the nucleic acid construct into a cell.

The invention also provides for the use of the fusion proteins, polynucleotides, nucleic acid constructs, host cells described herein in detecting a target. In one or more embodiments, the target is a target RNA. The gRNA recognizes dCas13 in the target RNA and the fusion protein. In one or more embodiments, the assay is an intracellular assay.

The invention also provides a method of detecting a target comprising (1) incubating cells that express the fusion protein described herein and comprise a gRNA for the target, and (2) detecting a marker sequence. In one or more embodiments, the target is a target RNA. The gRNA recognizes dCas13 in the target RNA and fusion protein.

In one or more embodiments, the marker sequence is a fluorescent protein and detecting the marker sequence comprises detecting a fluorescent protein color.

The invention also includes a method of locating a target within a cell, comprising expressing in the cell a fusion protein described herein and a gRNA directed against the target, and detecting the location of a marker sequence in the cell. In one or more embodiments, the target is a target RNA. The gRNA recognizes dCas13 in the target RNA and the fusion protein.

The invention also provides a method of detecting a target RNA and a target DNA comprising (1) incubating a cell that expresses a fusion protein described herein and comprises a gRNA for the target RNA, and that expresses a protein in which dCas9 is fused to another marker sequence and comprises a sgRNA for the target DNA, and (2) detecting the marker sequence. The gRNA recognizes dCas13 in the target RNA and the fusion protein. The sgrnas recognize dCas9 in the target DNA and fusion protein.

The invention also includes a method of diagnosing a disease associated with the identification, amount, or location of a target comprising detecting or locating the target using the methods described herein and diagnosing based on the detection or location.

The invention has the following advantages and beneficial effects:

(1) dCas13b-FPs is a novel protein system for targeting RNA, which is different from the traditional RNA molecular probe and RNA aptamer method. The novel RNA protein system has the characteristics of specificity and stable combination with endogenous target RNA.

(2) The invention can mark the target RNA by a transfection method only after constructing the gRNA plasmid, and compared with the method that a period of weeks or even months is consumed by knocking in a section of aptamer into the gene sequence of the target RNA in advance, the invention greatly simplifies the steps of RNA marking and shortens the time required by RNA marking. The above innovations are beneficial to the quick and effective marking of target RNA, and provide a new tool for more conveniently and quickly researching the positioning and dynamic change of RNA and the relation with functions.

Drawings

FIG. 1: dCas13b-EGFP labels NEAT1 results in targeting the gRNA effect of NEAT 1.

FIG. 2: the result of labeling NEAT1 after optimization of the dspcas 13b fused fluorescent protein.

FIG. 3: the result of marking SaIII by dCas13b-3 xEGFP after 1 hour of thermal stimulation or 6 hours of treatment with sodium arsenite under the action of gRNA targeting SaIII.

FIG. 4: the result of labeling MUC4 by dPspCas13b-3 xEGFP under the action of gRNA targeting MUC 4.

FIG. 5: the result of labeling 24 XGCN 4 with dPspCas13b-3 XEGFP under the action of gRNA targeting GCN 4.

FIG. 6: and (3) labeling mRNA after optimizing the dPspCas13b fused fluorescent protein.

FIG. 7: results of CRISPR-Cas13 dual color labeling of RNA.

FIG. 8: results of CRISPR-Cas13 combined CRISPR-Cas9 dual-color labeling of RNA and DNA.

Detailed Description

The inventor carries out enzyme activity deletion mutation on a plurality of CRISPR-Cas13 proteins and then fuses the proteins with fluorescent protein to obtain the recombinant protein which can be used for living cell RNA labeling.

Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. Test methods in which specific conditions are not specified in the following examples are generally carried out under conventional conditions or under conditions recommended by the respective manufacturers.

When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any value therebetween can be selected unless the invention otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, and materials used in the examples, the invention may be practiced using any method, device, and material that is similar or equivalent to the methods, devices, and materials described in examples herein, in addition to those described in prior art practice and the description herein.

Unless otherwise indicated, the experimental methods, detection methods, and preparation methods disclosed herein all employ techniques conventional in the art of molecular biology, biochemistry, chromatin structure and analysis, analytical chemistry, cell culture, recombinant DNA technology, and related arts.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

The fusion proteins of the invention comprise a dCas protein with a deleted or reduced RNA nuclease activity, a marker and optionally an intracellular localization sequence.

CRISPR-Cas systems are a class of acquired immune systems that are widely found in bacteria and archaea to protect hosts from foreign virus invasion. The CRISPR-Cas13 is a protein which can cut RNA in a targeted mode under the mediation of guide RNA or nonspecifically cut RNA after being activated by targeted RNA, and is developed and used for experiments such as the knockdown of cell RNA, the specific editing of RNA base, the detection of exogenous virus RNA and the like. The different Cas13 families comprise at least four known subtypes, including Cas13a (also referred to as C2), cas13b, cas13C and Cas13d. Cas13 proteins suitable for use herein include, but are not limited to: proteins derived from the following species: lachnospiraceae bacteria ((Lba) Cas13 a), leptotrichia wadei ((Lwa) Cas13 a), prevotella sp.P5-125 ((Psp) Cas13 b), porphyromonas gulae ((Pgu) Cas13 b), porphyromonas gulae ((Ran) Cas13 b), eubacterium siarum DSM15702 ((Es) Cas13 d), anaerobic digger swagenoome 15706 ((Adm) Cas13 d) and Ruminococcocus flavefaciens XPD3002 ((Rfx) Cas13 d).

Cas13 family members contain two HEPN domains that produce rnase activity. Cas13 proteins suitable for use herein also include dCas13 proteins with missing or reduced rnase activity. dCas13 can be obtained by mutating or modifying a Cas13 protein. In one or more embodiments, the mutation is located in one or both HEPN domains of the Cas13 protein. Such mutations include insertions, deletions or substitutions having one or more (e.g., within 20, within 15, within 10, within 8, within 5 or within 3) amino acids in the amino acid sequence, while the rnase activity of the sequence is deleted or reduced. While the rnase activity of dCas13 is deleted or reduced, other activities or functions are unaffected or substantially unaffected, such as activities of RNA recognition, recruitment of grnas, complex formation with grnas, binding to DNA, and the like. Alternatively, cas13 proteins suitable for use herein also include Cas13 protein mutants having at least 70%, preferably at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, or preferably at least 97% sequence identity to a wild-type Cas13 protein or to a dCas13 protein with deletion or reduction of rnase activity as described herein, which Cas13 protein mutants still have rnase activity deleted or reduced while retaining their function other than rnase activity; preferably, these Cas13 protein mutants are from the same species as their wild-type Cas13 protein. Exemplary dCas13 proteins are shown below: dLbaCas13a (position 18-1456 of SEQ ID NO: 1), dLwaCas13a (position 18-1171 of SEQ ID NO: 2), dPspCas13b (position 9-1089 of SEQ ID NO: 3), dPguCas13b (position 9-1183 of SEQ ID NO: 4), dRanCas13b (position 9-1103 of SEQ ID NO: 5), dAdmCas13d (position 18-966 of SEQ ID NO: 6), dEsCas13d (position 18-974 of SEQ ID NO: 7), dRfxCas13d (position 18-986 of SEQ ID NO: 8), and sequences having at least 70%, preferably at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, or preferably at least 97% sequence identity to these dCas13 proteins, the RNA enzyme activity being deleted or reduced but retaining its RNA enzyme activity function, preferably from the same species as the Cas13 protein from which it is derived from.

As used herein, a "marker sequence" or "marker" is a substance used to represent the results of an assay in a manner that facilitates detection or observation. The marker may be a polypeptide, protein, small molecule, or other molecule. Illustratively, the label may be an optically active polypeptide or a functional fragment thereof. A protein-based "optically active polypeptide" is a polypeptide that has the ability to emit fluorescence. Functional fragments of an optically active polypeptide include fragments that can undergo a change in the same or similar fluorescent properties as a parent optically active polypeptide. Examples of optically active polypeptides include "fluorescent proteins," which refer to proteins that fluoresce under irradiation with excitation light. Fluorescent proteins and sequences thereof useful in the present invention are known in the art. In an exemplary embodiment, EGFP (positions 1466-1704 of SEQ ID NO: 1), sfGFP (positions 1123-1360 of SEQ ID NO: 9), mNeonGreen (positions 1111-1345 of SEQ ID NO: 11) fluorescent proteins are used. In the fusion proteins of the invention, one or more optically active polypeptides (e.g., fluorescent proteins) are operably linked to dCas protein. Any of the optically active polypeptides may be located at the N-terminus, C-terminus or within dCas protein. In a preferred embodiment, the plurality of optically active polypeptides are located consecutively at the C-terminus of the dCas protein.

The fusion proteins herein may also optionally comprise intracellular localization sequences that serve to direct the fusion protein into a desired organelle. The organelles include cytoplasm, mitochondria, nucleus, endoplasmic reticulum, cell membrane, golgi apparatus, lysosomes, peroxisomes and the like. Intracellular localization sequences may be located at the N-terminus and/or C-terminus of the sequence to be expressed. In one or more embodiments, the intracellular localization sequence is a nuclear localization signal. Intracellular localization sequences suitable for various organelles are known in the art, and exemplary nuclear localization signals are shown at positions 2-17 of SEQ ID NO:1 or 1363-1369 of SEQ ID NO: 9. The nuclear localization signal may be located at the N-terminus or the C-terminus or both of the sequence to be expressed (e.g., a fusion polypeptide of dCas with a fluorescent protein).

The optically active polypeptide, dCas protein and nuclear localization signal forming the fusion protein herein may be linked to each other or to the plurality of optically active polypeptides directly or via linkers well known in the art. Herein, a linker is a polypeptide fragment that connects different proteins or polypeptides, with the purpose of maintaining the connected proteins or polypeptides in their respective spatial conformations, so as to maintain the function or activity of the proteins or polypeptides. Exemplary linkers include linkers containing G and/or S. In addition to glycine and serine, other known amino acid residues may be contained in the linker, such as alanine (a), leucine (L), threonine (T), glutamic acid (E), phenylalanine (F), arginine (R), glutamine (Q), and the like. The linker may be 1-25 amino acid residues in length, for example 1-15, 3-15, 5-20 amino acid residues. In certain embodiments, the proteins, polypeptides or sequences of the invention are linked by (GGGS) n, where n is an integer from 1 to 5. In one or more embodiments, the linker sequence is a short peptide chain of one or more flexible amino acids, such as LE, KL. Linkers suitable for use between functional polypeptides of the invention include, but are not limited to: LEALPAT, SGGRSG, GGGSGSM, SR, SNSKPGFHM, LE, SGLRSCLMH, SNSAVDGTM, EGALEGTSGGGSM, EGALEALPVAT, SGLRS, KL, GSIDGS, EALPVAT, SGLRS, SGLRSRRYRRYRHM, EGALEGS, SGLRSHM, GIVPHGAA, GSGSPKKKRKVSR.

The invention also includes mutants of said polypeptides or proteins. The mutant comprises: an amino acid sequence that has at least 70%, at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 97% sequence identity to a reference sequence and retains the biological activity (e.g., binding to a gRNA, fluorescence excitation, nuclear localization) of the reference sequence. Sequence identity between two aligned sequences can be calculated using, for example, BLASTp from NCBI. Mutants also include amino acid sequences that have one or several mutations (insertions, deletions, or substitutions) in the amino acid sequence while still retaining the biological activity of the reference sequence. The number of mutations typically means within 1-20, such as 1-15, 1-10, 1-8, 1-5, or 1-3. The substitution is preferably a conservative substitution. For example, conservative substitutions with amino acids that are similar or analogous in performance are not generally known in the art to alter the function of a protein or polypeptide. "amino acids with similar or analogous properties" include, for example, families of amino acid residues with analogous side chains, including amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine tryptophan, histidine). Thus, substitution of one or more sites with another amino acid residue from the same side chain species in the polypeptide of the invention will not substantially affect its activity.

The present invention includes polynucleotides encoding the polypeptides or proteins of the present invention. The polynucleotide of the present invention may be in the form of DNA or RNA. The form of DNA includes cDNA, genomic DNA or artificially synthesized DNA. The DNA may be single-stranded or double-stranded. The DNA may be the coding strand or the non-coding strand. The invention also includes degenerate variants of polynucleotides that encode a polypeptide or protein, i.e., polynucleotides that encode the same amino acid sequence but differ in nucleotide sequence.

Polynucleotides described herein include sequences that are altered by codon optimization, so long as the amino acid sequence encoded by the polynucleotide is not altered. Codon-optimized sequences may exhibit more suitable expressivity for a particular species. Methods for codon optimizing polynucleotide sequences are well known in the art.

The polynucleotide of the invention may be a fusion protein coding sequence as described herein or a complement thereof. Herein, a coding sequence refers to a portion of a nucleic acid sequence that directly determines the amino acid sequence of its protein product (e.g., CAR, single chain antibody, hinge region, transmembrane region, intracellular signal region, or anti-TCR antibody, etc.). The boundaries of the coding sequence are generally determined by a ribosome binding site (for prokaryotic cells) immediately upstream of the 5 'open reading frame of the mRNA and a transcription termination sequence immediately downstream of the 3' open reading frame of the mRNA. A coding sequence can include, but is not limited to, DNA, cDNA, and recombinant nucleic acid sequences. In certain embodiments, the coding sequence or expression cassette is integrated into the genome of the cell. Thus, in these embodiments, the cell described herein has stably integrated into its genome an expression cassette comprising a nucleic acid encoding a fusion protein described herein. An exemplary polynucleotide is shown in SEQ ID NO 46.

The invention also relates to nucleic acid constructs comprising a polynucleotide as described herein, and one or more control sequences operably linked to the sequences. The polynucleotides of the invention may be manipulated in a variety of ways to ensure expression of the polypeptide or protein. The nucleic acid construct may be manipulated prior to insertion into the vector, depending on the type of expression vector or requirements. Techniques for altering polynucleotide sequences using recombinant DNA methods are known in the art.

The control sequence may be an appropriate promoter sequence. The promoter sequence is typically operably linked to the coding sequence of the protein to be expressed. The promoter may be any nucleotide sequence which shows transcriptional activity in the host cell of choice including mutant, truncated, and hybrid promoters, and may be obtained from genes encoding extracellular or intracellular polypeptides either homologous or heterologous to the host cell. The control sequence may also be a suitable transcription terminator sequence, a sequence recognized by a host cell to terminate transcription. The terminator sequence is operably linked to the 3' terminus of the nucleotide sequence encoding the polypeptide. Any terminator which is functional in the host cell of choice may be used in the present invention. The control sequence may also be a suitable leader sequence, a nontranslated region of an mRNA which is important for translation by the host cell. The leader sequence is operably linked to the 5' terminus of the nucleotide sequence encoding the polypeptide. Any terminator which is functional in the host cell of choice may be used in the present invention.

In certain embodiments, the nucleic acid construct is a vector. The vector may be a cloning vector, an expression vector, or a homologous recombinant vector. The polynucleotides of the present invention can be cloned into many types of vectors, for example, plasmids, phagemids, phage derivatives, animal viruses, and cosmids. Cloning vectors may be used to provide the coding sequences for the fusion proteins of the invention. The expression vector may be provided to the cell in the form of a viral vector. Expression of a polynucleotide of the invention is typically achieved by operably linking the polynucleotide of the invention to a promoter and incorporating the construct into an expression vector. The vector may be suitable for replication and integration into eukaryotic cells. Typical expression vectors contain transcriptional and translational terminators, initiation sequences, and promoters that may be used to regulate the expression of the desired nucleic acid sequence. Viral vector technology is well known in the art and is described, for example, in Sambrook et al (2001, molecular cloning. Viruses that can be used as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. Homologous recombinant vectors are used to integrate the expression cassettes described herein into the host genome.

Generally, suitable vectors comprise an origin of replication functional in at least one organism, a promoter sequence, a convenient restriction enzyme site and one or more selectable markers. An example of a suitable promoter is the immediate early Cytomegalovirus (CMV) promoter sequence. However, other constitutive promoter sequences may be used, and promoter sequences suitable for expressing the fusion proteins of the present invention in a variety of cells are well known in the art.

To assess the expression of the polypeptide or protein, the expression vector introduced into the cells may also contain a selectable marker gene and/or a reporter gene to facilitate identification and selection of expressing cells from the population of cells sought to be transfected or infected by the viral vector. In other aspects, the selectable marker may be carried on a separate piece of DNA and used in a co-transfection procedure. Both the selectable marker and the reporter gene may be flanked by appropriate regulatory sequences to enable expression in a host cell. Useful selectable markers include, for example, antibiotic resistance genes, such as neo and the like. The reporter gene is used to identify potentially transfected cells and to evaluate the functionality of the regulatory sequences. After the DNA has been introduced into the recipient cell, the expression of the reporter gene is assayed at an appropriate time. Suitable reporter genes may include genes encoding luciferase, β -galactosidase, chloramphenicol acetyltransferase, secreted alkaline phosphatase, or green fluorescent protein. Suitable expression systems are well known and can be prepared using known techniques or obtained commercially.

The polynucleotides described herein can generally be obtained by PCR amplification. Specifically, primers can be designed based on the nucleotide sequences disclosed herein, particularly open reading frame sequences, and the relevant sequences can be amplified using commercially available cDNA libraries or cDNA libraries prepared by conventional methods known to those skilled in the art as templates. When the sequence is long, two or more PCR amplifications are often required, and then the amplified fragments are spliced together in the correct order. Alternatively, the nucleic acid molecules described herein can also be synthesized directly.

Methods for introducing and expressing genes into cells are known in the art. The polynucleotide can be readily introduced into a host cell by any method known in the art, for example, mammalian, bacterial, yeast or insect cells. Generally, polynucleotides can be transferred into host cells by physical, chemical, or biological means. Physical methods for introducing polynucleotides into host cells include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, and the like. Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors. Chemical means of introducing polynucleotides into host cells include colloidal dispersion systems such as macromolecular complexes, nanocapsules, microspheres, beads; and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes.

Biological methods for introducing polynucleotides into host cells include transfection with viral vectors or mRNA, particularly retroviral vectors. Other viral vectors may be derived from lentiviruses, poxviruses, herpes simplex virus I, adenoviruses, adeno-associated viruses, and the like. Many virus-based systems have been developed for gene transfer into mammalian cells, such as retrovirus-based systems. The selected gene can be inserted into a vector and packaged into a retroviral particle using techniques known in the art. The recombinant virus can then be isolated and delivered to the subject cells in vivo or ex vivo. Many retroviral systems are known in the art. Lentiviruses are a genus of the family retroviridae, and a lentivirus vector is a more complex retroviral vector. Reagents for lentiviral packaging are well known in the art, as are conventional lentiviral vector systems including pRsv-REV, pMDlg-pRRE, pMD2G and the desired interference plasmid. In one embodiment, the vector pHAGE-EF1 alpha-IRES-puro is used to express dCas13 fusion protein (which can be replaced by any protein eukaryotic expression plasmid such as pcDNA3, etc.), and the vector crRNA-backbone vector is used to express gRNA (which can be replaced by any RNA expression vector such as pLKO.1, etc.).

Herein, a host cell refers to a cell capable of receiving and containing a polynucleotide described herein. An ideal host cell would satisfy both the conditions of ease of acquisition and proliferation. The "host cell" of the present invention may be prokaryotic and eukaryotic cells, including bacterial cells, yeast cells, insect cells, mammalian cells, and the like. The host cell is preferably a variety of cells which facilitate expression of the gene product or fermentative production of such cells, which are well known and commonly used in the art. In certain embodiments, the invention provides a genetically modified cell comprising a polynucleotide as described herein, or comprising a nucleic acid construct as described herein, or prepared by a method as described herein, or stably expressing a fusion protein as described herein.

After transformation of the host cell, the resulting transformant can be cultured by conventional methods to allow expression of the fusion protein described herein. The medium used in the culture may be selected from various conventional media depending on the host cell used. The recombinant fusion proteins herein can be isolated and purified using various isolation methods known in the art. Such methods are well known to those skilled in the art and include, but are not limited to: conventional renaturation treatment, treatment with a protein precipitant (such as salt precipitation), centrifugation, cell lysis by osmosis, sonication, ultracentrifugation, molecular sieve chromatography (gel filtration), adsorption chromatography, ion exchange chromatography, high Performance Liquid Chromatography (HPLC), and other various liquid chromatography techniques and combinations thereof.

Thus, host cells containing the proteins described herein or their coding sequences or expression vectors are also included herein. Such host cells can constitutively express the proteins described herein, can also express the proteins described herein under certain induction conditions, and can also specifically express the proteins described herein in different host cell types. Methods of how to make host cells constitutively express, inducibly express, or specifically express the proteins of the invention are well known in the art. For example, in certain embodiments, inducible promoters are used to construct expression vectors of the invention to achieve inducible expression of the protein. In certain embodiments, tissue-specific expression of the protein is achieved using a tissue-specific expression promoter or associating the coding sequence of the protein with a tissue-specific gene.

The knock-in vector is used to knock the polynucleotide sequences described herein into a region of interest in the genome. Typically, the knock-in vector will contain, in addition to the polynucleotide sequence, a 5 'homology arm and a 3' homology arm required for homologous recombination of the genome. In certain embodiments, the nucleic acid constructs herein comprise a 5 'homology arm, a polynucleotide sequence described herein, and a 3' homology arm. When using knock-in vectors, the CRISPR/Cas9 technique can be simultaneously utilized to homologously recombine the polynucleotide sequence to the location of interest. The CRISPR/Cas9 technology is used for guiding Cas9 nuclease to modify a genome at an insertion position by designing a guide RNA aiming at a target gene, so that the homologous recombination efficiency of a gene modification region is increased, and a target fragment contained in a gene knock-in vector is subjected to homologous recombination to a target site.

Also provided herein is a detection composition comprising the fusion protein or polynucleotide described herein, a gRNA for a target, and a reagent for detecting a label. Also provided herein is a detection kit comprising (1) a fusion protein described herein, or a coding sequence of said fusion protein or a complement thereof, or a nucleic acid construct comprising said coding sequence or a complement thereof, (2) a gRNA directed against a target or a nucleic acid construct comprising said gRNA or a complement thereof, and (3) optionally reagents for detecting a marker. The kit may also contain various reagents suitable for transfecting the polynucleotide or nucleic acid construct into a cell, and optionally instructions directing a person of skill in the art to transfect the nucleic acid construct into a cell.

The gRNA is a guide RNA for guiding CRISPR-Cas13 targeting to a target RNA, comprising a Cas13 protein recognition region and a target RNA recognition region. Typically, the target RNA recognition region can be fully or partially paired with a spacer (spacer) in the target RNA. Methods of designing grnas from different Cas13 proteins and target RNAs are known in the art. Exemplary gRNA sequences are shown in SEQ ID NOS: 19-42.

The invention also includes a method of detecting a target RNA comprising expressing in a cell a fusion protein described herein and a gRNA directed against the target RNA, and detecting a marker. The target RNA can be any type of RNA including mRNA, tRNA, rRNA, and the like. In the cell, the protein recognition region of the gRNA recognizes dCas13 protein in the fusion protein, and the target RNA recognition region of the gRNA recognizes the target RNA, thereby forming a complex of the fusion protein, the target RNA, and the gRNA. And the real-time fluorescence detection of the target RNA is realized through the color development of the fluorescent protein in the fusion protein. Exemplary Cas proteins and protein recognition regions of grnas are shown in table 2.

The invention also includes a method of localizing a target RNA within a cell, comprising expressing a fusion protein described herein and a gRNA for the target RNA in the cell, and detecting the location of a marker in the cell.

The invention also includes a method of diagnosing a disease associated with the identification, amount, or location of a target RNA, comprising detecting or locating the target RNA using the methods described herein, and diagnosing based on the detection or location.

The present invention is described in further detail by referring to the following experimental examples. These examples are provided for illustrative purposes only and are not intended to be limiting unless otherwise specified. Accordingly, the present invention should in no way be construed as limited to the following examples, but rather should be construed to include any and all variations which become apparent in light of the teachings provided herein. The methods and reagents used in the examples are, unless otherwise indicated, conventional in the art.

Examples

Example 1 construction of gRNA expression plasmid

Designing a gRNA primer, wherein a forward primer is as follows: 5'CACC + spacer sequence, and the reverse primer is 5' CAAC + spacer reverse complementary sequence, the preferred spacer sequence is in the length range of 20-30nt, and is in reverse complementary pairing with the binding site of the target RNA sequence. In the examples, the selected target RNAs are respectively long non-coding RNA NEAT1, non-coding RNA SaIII, endogenous mRNA MUC4 and exogenous overexpression mRNA GCN4, and the sequences of the spacer are shown in Table 1. The protein recognition regions of the grnas corresponding to each dCas13 protein are shown in table 2.

TABLE 1

TABLE 2

Annealing of gRNA primers, wherein the annealing system is as follows: forward primer (10. Mu.M) 10. Mu.L, reverse primer (10. Mu.M) 10. Mu.L, ddH ₂ O30. Mu.L, 50. Mu.L in total. Annealing conditions: after denaturation at 95 ℃ for 5 min, slowly cool to room temperature.

The plasmid was digested with BbsI-HF (NEB) for 4 hours, and then recovered by agarose gel electrophoresis. And annealing double chains with gRNA and connecting the double chains with a gRNA by using T4 DNA ligase (NEB), wherein the reaction system is as follows:

TABLE 3

After 10 minutes of ligation at room temperature, trans-T1 competence (Beijing holotype gold organisms) was transformed and plated with LB plates containing ampicillin. After 10 hours of culture at 37 ℃, the single clone was picked up in 1mL of medium, and after positive clones were identified by sanger sequencing, 100mL of LB liquid medium containing 100. Mu.g/mL was inoculated, cultured at 37 ℃ for 16-20 hours, and extracted using a plasmid Large extraction kit (MACHEREY-NAGEL).

Example 2 Cas13 marker protein screening

In order to achieve specific labeling of target RNA in living cells, the inventors constructed recombinant proteins comprising 8 Cas13 proteins and green fluorescent protein EGFP from different sources, and the sequences of the recombinant proteins were as follows: dLbaCas13a-EGFP (SEQ ID NO: 1), dLwaCas13a-EGFP (SEQ ID NO: 2), dPspCas13b-EGFP (SEQ ID NO: 3), dPguCas13b-EGFP (SEQ ID NO: 4), dRanCas13b-EGFP (SEQ ID NO: 5), dAdmCas13d-EGFP (SEQ ID NO: 6), dEsCas13d-EGFP (SEQ ID NO: 7), dRfxCas13d-EGFP (SEQ ID NO: 8). The sequences of gRNAs targeting NEAT1 are shown in SEQ ID NOS: 19-34. Under the mediation of gNEAT1, the corresponding dCas13-EGFP can specifically bind to the objective NEAT1, thereby generating a specific labeling signal. Therefore, dCas13-EGFP and gRNA are transferred to a cell of HeLa-NONO-KI, and dCas13 protein capable of effectively marking target RNA is screened out through the strength of a signal marked by the dCas13-EGFP on the target RNA. Transfection was performed using Lipo3000 transfection reagent (Thermo Fisher scientific) in the following protocol:

TABLE 4

Cell culture	12-hole plate
		Opti-MEM (2 tubes)	Each 50 mu L
dCas13-EGFP (tube 1)	0.2μg
		gNEAT1-1 (tube 1)	0.4μg
gNEAT1-2 (tube 1)	0.4μg
		P3000 (pipe 1)	2μL
Lipo3000 (tube 2)	2μL

24 hours after transfection, cells were transferred to 35mm glass plates (Cellvis), and 36-48 hours later, they were changed to serum-free live cell culture medium, and signals were observed under a Delta-vision microscope at 60-fold mirror and photographed at 50% exposure intensity and 0.2 second exposure time, processed, and analyzed for results. As shown in FIG. 1, only dPspCas13b-EGFP and dPguCas13b-EGFP showed significant labeling effect on NEAT1, and the labeling effect of dPspCas13b-EGFP was better. However, the reported dLwaCas13a (Abudayyeh et al, 2017) and dRfxCas13d (Wang et al, 2019) for RNA labeling have no obvious labeling effect or cannot non-specifically label the target RNA.

Example 3 fluorescent protein optimization for the dPspCas13b-EGFP labeling System

To increase the fluorescence intensity of the marker signal, the inventors adopted the replacement of other more efficient luminescent proteins for optimization, including sfGFP protein, mneon green protein with fluorescence intensity nearly 3-fold higher than EGFP, 2 xmeon green, 3 × sfGFP and 3 × EGFP proteins in tandem, which can promote efficient folding of the fusion protein. The sequence of the recombinant protein is as follows; dPspCas13b-sfGFP (SEQ ID NO. 9); dPspCas13b-3 XSfGFP (SEQ ID NO. 10); dPspCas13b-mNeonGreen (SEQ ID NO. 11); dPspCas13b-2 XmNeonGreen (SEQ ID NO. 12); dPspCas13b-3 × EGFP (SEQ ID NO. 13). The gRNAs targeting NEAT1 (SEQ ID NO. 23-24), the cell culture conditions and methods, the transfection mode and imaging conditions were the same as in example 2. Through microscope shooting and calculation of signal to noise ratio, the result is shown in figure 2, and the dPspCas13b system fused with 3 xEGFP can mark better signals.

Example 4 labeling of other RNAs with dPspCas13b-3 xEGFP

To further prove the universality of the dPspCas13b-3 xEGFP labeled RNA, the inventors further selected three RNAs including a non-coding RNA SatIII, an endogenous mRNA MUC4, and an exogenous over-expression mRNA GCN4 as labeled objects, and designed two to three gRNAs respectively for them. The sequence of gRNA is shown in SEQ ID NO 35-42, wherein the spacer sequence is shown in Table 1.

dCas13-3 xEGFP and gRNA were transfected into HeLa cells using Lipo3000 transfection reagent (Thermo Fisher scientific) as follows:

wherein pmRuby3-HSF1 is a marker protein expression plasmid of substructure nSBs in the nucleus of the cell where SatIII is located, pmRuby3-24 xGCN 4 is an expression plasmid of exogenous GCN4 RNA, and the sequence of GCN4 RNA is shown as SEQ ID NO. 43. 24 hours after transfection, cells were transferred to 35mm glass plates (Cellvis) and, 36-48 hours later, replaced with serum-free live cell culture medium. For the labeling of MUC4 and GCN4, the signals were observed and imaged directly under a Delta-vision microscope at a 60-fold mirror, and the results were processed and analyzed. For the marker of SatIII, the signal is observed and imaged under a Delta-vision microscope at 60 times after being thermally stimulated at 42 ℃ for 1 hour and then revived at 37 ℃ for 1 hour, and the result is processed and analyzed, or the signal is observed and imaged under the Delta-vision microscope at 60 times after being treated with 0.1mM sodium arsenite for 6 hours, and the result is processed and analyzed. As shown in FIGS. 3, 4 and 5, respectively, the dPspCas13b-3 xEGFP has good labeling effect on non-coding RNA SatIII, endogenous mRNA MUC4, exogenous over-expression mRNA GCN4 and the like under the mediation effect of gRNA.

Example 5 mRNA tagging after optimization of the dPspCas13b fused fluorescent protein

To more efficiently label the RNA of the cytoplasmic distribution, the inventors further optimized the dPspCas13b fused fluorescent protein as well as the nuclear localization signal, including dPspCas13b-3 XSfGFP-3 XNLS fused with 3 XSfGFP and 3 nuclear localization signals (SEQ ID NO: 10), dPspCas13b-3 XSfGFP-2 XNLS fused with 3 XSfGFP and 2 nuclear localization signals (SEQ ID NO: 14), dPsas 13b-2 XmNeon Green-NLS fused with 2 XmNeon Green and 1 nuclear localization signal (SEQ ID NO: 15), dPsas 13b-2 XmNeon Green-2 XNLS fused with 2 XmNeon Green and 2 nuclear localization signals (SEQ ID NO: 12). By using grnas: gGCN4-2 (SEQ ID NO. 41) and gMUC4-2 (SEQ ID NO. 38) labeled GCN4 and MUC4 mRNAs, and as a result, as shown in FIG. 6, the dPspCas13b-3 XsfGFP-3 XNLS and dPsas 13b-2 XmNeon Green-NLS recombinant proteins can effectively label RNA localized in cytoplasm, and the dPspCas13b-3 XsfGFP-3 XNLS recombinant proteins have better labeling effect on RNA localized in cytoplasm and nucleus. The conditions and methods for culturing the above cells, the transfection method and the imaging conditions were the same as in example 4.

Example 6 Simultaneous two-color labeling of intracellular RNA with dPspCas13b and dPguCas13b

Using green fluorescent protein-labeled dPspCas13b (dPspCas 13b-3 xEGFP, SEQ ID NO. 13) and red fluorescent protein-labeled dPguCas13b (dPguCas 13b-3 xmRuby 3, SEQ ID NO. 16), NEAT1 and SatIII were labeled, respectively, so that these two RNAs were labeled with different colors, or simultaneously labeled SatIII so that this RNA was labeled with different colors at the same time. The grnas used were as follows: psp-gNEAT1-1 (SEQ ID NO. 19), gSatIII-1 and gSatIII-2 (SEQ ID NO. 35-36). Two sets of marker system plasmids were transfected into HeLa cells using Lipo3000 transfection reagent (Thermo Fisher scientific) in the following protocol:

24 hours after transfection, cells were transferred to 35mm glass plates (Cellvis), and 36-48 hours later, they were changed to serum-free live cell culture medium, and signals were observed under a Delta-vision microscope at 60-fold mirror and photographed at 50% exposure intensity and 0.2 second exposure time, processed, and analyzed for results. The results are shown in figure 7, where a green signal for tag NEAT1 and a red signal for tag SatIII can be seen using the doppcs 13b system targeting NEAT1 and the dppgusas 13b system targeting SatIII, respectively. Co-localized green and red signals were seen when dppcas 13b and dppguscas 13b were targeted to SatIII simultaneously.

Example 7 Simultaneous labeling of intracellular DNA and RNA with the CRISPR-dCas13 and CRISPR-dCas9 systems

DNA and RNA from MUC4 or SatIII were labeled with red fluorescent protein labeled dPspCas13b-mScarlet, SEQ ID NO:17 and green fluorescent protein labeled dCas9 (dCas 9-mEmerald, SEQ ID NO: 18), respectively. sgRNA used: sgMUC4 targeting MUC4 DNA (SEQ ID NO. 44), sgSatIII targeting SatIII DNA (SEQ ID NO. 45). gRNA used: gMUC4-2 targeting MUC4 RNA (SEQ ID NO. 38), gSatIII-1 targeting SatIII RNA (SEQ ID NO. 35). Two sets of marker system plasmids were transfected into HeLa cells using Lipo3000 transfection reagent (Thermo Fisher scientific) as follows:

24 hours after transfection, cells were transferred to 35mm glass plates (Cellvis), and 36-48 hours later, they were changed to serum-free live cell culture medium, and signals were observed under a Delta-vision microscope at 60-fold mirror and photographed at 50% exposure intensity and 0.2 second exposure time, processed, and analyzed for results. As a result, as shown in fig. 8, a green signal of labeled MUC4 DNA and a red signal of labeled MUC4 RNA were seen using the dCas9 system targeting MUC4 DNA and the dspcas 13b system targeting MUC4 RNA. The green signal for labeled MUC4 DNA and the red signal for labeled MUC4 RNA can be seen using the dCas9 system targeting SatIII DNA and the dPspCas13b system targeting SatIII RNA

The experiment shows that the living cell RNA marking method provided by the invention has the following characteristics: the detection efficiency and accuracy are high, the detection is convenient, and the RNA positioned in cytoplasm and cell nucleus can be marked simultaneously.

The advantages are favorable for the popularization and the application of the method in the research of RNA living cells, and provide a convenient and quick tool for the research of the dynamic change and the functional relationship of RNA by the living cells.

While the invention has been described with respect to a preferred embodiment, it will be understood by those skilled in the art that the foregoing and other changes, omissions and deviations in the form and detail thereof may be made without departing from the scope of this invention. Those skilled in the art can make various changes, modifications and equivalent arrangements, which are equivalent to the embodiments of the present invention, without departing from the spirit and scope of the present invention, and which may be made by utilizing the techniques disclosed above; meanwhile, any changes, modifications and variations of the above-described embodiments, which are equivalent to those of the technical spirit of the present invention, are within the scope of the technical solution of the present invention.

Sequence listing

<110> Shanghai Living sciences research institute of Chinese academy of sciences

<120> fusion protein for RNA labeling of living cells and application thereof

<130> 198413

<141> 2019-11-15

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Met Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys

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Lys Ala Ser Met Lys Ile Ser Lys Val Arg Glu Glu Asn Arg Gly Ala

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Lys Leu Thr Val Asn Ala Lys Thr Ala Val Val Ser Glu Asn Arg Ser

35 40 45

Gln Glu Gly Ile Leu Tyr Asn Asp Pro Ser Arg Tyr Gly Lys Ser Arg

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Lys Asn Asp Glu Asp Arg Asp Arg Tyr Ile Glu Ser Arg Leu Lys Ser

65 70 75 80

Ser Gly Lys Leu Tyr Arg Ile Phe Asn Glu Asp Lys Asn Lys Arg Glu

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

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Arg Arg Asn Gly Leu Val Leu Ser Asp Met Leu Ser Val Asp Asp Arg

115 120 125

Ala Phe Glu Lys Ala Phe Glu Lys Tyr Ala Glu Leu Ser Tyr Thr Asn

130 135 140

Arg Arg Asn Lys Val Ser Gly Ser Pro Ala Phe Glu Thr Cys Gly Val

145 150 155 160

Asp Ala Ala Thr Ala Glu Arg Leu Lys Gly Ile Ile Ser Glu Thr Asn

165 170 175

Phe Ile Asn Arg Ile Lys Asn Asn Ile Asp Asn Lys Val Ser Glu Asp

180 185 190

Ile Ile Asp Arg Ile Ile Ala Lys Tyr Leu Lys Lys Ser Leu Cys Arg

195 200 205

Glu Arg Val Lys Arg Gly Leu Lys Lys Leu Leu Met Asn Ala Phe Asp

210 215 220

Leu Pro Tyr Ser Asp Pro Asp Ile Asp Val Gln Arg Asp Phe Ile Asp

225 230 235 240

Tyr Val Leu Glu Asp Phe Tyr His Val Arg Ala Lys Ser Gln Val Ser

245 250 255

Arg Ser Ile Lys Asn Met Asn Met Pro Val Gln Pro Glu Gly Asp Gly

260 265 270

Lys Phe Ala Ile Thr Val Ser Lys Gly Gly Thr Glu Ser Gly Asn Lys

275 280 285

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

290 295 300

Ser Leu Asp Glu Arg Val Arg Asp Asp Met Leu Arg Arg Met Arg Arg

305 310 315 320

Leu Val Val Leu Tyr Phe Tyr Gly Ser Asp Asp Ser Lys Leu Ser Asp

325 330 335

Val Asn Glu Lys Phe Asp Val Trp Glu Asp His Ala Ala Arg Arg Val

340 345 350

Asp Asn Arg Glu Phe Ile Lys Leu Pro Leu Glu Asn Lys Leu Ala Asn

355 360 365

Gly Lys Thr Asp Lys Asp Ala Glu Arg Ile Arg Lys Asn Thr Val Lys

370 375 380

Glu Leu Tyr Arg Asn Gln Asn Ile Gly Cys Tyr Arg Gln Ala Val Lys

385 390 395 400

Ala Val Glu Glu Asp Asn Asn Gly Arg Tyr Phe Asp Asp Lys Met Leu

405 410 415

Asn Met Phe Phe Ile His Arg Ile Glu Tyr Gly Val Glu Lys Ile Tyr

420 425 430

Ala Asn Leu Lys Gln Val Thr Glu Phe Lys Ala Arg Thr Gly Tyr Leu

435 440 445

Ser Glu Lys Ile Trp Lys Asp Leu Ile Asn Tyr Ile Ser Ile Lys Tyr

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Ile Ala Met Gly Lys Ala Val Tyr Asn Tyr Ala Met Asp Glu Leu Asn

465 470 475 480

Ala Ser Asp Lys Lys Glu Ile Glu Leu Gly Lys Ile Ser Glu Glu Tyr

485 490 495

Leu Ser Gly Ile Ser Ser Phe Asp Tyr Glu Leu Ile Lys Ala Glu Glu

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Met Leu Gln Arg Glu Thr Ala Val Tyr Val Ala Phe Ala Ala Arg His

515 520 525

Leu Ser Ser Gln Thr Val Glu Leu Asp Ser Glu Asn Ser Asp Phe Leu

530 535 540

Leu Leu Lys Pro Lys Gly Thr Met Asp Lys Asn Asp Lys Asn Lys Leu

545 550 555 560

Ala Ser Asn Asn Ile Leu Asn Phe Leu Lys Asp Lys Glu Thr Leu Arg

565 570 575

Asp Thr Ile Leu Gln Tyr Phe Gly Gly His Ser Leu Trp Thr Asp Phe

580 585 590

Pro Phe Asp Lys Tyr Leu Ala Gly Gly Lys Asp Asp Val Asp Phe Leu

595 600 605

Thr Asp Leu Lys Asp Val Ile Tyr Ser Met Ala Asn Asp Ser Phe Ala

610 615 620

Tyr Ala Thr Glu Asn His Asn Asn Gly Lys Trp Asn Lys Glu Leu Ile

625 630 635 640

Ser Ala Met Phe Glu His Glu Thr Glu Arg Met Thr Val Val Met Lys

645 650 655

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

660 665 670

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

675 680 685

Ser Gln Val Pro Ser Phe Asn Lys Val Phe Val Arg Lys Asn Phe Pro

690 695 700

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

705 710 715 720

Ala Asp Ala Asp Lys Gly Glu Asn Glu Leu Lys Phe Tyr Asn Ala Leu

725 730 735

Tyr Tyr Met Phe Lys Glu Ile Tyr Tyr Asn Ala Phe Leu Asn Asp Lys

740 745 750

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

755 760 765

Tyr Asp Arg Asn Lys Glu Arg Asn Leu Lys Asp Arg Ile Lys Ser Ala

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Gly Ser Asp Glu Lys Lys Lys Leu Arg Glu Gln Leu Gln Asn Tyr Ile

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Ala Glu Asn Asp Phe Gly Gln Arg Ile Lys Asn Ile Val Gln Val Asn

805 810 815

Pro Asp Tyr Thr Leu Ala Gln Ile Cys Gln Leu Ile Met Thr Glu Tyr

820 825 830

Asn Gln Gln Asn Asn Gly Cys Met Gln Lys Lys Ser Ala Ala Arg Lys

835 840 845

Asp Ile Asn Lys Asp Ser Tyr Gln His Tyr Lys Met Leu Leu Leu Val

850 855 860

Asn Leu Arg Lys Ala Phe Leu Glu Phe Ile Lys Glu Asn Tyr Ala Phe

865 870 875 880

Val Leu Lys Pro Tyr Lys His Asp Leu Cys Asp Lys Ala Asp Phe Val

885 890 895

Pro Asp Phe Ala Lys Tyr Val Lys Pro Tyr Ala Gly Leu Ile Ser Arg

900 905 910

Val Ala Gly Ser Ser Glu Leu Gln Lys Trp Tyr Ile Val Ser Arg Phe

915 920 925

Leu Ser Pro Ala Gln Ala Asn His Met Leu Gly Phe Leu His Ser Tyr

930 935 940

Lys Gln Tyr Val Trp Asp Ile Tyr Arg Arg Ala Ser Glu Thr Gly Thr

945 950 955 960

Glu Ile Asn His Ser Ile Ala Glu Asp Lys Ile Ala Gly Val Asp Ile

965 970 975

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

980 985 990

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

995 1000 1005

Glu Tyr Ile Ser Ser Tyr Leu Asp Phe Glu Tyr Asp Gly Gly Asn Tyr

1010 1015 1020

Lys Asp Ser Leu Asn Arg Phe Cys Asn Ser Asp Ala Val Asn Asp Gln

1025 1030 1035 1040

Lys Val Ala Leu Tyr Tyr Asp Gly Glu His Pro Lys Leu Asn Arg Asn

1045 1050 1055

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

1060 1065 1070

Thr Asp Arg Val Ser Arg Ser Asp Ile Val Glu Tyr Tyr Lys Leu Lys

1075 1080 1085

Lys Glu Thr Ser Gln Tyr Gln Thr Lys Gly Ile Phe Asp Ser Glu Asp

1090 1095 1100

Glu Gln Lys Asn Ile Lys Lys Phe Gln Glu Met Lys Asn Ile Val Glu

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Phe Arg Asp Leu Met Asp Tyr Ser Glu Ile Ala Asp Glu Leu Gln Gly

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Gln Leu Ile Asn Trp Ile Tyr Leu Arg Glu Arg Asp Leu Met Asn Phe

1140 1145 1150

Gln Leu Gly Tyr His Tyr Ala Cys Leu Asn Asn Asp Ser Asn Lys Gln

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

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Asn Gly Ala Ile Leu Tyr Gln Ile Cys Ala Met Tyr Ile Asn Gly Leu

1185 1190 1195 1200

Pro Leu Tyr Tyr Val Asp Lys Asp Ser Ser Glu Trp Thr Val Ser Asp

1205 1210 1215

Gly Lys Glu Ser Thr Gly Ala Lys Ile Gly Glu Phe Tyr Arg Tyr Ala

1220 1225 1230

Lys Ser Phe Glu Asn Thr Ser Asp Cys Tyr Ala Ser Gly Leu Glu Ile

1235 1240 1245

Phe Glu Asn Ile Ser Glu His Asp Asn Ile Thr Glu Leu Ala Asn Tyr

1250 1255 1260

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

1265 1270 1275 1280

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

1285 1290 1295

Arg Lys Asn Val Pro Thr Ile Leu Tyr Asn Ile Leu Leu Gln His Phe

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Val Asn Val Arg Phe Glu Phe Val Ser Gly Lys Lys Met Ile Gly Ile

1315 1320 1325

Asp Lys Lys Asp Arg Lys Ile Ala Lys Glu Lys Glu Cys Ala Arg Ile

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Thr Ile Arg Glu Lys Asn Gly Val Tyr Ser Glu Gln Phe Thr Tyr Lys

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Leu Lys Asn Gly Thr Val Tyr Val Asp Ala Arg Asp Lys Arg Tyr Leu

1365 1370 1375

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

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Glu Met Ile Glu Val Lys Glu Lys Lys Lys Pro Ser Asp Asn Asn Thr

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Gly Lys Gly Tyr Ser Lys Arg Asp Arg Gln Gln Asp Arg Lys Glu Tyr

1410 1415 1420

Asp Lys Tyr Lys Glu Lys Lys Lys Lys Glu Gly Asn Phe Leu Ser Gly

1425 1430 1435 1440

Met Gly Gly Asn Ile Asn Trp Asp Glu Ile Asn Ala Gln Leu Lys Asn

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Ser Leu Glu Ala Leu Pro Val Ala Thr Met Val Ser Lys Gly Glu Glu

1460 1465 1470

Leu Phe Thr Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val

1475 1480 1485

Asn Gly His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr

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Tyr Gly Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro

1505 1510 1515 1520

Val Pro Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys

1525 1530 1535

Phe Ser Arg Tyr Pro Asp His Met Lys Gln His Asp Phe Phe Lys Ser

1540 1545 1550

Ala Met Pro Glu Gly Tyr Val Gln Glu Arg Thr Ile Phe Phe Lys Asp

1555 1560 1565

Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr

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Leu Val Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly

1585 1590 1595 1600

Asn Ile Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val

1605 1610 1615

Tyr Ile Met Ala Asp Lys Gln Lys Asn Gly Ile Lys Val Asn Phe Lys

1620 1625 1630

Ile Arg His Asn Ile Glu Asp Gly Ser Val Gln Leu Ala Asp His Tyr

1635 1640 1645

Gln Gln Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn

1650 1655 1660

His Tyr Leu Ser Thr Gln Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys

1665 1670 1675 1680

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

1685 1690 1695

Leu Gly Met Asp Glu Leu Tyr Lys Ser Asn Ser Lys Pro Gly Phe His

1700 1705 1710

Met Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys

1715 1720 1725

Lys Gln Arg Val Gln Leu Ser Asp Tyr Lys Asp His Asp Gly Asp Tyr

1730 1735 1740

Lys Asp His Asp Ile Asp Tyr Lys Asp Asp Asp Asp Lys

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Met Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys

1 5 10 15

Lys Ala Ser Lys Val Thr Lys Val Asp Gly Ile Ser His Lys Lys Tyr

20 25 30

Ile Glu Glu Gly Lys Leu Val Lys Ser Thr Ser Glu Glu Asn Arg Thr

35 40 45

Ser Glu Arg Leu Ser Glu Leu Leu Ser Ile Arg Leu Asp Ile Tyr Ile

50 55 60

Lys Asn Pro Asp Asn Ala Ser Glu Glu Glu Asn Arg Ile Arg Arg Glu

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Asn Leu Lys Lys Phe Phe Ser Asn Lys Val Leu His Leu Lys Asp Ser

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

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

115 120 125

Ser Phe Ser Val Leu Lys Lys Ile Leu Leu Asn Glu Asp Val Asn Ser

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

145 150 155 160

Ile Asn Ser Leu Lys Tyr Ser Phe Glu Glu Asn Lys Ala Asn Tyr Gln

165 170 175

Lys Ile Asn Glu Asn Asn Val Glu Lys Val Gly Gly Lys Ser Lys Arg

180 185 190

Asn Ile Ile Tyr Asp Tyr Tyr Arg Glu Ser Ala Lys Arg Asn Asp Tyr

195 200 205

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

210 215 220

Ile Glu Lys Leu Phe Phe Leu Ile Glu Asn Ser Lys Lys His Glu Lys

225 230 235 240

Tyr Lys Ile Arg Glu Tyr Tyr His Lys Ile Ile Gly Arg Lys Asn Asp

245 250 255

Lys Glu Asn Phe Ala Lys Ile Ile Tyr Glu Glu Ile Gln Asn Val Asn

260 265 270

Asn Ile Lys Glu Leu Ile Glu Lys Ile Pro Asp Met Ser Glu Leu Lys

275 280 285

Lys Ser Gln Val Phe Tyr Lys Tyr Tyr Leu Asp Lys Glu Glu Leu Asn

290 295 300

Asp Lys Asn Ile Lys Tyr Ala Phe Cys His Phe Val Glu Ile Glu Met

305 310 315 320

Ser Gln Leu Leu Lys Asn Tyr Val Tyr Lys Arg Leu Ser Asn Ile Ser

325 330 335

Asn Asp Lys Ile Lys Arg Ile Phe Glu Tyr Gln Asn Leu Lys Lys Leu

340 345 350

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

355 360 365

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

370 375 380

Phe Ile Ala Arg Asn Arg Gln Asn Glu Ala Phe Leu Arg Asn Ile Ile

385 390 395 400

Gly Val Ser Ser Val Ala Tyr Phe Ser Leu Arg Asn Ile Leu Glu Thr

405 410 415

Glu Asn Glu Asn Asp Ile Thr Gly Arg Met Arg Gly Lys Thr Val Lys

420 425 430

Asn Asn Lys Gly Glu Glu Lys Tyr Val Ser Gly Glu Val Asp Lys Ile

435 440 445

Tyr Asn Glu Asn Lys Gln Asn Glu Val Lys Glu Asn Leu Lys Met Phe

450 455 460

Tyr Ser Tyr Asp Phe Asn Met Asp Asn Lys Asn Glu Ile Glu Asp Phe

465 470 475 480

Phe Ala Asn Ile Asp Glu Ala Ile Ser Ser Ile Ala His Gly Ile Val

485 490 495

Ala Phe Asn Leu Glu Leu Glu Gly Lys Asp Ile Phe Ala Phe Lys Asn

500 505 510

Ile Ala Pro Ser Glu Ile Ser Lys Lys Met Phe Gln Asn Glu Ile Asn

515 520 525

Glu Lys Lys Leu Lys Leu Lys Ile Phe Lys Gln Leu Asn Ser Ala Asn

530 535 540

Val Phe Asn Tyr Tyr Glu Lys Asp Val Ile Ile Lys Tyr Leu Lys Asn

545 550 555 560

Thr Lys Phe Asn Phe Val Asn Lys Asn Ile Pro Phe Val Pro Ser Phe

565 570 575

Thr Lys Leu Tyr Asn Lys Ile Glu Asp Leu Arg Asn Thr Leu Lys Phe

580 585 590

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

595 600 605

Leu Leu Lys Asn Ile Tyr Tyr Gly Glu Phe Leu Asn Lys Phe Val Lys

610 615 620

Asn Ser Lys Val Phe Phe Lys Ile Thr Asn Glu Val Ile Lys Ile Asn

625 630 635 640

Lys Gln Arg Asn Gln Lys Thr Gly His Tyr Lys Tyr Gln Lys Phe Glu

645 650 655

Asn Ile Glu Lys Thr Val Pro Val Glu Tyr Leu Ala Ile Ile Gln Ser

660 665 670

Arg Glu Met Ile Asn Asn Gln Asp Lys Glu Glu Lys Asn Thr Tyr Ile

675 680 685

Asp Phe Ile Gln Gln Ile Phe Leu Lys Gly Phe Ile Asp Tyr Leu Asn

690 695 700

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

705 710 715 720

Asp Ile Phe Ser Lys Ile Lys Ile Lys Lys Asp Asn Lys Glu Lys Tyr

725 730 735

Asp Lys Ile Leu Lys Asn Tyr Glu Lys His Asn Arg Asn Lys Glu Ile

740 745 750

Pro His Glu Ile Asn Glu Phe Val Arg Glu Ile Lys Leu Gly Lys Ile

755 760 765

Leu Lys Tyr Thr Glu Asn Leu Asn Met Phe Tyr Leu Ile Leu Lys Leu

770 775 780

Leu Asn His Lys Glu Leu Thr Asn Leu Lys Gly Ser Leu Glu Lys Tyr

785 790 795 800

Gln Ser Ala Asn Lys Glu Glu Thr Phe Ser Asp Glu Leu Glu Leu Ile

805 810 815

Asn Leu Leu Asn Leu Asp Asn Asn Arg Val Thr Glu Asp Phe Glu Leu

820 825 830

Glu Ala Asn Glu Ile Gly Lys Phe Leu Asp Phe Asn Glu Asn Lys Ile

835 840 845

Lys Asp Arg Lys Glu Leu Lys Lys Phe Asp Thr Asn Lys Ile Tyr Phe

850 855 860

Asp Gly Glu Asn Ile Ile Lys His Arg Ala Phe Tyr Asn Ile Lys Lys

865 870 875 880

Tyr Gly Met Leu Asn Leu Leu Glu Lys Ile Ala Asp Lys Ala Lys Tyr

885 890 895

Lys Ile Ser Leu Lys Glu Leu Lys Glu Tyr Ser Asn Lys Lys Asn Glu

900 905 910

Ile Glu Lys Asn Tyr Thr Met Gln Gln Asn Leu His Arg Lys Tyr Ala

915 920 925

Arg Pro Lys Lys Asp Glu Lys Phe Asn Asp Glu Asp Tyr Lys Glu Tyr

930 935 940

Glu Lys Ala Ile Gly Asn Ile Gln Lys Tyr Thr His Leu Lys Asn Lys

945 950 955 960

Val Glu Phe Asn Glu Leu Asn Leu Leu Gln Gly Leu Leu Leu Lys Ile

965 970 975

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

980 985 990

Phe Arg Leu Lys Gly Glu Phe Pro Glu Asn His Tyr Ile Glu Glu Ile

995 1000 1005

Phe Asn Phe Asp Asn Ser Lys Asn Val Lys Tyr Lys Ser Gly Gln Ile

1010 1015 1020

Val Glu Lys Tyr Ile Asn Phe Tyr Lys Glu Leu Tyr Lys Asp Asn Val

1025 1030 1035 1040

Glu Lys Arg Ser Ile Tyr Ser Asp Lys Lys Val Lys Lys Leu Lys Gln

1045 1050 1055

Glu Lys Lys Asp Leu Tyr Ile Ala Asn Tyr Ile Ala Ala Phe Asn Tyr

1060 1065 1070

Ile Pro His Ala Glu Ile Ser Leu Leu Glu Val Leu Glu Asn Leu Arg

1075 1080 1085

Lys Leu Leu Ser Tyr Asp Arg Lys Leu Lys Asn Ala Ile Met Lys Ser

1090 1095 1100

Ile Val Asp Ile Leu Lys Glu Tyr Gly Phe Val Ala Thr Phe Lys Ile

1105 1110 1115 1120

Gly Ala Asp Lys Lys Ile Glu Ile Gln Thr Leu Glu Ser Glu Lys Ile

1125 1130 1135

Val His Leu Lys Asn Leu Lys Lys Lys Lys Leu Met Thr Asp Arg Asn

1140 1145 1150

Ser Glu Glu Leu Cys Glu Leu Val Lys Val Met Phe Glu Tyr Lys Ala

1155 1160 1165

Leu Glu Gly Leu Glu Ala Leu Pro Val Ala Thr Met Val Ser Lys Gly

1170 1175 1180

Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly

1185 1190 1195 1200

Asp Val Asn Gly His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp

1205 1210 1215

Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys

1220 1225 1230

Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val

1235 1240 1245

Gln Cys Phe Ser Arg Tyr Pro Asp His Met Lys Gln His Asp Phe Phe

1250 1255 1260

Lys Ser Ala Met Pro Glu Gly Tyr Val Gln Glu Arg Thr Ile Phe Phe

1265 1270 1275 1280

Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly

1285 1290 1295

Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu

1300 1305 1310

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

1315 1320 1325

Asn Val Tyr Ile Met Ala Asp Lys Gln Lys Asn Gly Ile Lys Val Asn

1330 1335 1340

Phe Lys Ile Arg His Asn Ile Glu Asp Gly Ser Val Gln Leu Ala Asp

1345 1350 1355 1360

His Tyr Gln Gln Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro

1365 1370 1375

Asp Asn His Tyr Leu Ser Thr Gln Ser Ala Leu Ser Lys Asp Pro Asn

1380 1385 1390

Glu Lys Arg Asp His Met Val Leu Leu Glu Phe Val Thr Ala Ala Gly

1395 1400 1405

Ile Thr Leu Gly Met Asp Glu Leu Tyr Lys Ser Asn Ser Lys Pro Gly

1410 1415 1420

Phe His Met Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys

1425 1430 1435 1440

Lys Lys Lys Gln Arg Val Gln Leu Ser Asp Tyr Lys Asp His Asp Gly

1445 1450 1455

Asp Tyr Lys Asp His Asp Ile Asp Tyr Lys Asp Asp Asp Asp Lys

1460 1465 1470

<210> 3

<211> 1400

<212> PRT

<213> Artificial Sequence

<400> 3

Met Pro Lys Lys Lys Arg Lys Val Asn Ile Pro Ala Leu Val Glu Asn

1 5 10 15

Gln Lys Lys Tyr Phe Gly Thr Tyr Ser Val Met Ala Met Leu Asn Ala

20 25 30

Gln Thr Val Leu Asp His Ile Gln Lys Val Ala Asp Ile Glu Gly Glu

35 40 45

Gln Asn Glu Asn Asn Glu Asn Leu Trp Phe His Pro Val Met Ser His

50 55 60

Leu Tyr Asn Ala Lys Asn Gly Tyr Asp Lys Gln Pro Glu Lys Thr Met

65 70 75 80

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

85 90 95

Ala Glu Asn Gln Arg Glu Tyr Ser Asn Gly Lys Tyr Lys Gln Asn Arg

100 105 110

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

115 120 125

Gly Val Leu Lys Met Tyr Arg Asp Leu Thr Asn Ala Tyr Lys Thr Tyr

130 135 140

Glu Glu Lys Leu Asn Asp Gly Cys Glu Phe Leu Thr Ser Thr Glu Gln

145 150 155 160

Pro Leu Ser Gly Met Ile Asn Asn Tyr Tyr Thr Val Ala Leu Arg Asn

165 170 175

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

180 185 190

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

195 200 205

Gln Val Asn Thr Gly Phe Phe Leu Ser Leu Gln Asp Tyr Asn Gly Asp

210 215 220

Thr Gln Lys Lys Leu His Leu Ser Gly Val Gly Ile Ala Leu Leu Ile

225 230 235 240

Cys Leu Phe Leu Asp Lys Gln Tyr Ile Asn Ile Phe Leu Ser Arg Leu

245 250 255

Pro Ile Phe Ser Ser Tyr Asn Ala Gln Ser Glu Glu Arg Arg Ile Ile

260 265 270

Ile Arg Ser Phe Gly Ile Asn Ser Ile Lys Leu Pro Lys Asp Arg Ile

275 280 285

His Ser Glu Lys Ser Asn Lys Ser Val Ala Met Asp Met Leu Asn Glu

290 295 300

Val Lys Arg Cys Pro Asp Glu Leu Phe Thr Thr Leu Ser Ala Glu Lys

305 310 315 320

Gln Ser Arg Phe Arg Ile Ile Ser Asp Asp His Asn Glu Val Leu Met

325 330 335

Lys Arg Ser Ser Asp Arg Phe Val Pro Leu Leu Leu Gln Tyr Ile Asp

340 345 350

Tyr Gly Lys Leu Phe Asp His Ile Arg Phe His Val Asn Met Gly Lys

355 360 365

Leu Arg Tyr Leu Leu Lys Ala Asp Lys Thr Cys Ile Asp Gly Gln Thr

370 375 380

Arg Val Arg Val Ile Glu Gln Pro Leu Asn Gly Phe Gly Arg Leu Glu

385 390 395 400

Glu Ala Glu Thr Met Arg Lys Gln Glu Asn Gly Thr Phe Gly Asn Ser

405 410 415

Gly Ile Arg Ile Arg Asp Phe Glu Asn Met Lys Arg Asp Asp Ala Asn

420 425 430

Pro Ala Asn Tyr Pro Tyr Ile Val Asp Thr Tyr Thr His Tyr Ile Leu

435 440 445

Glu Asn Asn Lys Val Glu Met Phe Ile Asn Asp Lys Glu Asp Ser Ala

450 455 460

Pro Leu Leu Pro Val Ile Glu Asp Asp Arg Tyr Val Val Lys Thr Ile

465 470 475 480

Pro Ser Cys Arg Met Ser Thr Leu Glu Ile Pro Ala Met Ala Phe His

485 490 495

Met Phe Leu Phe Gly Ser Lys Lys Thr Glu Lys Leu Ile Val Asp Val

500 505 510

His Asn Arg Tyr Lys Arg Leu Phe Gln Ala Met Gln Lys Glu Glu Val

515 520 525

Thr Ala Glu Asn Ile Ala Ser Phe Gly Ile Ala Glu Ser Asp Leu Pro

530 535 540

Gln Lys Ile Leu Asp Leu Ile Ser Gly Asn Ala His Gly Lys Asp Val

545 550 555 560

Asp Ala Phe Ile Arg Leu Thr Val Asp Asp Met Leu Thr Asp Thr Glu

565 570 575

Arg Arg Ile Lys Arg Phe Lys Asp Asp Arg Lys Ser Ile Arg Ser Ala

580 585 590

Asp Asn Lys Met Gly Lys Arg Gly Phe Lys Gln Ile Ser Thr Gly Lys

595 600 605

Leu Ala Asp Phe Leu Ala Lys Asp Ile Val Leu Phe Gln Pro Ser Val

610 615 620

Asn Asp Gly Glu Asn Lys Ile Thr Gly Leu Asn Tyr Arg Ile Met Gln

625 630 635 640

Ser Ala Ile Ala Val Tyr Asp Ser Gly Asp Asp Tyr Glu Ala Lys Gln

645 650 655

Gln Phe Lys Leu Met Phe Glu Lys Ala Arg Leu Ile Gly Lys Gly Thr

660 665 670

Thr Glu Pro His Pro Phe Leu Tyr Lys Val Phe Ala Arg Ser Ile Pro

675 680 685

Ala Asn Ala Val Glu Phe Tyr Glu Arg Tyr Leu Ile Glu Arg Lys Phe

690 695 700

Tyr Leu Thr Gly Leu Ser Asn Glu Ile Lys Lys Gly Asn Arg Val Asp

705 710 715 720

Val Pro Phe Ile Arg Arg Asp Gln Asn Lys Trp Lys Thr Pro Ala Met

725 730 735

Lys Thr Leu Gly Arg Ile Tyr Ser Glu Asp Leu Pro Val Glu Leu Pro

740 745 750

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

755 760 765

Gln Met Glu Gly Ile Asp Phe Asn Asn Ala Asn Val Thr Tyr Leu Ile

770 775 780

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

785 790 795 800

Gln Trp Asn Arg Asn Tyr Arg Tyr Met Asp Met Leu Lys Gly Glu Tyr

805 810 815

Asp Arg Lys Gly Ser Leu Gln His Cys Phe Thr Ser Val Glu Glu Arg

820 825 830

Glu Gly Leu Trp Lys Glu Arg Ala Ser Arg Thr Glu Arg Tyr Arg Lys

835 840 845

Gln Ala Ser Asn Lys Ile Arg Ser Asn Arg Gln Met Arg Asn Ala Ser

850 855 860

Ser Glu Glu Ile Glu Thr Ile Leu Asp Lys Arg Leu Ser Asn Ser Arg

865 870 875 880

Asn Glu Tyr Gln Lys Ser Glu Lys Val Ile Arg Arg Tyr Arg Val Gln

885 890 895

Asp Ala Leu Leu Phe Leu Leu Ala Lys Lys Thr Leu Thr Glu Leu Ala

900 905 910

Asp Phe Asp Gly Glu Arg Phe Lys Leu Lys Glu Ile Met Pro Asp Ala

915 920 925

Glu Lys Gly Ile Leu Ser Glu Ile Met Pro Met Ser Phe Thr Phe Glu

930 935 940

Lys Gly Gly Lys Lys Tyr Thr Ile Thr Ser Glu Gly Met Lys Leu Lys

945 950 955 960

Asn Tyr Gly Asp Phe Phe Val Leu Ala Ser Asp Lys Arg Ile Gly Asn

965 970 975

Leu Leu Glu Leu Val Gly Ser Asp Ile Val Ser Lys Glu Asp Ile Met

980 985 990

Glu Glu Phe Asn Lys Tyr Asp Gln Cys Arg Pro Glu Ile Ser Ser Ile

995 1000 1005

Val Phe Asn Leu Glu Lys Trp Ala Phe Asp Thr Tyr Pro Glu Leu Ser

1010 1015 1020

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

1025 1030 1035 1040

Ile Leu Leu Asn Asn Lys Asn Ile Asn Lys Glu Gln Ser Asp Ile Leu

1045 1050 1055

Arg Lys Ile Arg Asn Ala Phe Asp Ala Asn Asn Tyr Pro Asp Lys Gly

1060 1065 1070

Val Val Glu Ile Lys Ala Leu Pro Glu Ile Ala Met Ser Ile Lys Lys

1075 1080 1085

Ala Phe Gly Glu Tyr Ala Ile Met Lys Glu Gly Ala Leu Glu Ala Leu

1090 1095 1100

Pro Val Ala Thr Met Val Ser Lys Gly Glu Glu Leu Phe Thr Gly Val

1105 1110 1115 1120

Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe

1125 1130 1135

Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr

1140 1145 1150

Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr

1155 1160 1165

Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro

1170 1175 1180

Asp His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly

1185 1190 1195 1200

Tyr Val Gln Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly Asn Tyr Lys

1205 1210 1215

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

1220 1225 1230

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

1235 1240 1245

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

1250 1255 1260

Lys Gln Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg His Asn Ile

1265 1270 1275 1280

Glu Asp Gly Ser Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro

1285 1290 1295

Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr

1300 1305 1310

Gln Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met Val

1315 1320 1325

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

1330 1335 1340

Leu Tyr Lys Ser Asn Ser Lys Pro Gly Phe His Met Lys Arg Pro Ala

1345 1350 1355 1360

Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Gln Arg Val Gln

1365 1370 1375

Leu Ser Asp Tyr Lys Asp His Asp Gly Asp Tyr Lys Asp His Asp Ile

1380 1385 1390

Asp Tyr Lys Asp Asp Asp Asp Lys

1395 1400

<210> 4

<211> 1483

<212> PRT

<213> Artificial Sequence

<400> 4

Met Pro Lys Lys Lys Arg Lys Val Thr Glu Gln Ser Glu Arg Pro Tyr

1 5 10 15

Asn Gly Thr Tyr Tyr Thr Leu Glu Asp Lys His Phe Trp Ala Ala Phe

20 25 30

Leu Asn Leu Ala Arg His Asn Ala Tyr Ile Thr Leu Thr His Ile Asp

35 40 45

Arg Gln Leu Ala Tyr Ser Lys Ala Asp Ile Thr Asn Asp Gln Asp Val

50 55 60

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

65 70 75 80

Lys Ser Arg Leu Arg Ser Leu Ile Leu Lys His Phe Ser Phe Leu Glu

85 90 95

Gly Ala Ala Tyr Gly Lys Lys Leu Phe Glu Ser Lys Ser Ser Gly Asn

100 105 110

Lys Ser Ser Lys Asn Lys Glu Leu Thr Lys Lys Glu Lys Glu Glu Leu

115 120 125

Gln Ala Asn Ala Leu Ser Leu Asp Asn Leu Lys Ser Ile Leu Phe Asp

130 135 140

Phe Leu Gln Lys Leu Lys Asp Phe Arg Asn Tyr Tyr Ser Ala Tyr Arg

145 150 155 160

His Ser Gly Ser Ser Glu Leu Pro Leu Phe Asp Gly Asn Met Leu Gln

165 170 175

Arg Leu Tyr Asn Val Phe Asp Val Ser Val Gln Arg Val Lys Ile Asp

180 185 190

His Glu His Asn Asp Glu Val Asp Pro His Tyr His Phe Asn His Leu

195 200 205

Val Arg Lys Gly Lys Lys Asp Arg Tyr Gly His Asn Asp Asn Pro Ser

210 215 220

Phe Lys His His Phe Val Asp Gly Glu Gly Met Val Thr Glu Ala Gly

225 230 235 240

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

245 250 255

Met Gln Lys Lys Ile Arg Gly Phe Lys Gly Gly Thr Glu Thr Tyr Gln

260 265 270

Gln Met Thr Asn Glu Val Phe Cys Arg Ser Arg Ile Ser Leu Pro Lys

275 280 285

Leu Lys Leu Glu Ser Leu Arg Met Asp Asp Trp Met Leu Leu Asp Met

290 295 300

Leu Asn Glu Leu Val Arg Cys Pro Lys Pro Leu Tyr Asp Arg Leu Arg

305 310 315 320

Glu Asp Asp Arg Ala Cys Phe Arg Val Pro Val Asp Ile Leu Pro Asp

325 330 335

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

340 345 350

Val Arg His Gln Asp Arg Phe Pro Tyr Phe Ala Leu Arg Tyr Phe Asp

355 360 365

Leu Lys Lys Val Phe Thr Ser Leu Arg Phe His Ile Asp Leu Gly Thr

370 375 380

Tyr His Phe Ala Ile Tyr Lys Lys Met Ile Gly Glu Gln Pro Glu Asp

385 390 395 400

Arg His Leu Thr Arg Asn Leu Tyr Gly Phe Gly Arg Ile Gln Asp Phe

405 410 415

Ala Glu Glu His Arg Pro Glu Glu Trp Lys Arg Leu Val Arg Asp Leu

420 425 430

Asp Tyr Phe Glu Thr Gly Asp Lys Pro Tyr Ile Ser Gln Thr Ser Pro

435 440 445

His Tyr His Ile Glu Lys Gly Lys Ile Gly Leu Arg Phe Met Pro Glu

450 455 460

Gly Gln His Leu Trp Pro Ser Pro Glu Val Gly Thr Thr Arg Thr Gly

465 470 475 480

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

485 490 495

Ser Val His Glu Leu Met Pro Met Met Phe Tyr Tyr Phe Leu Leu Arg

500 505 510

Glu Lys Tyr Ser Glu Glu Val Ser Ala Glu Arg Val Gln Gly Arg Ile

515 520 525

Lys Arg Val Ile Glu Asp Val Tyr Ala Val Tyr Asp Ala Phe Ala Arg

530 535 540

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

545 550 555 560

Gly Ile Arg Arg Gly His Leu Pro Arg Gln Met Ile Ala Ile Leu Ser

565 570 575

Gln Glu His Lys Asp Met Glu Glu Lys Ile Arg Lys Lys Leu Gln Glu

580 585 590

Met Met Ala Asp Thr Asp His Arg Leu Asp Met Leu Asp Arg Gln Thr

595 600 605

Asp Arg Lys Ile Arg Ile Gly Arg Lys Asn Ala Gly Leu Pro Lys Ser

610 615 620

Gly Val Ile Ala Asp Trp Leu Val Arg Asp Met Met Arg Phe Gln Pro

625 630 635 640

Val Ala Lys Asp Ala Ser Gly Lys Pro Leu Asn Asn Ser Lys Ala Asn

645 650 655

Ser Thr Glu Tyr Arg Met Leu Gln Arg Ala Leu Ala Leu Phe Gly Gly

660 665 670

Glu Lys Glu Arg Leu Thr Pro Tyr Phe Arg Gln Met Asn Leu Thr Gly

675 680 685

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

690 695 700

Thr Asn Ile Leu Ser Phe Tyr Arg Ser Tyr Leu Arg Ala Arg Lys Ala

705 710 715 720

Phe Leu Glu Arg Ile Gly Arg Ser Asp Arg Val Glu Asn Arg Pro Phe

725 730 735

Leu Leu Leu Lys Glu Pro Lys Thr Asp Arg Gln Thr Leu Val Ala Gly

740 745 750

Trp Lys Gly Glu Phe His Leu Pro Arg Gly Ile Phe Thr Glu Ala Val

755 760 765

Arg Asp Cys Leu Ile Glu Met Gly His Asp Glu Val Ala Ser Tyr Lys

770 775 780

Glu Val Gly Phe Met Ala Lys Ala Val Pro Leu Tyr Phe Glu Arg Ala

785 790 795 800

Cys Glu Asp Arg Val Gln Pro Phe Tyr Asp Ser Pro Phe Asn Val Gly

805 810 815

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

820 825 830

Ala Glu Glu Trp Glu Arg Gly Lys Glu Arg Phe Arg Asp Leu Glu Ala

835 840 845

Trp Ser Tyr Ser Ala Ala Arg Arg Ile Glu Asp Ala Phe Ala Gly Ile

850 855 860

Glu Tyr Ala Ser Pro Gly Asn Lys Lys Lys Ile Glu Gln Leu Leu Arg

865 870 875 880

Asp Leu Ser Leu Trp Glu Ala Phe Glu Ser Lys Leu Lys Val Arg Ala

885 890 895

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

900 905 910

Glu His Pro Tyr His Asp Phe Lys Ser Trp Gln Lys Phe Glu Arg Glu

915 920 925

Leu Arg Leu Val Lys Asn Gln Asp Ile Ile Thr Trp Met Met Cys Arg

930 935 940

Asp Leu Met Glu Glu Asn Lys Val Glu Gly Leu Asp Thr Gly Thr Leu

945 950 955 960

Tyr Leu Lys Asp Ile Arg Pro Asn Val Gln Glu Gln Gly Ser Leu Asn

965 970 975

Val Leu Asn Arg Val Lys Pro Met Arg Leu Pro Val Val Val Tyr Arg

980 985 990

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

995 1000 1005

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

1010 1015 1020

Lys Ser Phe Val Lys Asp Arg Arg Leu Asn Gly Leu Phe Ser Phe Val

1025 1030 1035 1040

Asp Thr Gly Gly Leu Ala Met Glu Gln Tyr Pro Ile Ser Lys Leu Arg

1045 1050 1055

Val Glu Tyr Glu Leu Ala Lys Tyr Gln Thr Ala Arg Val Cys Val Phe

1060 1065 1070

Glu Leu Thr Leu Arg Leu Glu Glu Ser Leu Leu Thr Arg Tyr Pro His

1075 1080 1085

Leu Pro Asp Glu Ser Phe Arg Glu Met Leu Glu Ser Trp Ser Asp Pro

1090 1095 1100

Leu Leu Ala Lys Trp Pro Glu Leu His Gly Lys Val Arg Leu Leu Ile

1105 1110 1115 1120

Ala Val Arg Asn Ala Phe Ser Ala Asn Gln Tyr Pro Met Tyr Asp Glu

1125 1130 1135

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

1140 1145 1150

Ile Glu Glu Arg Met Gly Leu Asn Ile Ala His Arg Leu Ser Glu Glu

1155 1160 1165

Val Lys Gln Ala Lys Glu Thr Val Glu Arg Ile Ile Gln Ala Ser Leu

1170 1175 1180

Glu Ala Leu Pro Val Ala Thr Met Val Ser Lys Gly Glu Glu Leu Phe

1185 1190 1195 1200

Thr Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly

1205 1210 1215

His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly

1220 1225 1230

Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro

1235 1240 1245

Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser

1250 1255 1260

Arg Tyr Pro Asp His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met

1265 1270 1275 1280

Pro Glu Gly Tyr Val Gln Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly

1285 1290 1295

Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val

1300 1305 1310

Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile

1315 1320 1325

Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile

1330 1335 1340

Met Ala Asp Lys Gln Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg

1345 1350 1355 1360

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

1365 1370 1375

Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr

1380 1385 1390

Leu Ser Thr Gln Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp

1395 1400 1405

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

1410 1415 1420

Met Asp Glu Leu Tyr Lys Ser Asn Ser Lys Pro Gly Phe His Met Lys

1425 1430 1435 1440

Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Gln

1445 1450 1455

Arg Val Gln Leu Ser Asp Tyr Lys Asp His Asp Gly Asp Tyr Lys Asp

1460 1465 1470

His Asp Ile Asp Tyr Lys Asp Asp Asp Asp Lys

1475 1480

<210> 5

<211> 1403

<212> PRT

<213> Artificial Sequence

<400> 5

Met Pro Lys Lys Lys Arg Lys Val Glu Lys Pro Leu Leu Pro Asn Val

1 5 10 15

Tyr Thr Leu Lys His Lys Phe Phe Trp Gly Ala Phe Leu Asn Ile Ala

20 25 30

Arg His Asn Ala Phe Ile Thr Ile Cys His Ile Asn Glu Gln Leu Gly

35 40 45

Leu Lys Thr Pro Ser Asn Asp Asp Lys Ile Val Asp Val Val Cys Glu

50 55 60

Thr Trp Asn Asn Ile Leu Asn Asn Asp His Asp Leu Leu Lys Lys Ser

65 70 75 80

Gln Leu Thr Glu Leu Ile Leu Lys His Phe Pro Phe Leu Thr Ala Met

85 90 95

Cys Tyr His Pro Pro Lys Lys Glu Gly Lys Lys Lys Gly His Gln Lys

100 105 110

Glu Gln Gln Lys Glu Lys Glu Ser Glu Ala Gln Ser Gln Ala Glu Ala

115 120 125

Leu Asn Pro Ser Lys Leu Ile Glu Ala Leu Glu Ile Leu Val Asn Gln

130 135 140

Leu His Ser Leu Arg Asn Tyr Tyr Ser Ala Tyr Lys His Lys Lys Pro

145 150 155 160

Asp Ala Glu Lys Asp Ile Phe Lys His Leu Tyr Lys Ala Phe Asp Ala

165 170 175

Ser Leu Arg Met Val Lys Glu Asp Tyr Lys Ala His Phe Thr Val Asn

180 185 190

Leu Thr Arg Asp Phe Ala His Leu Asn Arg Lys Gly Lys Asn Lys Gln

195 200 205

Asp Asn Pro Asp Phe Asn Arg Tyr Arg Phe Glu Lys Asp Gly Phe Phe

210 215 220

Thr Glu Ser Gly Leu Leu Phe Phe Thr Asn Leu Phe Leu Asp Lys Arg

225 230 235 240

Asp Ala Tyr Trp Met Leu Lys Lys Val Ser Gly Phe Lys Ala Ser His

245 250 255

Lys Gln Arg Glu Lys Met Thr Thr Glu Val Phe Cys Arg Ser Arg Ile

260 265 270

Leu Leu Pro Lys Leu Arg Leu Glu Ser Arg Tyr Asp His Asn Gln Met

275 280 285

Leu Leu Asp Met Leu Ser Glu Leu Ser Arg Cys Pro Lys Leu Leu Tyr

290 295 300

Glu Lys Leu Ser Glu Glu Asn Lys Lys His Phe Gln Val Glu Ala Asp

305 310 315 320

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

325 330 335

Leu Ile Arg His Gln Asp Arg Phe Pro Tyr Phe Ala Leu Arg Tyr Leu

340 345 350

Asp Leu Asn Glu Ser Phe Lys Ser Ile Arg Phe Gln Val Asp Leu Gly

355 360 365

Thr Tyr His Tyr Cys Ile Tyr Asp Lys Lys Ile Gly Asp Glu Gln Glu

370 375 380

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

385 390 395 400

Phe Thr Glu Ile Asn Arg Pro Gln Glu Trp Lys Ala Leu Thr Lys Asp

405 410 415

Leu Asp Tyr Lys Glu Thr Ser Asn Gln Pro Phe Ile Ser Lys Thr Thr

420 425 430

Pro His Tyr His Ile Thr Asp Asn Lys Ile Gly Phe Arg Leu Gly Thr

435 440 445

Ser Lys Glu Leu Tyr Pro Ser Leu Glu Ile Lys Asp Gly Ala Asn Arg

450 455 460

Ile Ala Lys Tyr Pro Tyr Asn Ser Gly Phe Val Ala His Ala Phe Ile

465 470 475 480

Ser Val His Glu Leu Leu Pro Leu Met Phe Tyr Gln His Leu Thr Gly

485 490 495

Lys Ser Glu Asp Leu Leu Lys Glu Thr Val Arg His Ile Gln Arg Ile

500 505 510

Tyr Lys Asp Phe Glu Glu Glu Arg Ile Asn Thr Ile Glu Asp Leu Glu

515 520 525

Lys Ala Asn Gln Gly Arg Leu Pro Leu Gly Ala Phe Pro Lys Gln Met

530 535 540

Leu Gly Leu Leu Gln Asn Lys Gln Pro Asp Leu Ser Glu Lys Ala Lys

545 550 555 560

Ile Lys Ile Glu Lys Leu Ile Ala Glu Thr Lys Leu Leu Ser His Arg

565 570 575

Leu Asn Thr Lys Leu Lys Ser Ser Pro Lys Leu Gly Lys Arg Arg Glu

580 585 590

Lys Leu Ile Lys Thr Gly Val Leu Ala Asp Trp Leu Val Lys Asp Phe

595 600 605

Met Arg Phe Gln Pro Val Ala Tyr Asp Ala Gln Asn Gln Pro Ile Lys

610 615 620

Ser Ser Lys Ala Asn Ser Thr Glu Phe Trp Phe Ile Arg Arg Ala Leu

625 630 635 640

Ala Leu Tyr Gly Gly Glu Lys Asn Arg Leu Glu Gly Tyr Phe Lys Gln

645 650 655

Thr Asn Leu Ile Gly Asn Thr Asn Pro His Pro Phe Leu Asn Lys Phe

660 665 670

Asn Trp Lys Ala Cys Arg Asn Leu Val Asp Phe Tyr Gln Gln Tyr Leu

675 680 685

Glu Gln Arg Glu Lys Phe Leu Glu Ala Ile Lys Asn Gln Pro Trp Glu

690 695 700

Pro Tyr Gln Tyr Cys Leu Leu Leu Lys Ile Pro Lys Glu Asn Arg Lys

705 710 715 720

Asn Leu Val Lys Gly Trp Glu Gln Gly Gly Ile Ser Leu Pro Arg Gly

725 730 735

Leu Phe Thr Glu Ala Ile Arg Glu Thr Leu Ser Glu Asp Leu Met Leu

740 745 750

Ser Lys Pro Ile Arg Lys Glu Ile Lys Lys His Gly Arg Val Gly Phe

755 760 765

Ile Ser Arg Ala Ile Thr Leu Tyr Phe Lys Glu Lys Tyr Gln Asp Lys

770 775 780

His Gln Ser Phe Tyr Asn Leu Ser Tyr Lys Leu Glu Ala Lys Ala Pro

785 790 795 800

Leu Leu Lys Arg Glu Glu His Tyr Glu Tyr Trp Gln Gln Asn Lys Pro

805 810 815

Gln Ser Pro Thr Glu Ser Gln Arg Leu Glu Leu His Thr Ser Asp Arg

820 825 830

Trp Lys Asp Tyr Leu Leu Tyr Lys Arg Trp Gln His Leu Glu Lys Lys

835 840 845

Leu Arg Leu Tyr Arg Asn Gln Asp Val Met Leu Trp Leu Met Thr Leu

850 855 860

Glu Leu Thr Lys Asn His Phe Lys Glu Leu Asn Leu Asn Tyr His Gln

865 870 875 880

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

885 890 895

Leu Asn Pro Leu Asn Gln Thr Leu Pro Met Val Leu Pro Val Lys Val

900 905 910

Tyr Pro Ala Thr Ala Phe Gly Glu Val Gln Tyr His Lys Thr Pro Ile

915 920 925

Arg Thr Val Tyr Ile Arg Glu Glu His Thr Lys Ala Leu Lys Met Gly

930 935 940

Asn Phe Lys Ala Leu Val Lys Asp Arg Arg Leu Asn Gly Leu Phe Ser

945 950 955 960

Phe Ile Lys Glu Glu Asn Asp Thr Gln Lys His Pro Ile Ser Gln Leu

965 970 975

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

980 985 990

Phe Lys Glu Thr Leu Ser Leu Glu Glu Lys Leu Leu Asn Lys His Thr

995 1000 1005

Ser Leu Ser Ser Leu Glu Asn Glu Phe Arg Ala Leu Leu Glu Glu Trp

1010 1015 1020

Lys Lys Glu Tyr Ala Ala Ser Ser Met Val Thr Asp Glu His Ile Ala

1025 1030 1035 1040

Phe Ile Ala Ser Val Arg Asn Ala Phe Cys Ala Asn Gln Tyr Pro Phe

1045 1050 1055

Tyr Lys Glu Ala Leu His Ala Pro Ile Pro Leu Phe Thr Val Ala Gln

1060 1065 1070

Pro Thr Thr Glu Glu Lys Asp Gly Leu Gly Ile Ala Glu Ala Leu Leu

1075 1080 1085

Lys Val Leu Arg Glu Tyr Cys Glu Ile Val Lys Ser Gln Ile Gly Leu

1090 1095 1100

Glu Ala Leu Pro Val Ala Thr Met Val Ser Lys Gly Glu Glu Leu Phe

1105 1110 1115 1120

Thr Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly

1125 1130 1135

His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly

1140 1145 1150

Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro

1155 1160 1165

Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser

1170 1175 1180

Arg Tyr Pro Asp His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met

1185 1190 1195 1200

Pro Glu Gly Tyr Val Gln Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly

1205 1210 1215

Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val

1220 1225 1230

Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile

1235 1240 1245

Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile

1250 1255 1260

Met Ala Asp Lys Gln Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg

1265 1270 1275 1280

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

1285 1290 1295

Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr

1300 1305 1310

Leu Ser Thr Gln Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp

1315 1320 1325

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

1330 1335 1340

Met Asp Glu Leu Tyr Lys Ser Asn Ser Lys Pro Gly Phe His Met Lys

1345 1350 1355 1360

Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Gln

1365 1370 1375

Arg Val Gln Leu Ser Asp Tyr Lys Asp His Asp Gly Asp Tyr Lys Asp

1380 1385 1390

His Asp Ile Asp Tyr Lys Asp Asp Asp Asp Lys

1395 1400

<210> 6

<211> 1266

<212> PRT

<213> Artificial Sequence

<400> 6

Met Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys

1 5 10 15

Lys Ala Ser Met Asn Asn Lys Arg Lys Thr Lys Ala Lys Ala Ala Gly

20 25 30

Leu Lys Ser Val Phe Phe Asp Gln Lys Gln Ala Val Leu Thr Thr Phe

35 40 45

Ala Lys Gly Asn Asn Ser Gln Ile Glu Lys Lys Val Val Asn Ser Glu

50 55 60

Val Lys Asp Leu Arg Gln Pro Pro Ala Phe Asp Leu Glu Leu Lys Glu

65 70 75 80

Lys Thr Phe Tyr Ile Ser Gly Lys Asn Asn Ile Asn Thr Ser Arg Glu

85 90 95

Asn Pro Leu Ala Ser Ala Ser Leu Pro Leu Ser Lys Arg Gln Arg Ile

100 105 110

Arg Ala Glu Arg Ile Lys Arg Ala Arg Glu Glu Asn Arg Pro Tyr His

115 120 125

Asn Val Lys Arg Val Gly Glu Asp Asp Leu Arg Ala Lys Ala Asp Leu

130 135 140

Glu Lys His Tyr Phe Gly Lys Glu Tyr Ser Asp Asn Leu Lys Ile Gln

145 150 155 160

Ile Ile Tyr Asn Ile Leu Asp Ile Asn Lys Ile Ile Ser Pro Tyr Ile

165 170 175

Asn Asp Ile Val Tyr Ser Met Asn Asn Leu Ala Arg Asn Asp Glu Tyr

180 185 190

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

195 200 205

Tyr Ser Ser Phe Met Ser Pro Asn Lys Asp Leu Glu Lys Glu Lys Lys

210 215 220

Phe Ser Phe His Arg Glu Asn Tyr Lys Lys Phe Val Glu Ala Ser Lys

225 230 235 240

Pro Tyr Met Arg Tyr Tyr Gly Lys Val Phe Ile Arg Asp Val Lys Lys

245 250 255

Ser Lys Leu Ser Thr Gly Lys Gly Glu Lys Ile Glu Val Met Tyr Arg

260 265 270

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

275 280 285

Gln Ser Ile Met Ala Asn Asp Ile Gly Asn Lys Ser Ser Ile Leu Ala

290 295 300

Ile Glu Lys Tyr Pro Ala Arg Phe Val Gly Phe Leu Ser Asp Leu Leu

305 310 315 320

Lys Thr Lys Thr Asn Asp Val Asn Arg Met Phe Ile Asp Asn Asn Ser

325 330 335

Gln Thr Asn Phe Trp Val Leu Phe Ser Ile Phe Gly Leu Gln Asp His

340 345 350

Thr Ser Gly Ala Asp Lys Ile Cys Arg Asn Phe Tyr Asp Phe Val Ile

355 360 365

Lys Ala Asp Ser Lys Asn Leu Gly Phe Ser Leu Lys Lys Ile Arg Glu

370 375 380

Leu Met Leu Asp Leu Pro Asn Ala Asn Met Leu Arg Asp His Gln Phe

385 390 395 400

Asp Thr Val Arg Ser Lys Phe Tyr Thr Leu Leu Asp Phe Ile Ile Tyr

405 410 415

Gln His Tyr Leu Glu Glu Lys Ser Arg Ile Asp Asn Met Val Glu Lys

420 425 430

Leu Arg Met Thr Leu Lys Glu Glu Glu Lys Glu Val Leu Tyr Ala Ala

435 440 445

Glu Ala Lys Ile Val Trp Asn Ala Ile Gly Ala Lys Val Ile Asn Lys

450 455 460

Leu Val Pro Met Met Asn Gly Asp Ala Leu Lys Glu Ile Lys Arg Lys

465 470 475 480

Asn Arg Asp Arg Lys Leu Pro Gln Ser Val Ile Ala Thr Val Gln Val

485 490 495

Asn Ser Asp Ala Asn Val Phe Ser Gly Leu Ile Tyr Phe Leu Thr Leu

500 505 510

Phe Leu Asp Gly Lys Glu Ile Asn Glu Met Val Ser Asn Leu Ile Thr

515 520 525

Lys Phe Glu Asn Ile Asp Ser Leu Leu His Val Asp Arg Glu Ile Tyr

530 535 540

Lys Ser Asp Glu Lys Asp Leu Asp Leu Glu Ile Glu Lys Leu Ala Leu

545 550 555 560

Phe Phe Lys Gly Val Val Arg Pro Asn Ala Lys Thr Asp Thr Gly Ala

565 570 575

Gly Glu Ile Ser Lys Ser Phe Ser Ile Phe Gln Ser Ala Glu Arg Ile

580 585 590

Ile Glu Glu Leu Lys Phe Ile Lys Asn Val Thr Arg Met Asp Asn Glu

595 600 605

Ile Phe Pro Ser Glu Gly Val Phe Leu Asp Ala Ala Asn Val Leu Gly

610 615 620

Val Arg Gly Asp Asp Phe Asp Phe Ser Asn Glu Phe Val Gly Asp Asp

625 630 635 640

Leu His Ser Asp Ala Asn Lys Lys Ile Ile Asn Lys Ile Asn Gly Thr

645 650 655

Lys Glu Asp Arg Asn Leu Arg Asn Phe Ile Ile Asn Asn Val Val Lys

660 665 670

Ser Arg Arg Phe Gln Tyr Ile Ala Arg His Met Asn Thr His Tyr Val

675 680 685

Lys Gln Leu Ala Asn Asn Glu Thr Leu Asn Arg Phe Val Leu Asn Lys

690 695 700

Met Gly Asp Ala Lys Ile Ile Asn Arg Tyr Tyr Glu Ser Ile Ser Gly

705 710 715 720

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

725 730 735

Arg Leu Arg Ser Phe Ser Phe Glu Asp Leu Asn Asp Val Lys Gln Lys

740 745 750

Val Arg Pro Gly Thr Asn Glu Ser Ile Glu Lys Glu Lys Lys Lys Ala

755 760 765

Leu Val Gly Leu Cys Leu Thr Ile Gln Tyr Leu Val Tyr Lys Asn Leu

770 775 780

Val Asn Ile Asn Ala Arg Tyr Thr Thr Ala Phe Tyr Cys Leu Glu Arg

785 790 795 800

Asp Ser Lys Leu Lys Gly Phe Gly Val Asp Val Trp Arg Asp Phe Glu

805 810 815

Ser Tyr Thr Ala Leu Thr Asn His Phe Ile Lys Glu Gly Tyr Leu Pro

820 825 830

Val Arg Lys Ala Glu Ile Leu Arg Ala Asn Leu Lys His Leu Asp Cys

835 840 845

Glu Asp Gly Phe Lys Tyr Tyr Ala Asn Gln Val Thr Ala Leu Asn Ala

850 855 860

Ile Arg Val Ala Tyr Lys Tyr Ile Asn Glu Ile Lys Ser Val His Ser

865 870 875 880

Tyr Phe Ala Leu Tyr His Tyr Ile Met Gln Arg His Leu Tyr Asp Ser

885 890 895

Leu Gln Ala Lys Ala Lys Asp Ser Ser Gly Phe Val Ile Asp Ala Leu

900 905 910

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

915 920 925

Leu His Ser Pro Phe Gly Tyr Asn Thr Ala Arg Tyr Lys Asn Leu Ser

930 935 940

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

945 950 955 960

Leu Ser Thr Asn Asp Ser Leu Glu Ala Leu Pro Val Ala Thr Met Val

965 970 975

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

980 985 990

Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly Glu Gly

995 1000 1005

Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile Cys Thr

1010 1015 1020

Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr Leu Thr

1025 1030 1035 1040

Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp His Met Lys Gln His

1045 1050 1055

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

1060 1065 1070

Ile Phe Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val Lys

1075 1080 1085

Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly Ile Asp

1090 1095 1100

Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr Asn Tyr

1105 1110 1115 1120

Asn Ser His Asn Val Tyr Ile Met Ala Asp Lys Gln Lys Asn Gly Ile

1125 1130 1135

Lys Val Asn Phe Lys Ile Arg His Asn Ile Glu Asp Gly Ser Val Gln

1140 1145 1150

Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile Gly Asp Gly Pro Val

1155 1160 1165

Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln Ser Ala Leu Ser Lys

1170 1175 1180

Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu Glu Phe Val Thr

1185 1190 1195 1200

Ala Ala Gly Ile Thr Leu Gly Met Asp Glu Leu Tyr Lys Ser Asn Ser

1205 1210 1215

Lys Pro Gly Phe His Met Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly

1220 1225 1230

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

1235 1240 1245

His Asp Gly Asp Tyr Lys Asp His Asp Ile Asp Tyr Lys Asp Asp Asp

1250 1255 1260

Asp Lys

1265

<210> 7

<211> 1274

<212> PRT

<213> Artificial Sequence

<400> 7

Met Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys

1 5 10 15

Lys Ala Ser Met Gly Lys Lys Ile His Ala Arg Asp Leu Arg Glu Gln

20 25 30

Arg Lys Thr Asp Arg Thr Glu Lys Phe Ala Asp Gln Asn Lys Lys Arg

35 40 45

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

50 55 60

Ser Val Ser Ser Val Ser Ser Lys Lys Asp Asn Val Thr Lys Ser Met

65 70 75 80

Ala Lys Ala Ala Gly Val Lys Ser Val Phe Ala Val Gly Asn Thr Val

85 90 95

Tyr Met Thr Ser Phe Gly Arg Gly Asn Asp Ala Val Leu Glu Gln Lys

100 105 110

Ile Val Asp Thr Ser His Glu Pro Leu Asn Ile Asp Asp Pro Ala Tyr

115 120 125

Gln Leu Asn Val Val Thr Met Asn Gly Tyr Ser Val Thr Gly His Arg

130 135 140

Gly Glu Thr Val Ser Ala Val Thr Asp Asn Pro Leu Arg Arg Phe Asn

145 150 155 160

Gly Arg Lys Lys Asp Glu Pro Glu Gln Ser Val Pro Thr Asp Met Leu

165 170 175

Cys Leu Lys Pro Thr Leu Glu Lys Lys Phe Phe Gly Lys Glu Phe Asp

180 185 190

Asp Asn Ile His Ile Gln Leu Ile Tyr Asn Ile Leu Asp Ile Glu Lys

195 200 205

Ile Leu Ala Val Tyr Ser Thr Asn Ala Ile Tyr Ala Leu Asn Asn Met

210 215 220

Ser Ala Asp Glu Asn Ile Glu Asn Ser Asp Phe Phe Met Lys Arg Thr

225 230 235 240

Thr Asp Glu Thr Phe Asp Asp Phe Glu Lys Lys Lys Glu Ser Thr Asn

245 250 255

Ser Arg Glu Lys Ala Asp Phe Asp Ala Phe Glu Lys Phe Ile Gly Asn

260 265 270

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

275 280 285

Pro Lys Gly Lys Ala Lys Asn Val Leu Arg Glu Asp Lys Glu Leu Tyr

290 295 300

Ser Val Leu Thr Leu Ile Gly Lys Leu Ala His Trp Cys Val Ala Ser

305 310 315 320

Glu Glu Gly Arg Ala Glu Phe Trp Leu Tyr Lys Leu Asp Glu Leu Lys

325 330 335

Asp Asp Phe Lys Asn Val Leu Asp Val Val Tyr Asn Arg Pro Val Glu

340 345 350

Glu Ile Asn Asn Arg Phe Ile Glu Asn Asn Lys Val Asn Ile Gln Ile

355 360 365

Leu Gly Ser Val Tyr Lys Asn Thr Asp Ile Ala Glu Leu Val Arg Ser

370 375 380

Tyr Tyr Glu Phe Leu Ile Thr Lys Lys Tyr Lys Asn Met Gly Phe Ser

385 390 395 400

Ile Lys Lys Leu Arg Glu Ser Met Leu Glu Gly Lys Gly Tyr Ala Asp

405 410 415

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

420 425 430

Ile Leu Tyr Thr Gly Tyr Ile Asn Glu Asp Ser Asp Arg Ala Asp Asp

435 440 445

Leu Val Asn Thr Leu Arg Ser Ser Leu Lys Glu Asp Asp Lys Thr Thr

450 455 460

Val Tyr Cys Lys Glu Ala Asp Tyr Leu Trp Lys Lys Tyr Arg Glu Ser

465 470 475 480

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

485 490 495

Ser Lys Ser Asn Ile Glu Ile Gln Glu Asp Lys Leu Arg Lys Cys Phe

500 505 510

Ile Ser Tyr Ala Asp Ser Val Ser Glu Phe Thr Lys Leu Ile Tyr Leu

515 520 525

Leu Thr Arg Phe Leu Ser Gly Lys Glu Ile Asn Asp Leu Val Thr Thr

530 535 540

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

545 550 555 560

Glu Leu Gly Leu Asp Arg Thr Phe Thr Ala Glu Tyr Ser Phe Phe Glu

565 570 575

Gly Ser Thr Lys Tyr Leu Ala Glu Leu Val Glu Leu Asn Ser Phe Val

580 585 590

Lys Ser Cys Ser Phe Asp Ile Asn Ala Lys Arg Thr Met Tyr Arg Asp

595 600 605

Ala Leu Asp Ile Leu Gly Ile Glu Ser Asp Lys Thr Glu Glu Asp Ile

610 615 620

Glu Lys Met Ile Asp Asn Ile Leu Gln Ile Asp Ala Asn Gly Asp Lys

625 630 635 640

Lys Leu Lys Lys Asn Asn Gly Leu Arg Asn Phe Ile Ala Ser Asn Val

645 650 655

Ile Asp Ser Asn Arg Phe Lys Tyr Leu Val Arg Tyr Gly Asn Pro Lys

660 665 670

Lys Ile Arg Glu Thr Ala Lys Cys Lys Pro Ala Val Arg Phe Val Leu

675 680 685

Asn Glu Ile Pro Asp Ala Gln Ile Glu Arg Tyr Tyr Glu Ala Cys Cys

690 695 700

Pro Lys Asn Thr Ala Leu Cys Ser Ala Asn Lys Arg Arg Glu Lys Leu

705 710 715 720

Ala Asp Met Ile Ala Glu Ile Lys Phe Glu Asn Phe Ser Asp Ala Gly

725 730 735

Asn Tyr Gln Lys Ala Asn Val Thr Ser Arg Thr Ser Glu Ala Glu Ile

740 745 750

Lys Arg Lys Asn Gln Ala Ile Ile Arg Leu Tyr Leu Thr Val Met Tyr

755 760 765

Ile Met Leu Lys Asn Leu Val Asn Val Asn Ala Arg Tyr Val Ile Ala

770 775 780

Phe His Cys Val Glu Arg Asp Thr Lys Leu Tyr Ala Glu Ser Gly Leu

785 790 795 800

Glu Val Gly Asn Ile Glu Lys Asn Lys Thr Asn Leu Thr Met Ala Val

805 810 815

Met Gly Val Lys Leu Glu Asn Gly Ile Ile Lys Thr Glu Phe Asp Lys

820 825 830

Ser Phe Ala Glu Asn Ala Ala Asn Arg Tyr Leu Arg Asn Ala Arg Trp

835 840 845

Tyr Lys Leu Ile Leu Asp Asn Leu Lys Lys Ser Glu Arg Ala Val Val

850 855 860

Asn Glu Phe Ala Asn Thr Val Cys Ala Leu Asn Ala Ile Arg Asn Ile

865 870 875 880

Asn Ile Asn Ile Lys Glu Ile Lys Glu Val Glu Asn Tyr Phe Ala Leu

885 890 895

Tyr His Tyr Leu Ile Gln Lys His Leu Glu Asn Arg Phe Ala Asp Lys

900 905 910

Lys Val Glu Arg Asp Thr Gly Asp Phe Ile Ser Lys Leu Glu Glu His

915 920 925

Lys Thr Tyr Cys Lys Asp Phe Val Lys Ala Tyr Cys Thr Pro Phe Gly

930 935 940

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

945 950 955 960

Lys Asn Tyr Pro Gly Lys Asp Asp Ser Asp Glu Gln Lys Gly Leu Glu

965 970 975

Ala Leu Pro Val Ala Thr Met Val Ser Lys Gly Glu Glu Leu Phe Thr

980 985 990

Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly His

995 1000 1005

Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly Lys

1010 1015 1020

Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp

1025 1030 1035 1040

Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser Arg

1045 1050 1055

Tyr Pro Asp His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met Pro

1060 1065 1070

Glu Gly Tyr Val Gln Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly Asn

1075 1080 1085

Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val Asn

1090 1095 1100

Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile Leu

1105 1110 1115 1120

Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile Met

1125 1130 1135

Ala Asp Lys Gln Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg His

1140 1145 1150

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

1155 1160 1165

Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu

1170 1175 1180

Ser Thr Gln Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His

1185 1190 1195 1200

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

1205 1210 1215

Asp Glu Leu Tyr Lys Ser Asn Ser Lys Pro Gly Phe His Met Lys Arg

1220 1225 1230

Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Gln Arg

1235 1240 1245

Val Gln Leu Ser Asp Tyr Lys Asp His Asp Gly Asp Tyr Lys Asp His

1250 1255 1260

Asp Ile Asp Tyr Lys Asp Asp Asp Asp Lys

1265 1270

<210> 8

<211> 1286

<212> PRT

<213> Artificial Sequence

<400> 8

Met Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys

1 5 10 15

Lys Ala Ser Ile Glu Lys Lys Lys Ser Phe Ala Lys Gly Met Gly Val

20 25 30

Lys Ser Thr Leu Val Ser Gly Ser Lys Val Tyr Met Thr Thr Phe Ala

35 40 45

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

50 55 60

Arg Ser Val Asn Glu Gly Glu Ala Phe Ser Ala Glu Met Ala Asp Lys

65 70 75 80

Asn Ala Gly Tyr Lys Ile Gly Asn Ala Lys Phe Ser His Pro Lys Gly

85 90 95

Tyr Ala Val Val Ala Asn Asn Pro Leu Tyr Thr Gly Pro Val Gln Gln

100 105 110

Asp Met Leu Gly Leu Lys Glu Thr Leu Glu Lys Arg Tyr Phe Gly Glu

115 120 125

Ser Ala Asp Gly Asn Asp Asn Ile Cys Ile Gln Val Ile His Asn Ile

130 135 140

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

145 150 155 160

Ala Val Asn Asn Ile Ser Gly Leu Asp Lys Asp Ile Ile Gly Phe Gly

165 170 175

Lys Phe Ser Thr Val Tyr Thr Tyr Asp Glu Phe Lys Asp Pro Glu His

180 185 190

His Arg Ala Ala Phe Asn Asn Asn Asp Lys Leu Ile Asn Ala Ile Lys

195 200 205

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

210 215 220

Tyr Phe Gly Gln Ala Phe Phe Ser Lys Glu Gly Arg Asn Tyr Ile Ile

225 230 235 240

Asn Tyr Gly Asn Glu Cys Tyr Asp Ile Leu Ala Leu Leu Ser Gly Leu

245 250 255

Ala His Trp Val Val Ala Asn Asn Glu Glu Glu Ser Arg Ile Ser Arg

260 265 270

Thr Trp Leu Tyr Asn Leu Asp Lys Asn Leu Asp Asn Glu Tyr Ile Ser

275 280 285

Thr Leu Asn Tyr Leu Tyr Asp Arg Ile Thr Asn Glu Leu Thr Asn Ser

290 295 300

Phe Ser Lys Asn Ser Ala Ala Asn Val Asn Tyr Ile Ala Glu Thr Leu

305 310 315 320

Gly Ile Asn Pro Ala Glu Phe Ala Glu Gln Tyr Phe Arg Phe Ser Ile

325 330 335

Met Lys Glu Gln Lys Asn Leu Gly Phe Asn Ile Thr Lys Leu Arg Glu

340 345 350

Val Met Leu Asp Arg Lys Asp Met Ser Glu Ile Arg Lys Asn His Lys

355 360 365

Val Phe Asp Ser Ile Arg Thr Lys Val Tyr Thr Met Met Asp Phe Val

370 375 380

Ile Tyr Arg Tyr Tyr Ile Glu Glu Asp Ala Lys Val Ala Ala Ala Asn

385 390 395 400

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

405 410 415

Val Ile Asn Leu Arg Gly Ser Phe Asn Asp Asp Gln Lys Asp Ala Leu

420 425 430

Tyr Tyr Asp Glu Ala Asn Arg Ile Trp Arg Lys Leu Glu Asn Ile Met

435 440 445

His Asn Ile Lys Glu Phe Arg Gly Asn Lys Thr Arg Glu Tyr Lys Lys

450 455 460

Lys Asp Ala Pro Arg Leu Pro Arg Ile Leu Pro Ala Gly Arg Asp Val

465 470 475 480

Ser Ala Phe Ser Lys Leu Met Tyr Ala Leu Thr Met Phe Leu Asp Gly

485 490 495

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

500 505 510

Ile Gln Ser Phe Leu Lys Val Met Pro Leu Ile Gly Val Asn Ala Lys

515 520 525

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

530 535 540

Glu Leu Arg Leu Ile Lys Ser Phe Ala Arg Met Gly Glu Pro Ile Ala

545 550 555 560

Asp Ala Arg Arg Ala Met Tyr Ile Asp Ala Ile Arg Ile Leu Gly Thr

565 570 575

Asn Leu Ser Tyr Asp Glu Leu Lys Ala Leu Ala Asp Thr Phe Ser Leu

580 585 590

Asp Glu Asn Gly Asn Lys Leu Lys Lys Gly Lys His Gly Met Arg Asn

595 600 605

Phe Ile Ile Asn Asn Val Ile Ser Asn Lys Arg Phe His Tyr Leu Ile

610 615 620

Arg Tyr Gly Asp Pro Ala His Leu His Glu Ile Ala Lys Asn Glu Ala

625 630 635 640

Val Val Lys Phe Val Leu Gly Arg Ile Ala Asp Ile Gln Lys Lys Gln

645 650 655

Gly Gln Asn Gly Lys Asn Gln Ile Asp Arg Tyr Tyr Glu Thr Cys Ile

660 665 670

Gly Lys Asp Lys Gly Lys Ser Val Ser Glu Lys Val Asp Ala Leu Thr

675 680 685

Lys Ile Ile Thr Gly Met Asn Tyr Asp Gln Phe Asp Lys Lys Arg Ser

690 695 700

Val Ile Glu Asp Thr Gly Arg Glu Asn Ala Glu Arg Glu Lys Phe Lys

705 710 715 720

Lys Ile Ile Ser Leu Tyr Leu Thr Val Ile Tyr His Ile Leu Lys Asn

725 730 735

Ile Val Asn Ile Asn Ala Arg Tyr Val Ile Gly Phe His Cys Val Glu

740 745 750

Arg Asp Ala Gln Leu Tyr Lys Glu Lys Gly Tyr Asp Ile Asn Leu Lys

755 760 765

Lys Leu Glu Glu Lys Gly Phe Ser Ser Val Thr Lys Leu Cys Ala Gly

770 775 780

Ile Asp Glu Thr Ala Pro Asp Lys Arg Lys Asp Val Glu Lys Glu Met

785 790 795 800

Ala Glu Arg Ala Lys Glu Ser Ile Asp Ser Leu Glu Ser Ala Asn Pro

805 810 815

Lys Leu Tyr Ala Asn Tyr Ile Lys Tyr Ser Asp Glu Lys Lys Ala Glu

820 825 830

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

835 840 845

Ala Tyr Leu Arg Asn Thr Lys Trp Asn Val Ile Ile Arg Glu Asp Leu

850 855 860

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

865 870 875 880

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

885 890 895

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

900 905 910

Ile Met Asn Glu Arg Tyr Glu Lys Ser Ser Gly Lys Val Ser Glu Tyr

915 920 925

Phe Asp Ala Val Asn Asp Glu Lys Lys Tyr Asn Asp Arg Leu Leu Lys

930 935 940

Leu Leu Cys Val Pro Phe Gly Tyr Cys Ile Pro Arg Phe Lys Asn Leu

945 950 955 960

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

965 970 975

Glu Lys Lys Lys Val Ser Gly Asn Ser Ser Leu Glu Ala Leu Pro Val

980 985 990

Ala Thr Met Val Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro

995 1000 1005

Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val

1010 1015 1020

Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys

1025 1030 1035 1040

Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val

1045 1050 1055

Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp His

1060 1065 1070

Met Lys Gln His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val

1075 1080 1085

Gln Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg

1090 1095 1100

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

1105 1110 1115 1120

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

1125 1130 1135

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

1140 1145 1150

Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg His Asn Ile Glu Asp

1155 1160 1165

Gly Ser Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile Gly

1170 1175 1180

Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln Ser

1185 1190 1195 1200

Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu

1205 1210 1215

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

1220 1225 1230

Lys Ser Asn Ser Lys Pro Gly Phe His Met Lys Arg Pro Ala Ala Thr

1235 1240 1245

Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Gln Arg Val Gln Leu Ser

1250 1255 1260

Asp Tyr Lys Asp His Asp Gly Asp Tyr Lys Asp His Asp Ile Asp Tyr

1265 1270 1275 1280

Lys Asp Asp Asp Asp Lys

1285

<210> 9

<211> 1369

<212> PRT

<213> Artificial Sequence

<400> 9

Met Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys

1 5 10 15

Lys Ala Ser Met Pro Lys Lys Lys Arg Lys Val Asn Ile Pro Ala Leu

20 25 30

Val Glu Asn Gln Lys Lys Tyr Phe Gly Thr Tyr Ser Val Met Ala Met

35 40 45

Leu Asn Ala Gln Thr Val Leu Asp His Ile Gln Lys Val Ala Asp Ile

50 55 60

Glu Gly Glu Gln Asn Glu Asn Asn Glu Asn Leu Trp Phe His Pro Val

65 70 75 80

Met Ser His Leu Tyr Asn Ala Lys Asn Gly Tyr Asp Lys Gln Pro Glu

85 90 95

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

100 105 110

Lys Ile Met Ala Glu Asn Gln Arg Glu Tyr Ser Asn Gly Lys Tyr Lys

115 120 125

Gln Asn Arg Val Glu Val Asn Ser Asn Asp Ile Phe Glu Val Leu Lys

130 135 140

Arg Ala Phe Gly Val Leu Lys Met Tyr Arg Asp Leu Thr Asn Ala Tyr

145 150 155 160

Lys Thr Tyr Glu Glu Lys Leu Asn Asp Gly Cys Glu Phe Leu Thr Ser

165 170 175

Thr Glu Gln Pro Leu Ser Gly Met Ile Asn Asn Tyr Tyr Thr Val Ala

180 185 190

Leu Arg Asn Met Asn Glu Arg Tyr Gly Tyr Lys Thr Glu Asp Leu Ala

195 200 205

Phe Ile Gln Asp Lys Arg Phe Lys Phe Val Lys Asp Ala Tyr Gly Lys

210 215 220

Lys Lys Ser Gln Val Asn Thr Gly Phe Phe Leu Ser Leu Gln Asp Tyr

225 230 235 240

Asn Gly Asp Thr Gln Lys Lys Leu His Leu Ser Gly Val Gly Ile Ala

245 250 255

Leu Leu Ile Cys Leu Phe Leu Asp Lys Gln Tyr Ile Asn Ile Phe Leu

260 265 270

Ser Arg Leu Pro Ile Phe Ser Ser Tyr Asn Ala Gln Ser Glu Glu Arg

275 280 285

Arg Ile Ile Ile Arg Ser Phe Gly Ile Asn Ser Ile Lys Leu Pro Lys

290 295 300

Asp Arg Ile His Ser Glu Lys Ser Asn Lys Ser Val Ala Met Asp Met

305 310 315 320

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

325 330 335

Ala Glu Lys Gln Ser Arg Phe Arg Ile Ile Ser Asp Asp His Asn Glu

340 345 350

Val Leu Met Lys Arg Ser Ser Asp Arg Phe Val Pro Leu Leu Leu Gln

355 360 365

Tyr Ile Asp Tyr Gly Lys Leu Phe Asp His Ile Arg Phe His Val Asn

370 375 380

Met Gly Lys Leu Arg Tyr Leu Leu Lys Ala Asp Lys Thr Cys Ile Asp

385 390 395 400

Gly Gln Thr Arg Val Arg Val Ile Glu Gln Pro Leu Asn Gly Phe Gly

405 410 415

Arg Leu Glu Glu Ala Glu Thr Met Arg Lys Gln Glu Asn Gly Thr Phe

420 425 430

Gly Asn Ser Gly Ile Arg Ile Arg Asp Phe Glu Asn Met Lys Arg Asp

435 440 445

Asp Ala Asn Pro Ala Asn Tyr Pro Tyr Ile Val Asp Thr Tyr Thr His

450 455 460

Tyr Ile Leu Glu Asn Asn Lys Val Glu Met Phe Ile Asn Asp Lys Glu

465 470 475 480

Asp Ser Ala Pro Leu Leu Pro Val Ile Glu Asp Asp Arg Tyr Val Val

485 490 495

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

500 505 510

Ala Phe His Met Phe Leu Phe Gly Ser Lys Lys Thr Glu Lys Leu Ile

515 520 525

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

530 535 540

Glu Glu Val Thr Ala Glu Asn Ile Ala Ser Phe Gly Ile Ala Glu Ser

545 550 555 560

Asp Leu Pro Gln Lys Ile Leu Asp Leu Ile Ser Gly Asn Ala His Gly

565 570 575

Lys Asp Val Asp Ala Phe Ile Arg Leu Thr Val Asp Asp Met Leu Thr

580 585 590

Asp Thr Glu Arg Arg Ile Lys Arg Phe Lys Asp Asp Arg Lys Ser Ile

595 600 605

Arg Ser Ala Asp Asn Lys Met Gly Lys Arg Gly Phe Lys Gln Ile Ser

610 615 620

Thr Gly Lys Leu Ala Asp Phe Leu Ala Lys Asp Ile Val Leu Phe Gln

625 630 635 640

Pro Ser Val Asn Asp Gly Glu Asn Lys Ile Thr Gly Leu Asn Tyr Arg

645 650 655

Ile Met Gln Ser Ala Ile Ala Val Tyr Asp Ser Gly Asp Asp Tyr Glu

660 665 670

Ala Lys Gln Gln Phe Lys Leu Met Phe Glu Lys Ala Arg Leu Ile Gly

675 680 685

Lys Gly Thr Thr Glu Pro His Pro Phe Leu Tyr Lys Val Phe Ala Arg

690 695 700

Ser Ile Pro Ala Asn Ala Val Glu Phe Tyr Glu Arg Tyr Leu Ile Glu

705 710 715 720

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

725 730 735

Arg Val Asp Val Pro Phe Ile Arg Arg Asp Gln Asn Lys Trp Lys Thr

740 745 750

Pro Ala Met Lys Thr Leu Gly Arg Ile Tyr Ser Glu Asp Leu Pro Val

755 760 765

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

770 775 780

Ser Leu Pro Gln Met Glu Gly Ile Asp Phe Asn Asn Ala Asn Val Thr

785 790 795 800

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

805 810 815

Thr Phe Tyr Gln Trp Asn Arg Asn Tyr Arg Tyr Met Asp Met Leu Lys

820 825 830

Gly Glu Tyr Asp Arg Lys Gly Ser Leu Gln His Cys Phe Thr Ser Val

835 840 845

Glu Glu Arg Glu Gly Leu Trp Lys Glu Arg Ala Ser Arg Thr Glu Arg

850 855 860

Tyr Arg Lys Gln Ala Ser Asn Lys Ile Arg Ser Asn Arg Gln Met Arg

865 870 875 880

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

885 890 895

Asn Ser Arg Asn Glu Tyr Gln Lys Ser Glu Lys Val Ile Arg Arg Tyr

900 905 910

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

915 920 925

Glu Leu Ala Asp Phe Asp Gly Glu Arg Phe Lys Leu Lys Glu Ile Met

930 935 940

Pro Asp Ala Glu Lys Gly Ile Leu Ser Glu Ile Met Pro Met Ser Phe

945 950 955 960

Thr Phe Glu Lys Gly Gly Lys Lys Tyr Thr Ile Thr Ser Glu Gly Met

965 970 975

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

980 985 990

Ile Gly Asn Leu Leu Glu Leu Val Gly Ser Asp Ile Val Ser Lys Glu

995 1000 1005

Asp Ile Met Glu Glu Phe Asn Lys Tyr Asp Gln Cys Arg Pro Glu Ile

1010 1015 1020

Ser Ser Ile Val Phe Asn Leu Glu Lys Trp Ala Phe Asp Thr Tyr Pro

1025 1030 1035 1040

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

1045 1050 1055

Ile Leu Lys Ile Leu Leu Asn Asn Lys Asn Ile Asn Lys Glu Gln Ser

1060 1065 1070

Asp Ile Leu Arg Lys Ile Arg Asn Ala Phe Asp Ala Asn Asn Tyr Pro

1075 1080 1085

Asp Lys Gly Val Val Glu Ile Lys Ala Leu Pro Glu Ile Ala Met Ser

1090 1095 1100

Ile Lys Lys Ala Phe Gly Glu Tyr Ala Ile Met Lys Gly Gly Gly Ser

1105 1110 1115 1120

Gly Ser Met Arg Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile

1125 1130 1135

Leu Val Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Arg

1140 1145 1150

Gly Glu Gly Glu Gly Asp Ala Thr Asn Gly Lys Leu Thr Leu Lys Phe

1155 1160 1165

Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr

1170 1175 1180

Thr Leu Thr Tyr Gly Val Gln Cys Phe Ala Arg Tyr Pro Asp His Met

1185 1190 1195 1200

Lys Gln His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gln

1205 1210 1215

Glu Arg Thr Ile Ser Phe Lys Asp Asp Gly Thr Tyr Lys Thr Arg Ala

1220 1225 1230

Glu Val Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys

1235 1240 1245

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

1250 1255 1260

Tyr Asn Phe Asn Ser His Asn Val Tyr Ile Thr Ala Asp Lys Gln Lys

1265 1270 1275 1280

Asn Gly Ile Lys Ala Asn Phe Lys Ile Arg His Asn Val Glu Asp Gly

1285 1290 1295

Ser Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile Gly Asp

1300 1305 1310

Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln Ser Val

1315 1320 1325

Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu Glu

1330 1335 1340

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

1345 1350 1355 1360

Leu Glu Pro Lys Lys Lys Arg Lys Val

1365

<210> 10

<211> 1857

<212> PRT

<213> Artificial Sequence

<400> 10

Met Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys

1 5 10 15

Lys Ala Ser Met Pro Lys Lys Lys Arg Lys Val Asn Ile Pro Ala Leu

20 25 30

Val Glu Asn Gln Lys Lys Tyr Phe Gly Thr Tyr Ser Val Met Ala Met

35 40 45

Leu Asn Ala Gln Thr Val Leu Asp His Ile Gln Lys Val Ala Asp Ile

50 55 60

Glu Gly Glu Gln Asn Glu Asn Asn Glu Asn Leu Trp Phe His Pro Val

65 70 75 80

Met Ser His Leu Tyr Asn Ala Lys Asn Gly Tyr Asp Lys Gln Pro Glu

85 90 95

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

100 105 110

Lys Ile Met Ala Glu Asn Gln Arg Glu Tyr Ser Asn Gly Lys Tyr Lys

115 120 125

Gln Asn Arg Val Glu Val Asn Ser Asn Asp Ile Phe Glu Val Leu Lys

130 135 140

Arg Ala Phe Gly Val Leu Lys Met Tyr Arg Asp Leu Thr Asn Ala Tyr

145 150 155 160

Lys Thr Tyr Glu Glu Lys Leu Asn Asp Gly Cys Glu Phe Leu Thr Ser

165 170 175

Thr Glu Gln Pro Leu Ser Gly Met Ile Asn Asn Tyr Tyr Thr Val Ala

180 185 190

Leu Arg Asn Met Asn Glu Arg Tyr Gly Tyr Lys Thr Glu Asp Leu Ala

195 200 205

Phe Ile Gln Asp Lys Arg Phe Lys Phe Val Lys Asp Ala Tyr Gly Lys

210 215 220

Lys Lys Ser Gln Val Asn Thr Gly Phe Phe Leu Ser Leu Gln Asp Tyr

225 230 235 240

Asn Gly Asp Thr Gln Lys Lys Leu His Leu Ser Gly Val Gly Ile Ala

245 250 255

Leu Leu Ile Cys Leu Phe Leu Asp Lys Gln Tyr Ile Asn Ile Phe Leu

260 265 270

Ser Arg Leu Pro Ile Phe Ser Ser Tyr Asn Ala Gln Ser Glu Glu Arg

275 280 285

Arg Ile Ile Ile Arg Ser Phe Gly Ile Asn Ser Ile Lys Leu Pro Lys

290 295 300

Asp Arg Ile His Ser Glu Lys Ser Asn Lys Ser Val Ala Met Asp Met

305 310 315 320

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

325 330 335

Ala Glu Lys Gln Ser Arg Phe Arg Ile Ile Ser Asp Asp His Asn Glu

340 345 350

Val Leu Met Lys Arg Ser Ser Asp Arg Phe Val Pro Leu Leu Leu Gln

355 360 365

Tyr Ile Asp Tyr Gly Lys Leu Phe Asp His Ile Arg Phe His Val Asn

370 375 380

Met Gly Lys Leu Arg Tyr Leu Leu Lys Ala Asp Lys Thr Cys Ile Asp

385 390 395 400

Gly Gln Thr Arg Val Arg Val Ile Glu Gln Pro Leu Asn Gly Phe Gly

405 410 415

Arg Leu Glu Glu Ala Glu Thr Met Arg Lys Gln Glu Asn Gly Thr Phe

420 425 430

Gly Asn Ser Gly Ile Arg Ile Arg Asp Phe Glu Asn Met Lys Arg Asp

435 440 445

Asp Ala Asn Pro Ala Asn Tyr Pro Tyr Ile Val Asp Thr Tyr Thr His

450 455 460

Tyr Ile Leu Glu Asn Asn Lys Val Glu Met Phe Ile Asn Asp Lys Glu

465 470 475 480

Asp Ser Ala Pro Leu Leu Pro Val Ile Glu Asp Asp Arg Tyr Val Val

485 490 495

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

500 505 510

Ala Phe His Met Phe Leu Phe Gly Ser Lys Lys Thr Glu Lys Leu Ile

515 520 525

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

530 535 540

Glu Glu Val Thr Ala Glu Asn Ile Ala Ser Phe Gly Ile Ala Glu Ser

545 550 555 560

Asp Leu Pro Gln Lys Ile Leu Asp Leu Ile Ser Gly Asn Ala His Gly

565 570 575

Lys Asp Val Asp Ala Phe Ile Arg Leu Thr Val Asp Asp Met Leu Thr

580 585 590

Asp Thr Glu Arg Arg Ile Lys Arg Phe Lys Asp Asp Arg Lys Ser Ile

595 600 605

Arg Ser Ala Asp Asn Lys Met Gly Lys Arg Gly Phe Lys Gln Ile Ser

610 615 620

Thr Gly Lys Leu Ala Asp Phe Leu Ala Lys Asp Ile Val Leu Phe Gln

625 630 635 640

Pro Ser Val Asn Asp Gly Glu Asn Lys Ile Thr Gly Leu Asn Tyr Arg

645 650 655

Ile Met Gln Ser Ala Ile Ala Val Tyr Asp Ser Gly Asp Asp Tyr Glu

660 665 670

Ala Lys Gln Gln Phe Lys Leu Met Phe Glu Lys Ala Arg Leu Ile Gly

675 680 685

Lys Gly Thr Thr Glu Pro His Pro Phe Leu Tyr Lys Val Phe Ala Arg

690 695 700

Ser Ile Pro Ala Asn Ala Val Glu Phe Tyr Glu Arg Tyr Leu Ile Glu

705 710 715 720

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

725 730 735

Arg Val Asp Val Pro Phe Ile Arg Arg Asp Gln Asn Lys Trp Lys Thr

740 745 750

Pro Ala Met Lys Thr Leu Gly Arg Ile Tyr Ser Glu Asp Leu Pro Val

755 760 765

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

770 775 780

Ser Leu Pro Gln Met Glu Gly Ile Asp Phe Asn Asn Ala Asn Val Thr

785 790 795 800

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

805 810 815

Thr Phe Tyr Gln Trp Asn Arg Asn Tyr Arg Tyr Met Asp Met Leu Lys

820 825 830

Gly Glu Tyr Asp Arg Lys Gly Ser Leu Gln His Cys Phe Thr Ser Val

835 840 845

Glu Glu Arg Glu Gly Leu Trp Lys Glu Arg Ala Ser Arg Thr Glu Arg

850 855 860

Tyr Arg Lys Gln Ala Ser Asn Lys Ile Arg Ser Asn Arg Gln Met Arg

865 870 875 880

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

885 890 895

Asn Ser Arg Asn Glu Tyr Gln Lys Ser Glu Lys Val Ile Arg Arg Tyr

900 905 910

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

915 920 925

Glu Leu Ala Asp Phe Asp Gly Glu Arg Phe Lys Leu Lys Glu Ile Met

930 935 940

Pro Asp Ala Glu Lys Gly Ile Leu Ser Glu Ile Met Pro Met Ser Phe

945 950 955 960

Thr Phe Glu Lys Gly Gly Lys Lys Tyr Thr Ile Thr Ser Glu Gly Met

965 970 975

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

980 985 990

Ile Gly Asn Leu Leu Glu Leu Val Gly Ser Asp Ile Val Ser Lys Glu

995 1000 1005

Asp Ile Met Glu Glu Phe Asn Lys Tyr Asp Gln Cys Arg Pro Glu Ile

1010 1015 1020

Ser Ser Ile Val Phe Asn Leu Glu Lys Trp Ala Phe Asp Thr Tyr Pro

1025 1030 1035 1040

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

1045 1050 1055

Ile Leu Lys Ile Leu Leu Asn Asn Lys Asn Ile Asn Lys Glu Gln Ser

1060 1065 1070

Asp Ile Leu Arg Lys Ile Arg Asn Ala Phe Asp Ala Asn Asn Tyr Pro

1075 1080 1085

Asp Lys Gly Val Val Glu Ile Lys Ala Leu Pro Glu Ile Ala Met Ser

1090 1095 1100

Ile Lys Lys Ala Phe Gly Glu Tyr Ala Ile Met Lys Gly Gly Gly Ser

1105 1110 1115 1120

Gly Ser Met Arg Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile

1125 1130 1135

Leu Val Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Arg

1140 1145 1150

Gly Glu Gly Glu Gly Asp Ala Thr Asn Gly Lys Leu Thr Leu Lys Phe

1155 1160 1165

Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr

1170 1175 1180

Thr Leu Thr Tyr Gly Val Gln Cys Phe Ala Arg Tyr Pro Asp His Met

1185 1190 1195 1200

Lys Gln His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gln

1205 1210 1215

Glu Arg Thr Ile Ser Phe Lys Asp Asp Gly Thr Tyr Lys Thr Arg Ala

1220 1225 1230

Glu Val Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys

1235 1240 1245

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

1250 1255 1260

Tyr Asn Phe Asn Ser His Asn Val Tyr Ile Thr Ala Asp Lys Gln Lys

1265 1270 1275 1280

Asn Gly Ile Lys Ala Asn Phe Lys Ile Arg His Asn Val Glu Asp Gly

1285 1290 1295

Ser Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile Gly Asp

1300 1305 1310

Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln Ser Val

1315 1320 1325

Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu Glu

1330 1335 1340

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

1345 1350 1355 1360

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

1365 1370 1375

Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly His Lys

1380 1385 1390

Phe Ser Val Arg Gly Glu Gly Glu Gly Asp Ala Thr Asn Gly Lys Leu

1395 1400 1405

Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro

1410 1415 1420

Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ala Arg Tyr

1425 1430 1435 1440

Pro Asp His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met Pro Glu

1445 1450 1455

Gly Tyr Val Gln Glu Arg Thr Ile Ser Phe Lys Asp Asp Gly Thr Tyr

1460 1465 1470

Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val Asn Arg

1475 1480 1485

Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly

1490 1495 1500

His Lys Leu Glu Tyr Asn Phe Asn Ser His Asn Val Tyr Ile Thr Ala

1505 1510 1515 1520

Asp Lys Gln Lys Asn Gly Ile Lys Ala Asn Phe Lys Ile Arg His Asn

1525 1530 1535

Val Glu Asp Gly Ser Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr

1540 1545 1550

Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser

1555 1560 1565

Thr Gln Ser Val Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met

1570 1575 1580

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

1585 1590 1595 1600

Glu Leu Tyr Lys Gly Ser Ile Asp Gly Ser Met Arg Lys Gly Glu Glu

1605 1610 1615

Leu Phe Thr Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val

1620 1625 1630

Asn Gly His Lys Phe Ser Val Arg Gly Glu Gly Glu Gly Asp Ala Thr

1635 1640 1645

Asn Gly Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro

1650 1655 1660

Val Pro Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys

1665 1670 1675 1680

Phe Ala Arg Tyr Pro Asp His Met Lys Gln His Asp Phe Phe Lys Ser

1685 1690 1695

Ala Met Pro Glu Gly Tyr Val Gln Glu Arg Thr Ile Ser Phe Lys Asp

1700 1705 1710

Asp Gly Thr Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr

1715 1720 1725

Leu Val Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly

1730 1735 1740

Asn Ile Leu Gly His Lys Leu Glu Tyr Asn Phe Asn Ser His Asn Val

1745 1750 1755 1760

Tyr Ile Thr Ala Asp Lys Gln Lys Asn Gly Ile Lys Ala Asn Phe Lys

1765 1770 1775

Ile Arg His Asn Val Glu Asp Gly Ser Val Gln Leu Ala Asp His Tyr

1780 1785 1790

Gln Gln Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn

1795 1800 1805

His Tyr Leu Ser Thr Gln Ser Val Leu Ser Lys Asp Pro Asn Glu Lys

1810 1815 1820

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

1825 1830 1835 1840

His Gly Met Asp Glu Leu Tyr Lys Leu Glu Pro Lys Lys Lys Arg Lys

1845 1850 1855

Val

<210> 11

<211> 1398

<212> PRT

<213> Artificial Sequence

<400> 11

Met Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys

1 5 10 15

Lys Ala Ser Asn Ile Pro Ala Leu Val Glu Asn Gln Lys Lys Tyr Phe

20 25 30

Gly Thr Tyr Ser Val Met Ala Met Leu Asn Ala Gln Thr Val Leu Asp

35 40 45

His Ile Gln Lys Val Ala Asp Ile Glu Gly Glu Gln Asn Glu Asn Asn

50 55 60

Glu Asn Leu Trp Phe His Pro Val Met Ser His Leu Tyr Asn Ala Lys

65 70 75 80

Asn Gly Tyr Asp Lys Gln Pro Glu Lys Thr Met Phe Ile Ile Glu Arg

85 90 95

Leu Gln Ser Tyr Phe Pro Phe Leu Lys Ile Met Ala Glu Asn Gln Arg

100 105 110

Glu Tyr Ser Asn Gly Lys Tyr Lys Gln Asn Arg Val Glu Val Asn Ser

115 120 125

Asn Asp Ile Phe Glu Val Leu Lys Arg Ala Phe Gly Val Leu Lys Met

130 135 140

Tyr Arg Asp Leu Thr Asn Ala Tyr Lys Thr Tyr Glu Glu Lys Leu Asn

145 150 155 160

Asp Gly Cys Glu Phe Leu Thr Ser Thr Glu Gln Pro Leu Ser Gly Met

165 170 175

Ile Asn Asn Tyr Tyr Thr Val Ala Leu Arg Asn Met Asn Glu Arg Tyr

180 185 190

Gly Tyr Lys Thr Glu Asp Leu Ala Phe Ile Gln Asp Lys Arg Phe Lys

195 200 205

Phe Val Lys Asp Ala Tyr Gly Lys Lys Lys Ser Gln Val Asn Thr Gly

210 215 220

Phe Phe Leu Ser Leu Gln Asp Tyr Asn Gly Asp Thr Gln Lys Lys Leu

225 230 235 240

His Leu Ser Gly Val Gly Ile Ala Leu Leu Ile Cys Leu Phe Leu Asp

245 250 255

Lys Gln Tyr Ile Asn Ile Phe Leu Ser Arg Leu Pro Ile Phe Ser Ser

260 265 270

Tyr Asn Ala Gln Ser Glu Glu Arg Arg Ile Ile Ile Arg Ser Phe Gly

275 280 285

Ile Asn Ser Ile Lys Leu Pro Lys Asp Arg Ile His Ser Glu Lys Ser

290 295 300

Asn Lys Ser Val Ala Met Asp Met Leu Asn Glu Val Lys Arg Cys Pro

305 310 315 320

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

325 330 335

Ile Ile Ser Asp Asp His Asn Glu Val Leu Met Lys Arg Ser Ser Asp

340 345 350

Arg Phe Val Pro Leu Leu Leu Gln Tyr Ile Asp Tyr Gly Lys Leu Phe

355 360 365

Asp His Ile Arg Phe His Val Asn Met Gly Lys Leu Arg Tyr Leu Leu

370 375 380

Lys Ala Asp Lys Thr Cys Ile Asp Gly Gln Thr Arg Val Arg Val Ile

385 390 395 400

Glu Gln Pro Leu Asn Gly Phe Gly Arg Leu Glu Glu Ala Glu Thr Met

405 410 415

Arg Lys Gln Glu Asn Gly Thr Phe Gly Asn Ser Gly Ile Arg Ile Arg

420 425 430

Asp Phe Glu Asn Met Lys Arg Asp Asp Ala Asn Pro Ala Asn Tyr Pro

435 440 445

Tyr Ile Val Asp Thr Tyr Thr His Tyr Ile Leu Glu Asn Asn Lys Val

450 455 460

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

465 470 475 480

Ile Glu Asp Asp Arg Tyr Val Val Lys Thr Ile Pro Ser Cys Arg Met

485 490 495

Ser Thr Leu Glu Ile Pro Ala Met Ala Phe His Met Phe Leu Phe Gly

500 505 510

Ser Lys Lys Thr Glu Lys Leu Ile Val Asp Val His Asn Arg Tyr Lys

515 520 525

Arg Leu Phe Gln Ala Met Gln Lys Glu Glu Val Thr Ala Glu Asn Ile

530 535 540

Ala Ser Phe Gly Ile Ala Glu Ser Asp Leu Pro Gln Lys Ile Leu Asp

545 550 555 560

Leu Ile Ser Gly Asn Ala His Gly Lys Asp Val Asp Ala Phe Ile Arg

565 570 575

Leu Thr Val Asp Asp Met Leu Thr Asp Thr Glu Arg Arg Ile Lys Arg

580 585 590

Phe Lys Asp Asp Arg Lys Ser Ile Arg Ser Ala Asp Asn Lys Met Gly

595 600 605

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

610 615 620

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

625 630 635 640

Lys Ile Thr Gly Leu Asn Tyr Arg Ile Met Gln Ser Ala Ile Ala Val

645 650 655

Tyr Asp Ser Gly Asp Asp Tyr Glu Ala Lys Gln Gln Phe Lys Leu Met

660 665 670

Phe Glu Lys Ala Arg Leu Ile Gly Lys Gly Thr Thr Glu Pro His Pro

675 680 685

Phe Leu Tyr Lys Val Phe Ala Arg Ser Ile Pro Ala Asn Ala Val Glu

690 695 700

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

705 710 715 720

Ser Asn Glu Ile Lys Lys Gly Asn Arg Val Asp Val Pro Phe Ile Arg

725 730 735

Arg Asp Gln Asn Lys Trp Lys Thr Pro Ala Met Lys Thr Leu Gly Arg

740 745 750

Ile Tyr Ser Glu Asp Leu Pro Val Glu Leu Pro Arg Gln Met Phe Asp

755 760 765

Asn Glu Ile Lys Ser His Leu Lys Ser Leu Pro Gln Met Glu Gly Ile

770 775 780

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

785 790 795 800

Arg Val Leu Asp Asp Asp Phe Gln Thr Phe Tyr Gln Trp Asn Arg Asn

805 810 815

Tyr Arg Tyr Met Asp Met Leu Lys Gly Glu Tyr Asp Arg Lys Gly Ser

820 825 830

Leu Gln His Cys Phe Thr Ser Val Glu Glu Arg Glu Gly Leu Trp Lys

835 840 845

Glu Arg Ala Ser Arg Thr Glu Arg Tyr Arg Lys Gln Ala Ser Asn Lys

850 855 860

Ile Arg Ser Asn Arg Gln Met Arg Asn Ala Ser Ser Glu Glu Ile Glu

865 870 875 880

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

885 890 895

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

900 905 910

Leu Leu Ala Lys Lys Thr Leu Thr Glu Leu Ala Asp Phe Asp Gly Glu

915 920 925

Arg Phe Lys Leu Lys Glu Ile Met Pro Asp Ala Glu Lys Gly Ile Leu

930 935 940

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

945 950 955 960

Tyr Thr Ile Thr Ser Glu Gly Met Lys Leu Lys Asn Tyr Gly Asp Phe

965 970 975

Phe Val Leu Ala Ser Asp Lys Arg Ile Gly Asn Leu Leu Glu Leu Val

980 985 990

Gly Ser Asp Ile Val Ser Lys Glu Asp Ile Met Glu Glu Phe Asn Lys

995 1000 1005

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

1010 1015 1020

Lys Trp Ala Phe Asp Thr Tyr Pro Glu Leu Ser Ala Arg Val Asp Arg

1025 1030 1035 1040

Glu Glu Lys Val Asp Phe Lys Ser Ile Leu Lys Ile Leu Leu Asn Asn

1045 1050 1055

Lys Asn Ile Asn Lys Glu Gln Ser Asp Ile Leu Arg Lys Ile Arg Asn

1060 1065 1070

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

1075 1080 1085

Ala Leu Pro Glu Ile Ala Met Ser Ile Lys Lys Ala Phe Gly Glu Tyr

1090 1095 1100

Ala Ile Met Lys Ser Arg Val Ser Lys Gly Glu Glu Asp Asn Met Ala

1105 1110 1115 1120

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

1125 1130 1135

Val Asp Phe Asp Met Val Gly Gln Gly Thr Gly Asn Pro Asn Asp Gly

1140 1145 1150

Tyr Glu Glu Leu Asn Leu Lys Ser Thr Lys Gly Asp Leu Gln Phe Ser

1155 1160 1165

Pro Trp Ile Leu Val Pro His Ile Gly Tyr Gly Phe His Gln Tyr Leu

1170 1175 1180

Pro Tyr Pro Asp Gly Met Ser Pro Phe Gln Ala Ala Met Val Asp Gly

1185 1190 1195 1200

Ser Gly Tyr Gln Val His Arg Thr Met Gln Phe Glu Asp Gly Ala Ser

1205 1210 1215

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

1220 1225 1230

Glu Ala Gln Val Lys Gly Thr Gly Phe Pro Ala Asp Gly Pro Val Met

1235 1240 1245

Thr Asn Ser Leu Thr Ala Ala Asp Trp Cys Arg Ser Lys Lys Thr Tyr

1250 1255 1260

Pro Asn Asp Lys Thr Ile Ile Ser Thr Phe Lys Trp Ser Tyr Thr Thr

1265 1270 1275 1280

Gly Asn Gly Lys Arg Tyr Arg Ser Thr Ala Arg Thr Thr Tyr Thr Phe

1285 1290 1295

Ala Lys Pro Met Ala Ala Asn Tyr Leu Lys Asn Gln Pro Met Tyr Val

1300 1305 1310

Phe Arg Lys Thr Glu Leu Lys His Ser Lys Thr Glu Leu Asn Phe Lys

1315 1320 1325

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

1330 1335 1340

Lys Ser Gly Leu Arg Ser Cys Leu His Met Lys Arg Pro Ala Ala Thr

1345 1350 1355 1360

Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Gln Arg Val Gln Leu Ser

1365 1370 1375

Asp Tyr Lys Asp His Asp Gly Asp Tyr Lys Asp His Asp Ile Asp Tyr

1380 1385 1390

Lys Asp Asp Asp Asp Lys

1395

<210> 12

<211> 1642

<212> PRT

<213> Artificial Sequence

<400> 12

Met Pro Lys Lys Lys Arg Lys Val Asn Ile Pro Ala Leu Val Glu Asn

1 5 10 15

Gln Lys Lys Tyr Phe Gly Thr Tyr Ser Val Met Ala Met Leu Asn Ala

20 25 30

Gln Thr Val Leu Asp His Ile Gln Lys Val Ala Asp Ile Glu Gly Glu

35 40 45

Gln Asn Glu Asn Asn Glu Asn Leu Trp Phe His Pro Val Met Ser His

50 55 60

Leu Tyr Asn Ala Lys Asn Gly Tyr Asp Lys Gln Pro Glu Lys Thr Met

65 70 75 80

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

85 90 95

Ala Glu Asn Gln Arg Glu Tyr Ser Asn Gly Lys Tyr Lys Gln Asn Arg

100 105 110

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

115 120 125

Gly Val Leu Lys Met Tyr Arg Asp Leu Thr Asn Ala Tyr Lys Thr Tyr

130 135 140

Glu Glu Lys Leu Asn Asp Gly Cys Glu Phe Leu Thr Ser Thr Glu Gln

145 150 155 160

Pro Leu Ser Gly Met Ile Asn Asn Tyr Tyr Thr Val Ala Leu Arg Asn

165 170 175

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

180 185 190

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

195 200 205

Gln Val Asn Thr Gly Phe Phe Leu Ser Leu Gln Asp Tyr Asn Gly Asp

210 215 220

Thr Gln Lys Lys Leu His Leu Ser Gly Val Gly Ile Ala Leu Leu Ile

225 230 235 240

Cys Leu Phe Leu Asp Lys Gln Tyr Ile Asn Ile Phe Leu Ser Arg Leu

245 250 255

Pro Ile Phe Ser Ser Tyr Asn Ala Gln Ser Glu Glu Arg Arg Ile Ile

260 265 270

Ile Arg Ser Phe Gly Ile Asn Ser Ile Lys Leu Pro Lys Asp Arg Ile

275 280 285

His Ser Glu Lys Ser Asn Lys Ser Val Ala Met Asp Met Leu Asn Glu

290 295 300

Val Lys Arg Cys Pro Asp Glu Leu Phe Thr Thr Leu Ser Ala Glu Lys

305 310 315 320

Gln Ser Arg Phe Arg Ile Ile Ser Asp Asp His Asn Glu Val Leu Met

325 330 335

Lys Arg Ser Ser Asp Arg Phe Val Pro Leu Leu Leu Gln Tyr Ile Asp

340 345 350

Tyr Gly Lys Leu Phe Asp His Ile Arg Phe His Val Asn Met Gly Lys

355 360 365

Leu Arg Tyr Leu Leu Lys Ala Asp Lys Thr Cys Ile Asp Gly Gln Thr

370 375 380

Arg Val Arg Val Ile Glu Gln Pro Leu Asn Gly Phe Gly Arg Leu Glu

385 390 395 400

Glu Ala Glu Thr Met Arg Lys Gln Glu Asn Gly Thr Phe Gly Asn Ser

405 410 415

Gly Ile Arg Ile Arg Asp Phe Glu Asn Met Lys Arg Asp Asp Ala Asn

420 425 430

Pro Ala Asn Tyr Pro Tyr Ile Val Asp Thr Tyr Thr His Tyr Ile Leu

435 440 445

Glu Asn Asn Lys Val Glu Met Phe Ile Asn Asp Lys Glu Asp Ser Ala

450 455 460

Pro Leu Leu Pro Val Ile Glu Asp Asp Arg Tyr Val Val Lys Thr Ile

465 470 475 480

Pro Ser Cys Arg Met Ser Thr Leu Glu Ile Pro Ala Met Ala Phe His

485 490 495

Met Phe Leu Phe Gly Ser Lys Lys Thr Glu Lys Leu Ile Val Asp Val

500 505 510

His Asn Arg Tyr Lys Arg Leu Phe Gln Ala Met Gln Lys Glu Glu Val

515 520 525

Thr Ala Glu Asn Ile Ala Ser Phe Gly Ile Ala Glu Ser Asp Leu Pro

530 535 540

Gln Lys Ile Leu Asp Leu Ile Ser Gly Asn Ala His Gly Lys Asp Val

545 550 555 560

Asp Ala Phe Ile Arg Leu Thr Val Asp Asp Met Leu Thr Asp Thr Glu

565 570 575

Arg Arg Ile Lys Arg Phe Lys Asp Asp Arg Lys Ser Ile Arg Ser Ala

580 585 590

Asp Asn Lys Met Gly Lys Arg Gly Phe Lys Gln Ile Ser Thr Gly Lys

595 600 605

Leu Ala Asp Phe Leu Ala Lys Asp Ile Val Leu Phe Gln Pro Ser Val

610 615 620

Asn Asp Gly Glu Asn Lys Ile Thr Gly Leu Asn Tyr Arg Ile Met Gln

625 630 635 640

Ser Ala Ile Ala Val Tyr Asp Ser Gly Asp Asp Tyr Glu Ala Lys Gln

645 650 655

Gln Phe Lys Leu Met Phe Glu Lys Ala Arg Leu Ile Gly Lys Gly Thr

660 665 670

Thr Glu Pro His Pro Phe Leu Tyr Lys Val Phe Ala Arg Ser Ile Pro

675 680 685

Ala Asn Ala Val Glu Phe Tyr Glu Arg Tyr Leu Ile Glu Arg Lys Phe

690 695 700

Tyr Leu Thr Gly Leu Ser Asn Glu Ile Lys Lys Gly Asn Arg Val Asp

705 710 715 720

Val Pro Phe Ile Arg Arg Asp Gln Asn Lys Trp Lys Thr Pro Ala Met

725 730 735

Lys Thr Leu Gly Arg Ile Tyr Ser Glu Asp Leu Pro Val Glu Leu Pro

740 745 750

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

755 760 765

Gln Met Glu Gly Ile Asp Phe Asn Asn Ala Asn Val Thr Tyr Leu Ile

770 775 780

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

785 790 795 800

Gln Trp Asn Arg Asn Tyr Arg Tyr Met Asp Met Leu Lys Gly Glu Tyr

805 810 815

Asp Arg Lys Gly Ser Leu Gln His Cys Phe Thr Ser Val Glu Glu Arg

820 825 830

Glu Gly Leu Trp Lys Glu Arg Ala Ser Arg Thr Glu Arg Tyr Arg Lys

835 840 845

Gln Ala Ser Asn Lys Ile Arg Ser Asn Arg Gln Met Arg Asn Ala Ser

850 855 860

Ser Glu Glu Ile Glu Thr Ile Leu Asp Lys Arg Leu Ser Asn Ser Arg

865 870 875 880

Asn Glu Tyr Gln Lys Ser Glu Lys Val Ile Arg Arg Tyr Arg Val Gln

885 890 895

Asp Ala Leu Leu Phe Leu Leu Ala Lys Lys Thr Leu Thr Glu Leu Ala

900 905 910

Asp Phe Asp Gly Glu Arg Phe Lys Leu Lys Glu Ile Met Pro Asp Ala

915 920 925

Glu Lys Gly Ile Leu Ser Glu Ile Met Pro Met Ser Phe Thr Phe Glu

930 935 940

Lys Gly Gly Lys Lys Tyr Thr Ile Thr Ser Glu Gly Met Lys Leu Lys

945 950 955 960

Asn Tyr Gly Asp Phe Phe Val Leu Ala Ser Asp Lys Arg Ile Gly Asn

965 970 975

Leu Leu Glu Leu Val Gly Ser Asp Ile Val Ser Lys Glu Asp Ile Met

980 985 990

Glu Glu Phe Asn Lys Tyr Asp Gln Cys Arg Pro Glu Ile Ser Ser Ile

995 1000 1005

Val Phe Asn Leu Glu Lys Trp Ala Phe Asp Thr Tyr Pro Glu Leu Ser

1010 1015 1020

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

1025 1030 1035 1040

Ile Leu Leu Asn Asn Lys Asn Ile Asn Lys Glu Gln Ser Asp Ile Leu

1045 1050 1055

Arg Lys Ile Arg Asn Ala Phe Asp Ala Asn Asn Tyr Pro Asp Lys Gly

1060 1065 1070

Val Val Glu Ile Lys Ala Leu Pro Glu Ile Ala Met Ser Ile Lys Lys

1075 1080 1085

Ala Phe Gly Glu Tyr Ala Ile Met Lys Glu Gly Ala Leu Glu Gly Thr

1090 1095 1100

Ser Gly Gly Gly Ser Met Val Ser Lys Gly Glu Glu Asp Asn Met Ala

1105 1110 1115 1120

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

1125 1130 1135

Val Asp Phe Asp Met Val Gly Gln Gly Thr Gly Asn Pro Asn Asp Gly

1140 1145 1150

Tyr Glu Glu Leu Asn Leu Lys Ser Thr Lys Gly Asp Leu Gln Phe Ser

1155 1160 1165

Pro Trp Ile Leu Val Pro His Ile Gly Tyr Gly Phe His Gln Tyr Leu

1170 1175 1180

Pro Tyr Pro Asp Gly Met Ser Pro Phe Gln Ala Ala Met Val Asp Gly

1185 1190 1195 1200

Ser Gly Tyr Gln Val His Arg Thr Met Gln Phe Glu Asp Gly Ala Ser

1205 1210 1215

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

1220 1225 1230

Glu Ala Gln Val Lys Gly Thr Gly Phe Pro Ala Asp Gly Pro Val Met

1235 1240 1245

Thr Asn Ser Leu Thr Ala Ala Asp Trp Cys Arg Ser Lys Lys Thr Tyr

1250 1255 1260

Pro Asn Asp Lys Thr Ile Ile Ser Thr Phe Lys Trp Ser Tyr Thr Thr

1265 1270 1275 1280

Gly Asn Gly Lys Arg Tyr Arg Ser Thr Ala Arg Thr Thr Tyr Thr Phe

1285 1290 1295

Ala Lys Pro Met Ala Ala Asn Tyr Leu Lys Asn Gln Pro Met Tyr Val

1300 1305 1310

Phe Arg Lys Thr Glu Leu Lys His Ser Lys Thr Glu Leu Asn Phe Lys

1315 1320 1325

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

1330 1335 1340

Lys Ser Asn Ser Ala Val Asp Gly Thr Met Val Ser Lys Gly Glu Glu

1345 1350 1355 1360

Asp Asn Met Ala Ser Leu Pro Ala Thr His Glu Leu His Ile Phe Gly

1365 1370 1375

Ser Ile Asn Gly Val Asp Phe Asp Met Val Gly Gln Gly Thr Gly Asn

1380 1385 1390

Pro Asn Asp Gly Tyr Glu Glu Leu Asn Leu Lys Ser Thr Lys Gly Asp

1395 1400 1405

Leu Gln Phe Ser Pro Trp Ile Leu Val Pro His Ile Gly Tyr Gly Phe

1410 1415 1420

His Gln Tyr Leu Pro Tyr Pro Asp Gly Met Ser Pro Phe Gln Ala Ala

1425 1430 1435 1440

Met Val Asp Gly Ser Gly Tyr Gln Val His Arg Thr Met Gln Phe Glu

1445 1450 1455

Asp Gly Ala Ser Leu Thr Val Asn Tyr Arg Tyr Thr Tyr Glu Gly Ser

1460 1465 1470

His Ile Lys Gly Glu Ala Gln Val Lys Gly Thr Gly Phe Pro Ala Asp

1475 1480 1485

Gly Pro Val Met Thr Asn Ser Leu Thr Ala Ala Asp Trp Cys Arg Ser

1490 1495 1500

Lys Lys Thr Tyr Pro Asn Asp Lys Thr Ile Ile Ser Thr Phe Lys Trp

1505 1510 1515 1520

Ser Tyr Thr Thr Gly Asn Gly Lys Arg Tyr Arg Ser Thr Ala Arg Thr

1525 1530 1535

Thr Tyr Thr Phe Ala Lys Pro Met Ala Ala Asn Tyr Leu Lys Asn Gln

1540 1545 1550

Pro Met Tyr Val Phe Arg Lys Thr Glu Leu Lys His Ser Lys Thr Glu

1555 1560 1565

Leu Asn Phe Lys Glu Trp Gln Lys Ala Phe Thr Asp Val Met Gly Met

1570 1575 1580

Asp Glu Leu Tyr Lys Ser Gly Leu Arg Ser Cys Leu His Met Lys Arg

1585 1590 1595 1600

Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Gln Arg

1605 1610 1615

Val Gln Leu Ser Asp Tyr Lys Asp His Asp Gly Asp Tyr Lys Asp His

1620 1625 1630

Asp Ile Asp Tyr Lys Asp Asp Asp Asp Lys

1635 1640

<210> 13

<211> 1883

<212> PRT

<213> Artificial Sequence

<400> 13

Met Pro Lys Lys Lys Arg Lys Val Asn Ile Pro Ala Leu Val Glu Asn

1 5 10 15

Gln Lys Lys Tyr Phe Gly Thr Tyr Ser Val Met Ala Met Leu Asn Ala

20 25 30

Gln Thr Val Leu Asp His Ile Gln Lys Val Ala Asp Ile Glu Gly Glu

35 40 45

Gln Asn Glu Asn Asn Glu Asn Leu Trp Phe His Pro Val Met Ser His

50 55 60

Leu Tyr Asn Ala Lys Asn Gly Tyr Asp Lys Gln Pro Glu Lys Thr Met

65 70 75 80

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

85 90 95

Ala Glu Asn Gln Arg Glu Tyr Ser Asn Gly Lys Tyr Lys Gln Asn Arg

100 105 110

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

115 120 125

Gly Val Leu Lys Met Tyr Arg Asp Leu Thr Asn Ala Tyr Lys Thr Tyr

130 135 140

Glu Glu Lys Leu Asn Asp Gly Cys Glu Phe Leu Thr Ser Thr Glu Gln

145 150 155 160

Pro Leu Ser Gly Met Ile Asn Asn Tyr Tyr Thr Val Ala Leu Arg Asn

165 170 175

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

180 185 190

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

195 200 205

Gln Val Asn Thr Gly Phe Phe Leu Ser Leu Gln Asp Tyr Asn Gly Asp

210 215 220

Thr Gln Lys Lys Leu His Leu Ser Gly Val Gly Ile Ala Leu Leu Ile

225 230 235 240

Cys Leu Phe Leu Asp Lys Gln Tyr Ile Asn Ile Phe Leu Ser Arg Leu

245 250 255

Pro Ile Phe Ser Ser Tyr Asn Ala Gln Ser Glu Glu Arg Arg Ile Ile

260 265 270

Ile Arg Ser Phe Gly Ile Asn Ser Ile Lys Leu Pro Lys Asp Arg Ile

275 280 285

His Ser Glu Lys Ser Asn Lys Ser Val Ala Met Asp Met Leu Asn Glu

290 295 300

Val Lys Arg Cys Pro Asp Glu Leu Phe Thr Thr Leu Ser Ala Glu Lys

305 310 315 320

Gln Ser Arg Phe Arg Ile Ile Ser Asp Asp His Asn Glu Val Leu Met

325 330 335

Lys Arg Ser Ser Asp Arg Phe Val Pro Leu Leu Leu Gln Tyr Ile Asp

340 345 350

Tyr Gly Lys Leu Phe Asp His Ile Arg Phe His Val Asn Met Gly Lys

355 360 365

Leu Arg Tyr Leu Leu Lys Ala Asp Lys Thr Cys Ile Asp Gly Gln Thr

370 375 380

Arg Val Arg Val Ile Glu Gln Pro Leu Asn Gly Phe Gly Arg Leu Glu

385 390 395 400

Glu Ala Glu Thr Met Arg Lys Gln Glu Asn Gly Thr Phe Gly Asn Ser

405 410 415

Gly Ile Arg Ile Arg Asp Phe Glu Asn Met Lys Arg Asp Asp Ala Asn

420 425 430

Pro Ala Asn Tyr Pro Tyr Ile Val Asp Thr Tyr Thr His Tyr Ile Leu

435 440 445

Glu Asn Asn Lys Val Glu Met Phe Ile Asn Asp Lys Glu Asp Ser Ala

450 455 460

Pro Leu Leu Pro Val Ile Glu Asp Asp Arg Tyr Val Val Lys Thr Ile

465 470 475 480

Pro Ser Cys Arg Met Ser Thr Leu Glu Ile Pro Ala Met Ala Phe His

485 490 495

Met Phe Leu Phe Gly Ser Lys Lys Thr Glu Lys Leu Ile Val Asp Val

500 505 510

His Asn Arg Tyr Lys Arg Leu Phe Gln Ala Met Gln Lys Glu Glu Val

515 520 525

Thr Ala Glu Asn Ile Ala Ser Phe Gly Ile Ala Glu Ser Asp Leu Pro

530 535 540

Gln Lys Ile Leu Asp Leu Ile Ser Gly Asn Ala His Gly Lys Asp Val

545 550 555 560

Asp Ala Phe Ile Arg Leu Thr Val Asp Asp Met Leu Thr Asp Thr Glu

565 570 575

Arg Arg Ile Lys Arg Phe Lys Asp Asp Arg Lys Ser Ile Arg Ser Ala

580 585 590

Asp Asn Lys Met Gly Lys Arg Gly Phe Lys Gln Ile Ser Thr Gly Lys

595 600 605

Leu Ala Asp Phe Leu Ala Lys Asp Ile Val Leu Phe Gln Pro Ser Val

610 615 620

Asn Asp Gly Glu Asn Lys Ile Thr Gly Leu Asn Tyr Arg Ile Met Gln

625 630 635 640

Ser Ala Ile Ala Val Tyr Asp Ser Gly Asp Asp Tyr Glu Ala Lys Gln

645 650 655

Gln Phe Lys Leu Met Phe Glu Lys Ala Arg Leu Ile Gly Lys Gly Thr

660 665 670

Thr Glu Pro His Pro Phe Leu Tyr Lys Val Phe Ala Arg Ser Ile Pro

675 680 685

Ala Asn Ala Val Glu Phe Tyr Glu Arg Tyr Leu Ile Glu Arg Lys Phe

690 695 700

Tyr Leu Thr Gly Leu Ser Asn Glu Ile Lys Lys Gly Asn Arg Val Asp

705 710 715 720

Val Pro Phe Ile Arg Arg Asp Gln Asn Lys Trp Lys Thr Pro Ala Met

725 730 735

Lys Thr Leu Gly Arg Ile Tyr Ser Glu Asp Leu Pro Val Glu Leu Pro

740 745 750

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

755 760 765

Gln Met Glu Gly Ile Asp Phe Asn Asn Ala Asn Val Thr Tyr Leu Ile

770 775 780

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

785 790 795 800

Gln Trp Asn Arg Asn Tyr Arg Tyr Met Asp Met Leu Lys Gly Glu Tyr

805 810 815

Asp Arg Lys Gly Ser Leu Gln His Cys Phe Thr Ser Val Glu Glu Arg

820 825 830

Glu Gly Leu Trp Lys Glu Arg Ala Ser Arg Thr Glu Arg Tyr Arg Lys

835 840 845

Gln Ala Ser Asn Lys Ile Arg Ser Asn Arg Gln Met Arg Asn Ala Ser

850 855 860

Ser Glu Glu Ile Glu Thr Ile Leu Asp Lys Arg Leu Ser Asn Ser Arg

865 870 875 880

Asn Glu Tyr Gln Lys Ser Glu Lys Val Ile Arg Arg Tyr Arg Val Gln

885 890 895

Asp Ala Leu Leu Phe Leu Leu Ala Lys Lys Thr Leu Thr Glu Leu Ala

900 905 910

Asp Phe Asp Gly Glu Arg Phe Lys Leu Lys Glu Ile Met Pro Asp Ala

915 920 925

Glu Lys Gly Ile Leu Ser Glu Ile Met Pro Met Ser Phe Thr Phe Glu

930 935 940

Lys Gly Gly Lys Lys Tyr Thr Ile Thr Ser Glu Gly Met Lys Leu Lys

945 950 955 960

Asn Tyr Gly Asp Phe Phe Val Leu Ala Ser Asp Lys Arg Ile Gly Asn

965 970 975

Leu Leu Glu Leu Val Gly Ser Asp Ile Val Ser Lys Glu Asp Ile Met

980 985 990

Glu Glu Phe Asn Lys Tyr Asp Gln Cys Arg Pro Glu Ile Ser Ser Ile

995 1000 1005

Val Phe Asn Leu Glu Lys Trp Ala Phe Asp Thr Tyr Pro Glu Leu Ser

1010 1015 1020

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

1025 1030 1035 1040

Ile Leu Leu Asn Asn Lys Asn Ile Asn Lys Glu Gln Ser Asp Ile Leu

1045 1050 1055

Arg Lys Ile Arg Asn Ala Phe Asp Ala Asn Asn Tyr Pro Asp Lys Gly

1060 1065 1070

Val Val Glu Ile Lys Ala Leu Pro Glu Ile Ala Met Ser Ile Lys Lys

1075 1080 1085

Ala Phe Gly Glu Tyr Ala Ile Met Lys Glu Gly Ala Leu Glu Ala Leu

1090 1095 1100

Pro Val Ala Thr Met Val Ser Lys Gly Glu Glu Leu Phe Thr Gly Val

1105 1110 1115 1120

Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe

1125 1130 1135

Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr

1140 1145 1150

Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr

1155 1160 1165

Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro

1170 1175 1180

Asp His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly

1185 1190 1195 1200

Tyr Val Gln Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly Asn Tyr Lys

1205 1210 1215

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

1220 1225 1230

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

1235 1240 1245

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

1250 1255 1260

Lys Gln Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg His Asn Ile

1265 1270 1275 1280

Glu Asp Gly Ser Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro

1285 1290 1295

Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr

1300 1305 1310

Gln Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met Val

1315 1320 1325

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

1330 1335 1340

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

1345 1350 1355 1360

Thr Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly

1365 1370 1375

His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly

1380 1385 1390

Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro

1395 1400 1405

Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser

1410 1415 1420

Arg Tyr Pro Asp His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met

1425 1430 1435 1440

Pro Glu Gly Tyr Val Gln Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly

1445 1450 1455

Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val

1460 1465 1470

Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile

1475 1480 1485

Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile

1490 1495 1500

Met Ala Asp Lys Gln Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg

1505 1510 1515 1520

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

1525 1530 1535

Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr

1540 1545 1550

Leu Ser Thr Gln Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp

1555 1560 1565

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

1570 1575 1580

Met Asp Glu Leu Tyr Lys Lys Leu Val Ser Lys Gly Glu Glu Leu Phe

1585 1590 1595 1600

Thr Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly

1605 1610 1615

His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly

1620 1625 1630

Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro

1635 1640 1645

Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser

1650 1655 1660

Arg Tyr Pro Asp His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met

1665 1670 1675 1680

Pro Glu Gly Tyr Val Gln Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly

1685 1690 1695

Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val

1700 1705 1710

Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile

1715 1720 1725

Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile

1730 1735 1740

Met Ala Asp Lys Gln Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg

1745 1750 1755 1760

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

1765 1770 1775

Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr

1780 1785 1790

Leu Ser Thr Gln Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp

1795 1800 1805

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

1810 1815 1820

Met Asp Glu Leu Tyr Lys Ser Asn Ser Lys Pro Gly Phe His Met Lys

1825 1830 1835 1840

Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Gln

1845 1850 1855

Arg Val Gln Leu Ser Asp Tyr Lys Asp His Asp Gly Asp Tyr Lys Asp

1860 1865 1870

His Asp Ile Asp Tyr Lys Asp Asp Asp Asp Lys

1875 1880

<210> 14

<211> 1838

<212> PRT

<213> Artificial Sequence

<400> 14

Met Pro Lys Lys Lys Arg Lys Val Asn Ile Pro Ala Leu Val Glu Asn

1 5 10 15

Gln Lys Lys Tyr Phe Gly Thr Tyr Ser Val Met Ala Met Leu Asn Ala

20 25 30

Gln Thr Val Leu Asp His Ile Gln Lys Val Ala Asp Ile Glu Gly Glu

35 40 45

Gln Asn Glu Asn Asn Glu Asn Leu Trp Phe His Pro Val Met Ser His

50 55 60

Leu Tyr Asn Ala Lys Asn Gly Tyr Asp Lys Gln Pro Glu Lys Thr Met

65 70 75 80

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

85 90 95

Ala Glu Asn Gln Arg Glu Tyr Ser Asn Gly Lys Tyr Lys Gln Asn Arg

100 105 110

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

115 120 125

Gly Val Leu Lys Met Tyr Arg Asp Leu Thr Asn Ala Tyr Lys Thr Tyr

130 135 140

Glu Glu Lys Leu Asn Asp Gly Cys Glu Phe Leu Thr Ser Thr Glu Gln

145 150 155 160

Pro Leu Ser Gly Met Ile Asn Asn Tyr Tyr Thr Val Ala Leu Arg Asn

165 170 175

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

180 185 190

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

195 200 205

Gln Val Asn Thr Gly Phe Phe Leu Ser Leu Gln Asp Tyr Asn Gly Asp

210 215 220

Thr Gln Lys Lys Leu His Leu Ser Gly Val Gly Ile Ala Leu Leu Ile

225 230 235 240

Cys Leu Phe Leu Asp Lys Gln Tyr Ile Asn Ile Phe Leu Ser Arg Leu

245 250 255

Pro Ile Phe Ser Ser Tyr Asn Ala Gln Ser Glu Glu Arg Arg Ile Ile

260 265 270

Ile Arg Ser Phe Gly Ile Asn Ser Ile Lys Leu Pro Lys Asp Arg Ile

275 280 285

His Ser Glu Lys Ser Asn Lys Ser Val Ala Met Asp Met Leu Asn Glu

290 295 300

Val Lys Arg Cys Pro Asp Glu Leu Phe Thr Thr Leu Ser Ala Glu Lys

305 310 315 320

Gln Ser Arg Phe Arg Ile Ile Ser Asp Asp His Asn Glu Val Leu Met

325 330 335

Lys Arg Ser Ser Asp Arg Phe Val Pro Leu Leu Leu Gln Tyr Ile Asp

340 345 350

Tyr Gly Lys Leu Phe Asp His Ile Arg Phe His Val Asn Met Gly Lys

355 360 365

Leu Arg Tyr Leu Leu Lys Ala Asp Lys Thr Cys Ile Asp Gly Gln Thr

370 375 380

Arg Val Arg Val Ile Glu Gln Pro Leu Asn Gly Phe Gly Arg Leu Glu

385 390 395 400

Glu Ala Glu Thr Met Arg Lys Gln Glu Asn Gly Thr Phe Gly Asn Ser

405 410 415

Gly Ile Arg Ile Arg Asp Phe Glu Asn Met Lys Arg Asp Asp Ala Asn

420 425 430

Pro Ala Asn Tyr Pro Tyr Ile Val Asp Thr Tyr Thr His Tyr Ile Leu

435 440 445

Glu Asn Asn Lys Val Glu Met Phe Ile Asn Asp Lys Glu Asp Ser Ala

450 455 460

Pro Leu Leu Pro Val Ile Glu Asp Asp Arg Tyr Val Val Lys Thr Ile

465 470 475 480

Pro Ser Cys Arg Met Ser Thr Leu Glu Ile Pro Ala Met Ala Phe His

485 490 495

Met Phe Leu Phe Gly Ser Lys Lys Thr Glu Lys Leu Ile Val Asp Val

500 505 510

His Asn Arg Tyr Lys Arg Leu Phe Gln Ala Met Gln Lys Glu Glu Val

515 520 525

Thr Ala Glu Asn Ile Ala Ser Phe Gly Ile Ala Glu Ser Asp Leu Pro

530 535 540

Gln Lys Ile Leu Asp Leu Ile Ser Gly Asn Ala His Gly Lys Asp Val

545 550 555 560

Asp Ala Phe Ile Arg Leu Thr Val Asp Asp Met Leu Thr Asp Thr Glu

565 570 575

Arg Arg Ile Lys Arg Phe Lys Asp Asp Arg Lys Ser Ile Arg Ser Ala

580 585 590

Asp Asn Lys Met Gly Lys Arg Gly Phe Lys Gln Ile Ser Thr Gly Lys

595 600 605

Leu Ala Asp Phe Leu Ala Lys Asp Ile Val Leu Phe Gln Pro Ser Val

610 615 620

Asn Asp Gly Glu Asn Lys Ile Thr Gly Leu Asn Tyr Arg Ile Met Gln

625 630 635 640

Ser Ala Ile Ala Val Tyr Asp Ser Gly Asp Asp Tyr Glu Ala Lys Gln

645 650 655

Gln Phe Lys Leu Met Phe Glu Lys Ala Arg Leu Ile Gly Lys Gly Thr

660 665 670

Thr Glu Pro His Pro Phe Leu Tyr Lys Val Phe Ala Arg Ser Ile Pro

675 680 685

Ala Asn Ala Val Glu Phe Tyr Glu Arg Tyr Leu Ile Glu Arg Lys Phe

690 695 700

Tyr Leu Thr Gly Leu Ser Asn Glu Ile Lys Lys Gly Asn Arg Val Asp

705 710 715 720

Val Pro Phe Ile Arg Arg Asp Gln Asn Lys Trp Lys Thr Pro Ala Met

725 730 735

Lys Thr Leu Gly Arg Ile Tyr Ser Glu Asp Leu Pro Val Glu Leu Pro

740 745 750

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

755 760 765

Gln Met Glu Gly Ile Asp Phe Asn Asn Ala Asn Val Thr Tyr Leu Ile

770 775 780

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

785 790 795 800

Gln Trp Asn Arg Asn Tyr Arg Tyr Met Asp Met Leu Lys Gly Glu Tyr

805 810 815

Asp Arg Lys Gly Ser Leu Gln His Cys Phe Thr Ser Val Glu Glu Arg

820 825 830

Glu Gly Leu Trp Lys Glu Arg Ala Ser Arg Thr Glu Arg Tyr Arg Lys

835 840 845

Gln Ala Ser Asn Lys Ile Arg Ser Asn Arg Gln Met Arg Asn Ala Ser

850 855 860

Ser Glu Glu Ile Glu Thr Ile Leu Asp Lys Arg Leu Ser Asn Ser Arg

865 870 875 880

Asn Glu Tyr Gln Lys Ser Glu Lys Val Ile Arg Arg Tyr Arg Val Gln

885 890 895

Asp Ala Leu Leu Phe Leu Leu Ala Lys Lys Thr Leu Thr Glu Leu Ala

900 905 910

Asp Phe Asp Gly Glu Arg Phe Lys Leu Lys Glu Ile Met Pro Asp Ala

915 920 925

Glu Lys Gly Ile Leu Ser Glu Ile Met Pro Met Ser Phe Thr Phe Glu

930 935 940

Lys Gly Gly Lys Lys Tyr Thr Ile Thr Ser Glu Gly Met Lys Leu Lys

945 950 955 960

Asn Tyr Gly Asp Phe Phe Val Leu Ala Ser Asp Lys Arg Ile Gly Asn

965 970 975

Leu Leu Glu Leu Val Gly Ser Asp Ile Val Ser Lys Glu Asp Ile Met

980 985 990

Glu Glu Phe Asn Lys Tyr Asp Gln Cys Arg Pro Glu Ile Ser Ser Ile

995 1000 1005

Val Phe Asn Leu Glu Lys Trp Ala Phe Asp Thr Tyr Pro Glu Leu Ser

1010 1015 1020

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

1025 1030 1035 1040

Ile Leu Leu Asn Asn Lys Asn Ile Asn Lys Glu Gln Ser Asp Ile Leu

1045 1050 1055

Arg Lys Ile Arg Asn Ala Phe Asp Ala Asn Asn Tyr Pro Asp Lys Gly

1060 1065 1070

Val Val Glu Ile Lys Ala Leu Pro Glu Ile Ala Met Ser Ile Lys Lys

1075 1080 1085

Ala Phe Gly Glu Tyr Ala Ile Met Lys Gly Gly Gly Ser Gly Ser Met

1090 1095 1100

Arg Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu Val Glu

1105 1110 1115 1120

Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Arg Gly Glu Gly

1125 1130 1135

Glu Gly Asp Ala Thr Asn Gly Lys Leu Thr Leu Lys Phe Ile Cys Thr

1140 1145 1150

Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr Leu Thr

1155 1160 1165

Tyr Gly Val Gln Cys Phe Ala Arg Tyr Pro Asp His Met Lys Gln His

1170 1175 1180

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

1185 1190 1195 1200

Ile Ser Phe Lys Asp Asp Gly Thr Tyr Lys Thr Arg Ala Glu Val Lys

1205 1210 1215

Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly Ile Asp

1220 1225 1230

Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr Asn Phe

1235 1240 1245

Asn Ser His Asn Val Tyr Ile Thr Ala Asp Lys Gln Lys Asn Gly Ile

1250 1255 1260

Lys Ala Asn Phe Lys Ile Arg His Asn Val Glu Asp Gly Ser Val Gln

1265 1270 1275 1280

Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile Gly Asp Gly Pro Val

1285 1290 1295

Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln Ser Val Leu Ser Lys

1300 1305 1310

Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu Glu Phe Val Thr

1315 1320 1325

Ala Ala Gly Ile Thr His Gly Met Asp Glu Leu Tyr Lys Ser Gly Gly

1330 1335 1340

Arg Ser Gly Met Arg Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro

1345 1350 1355 1360

Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val

1365 1370 1375

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

1380 1385 1390

Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val

1395 1400 1405

Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ala Arg Tyr Pro Asp His

1410 1415 1420

Met Lys Gln His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val

1425 1430 1435 1440

Gln Glu Arg Thr Ile Ser Phe Lys Asp Asp Gly Thr Tyr Lys Thr Arg

1445 1450 1455

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

1460 1465 1470

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

1475 1480 1485

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

1490 1495 1500

Lys Asn Gly Ile Lys Ala Asn Phe Lys Ile Arg His Asn Val Glu Asp

1505 1510 1515 1520

Gly Ser Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile Gly

1525 1530 1535

Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln Ser

1540 1545 1550

Val Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu

1555 1560 1565

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

1570 1575 1580

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

1585 1590 1595 1600

Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly His

1605 1610 1615

Lys Phe Ser Val Arg Gly Glu Gly Glu Gly Asp Ala Thr Asn Gly Lys

1620 1625 1630

Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp

1635 1640 1645

Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ala Arg

1650 1655 1660

Tyr Pro Asp His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met Pro

1665 1670 1675 1680

Glu Gly Tyr Val Gln Glu Arg Thr Ile Ser Phe Lys Asp Asp Gly Thr

1685 1690 1695

Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val Asn

1700 1705 1710

Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile Leu

1715 1720 1725

Gly His Lys Leu Glu Tyr Asn Phe Asn Ser His Asn Val Tyr Ile Thr

1730 1735 1740

Ala Asp Lys Gln Lys Asn Gly Ile Lys Ala Asn Phe Lys Ile Arg His

1745 1750 1755 1760

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

1765 1770 1775

Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu

1780 1785 1790

Ser Thr Gln Ser Val Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His

1795 1800 1805

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

1810 1815 1820

Asp Glu Leu Tyr Lys Leu Glu Pro Lys Lys Lys Arg Lys Val

1825 1830 1835

<210> 15

<211> 1625

<212> PRT

<213> Artificial Sequence

<400> 15

Met Pro Lys Lys Lys Arg Lys Val Asn Ile Pro Ala Leu Val Glu Asn

1 5 10 15

Gln Lys Lys Tyr Phe Gly Thr Tyr Ser Val Met Ala Met Leu Asn Ala

20 25 30

Gln Thr Val Leu Asp His Ile Gln Lys Val Ala Asp Ile Glu Gly Glu

35 40 45

Gln Asn Glu Asn Asn Glu Asn Leu Trp Phe His Pro Val Met Ser His

50 55 60

Leu Tyr Asn Ala Lys Asn Gly Tyr Asp Lys Gln Pro Glu Lys Thr Met

65 70 75 80

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

85 90 95

Ala Glu Asn Gln Arg Glu Tyr Ser Asn Gly Lys Tyr Lys Gln Asn Arg

100 105 110

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

115 120 125

Gly Val Leu Lys Met Tyr Arg Asp Leu Thr Asn Ala Tyr Lys Thr Tyr

130 135 140

Glu Glu Lys Leu Asn Asp Gly Cys Glu Phe Leu Thr Ser Thr Glu Gln

145 150 155 160

Pro Leu Ser Gly Met Ile Asn Asn Tyr Tyr Thr Val Ala Leu Arg Asn

165 170 175

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

180 185 190

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

195 200 205

Gln Val Asn Thr Gly Phe Phe Leu Ser Leu Gln Asp Tyr Asn Gly Asp

210 215 220

Thr Gln Lys Lys Leu His Leu Ser Gly Val Gly Ile Ala Leu Leu Ile

225 230 235 240

Cys Leu Phe Leu Asp Lys Gln Tyr Ile Asn Ile Phe Leu Ser Arg Leu

245 250 255

Pro Ile Phe Ser Ser Tyr Asn Ala Gln Ser Glu Glu Arg Arg Ile Ile

260 265 270

Ile Arg Ser Phe Gly Ile Asn Ser Ile Lys Leu Pro Lys Asp Arg Ile

275 280 285

His Ser Glu Lys Ser Asn Lys Ser Val Ala Met Asp Met Leu Asn Glu

290 295 300

Val Lys Arg Cys Pro Asp Glu Leu Phe Thr Thr Leu Ser Ala Glu Lys

305 310 315 320

Gln Ser Arg Phe Arg Ile Ile Ser Asp Asp His Asn Glu Val Leu Met

325 330 335

Lys Arg Ser Ser Asp Arg Phe Val Pro Leu Leu Leu Gln Tyr Ile Asp

340 345 350

Tyr Gly Lys Leu Phe Asp His Ile Arg Phe His Val Asn Met Gly Lys

355 360 365

Leu Arg Tyr Leu Leu Lys Ala Asp Lys Thr Cys Ile Asp Gly Gln Thr

370 375 380

Arg Val Arg Val Ile Glu Gln Pro Leu Asn Gly Phe Gly Arg Leu Glu

385 390 395 400

Glu Ala Glu Thr Met Arg Lys Gln Glu Asn Gly Thr Phe Gly Asn Ser

405 410 415

Gly Ile Arg Ile Arg Asp Phe Glu Asn Met Lys Arg Asp Asp Ala Asn

420 425 430

Pro Ala Asn Tyr Pro Tyr Ile Val Asp Thr Tyr Thr His Tyr Ile Leu

435 440 445

Glu Asn Asn Lys Val Glu Met Phe Ile Asn Asp Lys Glu Asp Ser Ala

450 455 460

Pro Leu Leu Pro Val Ile Glu Asp Asp Arg Tyr Val Val Lys Thr Ile

465 470 475 480

Pro Ser Cys Arg Met Ser Thr Leu Glu Ile Pro Ala Met Ala Phe His

485 490 495

Met Phe Leu Phe Gly Ser Lys Lys Thr Glu Lys Leu Ile Val Asp Val

500 505 510

His Asn Arg Tyr Lys Arg Leu Phe Gln Ala Met Gln Lys Glu Glu Val

515 520 525

Thr Ala Glu Asn Ile Ala Ser Phe Gly Ile Ala Glu Ser Asp Leu Pro

530 535 540

Gln Lys Ile Leu Asp Leu Ile Ser Gly Asn Ala His Gly Lys Asp Val

545 550 555 560

Asp Ala Phe Ile Arg Leu Thr Val Asp Asp Met Leu Thr Asp Thr Glu

565 570 575

Arg Arg Ile Lys Arg Phe Lys Asp Asp Arg Lys Ser Ile Arg Ser Ala

580 585 590

Asp Asn Lys Met Gly Lys Arg Gly Phe Lys Gln Ile Ser Thr Gly Lys

595 600 605

Leu Ala Asp Phe Leu Ala Lys Asp Ile Val Leu Phe Gln Pro Ser Val

610 615 620

Asn Asp Gly Glu Asn Lys Ile Thr Gly Leu Asn Tyr Arg Ile Met Gln

625 630 635 640

Ser Ala Ile Ala Val Tyr Asp Ser Gly Asp Asp Tyr Glu Ala Lys Gln

645 650 655

Gln Phe Lys Leu Met Phe Glu Lys Ala Arg Leu Ile Gly Lys Gly Thr

660 665 670

Thr Glu Pro His Pro Phe Leu Tyr Lys Val Phe Ala Arg Ser Ile Pro

675 680 685

Ala Asn Ala Val Glu Phe Tyr Glu Arg Tyr Leu Ile Glu Arg Lys Phe

690 695 700

Tyr Leu Thr Gly Leu Ser Asn Glu Ile Lys Lys Gly Asn Arg Val Asp

705 710 715 720

Val Pro Phe Ile Arg Arg Asp Gln Asn Lys Trp Lys Thr Pro Ala Met

725 730 735

Lys Thr Leu Gly Arg Ile Tyr Ser Glu Asp Leu Pro Val Glu Leu Pro

740 745 750

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

755 760 765

Gln Met Glu Gly Ile Asp Phe Asn Asn Ala Asn Val Thr Tyr Leu Ile

770 775 780

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

785 790 795 800

Gln Trp Asn Arg Asn Tyr Arg Tyr Met Asp Met Leu Lys Gly Glu Tyr

805 810 815

Asp Arg Lys Gly Ser Leu Gln His Cys Phe Thr Ser Val Glu Glu Arg

820 825 830

Glu Gly Leu Trp Lys Glu Arg Ala Ser Arg Thr Glu Arg Tyr Arg Lys

835 840 845

Gln Ala Ser Asn Lys Ile Arg Ser Asn Arg Gln Met Arg Asn Ala Ser

850 855 860

Ser Glu Glu Ile Glu Thr Ile Leu Asp Lys Arg Leu Ser Asn Ser Arg

865 870 875 880

Asn Glu Tyr Gln Lys Ser Glu Lys Val Ile Arg Arg Tyr Arg Val Gln

885 890 895

Asp Ala Leu Leu Phe Leu Leu Ala Lys Lys Thr Leu Thr Glu Leu Ala

900 905 910

Asp Phe Asp Gly Glu Arg Phe Lys Leu Lys Glu Ile Met Pro Asp Ala

915 920 925

Glu Lys Gly Ile Leu Ser Glu Ile Met Pro Met Ser Phe Thr Phe Glu

930 935 940

Lys Gly Gly Lys Lys Tyr Thr Ile Thr Ser Glu Gly Met Lys Leu Lys

945 950 955 960

Asn Tyr Gly Asp Phe Phe Val Leu Ala Ser Asp Lys Arg Ile Gly Asn

965 970 975

Leu Leu Glu Leu Val Gly Ser Asp Ile Val Ser Lys Glu Asp Ile Met

980 985 990

Glu Glu Phe Asn Lys Tyr Asp Gln Cys Arg Pro Glu Ile Ser Ser Ile

995 1000 1005

Val Phe Asn Leu Glu Lys Trp Ala Phe Asp Thr Tyr Pro Glu Leu Ser

1010 1015 1020

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

1025 1030 1035 1040

Ile Leu Leu Asn Asn Lys Asn Ile Asn Lys Glu Gln Ser Asp Ile Leu

1045 1050 1055

Arg Lys Ile Arg Asn Ala Phe Asp Ala Asn Asn Tyr Pro Asp Lys Gly

1060 1065 1070

Val Val Glu Ile Lys Ala Leu Pro Glu Ile Ala Met Ser Ile Lys Lys

1075 1080 1085

Ala Phe Gly Glu Tyr Ala Ile Met Lys Glu Gly Ala Leu Glu Gly Thr

1090 1095 1100

Ser Gly Gly Gly Ser Met Val Ser Lys Gly Glu Glu Asp Asn Met Ala

1105 1110 1115 1120

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

1125 1130 1135

Val Asp Phe Asp Met Val Gly Gln Gly Thr Gly Asn Pro Asn Asp Gly

1140 1145 1150

Tyr Glu Glu Leu Asn Leu Lys Ser Thr Lys Gly Asp Leu Gln Phe Ser

1155 1160 1165

Pro Trp Ile Leu Val Pro His Ile Gly Tyr Gly Phe His Gln Tyr Leu

1170 1175 1180

Pro Tyr Pro Asp Gly Met Ser Pro Phe Gln Ala Ala Met Val Asp Gly

1185 1190 1195 1200

Ser Gly Tyr Gln Val His Arg Thr Met Gln Phe Glu Asp Gly Ala Ser

1205 1210 1215

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

1220 1225 1230

Glu Ala Gln Val Lys Gly Thr Gly Phe Pro Ala Asp Gly Pro Val Met

1235 1240 1245

Thr Asn Ser Leu Thr Ala Ala Asp Trp Cys Arg Ser Lys Lys Thr Tyr

1250 1255 1260

Pro Asn Asp Lys Thr Ile Ile Ser Thr Phe Lys Trp Ser Tyr Thr Thr

1265 1270 1275 1280

Gly Asn Gly Lys Arg Tyr Arg Ser Thr Ala Arg Thr Thr Tyr Thr Phe

1285 1290 1295

Ala Lys Pro Met Ala Ala Asn Tyr Leu Lys Asn Gln Pro Met Tyr Val

1300 1305 1310

Phe Arg Lys Thr Glu Leu Lys His Ser Lys Thr Glu Leu Asn Phe Lys

1315 1320 1325

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

1330 1335 1340

Lys Ser Asn Ser Ala Val Asp Gly Thr Met Val Ser Lys Gly Glu Glu

1345 1350 1355 1360

Asp Asn Met Ala Ser Leu Pro Ala Thr His Glu Leu His Ile Phe Gly

1365 1370 1375

Ser Ile Asn Gly Val Asp Phe Asp Met Val Gly Gln Gly Thr Gly Asn

1380 1385 1390

Pro Asn Asp Gly Tyr Glu Glu Leu Asn Leu Lys Ser Thr Lys Gly Asp

1395 1400 1405

Leu Gln Phe Ser Pro Trp Ile Leu Val Pro His Ile Gly Tyr Gly Phe

1410 1415 1420

His Gln Tyr Leu Pro Tyr Pro Asp Gly Met Ser Pro Phe Gln Ala Ala

1425 1430 1435 1440

Met Val Asp Gly Ser Gly Tyr Gln Val His Arg Thr Met Gln Phe Glu

1445 1450 1455

Asp Gly Ala Ser Leu Thr Val Asn Tyr Arg Tyr Thr Tyr Glu Gly Ser

1460 1465 1470

His Ile Lys Gly Glu Ala Gln Val Lys Gly Thr Gly Phe Pro Ala Asp

1475 1480 1485

Gly Pro Val Met Thr Asn Ser Leu Thr Ala Ala Asp Trp Cys Arg Ser

1490 1495 1500

Lys Lys Thr Tyr Pro Asn Asp Lys Thr Ile Ile Ser Thr Phe Lys Trp

1505 1510 1515 1520

Ser Tyr Thr Thr Gly Asn Gly Lys Arg Tyr Arg Ser Thr Ala Arg Thr

1525 1530 1535

Thr Tyr Thr Phe Ala Lys Pro Met Ala Ala Asn Tyr Leu Lys Asn Gln

1540 1545 1550

Pro Met Tyr Val Phe Arg Lys Thr Glu Leu Lys His Ser Lys Thr Glu

1555 1560 1565

Leu Asn Phe Lys Glu Trp Gln Lys Ala Phe Thr Asp Val Met Gly Met

1570 1575 1580

Asp Glu Leu Tyr Lys Ser Gly Leu Arg Ser Cys Leu Glu Gln Arg Val

1585 1590 1595 1600

Gln Leu Ser Asp Tyr Lys Asp His Asp Gly Asp Tyr Lys Asp His Asp

1605 1610 1615

Ile Asp Tyr Lys Asp Asp Asp Asp Lys

1620 1625

<210> 16

<211> 1934

<212> PRT

<213> Artificial Sequence

<400> 16

Met Pro Lys Lys Lys Arg Lys Val Thr Glu Gln Ser Glu Arg Pro Tyr

1 5 10 15

Asn Gly Thr Tyr Tyr Thr Leu Glu Asp Lys His Phe Trp Ala Ala Phe

20 25 30

Leu Asn Leu Ala Arg His Asn Ala Tyr Ile Thr Leu Thr His Ile Asp

35 40 45

Arg Gln Leu Ala Tyr Ser Lys Ala Asp Ile Thr Asn Asp Gln Asp Val

50 55 60

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

65 70 75 80

Lys Ser Arg Leu Arg Ser Leu Ile Leu Lys His Phe Ser Phe Leu Glu

85 90 95

Gly Ala Ala Tyr Gly Lys Lys Leu Phe Glu Ser Lys Ser Ser Gly Asn

100 105 110

Lys Ser Ser Lys Asn Lys Glu Leu Thr Lys Lys Glu Lys Glu Glu Leu

115 120 125

Gln Ala Asn Ala Leu Ser Leu Asp Asn Leu Lys Ser Ile Leu Phe Asp

130 135 140

Phe Leu Gln Lys Leu Lys Asp Phe Arg Asn Tyr Tyr Ser Ala Tyr Arg

145 150 155 160

His Ser Gly Ser Ser Glu Leu Pro Leu Phe Asp Gly Asn Met Leu Gln

165 170 175

Arg Leu Tyr Asn Val Phe Asp Val Ser Val Gln Arg Val Lys Ile Asp

180 185 190

His Glu His Asn Asp Glu Val Asp Pro His Tyr His Phe Asn His Leu

195 200 205

Val Arg Lys Gly Lys Lys Asp Arg Tyr Gly His Asn Asp Asn Pro Ser

210 215 220

Phe Lys His His Phe Val Asp Gly Glu Gly Met Val Thr Glu Ala Gly

225 230 235 240

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

245 250 255

Met Gln Lys Lys Ile Arg Gly Phe Lys Gly Gly Thr Glu Thr Tyr Gln

260 265 270

Gln Met Thr Asn Glu Val Phe Cys Arg Ser Arg Ile Ser Leu Pro Lys

275 280 285

Leu Lys Leu Glu Ser Leu Arg Met Asp Asp Trp Met Leu Leu Asp Met

290 295 300

Leu Asn Glu Leu Val Arg Cys Pro Lys Pro Leu Tyr Asp Arg Leu Arg

305 310 315 320

Glu Asp Asp Arg Ala Cys Phe Arg Val Pro Val Asp Ile Leu Pro Asp

325 330 335

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

340 345 350

Val Arg His Gln Asp Arg Phe Pro Tyr Phe Ala Leu Arg Tyr Phe Asp

355 360 365

Leu Lys Lys Val Phe Thr Ser Leu Arg Phe His Ile Asp Leu Gly Thr

370 375 380

Tyr His Phe Ala Ile Tyr Lys Lys Met Ile Gly Glu Gln Pro Glu Asp

385 390 395 400

Arg His Leu Thr Arg Asn Leu Tyr Gly Phe Gly Arg Ile Gln Asp Phe

405 410 415

Ala Glu Glu His Arg Pro Glu Glu Trp Lys Arg Leu Val Arg Asp Leu

420 425 430

Asp Tyr Phe Glu Thr Gly Asp Lys Pro Tyr Ile Ser Gln Thr Ser Pro

435 440 445

His Tyr His Ile Glu Lys Gly Lys Ile Gly Leu Arg Phe Met Pro Glu

450 455 460

Gly Gln His Leu Trp Pro Ser Pro Glu Val Gly Thr Thr Arg Thr Gly

465 470 475 480

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

485 490 495

Ser Val His Glu Leu Met Pro Met Met Phe Tyr Tyr Phe Leu Leu Arg

500 505 510

Glu Lys Tyr Ser Glu Glu Val Ser Ala Glu Arg Val Gln Gly Arg Ile

515 520 525

Lys Arg Val Ile Glu Asp Val Tyr Ala Val Tyr Asp Ala Phe Ala Arg

530 535 540

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

545 550 555 560

Gly Ile Arg Arg Gly His Leu Pro Arg Gln Met Ile Ala Ile Leu Ser

565 570 575

Gln Glu His Lys Asp Met Glu Glu Lys Ile Arg Lys Lys Leu Gln Glu

580 585 590

Met Met Ala Asp Thr Asp His Arg Leu Asp Met Leu Asp Arg Gln Thr

595 600 605

Asp Arg Lys Ile Arg Ile Gly Arg Lys Asn Ala Gly Leu Pro Lys Ser

610 615 620

Gly Val Ile Ala Asp Trp Leu Val Arg Asp Met Met Arg Phe Gln Pro

625 630 635 640

Val Ala Lys Asp Ala Ser Gly Lys Pro Leu Asn Asn Ser Lys Ala Asn

645 650 655

Ser Thr Glu Tyr Arg Met Leu Gln Arg Ala Leu Ala Leu Phe Gly Gly

660 665 670

Glu Lys Glu Arg Leu Thr Pro Tyr Phe Arg Gln Met Asn Leu Thr Gly

675 680 685

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

690 695 700

Thr Asn Ile Leu Ser Phe Tyr Arg Ser Tyr Leu Arg Ala Arg Lys Ala

705 710 715 720

Phe Leu Glu Arg Ile Gly Arg Ser Asp Arg Val Glu Asn Arg Pro Phe

725 730 735

Leu Leu Leu Lys Glu Pro Lys Thr Asp Arg Gln Thr Leu Val Ala Gly

740 745 750

Trp Lys Gly Glu Phe His Leu Pro Arg Gly Ile Phe Thr Glu Ala Val

755 760 765

Arg Asp Cys Leu Ile Glu Met Gly His Asp Glu Val Ala Ser Tyr Lys

770 775 780

Glu Val Gly Phe Met Ala Lys Ala Val Pro Leu Tyr Phe Glu Arg Ala

785 790 795 800

Cys Glu Asp Arg Val Gln Pro Phe Tyr Asp Ser Pro Phe Asn Val Gly

805 810 815

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

820 825 830

Ala Glu Glu Trp Glu Arg Gly Lys Glu Arg Phe Arg Asp Leu Glu Ala

835 840 845

Trp Ser Tyr Ser Ala Ala Arg Arg Ile Glu Asp Ala Phe Ala Gly Ile

850 855 860

Glu Tyr Ala Ser Pro Gly Asn Lys Lys Lys Ile Glu Gln Leu Leu Arg

865 870 875 880

Asp Leu Ser Leu Trp Glu Ala Phe Glu Ser Lys Leu Lys Val Arg Ala

885 890 895

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

900 905 910

Glu His Pro Tyr His Asp Phe Lys Ser Trp Gln Lys Phe Glu Arg Glu

915 920 925

Leu Arg Leu Val Lys Asn Gln Asp Ile Ile Thr Trp Met Met Cys Arg

930 935 940

Asp Leu Met Glu Glu Asn Lys Val Glu Gly Leu Asp Thr Gly Thr Leu

945 950 955 960

Tyr Leu Lys Asp Ile Arg Pro Asn Val Gln Glu Gln Gly Ser Leu Asn

965 970 975

Val Leu Asn Arg Val Lys Pro Met Arg Leu Pro Val Val Val Tyr Arg

980 985 990

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

995 1000 1005

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

1010 1015 1020

Lys Ser Phe Val Lys Asp Arg Arg Leu Asn Gly Leu Phe Ser Phe Val

1025 1030 1035 1040

Asp Thr Gly Gly Leu Ala Met Glu Gln Tyr Pro Ile Ser Lys Leu Arg

1045 1050 1055

Val Glu Tyr Glu Leu Ala Lys Tyr Gln Thr Ala Arg Val Cys Val Phe

1060 1065 1070

Glu Leu Thr Leu Arg Leu Glu Glu Ser Leu Leu Thr Arg Tyr Pro His

1075 1080 1085

Leu Pro Asp Glu Ser Phe Arg Glu Met Leu Glu Ser Trp Ser Asp Pro

1090 1095 1100

Leu Leu Ala Lys Trp Pro Glu Leu His Gly Lys Val Arg Leu Leu Ile

1105 1110 1115 1120

Ala Val Arg Asn Ala Phe Ser Ala Asn Gln Tyr Pro Met Tyr Asp Glu

1125 1130 1135

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

1140 1145 1150

Ile Glu Glu Arg Met Gly Leu Asn Ile Ala His Arg Leu Ser Glu Glu

1155 1160 1165

Val Lys Gln Ala Lys Glu Thr Val Glu Arg Ile Ile Gln Ala Ser Leu

1170 1175 1180

Glu Ala Leu Pro Val Ala Thr Met Val Ser Lys Gly Glu Glu Leu Ile

1185 1190 1195 1200

Lys Glu Asn Met Arg Met Lys Val Val Met Glu Gly Ser Val Asn Gly

1205 1210 1215

His Gln Phe Lys Cys Thr Gly Glu Gly Glu Gly Arg Pro Tyr Glu Gly

1220 1225 1230

Val Gln Thr Met Arg Ile Lys Val Ile Glu Gly Gly Pro Leu Pro Phe

1235 1240 1245

Ala Phe Asp Ile Leu Ala Thr Ser Phe Met Tyr Gly Ser Arg Thr Phe

1250 1255 1260

Ile Lys Tyr Pro Ala Asp Ile Pro Asp Phe Phe Lys Gln Ser Phe Pro

1265 1270 1275 1280

Glu Gly Phe Thr Trp Glu Arg Val Thr Arg Tyr Glu Asp Gly Gly Val

1285 1290 1295

Val Thr Val Thr Gln Asp Thr Ser Leu Glu Asp Gly Glu Leu Val Tyr

1300 1305 1310

Asn Val Lys Val Arg Gly Val Asn Phe Pro Ser Asn Gly Pro Val Met

1315 1320 1325

Gln Lys Lys Thr Lys Gly Trp Glu Pro Asn Thr Glu Met Met Tyr Pro

1330 1335 1340

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

1345 1350 1355 1360

Gly Gly Gly His Leu His Cys Asn Phe Val Thr Thr Tyr Arg Ser Lys

1365 1370 1375

Lys Thr Val Gly Asn Ile Lys Met Pro Gly Val His Ala Val Asp His

1380 1385 1390

Arg Leu Glu Arg Ile Glu Glu Ser Asp Asn Glu Thr Tyr Val Val Gln

1395 1400 1405

Arg Glu Val Ala Val Ala Lys Tyr Ser Asn Leu Gly Gly Gly Met Asp

1410 1415 1420

Glu Leu Tyr Lys Ser Gly Leu Arg Ser Val Ser Lys Gly Glu Glu Leu

1425 1430 1435 1440

Ile Lys Glu Asn Met Arg Met Lys Val Val Met Glu Gly Ser Val Asn

1445 1450 1455

Gly His Gln Phe Lys Cys Thr Gly Glu Gly Glu Gly Arg Pro Tyr Glu

1460 1465 1470

Gly Val Gln Thr Met Arg Ile Lys Val Ile Glu Gly Gly Pro Leu Pro

1475 1480 1485

Phe Ala Phe Asp Ile Leu Ala Thr Ser Phe Met Tyr Gly Ser Arg Thr

1490 1495 1500

Phe Ile Lys Tyr Pro Ala Asp Ile Pro Asp Phe Phe Lys Gln Ser Phe

1505 1510 1515 1520

Pro Glu Gly Phe Thr Trp Glu Arg Val Thr Arg Tyr Glu Asp Gly Gly

1525 1530 1535

Val Val Thr Val Thr Gln Asp Thr Ser Leu Glu Asp Gly Glu Leu Val

1540 1545 1550

Tyr Asn Val Lys Val Arg Gly Val Asn Phe Pro Ser Asn Gly Pro Val

1555 1560 1565

Met Gln Lys Lys Thr Lys Gly Trp Glu Pro Asn Thr Glu Met Met Tyr

1570 1575 1580

Pro Ala Asp Gly Gly Leu Arg Gly Tyr Thr Asp Ile Ala Leu Lys Val

1585 1590 1595 1600

Asp Gly Gly Gly His Leu His Cys Asn Phe Val Thr Thr Tyr Arg Ser

1605 1610 1615

Lys Lys Thr Val Gly Asn Ile Lys Met Pro Gly Val His Ala Val Asp

1620 1625 1630

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

1635 1640 1645

Gln Arg Glu Val Ala Val Ala Lys Tyr Ser Asn Leu Gly Gly Gly Met

1650 1655 1660

Asp Glu Leu Tyr Lys Lys Leu Val Ser Lys Gly Glu Glu Leu Ile Lys

1665 1670 1675 1680

Glu Asn Met Arg Met Lys Val Val Met Glu Gly Ser Val Asn Gly His

1685 1690 1695

Gln Phe Lys Cys Thr Gly Glu Gly Glu Gly Arg Pro Tyr Glu Gly Val

1700 1705 1710

Gln Thr Met Arg Ile Lys Val Ile Glu Gly Gly Pro Leu Pro Phe Ala

1715 1720 1725

Phe Asp Ile Leu Ala Thr Ser Phe Met Tyr Gly Ser Arg Thr Phe Ile

1730 1735 1740

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

1745 1750 1755 1760

Gly Phe Thr Trp Glu Arg Val Thr Arg Tyr Glu Asp Gly Gly Val Val

1765 1770 1775

Thr Val Thr Gln Asp Thr Ser Leu Glu Asp Gly Glu Leu Val Tyr Asn

1780 1785 1790

Val Lys Val Arg Gly Val Asn Phe Pro Ser Asn Gly Pro Val Met Gln

1795 1800 1805

Lys Lys Thr Lys Gly Trp Glu Pro Asn Thr Glu Met Met Tyr Pro Ala

1810 1815 1820

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

1825 1830 1835 1840

Gly Gly His Leu His Cys Asn Phe Val Thr Thr Tyr Arg Ser Lys Lys

1845 1850 1855

Thr Val Gly Asn Ile Lys Met Pro Gly Val His Ala Val Asp His Arg

1860 1865 1870

Leu Glu Arg Ile Glu Glu Ser Asp Asn Glu Thr Tyr Val Val Gln Arg

1875 1880 1885

Glu Val Ala Val Ala Lys Tyr Ser Asn Leu Gly Gly Gly Met Asp Glu

1890 1895 1900

Leu Tyr Lys Ser Gly Leu Arg Ser Arg Arg Tyr Arg His Met Lys Arg

1905 1910 1915 1920

Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys

1925 1930

<210> 17

<211> 1386

<212> PRT

<213> Artificial Sequence

<400> 17

Met Pro Lys Lys Lys Arg Lys Val Asn Ile Pro Ala Leu Val Glu Asn

1 5 10 15

Gln Lys Lys Tyr Phe Gly Thr Tyr Ser Val Met Ala Met Leu Asn Ala

20 25 30

Gln Thr Val Leu Asp His Ile Gln Lys Val Ala Asp Ile Glu Gly Glu

35 40 45

Gln Asn Glu Asn Asn Glu Asn Leu Trp Phe His Pro Val Met Ser His

50 55 60

Leu Tyr Asn Ala Lys Asn Gly Tyr Asp Lys Gln Pro Glu Lys Thr Met

65 70 75 80

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

85 90 95

Ala Glu Asn Gln Arg Glu Tyr Ser Asn Gly Lys Tyr Lys Gln Asn Arg

100 105 110

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

115 120 125

Gly Val Leu Lys Met Tyr Arg Asp Leu Thr Asn Ala Tyr Lys Thr Tyr

130 135 140

Glu Glu Lys Leu Asn Asp Gly Cys Glu Phe Leu Thr Ser Thr Glu Gln

145 150 155 160

Pro Leu Ser Gly Met Ile Asn Asn Tyr Tyr Thr Val Ala Leu Arg Asn

165 170 175

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

180 185 190

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

195 200 205

Gln Val Asn Thr Gly Phe Phe Leu Ser Leu Gln Asp Tyr Asn Gly Asp

210 215 220

Thr Gln Lys Lys Leu His Leu Ser Gly Val Gly Ile Ala Leu Leu Ile

225 230 235 240

Cys Leu Phe Leu Asp Lys Gln Tyr Ile Asn Ile Phe Leu Ser Arg Leu

245 250 255

Pro Ile Phe Ser Ser Tyr Asn Ala Gln Ser Glu Glu Arg Arg Ile Ile

260 265 270

Ile Arg Ser Phe Gly Ile Asn Ser Ile Lys Leu Pro Lys Asp Arg Ile

275 280 285

His Ser Glu Lys Ser Asn Lys Ser Val Ala Met Asp Met Leu Asn Glu

290 295 300

Val Lys Arg Cys Pro Asp Glu Leu Phe Thr Thr Leu Ser Ala Glu Lys

305 310 315 320

Gln Ser Arg Phe Arg Ile Ile Ser Asp Asp His Asn Glu Val Leu Met

325 330 335

Lys Arg Ser Ser Asp Arg Phe Val Pro Leu Leu Leu Gln Tyr Ile Asp

340 345 350

Tyr Gly Lys Leu Phe Asp His Ile Arg Phe His Val Asn Met Gly Lys

355 360 365

Leu Arg Tyr Leu Leu Lys Ala Asp Lys Thr Cys Ile Asp Gly Gln Thr

370 375 380

Arg Val Arg Val Ile Glu Gln Pro Leu Asn Gly Phe Gly Arg Leu Glu

385 390 395 400

Glu Ala Glu Thr Met Arg Lys Gln Glu Asn Gly Thr Phe Gly Asn Ser

405 410 415

Gly Ile Arg Ile Arg Asp Phe Glu Asn Met Lys Arg Asp Asp Ala Asn

420 425 430

Pro Ala Asn Tyr Pro Tyr Ile Val Asp Thr Tyr Thr His Tyr Ile Leu

435 440 445

Glu Asn Asn Lys Val Glu Met Phe Ile Asn Asp Lys Glu Asp Ser Ala

450 455 460

Pro Leu Leu Pro Val Ile Glu Asp Asp Arg Tyr Val Val Lys Thr Ile

465 470 475 480

Pro Ser Cys Arg Met Ser Thr Leu Glu Ile Pro Ala Met Ala Phe His

485 490 495

Met Phe Leu Phe Gly Ser Lys Lys Thr Glu Lys Leu Ile Val Asp Val

500 505 510

His Asn Arg Tyr Lys Arg Leu Phe Gln Ala Met Gln Lys Glu Glu Val

515 520 525

Thr Ala Glu Asn Ile Ala Ser Phe Gly Ile Ala Glu Ser Asp Leu Pro

530 535 540

Gln Lys Ile Leu Asp Leu Ile Ser Gly Asn Ala His Gly Lys Asp Val

545 550 555 560

Asp Ala Phe Ile Arg Leu Thr Val Asp Asp Met Leu Thr Asp Thr Glu

565 570 575

Arg Arg Ile Lys Arg Phe Lys Asp Asp Arg Lys Ser Ile Arg Ser Ala

580 585 590

Asp Asn Lys Met Gly Lys Arg Gly Phe Lys Gln Ile Ser Thr Gly Lys

595 600 605

Leu Ala Asp Phe Leu Ala Lys Asp Ile Val Leu Phe Gln Pro Ser Val

610 615 620

Asn Asp Gly Glu Asn Lys Ile Thr Gly Leu Asn Tyr Arg Ile Met Gln

625 630 635 640

Ser Ala Ile Ala Val Tyr Asp Ser Gly Asp Asp Tyr Glu Ala Lys Gln

645 650 655

Gln Phe Lys Leu Met Phe Glu Lys Ala Arg Leu Ile Gly Lys Gly Thr

660 665 670

Thr Glu Pro His Pro Phe Leu Tyr Lys Val Phe Ala Arg Ser Ile Pro

675 680 685

Ala Asn Ala Val Glu Phe Tyr Glu Arg Tyr Leu Ile Glu Arg Lys Phe

690 695 700

Tyr Leu Thr Gly Leu Ser Asn Glu Ile Lys Lys Gly Asn Arg Val Asp

705 710 715 720

Val Pro Phe Ile Arg Arg Asp Gln Asn Lys Trp Lys Thr Pro Ala Met

725 730 735

Lys Thr Leu Gly Arg Ile Tyr Ser Glu Asp Leu Pro Val Glu Leu Pro

740 745 750

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

755 760 765

Gln Met Glu Gly Ile Asp Phe Asn Asn Ala Asn Val Thr Tyr Leu Ile

770 775 780

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

785 790 795 800

Gln Trp Asn Arg Asn Tyr Arg Tyr Met Asp Met Leu Lys Gly Glu Tyr

805 810 815

Asp Arg Lys Gly Ser Leu Gln His Cys Phe Thr Ser Val Glu Glu Arg

820 825 830

Glu Gly Leu Trp Lys Glu Arg Ala Ser Arg Thr Glu Arg Tyr Arg Lys

835 840 845

Gln Ala Ser Asn Lys Ile Arg Ser Asn Arg Gln Met Arg Asn Ala Ser

850 855 860

Ser Glu Glu Ile Glu Thr Ile Leu Asp Lys Arg Leu Ser Asn Ser Arg

865 870 875 880

Asn Glu Tyr Gln Lys Ser Glu Lys Val Ile Arg Arg Tyr Arg Val Gln

885 890 895

Asp Ala Leu Leu Phe Leu Leu Ala Lys Lys Thr Leu Thr Glu Leu Ala

900 905 910

Asp Phe Asp Gly Glu Arg Phe Lys Leu Lys Glu Ile Met Pro Asp Ala

915 920 925

Glu Lys Gly Ile Leu Ser Glu Ile Met Pro Met Ser Phe Thr Phe Glu

930 935 940

Lys Gly Gly Lys Lys Tyr Thr Ile Thr Ser Glu Gly Met Lys Leu Lys

945 950 955 960

Asn Tyr Gly Asp Phe Phe Val Leu Ala Ser Asp Lys Arg Ile Gly Asn

965 970 975

Leu Leu Glu Leu Val Gly Ser Asp Ile Val Ser Lys Glu Asp Ile Met

980 985 990

Glu Glu Phe Asn Lys Tyr Asp Gln Cys Arg Pro Glu Ile Ser Ser Ile

995 1000 1005

Val Phe Asn Leu Glu Lys Trp Ala Phe Asp Thr Tyr Pro Glu Leu Ser

1010 1015 1020

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

1025 1030 1035 1040

Ile Leu Leu Asn Asn Lys Asn Ile Asn Lys Glu Gln Ser Asp Ile Leu

1045 1050 1055

Arg Lys Ile Arg Asn Ala Phe Asp Ala Asn Asn Tyr Pro Asp Lys Gly

1060 1065 1070

Val Val Glu Ile Lys Ala Leu Pro Glu Ile Ala Met Ser Ile Lys Lys

1075 1080 1085

Ala Phe Gly Glu Tyr Ala Ile Met Lys Glu Gly Ala Leu Glu Gly Ser

1090 1095 1100

Val Ser Lys Gly Glu Ala Val Ile Lys Glu Phe Met Arg Phe Lys Val

1105 1110 1115 1120

His Met Glu Gly Ser Met Asn Gly His Glu Phe Glu Ile Glu Gly Glu

1125 1130 1135

Gly Glu Gly Arg Pro Tyr Glu Gly Thr Gln Thr Ala Lys Leu Lys Val

1140 1145 1150

Thr Lys Gly Gly Pro Leu Pro Phe Ser Trp Asp Ile Leu Ser Pro Gln

1155 1160 1165

Phe Met Tyr Gly Ser Arg Ala Phe Thr Lys His Pro Ala Asp Ile Pro

1170 1175 1180

Asp Tyr Tyr Lys Gln Ser Phe Pro Glu Gly Phe Lys Trp Glu Arg Val

1185 1190 1195 1200

Met Asn Phe Glu Asp Gly Gly Ala Val Thr Val Thr Gln Asp Thr Ser

1205 1210 1215

Leu Glu Asp Gly Thr Leu Ile Tyr Lys Val Lys Leu Arg Gly Thr Asn

1220 1225 1230

Phe Pro Pro Asp Gly Pro Val Met Gln Lys Lys Thr Met Gly Trp Glu

1235 1240 1245

Ala Ser Thr Glu Arg Leu Tyr Pro Glu Asp Gly Val Leu Lys Gly Asp

1250 1255 1260

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

1265 1270 1275 1280

Phe Lys Thr Thr Tyr Lys Ala Lys Lys Pro Val Gln Met Pro Gly Ala

1285 1290 1295

Tyr Asn Val Asp Arg Lys Leu Asp Ile Thr Ser His Asn Glu Asp Tyr

1300 1305 1310

Thr Val Val Glu Gln Tyr Glu Arg Ser Glu Gly Arg His Ser Thr Gly

1315 1320 1325

Gly Met Asp Glu Leu Tyr Lys Ser Gly Leu Arg Ser His Met Lys Arg

1330 1335 1340

Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys Gln Arg

1345 1350 1355 1360

Val Gln Leu Ser Asp Tyr Lys Asp His Asp Gly Asp Tyr Lys Asp His

1365 1370 1375

Asp Ile Asp Tyr Lys Asp Asp Asp Asp Lys

1380 1385

<210> 18

<211> 1637

<212> PRT

<213> Artificial Sequence

<400> 18

Met Ala Pro Lys Lys Lys Arg Lys Val Gly Ile His Gly Val Pro Ala

1 5 10 15

Ala Asp Lys Lys Tyr Ser Ile Gly Leu Ala Ile Gly Thr Asn Ser Val

20 25 30

Gly Trp Ala Val Ile Thr Asp Glu Tyr Lys Val Pro Ser Lys Lys Phe

35 40 45

Lys Val Leu Gly Asn Thr Asp Arg His Ser Ile Lys Lys Asn Leu Ile

50 55 60

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

65 70 75 80

Lys Arg Thr Ala Arg Arg Arg Tyr Thr Arg Arg Lys Asn Arg Ile Cys

85 90 95

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

100 105 110

Phe Phe His Arg Leu Glu Glu Ser Phe Leu Val Glu Glu Asp Lys Lys

115 120 125

His Glu Arg His Pro Ile Phe Gly Asn Ile Val Asp Glu Val Ala Tyr

130 135 140

His Glu Lys Tyr Pro Thr Ile Tyr His Leu Arg Lys Lys Leu Val Asp

145 150 155 160

Ser Thr Asp Lys Ala Asp Leu Arg Leu Ile Tyr Leu Ala Leu Ala His

165 170 175

Met Ile Lys Phe Arg Gly His Phe Leu Ile Glu Gly Asp Leu Asn Pro

180 185 190

Asp Asn Ser Asp Val Asp Lys Leu Phe Ile Gln Leu Val Gln Thr Tyr

195 200 205

Asn Gln Leu Phe Glu Glu Asn Pro Ile Asn Ala Ser Gly Val Asp Ala

210 215 220

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

225 230 235 240

Leu Ile Ala Gln Leu Pro Gly Glu Lys Lys Asn Gly Leu Phe Gly Asn

245 250 255

Leu Ile Ala Leu Ser Leu Gly Leu Thr Pro Asn Phe Lys Ser Asn Phe

260 265 270

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

275 280 285

Asp Asp Leu Asp Asn Leu Leu Ala Gln Ile Gly Asp Gln Tyr Ala Asp

290 295 300

Leu Phe Leu Ala Ala Lys Asn Leu Ser Asp Ala Ile Leu Leu Ser Asp

305 310 315 320

Ile Leu Arg Val Asn Thr Glu Ile Thr Lys Ala Pro Leu Ser Ala Ser

325 330 335

Met Ile Lys Arg Tyr Asp Glu His His Gln Asp Leu Thr Leu Leu Lys

340 345 350

Ala Leu Val Arg Gln Gln Leu Pro Glu Lys Tyr Lys Glu Ile Phe Phe

355 360 365

Asp Gln Ser Lys Asn Gly Tyr Ala Gly Tyr Ile Asp Gly Gly Ala Ser

370 375 380

Gln Glu Glu Phe Tyr Lys Phe Ile Lys Pro Ile Leu Glu Lys Met Asp

385 390 395 400

Gly Thr Glu Glu Leu Leu Val Lys Leu Asn Arg Glu Asp Leu Leu Arg

405 410 415

Lys Gln Arg Thr Phe Asp Asn Gly Ser Ile Pro His Gln Ile His Leu

420 425 430

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

435 440 445

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

450 455 460

Pro Tyr Tyr Val Gly Pro Leu Ala Arg Gly Asn Ser Arg Phe Ala Trp

465 470 475 480

Met Thr Arg Lys Ser Glu Glu Thr Ile Thr Pro Trp Asn Phe Glu Glu

485 490 495

Val Val Asp Lys Gly Ala Ser Ala Gln Ser Phe Ile Glu Arg Met Thr

500 505 510

Asn Phe Asp Lys Asn Leu Pro Asn Glu Lys Val Leu Pro Lys His Ser

515 520 525

Leu Leu Tyr Glu Tyr Phe Thr Val Tyr Asn Glu Leu Thr Lys Val Lys

530 535 540

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

545 550 555 560

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

565 570 575

Val Lys Gln Leu Lys Glu Asp Tyr Phe Lys Lys Ile Glu Cys Phe Asp

580 585 590

Ser Val Glu Ile Ser Gly Val Glu Asp Arg Phe Asn Ala Ser Leu Gly

595 600 605

Thr Tyr His Asp Leu Leu Lys Ile Ile Lys Asp Lys Asp Phe Leu Asp

610 615 620

Asn Glu Glu Asn Glu Asp Ile Leu Glu Asp Ile Val Leu Thr Leu Thr

625 630 635 640

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

645 650 655

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

660 665 670

Thr Gly Trp Gly Arg Leu Ser Arg Lys Leu Ile Asn Gly Ile Arg Asp

675 680 685

Lys Gln Ser Gly Lys Thr Ile Leu Asp Phe Leu Lys Ser Asp Gly Phe

690 695 700

Ala Asn Arg Asn Phe Met Gln Leu Ile His Asp Asp Ser Leu Thr Phe

705 710 715 720

Lys Glu Asp Ile Gln Lys Ala Gln Val Ser Gly Gln Gly Asp Ser Leu

725 730 735

His Glu His Ile Ala Asn Leu Ala Gly Ser Pro Ala Ile Lys Lys Gly

740 745 750

Ile Leu Gln Thr Val Lys Val Val Asp Glu Leu Val Lys Val Met Gly

755 760 765

Arg His Lys Pro Glu Asn Ile Val Ile Glu Met Ala Arg Glu Asn Gln

770 775 780

Thr Thr Gln Lys Gly Gln Lys Asn Ser Arg Glu Arg Met Lys Arg Ile

785 790 795 800

Glu Glu Gly Ile Lys Glu Leu Gly Ser Gln Ile Leu Lys Glu His Pro

805 810 815

Val Glu Asn Thr Gln Leu Gln Asn Glu Lys Leu Tyr Leu Tyr Tyr Leu

820 825 830

Gln Asn Gly Arg Asp Met Tyr Val Asp Gln Glu Leu Asp Ile Asn Arg

835 840 845

Leu Ser Asp Tyr Asp Val Asp Ala Ile Val Pro Gln Ser Phe Leu Lys

850 855 860

Asp Asp Ser Ile Asp Asn Lys Val Leu Thr Arg Ser Asp Lys Asn Arg

865 870 875 880

Gly Lys Ser Asp Asn Val Pro Ser Glu Glu Val Val Lys Lys Met Lys

885 890 895

Asn Tyr Trp Arg Gln Leu Leu Asn Ala Lys Leu Ile Thr Gln Arg Lys

900 905 910

Phe Asp Asn Leu Thr Lys Ala Glu Arg Gly Gly Leu Ser Glu Leu Asp

915 920 925

Lys Ala Gly Phe Ile Lys Arg Gln Leu Val Glu Thr Arg Gln Ile Thr

930 935 940

Lys His Val Ala Gln Ile Leu Asp Ser Arg Met Asn Thr Lys Tyr Asp

945 950 955 960

Glu Asn Asp Lys Leu Ile Arg Glu Val Lys Val Ile Thr Leu Lys Ser

965 970 975

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

980 985 990

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

995 1000 1005

Val Gly Thr Ala Leu Ile Lys Lys Tyr Pro Lys Leu Glu Ser Glu Phe

1010 1015 1020

Val Tyr Gly Asp Tyr Lys Val Tyr Asp Val Arg Lys Met Ile Ala Lys

1025 1030 1035 1040

Ser Glu Gln Glu Ile Gly Lys Ala Thr Ala Lys Tyr Phe Phe Tyr Ser

1045 1050 1055

Asn Ile Met Asn Phe Phe Lys Thr Glu Ile Thr Leu Ala Asn Gly Glu

1060 1065 1070

Ile Arg Lys Arg Pro Leu Ile Glu Thr Asn Gly Glu Thr Gly Glu Ile

1075 1080 1085

Val Trp Asp Lys Gly Arg Asp Phe Ala Thr Val Arg Lys Val Leu Ser

1090 1095 1100

Met Pro Gln Val Asn Ile Val Lys Lys Thr Glu Val Gln Thr Gly Gly

1105 1110 1115 1120

Phe Ser Lys Glu Ser Ile Leu Pro Lys Arg Asn Ser Asp Lys Leu Ile

1125 1130 1135

Ala Arg Lys Lys Asp Trp Asp Pro Lys Lys Tyr Gly Gly Phe Asp Ser

1140 1145 1150

Pro Thr Val Ala Tyr Ser Val Leu Val Val Ala Lys Val Glu Lys Gly

1155 1160 1165

Lys Ser Lys Lys Leu Lys Ser Val Lys Glu Leu Leu Gly Ile Thr Ile

1170 1175 1180

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

1185 1190 1195 1200

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

1205 1210 1215

Tyr Ser Leu Phe Glu Leu Glu Asn Gly Arg Lys Arg Met Leu Ala Ser

1220 1225 1230

Ala Gly Glu Leu Gln Lys Gly Asn Glu Leu Ala Leu Pro Ser Lys Tyr

1235 1240 1245

Val Asn Phe Leu Tyr Leu Ala Ser His Tyr Glu Lys Leu Lys Gly Ser

1250 1255 1260

Pro Glu Asp Asn Glu Gln Lys Gln Leu Phe Val Glu Gln His Lys His

1265 1270 1275 1280

Tyr Leu Asp Glu Ile Ile Glu Gln Ile Ser Glu Phe Ser Lys Arg Val

1285 1290 1295

Ile Leu Ala Asp Ala Asn Leu Asp Lys Val Leu Ser Ala Tyr Asn Lys

1300 1305 1310

His Arg Asp Lys Pro Ile Arg Glu Gln Ala Glu Asn Ile Ile His Leu

1315 1320 1325

Phe Thr Leu Thr Asn Leu Gly Ala Pro Ala Ala Phe Lys Tyr Phe Asp

1330 1335 1340

Thr Thr Ile Asp Arg Lys Arg Tyr Thr Ser Thr Lys Glu Val Leu Asp

1345 1350 1355 1360

Ala Thr Leu Ile His Gln Ser Ile Thr Gly Leu Tyr Glu Thr Arg Ile

1365 1370 1375

Asp Leu Ser Gln Leu Gly Gly Asp Gly Ser Thr Ser Gly Ser Pro Lys

1380 1385 1390

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

1395 1400 1405

Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly His

1410 1415 1420

Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly Lys

1425 1430 1435 1440

Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp

1445 1450 1455

Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ala Arg

1460 1465 1470

Tyr Pro Asp His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met Pro

1475 1480 1485

Glu Gly Tyr Val Gln Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly Asn

1490 1495 1500

Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val Asn

1505 1510 1515 1520

Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile Leu

1525 1530 1535

Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Lys Val Tyr Ile Thr

1540 1545 1550

Ala Asp Lys Gln Lys Asn Gly Ile Lys Val Asn Phe Lys Thr Arg His

1555 1560 1565

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

1570 1575 1580

Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu

1585 1590 1595 1600

Ser Thr Gln Ser Lys Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His

1605 1610 1615

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

1620 1625 1630

Asp Glu Leu Tyr Lys

1635

<210> 19

<211> 65

<212> DNA

<213> Artificial Sequence

<400> 19

gctggagaag atagcccaag aaagagggca ataacggttt tcagatcaca catgtagtaa 60

aggca 65

<210> 20

<211> 65

<212> DNA

<213> Artificial Sequence

<400> 20

gctggagaag atagcccaag aaagagggca ataacaattg tttgcatcat ccccaagtca 60

ttggt 65

<210> 21

<211> 66

<212> DNA

<213> Artificial Sequence

<400> 21

gatttagact accccaaaaa cgaaggggac taaaacggtt ttcagatcac acatgtagta 60

aaggca 66

<210> 22

<211> 66

<212> DNA

<213> Artificial Sequence

<400> 22

gatttagact accccaaaaa cgaaggggac taaaacaatt gtttgcatca tccccaagtc 60

attggt 66

<210> 23

<211> 66

<212> DNA

<213> Artificial Sequence

<400> 23

ggttttcaga tcacacatgt agtaaaggca gttgtggaag gtccagtttt gaggggctat 60

tacaac 66

<210> 24

<211> 66

<212> DNA

<213> Artificial Sequence

<400> 24

aattgtttgc atcatcccca agtcattggt gttgtggaag gtccagtttt gaggggctat 60

tacaac 66

<210> 25

<211> 66

<212> DNA

<213> Artificial Sequence

<400> 25

ggttttcaga tcacacatgt agtaaaggca gttggatcta ccctctattt gaagggtaca 60

cacaac 66

<210> 26

<211> 66

<212> DNA

<213> Artificial Sequence

<400> 26

aattgtttgc atcatcccca agtcattggt gttggatcta ccctctattt gaagggtaca 60

cacaac 66

<210> 27

<211> 66

<212> DNA

<213> Artificial Sequence

<400> 27

ggttttcaga tcacacatgt agtaaaggca gttgggactg ctctcacttt gaagggtatt 60

cacaac 66

<210> 28

<211> 66

<212> DNA

<213> Artificial Sequence

<400> 28

aattgtttgc atcatcccca agtcattggt gttgggactg ctctcacttt gaagggtatt 60

cacaac 66

<210> 29

<211> 61

<212> DNA

<213> Artificial Sequence

<400> 29

gcacctctgc aaaactgcag gggtctaaaa cggttttcag atcacacatg tagtaaaggc 60

a 61

<210> 30

<211> 61

<212> DNA

<213> Artificial Sequence

<400> 30

gcacctctgc aaaactgcag gggtctaaaa caattgtttg catcatcccc aagtcattgg 60

t 61

<210> 31

<211> 61

<212> DNA

<213> Artificial Sequence

<400> 31

gcacccgtgc aaaaatgcag gggtctaaaa cggttttcag atcacacatg tagtaaaggc 60

a 61

<210> 32

<211> 61

<212> DNA

<213> Artificial Sequence

<400> 32

gcacccgtgc aaaaatgcag gggtctaaaa caattgtttg catcatcccc aagtcattgg 60

t 61

<210> 33

<211> 61

<212> DNA

<213> Artificial Sequence

<400> 33

gaacccctac caactggtcg gggtttgaaa cggttttcag atcacacatg tagtaaaggc 60

a 61

<210> 34

<211> 61

<212> DNA

<213> Artificial Sequence

<400> 34

gaacccctac caactggtcg gggtttgaaa caattgtttg catcatcccc aagtcattgg 60

t 61

<210> 35

<211> 66

<212> DNA

<213> Artificial Sequence

<400> 35

gttgaatcca ttccattgca ttccattcat gttgtggaag gtccagtttt gaggggctat 60

tacaac 66

<210> 36

<211> 59

<212> DNA

<213> Artificial Sequence

<400> 36

gattccaatc catgccattc cacgttgtgg aaggtccagt tttgaggggc tattacaac 59

<210> 37

<211> 59

<212> DNA

<213> Artificial Sequence

<400> 37

gattccaatc catgccattc cacgttgtgg aaggtccagt tttgaggggc tattacaac 59

<210> 38

<211> 56

<212> DNA

<213> Artificial Sequence

<400> 38

gtgacctgtg gatgctgagg gttgtggaag gtccagtttt gaggggctat tacaac 56

<210> 39

<211> 57

<212> DNA

<213> Artificial Sequence

<400> 39

gacctgtgga tgctgaggaa ggttgtggaa ggtccagttt tgaggggcta ttacaac 57

<210> 40

<211> 59

<212> DNA

<213> Artificial Sequence

<400> 40

gcagttcttc tccactgcca gaagttgtgg aaggtccagt tttgaggggc tattacaac 59

<210> 41

<211> 59

<212> DNA

<213> Artificial Sequence

<400> 41

gcagttcttc tccactgcca gaagttgtgg aaggtccagt tttgaggggc tattacaac 59

<210> 42

<211> 57

<212> DNA

<213> Artificial Sequence

<400> 42

gctacctcat tttccaggtg ggttgtggaa ggtccagttt tgaggggcta ttacaac 57

<210> 43

<211> 57

<212> DNA

<213> Artificial Sequence

<400> 43

gaagaactgc tttcaaagaa ttaccacctg gaaaatgagg tagctagact gaaaaag 57

<210> 44

<211> 142

<212> DNA

<213> Artificial Sequence

<400> 44

ggcgtgacct gtggatgctg gtttgagagc taccggagca gacgatatgg cgtcgctccg 60

gtagcaagtt caaataaggc tagtccgtta tcaacttgga gcagacgata tggcgtcgct 120

ccaagtggca ccgagtcggt gc 142

<210> 45

<211> 142

<212> DNA

<213> Artificial Sequence

<400> 45

aatggaatca acccgagtac gtttgagagc taccggagca gacgatatgg cgtcgctccg 60

gtagcaagtt caaataaggc tagtccgtta tcaacttgga gcagacgata tggcgtcgct 120

ccaagtggca ccgagtcggt gc 142

<210> 46

<211> 4224

<212> DNA

<213> Artificial Sequence

<400> 46

atgcccaaaa agaagaggaa agtgaacatc cccgctctgg tggaaaacca gaagaagtac 60

tttggcacct acagcgtgat ggccatgctg aacgctcaga ccgtgctgga ccacatccag 120

aaggtggccg atattgaggg cgagcagaac gagaacaacg agaatctgtg gtttcacccc 180

gtgatgagcc acctgtacaa cgccaagaac ggctacgaca agcagcccga gaaaaccatg 240

ttcatcatcg agcggctgca gagctacttc ccattcctga agatcatggc cgagaaccag 300

agagagtaca gcaacggcaa gtacaagcag aaccgcgtgg aagtgaacag caacgacatc 360

ttcgaggtgc tgaagcgcgc cttcggcgtg ctgaagatgt acagggacct gaccaacgcc 420

tacaagacct acgaggaaaa gctgaacgac ggctgcgagt tcctgaccag cacagagcaa 480

cctctgagcg gcatgatcaa caactactac acagtggccc tgcggaacat gaacgagaga 540

tacggctaca agacagagga cctggccttc atccaggaca agcggttcaa gttcgtgaag 600

gacgcctacg gcaagaaaaa gtcccaagtg aataccggat tcttcctgag cctgcaggac 660

tacaacggcg acacacagaa gaagctgcac ctgagcggag tgggaatcgc cctgctgatc 720

tgcctgttcc tggacaagca gtacatcaac atctttctga gcaggctgcc catcttctcc 780

agctacaatg cccagagcga ggaacggcgg atcatcatca gatccttcgg catcaacagc 840

atcaagctgc ccaaggaccg gatccacagc gagaagtcca acaagagcgt ggccatggat 900

atgctcaacg aagtgaagcg gtgccccgac gagctgttca caacactgtc tgccgagaag 960

cagtcccggt tcagaatcat cagcgacgac cacaatgaag tgctgatgaa gcggagcagc 1020

gacagattcg tgcctctgct gctgcagtat atcgattacg gcaagctgtt cgaccacatc 1080

aggttccacg tgaacatggg caagctgaga tacctgctga aggccgacaa gacctgcatc 1140

gacggccaga ccagagtcag agtgatcgag cagcccctga acggcttcgg cagactggaa 1200

gaggccgaga caatgcggaa gcaagagaac ggcaccttcg gcaacagcgg catccggatc 1260

agagacttcg agaacatgaa gcgggacgac gccaatcctg ccaactatcc ctacatcgtg 1320

gacacctaca cacactacat cctggaaaac aacaaggtcg agatgtttat caacgacaaa 1380

gaggacagcg ccccactgct gcccgtgatc gaggatgata gatacgtggt caagacaatc 1440

cccagctgcc ggatgagcac cctggaaatt ccagccatgg ccttccacat gtttctgttc 1500

ggcagcaaga aaaccgagaa gctgatcgtg gacgtgcaca accggtacaa gagactgttc 1560

caggccatgc agaaagaaga agtgaccgcc gagaatatcg ccagcttcgg aatcgccgag 1620

agcgacctgc ctcagaagat cctggatctg atcagcggca atgcccacgg caaggatgtg 1680

gacgccttca tcagactgac cgtggacgac atgctgaccg acaccgagcg gagaatcaag 1740

agattcaagg acgaccggaa gtccattcgg agcgccgaca acaagatggg aaagagaggc 1800

ttcaagcaga tctccacagg caagctggcc gacttcctgg ccaaggacat cgtgctgttt 1860

cagcccagcg tgaacgatgg cgagaacaag atcaccggcc tgaactaccg gatcatgcag 1920

agcgccattg ccgtgtacga tagcggcgac gattacgagg ccaagcagca gttcaagctg 1980

atgttcgaga aggcccggct gatcggcaag ggcacaacag agcctcatcc atttctgtac 2040

aaggtgttcg cccgcagcat ccccgccaat gccgtcgagt tctacgagcg ctacctgatc 2100

gagcggaagt tctacctgac cggcctgtcc aacgagatca agaaaggcaa cagagtggat 2160

gtgcccttca tccggcggga ccagaacaag tggaaaacac ccgccatgaa gaccctgggc 2220

agaatctaca gcgaggatct gcccgtggaa ctgcccagac agatgttcga caatgagatc 2280

aagtcccacc tgaagtccct gccacagatg gaaggcatcg acttcaacaa tgccaacgtg 2340

acctatctga tcgccgagta catgaagaga gtgctggacg acgacttcca gaccttctac 2400

cagtggaacc gcaactaccg gtacatggac atgcttaagg gcgagtacga cagaaagggc 2460

tccctgcagc actgcttcac cagcgtggaa gagagagaag gcctctggaa agagcgggcc 2520

tccagaacag agcggtacag aaagcaggcc agcaacaaga tccgcagcaa ccggcagatg 2580

agaaacgcca gcagcgaaga gatcgagaca atcctggata agcggctgag caacagccgg 2640

aacgagtacc agaaaagcga gaaagtgatc cggcgctaca gagtgcagga tgccctgctg 2700

tttctgctgg ccaaaaagac cctgaccgaa ctggccgatt tcgacggcga gaggttcaaa 2760

ctgaaagaaa tcatgcccga cgccgagaag ggaatcctga gcgagatcat gcccatgagc 2820

ttcaccttcg agaaaggcgg caagaagtac accatcacca gcgagggcat gaagctgaag 2880

aactacggcg acttctttgt gctggctagc gacaagagga tcggcaacct gctggaactc 2940

gtgggcagcg acatcgtgtc caaagaggat atcatggaag agttcaacaa atacgaccag 3000

tgcaggcccg agatcagctc catcgtgttc aacctggaaa agtgggcctt cgacacatac 3060

cccgagctgt ctgccagagt ggaccgggaa gagaaggtgg acttcaagag catcctgaaa 3120

atcctgctga acaacaagaa catcaacaaa gagcagagcg acatcctgcg gaagatccgg 3180

aacgccttcg atgccaacaa ttaccccgac aaaggcgtgg tggaaatcaa ggccctgcct 3240

gagatcgcca tgagcatcaa gaaggccttt ggggagtacg ccatcatgaa ggagggagct 3300

ctagaggcgc taccggtcgc caccatggtg agcaagggcg aggagctgtt caccggggtg 3360

gtgcccatcc tggtcgagct ggacggcgac gtaaacggcc acaagttcag cgtgtccggc 3420

gagggcgagg gcgatgccac ctacggcaag ctgaccctga agttcatctg caccaccggc 3480

aagctgcccg tgccctggcc caccctcgtg accaccctga cctacggcgt gcagtgcttc 3540

agccgctacc ccgaccacat gaagcagcac gacttcttca agtccgccat gcccgaaggc 3600

tacgtccagg agcgcaccat cttcttcaag gacgacggca actacaagac ccgcgccgag 3660

gtgaagttcg agggcgacac cctggtgaac cgcatcgagc tgaagggcat cgacttcaag 3720

gaggacggca acatcctggg gcacaagctg gagtacaact acaacagcca caacgtctat 3780

atcatggccg acaagcagaa gaacggcatc aaggtgaact tcaagatccg ccacaacatc 3840

gaggacggca gcgtgcagct cgccgaccac taccagcaga acacccccat cggcgacggc 3900

cccgtgctgc tgcccgacaa ccactacctg agcacccagt ccgccctgag caaagacccc 3960

aacgagaagc gcgatcacat ggtcctgctg gagttcgtga ccgccgccgg gatcactctc 4020

ggcatggacg agctgtacaa gtccggactc agatctaagc tttcgaattc taagccagga 4080

ttccatatga agcgacctgc cgccacaaag aaggctggac aggctaagaa gaagaaacaa 4140

cgcgtgcagc taagcgacta caaagaccat gacggtgatt ataaagatca tgacatcgat 4200

tacaaggatg acgatgacaa gtaa 4224

Claims (16)

1. A fusion protein comprising a dCas protein having a deleted or reduced RNA nuclease activity, which dCas protein is a dCas13 protein, one or more marker sequences and optionally one or more nuclear localization signals, the sequence of the dCas13 protein being selected from any one of: positions 9-1089 of SEQ ID NO.3 and positions 9-1183 of SEQ ID NO.4, wherein the sequence of the nuclear localization signal is selected from one or more of the following sequences: positions 2-17 of SEQ ID NO.1 and positions 1363-1369 of SEQ ID NO. 9.

2. The fusion protein of claim 1, wherein the fusion protein has one or more characteristics selected from the group consisting of:

the dCas protein is located at the N-terminus of the marker sequence,

the fusion protein comprises a plurality of marker sequences,

the marker sequence is a fluorescent protein,

the nuclear localization signal is located at the N-terminus of dCas and/or at the C-terminus of the marker sequence.

3. The fusion protein of claim 1 or 2, wherein the fusion protein has, from N-terminus to C-terminus, one or more nuclear localization signals, dCas protein, one or more marker sequences, and one or more nuclear localization signals.

4. The fusion protein of claim 1 or 2, wherein the sequence of the fusion protein is selected from any one of SEQ ID NOs 3-4 and 9-18.

5. A polynucleotide selected from the group consisting of:

(1) A polynucleotide encoding the fusion protein of any one of claims 1-4; and

(2) (1) the complementary sequence of said polynucleotide.

6. A nucleic acid construct comprising the polynucleotide of claim 5.

7. The nucleic acid construct of claim 6, wherein said nucleic acid construct is a cloning vector or an expression vector.

8. A host cell, wherein said host cell

(1) Expressing the fusion protein of any one of claims 1-4;

(2) Comprising the polynucleotide of claim 5; or

(3) Comprising the nucleic acid construct of claim 6 or 7.

9. A detection kit comprises

(1) The fusion protein of any one of claims 1 to 4, the polynucleotide of claim 5, the nucleic acid construct of claim 6 or 7 and/or the cell of claim 8, and

(2) Reagents for detecting the marker sequence.

10. The detection kit of claim 9, further comprising a gRNA directed to a target that is a target RNA that recognizes dCas13 in the target RNA and the fusion protein, or a nucleic acid construct comprising the gRNA or a complementary sequence thereof.

11. The kit of claim 9 or 10, further comprising an agent for introducing said fusion protein, polynucleotide or nucleic acid construct into a cell, and optionally instructions.

12. Use of the fusion protein of any one of claims 1-4, the polynucleotide of claim 5, the nucleic acid construct of claim 6 or 7, or the cell of claim 8 in the preparation of a kit for detecting a target, said target being a target RNA.

13. A method of detecting a target comprising (1) incubating cells that express the fusion protein of any one of claims 1-4 and comprise grnas for the target, which are target RNAs that recognize dCas13 in the target RNA and the fusion protein, and (2) detecting the marker sequence, the method being for non-disease diagnostic and therapeutic purposes.

14. The method of claim 13, wherein the marker sequence is a fluorescent protein.

15. A method of localizing a target within a cell, comprising, (1) incubating a cell that expresses the fusion protein of any one of claims 1-4 and comprises a gRNA directed against the target, which is a target RNA, and (2) detecting the location of a marker sequence in the cell, the gRNA recognizing dCas13 in the target RNA and the fusion protein.

16. The method of claim 15, wherein the marker sequence is a fluorescent protein.

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