CN114835818B - Gene editing fusion protein, adenine base editor constructed by same and application thereof - Google Patents

Abstract

The invention relates to a gene editing fusion protein, an adenine base editor constructed therefrom and its application. The amino acid sequence of the gene editing fusion protein is one of the sequences shown in SEQ ID NO. 2-4. The adenine base editor constructed based on the gene editing fusion protein also includes a crRNA array insertion region to combine adenine residues at multiple sites in the genome. Converted to guanine. The adenine base editor constructed by the present invention solves the problems of the existing adenine base editor's limited operable range on the genome, low efficiency and complicated operation during the base editing process of multiple sites. An adenine base editor with multiple editing sites, a large editing window, and high editing efficiency and editing activity is provided.

Description

A kind of gene editing fusion protein, its constructed adenine base editor and its application

Technical field

The invention relates to the field of biotechnology, and in particular to a gene editing fusion protein, an adenine base editor constructed therefrom and its application.

Background technique

Gene editing is a technical means to achieve gene knockout, insertion of foreign DNA fragments or DNA base mutation by introducing sequence changes at specific sites on DNA. The CRISPR/Cas system is widely used in gene editing. Three CRISPR/Cas systems have been discovered so far, Type I, Type II and Type III. Among them, the Type II system is currently the most successfully modified artificial nuclease, requiring only one The Cas9 protein can exert the immune effect of the CRISPR system. In this system, crRNA (CRISPR-derived RNA) combines with tracrRNA (trans-activating crRNA) through base pairing to form a tracrRNA/crRNA complex. This complex guides the nuclease Cas9 protein to cleave at the sequence target site paired with crRNA. Cut double-stranded DNA. The process includes three stages: (1) Obtaining the spacer region of CRISPR: the bacterium integrates a short DNA sequence of the invading phage or plasmid into the repeat sequence of its own genome, that is, between the two repeat sequences at the 5' end of CRISPR. Thus, highly variable spacer regions are obtained; (2) Expression of CRISPR loci and maturation of crRNA: CRISPR loci are first transcribed into precursor CRISPR RNA (pre-crRNA), and then sheared under the action of Cas9 and nucleases Cut into mature crRNA; (3) Cleavage of exogenous genetic material by the CRISPR/Cas system: Mature tracrRNA, crRNA and Cas9 form a ribonucleoprotein complex, and crRNA recognizes and binds to the exogenous matching DNA sequence, thereby mediating Cleavage of foreign genetic material by ribonucleoprotein complexes.

In order to simplify the operation process and improve editing efficiency, crRNA and tracrRNA are often constructed into a chimeric sgRNA (small guide RNA) for expression, that is, only sgRNA and Cas9 protein need to be expressed to perform gene editing. At present, in addition to the CRISPR/Cas9 system, the CRISPR/Cpf1 system is also often used in gene editing. Unlike the CRISPR/Cas9 system, CRISPR/Cpf1 only requires crRNA to function, and Cpf1 itself has RNase activity. Immature mRNA sequences containing multiple crRNAs can be cut and processed, so a crRNA array containing multiple crRNAs can be designed to generate multiple crRNAs with independent functions and guide Cpf1 to target corresponding targets in the genome, achieving multiple goals. Simultaneous editing of several sites.

Many species lack the NHEJ pathway (even if it is active, it is weak), and the HDR pathway requires the participation of homologous templates to function, and there will be a competitive relationship between the two repair mechanisms, which leads to genes based on the above methods. The editing process has a high fatality rate and low editing efficiency. After inactivating the DNase of Cas9, nCas9, which can only cut one DNA strand, and dCas9, which cannot cut DNA, can be obtained. nCas9 and dCas9 can still bind to specific sites in the genome under the guidance of sgRNA, but will not produce lethal double-strand breaks. The tRNA adenosine deaminase TadA mutant TadA7.10 of Escherichia coli can deaminate adenine (A) to form inosine (I). Inosine will be read and copied as guanine (G) at the DNA level. , and finally achieve the conversion of A→G. Therefore, the fusion protein (dCas9-ABE or nCas9-ABE) obtained by fusing TadA7.10 to the N terminus of nCas9 or dCas9 can achieve A→G conversion at specific sites on the genome under the guidance of sgRNA, which is called Adenine base editing system.

Chinese patent CN201811613264.9 discloses a CRISPR/Cas9-mediated adenine base editing system that realizes single-base site-directed substitution (A>G) and is used to improve broad-spectrum resistance to rice blast. However, When this system is used for multi-site base editing, multiple corresponding sgRNA expression cassettes need to be constructed, which not only increases the complexity of the construction process, but also reduces the stability of the DNA sequence due to the repeated use of promoters and other components, and The site recognized by Cas9 requires a PAM sequence with NGG (N=A, T, C, G), which limits the operable range of Cas9-based cytosine base editors on the genome; Chinese patent CN201811563073.6 disclosed A plant base editing method is provided, which includes a base editing fusion protein formed by a nuclease-inactivated CRISPR effector protein and a DNA-dependent adenine deaminase, and the CRISPR effector protein is Cas9 nuclease or Cpf1 nuclease, The DNA-dependent adenine deaminase is a variant of the Escherichia coli tRNA adenine deaminase TadA (ecTadA) that contains one or more sets of mutations selected from the following relative to wild-type ecTadA: 1) A106V and D108N ;2) D147Y and E155V; 3) L84F, H123Y and I156F; 4) A142N; 5) H36L, R51L, S146C and K157N; 6) P48S/T/A; 7) A142N; 8) W23L/R; 9) R152H /P; Chinese Patent 201811578853.8 discloses a base editing system based on CPF1 protein, in which the base editing fusion protein contains Cpf1 (D917A mutation) with missing DNA cleavage activity and deaminase. The mutant of deaminase is the same as above. One or more C to T or A to G substitutions in the target sequence can be achieved. The above systems only use the ABE7.9 (TadA7.9) and ABE7.10 (TadA7.10) mutants of ecTadA, which are currently widely used, and the performance of the base editor needs to be further improved. Therefore, the present invention aims to find an adenine base editor with multiple editing sites, a large editing window, and high editing efficiency and editing activity.

Contents of the invention

In order to solve the above technical problems, the present invention provides an adenine base editor based on CRISPR/Cpf1, which overcomes the limited operational range of the existing A>G adenine base editor on the genome, and in The problem of low efficiency and complex operation in the multi-site base editing process.

The first object of the present invention is to provide a gene editing fusion protein whose amino acid sequence is one of the sequences shown in SEQ ID NO. 2-4. Among them, SEQ ID NO.2 is the fusion protein sequence containing TadA8.20, SEQ ID NO.3 is the fusion protein sequence containing TadA8e, and SEQ ID NO.4 is the fusion protein sequence containing TadA9.

The invention provides a gene editing fusion protein that can recognize TTV as PAM, wherein V=A, C, G. When the fusion protein is used for gene editing, the editing window is at the 9th base of crRNA. base, between the 7th base and the 9th base, or between the 4th base and the 23rd base, edit the adenine base into guanine.

The second object of the present invention is to provide an adenine base editor, which includes the above-mentioned gene editing fusion protein and a crRNA array insertion region. The crRNA inserted in the insertion region of the crRNA array matches the DNase-inactivated Cpf1 mutant dCpf1, and guides the DNase-inactivated Cpf1 mutant dCpf1 to cut and edit specific target sites.

Further, the nucleotide sequence of the crRNA array insertion region is shown in SEQ ID NO. 5. The crRNA array insertion region contains two forward repeating crRNA handle sequences at both ends, and two reverse Eco31I enzyme cutting sites are inserted in the middle. The required recognition sequence or crRNA array can be placed through enzyme cutting connection. to between two handle sequences.

Furthermore, the above gene editing fusion protein regulates expression through the inducible promoter P _grac100 .

Furthermore, the crRNA array insertion region regulates expression through the constitutive promoter P _veg .

Further, the above-mentioned adenine base editor is obtained by integrating the gene encoding the fusion protein of one of SEQ ID NO. 2-4 into an expression vector and inserting the crRNA array insertion region into the expression vector.

Further, when an adenine base editor is used for gene editing, the above-mentioned expression vector is introduced into eukaryotes or prokaryotes.

Further, the adenine base editor includes: a plasmid containing the above-mentioned adenine base editor and the above-mentioned crRNA array insertion region.

Further, the nucleotide sequence of the above plasmid is one of SEQ ID NO. 9-11. Among them, SEQ ID NO.9 is the plasmid sequence containing TadA8.20, SEQ ID NO.10 is the plasmid sequence containing TadA8e, and SEQ ID NO.11 is the plasmid sequence containing TadA9.

The third object of the present invention is to provide the application of the above-mentioned adenine base editor in gene editing.

Further, the above-mentioned adenine base editor is used to convert adenine into guanine at multiple sites on the Bacillus subtilis genome.

Further, the above-mentioned adenine base editor is used to obtain mutants or to inactivate extracellular proteases.

Further, Bacillus subtilis is Bacillus subtilis 168.

Through the above solutions, the present invention at least has the following advantages:

The present invention designs and constructs an adenine base editor (dCpf1-ABE) based on CRISPR/Cpf1. Using a crRNA array, it can perform base (A → G) at 5 sites in the genome at the same time, thereby producing extremely rich The combination of mutants has broadened the operable range of the adenine base editor on the genome. The editing efficiency of some sites has reached 100%, with high editing activity and a large editing window.

The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the following is a description of the preferred embodiments of the present invention in conjunction with detailed drawings.

Description of drawings

In order to make the content of the present invention easier to understand clearly, the present invention will be described in further detail below based on specific embodiments of the present invention and in conjunction with the accompanying drawings.

Figure 1 is a schematic diagram of an adenine base editor based on CRISPR/Cpf1;

Figure 2 shows the plasmid map of the Bacillus subtilis adenine base editing system;

Figure 3 shows the multi-site base editing mediated by the adenine base editor constructed when adenosine deaminase selects TadA9;

Figure 4 shows the specific composition of the mutants produced after processing by the multi-site adenine base editing system;

Figure 5 shows the proteolysis situation after using a multi-site adenine base editing system to inactivate extracellular proteases.

Detailed ways

The present invention will be further described below in conjunction with the accompanying drawings and specific examples, so that those skilled in the art can better understand and implement the present invention, but the examples are not intended to limit the present invention.

Materials and reagents involved in the experiment:

DNA polymerase was purchased from Takara Company, restriction endonuclease and T4 ligase were purchased from NEB Company, plasmid extraction kit was purchased from Sangon Bioengineering (Shanghai) Co., Ltd., and PCR product nucleic acid purification kit was purchased from ThermoScientific Company.

The cells were cultured in LB medium, which contained: tryptone 10g/L, yeast powder 5g/L, and NaCl 10g/L. The final concentration of kanamycin in the culture medium was 50 μg/mL, and the final concentration of IPTG was 1 mM.

Example 1 Design and construction of adenine base editor based on CRISPR/Cpf1

As shown in Figure 1A, an adenine editing system based on CRISPR/Cpf1 was constructed, which consists of the following two basic components:

(1) A fusion protein composed of the tRNA adenosine deaminase TadA mutant of Escherichia coli and the DNase inactive mutant (D917A) dCpf1 of Cpf1, that is, the adenine base editor dCpf1-ABE. This fusion protein can be used in With the help of dCpf1, it binds to a specific target site in the genome and converts adenine (A) there into guanine (G) under the action of adenine deaminase;

Specifically, the mutants TadA8.17 (TadA7.10 V82S, Q154R), TadA8.20 (TadA7.10 I76Y, V82S, Y123H, Y147R, Q154R), and TadA8e (TadA7 .10 A109S, T111R, D119N, H122N, Y147D, F149Y, T166I, D167N) and TadA9 (TadA7.10 V82S, A109S, T111R, D119N, H122N, Y147D, F149Y, Q154R, T166I, D167N) Through the short peptide linker (SGGSSGGSSGSETPGTSESATPESSGGSSGGS ) is fused to the N terminus of dCpf1, and the resulting fusion amino acid sequences are shown in Sequences 1-4 respectively. In addition, a crRNA array insertion region whose DNA sequence is shown in 5 was also designed. This region contains two direct repeat crRNA handle sequences at both ends, and two reverse Eco31I restriction sites are inserted in the middle. , the required recognition sequence or crRNA array can be placed between the two handle sequences through enzymatic ligation.

(2) crRNA that matches Cpf1. The crRNA contains a fixed handle sequence and a recognition sequence complementary to the target target. Under the interaction between dCpf1 and the crRNA handle sequence, dCpf1-ABE will combine with crRNA to form a complex, and Under the action of complementary sequences, specific targets in the genome are identified and targeted to achieve base editing (A→G). Since dCpf1 still has RNase activity, multiple crRNAs can be expressed in the form of an array. After the crRNA array is cleaved by dCpf1, dCpf1-ABE can be targeted to multiple sites to achieve the base editing (A→G) process ( Figure 1B).

Example 2 Application of CRISPR/Cpf1-based adenine base editor in multi-site base editing

The CRISPR/Cpf1-based adenine base editing system was verified and applied in Bacillus subtilis. As shown in Figure 2, the IPTG-inducible P _grac100 promoter was used to express different structures of the adenine base editor dCpf1-ABE, and the crRNA array insertion region was placed behind the constitutive promoter P _veg to achieve expression of the crRNA array. , the above two expression cassettes were placed on a plasmid containing the temperature-sensitive replicon pE194 for base editing (A→G) in Bacillus subtilis.

Plasmid construction specifically includes the following steps: the plasmid backbone used is from pJOE8999 (Altenbuchner, J., 2016. Editing of the Bacillus subtilis genome by the CRISPR-Cas9 system. Applied and Environmental Microbiology 82, 5421–5427), which is expressed in the large intestine. Both Bacillus subtilis and Bacillus subtilis are kanamycin resistant (KanR), and have multi-copy replicon pBR322, which can be used for plasmid construction and preservation in E. coli, while Bacillus subtilis has a temperature-sensitive replication pE194 (can be stably replicated at 30°C but will be eliminated at 50°C); the P _grac100 promoter and its repressor protein gene lacI and dCpf1 proteins are all from the plasmid pLCg6-dCpf1 (Wu, Y., Liu, Y. , Lv, ; The crRNA array insertion region and promoter P _veg are from plasmid pcra2 (Wu, Y., Liu, Y., Lv, X., Li, J., Du, G., Liu, L., 2020. CAMERS-B :CRISPR/Cpf1 assisted multiple-genes editing and regulation system for Bacillus subtilis.Biotechnology and Bioengineering 117,1817–1825); Several adenine deaminase mutants are obtained through gene synthesis. After the above fragments were amplified by PCR, they were connected using a seamless connection kit (Beyotime D7010M), and transformed into E. coli for sequencing and storage. Contains TadA7.10 mutants TadA8.17 (TadA7.10 V82S, Q154R), TadA8.20 (TadA7.10 I76Y, V82S, Y123H, Y147R, Q154R), TadA8e (TadA7.10 A109S, T111R, D119N, H122N , Y147D, F149Y, T166I, D167N) and TadA9 (TadA7.10V82S, A109S, T111R, D119N, H122N, Y147D, F149Y, Q154R, T166I, D167N) plasmid sequences are shown in SEQ ID NO.8-11, respectively. Please see https://benchling.com/s/seq-8cOWQiJn0nzb9DwUWoQo? for the plasmids shown in 9-11? m=slm-JrgZjL6OUp4Dod4GvNOX, https://benchling.com/s/seq-7MMzFTpA45YTqhfwW7KV? m＝slm-PWCavDFpL7MmrQywyplb,https://benchling.com/s/seq-jtNb6AEo2Q5lPsP42jhH? m=slm-HJP8s8AVmOcAoKe0UnJv.

Using 5 sites in the aprE gene and nprE gene of Bacillus subtilis as targets, we performed multi-site base editing and designed a total of 5 crRNAs as shown in Table 1. Through SOMACA (Synthetic Oligos MediatedAssembly of crRNA Array) method (Reference: Wu, Y., Liu, Y., Lv, X., Li, J., Du, G., Liu, L., 2020. CAMERS-B: CRISPR/Cpf1 assisted multiple-genes editing and regulation system for Bacillus subtilis. Biotechnology and Bioengineering 117, 1817–1825.) was assembled into the crRNA array insertion region to obtain an editing plasmid that can complete base editing (A→G) of the above five sites.

Specifically, when expressing a single crRNA, the crRNA can be directly obtained by annealing a pair of primers with overlapping regions (primer concentration is 10uM, 10uL of upstream and downstream primers in a 20uL system; reaction conditions are: 98°C 2min, 0.1°C/S Cool to 4°C and then incubate.), dilute the product 10 times, take 1uL and connect it to the vector digested with Eco31I. When designing multiple crRNAs to form crRNA arrays, first perform PCR on multiple pairs of primers with overlapping regions (the primer concentration is 10uM, the 20uL system contains 10uL of DNA polymerase and 5uL of upstream and downstream primers; use standard PCR procedures, extension time 5 seconds, 10 cycles). After dilution 10 times, double-stranded DNA with Eco31I at both ends can be obtained. Take 1 μL of each double-stranded DNA above and perform golden gate assembly with the plasmid. After transforming the above product into E. coli, select one primer each on the plasmid backbone and crRNA for colony PCR, and select single colonies with bands for sequencing to screen for positive clones containing the desired crRNA.

Table 1 crRNA used to guide multi-site base editing (A→G)

The steps for multi-site base editing (A→G) and analysis are as follows: first, transform the editing plasmid into Bacillus subtilis 168, spread on a plate containing kanamycin, and culture at 30°C for 12 hours; then, Pick any single colony and inoculate it into a 14 mL shaking tube containing 2 mL of LB medium (containing kanamycin), and culture it with shaking at 30°C for 12 hours; then, transfer 5 μL of bacterial liquid to a 14 mL shaking tube containing 2 mL of LB medium. Base (containing kanamycin and IPTG) in a 14 mL shaking tube, shake culture at 30°C for 12 hours to induce the expression of the base editing system for multi-site base editing (A→G); finally, take 1 μL of the induced bacterial liquid Into a 50 μL PCR reaction system, amplify the aprE and nprE genes and conduct sanger sequencing analysis. The primers used for aprE and nprE amplification are shown in Table 2 respectively. After purification, the above DNA fragments were subjected to sanger sequencing using the primers shown in Table 2, and sequenced using BEAT software (https://hanlab.cc/beat/) Analyze the results. Since the plasmid used is temperature-sensitive, after editing is completed, the bacterial solution can be streaked onto an LB plate without antibiotics and cultured at 50°C overnight to eliminate the plasmid.

Table 2 Primer sequences

The multi-site base editing situation mediated by the adenine base editor (dCpf1-ABE) containing different adenine deaminase TadA mutants is shown in Table 3: among them, the base editing efficiency is the highest when TadA9 is fused to dCpf1 , all 5 sites have A converted to G, and the editing window is between the 4th base and the 23rd base of crRNA, and the editing efficiency of some sites reaches 100%; the base editing efficiency when fused to TadA8e Slightly lower than TadA9, A is converted to G only in site 2, site 3 and site 4, and the editing window is also narrow, between the 7th and 9th base of crRNA; When fused to TadA8.20, the base editing efficiency is lower than that of TadA9 and TadA8e. A is converted to G only in sites 2 and 3, and the editing window is also narrow. Editing only occurs at the 9th base of crRNA. ; However, when fused with TadA8.17, base editing cannot be achieved at any of the five sites.

Table 3 Adenine base editor-mediated multi-site base editing (A→G) and its efficiency

Example 3 Effect of induction time on multi-site base editing efficiency

Since the adenine base editor containing TadA7.10 mutant TadA9 has the highest efficiency, it can achieve simultaneous editing of five sites. Therefore, the effect of IPTG induction time on the base editing efficiency of the base editor was also investigated.

As shown in Table 4, as the induction time increases, the editing efficiency of each site increases to a certain extent, but the amplitude is limited, and the editing window does not change with the extension of the induction time. The above results indicate that induction for 12 hours is sufficient to achieve relatively complete editing. Among them, the editing and sequencing results after 36 hours of induction are shown in Figure 3.

Table 4 Effect of induction time on multi-site base editing efficiency

Example 4 Analysis of mutants generated by multi-site adenine base editing system

In order to analyze the specific composition of the mutants obtained after using adenine base editing treatment, the bacterial solution containing the adenine deaminase TadA7.10 mutant TadA9 after induction treatment with the adenine base editor for 36 hours was streaked to the point without antibiotics on an LB plate and incubate at 37°C overnight. Then, 8 single colonies were picked to amplify aprE and nprE loci respectively for sequencing analysis.

As shown in Figure 4, only a specific crRNA array needs to be designed and constructed to produce abundant mutants with different mutation combinations at the same time, which is very valuable for protein evolution and strain modification; in addition, we also observed The mutation sites that were not detected using mixed template sequencing (such as A10G in site 2, A11, A12G and A15G in site 3) indicate that there may be very low-efficiency mutations at some sites, and these mutations cannot pass The method in Example 2 was detected, which also shows that the base editor has a larger editing window. In addition, due to the small number of picked colonies, some low-frequency mutation sites in Table 4 may not be detected in the above mutants.

Example 5 Application of multi-site adenine base editor in inactivation of extracellular proteases

There are six main proteases in Bacillus subtilis. These proteases will hydrolyze proteins secreted out of the cell, so they are extremely detrimental to the efficient secretion and expression of the target protein. Therefore, we used the 6 crRNAs shown in Table 5 to mutate A in the complementary strand of the 6 start codons (ATG, TTG or GTG) bolded in the table (A→G), so that the above start codons The T in the codon will be mutated to C and expression will not be initiated, resulting in the inactivation of the above-mentioned protease. After selecting a mutant strain in which all six proteases were inactive through sequencing analysis, the extracellular protease activity was detected using skim milk plates. The results showed that compared with the wild bacteria, the mutant strain no longer had a hydrolysis zone, indicating that the extracellular protease activity was has been successfully eliminated (Figure 5).

Table 5 crRNA used to guide extracellular protease inactivation

Comparative Example 1 Base editing mediated by other adenine deaminase TadA mutants

The earliest TadA mutant of adenine deaminase used in the CRISPR/Cas9-based adenine base editing system was TadA7.10, and an original TadA and a mutant TadA7.10 were often fused to the N-terminus of nCas9 at the same time. Chinese patent CN201811563073.6 and Chinese patent 201811578853.8 also used this mutant to construct an adenine base editing system and applied it in rice. Therefore, we further tried to fuse TadA and TadA7.10 to the N terminus of dCpf1 to construct a CRISPR/Cpf1-based adenine base editing system as shown in Sequence 6.

However, verification found that, like TadA8.17, TadA7.10 does not have any base editing (A→G) ability after fusion with dCpf1, indicating that dCpf1 does not match the above-mentioned TadA mutant and cannot complete base editing (A→ G); or the mutation efficiency generated by the above-mentioned adenine base editor is too low and therefore cannot be detected by the analysis method in Example 2.

Comparative Example 2 Base editing mediated by Cpf1 mutants with different DNase inactivations

In addition to the commonly used D917A, the double-site inactivated mutant ddCpf1 (D917A, E1006A) of dCpf1 also only inactivates its DNase activity but retains its RNase activity. Therefore, we constructed the sequence shown in sequence 7. The adenine base editor composed of TadA9 and ddCpf1 was verified using the 5 crRNAs in Example 2.

As shown in Table 6, the adenine base editor composed of TadA9 and ddCpf1 can also complete simultaneous mutation of 5 sites, but the mutation efficiency is lower than that of dCpf1.

Table 6 Base editing mediated by Cpf1 mutants with different DNase inactivations

Comparative Example 3: Effect of connection method on the constructed base editing system

As described in Example 1, the adenine deaminase mutants and dCpf1 in the present invention were connected using a short peptide linker (SGGSSGGSSGSETPGTSESATPESSGGSSGGS). In order to verify the impact of the connection on the base editing system, we tried to connect TadA9 and dCpf1 The short peptide on the protein is removed, allowing the two proteins to be directly linked. However, when the fusion protein after removing the linking peptide was verified using the five crRNAs in Example 3, it no longer had base editing activity, indicating that the linking peptide is necessary for the normal operation of the base editor.

Obviously, the above-mentioned embodiments are only examples for clear explanation and are not intended to limit the implementation. For those of ordinary skill in the art, other changes or modifications may be made based on the above description. An exhaustive list of all implementations is neither necessary nor possible. The obvious changes or modifications derived therefrom are still within the protection scope of the present invention.

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

785 790 795 800

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

805 810 815

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

820 825 830

Lys Lys Asn Asn Lys Ile Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys

835 840 845

Gly Glu Gly Tyr Lys Lys Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn

850 855 860

Lys Met Leu Pro Lys Val Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr

865 870 875 880

Asn Pro Ser Glu Asp Ile Leu Arg Ile Arg Asn His Ser Thr His Thr

885 890 895

Lys Asn Gly Ser Pro Gln Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile

900 905 910

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

915 920 925

His Pro Glu Trp Lys Asp Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg

930 935 940

Tyr Asn Ser Ile Asp Glu Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr

945 950 955 960

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

965 970 975

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

980 985 990

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

995 1000 1005

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

1010 1015 1020

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

1025 1030 1035 1040

His Pro Ala Lys Glu Ala Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys

1045 1050 1055

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

1060 1065 1070

Glu Asp Lys Phe Phe Phe His Cys Pro Ile Thr Ile Asn Phe Lys Ser

1075 1080 1085

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

1090 1095 1100

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

1105 1110 1115 1120

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

1125 1130 1135

Asp Thr Phe Asn Ile Ile Gly Asn Asp Arg Met Lys Thr Asn Tyr His

1140 1145 1150

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

1155 1160 1165

Trp Lys Lys Ile Asn Asn Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser

1170 1175 1180

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

1185 1190 1195 1200

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

1205 1210 1215

Val Glu Lys Gln Val Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys

1220 1225 1230

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

1235 1240 1245

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

1250 1255 1260

Met Gly Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr

1265 1270 1275 1280

Ser Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys

1285 1290 1295

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

1300 1305 1310

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

1315 1320 1325

Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr Ile Ala Ser

1330 1335 1340

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

1345 1350 1355 1360

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

1365 1370 1375

Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly Glu Cys Ile Lys Ala Ala

1380 1385 1390

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

1395 1400 1405

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

1410 1415 1420

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

1425 1430 1435 1440

Ser Arg Gln Ala Pro Lys Asn Met Pro Gln Asp Ala Asp Ala Asn Gly

1445 1450 1455

Ala Tyr His Ile Gly Leu Lys Gly Leu Met Leu Leu Gly Arg Ile Lys

1460 1465 1470

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

1475 1480 1485

Tyr Phe Glu Phe Val Gln Asn Arg Asn Asn Ser Gly Gly Ser Pro Lys

1490 1495 1500

Lys Lys Arg Lys Val

1505

<210> 2

<211> 1509

<212> PRT

<213> (artificial sequence)

<400> 2

Met Ser Glu Val Glu Phe Ser His Glu Tyr Trp Met Arg His Ala Leu

1 5 10 15

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

20 25 30

Val Leu Val Leu Asn Asn Arg Val Ile Gly Glu Gly Trp Asn Arg Ala

35 40 45

Ile Gly Leu His Asp Pro Thr Ala His Ala Glu Ile Met Ala Leu Arg

50 55 60

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

65 70 75 80

Tyr Ser Thr Phe Glu Pro Cys Val Met Cys Ala Gly Ala Met Ile His

85 90 95

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

100 105 110

Ala Ala Gly Ser Leu Met Asp Val Leu His His Pro Gly Met Asn His

115 120 125

Arg Val Glu Ile Thr Glu Gly Ile Leu Ala Asp Glu Cys Ala Ala Leu

130 135 140

Leu Cys Arg Phe Phe Arg Met Pro Arg Arg Val Phe Asn Ala Gln Lys

145 150 155 160

Lys Ala Gln Ser Ser Thr Asp Ser Gly Gly Ser Ser Gly Gly Ser Ser

165 170 175

Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Ser

180 185 190

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

195 200 205

Tyr Ser Leu Ser Lys Thr Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys

210 215 220

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

225 230 235 240

Arg Ala Lys Asp Tyr Lys Lys Ala Lys Gln Ile Ile Asp Lys Tyr His

245 250 255

Gln Phe Phe Ile Glu Glu Ile Leu Ser Ser Val Cys Ile Ser Glu Asp

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Ile Leu Trp Leu Lys Gln Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys

340 345 350

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

355 360 365

Ser Phe Lys Gly Trp Thr Thr Tyr Phe Lys Gly Phe His Glu Asn Arg

370 375 380

Lys Asn Val Tyr Ser Ser Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg

385 390 395 400

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

405 410 415

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

420 425 430

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

435 440 445

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

450 455 460

Ala Asn Phe Asn Asn Tyr Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn

465 470 475 480

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

485 490 495

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

500 505 510

Thr Leu Lys Lys Tyr Lys Met Ser Val Leu Phe Lys Gln Ile Leu Ser

515 520 525

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

530 535 540

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

545 550 555 560

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

565 570 575

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

580 585 590

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

595 600 605

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

610 615 620

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

625 630 635 640

Lys Lys Thr Glu Lys Ala Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu

645 650 655

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

660 665 670

Phe Glu Glu Ile Leu Ala Asn Phe Ala Ala Ile Pro Met Ile Phe Asp

675 680 685

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

690 695 700

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

705 710 715 720

Val Lys Ala Ile Lys Asp Leu Leu Asp Gln Thr Asn Asn Leu Leu His

725 730 735

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

740 745 750

Leu Asp Lys Asp Glu His Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe

755 760 765

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

770 775 780

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

785 790 795 800

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

805 810 815

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

820 825 830

Lys Lys Asn Asn Lys Ile Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys

835 840 845

Gly Glu Gly Tyr Lys Lys Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn

850 855 860

Lys Met Leu Pro Lys Val Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr

865 870 875 880

Asn Pro Ser Glu Asp Ile Leu Arg Ile Arg Asn His Ser Thr His Thr

885 890 895

Lys Asn Gly Ser Pro Gln Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile

900 905 910

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

915 920 925

His Pro Glu Trp Lys Asp Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg

930 935 940

Tyr Asn Ser Ile Asp Glu Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr

945 950 955 960

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

965 970 975

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

980 985 990

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

995 1000 1005

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

1010 1015 1020

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

1025 1030 1035 1040

His Pro Ala Lys Glu Ala Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys

1045 1050 1055

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

1060 1065 1070

Glu Asp Lys Phe Phe Phe His Cys Pro Ile Thr Ile Asn Phe Lys Ser

1075 1080 1085

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

1090 1095 1100

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

1105 1110 1115 1120

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

1125 1130 1135

Asp Thr Phe Asn Ile Ile Gly Asn Asp Arg Met Lys Thr Asn Tyr His

1140 1145 1150

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

1155 1160 1165

Trp Lys Lys Ile Asn Asn Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser

1170 1175 1180

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

1185 1190 1195 1200

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

1205 1210 1215

Val Glu Lys Gln Val Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys

1220 1225 1230

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

1235 1240 1245

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

1250 1255 1260

Met Gly Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr

1265 1270 1275 1280

Ser Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys

1285 1290 1295

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

1300 1305 1310

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

1315 1320 1325

Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr Ile Ala Ser

1330 1335 1340

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

1345 1350 1355 1360

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

1365 1370 1375

Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly Glu Cys Ile Lys Ala Ala

1380 1385 1390

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

1395 1400 1405

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

1410 1415 1420

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

1425 1430 1435 1440

Ser Arg Gln Ala Pro Lys Asn Met Pro Gln Asp Ala Asp Ala Asn Gly

1445 1450 1455

Ala Tyr His Ile Gly Leu Lys Gly Leu Met Leu Leu Gly Arg Ile Lys

1460 1465 1470

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

1475 1480 1485

Tyr Phe Glu Phe Val Gln Asn Arg Asn Asn Ser Gly Gly Ser Pro Lys

1490 1495 1500

Lys Lys Arg Lys Val

1505

<210> 3

<211> 1509

<212> PRT

<213> (artificial sequence)

<400> 3

Met Ser Glu Val Glu Phe Ser His Glu Tyr Trp Met Arg His Ala Leu

1 5 10 15

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

20 25 30

Val Leu Val Leu Asn Asn Arg Val Ile Gly Glu Gly Trp Asn Arg Ala

35 40 45

Ile Gly Leu His Asp Pro Thr Ala His Ala Glu Ile Met Ala Leu Arg

50 55 60

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

65 70 75 80

Tyr Val Thr Phe Glu Pro Cys Val Met Cys Ala Gly Ala Met Ile His

85 90 95

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

100 105 110

Ala Ala Gly Ser Leu Met Asn Val Leu Asn Tyr Pro Gly Met Asn His

115 120 125

Arg Val Glu Ile Thr Glu Gly Ile Leu Ala Asp Glu Cys Ala Ala Leu

130 135 140

Leu Cys Asp Phe Tyr Arg Met Pro Arg Gln Val Phe Asn Ala Gln Lys

145 150 155 160

Lys Ala Gln Ser Ser Ile Asn Ser Gly Gly Ser Ser Gly Gly Ser Ser

165 170 175

Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Ser

180 185 190

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

195 200 205

Tyr Ser Leu Ser Lys Thr Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys

210 215 220

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

225 230 235 240

Arg Ala Lys Asp Tyr Lys Lys Ala Lys Gln Ile Ile Asp Lys Tyr His

245 250 255

Gln Phe Phe Ile Glu Glu Ile Leu Ser Ser Val Cys Ile Ser Glu Asp

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Ile Leu Trp Leu Lys Gln Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys

340 345 350

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

355 360 365

Ser Phe Lys Gly Trp Thr Thr Tyr Phe Lys Gly Phe His Glu Asn Arg

370 375 380

Lys Asn Val Tyr Ser Ser Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg

385 390 395 400

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

405 410 415

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

420 425 430

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

435 440 445

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

450 455 460

Ala Asn Phe Asn Asn Tyr Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn

465 470 475 480

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

485 490 495

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

500 505 510

Thr Leu Lys Lys Tyr Lys Met Ser Val Leu Phe Lys Gln Ile Leu Ser

515 520 525

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

530 535 540

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

545 550 555 560

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

565 570 575

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

580 585 590

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

595 600 605

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

610 615 620

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

625 630 635 640

Lys Lys Thr Glu Lys Ala Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu

645 650 655

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

660 665 670

Phe Glu Glu Ile Leu Ala Asn Phe Ala Ala Ile Pro Met Ile Phe Asp

675 680 685

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

690 695 700

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

705 710 715 720

Val Lys Ala Ile Lys Asp Leu Leu Asp Gln Thr Asn Asn Leu Leu His

725 730 735

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

740 745 750

Leu Asp Lys Asp Glu His Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe

755 760 765

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

770 775 780

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

785 790 795 800

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

805 810 815

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

820 825 830

Lys Lys Asn Asn Lys Ile Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys

835 840 845

Gly Glu Gly Tyr Lys Lys Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn

850 855 860

Lys Met Leu Pro Lys Val Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr

865 870 875 880

Asn Pro Ser Glu Asp Ile Leu Arg Ile Arg Asn His Ser Thr His Thr

885 890 895

Lys Asn Gly Ser Pro Gln Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile

900 905 910

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

915 920 925

His Pro Glu Trp Lys Asp Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg

930 935 940

Tyr Asn Ser Ile Asp Glu Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr

945 950 955 960

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

965 970 975

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

980 985 990

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

995 1000 1005

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

1010 1015 1020

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

1025 1030 1035 1040

His Pro Ala Lys Glu Ala Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys

1045 1050 1055

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

1060 1065 1070

Glu Asp Lys Phe Phe Phe His Cys Pro Ile Thr Ile Asn Phe Lys Ser

1075 1080 1085

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

1090 1095 1100

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

1105 1110 1115 1120

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

1125 1130 1135

Asp Thr Phe Asn Ile Ile Gly Asn Asp Arg Met Lys Thr Asn Tyr His

1140 1145 1150

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

1155 1160 1165

Trp Lys Lys Ile Asn Asn Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser

1170 1175 1180

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

1185 1190 1195 1200

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

1205 1210 1215

Val Glu Lys Gln Val Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys

1220 1225 1230

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

1235 1240 1245

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

1250 1255 1260

Met Gly Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr

1265 1270 1275 1280

Ser Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys

1285 1290 1295

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

1300 1305 1310

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

1315 1320 1325

Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr Ile Ala Ser

1330 1335 1340

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

1345 1350 1355 1360

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

1365 1370 1375

Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly Glu Cys Ile Lys Ala Ala

1380 1385 1390

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

1395 1400 1405

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

1410 1415 1420

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

1425 1430 1435 1440

Ser Arg Gln Ala Pro Lys Asn Met Pro Gln Asp Ala Asp Ala Asn Gly

1445 1450 1455

Ala Tyr His Ile Gly Leu Lys Gly Leu Met Leu Leu Gly Arg Ile Lys

1460 1465 1470

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

1475 1480 1485

Tyr Phe Glu Phe Val Gln Asn Arg Asn Asn Ser Gly Gly Ser Pro Lys

1490 1495 1500

Lys Lys Arg Lys Val

1505

<210> 4

<211> 1509

<212> PRT

<213> (artificial sequence)

<400> 4

Met Ser Glu Val Glu Phe Ser His Glu Tyr Trp Met Arg His Ala Leu

1 5 10 15

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

20 25 30

Val Leu Val Leu Asn Asn Arg Val Ile Gly Glu Gly Trp Asn Arg Ala

35 40 45

Ile Gly Leu His Asp Pro Thr Ala His Ala Glu Ile Met Ala Leu Arg

50 55 60

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

65 70 75 80

Tyr Ser Thr Phe Glu Pro Cys Val Met Cys Ala Gly Ala Met Ile His

85 90 95

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

100 105 110

Ala Ala Gly Ser Leu Met Asn Val Leu Asn Tyr Pro Gly Met Asn His

115 120 125

Arg Val Glu Ile Thr Glu Gly Ile Leu Ala Asp Glu Cys Ala Ala Leu

130 135 140

Leu Cys Asp Phe Tyr Arg Met Pro Arg Arg Val Phe Asn Ala Gln Lys

145 150 155 160

Lys Ala Gln Ser Ser Ile Asn Ser Gly Gly Ser Ser Gly Gly Ser Ser

165 170 175

Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Ser

180 185 190

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

195 200 205

Tyr Ser Leu Ser Lys Thr Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys

210 215 220

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

225 230 235 240

Arg Ala Lys Asp Tyr Lys Lys Ala Lys Gln Ile Ile Asp Lys Tyr His

245 250 255

Gln Phe Phe Ile Glu Glu Ile Leu Ser Ser Val Cys Ile Ser Glu Asp

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Ile Leu Trp Leu Lys Gln Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys

340 345 350

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

355 360 365

Ser Phe Lys Gly Trp Thr Thr Tyr Phe Lys Gly Phe His Glu Asn Arg

370 375 380

Lys Asn Val Tyr Ser Ser Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg

385 390 395 400

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

405 410 415

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

420 425 430

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

435 440 445

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

450 455 460

Ala Asn Phe Asn Asn Tyr Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn

465 470 475 480

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

485 490 495

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

500 505 510

Thr Leu Lys Lys Tyr Lys Met Ser Val Leu Phe Lys Gln Ile Leu Ser

515 520 525

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

530 535 540

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

545 550 555 560

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

565 570 575

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

580 585 590

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

595 600 605

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

610 615 620

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

625 630 635 640

Lys Lys Thr Glu Lys Ala Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu

645 650 655

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

660 665 670

Phe Glu Glu Ile Leu Ala Asn Phe Ala Ala Ile Pro Met Ile Phe Asp

675 680 685

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

690 695 700

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

705 710 715 720

Val Lys Ala Ile Lys Asp Leu Leu Asp Gln Thr Asn Asn Leu Leu His

725 730 735

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

740 745 750

Leu Asp Lys Asp Glu His Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe

755 760 765

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

770 775 780

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

785 790 795 800

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

805 810 815

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

820 825 830

Lys Lys Asn Asn Lys Ile Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys

835 840 845

Gly Glu Gly Tyr Lys Lys Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn

850 855 860

Lys Met Leu Pro Lys Val Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr

865 870 875 880

Asn Pro Ser Glu Asp Ile Leu Arg Ile Arg Asn His Ser Thr His Thr

885 890 895

Lys Asn Gly Ser Pro Gln Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile

900 905 910

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

915 920 925

His Pro Glu Trp Lys Asp Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg

930 935 940

Tyr Asn Ser Ile Asp Glu Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr

945 950 955 960

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

965 970 975

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

980 985 990

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

995 1000 1005

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

1010 1015 1020

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

1025 1030 1035 1040

His Pro Ala Lys Glu Ala Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys

1045 1050 1055

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

1060 1065 1070

Glu Asp Lys Phe Phe Phe His Cys Pro Ile Thr Ile Asn Phe Lys Ser

1075 1080 1085

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

1090 1095 1100

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

1105 1110 1115 1120

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

1125 1130 1135

Asp Thr Phe Asn Ile Ile Gly Asn Asp Arg Met Lys Thr Asn Tyr His

1140 1145 1150

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

1155 1160 1165

Trp Lys Lys Ile Asn Asn Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser

1170 1175 1180

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

1185 1190 1195 1200

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

1205 1210 1215

Val Glu Lys Gln Val Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys

1220 1225 1230

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

1235 1240 1245

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

1250 1255 1260

Met Gly Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr

1265 1270 1275 1280

Ser Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys

1285 1290 1295

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

1300 1305 1310

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

1315 1320 1325

Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr Ile Ala Ser

1330 1335 1340

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

1345 1350 1355 1360

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

1365 1370 1375

Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly Glu Cys Ile Lys Ala Ala

1380 1385 1390

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

1395 1400 1405

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

1410 1415 1420

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

1425 1430 1435 1440

Ser Arg Gln Ala Pro Lys Asn Met Pro Gln Asp Ala Asp Ala Asn Gly

1445 1450 1455

Ala Tyr His Ile Gly Leu Lys Gly Leu Met Leu Leu Gly Arg Ile Lys

1460 1465 1470

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

1475 1480 1485

Tyr Phe Glu Phe Val Gln Asn Arg Asn Asn Ser Gly Gly Ser Pro Lys

1490 1495 1500

Lys Lys Arg Lys Val

1505

<210> 5

<211> 82

<212> DNA

<213> (artificial sequence)

<400> 5

gtctaagaac tttaaataat ttctactgtt gtagatagag accgtgaagt taataaggtc 60

tcaaatttct actgttgtag at 82

<210> 6

<211> 1707

<212> PRT

<213> (artificial sequence)

<400> 6

Met Ser Glu Val Glu Phe Ser His Glu Tyr Trp Met Arg His Ala Leu

1 5 10 15

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

20 25 30

Val Leu Val His Asn Asn Arg Val Ile Gly Glu Gly Trp Asn Arg Pro

35 40 45

Ile Gly Arg His Asp Pro Thr Ala His Ala Glu Ile Met Ala Leu Arg

50 55 60

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

65 70 75 80

Tyr Val Thr Leu Glu Pro Cys Val Met Cys Ala Gly Ala Met Ile His

85 90 95

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

100 105 110

Ala Ala Gly Ser Leu Met Asp Val Leu His His Pro Gly Met Asn His

115 120 125

Arg Val Glu Ile Thr Glu Gly Ile Leu Ala Asp Glu Cys Ala Ala Leu

130 135 140

Leu Ser Asp Phe Phe Arg Met Arg Arg Gln Glu Ile Lys Ala Gln Lys

145 150 155 160

Lys Ala Gln Ser Ser Thr Asp Ser Gly Gly Ser Ser Gly Gly Ser Ser

165 170 175

Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Ser

180 185 190

Gly Gly Ser Ser Gly Gly Ser Ser Ser Glu Val Glu Phe Ser His Glu Tyr

195 200 205

Trp Met Arg His Ala Leu Thr Leu Ala Lys Arg Ala Arg Asp Glu Arg

210 215 220

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

225 230 235 240

Glu Gly Trp Asn Arg Ala Ile Gly Leu His Asp Pro Thr Ala His Ala

245 250 255

Glu Ile Met Ala Leu Arg Gln Gly Gly Leu Val Met Gln Asn Tyr Arg

260 265 270

Leu Ile Asp Ala Thr Leu Tyr Val Thr Phe Glu Pro Cys Val Met Cys

275 280 285

Ala Gly Ala Met Ile His Ser Arg Ile Gly Arg Val Val Phe Gly Val

290 295 300

Arg Asn Ala Lys Thr Gly Ala Ala Gly Ser Leu Met Asp Val Leu His

305 310 315 320

Tyr Pro Gly Met Asn His Arg Val Glu Ile Thr Glu Gly Ile Leu Ala

325 330 335

Asp Glu Cys Ala Ala Leu Leu Cys Tyr Phe Phe Arg Met Pro Arg Gln

340 345 350

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

355 360 365

Ser Ser Gly Gly Ser Ser Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser

370 375 380

Ala Thr Pro Glu Ser Ser Gly Gly Ser Ser Gly Gly Ser Ser Ile Tyr

385 390 395 400

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

405 410 415

Leu Ile Pro Gln Gly Lys Thr Leu Glu Asn Ile Lys Ala Arg Gly Leu

420 425 430

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

435 440 445

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

450 455 460

Val Cys Ile Ser Glu Asp Leu Leu Gln Asn Tyr Ser Asp Val Tyr Phe

465 470 475 480

Lys Leu Lys Lys Ser Asp Asp Asp Asn Leu Gln Lys Asp Phe Lys Ser

485 490 495

Ala Lys Asp Thr Ile Lys Lys Gln Ile Ser Glu Tyr Ile Lys Asp Ser

500 505 510

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

515 520 525

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

530 535 540

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

545 550 555 560

Ala Leu Glu Ile Ile Lys Ser Phe Lys Gly Trp Thr Thr Tyr Phe Lys

565 570 575

Gly Phe His Glu Asn Arg Lys Asn Val Tyr Ser Ser Asn Asp Ile Pro

580 585 590

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

595 600 605

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

610 615 620

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

625 630 635 640

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

645 650 655

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

660 665 670

Gly Ile Thr Lys Phe Asn Thr Ile Ile Gly Gly Lys Phe Val Asn Gly

675 680 685

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

690 695 700

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

705 710 715 720

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

725 730 735

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

740 745 750

Glu Gln Ile Ala Ala Phe Lys Thr Val Glu Glu Lys Ser Ile Lys Glu

755 760 765

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

770 775 780

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

785 790 795 800

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

805 810 815

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

820 825 830

Glu Gln Glu Leu Ile Ala Lys Lys Thr Glu Lys Ala Lys Tyr Leu Ser

835 840 845

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

850 855 860

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

865 870 875 880

Ile Pro Met Ile Phe Asp Glu Ile Ala Gln Asn Lys Asp Asn Leu Ala

885 890 895

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

900 905 910

Ala Ser Ala Glu Asp Asp Val Lys Ala Ile Lys Asp Leu Leu Asp Gln

915 920 925

Thr Asn Asn Leu Leu His Lys Leu Lys Ile Phe His Ile Ser Gln Ser

930 935 940

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

945 950 955 960

Phe Glu Glu Cys Tyr Phe Glu Leu Ala Asn Ile Val Pro Leu Tyr Asn

965 970 975

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

980 985 990

Lys Leu Asn Phe Glu Asn Ser Thr Leu Ala Asn Gly Trp Asp Lys Asn

995 1000 1005

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

1010 1015 1020

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

1025 1030 1035 1040

Ala Ile Lys Glu Asn Lys Gly Glu Gly Tyr Lys Lys Ile Val Tyr Lys

1045 1050 1055

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

1060 1065 1070

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

1075 1080 1085

Asn His Ser Thr His Thr Lys Asn Gly Ser Pro Gln Lys Gly Tyr Glu

1090 1095 1100

Lys Phe Glu Phe Asn Ile Glu Asp Cys Arg Lys Phe Ile Asp Phe Tyr

1105 1110 1115 1120

Lys Gln Ser Ile Ser Lys His Pro Glu Trp Lys Asp Phe Gly Phe Arg

1125 1130 1135

Phe Ser Asp Thr Gln Arg Tyr Asn Ser Ile Asp Glu Phe Tyr Arg Glu

1140 1145 1150

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

1155 1160 1165

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

1170 1175 1180

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

1185 1190 1195 1200

Thr Leu Tyr Trp Lys Ala Leu Phe Asp Glu Arg Asn Leu Gln Asp Val

1205 1210 1215

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

1220 1225 1230

Ile Pro Lys Lys Ile Thr His Pro Ala Lys Glu Ala Ile Ala Asn Lys

1235 1240 1245

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

1250 1255 1260

Lys Asp Lys Arg Phe Thr Glu Asp Lys Phe Phe Phe His Cys Pro Ile

1265 1270 1275 1280

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

1285 1290 1295

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

1300 1305 1310

Ala Arg Gly Glu Arg His Leu Ala Tyr Tyr Thr Leu Val Asp Gly Lys

1315 1320 1325

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

1330 1335 1340

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

1345 1350 1355 1360

Asp Ser Ala Arg Lys Asp Trp Lys Lys Ile Asn Asn Ile Lys Glu Met

1365 1370 1375

Lys Glu Gly Tyr Leu Ser Gln Val Val His Glu Ile Ala Lys Leu Val

1380 1385 1390

Ile Glu Tyr Asn Ala Ile Val Val Phe Glu Asp Leu Asn Phe Gly Phe

1395 1400 1405

Lys Arg Gly Arg Phe Lys Val Glu Lys Gln Val Tyr Gln Lys Leu Glu

1410 1415 1420

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

1425 1430 1435 1440

Phe Asp Lys Thr Gly Gly Val Leu Arg Ala Tyr Gln Leu Thr Ala Pro

1445 1450 1455

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

1460 1465 1470

Val Pro Ala Gly Phe Thr Ser Lys Ile Cys Pro Val Thr Gly Phe Val

1475 1480 1485

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

1490 1495 1500

Phe Ser Lys Phe Asp Lys Ile Cys Tyr Asn Leu Asp Lys Gly Tyr Phe

1505 1510 1515 1520

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

1525 1530 1535

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

1540 1545 1550

Ser Asp Lys Asn His Asn Trp Asp Thr Arg Glu Val Tyr Pro Thr Lys

1555 1560 1565

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

1570 1575 1580

Glu Cys Ile Lys Ala Ala Ile Cys Gly Glu Ser Asp Lys Lys Phe Phe

1585 1590 1595 1600

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

1605 1610 1615

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

1620 1625 1630

Asn Gly Asn Phe Phe Asp Ser Arg Gln Ala Pro Lys Asn Met Pro Gln

1635 1640 1645

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

1650 1655 1660

Leu Leu Gly Arg Ile Lys Asn Asn Gln Glu Gly Lys Lys Leu Asn Leu

1665 1670 1675 1680

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

1685 1690 1695

Ser Gly Gly Ser Pro Lys Lys Lys Arg Lys Val

1700 1705

<210> 7

<211> 1509

<212> PRT

<213> (artificial sequence)

<400> 7

Met Ser Glu Val Glu Phe Ser His Glu Tyr Trp Met Arg His Ala Leu

1 5 10 15

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

20 25 30

Val Leu Val Leu Asn Asn Arg Val Ile Gly Glu Gly Trp Asn Arg Ala

35 40 45

Ile Gly Leu His Asp Pro Thr Ala His Ala Glu Ile Met Ala Leu Arg

50 55 60

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

65 70 75 80

Tyr Ser Thr Phe Glu Pro Cys Val Met Cys Ala Gly Ala Met Ile His

85 90 95

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

100 105 110

Ala Ala Gly Ser Leu Met Asn Val Leu Asn Tyr Pro Gly Met Asn His

115 120 125

Arg Val Glu Ile Thr Glu Gly Ile Leu Ala Asp Glu Cys Ala Ala Leu

130 135 140

Leu Cys Asp Phe Tyr Arg Met Pro Arg Arg Val Phe Asn Ala Gln Lys

145 150 155 160

Lys Ala Gln Ser Ser Ile Asn Ser Gly Gly Ser Ser Gly Gly Ser Ser

165 170 175

Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Ser

180 185 190

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

195 200 205

Tyr Ser Leu Ser Lys Thr Leu Arg Phe Glu Leu Ile Pro Gln Gly Lys

210 215 220

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

225 230 235 240

Arg Ala Lys Asp Tyr Lys Lys Ala Lys Gln Ile Ile Asp Lys Tyr His

245 250 255

Gln Phe Phe Ile Glu Glu Ile Leu Ser Ser Val Cys Ile Ser Glu Asp

260 265 270

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

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Ile Leu Trp Leu Lys Gln Ser Lys Asp Asn Gly Ile Glu Leu Phe Lys

340 345 350

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

355 360 365

Ser Phe Lys Gly Trp Thr Thr Tyr Phe Lys Gly Phe His Glu Asn Arg

370 375 380

Lys Asn Val Tyr Ser Ser Asn Asp Ile Pro Thr Ser Ile Ile Tyr Arg

385 390 395 400

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

405 410 415

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

420 425 430

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

435 440 445

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

450 455 460

Ala Asn Phe Asn Asn Tyr Leu Asn Gln Ser Gly Ile Thr Lys Phe Asn

465 470 475 480

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

485 490 495

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

500 505 510

Thr Leu Lys Lys Tyr Lys Met Ser Val Leu Phe Lys Gln Ile Leu Ser

515 520 525

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

530 535 540

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

545 550 555 560

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

565 570 575

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

580 585 590

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

595 600 605

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

610 615 620

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

625 630 635 640

Lys Lys Thr Glu Lys Ala Lys Tyr Leu Ser Leu Glu Thr Ile Lys Leu

645 650 655

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

660 665 670

Phe Glu Glu Ile Leu Ala Asn Phe Ala Ala Ile Pro Met Ile Phe Asp

675 680 685

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

690 695 700

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

705 710 715 720

Val Lys Ala Ile Lys Asp Leu Leu Asp Gln Thr Asn Asn Leu Leu His

725 730 735

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

740 745 750

Leu Asp Lys Asp Glu His Phe Tyr Leu Val Phe Glu Glu Cys Tyr Phe

755 760 765

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

770 775 780

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

785 790 795 800

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

805 810 815

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

820 825 830

Lys Lys Asn Asn Lys Ile Phe Asp Asp Lys Ala Ile Lys Glu Asn Lys

835 840 845

Gly Glu Gly Tyr Lys Lys Ile Val Tyr Lys Leu Leu Pro Gly Ala Asn

850 855 860

Lys Met Leu Pro Lys Val Phe Phe Ser Ala Lys Ser Ile Lys Phe Tyr

865 870 875 880

Asn Pro Ser Glu Asp Ile Leu Arg Ile Arg Asn His Ser Thr His Thr

885 890 895

Lys Asn Gly Ser Pro Gln Lys Gly Tyr Glu Lys Phe Glu Phe Asn Ile

900 905 910

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

915 920 925

His Pro Glu Trp Lys Asp Phe Gly Phe Arg Phe Ser Asp Thr Gln Arg

930 935 940

Tyr Asn Ser Ile Asp Glu Phe Tyr Arg Glu Val Glu Asn Gln Gly Tyr

945 950 955 960

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

965 970 975

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

980 985 990

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

995 1000 1005

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

1010 1015 1020

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

1025 1030 1035 1040

His Pro Ala Lys Glu Ala Ile Ala Asn Lys Asn Lys Asp Asn Pro Lys

1045 1050 1055

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

1060 1065 1070

Glu Asp Lys Phe Phe Phe His Cys Pro Ile Thr Ile Asn Phe Lys Ser

1075 1080 1085

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

1090 1095 1100

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

1105 1110 1115 1120

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

1125 1130 1135

Asp Thr Phe Asn Ile Ile Gly Asn Asp Arg Met Lys Thr Asn Tyr His

1140 1145 1150

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

1155 1160 1165

Trp Lys Lys Ile Asn Asn Ile Lys Glu Met Lys Glu Gly Tyr Leu Ser

1170 1175 1180

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

1185 1190 1195 1200

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

1205 1210 1215

Val Glu Lys Gln Val Tyr Gln Lys Leu Glu Lys Met Leu Ile Glu Lys

1220 1225 1230

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

1235 1240 1245

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

1250 1255 1260

Met Gly Lys Gln Thr Gly Ile Ile Tyr Tyr Val Pro Ala Gly Phe Thr

1265 1270 1275 1280

Ser Lys Ile Cys Pro Val Thr Gly Phe Val Asn Gln Leu Tyr Pro Lys

1285 1290 1295

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

1300 1305 1310

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

1315 1320 1325

Lys Asn Phe Gly Asp Lys Ala Ala Lys Gly Lys Trp Thr Ile Ala Ser

1330 1335 1340

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

1345 1350 1355 1360

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

1365 1370 1375

Lys Asp Tyr Ser Ile Glu Tyr Gly His Gly Glu Cys Ile Lys Ala Ala

1380 1385 1390

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

1395 1400 1405

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

1410 1415 1420

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

1425 1430 1435 1440

Ser Arg Gln Ala Pro Lys Asn Met Pro Gln Asp Ala Asp Ala Asn Gly

1445 1450 1455

Ala Tyr His Ile Gly Leu Lys Gly Leu Met Leu Leu Gly Arg Ile Lys

1460 1465 1470

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

1475 1480 1485

Tyr Phe Glu Phe Val Gln Asn Arg Asn Asn Ser Gly Gly Ser Pro Lys

1490 1495 1500

Lys Lys Arg Lys Val

1505

<210> 8

<211> 9445

<212> DNA

<213> (artificial sequence)

<400> 8

atgtcatgac attggtgtac agaaatggcg cagcaatggc aagaacgtcc cgggcggagc 60

tcaggcctta actcacatta attgcgttgc gctcactgcc cgctttccag tcgggaaacc 120

tgtcgtgcca gctgcattaa tgaatcggcc aacgcgcggg gagaggcggt ttgcgtattg 180

ggcgccaggg tggtttttct tttcaccagt gagacgggca acagctgatt gcccttcacc 240

gcctggccct gagagagttg cagcaagcgg tccacgctgg tttgccccag caggcgaaaa 300

tcctgtttga tggtggttaa cggcgggata taacatgagc tgtcttcggt atcgtcgtat 360

cccactaccg agatatccgc accaacgcgc agcccggact cggtaatggc gcgcattgcg 420

cccagcgcca tctgatcgtt ggcaaccagc atcgcagtgg gaacgatgcc ctcattcagc 480

atttgcatgg tttgttgaaa accggacatg gcactccagt cgccttcccg ttccgctatc 540

ggctgaattt gattgcgagt gagatattta tgccagccag ccagacgcag acgcgccgag 600

acagaactta atgggcccgc taacagcgcg atttgctggt gacccaatgc gaccagatgc 660

tccacgccca gtcgcgtacc gtcttcatgg gagaaaataa tactgttgat gggtgtctgg 720

tcagagacat caagaaataa cgccggaaca ttagtgcagg cagcttccac agcaatggca 780

tcctggtcat ccagcggata gttaatgatc agcccactga cgcgttgcgc gagaagattg 840

tgcaccgccg ttttacaggc ttcgacgccg cttcgttcta ccatcgacac caccacgctg 900

gcacccagtt gatcggcgcg agatttaatc gccgcgacaa tttgcgacgg cgcgtgcagg 960

gccagactgg aggtggcaac gccaatcagc aacgactgtt tgcccgccag ttgttgtgcc 1020

acgcggttgg gaatgtaatt cagctccgcc atcgccgctt ccactttttc ccgcgttttc 1080

gcagaaacgt ggctggcctg gttcaccacg cgggaaacgg tctgataaga gacaccggca 1140

tactctgcga catcgtataa cgttatactggt ttcatcaaaa tcgtctccct ccgtttgaat 1200

atttgattga tcgtaaccag atgaagcact ctttccacta tccctacagt gttatggctt 1260

gaacaatcac gaaacaataa ttggtacgta cgatctttca gccgactcaa acatcaaatc 1320

ttacaaatgt agtctttgaa agtattacat atgtaagatt taaatgcaac cgttttttcg 1380

gaaggaaatg atgacctcgt ttccaccgga attagcttgg taccagctat tgtaacataa 1440

tcggtacggg ggtgaaaaag ctaacggaaa agggagcgga aaagaatgat gtaagcgtga 1500

aaaatttttt aaaaaatctc ttgacattgg aagggagata tgttattata agaattgcgg 1560

aattgtgagc ggataacaat tcataattgt gagcggataa caattcaacc ccaaaggagg 1620

tgggatccat gagcgaagtt gaattcagcc acgagtactg gatgcgccat gcccttacac 1680

ttgccaaacg cgctcgcgat gaacgcgaag tcccagttgg cgccgttctt gttcttaaca 1740

accgcgtcat cggagaaggc tggaaccgcg ctatcggact tcatgatccg acagctcatg 1800

ccgaaattat ggctctgcgc caaggcggac ttgtcatgca gaattacaga cttattgatg 1860

ccacgcttta ctcaacgttc gaaccgtgcg tcatgtgcgc cggcgccatg attcatagcc 1920

gcatcggcag agttgtcttc ggcgtccgca atgctaaaac gggcgccgcc ggctccctta 1980

tggacgtcct tcattacccg ggcatgaatc accgcgttga aatcacagaa ggcattctgg 2040

ccgatgagtg cgccgctctg ctgtgctact tcttcagaat gccgagaaga gtcttcaacg 2100

cccagaagaa agcccaaagc agcacagact ctggaggatc atccggaggc agctctggaa 2160

gtgaaacacc aggaacaagc gaatcagcta caccagagtc ctctggaggc tcatctggag 2220

gaagctcaat ttatcaagaa tttgttaata aatatagttt aagtaaaact ctaagatttg 2280

agttaatccc acagggtaaa acacttgaaa acataaaagc aagaggtttg attttagatg 2340

atgagaaaag agctaaagac tacaaaaagg ctaaacaaat aattgataaa tatcatcagt 2400

tttttataga ggagatatta agttcggttt gtattagcga agatttatta caaaactatt 2460

ctgatgttta ttttaaactt aaaaagagtg atgatgataa tctacaaaaa gattttaaaa 2520

gtgcaaaaga tacgataaag aaacaaatat ctgaatat aaaggactca gagaaattta 2580

agaatttgtt taatcaaaac cttatcgatg ctaaaaaagg gcaagagtca gatttaattc 2640

tatggctaaa gcaatctaag gataatggta tagaactatt taaagccaat agtgatatca 2700

cagatataga tgaggcgtta gaaataatca aatcttttaa aggttggaca acttatttta 2760

agggttttca tgaaaataga aaaaatgttt atagtagcaa tgatattcct acatctatta 2820

tttataggat agtagatgat aatttgccta aatttctaga aaataaagct aagtatgaga 2880

gtttaaaaga caaagctcca gaagctataa actatgaaca aattaaaaaa gatttggcag 2940

aagagctaac ctttgatatt gactacaaaa catctgaagt taatcaaaga gttttttcac 3000

ttgatgaagt ttttgagata gcaaacttta ataattatct aaatcaaagt ggtattacta 3060

aatttaatac tattattggt ggtaaatttg taaatggtga aaatacaaag agaaaaggta 3120

taaatgaata tataaatcta tactcacagc aaataaatga taaaacactc aaaaaatata 3180

aaatgagtgt tttatttaag caaattttaa gtgatacaga atctaaatct tttgtaattg 3240

ataagttaga agatgatagt gatgtagtta caacgatgca aagtttttat gagcaaatag 3300

cagcttttaa aacagtagaa gaaaaatcta ttaaagaaac actatcttta ttatttgatg 3360

atttaaaagc tcaaaaactt gatttgagta aaatttattt taaaaatgat aaatctctta 3420

ctgatctatc acaacaagtt tttgatgatt atagtgttat tggtacagcg gtactagaat 3480

atataactca acaaatagca cctaaaaatc ttgataaccc tagtaagaaa gagcaagaat 3540

taatagccaa aaaaactgaa aaagcaaaat acttatctct agaaactata aagcttgcct 3600

tagaagaatt taataagcat agagatatag ataaacagtg taggtttgaa gaaatacttg 3660

caaactttgc ggctattccg atgatatttg atgaaatagc tcaaaacaaa gacaatttgg 3720

cacagatatc tatcaaatat caaaatcaag gtaaaaaaga cctacttcaa gctagtgcgg 3780

aagatgatgt taaagctatc aaggatcttt tagatcaaac taataatctc ttacataaac 3840

taaaaatatt tcatattagt cagtcagaag ataaggcaaa tattttagac aaggatgagc 3900

atttttatct agtatttgag gagtgctact ttgagctagc gaatatagtg cctctttata 3960

acaaaattag aaactata actcaaaagc catatagtga tgagaaattt aagctcaatt 4020

ttgagaactc gactttggct aatggttggg ataaaaataa agagcctgac aatacggcaa 4080

ttttatttat caaagatgat aaatattatc tgggtgtgat gaataagaaa aataacaaaa 4140

tatttgatga taaagctatc aaagaaaata aaggcgaggg ttataaaaaa attgtttata 4200

aacttttacc tggcgcaaat aaaatgttac ctaaggtttt cttttctgct aaatctataa 4260

aattttataa tcctagtgaa gatatactta gaataagaaa tcattccaca catacaaaaa 4320

atggtagtcc tcaaaaagga tatgaaaaat ttgagtttaa tattgaagat tgccgaaaat 4380

ttatagattt ttataaacag tctataagta agcatccgga gtggaaagat tttggattta 4440

gattttctga tactcaaaga tataattcta tagatgaatt ttatagagaa gttgaaaatc 4500

aaggctacaa actaactttt gaaaatat cagagagcta tattgatagc gtagttaatc 4560

agggtaaatt gtacctattc caaatctata ataaagattt ttcagcttat agcaaagggc 4620

gaccaaatct acatacttta tattggaaag cgctgtttga tgagagaaat cttcaagatg 4680

tggtttataa gctaaatggt gaggcagagc ttttttatcg taaacaatca atacctaaaa 4740

aaatcactca cccagctaaa gaggcaatag ctaataaaaa caaagataat cctaaaaaag 4800

agagtgtttt tgaatatgat ttaatcaaag ataaacgctt tactgaagat aagtttttct 4860

ttcactgtcc tattacaatc aattttaaat ctagtggagc taataagttt aatgatgaaa 4920

tcaatttatt gctaaaagaa aaagcaaatg atgttcatat attaagtata gctagaggtg 4980

aaagacattt agcttactat actttggtag atggtaaagg caatatcatc aaacaagata 5040

ctttcaacat cattggtaat gatagaatga aaacaaacta ccatgataag cttgctgcaa 5100

tagagaaaga tagggattca gctaggaaag actggaaaaa gataaataac atcaaagaga 5160

tgaaagaggg ctatctatct caggtagttc atgaaatagc taagctagtt atagagtata 5220

atgctattgt ggtttttgag gatttaaatt ttggatttaa aagagggcgt ttcaaggtag 5280

agaagcaggt ctatcaaaag ttagaaaaaa tgctaattga gaaactaaac tatctagttt 5340

tcaaagataa tgagtttgat aaaactgggg gagtgcttag agctttatcag ctaacagcac 5400

cttttgagac ttttaaaaag atgggtaaac aaacaggtat tatctactat gtaccagctg 5460

gttttacttc aaaaatttgt cctgtaactg gttttgtaaa tcagttatat cctaagtatg 5520

aaagtgtcag caaatctcaa gagttcttta gtaagtttga caagatttgt tataaccttg 5580

ataagggcta ttttgagttt agttttgatt ataaaaactt tggtgacaag gctgccaaag 5640

gcaagtggac tatagctagc tttgggagta gattgattaa ctttagaaat tcagataaaa 5700

atcataattg ggatactcga gaagtttatc caactaaaga gttggagaaa ttgctaaaag 5760

attattctat cgaatatggg catggcgaat gtatcaaagc agctatttgc ggtgagagcg 5820

acaaaaagttttttgctaag ctaactagtg tcctaaatac tatcttacaa atgcgtaact 5880

caaaaacagg tactgagtta gattatctaa tttcaccagt agcagatgta aatggcaatt 5940

tctttgattc gcgacaggcg ccaaaaaata tgcctcaaga tgctgatgcc aatggtgctt 6000

atcatattgg gctaaaaggt ctgatgctac taggtaggat caaaaataat caagagggca 6060

aaaaactcaa tttggttatc aaaaatgaag agtattttga gttcgtgcag aataggaata 6120

actctggtgg ttctcccaag aagaagagga aagtctaact gcagtataat cagaaacagc 6180

ccgcggatgt tgatctgcgg gctgtttttt attgatcgaa tggccatgac caaaatccct 6240

taacgtgaag ttttcgttcc actgagcgtc agaccccgta gaaaagatca aaggatcttc 6300

ttgagatcct ttttttctgc gcgtaatctg ctgcttgcaa acaaaaaaac caccgctacc 6360

agcggtggtt tgtttgccgg atcaagagct accaactctt tttccgaagg taactggctt 6420

cagcagagcg cagataccaa atactgtcct tctagtgtag ccgtagttag gccaccactt 6480

caagaactct gtagcaccgc ctacatacct cgctctgcta atcctgttac cagtggctgc 6540

tgccagtggc gataagtcgt gtcttaccgg gttggactca agacgatagt taccggataa 6600

ggcgcagcgg tcgggctgaa cggggggttc gtgcacacag cccagcttgg agcgaacgac 6660

ctacaccgaa ctgagatacc tacagcgtga gctatgagaa agcgccacgc ttcccgaagg 6720

gagaaaggcg gacaggtatc cggtaagcgg cagggtcgga acaggagagc gcacgaggga 6780

gcttccaggg ggaaacgcct ggtatcttta tagtcctgtc gggtttcgcc acctctgact 6840

tgagcgtcga tttttgtgat gctcgtcagg ggggcggagc ctatggaaaa acgccagcaa 6900

cgcggccttt ttacggttcc tggccttttg ctggcctttt gctcacatgt tctttcctgc 6960

gttatcccct gattctgtgg ataaccgtat taccgccttt gagtgagctg agacaggtca 7020

ttcagactgg ctaatgcacc cagtaaggca gcggtatcat caactcaaaa tggtatgcgt 7080

tttgacacat ccactatata tccgtgtcgt tctgtccact cctgaatccc attccagaaa 7140

ttctctagcg attccagaag tttctcagag tcggaaagtt gaccagacat tacgaactgg 7200

cacagatggt cataacctga aggaagatct gattgcttaa ctgcttcagt taagaccgaa 7260

gcgctcgtcg tataacagat gcgatgatgc agaccaatca acatggcacc tgccattgct 7320

acctgcacag tcaaggatgg tagaaatgtt gtcggtcctt gcacacgaat attacgccat 7380

ttgcctgcat attcaaacag ctcttctacg ataagggcac aaatcgcatc gtggaacgtt 7440

tgggcttcta ccgatttagc agtttgatac actttctcta agtatccacc tgaatcataa 7500

atcggcaaaa tagagaaaaa ttgaccatgt gtaagcggcc aatctgattc cacctgagat 7560

gcataatcta gtagaatctc ttcgctatca aaattcactt ccaccttcca ctcaccggtt 7620

gtccattcat ggctgaactc tgcttcctct gttgacatga cacacatcat ctcaatatcc 7680

gaatagggcc catcagtctg acgaccaaga gagccataaa caccaatagc cttaacatca 7740

tccccatatt tatccaatat tcgttcctta atttcatgaa caatcttcat tctttcttct 7800

ctagtcatta ttatggtcc attcactatt ctcattcccc tttcagataa ttttagattt 7860

gcttttctaa ataagaatat ttggagagca ccgttcttat tcagctatta aacccattat 7920

atcgggtttt tgaggggatt tcaactgcag acacctaaat tcaaaatcta tcggtcagat 7980

ttataccgat ttgattttat atattcttga ataacatacg ccgagttatc acataaaagc 8040

gggaaccaat catcaaattt aaacttcatt gcataatcca ttaaactctt aaattctacg 8100

attccttgtt catcaataaa ctcaatcatt tctttaatta atttatatct atctgttgtt 8160

gttttcttta ataattcatc aacatctaca ccgccataaa ctatcatatc ttctttttga 8220

tatttaaatt tattaggatc gtccatgtga agcatatatc tcacaagacc tttcacactt 8280

cctgcaatct gcggaatagt cgcattcaat tcttctgtaa ttattttat ctgttcataa 8340

gatttattac cctcatacat cactagaata tgataatgct cttttttcat cctatcttct 8400

gtatcagtat ccctatcatg taatggagac actacaaatt gaatgtgtaa ctcttttaaa 8460

tactctaacc actcggcttt tgctgattct ggatataaaa caaatgtcca attacgtcct 8520

cttgaatttt tcttgttttc agtttctttt attacatttt cgctcatgat ataataacgg 8580

tgctaataca tttaacaaaa tttagtcata gataggcagc atgccagtgc tgtctatctt 8640

tttttgttta aaatgcaccg tattcctcct ttgcatattt ttttattaga ataccggttg 8700

catctgattt gctaatatta tatttttctt tgattctatt taatatctca ttttcttctg 8760

ttgtaagtct taaagtaaca gcaacttttt tctcttcttt tctatctaca accatcactg 8820

tacctcccaa catctgtttt tttcacttta acataaaaaa caacctttta acattaaaaa 8880

cccaatattt atttatttgt ttggacaatg gacaatggac acctaggggg gaggtcgtag 8940

taccccccta tgttttctcc cctaaataac cccaaaaatc taagaaaaaa agacctcaaa 9000

aaggtcttta attaacatct caaatttcgc atttattcca atttcctttt tgcgtgtgat 9060

gcgttattaa cgttgatata atttaaattt tatttgacaa aaatgggctc gtgttgtaca 9120

ataaatgtag aggtagagac gcgaggtcta agaactttaa ataatttcta ctgttgtaga 9180

tagagaccgt gaagttaata aggtctcaaa tttctactgt tgtagatcgt ctctgaactg 9240

attcaagcaa gcttaaaccc agctcaatga gctgggtttt ttgtttgttt tttcaaactt 9300

agttagcttg gccagtgcct ctagagtcaa gtaaagagtc gacctgttac gaacggcaga 9360

tcagaatttt gtaataaaaa aagagcctgc tcattacact gcgggctctt tttcatggtc 9420

agaagacggg taaccaagat aacaa 9445

<210> 9

<211> 9445

<212> DNA

<213> (artificial sequence)

<400> 9

atgtcatgac attggtgtac agaaatggcg cagcaatggc aagaacgtcc cgggcggagc 60

tcaggcctta actcacatta attgcgttgc gctcactgcc cgctttccag tcgggaaacc 120

tgtcgtgcca gctgcattaa tgaatcggcc aacgcgcggg gagaggcggt ttgcgtattg 180

ggcgccaggg tggtttttct tttcaccagt gagacgggca acagctgatt gcccttcacc 240

gcctggccct gagagagttg cagcaagcgg tccacgctgg tttgccccag caggcgaaaa 300

tcctgtttga tggtggttaa cggcgggata taacatgagc tgtcttcggt atcgtcgtat 360

cccactaccg agatatccgc accaacgcgc agcccggact cggtaatggc gcgcattgcg 420

cccagcgcca tctgatcgtt ggcaaccagc atcgcagtgg gaacgatgcc ctcattcagc 480

atttgcatgg tttgttgaaa accggacatg gcactccagt cgccttcccg ttccgctatc 540

ggctgaattt gattgcgagt gagatattta tgccagccag ccagacgcag acgcgccgag 600

acagaactta atgggcccgc taacagcgcg atttgctggt gacccaatgc gaccagatgc 660

tccacgccca gtcgcgtacc gtcttcatgg gagaaaataa tactgttgat gggtgtctgg 720

tcagagacat caagaaataa cgccggaaca ttagtgcagg cagcttccac agcaatggca 780

tcctggtcat ccagcggata gttaatgatc agcccactga cgcgttgcgc gagaagattg 840

tgcaccgccg ttttacaggc ttcgacgccg cttcgttcta ccatcgacac caccacgctg 900

gcacccagtt gatcggcgcg agatttaatc gccgcgacaa tttgcgacgg cgcgtgcagg 960

gccagactgg aggtggcaac gccaatcagc aacgactgtt tgcccgccag ttgttgtgcc 1020

acgcggttgg gaatgtaatt cagctccgcc atcgccgctt ccactttttc ccgcgttttc 1080

gcagaaacgt ggctggcctg gttcaccacg cgggaaacgg tctgataaga gacaccggca 1140

tactctgcga catcgtataa cgttatactggt ttcatcaaaa tcgtctccct ccgtttgaat 1200

atttgattga tcgtaaccag atgaagcact ctttccacta tccctacagt gttatggctt 1260

gaacaatcac gaaacaataa ttggtacgta cgatctttca gccgactcaa acatcaaatc 1320

ttacaaatgt agtctttgaa agtattacat atgtaagatt taaatgcaac cgttttttcg 1380

gaaggaaatg atgacctcgt ttccaccgga attagcttgg taccagctat tgtaacataa 1440

tcggtacggg ggtgaaaaag ctaacggaaa agggagcgga aaagaatgat gtaagcgtga 1500

aaaatttttt aaaaaatctc ttgacattgg aagggagata tgttattata agaattgcgg 1560

aattgtgagc ggataacaat tcataattgt gagcggataa caattcaacc ccaaaggagg 1620

tgggatccat gagcgaagtc gagttctccc acgaatactg gatgcgccat gcccttacac 1680

ttgccaaacg cgctcgcgat gaacgcgaag tcccagttgg cgccgttctt gttcttaaca 1740

accgcgtcat cggagaaggc tggaaccgcg ctatcggact tcatgatccg acagctcatg 1800

ccgaaattat ggctctgcgc caaggcggac ttgtcatgca gaattacaga ctttatgatg 1860

ccacgcttta ctcaacgttc gaaccgtgcg tcatgtgcgc cggcgccatg attcatagcc 1920

gcatcggcag agttgtcttc ggcgtccgca atgctaaaac gggcgccgcc ggctccctta 1980

tggacgtcct tcatcacccg ggcatgaatc accgcgttga aatcacagaa ggcattctgg 2040

ccgatgagtg cgccgctctg ctgtgcagat tcttcagaat gccgagaaga gtcttcaacg 2100

cccagaagaa agcccaaagc agcacagact ctggaggatc atccggaggc agctctggaa 2160

gtgaaacacc aggaacaagc gaatcagcta caccagagtc ctctggaggc tcatctggag 2220

gaagctcaat ttatcaagaa tttgttaata aatatagttt aagtaaaact ctaagatttg 2280

agttaatccc acagggtaaa acacttgaaa acataaaagc aagaggtttg attttagatg 2340

atgagaaaag agctaaagac tacaaaaagg ctaaacaaat aattgataaa tatcatcagt 2400

tttttataga ggagatatta agttcggttt gtattagcga agatttatta caaaactatt 2460

ctgatgttta ttttaaactt aaaaagagtg atgatgataa tctacaaaaa gattttaaaa 2520

gtgcaaaaga tacgataaag aaacaaatat ctgaatat aaaggactca gagaaattta 2580

agaatttgtt taatcaaaac cttatcgatg ctaaaaaagg gcaagagtca gatttaattc 2640

tatggctaaa gcaatctaag gataatggta tagaactatt taaagccaat agtgatatca 2700

cagatataga tgaggcgtta gaaataatca aatcttttaa aggttggaca acttatttta 2760

agggttttca tgaaaataga aaaaatgttt atagtagcaa tgatattcct acatctatta 2820

tttataggat agtagatgat aatttgccta aatttctaga aaataaagct aagtatgaga 2880

gtttaaaaga caaagctcca gaagctataa actatgaaca aattaaaaaa gatttggcag 2940

aagagctaac ctttgatatt gactacaaaa catctgaagt taatcaaaga gttttttcac 3000

ttgatgaagt ttttgagata gcaaacttta ataattatct aaatcaaagt ggtattacta 3060

aatttaatac tattattggt ggtaaatttg taaatggtga aaatacaaag agaaaaggta 3120

taaatgaata tataaatcta tactcacagc aaataaatga taaaacactc aaaaaatata 3180

aaatgagtgt tttatttaag caaattttaa gtgatacaga atctaaatct tttgtaattg 3240

ataagttaga agatgatagt gatgtagtta caacgatgca aagtttttat gagcaaatag 3300

cagcttttaa aacagtagaa gaaaaatcta ttaaagaaac actatcttta ttatttgatg 3360

atttaaaagc tcaaaaactt gatttgagta aaatttattt taaaaatgat aaatctctta 3420

ctgatctatc acaacaagtt tttgatgatt atagtgttat tggtacagcg gtactagaat 3480

atataactca acaaatagca cctaaaaatc ttgataaccc tagtaagaaa gagcaagaat 3540

taatagccaa aaaaactgaa aaagcaaaat acttatctct agaaactata aagcttgcct 3600

tagaagaatt taataagcat agagatatag ataaacagtg taggtttgaa gaaatacttg 3660

caaactttgc ggctattccg atgatatttg atgaaatagc tcaaaacaaa gacaatttgg 3720

cacagatatc tatcaaatat caaaatcaag gtaaaaaaga cctacttcaa gctagtgcgg 3780

aagatgatgt taaagctatc aaggatcttt tagatcaaac taataatctc ttacataaac 3840

taaaaatatt tcatattagt cagtcagaag ataaggcaaa tattttagac aaggatgagc 3900

atttttatct agtatttgag gagtgctact ttgagctagc gaatatagtg cctctttata 3960

acaaaattag aaactata actcaaaagc catatagtga tgagaaattt aagctcaatt 4020

ttgagaactc gactttggct aatggttggg ataaaaataa agagcctgac aatacggcaa 4080

ttttatttat caaagatgat aaatattatc tgggtgtgat gaataagaaa aataacaaaa 4140

tatttgatga taaagctatc aaagaaaata aaggcgaggg ttataaaaaa attgtttata 4200

aacttttacc tggcgcaaat aaaatgttac ctaaggtttt cttttctgct aaatctataa 4260

aattttataa tcctagtgaa gatatactta gaataagaaa tcattccaca catacaaaaa 4320

atggtagtcc tcaaaaagga tatgaaaaat ttgagtttaa tattgaagat tgccgaaaat 4380

ttatagattt ttataaacag tctataagta agcatccgga gtggaaagat tttggattta 4440

gattttctga tactcaaaga tataattcta tagatgaatt ttatagagaa gttgaaaatc 4500

aaggctacaa actaactttt gaaaatat cagagagcta tattgatagc gtagttaatc 4560

agggtaaatt gtacctattc caaatctata ataaagattt ttcagcttat agcaaagggc 4620

gaccaaatct acatacttta tattggaaag cgctgtttga tgagagaaat cttcaagatg 4680

tggtttataa gctaaatggt gaggcagagc ttttttatcg taaacaatca atacctaaaa 4740

aaatcactca cccagctaaa gaggcaatag ctaataaaaa caaagataat cctaaaaaag 4800

agagtgtttt tgaatatgat ttaatcaaag ataaacgctt tactgaagat aagtttttct 4860

ttcactgtcc tattacaatc aattttaaat ctagtggagc taataagttt aatgatgaaa 4920

tcaatttatt gctaaaagaa aaagcaaatg atgttcatat attaagtata gctagaggtg 4980

aaagacattt agcttactat actttggtag atggtaaagg caatatcatc aaacaagata 5040

ctttcaacat cattggtaat gatagaatga aaacaaacta ccatgataag cttgctgcaa 5100

tagagaaaga tagggattca gctaggaaag actggaaaaa gataaataac atcaaagaga 5160

tgaaagaggg ctatctatct caggtagttc atgaaatagc taagctagtt atagagtata 5220

atgctattgt ggtttttgag gatttaaatt ttggatttaa aagagggcgt ttcaaggtag 5280

agaagcaggt ctatcaaaag ttagaaaaaa tgctaattga gaaactaaac tatctagttt 5340

tcaaagataa tgagtttgat aaaactgggg gagtgcttag agctttatcag ctaacagcac 5400

cttttgagac ttttaaaaag atgggtaaac aaacaggtat tatctactat gtaccagctg 5460

gttttacttc aaaaatttgt cctgtaactg gttttgtaaa tcagttatat cctaagtatg 5520

aaagtgtcag caaatctcaa gagttcttta gtaagtttga caagatttgt tataaccttg 5580

ataagggcta ttttgagttt agttttgatt ataaaaactt tggtgacaag gctgccaaag 5640

gcaagtggac tatagctagc tttgggagta gattgattaa ctttagaaat tcagataaaa 5700

atcataattg ggatactcga gaagtttatc caactaaaga gttggagaaa ttgctaaaag 5760

attattctat cgaatatggg catggcgaat gtatcaaagc agctatttgc ggtgagagcg 5820

acaaaaagttttttgctaag ctaactagtg tcctaaatac tatcttacaa atgcgtaact 5880

caaaaacagg tactgagtta gattatctaa tttcaccagt agcagatgta aatggcaatt 5940

tctttgattc gcgacaggcg ccaaaaaata tgcctcaaga tgctgatgcc aatggtgctt 6000

atcatattgg gctaaaaggt ctgatgctac taggtaggat caaaaataat caagagggca 6060

aaaaactcaa tttggttatc aaaaatgaag agtattttga gttcgtgcag aataggaata 6120

actctggtgg ttctcccaag aagaagagga aagtctaact gcagtataat cagaaacagc 6180

ccgcggatgt tgatctgcgg gctgtttttt attgatcgaa tggccatgac caaaatccct 6240

taacgtgaag ttttcgttcc actgagcgtc agaccccgta gaaaagatca aaggatcttc 6300

ttgagatcct ttttttctgc gcgtaatctg ctgcttgcaa acaaaaaaac caccgctacc 6360

agcggtggtt tgtttgccgg atcaagagct accaactctt tttccgaagg taactggctt 6420

cagcagagcg cagataccaa atactgtcct tctagtgtag ccgtagttag gccaccactt 6480

caagaactct gtagcaccgc ctacatacct cgctctgcta atcctgttac cagtggctgc 6540

tgccagtggc gataagtcgt gtcttaccgg gttggactca agacgatagt taccggataa 6600

ggcgcagcgg tcgggctgaa cggggggttc gtgcacacag cccagcttgg agcgaacgac 6660

ctacaccgaa ctgagatacc tacagcgtga gctatgagaa agcgccacgc ttcccgaagg 6720

gagaaaggcg gacaggtatc cggtaagcgg cagggtcgga acaggagagc gcacgaggga 6780

gcttccaggg ggaaacgcct ggtatcttta tagtcctgtc gggtttcgcc acctctgact 6840

tgagcgtcga tttttgtgat gctcgtcagg ggggcggagc ctatggaaaa acgccagcaa 6900

cgcggccttt ttacggttcc tggccttttg ctggcctttt gctcacatgt tctttcctgc 6960

gttatcccct gattctgtgg ataaccgtat taccgccttt gagtgagctg agacaggtca 7020

ttcagactgg ctaatgcacc cagtaaggca gcggtatcat caactcaaaa tggtatgcgt 7080

tttgacacat ccactatata tccgtgtcgt tctgtccact cctgaatccc attccagaaa 7140

ttctctagcg attccagaag tttctcagag tcggaaagtt gaccagacat tacgaactgg 7200

cacagatggt cataacctga aggaagatct gattgcttaa ctgcttcagt taagaccgaa 7260

gcgctcgtcg tataacagat gcgatgatgc agaccaatca acatggcacc tgccattgct 7320

acctgcacag tcaaggatgg tagaaatgtt gtcggtcctt gcacacgaat attacgccat 7380

ttgcctgcat attcaaacag ctcttctacg ataagggcac aaatcgcatc gtggaacgtt 7440

tgggcttcta ccgatttagc agtttgatac actttctcta agtatccacc tgaatcataa 7500

atcggcaaaa tagagaaaaa ttgaccatgt gtaagcggcc aatctgattc cacctgagat 7560

gcataatcta gtagaatctc ttcgctatca aaattcactt ccaccttcca ctcaccggtt 7620

gtccattcat ggctgaactc tgcttcctct gttgacatga cacacatcat ctcaatatcc 7680

gaatagggcc catcagtctg acgaccaaga gagccataaa caccaatagc cttaacatca 7740

tccccatatt tatccaatat tcgttcctta atttcatgaa caatcttcat tctttcttct 7800

ctagtcatta ttatggtcc attcactatt ctcattcccc tttcagataa ttttagattt 7860

gcttttctaa ataagaatat ttggagagca ccgttcttat tcagctatta aacccattat 7920

atcgggtttt tgaggggatt tcaactgcag acacctaaat tcaaaatcta tcggtcagat 7980

ttataccgat ttgattttat atattcttga ataacatacg ccgagttatc acataaaagc 8040

gggaaccaat catcaaattt aaacttcatt gcataatcca ttaaactctt aaattctacg 8100

attccttgtt catcaataaa ctcaatcatt tctttaatta atttatatct atctgttgtt 8160

gttttcttta ataattcatc aacatctaca ccgccataaa ctatcatatc ttctttttga 8220

tatttaaatt tattaggatc gtccatgtga agcatatatc tcacaagacc tttcacactt 8280

cctgcaatct gcggaatagt cgcattcaat tcttctgtaa ttattttat ctgttcataa 8340

gatttattac cctcatacat cactagaata tgataatgct cttttttcat cctatcttct 8400

gtatcagtat ccctatcatg taatggagac actacaaatt gaatgtgtaa ctcttttaaa 8460

tactctaacc actcggcttt tgctgattct ggatataaaa caaatgtcca attacgtcct 8520

cttgaatttt tcttgttttc agtttctttt attacatttt cgctcatgat ataataacgg 8580

tgctaataca tttaacaaaa tttagtcata gataggcagc atgccagtgc tgtctatctt 8640

tttttgttta aaatgcaccg tattcctcct ttgcatattt ttttattaga ataccggttg 8700

catctgattt gctaatatta tatttttctt tgattctatt taatatctca ttttcttctg 8760

ttgtaagtct taaagtaaca gcaacttttt tctcttcttt tctatctaca accatcactg 8820

tacctcccaa catctgtttt tttcacttta acataaaaaa caacctttta acattaaaaa 8880

cccaatattt atttatttgt ttggacaatg gacaatggac acctaggggg gaggtcgtag 8940

taccccccta tgttttctcc cctaaataac cccaaaaatc taagaaaaaa agacctcaaa 9000

aaggtcttta attaacatct caaatttcgc atttattcca atttcctttt tgcgtgtgat 9060

gcgttattaa cgttgatata atttaaattt tatttgacaa aaatgggctc gtgttgtaca 9120

ataaatgtag aggtagagac gcgaggtcta agaactttaa ataatttcta ctgttgtaga 9180

tagagaccgt gaagttaata aggtctcaaa tttctactgt tgtagatcgt ctctgaactg 9240

attcaagcaa gcttaaaccc agctcaatga gctgggtttt ttgtttgttt tttcaaactt 9300

agttagcttg gccagtgcct ctagagtcaa gtaaagagtc gacctgttac gaacggcaga 9360

tcagaatttt gtaataaaaa aagagcctgc tcattacact gcgggctctt tttcatggtc 9420

agaagacggg taaccaagat aacaa 9445

<210> 10

<211> 9445

<212> DNA

<213> (artificial sequence)

<400> 10

atgtcatgac attggtgtac agaaatggcg cagcaatggc aagaacgtcc cgggcggagc 60

tcaggcctta actcacatta attgcgttgc gctcactgcc cgctttccag tcgggaaacc 120

tgtcgtgcca gctgcattaa tgaatcggcc aacgcgcggg gagaggcggt ttgcgtattg 180

ggcgccaggg tggtttttct tttcaccagt gagacgggca acagctgatt gcccttcacc 240

gcctggccct gagagagttg cagcaagcgg tccacgctgg tttgccccag caggcgaaaa 300

tcctgtttga tggtggttaa cggcgggata taacatgagc tgtcttcggt atcgtcgtat 360

cccactaccg agatatccgc accaacgcgc agcccggact cggtaatggc gcgcattgcg 420

cccagcgcca tctgatcgtt ggcaaccagc atcgcagtgg gaacgatgcc ctcattcagc 480

atttgcatgg tttgttgaaa accggacatg gcactccagt cgccttcccg ttccgctatc 540

ggctgaattt gattgcgagt gagatattta tgccagccag ccagacgcag acgcgccgag 600

acagaactta atgggcccgc taacagcgcg atttgctggt gacccaatgc gaccagatgc 660

tccacgccca gtcgcgtacc gtcttcatgg gagaaaataa tactgttgat gggtgtctgg 720

tcagagacat caagaaataa cgccggaaca ttagtgcagg cagcttccac agcaatggca 780

tcctggtcat ccagcggata gttaatgatc agcccactga cgcgttgcgc gagaagattg 840

tgcaccgccg ttttacaggc ttcgacgccg cttcgttcta ccatcgacac caccacgctg 900

gcacccagtt gatcggcgcg agatttaatc gccgcgacaa tttgcgacgg cgcgtgcagg 960

gccagactgg aggtggcaac gccaatcagc aacgactgtt tgcccgccag ttgttgtgcc 1020

acgcggttgg gaatgtaatt cagctccgcc atcgccgctt ccactttttc ccgcgttttc 1080

gcagaaacgt ggctggcctg gttcaccacg cgggaaacgg tctgataaga gacaccggca 1140

tactctgcga catcgtataa cgttatactggt ttcatcaaaa tcgtctccct ccgtttgaat 1200

atttgattga tcgtaaccag atgaagcact ctttccacta tccctacagt gttatggctt 1260

gaacaatcac gaaacaataa ttggtacgta cgatctttca gccgactcaa acatcaaatc 1320

ttacaaatgt agtctttgaa agtattacat atgtaagatt taaatgcaac cgttttttcg 1380

gaaggaaatg atgacctcgt ttccaccgga attagcttgg taccagctat tgtaacataa 1440

tcggtacggg ggtgaaaaag ctaacggaaa agggagcgga aaagaatgat gtaagcgtga 1500

aaaatttttt aaaaaatctc ttgacattgg aagggagata tgttattata agaattgcgg 1560

aattgtgagc ggataacaat tcataattgt gagcggataa caattcaacc ccaaaggagg 1620

tgggatccat gagcgaagtc gagttctccc acgaatactg gatgcgccat gcccttacac 1680

ttgccaaacg cgctcgcgat gaacgcgaag tcccagttgg cgccgttctt gttcttaaca 1740

accgcgtcat cggagaaggc tggaaccgcg ctatcggact tcatgatccg acagctcatg 1800

ccgaaattat ggctctgcgc caaggcggac ttgtcatgca gaattacaga cttattgatg 1860

ccacgcttta cgtcacgttc gaaccgtgcg tcatgtgcgc cggcgccatg attcatagcc 1920

gcatcggcag agttgtcttc ggcgtccgca attcaaaaag aggcgccgcc ggctccctta 1980

tgaacgtcct taactacccg ggcatgaatc accgcgttga aatcacagaa ggcattctgg 2040

ccgatgagtg cgccgctctg ctgtgcgact tctatagaat gccgagacaa gtcttcaacg 2100

cccagaagaa agcccaaagc agcattaact ctggaggatc atccggaggc agctctggaa 2160

gtgaaacacc aggaacaagc gaatcagcta caccagagtc ctctggaggc tcatctggag 2220

gaagctcaat ttatcaagaa tttgttaata aatatagttt aagtaaaact ctaagatttg 2280

agttaatccc acagggtaaa acacttgaaa acataaaagc aagaggtttg attttagatg 2340

atgagaaaag agctaaagac tacaaaaagg ctaaacaaat aattgataaa tatcatcagt 2400

tttttataga ggagatatta agttcggttt gtattagcga agatttatta caaaactatt 2460

ctgatgttta ttttaaactt aaaaagagtg atgatgataa tctacaaaaa gattttaaaa 2520

gtgcaaaaga tacgataaag aaacaaatat ctgaatat aaaggactca gagaaattta 2580

agaatttgtt taatcaaaac cttatcgatg ctaaaaaagg gcaagagtca gatttaattc 2640

tatggctaaa gcaatctaag gataatggta tagaactatt taaagccaat agtgatatca 2700

cagatataga tgaggcgtta gaaataatca aatcttttaa aggttggaca acttatttta 2760

agggttttca tgaaaataga aaaaatgttt atagtagcaa tgatattcct acatctatta 2820

tttataggat agtagatgat aatttgccta aatttctaga aaataaagct aagtatgaga 2880

gtttaaaaga caaagctcca gaagctataa actatgaaca aattaaaaaa gatttggcag 2940

aagagctaac ctttgatatt gactacaaaa catctgaagt taatcaaaga gttttttcac 3000

ttgatgaagt ttttgagata gcaaacttta ataattatct aaatcaaagt ggtattacta 3060

aatttaatac tattattggt ggtaaatttg taaatggtga aaatacaaag agaaaaggta 3120

taaatgaata tataaatcta tactcacagc aaataaatga taaaacactc aaaaaatata 3180

aaatgagtgt tttatttaag caaattttaa gtgatacaga atctaaatct tttgtaattg 3240

ataagttaga agatgatagt gatgtagtta caacgatgca aagtttttat gagcaaatag 3300

cagcttttaa aacagtagaa gaaaaatcta ttaaagaaac actatcttta ttatttgatg 3360

atttaaaagc tcaaaaactt gatttgagta aaatttattt taaaaatgat aaatctctta 3420

ctgatctatc acaacaagtt tttgatgatt atagtgttat tggtacagcg gtactagaat 3480

atataactca acaaatagca cctaaaaatc ttgataaccc tagtaagaaa gagcaagaat 3540

taatagccaa aaaaactgaa aaagcaaaat acttatctct agaaactata aagcttgcct 3600

tagaagaatt taataagcat agagatatag ataaacagtg taggtttgaa gaaatacttg 3660

caaactttgc ggctattccg atgatatttg atgaaatagc tcaaaacaaa gacaatttgg 3720

cacagatatc tatcaaatat caaaatcaag gtaaaaaaga cctacttcaa gctagtgcgg 3780

aagatgatgt taaagctatc aaggatcttt tagatcaaac taataatctc ttacataaac 3840

taaaaatatt tcatattagt cagtcagaag ataaggcaaa tattttagac aaggatgagc 3900

atttttatct agtatttgag gagtgctact ttgagctagc gaatatagtg cctctttata 3960

acaaaattag aaactata actcaaaagc catatagtga tgagaaattt aagctcaatt 4020

ttgagaactc gactttggct aatggttggg ataaaaataa agagcctgac aatacggcaa 4080

ttttatttat caaagatgat aaatattatc tgggtgtgat gaataagaaa aataacaaaa 4140

tatttgatga taaagctatc aaagaaaata aaggcgaggg ttataaaaaa attgtttata 4200

aacttttacc tggcgcaaat aaaatgttac ctaaggtttt cttttctgct aaatctataa 4260

aattttataa tcctagtgaa gatatactta gaataagaaa tcattccaca catacaaaaa 4320

atggtagtcc tcaaaaagga tatgaaaaat ttgagtttaa tattgaagat tgccgaaaat 4380

ttatagattt ttataaacag tctataagta agcatccgga gtggaaagat tttggattta 4440

gattttctga tactcaaaga tataattcta tagatgaatt ttatagagaa gttgaaaatc 4500

aaggctacaa actaactttt gaaaatat cagagagcta tattgatagc gtagttaatc 4560

agggtaaatt gtacctattc caaatctata ataaagattt ttcagcttat agcaaagggc 4620

gaccaaatct acatacttta tattggaaag cgctgtttga tgagagaaat cttcaagatg 4680

tggtttataa gctaaatggt gaggcagagc ttttttatcg taaacaatca atacctaaaa 4740

aaatcactca cccagctaaa gaggcaatag ctaataaaaa caaagataat cctaaaaaag 4800

agagtgtttt tgaatatgat ttaatcaaag ataaacgctt tactgaagat aagtttttct 4860

ttcactgtcc tattacaatc aattttaaat ctagtggagc taataagttt aatgatgaaa 4920

tcaatttatt gctaaaagaa aaagcaaatg atgttcatat attaagtata gctagaggtg 4980

aaagacattt agcttactat actttggtag atggtaaagg caatatcatc aaacaagata 5040

ctttcaacat cattggtaat gatagaatga aaacaaacta ccatgataag cttgctgcaa 5100

tagagaaaga tagggattca gctaggaaag actggaaaaa gataaataac atcaaagaga 5160

tgaaagaggg ctatctatct caggtagttc atgaaatagc taagctagtt atagagtata 5220

atgctattgt ggtttttgag gatttaaatt ttggatttaa aagagggcgt ttcaaggtag 5280

agaagcaggt ctatcaaaag ttagaaaaaa tgctaattga gaaactaaac tatctagttt 5340

tcaaagataa tgagtttgat aaaactgggg gagtgcttag agctttatcag ctaacagcac 5400

cttttgagac ttttaaaaag atgggtaaac aaacaggtat tatctactat gtaccagctg 5460

gttttacttc aaaaatttgt cctgtaactg gttttgtaaa tcagttatat cctaagtatg 5520

aaagtgtcag caaatctcaa gagttcttta gtaagtttga caagatttgt tataaccttg 5580

ataagggcta ttttgagttt agttttgatt ataaaaactt tggtgacaag gctgccaaag 5640

gcaagtggac tatagctagc tttgggagta gattgattaa ctttagaaat tcagataaaa 5700

atcataattg ggatactcga gaagtttatc caactaaaga gttggagaaa ttgctaaaag 5760

attattctat cgaatatggg catggcgaat gtatcaaagc agctatttgc ggtgagagcg 5820

acaaaaagttttttgctaag ctaactagtg tcctaaatac tatcttacaa atgcgtaact 5880

caaaaacagg tactgagtta gattatctaa tttcaccagt agcagatgta aatggcaatt 5940

tctttgattc gcgacaggcg ccaaaaaata tgcctcaaga tgctgatgcc aatggtgctt 6000

atcatattgg gctaaaaggt ctgatgctac taggtaggat caaaaataat caagagggca 6060

aaaaactcaa tttggttatc aaaaatgaag agtattttga gttcgtgcag aataggaata 6120

actctggtgg ttctcccaag aagaagagga aagtctaact gcagtataat cagaaacagc 6180

ccgcggatgt tgatctgcgg gctgtttttt attgatcgaa tggccatgac caaaatccct 6240

taacgtgaag ttttcgttcc actgagcgtc agaccccgta gaaaagatca aaggatcttc 6300

ttgagatcct ttttttctgc gcgtaatctg ctgcttgcaa acaaaaaaac caccgctacc 6360

agcggtggtt tgtttgccgg atcaagagct accaactctt tttccgaagg taactggctt 6420

cagcagagcg cagataccaa atactgtcct tctagtgtag ccgtagttag gccaccactt 6480

caagaactct gtagcaccgc ctacatacct cgctctgcta atcctgttac cagtggctgc 6540

tgccagtggc gataagtcgt gtcttaccgg gttggactca agacgatagt taccggataa 6600

ggcgcagcgg tcgggctgaa cggggggttc gtgcacacag cccagcttgg agcgaacgac 6660

ctacaccgaa ctgagatacc tacagcgtga gctatgagaa agcgccacgc ttcccgaagg 6720

gagaaaggcg gacaggtatc cggtaagcgg cagggtcgga acaggagagc gcacgaggga 6780

gcttccaggg ggaaacgcct ggtatcttta tagtcctgtc gggtttcgcc acctctgact 6840

tgagcgtcga tttttgtgat gctcgtcagg ggggcggagc ctatggaaaa acgccagcaa 6900

cgcggccttt ttacggttcc tggccttttg ctggcctttt gctcacatgt tctttcctgc 6960

gttatcccct gattctgtgg ataaccgtat taccgccttt gagtgagctg agacaggtca 7020

ttcagactgg ctaatgcacc cagtaaggca gcggtatcat caactcaaaa tggtatgcgt 7080

tttgacacat ccactatata tccgtgtcgt tctgtccact cctgaatccc attccagaaa 7140

ttctctagcg attccagaag tttctcagag tcggaaagtt gaccagacat tacgaactgg 7200

cacagatggt cataacctga aggaagatct gattgcttaa ctgcttcagt taagaccgaa 7260

gcgctcgtcg tataacagat gcgatgatgc agaccaatca acatggcacc tgccattgct 7320

acctgcacag tcaaggatgg tagaaatgtt gtcggtcctt gcacacgaat attacgccat 7380

ttgcctgcat attcaaacag ctcttctacg ataagggcac aaatcgcatc gtggaacgtt 7440

tgggcttcta ccgatttagc agtttgatac actttctcta agtatccacc tgaatcataa 7500

atcggcaaaa tagagaaaaa ttgaccatgt gtaagcggcc aatctgattc cacctgagat 7560

gcataatcta gtagaatctc ttcgctatca aaattcactt ccaccttcca ctcaccggtt 7620

gtccattcat ggctgaactc tgcttcctct gttgacatga cacacatcat ctcaatatcc 7680

gaatagggcc catcagtctg acgaccaaga gagccataaa caccaatagc cttaacatca 7740

tccccatatt tatccaatat tcgttcctta atttcatgaa caatcttcat tctttcttct 7800

ctagtcatta ttatggtcc attcactatt ctcattcccc tttcagataa ttttagattt 7860

gcttttctaa ataagaatat ttggagagca ccgttcttat tcagctatta aacccattat 7920

atcgggtttt tgaggggatt tcaactgcag acacctaaat tcaaaatcta tcggtcagat 7980

ttataccgat ttgattttat atattcttga ataacatacg ccgagttatc acataaaagc 8040

gggaaccaat catcaaattt aaacttcatt gcataatcca ttaaactctt aaattctacg 8100

attccttgtt catcaataaa ctcaatcatt tctttaatta atttatatct atctgttgtt 8160

gttttcttta ataattcatc aacatctaca ccgccataaa ctatcatatc ttctttttga 8220

tatttaaatt tattaggatc gtccatgtga agcatatatc tcacaagacc tttcacactt 8280

cctgcaatct gcggaatagt cgcattcaat tcttctgtaa ttattttat ctgttcataa 8340

gatttattac cctcatacat cactagaata tgataatgct cttttttcat cctatcttct 8400

gtatcagtat ccctatcatg taatggagac actacaaatt gaatgtgtaa ctcttttaaa 8460

tactctaacc actcggcttt tgctgattct ggatataaaa caaatgtcca attacgtcct 8520

cttgaatttt tcttgttttc agtttctttt attacatttt cgctcatgat ataataacgg 8580

tgctaataca tttaacaaaa tttagtcata gataggcagc atgccagtgc tgtctatctt 8640

tttttgttta aaatgcaccg tattcctcct ttgcatattt ttttattaga ataccggttg 8700

catctgattt gctaatatta tatttttctt tgattctatt taatatctca ttttcttctg 8760

ttgtaagtct taaagtaaca gcaacttttt tctcttcttt tctatctaca accatcactg 8820

tacctcccaa catctgtttt tttcacttta acataaaaaa caacctttta acattaaaaa 8880

cccaatattt atttatttgt ttggacaatg gacaatggac acctaggggg gaggtcgtag 8940

taccccccta tgttttctcc cctaaataac cccaaaaatc taagaaaaaa agacctcaaa 9000

aaggtcttta attaacatct caaatttcgc atttattcca atttcctttt tgcgtgtgat 9060

gcgttattaa cgttgatata atttaaattt tatttgacaa aaatgggctc gtgttgtaca 9120

ataaatgtag aggtagagac gcgaggtcta agaactttaa ataatttcta ctgttgtaga 9180

tagagaccgt gaagttaata aggtctcaaa tttctactgt tgtagatcgt ctctgaactg 9240

attcaagcaa gcttaaaccc agctcaatga gctgggtttt ttgtttgttt tttcaaactt 9300

agttagcttg gccagtgcct ctagagtcaa gtaaagagtc gacctgttac gaacggcaga 9360

tcagaatttt gtaataaaaa aagagcctgc tcattacact gcgggctctt tttcatggtc 9420

agaagacggg taaccaagat aacaa 9445

<210> 11

<211> 9445

<212> DNA

<213> (artificial sequence)

<400> 11

atgtcatgac attggtgtac agaaatggcg cagcaatggc aagaacgtcc cgggcggagc 60

tcaggcctta actcacatta attgcgttgc gctcactgcc cgctttccag tcgggaaacc 120

tgtcgtgcca gctgcattaa tgaatcggcc aacgcgcggg gagaggcggt ttgcgtattg 180

ggcgccaggg tggtttttct tttcaccagt gagacgggca acagctgatt gcccttcacc 240

gcctggccct gagagagttg cagcaagcgg tccacgctgg tttgccccag caggcgaaaa 300

tcctgtttga tggtggttaa cggcgggata taacatgagc tgtcttcggt atcgtcgtat 360

cccactaccg agatatccgc accaacgcgc agcccggact cggtaatggc gcgcattgcg 420

cccagcgcca tctgatcgtt ggcaaccagc atcgcagtgg gaacgatgcc ctcattcagc 480

atttgcatgg tttgttgaaa accggacatg gcactccagt cgccttcccg ttccgctatc 540

ggctgaattt gattgcgagt gagatattta tgccagccag ccagacgcag acgcgccgag 600

acagaactta atgggcccgc taacagcgcg atttgctggt gacccaatgc gaccagatgc 660

tccacgccca gtcgcgtacc gtcttcatgg gagaaaataa tactgttgat gggtgtctgg 720

tcagagacat caagaaataa cgccggaaca ttagtgcagg cagcttccac agcaatggca 780

tcctggtcat ccagcggata gttaatgatc agcccactga cgcgttgcgc gagaagattg 840

tgcaccgccg ttttacaggc ttcgacgccg cttcgttcta ccatcgacac caccacgctg 900

gcacccagtt gatcggcgcg agatttaatc gccgcgacaa tttgcgacgg cgcgtgcagg 960

gccagactgg aggtggcaac gccaatcagc aacgactgtt tgcccgccag ttgttgtgcc 1020

acgcggttgg gaatgtaatt cagctccgcc atcgccgctt ccactttttc ccgcgttttc 1080

gcagaaacgt ggctggcctg gttcaccacg cgggaaacgg tctgataaga gacaccggca 1140

tactctgcga catcgtataa cgttatactggt ttcatcaaaa tcgtctccct ccgtttgaat 1200

atttgattga tcgtaaccag atgaagcact ctttccacta tccctacagt gttatggctt 1260

gaacaatcac gaaacaataa ttggtacgta cgatctttca gccgactcaa acatcaaatc 1320

ttacaaatgt agtctttgaa agtattacat atgtaagatt taaatgcaac cgttttttcg 1380

gaaggaaatg atgacctcgt ttccaccgga attagcttgg taccagctat tgtaacataa 1440

tcggtacggg ggtgaaaaag ctaacggaaa agggagcgga aaagaatgat gtaagcgtga 1500

aaaatttttt aaaaaatctc ttgacattgg aagggagata tgttattata agaattgcgg 1560

aattgtgagc ggataacaat tcataattgt gagcggataa caattcaacc ccaaaggagg 1620

tgggatccat gagcgaagtc gagttctccc acgaatactg gatgcgccat gcccttacac 1680

ttgccaaacg cgctcgcgat gaacgcgaag tcccagttgg cgccgttctt gttcttaaca 1740

accgcgtcat cggagaaggc tggaaccgcg ctatcggact tcatgatccg acagctcatg 1800

ccgaaattat ggctctgcgc caaggcggac ttgtcatgca gaattacaga cttattgatg 1860

ccacgcttta ctcaacgttc gaaccgtgcg tcatgtgcgc cggcgccatg attcatagcc 1920

gcatcggcag agttgtcttc ggcgtccgca attcaaaaag aggcgccgcc ggctccctta 1980

tgaacgtcct taactacccg ggcatgaatc accgcgttga aatcacagaa ggcattctgg 2040

ccgatgagtg cgccgctctg ctgtgcgact tctatagaat gccgagaaga gtcttcaacg 2100

cccagaagaa agcccaaagc agcattaact ctggaggatc atccggaggc agctctggaa 2160

gtgaaacacc aggaacaagc gaatcagcta caccagagtc ctctggaggc tcatctggag 2220

gaagctcaat ttatcaagaa tttgttaata aatatagttt aagtaaaact ctaagatttg 2280

agttaatccc acagggtaaa acacttgaaa acataaaagc aagaggtttg attttagatg 2340

atgagaaaag agctaaagac tacaaaaagg ctaaacaaat aattgataaa tatcatcagt 2400

tttttataga ggagatatta agttcggttt gtattagcga agatttatta caaaactatt 2460

ctgatgttta ttttaaactt aaaaagagtg atgatgataa tctacaaaaa gattttaaaa 2520

gtgcaaaaga tacgataaag aaacaaatat ctgaatat aaaggactca gagaaattta 2580

agaatttgtt taatcaaaac cttatcgatg ctaaaaaagg gcaagagtca gatttaattc 2640

tatggctaaa gcaatctaag gataatggta tagaactatt taaagccaat agtgatatca 2700

cagatataga tgaggcgtta gaaataatca aatcttttaa aggttggaca acttatttta 2760

agggttttca tgaaaataga aaaaatgttt atagtagcaa tgatattcct acatctatta 2820

tttataggat agtagatgat aatttgccta aatttctaga aaataaagct aagtatgaga 2880

gtttaaaaga caaagctcca gaagctataa actatgaaca aattaaaaaa gatttggcag 2940

aagagctaac ctttgatatt gactacaaaa catctgaagt taatcaaaga gttttttcac 3000

ttgatgaagt ttttgagata gcaaacttta ataattatct aaatcaaagt ggtattacta 3060

aatttaatac tattattggt ggtaaatttg taaatggtga aaatacaaag agaaaaggta 3120

taaatgaata tataaatcta tactcacagc aaataaatga taaaacactc aaaaaatata 3180

aaatgagtgt tttatttaag caaattttaa gtgatacaga atctaaatct tttgtaattg 3240

ataagttaga agatgatagt gatgtagtta caacgatgca aagtttttat gagcaaatag 3300

cagcttttaa aacagtagaa gaaaaatcta ttaaagaaac actatcttta ttatttgatg 3360

atttaaaagc tcaaaaactt gatttgagta aaatttattt taaaaatgat aaatctctta 3420

ctgatctatc acaacaagtt tttgatgatt atagtgttat tggtacagcg gtactagaat 3480

atataactca acaaatagca cctaaaaatc ttgataaccc tagtaagaaa gagcaagaat 3540

taatagccaa aaaaactgaa aaagcaaaat acttatctct agaaactata aagcttgcct 3600

tagaagaatt taataagcat agagatatag ataaacagtg taggtttgaa gaaatacttg 3660

caaactttgc ggctattccg atgatatttg atgaaatagc tcaaaacaaa gacaatttgg 3720

cacagatatc tatcaaatat caaaatcaag gtaaaaaaga cctacttcaa gctagtgcgg 3780

aagatgatgt taaagctatc aaggatcttt tagatcaaac taataatctc ttacataaac 3840

taaaaatatt tcatattagt cagtcagaag ataaggcaaa tattttagac aaggatgagc 3900

atttttatct agtatttgag gagtgctact ttgagctagc gaatatagtg cctctttata 3960

acaaaattag aaactata actcaaaagc catatagtga tgagaaattt aagctcaatt 4020

ttgagaactc gactttggct aatggttggg ataaaaataa agagcctgac aatacggcaa 4080

ttttatttat caaagatgat aaatattatc tgggtgtgat gaataagaaa aataacaaaa 4140

tatttgatga taaagctatc aaagaaaata aaggcgaggg ttataaaaaa attgtttata 4200

aacttttacc tggcgcaaat aaaatgttac ctaaggtttt cttttctgct aaatctataa 4260

aattttataa tcctagtgaa gatatactta gaataagaaa tcattccaca catacaaaaa 4320

atggtagtcc tcaaaaagga tatgaaaaat ttgagtttaa tattgaagat tgccgaaaat 4380

ttatagattt ttataaacag tctataagta agcatccgga gtggaaagat tttggattta 4440

gattttctga tactcaaaga tataattcta tagatgaatt ttatagagaa gttgaaaatc 4500

aaggctacaa actaactttt gaaaatat cagagagcta tattgatagc gtagttaatc 4560

agggtaaatt gtacctattc caaatctata ataaagattt ttcagcttat agcaaagggc 4620

gaccaaatct acatacttta tattggaaag cgctgtttga tgagagaaat cttcaagatg 4680

tggtttataa gctaaatggt gaggcagagc ttttttatcg taaacaatca atacctaaaa 4740

aaatcactca cccagctaaa gaggcaatag ctaataaaaa caaagataat cctaaaaaag 4800

agagtgtttt tgaatatgat ttaatcaaag ataaacgctt tactgaagat aagtttttct 4860

ttcactgtcc tattacaatc aattttaaat ctagtggagc taataagttt aatgatgaaa 4920

tcaatttatt gctaaaagaa aaagcaaatg atgttcatat attaagtata gctagaggtg 4980

aaagacattt agcttactat actttggtag atggtaaagg caatatcatc aaacaagata 5040

ctttcaacat cattggtaat gatagaatga aaacaaacta ccatgataag cttgctgcaa 5100

tagagaaaga tagggattca gctaggaaag actggaaaaa gataaataac atcaaagaga 5160

tgaaagaggg ctatctatct caggtagttc atgaaatagc taagctagtt atagagtata 5220

atgctattgt ggtttttgag gatttaaatt ttggatttaa aagagggcgt ttcaaggtag 5280

agaagcaggt ctatcaaaag ttagaaaaaa tgctaattga gaaactaaac tatctagttt 5340

tcaaagataa tgagtttgat aaaactgggg gagtgcttag agctttatcag ctaacagcac 5400

cttttgagac ttttaaaaag atgggtaaac aaacaggtat tatctactat gtaccagctg 5460

gttttacttc aaaaatttgt cctgtaactg gttttgtaaa tcagttatat cctaagtatg 5520

aaagtgtcag caaatctcaa gagttcttta gtaagtttga caagatttgt tataaccttg 5580

ataagggcta ttttgagttt agttttgatt ataaaaactt tggtgacaag gctgccaaag 5640

gcaagtggac tatagctagc tttgggagta gattgattaa ctttagaaat tcagataaaa 5700

atcataattg ggatactcga gaagtttatc caactaaaga gttggagaaa ttgctaaaag 5760

attattctat cgaatatggg catggcgaat gtatcaaagc agctatttgc ggtgagagcg 5820

acaaaaagttttttgctaag ctaactagtg tcctaaatac tatcttacaa atgcgtaact 5880

caaaaacagg tactgagtta gattatctaa tttcaccagt agcagatgta aatggcaatt 5940

tctttgattc gcgacaggcg ccaaaaaata tgcctcaaga tgctgatgcc aatggtgctt 6000

atcatattgg gctaaaaggt ctgatgctac taggtaggat caaaaataat caagagggca 6060

aaaaactcaa tttggttatc aaaaatgaag agtattttga gttcgtgcag aataggaata 6120

actctggtgg ttctcccaag aagaagagga aagtctaact gcagtataat cagaaacagc 6180

ccgcggatgt tgatctgcgg gctgtttttt attgatcgaa tggccatgac caaaatccct 6240

taacgtgaag ttttcgttcc actgagcgtc agaccccgta gaaaagatca aaggatcttc 6300

ttgagatcct ttttttctgc gcgtaatctg ctgcttgcaa acaaaaaaac caccgctacc 6360

agcggtggtt tgtttgccgg atcaagagct accaactctt tttccgaagg taactggctt 6420

cagcagagcg cagataccaa atactgtcct tctagtgtag ccgtagttag gccaccactt 6480

caagaactct gtagcaccgc ctacatacct cgctctgcta atcctgttac cagtggctgc 6540

tgccagtggc gataagtcgt gtcttaccgg gttggactca agacgatagt taccggataa 6600

ggcgcagcgg tcgggctgaa cggggggttc gtgcacacag cccagcttgg agcgaacgac 6660

ctacaccgaa ctgagatacc tacagcgtga gctatgagaa agcgccacgc ttcccgaagg 6720

gagaaaggcg gacaggtatc cggtaagcgg cagggtcgga acaggagagc gcacgaggga 6780

gcttccaggg ggaaacgcct ggtatcttta tagtcctgtc gggtttcgcc acctctgact 6840

tgagcgtcga tttttgtgat gctcgtcagg ggggcggagc ctatggaaaa acgccagcaa 6900

cgcggccttt ttacggttcc tggccttttg ctggcctttt gctcacatgt tctttcctgc 6960

gttatcccct gattctgtgg ataaccgtat taccgccttt gagtgagctg agacaggtca 7020

ttcagactgg ctaatgcacc cagtaaggca gcggtatcat caactcaaaa tggtatgcgt 7080

tttgacacat ccactatata tccgtgtcgt tctgtccact cctgaatccc attccagaaa 7140

ttctctagcg attccagaag tttctcagag tcggaaagtt gaccagacat tacgaactgg 7200

cacagatggt cataacctga aggaagatct gattgcttaa ctgcttcagt taagaccgaa 7260

gcgctcgtcg tataacagat gcgatgatgc agaccaatca acatggcacc tgccattgct 7320

acctgcacag tcaaggatgg tagaaatgtt gtcggtcctt gcacacgaat attacgccat 7380

ttgcctgcat attcaaacag ctcttctacg ataagggcac aaatcgcatc gtggaacgtt 7440

tgggcttcta ccgatttagc agtttgatac actttctcta agtatccacc tgaatcataa 7500

atcggcaaaa tagagaaaaa ttgaccatgt gtaagcggcc aatctgattc cacctgagat 7560

gcataatcta gtagaatctc ttcgctatca aaattcactt ccaccttcca ctcaccggtt 7620

gtccattcat ggctgaactc tgcttcctct gttgacatga cacacatcat ctcaatatcc 7680

gaatagggcc catcagtctg acgaccaaga gagccataaa caccaatagc cttaacatca 7740

tccccatatt tatccaatat tcgttcctta atttcatgaa caatcttcat tctttcttct 7800

ctagtcatta ttatggtcc attcactatt ctcattcccc tttcagataa ttttagattt 7860

gcttttctaa ataagaatat ttggagagca ccgttcttat tcagctatta aacccattat 7920

atcgggtttt tgaggggatt tcaactgcag acacctaaat tcaaaatcta tcggtcagat 7980

ttataccgat ttgattttat atattcttga ataacatacg ccgagttatc acataaaagc 8040

gggaaccaat catcaaattt aaacttcatt gcataatcca ttaaactctt aaattctacg 8100

attccttgtt catcaataaa ctcaatcatt tctttaatta atttatatct atctgttgtt 8160

gttttcttta ataattcatc aacatctaca ccgccataaa ctatcatatc ttctttttga 8220

tatttaaatt tattaggatc gtccatgtga agcatatatc tcacaagacc tttcacactt 8280

cctgcaatct gcggaatagt cgcattcaat tcttctgtaa ttattttat ctgttcataa 8340

gatttattac cctcatacat cactagaata tgataatgct cttttttcat cctatcttct 8400

gtatcagtat ccctatcatg taatggagac actacaaatt gaatgtgtaa ctcttttaaa 8460

tactctaacc actcggcttt tgctgattct ggatataaaa caaatgtcca attacgtcct 8520

cttgaatttt tcttgttttc agtttctttt attacatttt cgctcatgat ataataacgg 8580

tgctaataca tttaacaaaa tttagtcata gataggcagc atgccagtgc tgtctatctt 8640

tttttgttta aaatgcaccg tattcctcct ttgcatattt ttttattaga ataccggttg 8700

catctgattt gctaatatta tatttttctt tgattctatt taatatctca ttttcttctg 8760

ttgtaagtct taaagtaaca gcaacttttt tctcttcttt tctatctaca accatcactg 8820

tacctcccaa catctgtttt tttcacttta acataaaaaa caacctttta acattaaaaa 8880

cccaatattt atttatttgt ttggacaatg gacaatggac acctaggggg gaggtcgtag 8940

taccccccta tgttttctcc cctaaataac cccaaaaatc taagaaaaaa agacctcaaa 9000

aaggtcttta attaacatct caaatttcgc atttattcca atttcctttt tgcgtgtgat 9060

gcgttattaa cgttgatata atttaaattt tatttgacaa aaatgggctc gtgttgtaca 9120

ataaatgtag aggtagagac gcgaggtcta agaactttaa ataatttcta ctgttgtaga 9180

tagagaccgt gaagttaata aggtctcaaa tttctactgt tgtagatcgt ctctgaactg 9240

attcaagcaa gcttaaaccc agctcaatga gctgggtttt ttgtttgttt tttcaaactt 9300

agttagcttg gccagtgcct ctagagtcaa gtaaagagtc gacctgttac gaacggcaga 9360

tcagaatttt gtaataaaaa aagagcctgc tcattacact gcgggctctt tttcatggtc 9420

agaagacggg taaccaagat aacaa 9445

Claims (8)

1. The application of the gene editing fusion protein in bacillus subtilis gene editing is characterized in that the amino acid sequence of the gene editing fusion protein is shown as SEQ ID NO. 4.

2. The bacillus subtilis adenine base editor is characterized by comprising a gene editing fusion protein and a crRNA array insertion region, wherein the amino acid sequence of the gene editing fusion protein is shown as SEQ ID NO.4, and the nucleotide sequence of the crRNA array insertion region is shown as SEQ ID NO. 5.

3. The bacillus subtilis adenine base editor of claim 2, wherein: the gene editing fusion protein passes through an inducible promoter P _grac100 Regulating and controlling expression.

4. The bacillus subtilis adenine base editor of claim 2, wherein: the crRNA array insertion region passes through the constitutive promoter P _veg Regulating and controlling expression.

5. The bacillus subtilis adenine base editor of claim 2, wherein: the bacillus subtilis adenine base editor contains a gene for encoding gene editing fusion protein and a plasmid of a crRNA array insertion region, and the nucleotide sequence of the plasmid is shown as SEQ ID NO. 11.

6. Use of the bacillus subtilis adenine base editor of any one of claims 2-5 in gene editing.

7. The use according to claim 6, characterized in that: the gene is edited to convert a plurality of adenine sites on the genome to guanine.

8. The use according to claim 6, characterized in that: the bacillus subtilis adenine base editor is used for obtaining mutants or inactivating extracellular proteases.