AU2018200081A1 - Avirulent, immunogenic flavivirus chimeras - Google Patents

Abstract

Chimeric flaviviruses that are avirulent and immunogenic are provided. The chimeric viruses are constructed to contain amino acid mutations in the nonstructural proteins of a flavivirus. Chimeric viruses containing the attenuation-mutated nonstructural genes of the virus are used as a backbone into which the structural protein genes of a second flavivirus strain are inserted. These chimeric viruses elicit pronounced immunogenicity yet lack the accompanying clinical symptoms of viral disease. The attenuated chimeric viruses are effective as immunogens or vaccines and may be combined in a pharmaceutical composition to confer simultaneous immunity against several strains of pathogenic flaviviruses. 9845429_ 1 (GHMatte) P47053.AU.5

Description

FIELD OF THE INVENTION

The present invention relates to the fields of immunology and virology and more particularly to avirulent, immunogenic flavivirus chimeras for the production of immunogenic, live, attenuated flavivirus vaccines.

BACKGROUND OF THE INVENTION

Dengue viruses are mosquito-borne pathogens of the genus Flavivirus (family Flaviviridae). Four serotypes of dengue virus (often abbreviated “DEN”) have been identified, including dengue-1, dengue-2, dengue-3 and dengue-4 (DEN-1 to DEN-4). The flavivirus genome is a single-stranded, positive-sense RNA approximately 11 kb in length, containing a 5'-noneoding region (5'NC); a coding region encoding the viral structural proteins; live nonstructural proteins, designated NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5; and a 3'-noncoding region (3'NC). The viral structural proteins include the capsid, premembrane/membrane and envelope. The structural and nonstructural proteins are translated as a single polyprotein. The polyprotein is then processed by cellular and viral proteases.

Transmitted by Aedes aegypti mosquitoes to humans in tropical and subtropical regions of the world, dengue viruses cause millions of cases of disease ever)’ year,

9845429_1 (GHMatters) P47053.AU.6

2018200081 04 Jan 2018 ranging from dengue fever to the often fatal dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Secondary infection of humans with a heterologous serotype of i'

DEN virus may induce an immunopathological response and is considered a possible risk factor for DHF/DSS. Therefore, the need exists for development of a vaccine that confers simultaneous protection against all dengue virus strains.

Since eradication of Aedes aegypti mosquitoes appears to be practically infeasible, development of safe, effective vaccines against all four serotypes of dengue virus is a World Elealth Organization priority. However, no approved, effective vaccine against any of the dengue virus strains is currently available. It has been demonstrated that serial passage of wild-type flaviviruses in various cell cultures, such as primary dog kidney (PDK) cells, produces virus variants that have reduced virulence, retain immunogenicity and produce no untoward clinical symptoms.

Live, attenuated dengue viruses of all four serotypes have been developed at

Mahidol University in Thailand by passaging the wild-type viruses in cell culture.

These are currently the most promising live, attenuated vaccine candidates for immunization against dengue virus infection and/or disease. These vaccine candidates have been designated by a combination of their dengue serotype, the cell line through which they were passaged and the number of times they were passaged. Thus, a dengue serotype 1 wild-type virus passaged in PDK cells 13 times is designated as DEN-1 PDK-13 virus(nucleotide sequence, SEQ ID NO:3; amino acid sequence, SEQ ID NO:4). The other vaccine candidates are DEN-2 PDK-53 (nucleotide sequence, SEQ ID NO:15; amino acid sequence, SEQ ID NO:16), DEN-3 PGMK-30/FRhL-3 (thirty passages in primary green monkey kidney cells, followed by three passages in fetal rhesus lung cells)(nucleotide sequence, SEQ ID NO:21; amino acid sequence,

SEQ ID NO:22) and DEN-4 PDK-48 (nucleotide sequence, SEQ ID NO:25; amino acid sequence, SEQ ID NO:26). These four candidate vaccine viruses were derived by tissue culture passage of wild-type parental DEN-1 16007 (nucleotide sequence, SEQ

ID NO:1; amino acid sequence, SEQ ID NO:2), DEN-2 16681( nucleotide sequence,

2018200081 04 Jan 2018

SEQ ID NO: 13; amino acid sequence, SEQ ID NO: 14), DEN-3 16562 ( nucleotide sequence, SEQ ID NO:19; amino acid sequence, SEQ ID NO:20) and DEN-4 1036 (nucleotide sequence, SEQ ID NO:23; amino acid sequence, SEQ ID NO:24) viruses, respectively.

Preliminary human clinical trials with these attenuated viruses have indicated that DEN-2 PDK-53 has the lowest infectious dose (50% minimal infectious dose of 5 plaque forming units or PFU) in humans, is strongly immunogenic, and produces no unacceptable clinical symptoms. The DEN-1 PDK-13, DEN-3 PGMK-30/FRhL-3 and

DEN-4 PDK-48 vaccine virus candidates have higher 50% minimal infectious doses of 10,000, 3500, and 150 PFU, respectively, in humans. The higher infectious doses required for the latter three vaccine candidates raises concerns regarding the relative efficacy of each serotype component in a tetravalent dengue virus vaccine. Although only one immunization with monovalent DEN-2 PDK-53 virus or DEN-4 PDK-48 virus was required to achieve 100% seroconversion in human subjects, a booster was needed to achieve the same seroconversion rate for DEN-1 PDK-13 and DEN-3 PGMK-30/FRhL-3 viruses, which have the two highest infectious doses for humans.

The DEN-2 PDK-53 virus vaccine candidate, henceforth abbreviated PDK-53, has several measurable biological markers associated with attenuation, including temperature sensitivity, small plaque size, decreased replication in mosquito C6/36 cell culture, decreased replication in intact mosquitoes, loss of neurovirulence for suckling mice and decreased incidence of viremia in monkeys. Clinical trials of the candidate PDK-53 vaccine have demonstrated its safety and immunogenicity in humans.

Furthermore, the PDK-53 vaccine induces dengue virus-specific T-cell memory responses in human vaccine recipients.

Except for DEN-2 PDK-53 virus, the number and identity of the genetic mutations that accrued during multiple passages in cell culture and that are associated with the attenuated phenotypes of the vaccine candidates are unknown. Neither the

2018200081 04 Jan 2018 relative contributions of such attenuation-associated mutations to the actual mechanism of attenuation, nor the potential for reverse mutations to revert any of the vaccine candidates to the virulent biological phenotype of the wild-type dengue virus are known for any of these four vaccine candidates. An understanding of the attenuation markers of a vaccine candidate is critical for the prediction of its stability and safety.

Accordingly, there is a need for aviruient. yet immunogenic, dengue viruses to be used in the development of dengue virus vaccines to confer protection against one or more dengue virus serotypes. What would be ideal is a vaccine that would simultaneously protect an individual against several virulent strains of this potentially dangerous family (Flaviviridae) of viruses. Therefore, a tetravalent vaccine that can be used to immunize an individual against all four dengue serotypes is particularly needed.

It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.

SUMMARY OF THE INVENTION

Immunogenic flavivirus chimeras, a dengue-2 virus backbone for preparing the flavivirus chimeras and methods for producing the flavivirus chimeras are described. The immunogenic flavivirus chimeras are provided, alone or in combination, in a pharmaceutically acceptable carrier as immunogenic compositions to minimize, inhibit, or immunize individuals against infection by one or more flaviviruses or flaviviral strains, particularly strains of the dengue virus serotypes DEN-1, DEN-2, DEN-3 and DEN-4. When combined, the immunogenic flavivirus chimeras may be used as multivalent vaccines to confer simultaneous protection against infection by more than one species or strain of flavivirus. Preferably, the flavivirus chimeras are combined in an immunogenic composition useful as a tetravalent vaccine against the four known dengue virus serotypes. The nucleic acid sequence for each of the DEN-1, DEN-3 and DEN-4 viruses is also provided, for use as probes to detect dengue virus in a biological sample.

9845429_1 (GHMatters) P47053.AU.6

2018200081 04 Jan 2018

The avirulent, immunogenic flavivirus chimeras provided herein contain the nonstructural protein genes of the attenuated dengue-2 virus, or the equivalent thereof, and one or more of the structural protein genes or immunogenic portions thereof of the flavivirus against which immunogenicity is to be conferred. For example, the preferred chimera contains the attenuated dengue-2 virus PDK-53 genome as the viral backbone, and the structural protein genes encoding capsid, premembrane/membrane, or envelope of the PDK-53 genome, or combinations thereof, are replaced with the corresponding structural protein genes from a flavivirus to be protected against, such as a different flavivirus or a different dengue virus serotype. The resulting viral chimera has the functional properties of the attenuated dengue-2 virus and is therefore avirulent, but expresses antigenic epitopes of the structural gene products and is therefore immunogenic.

In another embodiment, the preferred chimera is a nucleic acid chimera comprising a first nucleotide sequence encoding nonstructural proteins from an attentuated dengue-2 virus, and a second nucleotide sequence encoding a structural protein from a second flavivirus. In a further preferred embodiment, the attenuated dengue-2 virus is vaccine strain PDK-53. In a further preferred embodiment, the structural protein can be the C, prM or E protein of a flavivirus. Examples of flaviviruses from which the structural protein may be selected include, but are not limited to, dengue-1 virus, dengue-2 virus, dengue-3 virus, dengue-4 virus, West Nile virus, Japanese encephalitis virus, St. Louis encephalitis virus, yellow fever virus and tick-borne encephalitis virus. In a further embodiment, the structural protein may be selected from non-flavivirus species that are closely related to the flaviviruses, such as hepatitis C virus.

In evaluating the chimeric virus of the invention, it was unexpectedly discovered that the avirulence of the attenuated PDK-53 virus strain is attributable to the presence of specific amino acid substitution mutations in the nonstructural proteins and a nucleotide substitution mutation in the 5’ noncoding region. This nucleotide

2018200081 04 Jan 2018 substitution mutation occurs in the stem of a stem-loop structure that is conserved in all four dengue serotypes. In particular, a single mutation at NS1-53, a double mutation at NS 1-53 and at 5’NC-57, a double mutation at NS 1-53 and at NS3-250, and a triple mutation at NS 1-53, at 5’NC-57 and at NS3-250, can provide the attenuated DEN-2 virus of the present invention.

Furthermore, the genome of any dengue-2 virus containing non-conservative amino acid substitutions at these loci can be used as the backbone in the avirulent chimeras described herein. Furthermore, other flavivirus genomes containing analogous mutations at the same loci, after amino acid sequence or nucleotide sequence alignment and stem structure analysis can also be used as the backbone structure and are defined herein as being equivalent to attenuating mutations of the dengue-2 PDK-53 genome.

The backbone, that region of the chimera that comprises the 5 ’ and 3 ’ noncoding regions and the region encoding the nonstructural proteins, can also contain further mutations to maintain stability of the avirulent phenotype and to reduce the possibility that the avirulent virus or chimera might revert back to the virulent wildtype virus. For example, a second mutation in the stem of the stem/loop structure in the

5’ noncoding region will provide additional stability, if desired.

These chimeric viruses can comprise nucleotide and amino acid substitutions, deletions or insertions in their structural and nonstructural proteins in addition to those specifically described herein.

The structural and nonstructural proteins of the invention are to be understood to include any protein comprising or any gene encoding the sequence of the complete protein, an epitope of the protein, or any fragment comprising, for example, two or more amino acid residues thereof.

2018200081 04 Jan 2018

The present invention also provides a method for making the chimeric viruses of this invention using recombinant techniques, by inserting the required substitutions into the appropriate backbone genome.

The present invention also provides compositions comprising a pharmaceutically acceptable carrier and attenuated chimeric viruses of this invention which contain amino acid sequences derived from other dengue virus serotypes, other flavivirus species or other closely related species, such as hepatitis C virus. As an object of the invention, the amino acid sequences derived from other dengue virus serotypes, other flavivirus species or other closely related species, such as hepatitis C virus, are expressed in a host, host cell or cell culture. As a further object of the invention, proteins or polypeptides comprising the amino acid sequences derived from other dengue virus serotypes, other flavivirus species or other closely-related species, can act as immunogens and, thus, be used to induce an immunogenic response against other dengue virus serotypes, other flavivirus species or other closely related species.

The present invention also provides compositions comprising a pharmaceutically acceptable carrier, one or more attenuated chimeric viruses of this invention and further immunizing compositions. Examples of such further immunizing compositions include, but are not be limited to, dengue virus vaccines, yellow fever virus vaccines, tick-borne encephalitis virus vaccines, Japanese encephalitis virus vaccines, West Nile virus vaccines, hepatitis C virus vaccines or other virus vaccines. Such vaccines may be live attenuated virus vaccines, killed virus vaccines, subunit vaccines, recombinant DNA vector vaccines or any combination thereof.

A distinct advantage of the current invention is that it provides for mixtures of attenuated flavivirus chimeras to be used as vaccines in order to impart immunity against several flavivirus species simultaneously.

2018200081 04 Jan 2018

Thus, an object of the current invention is to provide a virus chimera containing amino acid or nucleotide substitutions which retain immunogenicity of the virus while preventing any pathogenic effects of the virus.

Another object of the present invention is to provide nucleic acid chimeras comprising nucleotide sequence from an attenuated dengue-2 virus and nucleotide sequence from a second flavivirus, wherein the nucleotide sequence from the second flavivirus directs the synthesis of flavivirus antigens.

Another object of the present invention is to provide compositions for vaccines comprising more than one flavivirus species.

Another object of the present invention is to provide a method for making immunogenic or vaccine compositions using recombinant techniques by inserting the required substitutions into an appropriate flavivirus genome.

Another object of the invention is to provide compositions and methods for imparting immunity against more than one flavivirus simultaneously.

Another object of the invention is to provide nucleic acid probes and primers for use in any of a number of rapid genetic tests that are diagnostic for each of the vaccine viruses of the current invention. This object of the invention may be embodied in polymerase chain reaction assays, hybridization assays or other nucleic acid sequence detection techniques known to the art. A particular embodiment of this object is an automated PCR-based nucleic acid detection system.

These and other objects, features and advantages of the present invention will become apparent after review of the following detailed description of the disclosed embodiments and the appended claims.

2018200081 04 Jan 2018

BRIEF DESCRIPTION OF THE FIGURES

FIGURE 1 schematically shows the genomic organization of the chimeric DEN2/DEN-l viruses. Designations of the chimeras are based on the DEN-2 virus-specific infectious clone backbones and the structural genes (C-prM-E) insert of DEN-1 viruses. Underlined letters of the backbone and insert viruses are used in the designations. D2/1 indicates DEN-2/DEN-1 chimera; the first letter following the hyphen is the DEN-2 viral backbone, parent 16681 (P), PDK53-E (E), or PDK53-V (V); the last letter indicates the structural genes from the parental DEN-1 16007 (P) strain or its vaccine derivative, strain PDK-13 (V). The PDK53-E backbone contains three DEN-2 PDK-53 virus-specific amino acid mutations (NSl-53-Asp, NS2A-181-Phe, and NS4A-75-Ala) as well as the 5’NC-57 mutation of PDK-53 virus. The PDK53-V backbone contains these same PDK-53 virus-specific loci plus the additional PDK-53 virus-specific NS3250-Val locus.

FIGURES 2A and 2B show the growth characteristics of the chimeric DEN2/DEN-l viruses in LLC-MK₂ cells. Stippled bars indicate DEN-1 16007 virus and the chimeric viruses expressing the structural proteins of DEN-1 16007 virus. Bars with stripes indicate DEN-1 PDK-13 virus and the chimeric viruses expressing structural proteins of PDK-13 virus. Blank bars indicate the three DEN-2 backbone viruses derived from infectious clones of DEN-2 16681 virus (P48) and the two variants (PDK53-E and PDK53-V; E48 and V48, respectively). Figure 2A: Mean (± SD) plaque diameters. Values were calculated from ten individual plaques of each virus on day 10 after infection, pp: pinpoint-size plaques less than 1 mm. Figure 2B: Temperature sensitivity (ts) and peak titers of chimeric viruses on day 8 or 10 after infection. The ts scores were based on the reduction of the virus titers at 38.7°C versus those at 37°C (-, +, 2+ and 3+ indicate titer reduction of less than or equal to 60%, 61-90%, 91-99%, >99%, respectively, calculated from at least three experiments). The graph bar heights represent the log₁₀ titers of the viruses at 37°C. The multiplicity of infection (m.o.i.) was approximately 0.001 PFU/cell.

2018200081 04 Jan 2018

FIGURE 3 shows the growth curves of DEN-1 16007, DEN-1 PDK-13, DEN-2 16681-P48, DEN-2 PDK53-E48, DEN-2 PDK53-V48 and chimeric DEN-2/DEN-1 viruses in C6/36 cells. Cells were infected at an approximate m.o.i. of 0.001 PFU/ml.

FIGURES 4A-C. Figure 4A: Mean plaque diameters ± SD in millimeters (n=12) of DEN-2 16681, PDK-53 and recombinant 16681/PDK-53 viruses at nine days after infection in LLC-MK₂ cells. Figure 4B: Peak replication titers at 6-8 days after infection of LLC-MK₂ cells at a m.o.i. of approximately 0.001 PFU/cell in a single experiment. Temperature sensitivity (ts) scores for viruses grown at 37 °C or 38.7 °C in LLC-MK₂ cells are shown above the graph bars for peak replication titers. Scores of (-), (+/-) and (+) indicate less than 81%, 81-89% and 90-97% reduction in viral titer, respectively, at 38.7 °C. Scores were determined at eight days after infection. Figure 4C: Average peak replication titers at 12 days after infection of C6/36 cells at a multiplicity of approximately 0.001 PFU/cell in two independent experiments.

Individual peak titers from the two experiments are indicated by vertical lines in each graph bar. The numerical designations for recombinant Px and Vx viruses (where x = 5'NC, NS1, and/or NS3 loci) indicate parental (P in virus designation) 16681 virusspecific loci engineered into the PDK-53 virus-specific infectious cDNA clone or reciprocal candidate PDK-53 vaccine (V in virus designation) virus-specific loci engineered into the 16681 clone, respectively. Cognate viruses are indicated in all three graphs by graph bars of identical solid or cross-hatching pattern. The cognate for P5 virus is V13 virus, assuming that the viral phenotype is determined predominantly by the 5'NC-57, NS 1-53 and NS3-250 loci. Both P5 and V13 viruses contain the 5'NC-57C (16681), NSl-53-Asp (PDK-53) andNS3-250- Val (PDK-53) loci within the genetic backgrounds of PDK-53 and 16681 viruses, respectively.

2018200081 04 Jan 2018

DETAILED DESCRIPTION OF THE INVENTION

The following description includes the best presently contemplated mode of carrying out the invention. This description is made for the purpose of illustrating the general principles of the inventions and should not be taken in a limiting sense.

Immunogenic flavivirus chimeras, a dengue-2 virus or dengue-2 virus equivalent backbone for preparing the flavivirus chimeras of this invention and methods for preparing the flavivirus chimeras are provided herein. The immunogenic flavivirus chimeras are useful, alone or in combination, in a pharmaceutically acceptable carrier as immunogenic compositions to minimize, inhibit, or immunize individuals against infection by one or more flaviviruses or flaviviral strains, particularly strains of the dengue virus serotypes DEN-1, DEN-2, DEN-3 and DEN-4. When combined, the immunogenic flavivirus chimeras may be used as a multivalent vaccine to confer simultaneous protection against infection. Preferably, the dengue virus chimeras are combined in an immunogenic composition useful as a tetravalent vaccine against the four known dengue virus serotypes.

Immunogenic flavivirus chimeras of the current invention are also useful, in combination with avirulent virus strains, in a pharmaceutically acceptable carrier, as immunogenic compositions to minimize, inhibit or immunize individuals against infection by multiple pathogenic species. For example, one or more of the immunogenic flavivirus chimeras of the current invention can be combined with avirulent virus serotypes of selected flaviviruses to provide a safe and effective tetravalent vaccine against the four known dengue virus serotypes. In a further embodiment, the flavivirus chimeras of the current invention may be combined with avirulent virus vaccines to provide a safe and effective vaccine against infection by multiple pathogenic species.

2018200081 04 Jan 2018

The present invention also provides compositions comprising a pharmaceutically acceptable carrier, one or more attenuated chimeric viruses of this invention and further immunizing compositions. Examples of such further immunizing compositions include, but are not be limited to, dengue virus vaccines, yellow fever vaccines, tick-home encephalitis vaccines, Japanese encephalitis vaccines, West Nile virus vaccines, hepatitis C virus vaccines or other virus vaccines. Such vaccines may be live attenuated virus vaccines, killed virus vaccines, subunit vaccines, recombinant DNA vector vaccines or any combination thereof.

The nucleic acid sequence for each of the DEN-1, DEN-3 and DEN-4 viruses is also provided for use as probes to detect dengue vims in a biological sample.

Chimeras of the present invention can comprise the backbone of the dengue-2 vims of an attenuated dengue-2 vims and further nucleotide sequences selected from more than one dengue vims serotype, other flavivirus species, other closely related species, such as hepatitis C vims, or any combination thereof. These chimeras can be used to induce an immunogenic response against more than one species selected from the dengue vims serotypes, flavivirus species, other closely related species or any combination thereof.

In another embodiment, the preferred chimera is a nucleic acid chimera comprising a first nucleotide sequence encoding nonstructural proteins from an attenuated dengue-2 vims, and a second nucleotide sequence encoding a structural protein from a second flavivirus. In a further preferred embodiment, the attenuated dengue-2 vims is vaccine strain PDK-53. In a further preferred embodiment, the structural protein can be the C protein of a flavivirus, the prM protein of a flavivirus, the E protein of a flavivirus, or any combination thereof. Examples of flaviviruses from which the structural protein may be selected include, but are not limited to, dengue-1 vims, dengue-2 vims, dengue-3 vims, dengue-4 vims, West Nile vims,

Japanese encephalitis vims, St. Louis encephalitis vims, yellow fever vims and tick2018200081 04 Jan 2018 borne encephalitis virus. In a further embodiment, the structural protein may be selected from non-flavivirus species that are closely related to the flaviviruses, such as hepatitis C virus.

The terms a, an and the as used herein are defined to mean one or more and include the plural unless the context is inappropriate.

The term residue is used herein to refer to an amino acid (D or L) or an amino acid mimetic that is incorporated into a peptide by an amide bond. As such, the amino acid may be a naturally occurring amino acid or, unless otherwise limited, may encompass known analogs of natural amino acids that function in a manner similar to the naturally occurring amino acids (i.e., amino acid mimetics). Moreover, an amide bond mimetic includes peptide backbone modifications well known to those skilled in the art.

Furthermore, one of skill in the art will recognize that individual substitutions, deletions or additions in the amino acid sequence, or in the nucleotide sequence encoding for the amino acids, which alter, add or delete a single amino acid or a small percentage of amino acids (typically less than 5%, more typically less than 1%) in an encoded sequence are conservatively modified variations, wherein the alterations result in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. The following six groups each contain amino acids that are conservative substitutions for one another:

1) Alanine (A), Serine (S), Threonine (T);

2) Aspartic acid (D), Glutamic acid (E);

3) Asparagine (N), Glutamine (Q);

4) Arginine (R), Lysine (K);

5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); and

6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W).

2018200081 04 Jan 2018

As used herein, the terms “virus chimera,” “chimeric virus,” “flavivirus chimera” and “chimeric flavivirus” means an infectious construct of the invention comprising a portion of the nucleotide sequence of a dengue-2 virus and further nucleotide sequence that is not from the same dengue-2 virus. Thus, examples of further nucleotide sequence include, but are not limited to, sequences from dengue-1 virus, dengue-2 virus, dengue-3 virus, dengue-4 virus, West Nile virus, Japanese encephalitis virus, St. Louis encephalitis virus, tick-bome encephalitis virus, yellow fever virus and any combination thereof.

As used herein, “infectious construct” indicates a virus, a viral construct, a viral chimera, a nucleic acid derived from a virus or any portion thereof, which may be used to infect a cell.

As used herein, “nucleic acid chimera” means a construct of the invention comprising nucleic acid comprising a portion of the nucleotide sequence of a dengue-2 virus and further nucleotide sequence that is not of the same origin as the nucleotide sequence of the dengue-2 virus. Correspondingly, any chimeric flavivirus or flavivirus chimera of the invention is to be recognized as an example of a nucleic acid chimera.

The structural and nonstructural proteins of the invention are to be understood to include any protein comprising or any gene encoding the sequence of the complete protein, an epitope of the protein, or any fragment comprising, for example, two or more amino acid residues thereof.

Nucleotide sequences of the RNA genome of the viruses and chimeras of the current invention are recited in the sequence listings in terms of DNA.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which this invention pertains. Although other materials and methods similar or equivalent to

2018200081 04 Jan 2018 those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

Flavivirus Chimeras

Dengue virus types 1-4 (DEN-1 to DEN-4) are mosquito-bome flavivirus pathogens. The flavivirus genome contains a 5'-noncoding region (5’-NC), followed by a capsid protein (C) encoding region, followed by a premembrane/membrane protein (prM) encoding region, followed by an envelope protein (E) encoding region, followed by the region encoding the nonstructural proteins (NS1-NS2A-NS2B-NS3-NS4A10 NS4B-NS5) and finally a 3’ noncoding region (3'NC). The viral structural proteins are C, prM and E, and the nonstructural proteins are NS1-NS5. The structural and nonstructural proteins are translated as a single polyprotein and processed by cellular and viral proteases.

The flavivirus chimeras of the invention are constructs formed by fusing nonstructural protein genes from one type, or serotype, of dengue virus or virus species of the flaviviridae, with protein genes, for example, structural protein genes, from a different type, or serotype, of dengue virus or virus species of the flaviviridae. Alternatively, a flavivirus chimera of the invention is a construct formed by fusing non20 structural protein genes from one type, or serotype, of dengue virus or virus species of the flaviviridae, with further nucleotide sequences that direct the synthesis of polypeptides or proteins selected from other dengue virus serotypes or other viruses of the flaviviridae.

The avirulent, immunogenic flavivirus chimeras provided herein contain the nonstructural protein genes of the attenuated dengue-2 virus, or the equivalent thereof, and one or more of the structural protein genes, or antigenic portions thereof, of the flavivirus against which immunogenicity is to be conferred. Suitable flaviviruses include, but are not limited to those listed in Table 1.

2018200081 04 Jan 2018

Other suitable flaviviruses for use in constructing the flavivirus chimeras of the invention are wild-type, virulent DEN-1 16007 (SEQ ID NO:1; SEQ ID NO:2), DEN-2 16681 (SEQ ID NO: 13; SEQ ID NO: 14), DEN-3 16562 (SEQ ID NO: 19; SEQ ID NO:20) and DEN-4 1036 (SEQ ID NO:23; SEQ ID NO:24) and attenuated, vaccine5 strain DEN-1 PDK-13 (SEQ ID NO:3; SEQ ID NO:4), DEN-2 PDK-53 (SEQ ID NO:15; SEQ ID NO:16), DEN-3 PMK-30/FRhL-3 (SEQ ID NO:21; SEQ ID NO:22) and DEN-4 PDK-48 (SEQ ID NO:25; SEQ ID NO:26). Further suitable flaviviruses, or variants of the above listed flaviviruses, are described herein. Genetic differences between the DEN-1, DEN-2, DEN-3 and DEN-4 wild type/attenuated virus pairs are shown in Tables 2-5 along with changes in the amino acid sequences encoded by the viral genomes.

The sequence listings for DEN-2 PDK-53 provided herein (SEQ ID NO.T5;

SEQ ID NO: 16) correspond to the DEN-2 PDK-53-V variant, wherein genome nucleotide position 5270 is mutated from an A to a T and amino acid position 1725 of the polyprotein or amino acid position 250 of the NS3 protein contains a valine residue. The DEN-2 PDK-53 variant without this nucleotide mutation, DEN-2 PDK-53-E, differs from PDK-53-V only in this one position. DEN-2 PDK-53-E has an A at nucleotide position 5270 and a glutamate at polyprotein amino acid position 1725, NS3 protein amino acid position 250 (Table 3).

The sequence listings for DEN-3 16562 provided herein (SEQ ID NO:21; SEQ ID NO:22) correspond to the variant wherein genome nucleotide position 1521 is a T and amino acid position 476 of the polyprotein or amino acid position 196 of the E protein contain a leucine. A second variant, present in DEN-3 16562 cultures has a T at nucleotide position 1521 and amino acid position 476 of the polyprotein or amino acid position 196 of the E protein contain a serine (Table 4).

The sequence listings for DEN-4 PDK-48 (SEQ ID NO:25; SEQ ID NO:26) correspond to the variant wherein genome nucleotide positions: 6957 is a T and amino

2018200081 04 Jan 2018 acid position 2286 of the polyprotein and amino acid position 44 of NS4B protein is a phenylalanine, 7546 is a T and amino acid position 2366 of the polyprotein and amino acid position 240 of NS4B protein is a valine, and 7623 is a T and amino acid position 2508 of the polyprotein and amino acid position 21 of NS5 protein is a tyrosine (Table

5).

Throughout the text, designations of the chimeras are based on the DEN-2 virus-specific infectious clone backbones and the structural genes (prM-E or C-prM-E) insert of other flaviviruses. Each designation begins with DEN-2 for the dengue-2 backbone, followed by the strain from which the structural genes are inserted. The particular backbone variant is reflected in the next letter. The particular DEN-2 backbone variant from which the chimera was constructed is indicated by the following letter placed after a hyphen, parent 16681 (P), PDK53-E (E), or PDK53-V (V); the last letter indicates the C-prM-E structural genes from the parental (P) strain or its vaccine derivative (V) or the prM-E structural genes from the parental (Pl) or its vaccine derivative (VI). For example; DEN-2/1-VP (SEQ ID NO:5; SEQ ID NO:6) denotes the chimera comprising the attenuated DEN-2 PDK-53V backbone comprising a valine at NS3-250 and the C-prM-E genes from wild-type DEN-1 16007; DEN-2/1-VV (SEQ ID NO:7; SEQ ID NO:8) denotes the DEN-2 PDK-53V backbone with the vaccine strain of dengue-1, DEN-1 PDK-13; DEN-2/1-VP1 (SEQ ID NO:27; SEQ ID NO:28) denotes the DEN-2 PDK-53V backbone and the prM-E genes from wild-type DEN-1 16007; DEN-2/3-VP1 (SEQ ID NO:9; SEQ ID ΝΟΤΟ) denotes the DEN-2 PDK-53V backbone and the prM-E genes from wild-type DEN-3 16562; DEN-2/4-VP1 (SEQ ID NOT 1; SEQ ID NOT2) denotes the DEN-2 PDK-53V backbone and the prM-E genes from wild-type DEN-4 1036; and DEN-2/WN-PP1 (SEQ ID NOT7; SEQ ID NOT8) denotes the DEN-2 16681 backbone and the prM-E genes from West Nile NY99.

Other chimeras of the present invention, denoted in the same manner, are clearly defined herein by the disclosed sequences. For instance, DEN-2/1-PV is defined herein as consisting of the wild-type dengue-2 backbone, DEN-2 16681, and the C-prM-E

0 genes of the vaccine strain of dengue-1, DEN-1 PDK-13.

2018200081 04 Jan 2018

The preferred chimera of the invention, for example, contains the attenuated dengue-2 virus PDK-53 genome as the viral backbone, in which the structural protein genes encoding C, prM and E proteins of the PDK-53 genome, or combinations thereof, are replaced with the corresponding structural protein genes from a flavivirus to be protected against, such as a different flavivirus or a different dengue virus strain.

Newly discovered flaviviruses or flavivirus pathogens can also be incorporated into the DEN-2 backbone. Genetic recombinations with related viruses such as hepatitis C virus (HCV) could also be used to produce the chimeras of this invention. The resulting viral chimera has the functional properties of the attenuated dengue-2 virus and is therefore avirulent, but expresses antigenic epitopes of the structural gene products and is therefore immunogenic.

Nine nucleotide mutations between the genomes of the wild type DEN-2 16681 virus and two attenuated PDK-53 virus strains are identified herein (Table 3). Three of these mutations are silent mutations in that they do not result in the production of an amino acid that differs from the amino acid in the same position in the wild type virus. The first mutation is a C-to-T (wild type-to-PDK-53) nucleotide mutation at genome nucleotide position 57 (nt 57) in the 5’ noncoding region. The second mutation is a Ato-T mutation at genome nucleotide position 524, encoding the amino acid substitution

Asp-to-Val in the structural protein premembrane region, prM-29.

In the nonstructural protein regions, a Gly-to-Asp (wild type-to-PDK-53) mutation was discovered at nonstructural protein NS 1-53 (genome nucleotide position 2579); a Leu-to-Phe (wild type-to-PDK-53) mutation was discovered at nonstructural protein NS2A-181 (genome nucleotide position 4018); a Glu-to-Val (wild type-toPDK-53) mutation was discovered at nonstructural protein NS3-250 (genome nucleotide position 5270); and a Gly-to-Ala mutation (wild type-to-PDK-53) was discovered at nonstructural protein NS4A-75 (genome nucleotide position 6599).

2018200081 04 Jan 2018

The attenuated PDK-53 virus strain has a mixed genotype at genome nt 5270. A significant portion (approximately 29%) of the virus population encodes the nonmutated NS3-250-Glu that is present in the wild type DEN-2 16681 virus rather than the NS3-250-Val mutation. As both genetic variants are avirulent, this mutation may not be necessary in an avirulent chimera.

It was unexpectedly discovered that the avirulence of the attenuated PDK-53 virus strain can be attributed to the presence of specific mutations in the nucleotide sequence encoding nonstructural proteins and in the 5’ noncoding region (Example 5).

In particular, a single mutation at NS 1 -53, a double mutation at NS 1 -53 and at 5’NC57, a double mutation atNSl-53 and at NS3-250 and a triple mutation at NS1-53, at 5’NC-57 and at NS3-250, result in attenuation of the DEN-2 virus. Therefore, the genome of any dengue-2 virus containing such non-conservative amino acid substitutions or nucleotide substitutions at these loci can be used as the backbone in the avirulent chimeras described herein. The backbone can also contain further mutations to maintain stability of the avirulent phenotype and to reduce the possibility that the avirulent virus or chimera might revert back to the virulent wild-type virus. For example, a second mutation in the stem of the stem/loop structure in the 5’ noncoding region will provide additional avirulent phenotype stability, if desired. The stem of the stem-loop structure is composed of nucleotide residues 11-16 (CUACGU) (SEQ ID NO:29) and nucleotide residues 56-61 (ACGUAG) (SEQ ID NO:30) of the dengue-2 virus RNA sense sequence, wherein the underlined nucleotide is C in wild-type DEN-2 16681 virus and U in PDK-53 virus. Mutations to this region disrupt potential secondary structures important for viral replication. In particular, mutations in the 5’ noncoding region have the ability to disrupt the function of the positive-sense RNA strand and the function of the negative-sense strand during replication. A single mutation in this short (only 6 nucleotide residues in length) stem structure in both DEN and Venezuelan equine encephalitis viruses disrupts the formation of the hairpin structure (Kinney et al., Virology 67,1269-1277, (1993)). Further mutations in this stem structure decrease the possibility of reversion at this locus, while maintaining

2018200081 04 Jan 2018 virus viability. Furthermore, flavivirus genomes containing an analogous stem structure that consists of short nucleotide sequences (stems consisting of 6 or more base pairs in the stem-loop structure) located in the 5' noncoding region and having one or more mutations in the stem structure may also be useful as the backbone structure of this invention.

Such mutations may be achieved by site-directed mutagenesis using techniques known to those skilled in the art. Furthermore, other flavivirus genomes containing analogous mutations at the same loci after amino acid sequence alignment, can be used as the backbone structure of the chimera of this invention and are defined herein as being equivalent to the dengue-2 PDK-53 genome. It will be understood by those skilled in the art that the virulence screening assays, as described herein and as are well known in the art, can be used to distinguish between virulent and avirulent backbone structures.

Construction of Flavivirus Chimeras

The flavivirus chimeras described herein can be produced by splicing one or more of the structural protein genes of the flavivirus against which immunity is desired into a PDK-53 dengue virus genome backbone, or the equivalent thereof as described above, using recombinant engineering techniques well known to those skilled in the art to remove the corresponding PDK-53 gene and replace it with the desired gene. Alternatively, using the sequences provided in the sequence listing, the nucleic acid molecules encoding the flavivirus proteins may be synthesized using known nucleic acid synthesis techniques and inserted into an appropriate vector. Avirulent, immunogenic virus is therefore produced using recombinant engineering techniques known to those skilled in the art.

As mentioned above, the gene to be inserted into the backbone encodes a flavivirus structural protein. Preferably the flavivirus gene to be inserted is a gene encoding a C protein, a PrM protein and/or an E protein. The sequence inserted into

2018200081 04 Jan 2018 the dengue-2 backbone can encode both the PrM and E structural proteins. The sequence inserted into the dengue-2 backbone can encode the C, prM and E structural proteins. The dengue virus backbone is the PDK-53 dengue-2 virus genome and includes either the spliced genes that encode the C, PrM and/or E structural proteins of dengue-1 (DEN-2/1), the spliced genes that encode the PrM and/or E structural proteins of dengue-3 (DEN-2/3), or the spliced genes encode the PrM and/or E structural proteins of dengue-4 (DEN-2/4). In a particular embodiment of this invention, the spliced gene that encodes the structural protein of dengue-3 virus directs the synthesis of an E protein that contains a leucine at amino acid position 345.

In a particular embodiment, the chimera of this invention encodes the C structural protein of dengue-2 virus and directs the synthesis of a C protein that contains a serine at amino acid position 100 and comprises a spliced gene encoding the structural proteins of dengue-4 which directs the synthesis of an E protein that contains a leucine at amino acid position 447.

In a further embodiment, the chimera of this invention encodes the C structural protein of dengue-2 virus and directs the synthesis of a C protein that contains a serine at amino acid position 100 and comprises a spliced gene encoding the structural proteins of dengue-4 which directs the synthesis of an E protein that contains a leucine at amino acid position 447 and a valine at amino acid position 364. The structural proteins described herein can be present as the only flavivirus structural protein or in any combination of flavivirus structural proteins in a viral chimera of this invention.

The chimeras of this invention are engineered by recombination of full genomelength cDNA clones derived from both DEN-2 16681 wild type virus and either of the PDK-53 dengue-2 virus variants (-E or -V(SEQ ID NO :15)). The uncloned PDK-53 vaccine contains a mixture of two genotypic variants, designated herein as PDK53-E and PDK53-V. The PDK53-V variant contains all nine PDK-53 vaccine-specific nucleotide mutations, including the Glu-to-Val mutation at amino acid position NS32018200081 04 Jan 2018

250. The PDK53-E variant contains eight of the nine mutations of the PDK-53 vaccine and the NS3-250-Glu of the parental 16681 virus. Infectious cDNA clones are constructed for both variants, and viruses derived from both clones are attenuated in mice. The phenotypic markers of attenuation of DEN-2 PDK-53 virus include small plaque size, temperature sensitivity (particularly in LLC-MK₂ cells), limited replication (particularly in C6/36 cells), attenuation for newborn mice (specifically loss of neuro virulence for suckling mice) and decreased incidence of viremia in monkeys. The chimeras that are useful as vaccine candidates are constructed in the genetic backgrounds of the two DEN-2 PDK-53 variants which all contain mutations in nonstructural regions of the genome, including 5'NC-57 C-to-T (16681-to-PDK-53) in the 5’ noncoding region, as well as mutations in the amino acid sequence of the nonstructural proteins, such as, for example, NS 1-53 Gly-to-Asp andNS3-250 Glu-toVal.

Suitable chimeric viruses or nucleic acid chimeras containing nucleotide sequences encoding structural proteins of other flaviviruses or dengue virus serotypes can be evaluated for usefulness as vaccines by screening them for the foregoing phenotypic markers of attenuation that indicate avirulence and by screening them for immunogenicity. Antigenicity and immunogenicity can be evaluated using in vitro or in vivo reactivity with flavivirus antibodies or immunoreactive serum using routine screening procedures known to those skilled in the art.

Flavivirus Vaccines

The preferred chimeric viruses and nucleic acid chimeras provide live, attenuated viruses useful as immunogens or vaccines. In a preferred embodiment, the chimeras exhibit high immunogenicity while at the same time producing no dangerous pathogenic or lethal effects.

Until now, an effective vaccine against all strains of dengue virus has been unavailable. Individual live attenuated vaccine candidates for all four serotypes have

2018200081 04 Jan 2018 been developed by serial passage of wild-type viruses in primary dog kidney (PDK) cells or other cell types. As described above, the PDK-53 virus is a useful dengue vaccine candidate. However, a vaccine derived from PDK-53 would only provide immunity against the DEN-2 serotype.

To prevent the possible occurrence of DHF/DSS in patients vaccinated against only one serotype of dengue vims, a tetravalent vaccine is needed to provide simultaneous immunity for all four serotypes of the vims. A tetravalent vaccine is produced by combining dengue-2 PDK-53 with the dengue-2/1, dengue-2/3, and dengue-2/4 chimeras described above in a suitable pharmaceutical carrier for administration as a multivalent vaccine.

The chimeric vimses or nucleic acid chimeras of this invention can comprise the structural genes of either wild-type or attenuated vims in a vimlent or an attenuated

DEN-2 vims backbone. For example, the chimera may express the structural protein genes of wild-type DEN-1 16007 vims or its candidate PDK-13 vaccine derivative in either of the DEN-2 PDK-53 backgrounds.

As described in Example 1, all of the chimeric DEN-2/1 vimses containing the

C, prM and E proteins of either DEN-1 16007 vims (DEN-2/1-EP and -VP chimeras) or PDK-13 vims (DEN-2/1-EV and -W (SEQ ID NO:7) chimeras) in the backbones of DEN-2 PDK-53 retain all of the phenotypic attenuation markers of the DEN-2 PDK-53 vims. The chimeric DEN-2/1-EP and -VP(SEQ ID NO:5) vimses, which contain the C, prM and E proteins of DEN-1 16007 vims are more genetically stable after passing in cell culture than the DEN-2/1-EV and -W vimses. The immunogenicity of the chimeric vimses expressing the structural proteins of DEN-1 16007 vims was higher as compared with the neutralizing antibody titers elicited by the PDK-13 vaccine vims and the chimeras expressing the structural proteins of the PDK-13 vims. Thus, the chimeric DEN-2/1-EP and -VP vimses, which express the structural genes of wild-type DEN-1

16007 vims within the genetic background of the two DEN-2 PDK-53 variants, are

2018200081 04 Jan 2018 potential DEN-1 vaccine candidates that are superior to the candidate PDK-13 vaccine. These two chimeras replicate well in LLC-MK₂ cells and retain the attenuation markers associated with DEN-2 PDK-53 virus, including small plaque size, temperature sensitivity, restricted replication in mosquito cells and attenuation for mice. They are at least as immunogenic as wild-type DEN-1 16007 virus in mice.

Other examples, such as DEN-2/3 and DEN-2/4 chimeras, in Examples 2-4, also showed that chimeric viruses containing structural protein genes from wild-type DEN-3 or DEN-4 virus within the DEN-2 PDK-53 backbones, are suitable vaccine candidates which retain all of the attenuated phenotypic markers of the DEN-2 PDK-53 viruses (Table 14), while providing immunogenicity against DEN-3 or DEN-4 virus. The strategy described herein of using a genetic background that contains the determinants of attenuation in nonstructural regions of the genome to express the structural protein genes of heterologous viruses has lead to development of live, attenuated flavivirus vaccine candidates that express wild-type structural protein genes of optimal immunogenicity. Thus, vaccine candidates for immunogenic variants of multiple flaviviral pathogens can be designed.

Viruses used in the chimeras described herein are typically grown using techniques known in the art. Virus plaque titrations are then performed and plaques counted in order to assess the viability and phenotypic characteristics of the growing cultures. Wild type viruses are passaged through cultured cell lines to derive attenuated candidate starting materials.

Chimeric infectious clones are constructed from the various dengue serotype clones available. The cloning of virus-specific cDNA fragments can also be accomplished, if desired. The cDNA fragments containing the structural protein or nonstructural protein genes are amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) from dengue virus RNA with various primers. Amplified fragments are cloned into the cleavage sites of other intermediate clones. Intermediate, chimeric

2018200081 04 Jan 2018 dengue virus clones are then sequenced to verify the accuracy of the inserted dengue virus-specific cDNA.

Full genome-length chimeric plasmids constructed by inserting the structural 5 protein or nonstructural protein gene region of dengue serotype viruses into vectors are obtainable using recombinant techniques well known to those skilled in the art.

Nucleotide and Amino Acid Analysis

The nucleotide sequence for DEN-2 16681 and corresponding PDK-53-V are provided in SEQ ID NO:13 and SEQ ID NO:15, respectively. Amino acid sequences for DEN-2 16681 and corresponding PDK-53-V are provided in SEQ ID NO:14 and SEQ ID NO: 16. The-E variant of PDK-53, which varies from PDK-53-V at nucleotide position 5270 and amino acid position 1725 of the polyprotein is further described in Table 3. A comparison of the critical nucleotide and amino acid substitutions that have been discovered between the parent strain and the attenuated virus is shown in Table 3. The sequence of the DEN-2 cDNA amplicons was amplified from DEN-2 viral genomic RNA by reverse transcriptase-polymerase chain reaction (RT-PCR).

Unlike PDK-53, which contains no amino acid mutations in the E protein relative to wild type dengue-2 virus, the Mahidol DEN-1, DEN-3 and DEN-4 attenuated viruses all have amino acid mutations in the E protein (Tables 2,4 & 5).

The wild-type DEN-3 16562 listed in the sequence listing (nucleotide sequence, SEQ ID NO: 19; amino acid sequence, SEQ ID NO:20) was shown to comprise traces of a variant comprising a T at nucleotide position 1521 which directs incorporation of a leucine at polyprotein position 476, amino acid residue position 476 of the E protein.

Each of the latter three viruses possess a Glu-to-Lys (parent-to-vaccine) mutation in the E protein, although the mutation is located at a different amino acid residue in the E protein. This substitution causes a shift from a negatively charged

2018200081 04 Jan 2018 amino acid to a positively charged one. The Glu-to-Lys substitution in the E protein of DEN-4 vaccine virus was the only mutation present in the E protein, while the E proteins of DEN-1 and DEN-3 vaccine viruses had five and three amino acid mutations, respectively.

The NS 1-5 3 mutation in the DEN-2 PDK-53 vaccine virus is significant for the attenuated phenotype of this virus, because the NSl-53-Gly of the DEN-2 16681 virus is conserved in nearly all flaviviruses, including the tick-bome viruses, sequenced to date. The Mahidol DEN-4 vaccine virus also contains an amino acid mutation in the

NS 1 protein at position 253. This locus, which is a Gln-to-His mutation in DEN-4 PDK-48 vaccine virus is Gin in all four wild serotypes of dengue virus. This Gin residue is unique to the dengue viruses within the flavivirus genus. The NS1 protein is a glycoprotein that is secreted from flavivirus-infected cells. It is present on the surface of the infected cell and NS 1-specific antibodies are present in the serum of virus15 infected individuals. Protection of animals immunized with NS 1 protein or passively with NS 1-specific antibody has been reported. The NS1 protein appears to participate in early viral RNA replication.

The mutations that occurred in the NS2A, NS2B, NS4A, and NS4B proteins of the DEN-1, -2, -3 and -4 attenuated strains were all conservative in nature. The NS4A75 and NS4A-95 mutations of DEN-2 and DEN-4 vaccine viruses, respectively, occurred at sites of amino acid conservation among dengue viruses, but not among flaviviruses in general.

The flaviviral NS3 protein possesses at least two recognized functions: the viral proteinase and RNA helicase/NTPase. The 698-aa long (DEN-2 virus) NS3 protein contains an amino-terminal serine protease domain (NS3-51-His, -75-Asp, -135-Ser catalytic triad) that is followed by sequence motifs for RNA helicase/NTPase functions (NS3-196-GAGKT (SEQ ID NO: 147), -284-DEAH, -459-GRIGR (SEQ ID NO: 148)).

None of the mutations in the NS3 proteins of DEN-1, DEN-2, or DEN-3 virus occurred

2018200081 04 Jan 2018 within, a recognized motif. The NS3-510 Tyr-to-Phe mutation in DEN-1 PDK-13 virus was conservative. Since the wild-type DEN-2, -3 and -4 viruses contain Phe at this position, it is unlikely that the Tyr-to-Phe mutation plays a role in the attenuation of DEN-1 virus. The NS3-182 Glu-to-Lys mutation in DEN-1 PDK-13 virus occurred at a position that is conserved as Asp or Glu in most mosquito-bome flaviviruses and it may play some role in attenuation. This mutation was located 15 amino acid residues upstream of the GAGKT (SEQ ID NO: 147) helicase motif. As noted in previous reports, the NS3-250-Glu in DEN-2 16681 virus is conserved in all mosquito-bome flaviviruses except for yellow fever virus.

Method of Administration

The viral chimeras described herein are individually or jointly combined with a pharmaceutically acceptable carrier or vehicle for administration as an immunogen or vaccine to humans or animals. The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable vehicle” are used herein to mean any composition or compound including, but not limited to, water or saline, a gel, salve, solvent, diluent, fluid ointment base, liposome, micelle, giant micelle, and the like, which is suitable for use in contact with living animal or human tissue without causing adverse physiological responses, and which does not interact with the other components of the composition in a deleterious manner.

The immunogenic or vaccine formulations may be conveniently presented in viral PFU unit dosage form and prepared by using conventional pharmaceutical techniques. Such techniques include the step of bringing into association the active ingredient and the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers. Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may

2018200081 04 Jan 2018 include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.

Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets commonly used by one of ordinary skill in the art.

Preferred unit dosage formulations are those containing a dose or unit, or an appropriate fraction thereof, of the administered ingredient. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of the present invention may include other agents commonly used by one of ordinary skill in the art.

The immunogenic or vaccine composition may be administered through different routes, such as oral or parenteral, including, but not limited to, buccal and sublingual, rectal, parenteral, aerosol, nasal, intramuscular, subcutaneous, intradermal, and topical. The composition may be administered in different forms, including, but not limited to, solutions, emulsions and suspensions, microspheres, particles, microparticles, nanoparticles and liposomes. It is expected that from about 1 to about 5 doses may be required per immunization regimen. Initial doses may range from about

100 to about 50,000 PFU, with a preferred dosage range of about 500 to about 20,000 PFU, a more preferred dosage range of from about 1000 to about 12,000 PFU and a most preferred dosage range of about 1000 to about 4000 PFU. Booster injections may range in dosage from about 100 to about 20,000 PFU, with a preferred dosage range of about 500 to about 15,000, a more preferred dosage range of about 500 to about 10,000 PFU, and a most preferred dosage range of about 1000 to about 5000 PFU. For example, the volume of administration will vary depending on the route of administration. Intramuscular injections may range in volume from about 0.1 ml to 1.0 ml.

2018200081 04 Jan 2018

The composition may be stored at temperatures of from about -100°C to about 4°C. The composition may also be stored in a lyophilized state at different temperatures including room temperature. The composition may be sterilized through conventional means known to one of ordinary skill in the art. Such means include, but are not limited to, filtration. The composition may also be combined with bacteriostatic agents, such as thimerosal, to inhibit bacterial growth.

Administration Schedule

The immunogenic or vaccine composition described herein may be 10 administered to humans, especially individuals traveling to regions where dengue virus infection is present, and also to inhabitants of those regions. The optimal time for administration of the composition is about one to three months before the initial infection. However, the composition may also be administered after initial infection to ameliorate disease progression, or after initial infection to treat the disease.

Adjuvants

A variety of adjuvants known to one of ordinary skill in the art may be administered in conjunction with the chimeric virus in the immunogen or vaccine composition of this invention. Such adjuvants include, but are not limited to, the following: polymers, co-polymers such as polyoxyethylene-polyoxypropylene copolymers, including block co-polymers, polymer Pl005, Freund’s complete adjuvant (for animals), Freund’s incomplete adjuvant; sorbitan monooleate, squalene, CRL-8300 adjuvant, alum, QS 21, muramyl dipeptide, CpG oligonucleotide motifs and combinations of CpG oligonucleotide motifs, trehalose, bacterial extracts, including mycobacterial extracts, detoxified endotoxins, membrane lipids, or combinations thereof.

2018200081 04 Jan 2018

Nucleic Acid Sequences

Nucleic acid sequences of the DEN-1 16007 (SEQ ID NO:1), DEN-1 PDK-13 (SEQ ID NO:3), DEN-2 16681 (SEQ ID NO:13), DEN-2 PDK-53 (SEQ ID NO:15), DEN-3 16562 (SEQ ID NO:19), DEN-3 PGMK-30/FRhL-3 (SEQ ID NO:21), DEN-4

1036 (SEQ ID NO:23) and DEN-4 PDK-13 (SEQ ID NO:25) viruses are useful for designing nucleic acid probes and primers for the detection of dengue virus in a sample or specimen with high sensitivity and specificity. Probes or primers corresponding to each viral subtype can be used to detect the presence of DEN-1 virus, DEN-3 virus and DEN-4 virus, respectively, to detect dengue virus infection in general in the sample, to diagnose infection with dengue virus, to distinguish between the various dengue virus subtypes, to quantify the amount of dengue virus in the sample, or to monitor the progress of therapies used to treat a dengue virus infection. The nucleic acid and corresponding amino acid sequences are also useful as laboratory research tools to study the organisms and the diseases and to develop therapies and treatments for the diseases.

Nucleic acid probes selectively hybridize with nucleic acid molecules encoding the DEN-1, DEN-3 and DEN-4 viruses or complementary sequences thereof. By “selective” or “selectively” is meant a sequence which does not hybridize with other nucleic acids to prevent adequate detection of the dengue virus. Therefore, in the design of hybridizing nucleic acids, selectivity will depend upon the other components present in a sample. The hybridizing nucleic acid should have at least 70% complementarity with the segment of the nucleic acid to which it hybridizes. As used herein to describe nucleic acids, the term “selectively hybridizes” excludes the occasional randomly hybridizing nucleic acids, and thus, has the same meaning as “specifically hybridizing.” The selectively hybridizing nucleic acid of this invention can have at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, and 99% complementarity with the segment of the sequence to which it hybridizes, preferably 85% or more.

2018200081 04 Jan 2018

The present invention also contemplates sequences, probes and primers which selectively hybridize to the encoding nucleic acid or the complementary, or opposite, strand of the nucleic acid. Specific hybridization with nucleic acid can occur with minor modifications or substitutions in the nucleic acid, so long as functional species5 specific hybridization capability is maintained. By “probe” is meant nucleic acid sequences that can be used as probes or primers for selective hybridization with complementary nucleic acid sequences for their detection or amplification, which probes can vary in length from about 5 to 100 nucleotides, or preferably from about 10 to 50 nucleotides, or most preferably about 18-24 nucleotides. Therefore, the terms probe or probes as used herein are defined to include primers. Isolated nucleic acids are provided herein that selectively hybridize with the species-specific nucleic acids under stringent conditions and should have at least five nucleotides complementary to the sequence of interest as described in Molecular Cloning: A Laboratory Manual, 2nd Ed., Sambrook, Fritsch and Maniatis, Cold Spring Harbor

Laboratory, Cold Spring Harbor, NY, (1989).

If used as primers, the composition preferably includes at least two nucleic acid molecules which hybridize to different regions of the target molecule so as to amplify a desired region. Depending on the length of the probe or primer, the target region can range between 70% complementary bases and full complementarity and still hybridize under stringent conditions. For example, for the purpose of detecting the presence of the dengue virus, the degree of complementarity between the hybridizing nucleic acid (probe or primer) and the sequence to which it hybridizes is at least enough to distinguish hybridization with a nucleic acid from other organisms.

The nucleic acid sequences encoding the DEN-1, DEN-3 or DEN-4 virus can be inserted into a vector, such as a plasmid, and recombinantly expressed in a living organism to produce recombinant dengue virus peptides and/or polypeptides.

2018200081 04 Jan 2018

Nucleic Acid Detection Methods

A rapid genetic test that is diagnostic for each of the vaccine viruses described herein is provided by the current invention. This embodiment of the invention enhances analyses of viruses isolated from the serum of vaccinated humans who developed a viremia, as well as enhancing characterization of viremia in nonhuman primates immunized with the Mahidol candidate vaccine viruses.

As provided in the complete nucleotide sequences of the wild-type parental and vaccine strains, and in the primer sequences provided in Table 16, the current invention comprises viruses specific probes and primers to detect one or more of the mutations that have been identified in the genome of each vaccine virus. Specific detection of two or more virus specific loci allows specific identification of the particular vaccine circulating in the serum of a vaccinee. Examples of such probes specifically designed to allow detection of each of the DEN-1, DEN-2, DEN-3 and DEN-4 vaccine virus15 specific loci in a TaqMan assay are provided in Table 16.

These sequences include a diagnostic TaqMan probe that serves to report the detection of the cDNA amplicon amplified from the viral genomic RNA template by using a reverse-transcriptase/polymerase chain reaction (RT/PCR), as well as the forward (F in Table 16) and reverse (R in Table 16) amplimers that are designed to amplify the cDNA amplicon, as described below. In certain instances, one of the amplimers has been designed to contain a vaccine virus-specific mutation (underlined residues in Table 16) at the 3'-terminal end of the amplimer, which effectively makes the test even more specific for the vaccine strain because extension of the primer at the target site, and consequently amplification, will occur only if the viral RNA template contains that specific mutation. The probes and primers listed in Table 15 and Table 16 serve as examples of useful diagnostic sequences and are not intended to limit the design or. scope of other probe and amplimer sequences that might be designed to detect the Mahidol vaccine virus-specific genetic mutations.

2018200081 04 Jan 2018

A recently developed, automated PCR-based nucleic acid sequence detection system is the TaqMan assay (Applied Biosystems), which is becoming widely used in diagnostic laboratories. The TaqMan assay is a highly specific and sensitive assay that permits automated, real time visualization and quantitation of PCR-generated amplicons from a sample nucleic acid template. TaqMan can determine the presence or absence of a specific sequence. In this assay, a forward and a reverse primer are designed to anneal upstream and downstream of the target mutation site, respectively.

A specific detector probe, which is designed to have a melting temperature of about 10 °C higher than either of the amplimers and containing the vaccine virus-specific nucleotide mutation or its complement (depending on the strand of RT/PCR amplicon that is being detected), constitutes the third primer component of this assay.

The probe is a fluorescent detector or reporter oligonucleotide that contains a 5'reporter dye and a 3'-quencher dye. The 5' end of the nucleotide is linked to one of a number of different fluorescent reporter dyes, such as FAM (6-carboxyfluorescein) or TET (tetrachloro-6-carboxyfluorescein). At the 3'-end of the probe, the quenching dye TAMRA (6-carboxytetramethylrhodamine) is attached via a linker. The quenching dye suppresses the fluorescence of the reporter dye in the intact probe, where both dyes are in close proximity. If the probe-specific target sequence is present in the RT/PCR amplicon, the probe will anneal between the forward and reverse primer sites in the amplicon. If the probe hybridizes to the target sequence, the 5'-3' nuclease activity of AmpliTaq Gold DNA polymerase (Applied Biosystems) cleaves the probe between the reporter dye and the quencher dye. The polymerase will not digest free probe. Because the polymerase diplaces the probe, polymerization and PCR amplification continue.

Once separated from the quencher dye, the reporter dye produces a fluorescence that is measured by the ABI PRISM Sequence Detection System. If the probe-specific target sequence is present in the amplicon, the level of fluorescence increases with, and is automatically measured at, each amplifying PCR cycle.

2018200081 04 Jan 2018

A probe designed to specifically detect a mutated locus in one of the Mahidol vaccine viral genomes will contain the vaccine-specific nucleotide in the middle of the probe. This probe will result in detectable fluorescence in the TaqMan assay if the viral RNA template is vaccine virus-specific. However, genomic RNA templates from wild5 type DEN viruses will have decreased efficiency of probe hybridization because of the single nucleotide mismatch (in the case of the parental viruses DEN viruses) or possibly more than one mismatch (as may occur in other wild-type DEN viruses) and will not result in significant fluorescence. The DNA polymerase is more likely to displace a mismatched probe from the RT/PCR amplicon template than to cleave the mismatched probe to release the reporter dye (TaqMan Allelic Discrimination assay, Applied Biosystems).

A more recently developed strategy for diagnostic genetic testing makes use of molecular beacons (Tyagi and Kramer, Nature Biotechnology 14:303-308(1996)). The molecular beacon strategy also utilizes primers for RT/PCR amplification of amplicons, and detection of a specific sequence within the amplicon by a probe containing reporter and quencher dyes at the probe termini. In this assay, the probe forms a stem-loop structure. The 5'- and 3'- terminal reporter dye and quencher dye, respectively, are located at the termini of the short stem structure, which brings the quencher dye in close juxtaposition with the reporter dye. The stem-structure is melted during the denaturation step of the RT/PCR assay. If the target viral RNA contains the target sequence and is amplified by the forward and reverse amplimers, the opened loop of the probed hybridizes to the target sequence during the annealing step of the cycle. When the probe is annealed to either strand of the amplicon template, the quencher and reporter dyes are separated, and the fluorescence of the reporter dye is detected. This is a real-time identification and quantitation assay that is very similar to to the TaqMan assay. The molecular beacons assay employs quencher and reporter dyes that differ from those used in the TaqMan assay.

2018200081 04 Jan 2018

The present invention is further illustrated by the following non-limiting examples, which are not to be construed in any way as imposing limitations upon the scope thereof. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to those skilled in the art without departing from the spirit of the present invention or the scope of the appended claims.

Example 1

Preparation of a Chimeric Dengue-1 Vaccine: PDK-53/Dengue-l

Viruses and cell cultures

Wild-type DEN-1 16007 and DEN-2 16681 viruses were available in the virus collection at the Centers for Disease Control and Prevention (Atlanta, GA). DEN-1 16007 virus was recovered from the serum of a patient with DHF/DSS in 1964 in

Thailand. The virus was isolated following three passages in grivet monkey kidney BS-C-1 cells and one passage in LLC-MK₂ cells, passaged twice in Toxorhynchites amboinensis mosquitoes, and then passaged in primary dog kidney (PDK) cells at the Center for Vaccine Development, Mahidol University, Thailand, to derive the candidate DEN-1 PDK-13 vaccine virus (Yoksan et al., “Dengue virus vaccine development:

study on biological markers of uncloned dengue 1-4 viruses serially passaged in primary kidney cells,” pp. 35-38, In Arbovirus research in Australia, Proceedings of the Fourth Symposium. CSIRO/OIMR, Brisbane, Australia (1986); Bhamarapravati & Sutee, Vaccine 18: 44-47 (2000)). A single LLC-MK₂ passage of this candidate vaccine virus (lot March 10,1989) was used, unless otherwise mentioned. Following the aforementioned mosquito passages, the 16007 virus was passaged once in LLCMK₂ cells for use.

Viruses were grown in LLC-MK₂ and C6/36 cells in Dulbecco’s modified minimal essential medium (DMEM) containing penicillin/streptomycin and 5% fetal bovine serum (FBS). Virus plaque titrations were performed in 6-well plates of

2018200081 04 Jan 2018 confluent Vero or LLC-MK₂ cells as described previously (Miller et al., Am. J. Trop. Med. & Hyg. 35: 1302-1309 (1986)). The first 4-ml overlay medium — containing 1% SeaKem LE agarose (FMC BioProducts, Rockland, Maine) in nutrient medium (0.165% lactalbumin hydrolysate [Difco Laboratories, Detroit, Mich.]), 0.033% yeast extract [Difco], Earl’s balanced salt solution, 25 mg/L of gentamycin sulfate [Bio Whittaker, Walkersville, Md.], 1.0 mg/L of amphotericin B [Fungizone, E. R. Squibb & Sons, Princeton, N.J.], and 2% FBS) — was added after adsorption of the 200-//1 virus inoculum for 1.5 h at 37°C. Following incubation at 37°C for 7 days, a second 2ml overlay containing an additional 80 /zg/ml of neutral red vital stain (GIBCO-BRL,

Gaithersburg, Md.) was added. Plaques were counted 8 to 11 days after infection.

Construction of chimeric D2/1 infectious clones pD2-16681-P48, pD2-PDK53-E48, pD2-PDK53-V48 vectors

Three DEN-2 vectors were used for construction of the chimeric D2/1 clones.

These were modified from the DEN-2 infectious clones reported by Kinney et al.

(Virology 230: 300-308 (1997)). Clone pD2-16681-P48 was modified from pD2/IC3 OP-A to contain cloning sites Mlul and NgoMIV at nucleotide positions 451 and 2380, respectively. The same cloning sites were introduced into both DEN-2 PDK-53 virusspecific clones, pD2/IC-130Vx-4 and -130Vc-K, and the modified clones were designated as pD2-PDK53-E48 and pD2-PDK53-V48, respectively. Two cloning errors were found in the original pD2/IC-130Vx-4 and -130Vc-K at nt-6665 and nt8840. These defects were corrected in pD2-PDK53-E48 and -V48. The introduced NgoMIV cloning site resulted in two nucleotide mutations (nt 2381 and 2382; TG to CC), which encoded a Val-to-Ala substitution at E-482. The nucleotide changes introduced at the Mlul site were silent. The Mlul site introduced at the C/prM junction was used to clone the prM-E genes of heterologous viruses.

2018200081 04 Jan 2018

Chimeric pD2/l-PP, -EP, -VP, -PV, -EV, and -VV

Two intermediate DEN-2 clones, pD2I-P and pD2I-E, were constructed by deleting the Hpal (nt-2676) to Xbal (3' terminus of viral genomic cDNA) fragments of pD2-16681-P48 and pD2-PDK53-E48, respectively. These intermediate clones were used to subclone DEN-1 virus-specific cDNA fragments. The cDNA fragments containing the C-prM-E genes of DEN-1 16007 or PDK-13 virus were amplified by reverse transcriptase - polymerase chain reaction (RT-PCR) from DEN-1 viral RNA with primers DEN-Bgl.5NC (5'-TAGAGAGCAGATCTCTG-3' (SEQ ID NO:31); conserved sequence in the 5'NCR of dengue viral genomes, underlined sequence is a

Bglll site) and cDl-2394.Ngo:

(5-TGTGACCATGCCGGCTGCGATGCACTCACCGA-3' (SEQ ID NO:32); underlined NgoMIV site followed by complementary sequence near the 3' end of the E gene of DEN-1 virus). Amplified fragments were cloned into the BglH-NgoMIV sites of the intermediate pD2I-P and pD2I-E clones. Intermediate, chimeric pD2/l clones were sequenced to verify the accuracy of the inserted DEN-1 virus-specific cDNA. Fragments excised from the intermediate pD2/l clones with Sstl (preceding the T7 promoter) and NgoMIV were cloned into the full genome-length DEN-2 vectors, pD216681-P48, pD2-PDK53-E48, and pD2-PDK53-V48. Six full genome-length chimeric pD2/l plasmids were constructed by inserting the C-prM-E gene region of DEN-1

16007 or PDK-13 virus into these three vectors (FIG. 1). The plasmids were designated pD2/l-XY and their virus derivatives were designated DEN2/1-XY, where X = the infectious DEN-2 clone background (P = parental 16881 clone, E = PDK53-E variant, V = PDK53-V variant) and Y = DEN-1 virus-specific C-prM-E insert (P = parental 16007 strain, V = PDK-13 vaccine candidate). The PDK53-E backbone contains three DEN-2 PDK-53 virus-specific amino acid mutations (NSl-53-Asp, NS2A-181-Phe and NS4A-75-Ala) as well as the 5’NC-57 mutation of PDK-53 virus. The PDK53-V backbone contains these same PDK-53 virus-specific loci plus the additional PDK-53 virus-specific NS3-250-Val locus.

2018200081 04 Jan 2018

Recovery of recombinant viruses

All recombinant plasmids were grown in Escherichia coli XL 1-Blue cells. Recombinant viral RNA was transcribed and capped with the cap analog m⁷GpppA from 200-400 ng of Xbal-linearized cDNA, and transfected into 3-4 x 10⁶ LLC-MK₂ or

BHK-21 cells by electroporation. Transfected cells were transferred to 75-cm² flasks in DMEM medium containing 10% FBS. Viral proteins expressed in the transfected cells were analyzed by indirect immunofluorescence assay (IFA). Virus-infected cells were fixed in ice-cold acetone for 30 min. DEN-1 and DEN-2 virus-specific monoclonal antibodies 1F1 and 3H5, respectively, were used in the assay, and binding was detected with fluorescein-labeled goat anti-mouse antibody. Viruses were harvested after 8 to 10 days, and were then passaged in LLC-MK₂ cells once (DEN-2-16681-P48, DEN-2 PDK53-E48 and -V48, DEN-2/1-PP, - EP, and -VP) or twice (DEN-2/1-PV, -EV, and W) to obtain working seeds. D2/1-EV and - W viruses were passaged a third time in LLC-MK₂ cells to obtain higher viral titers required for challenge or immunization of mice.

Characterization of the replication phenotypes of chimeric viruses in cell cultures

Plaque sizes were measured 10 days after infection in LLC-MK₂ cells. Mean plaque diameters were calculated from 10 plaques for each virus. Viral growth curves were performed in 75-cm² flasks of LLC-MK₂ or C6/36 cells at approximately 0.001 multiplicity of infection (m.o.i.). After adsorption for 2 h, 30 ml of DMEM medium (for LLC-MK₂ cells) or overlay nutrient medium (for C6/36 cells) containing 5% FBS and penicillin/streptomycin was added, and the cultures were incubated in 5% CO₂ at 37°C or 29°C, respectively. Aliquots of culture medium were harvested at 48-h intervals for 12 days, adjusted to 12.5% FBS, and stored at -80°C prior to titration.

Temperature sensitivity was tested in LLC-MK₂ cells. Cells grown in two sets of 75-cm² flasks were infected and incubated as described for the growth curve study. One set of cultures was incubated for 8 days at 37°C, the other at 38.7°C. The ratio of virus titer at 38.7°C versus the titer at 37°C was calculated. Virus was designated as

2018200081 04 Jan 2018 temperature-sensitive if the virus titer at 38.7°C was reduced 60% or greater, relative its titer at 37°C.

Sequencing of viral cDNA

Viral RNA was extracted from virus seed or by using the QIArnp Viral RNA kit (Qiagen, Valencia, Calif.). DEN-1 virus-specific primers were based on the published data of the Singapore strain S275/90 (Fu et al., Virology 88: 953-958 (1992)). Five to 7 overlapping viral cDNA fragments were amplified by RT-PCR with the Titan OneTube RT-PCR System (Roche Molecular Biochemicals, Indianapolis, Ind.). Both strands of the cDNA amplicons were sequenced directly. For sequencing of the DEN-1

PDK-13 viral genome, template genomic RNA was extracted directly from a vial of the candidate DEN-1 PDK-13 vaccine (lot March 10,1989). The 5'- and 3'- terminal sequences of the DEN-1 16007 and DEN-1 PDK-13 viral genomes were determined with the 5' RACE kit (GIBCO BRL) and by tailing the genomic RNA with poly(A).

Automated sequencing was performed as recommended on a PRISM 377 sequencer (Perkin-Elmer/Applied Biosystems, Foster City, Calif.).

Mouse studies

Litters of newborn, 1-day-old outbred white ICR mice were inoculated intracranially with 5,000 PFU of virus in a volume of 30 ml. They were observed daily for paralysis and death, and surviving mice were individually weighed once each week for 5 weeks.

Neutralizing antibody responses were tested in 3-week-old ICR mice. They were inoculated intraperitoneally with 10⁴ PFU of virus, and were boosted with the same amount of virus 3 weeks or 6 weeks later. Mice were bled 2 days prior to the boost and 3 weeks after boosting.

2018200081 04 Jan 2018

The ICR strain of inbred mice used above are not usually fatally susceptible to challenge with wild-type DEN-1 virus. Therefore, to fully test the ability of the DEN2/1 viral chimera to induce an effective immune response, it was necessary to utilize inbred AG-129 mice, which lack receptors for both interferon alpha/beta and interferon gamma (Muller et al., Science 264:1918-1921 (1994)), as these mice have been found to be susceptible to intraperitoneal challenge with high doses of wild-type DEN-1 virus, strain Mochizuki. Therefore, 3.5-4.5-week-old inbred AG-129 mice were immunized intraperitoneally with 10⁴ PFU of wild-type DEN-1 16007, Mahidol candidate vaccine DEN-1 PDK-13, chimeric DEN-2/1-EP or chimeric DEN-2/1-VP virus. These immunized mice were challenged intraperitoneally with a lethal dose of DEN-1 Mochizuki virus.

Neutralization Assays

Mouse serum samples were tested for neutralizing antibodies by serum- dilution plaque-reduction neutralization test (PRNT). Sixty PFU of DEN-1 16007 virus was incubated with serial 2-fold dilutions of heat-inactivated (56°C for 30 min) mouse serum specimens overnight at 4°C. The neutralizing antibody titer was identified as the highest serum dilution that reduced the number of virus plaques in the test by 50% or greater.

Results

To assess the potential of infectious cDNA clones derived from the two variants of DEN-2 16681 PDK-53 virus (PDK-53-E and PDK-53-V) to serve as vectors for vaccine development, we engineered chimeric DEN-2/DEN-1 cDNA clones (D2/1-EP,

D2/1-VP, D2/1-EV, and D2/1-VV) containing the structural genes (C-prM-E) of wildtype DEN-1 16007 virus or its vaccine derivative, strain PDK-13, within the backbone of these two vectors (FIG. 1). Two other chimeric clones, D2/1-PP andD2/l-PV, containing the structural genes (C-prM-E) of DEN-1 16007 or PDK-13 virus in the backbone of wild-type DEN-2 16681 virus, were also constructed for comparison (FIG.

1). We sequenced the entire full-length genomic cDNA in all of the infectious clones.

2018200081 04 Jan 2018

A silent cDNA artifact was incorporated into the chimeric clones at nt-297 (T-to-C). A silent mutation at nt-1575 (T-to-C) was engineered into all of the chimeric clones to remove the natural Xbal site in the E gene of the DEN-1 virus.

Titers after transfection of LLC-MK₂ or BHK-21 cells were 10⁴-10⁶ PFU/ml for the chimeric viruses D2/1-PP, -EP, and -VP containing the C-prM-E of DEN-1 16007 virus. These titers increased to 10^{6 5}-l 0⁷·⁵ PFU/ml after a single passage in LLC-MK2 cells, comparable to the titers obtained for their parental viruses. Lower titers of 10²10⁴ PFU/ml were obtained in transfected cells for the chimeric DEN-2/1-PV, -EV, and 10 VV viruses containing the C-prM-E of DEN-1 PDK-13 virus. D2/1-PV virus reached 10⁶ PFU/ml after 2 passages in LLC-MK2 cells, whereas D2/1-EV and -VV viruses reached titers of 10³·³ -10⁵·³ PFU/ml after two or three passages. Cells infected with any of the chimeric DEN-2/1 viruses were positive by IFA with monoclonal antibody 1F1 (specific for DEN-1 E protein) and negative with monoclonal antibody 3H5 (specific for DEN-2 E protein), indicating that appropriate DEN-1 E proteins were expressed by the chimeras. The DEN-2/1-PP, DEN-2/1-EP, and DEN-2/1-VP viral genomes were fully sequenced by directly analyzing overlapping RT-PCR fragments amplified from genomic viral RNA extracted from master seeds. All three genomes had the expected sequence.

Growth of the chimeric viruses in LLC-MK, and C6/36 cell cultures

All of the chimeric DEN-2/1 viruses produced smaller plaques, relative to the

6.8 ±0.4-mm plaque of wild-type DEN-1 16007 virus in LLC-MK₂ cells (FIG. 2 A). Both DEN-2/1-EP (3.1 ±0.3 mm) and -VP (2.8 ±0.3 mm) viral plaques were similar in size to those of DEN-1 PDK-13 virus (2.9 ±0.3 mm). The chimeric viruses DEN-2/1PV, DEN-2/1-EV, and DEN-2/1-VV containing the C-prM-E of DEN-1 PDK-13 virus formed tiny (1.3 ±0.3 mm) or pinpoint (<1 mm) plaques. The DEN-2 16681-P48 virus produced 3.5 ±0.3-mm plaques that were similar to plaques of wild-type DEN-2 16681 virus. The DEN-2 PDK53-V48 virus formed plaques that were smaller and fuzzier than those of the DEN-2 PDK53-E48 virus. The 5.1 ±0.3-mm plaques of DEN-2/1-PP

2018200081 04 Jan 2018 virus were larger than those of the other chimeric viruses, but smaller than those of DEN-1 16007 virus.

Viruses were tested for temperature sensitivity in LLC-MK₂ cells. Temperature 5 sensitivity was determined on day 8 or 10 after infection as indicated in FIG. 2B.

Temperature sensitivity was based on the reduction of virus titers at 38.7°C from those at 37°C. Temperature sensitivity was calculated from measurements taken in at least 3 experiments.

The DEN-2 PDK53-V variant (D2-PDK53-V48) was more temperature sensitive than DEN-2 PDK53-E virus (D2-PDK53-E48) and DEN-2 16681 virus (DEN-2-16681-P48) was somewhat temperature sensitive (70-87% titer reduction at 38.7°C). Multiple temperature sensitivity tests for DEN-2-PDK53-E48 virus resulted in 83%-97% growth reduction. The titer of DEN-1 16007 virus was reduced by 40% or less at 38.7°C , making it the least-temperature sensitive virus in this study. All of the chimeric viruses were temperature sensitive relative to DEN-1 16007 virus, and were at least as temperature-sensitive as PDK-13.

All of the DEN-1, DEN-2, and chimeric D2/1 viruses reached peak titers between 8 and 10 days after infection in LLC-MK₂ cells (FIG. 2B). The clone-derived viruses DEN-2-16681-P48, DEN-2-PDK53-E48, and DEN-2-PDK53-V48 replicated to IO⁷⁰ PFU/ml or greater, as did DEN-2 16681 and PDK-53 viruses. Although reaching similar peak titer, DEN-2-PDK53-V48 virus replicated slower than the DEN-2-PDK53E48 virus during the first 4 days after infection. Chimeric DEN-2/1-PP, DEN-2/1-EP,

DEN-2/1-VP, and DEN-2/1-PV viruses reached peak titers over 10^6,7PFU/ml, comparable to the peak titers of their parental DEN-1 and DEN-2 viruses. Chimeric DEN-2/1-EV and -VV viruses, which had peak titers of 10^{5 6}-10⁵·⁹ PFU/ml or lower in several separate experiments, replicated less efficiently than the other viruses.

2018200081 04 Jan 2018

The PDK-13 virus-specific chimeras result in lower virus titers recovered from transfected cells, relative to the 16007 virus-specific chimeras. Previous experiences with DEN-2/DEN-1 and DEN-2/DEN-4 chimeras indicate that chimeric viruses which exhibit crippled replication during transfection and later develop high virus titers after passage in cell culture often accrued unexpected mutations. Viruses of increased replicative ability may arise through selection of subpopulations of virus variants, resulting from incorporation errors during in vitro transcription of cDNA. Chimeric viruses that replicate well in transfected cells were more genetically stable after passage in LLC-MK₂ cells. Efficient replication with minimal passage in mammalian cell culture may be an important criterion of genetic stability and suitability for an infectious clone-derived vaccine virus.

Viral growth curves in C6/36 cells were monitored following infection of C6/36 cells at an approximate multiplicity of 0.001 PFU/ml (FIG. 3). The three DEN-2 backbone viruses, DEN-2-16681-P48, DEN-2-PDK53-E48 and DEN-2-PDK53-V48, replicated like the original DEN-2 16681 virus and the two PDK-53 variants, respectively. Both DEN-2-PDK53-E48 and DEN-2-PDK53-V48 viruses replicated about 4000-fold less efficiently than the DEN-2-16681-P48, DEN-1 16007 and PDK13 viruses in C6/36 cells. DEN-1 16007 and PDK-13 viruses replicated to high titers of 10^{8 7}and 10⁸·⁴· PFU/ml, respectively. The chimeric DEN-2/1-PP virus replicated to

IO⁵² PFU/ml, which was equivalent to the peak titers of the two DEN-2-PDK53 variants. Replication of chimeric DEN-2/1-EP and DEN-2/1-VP viruses was very inefficient in C6/36 cells. These viruses reached peak titers of lower than 10² PFU/ml.

Neurovirulence in suckling mice

Groups of newborn to one-day-old ICR mice (n=16) were inoculated intracranially with 5000 PFU of virus. Wild-type DEN-2 16681 virus was 100% fatal with average survival time at 14.1 ±1.6 days, while both clone-derived DEN-2PDK53-E48 and DEN-2-PDK53-V48 viruses failed to kill any ICR mice. Unlike DEN30 2 16681 virus, which typically kills 50% or greater of challenged mice, the wild-type

2018200081 04 Jan 2018

DEN-1 16007 virus caused only a single fatality (21 days after challenge) in the ICR mice. The DEN-1 PDK-13 virus did not kill any of the ICR mice. DEN-1 16007 virusinfected ICR mice had significantly lower mean body weights (p<0.00003, Student’s t test), relative to the control group inoculated with diluent, between 21-35 days after challenge. All of the ICR mouse groups challenged with five chimeric DEN-2/1 viruses (DEN-2/1-VV virus was not tested) had lower mean weights (p<0.02) when compared to the control group, but their mean weights were significantly greater (p<0.004) than the DEN-1 16007 group 28 days after infection. The mean body weights of ICR mouse groups challenged with 10⁴ PFU of DEN-1 16007 or PDK-13 virus were nearly identical to those of the ICR mice challenged with 5000 PFU of DEN-1 16007 virus between 7-35 days after challenge.

Immunogenicity of chimeric DEN-2/1 viruses in mice

Outbred ICR Mice: To test the immunogenicity of the chimeric viruses, groups 4 of 3-week-old ICR mice (n=8) were immunized intraperitoneally with 10 PFU of virus in Experiment 1 and Experiment 2 (Table 7). In Experiment 1, the mice were bled 20 days after primary immunization and then boosted 2 days later. In Experiment 2, the mice were bled 41 days after primary immunization and boosted 2 days later. Table 7 shows the reciprocal, 50% plaque-reduction endpoint PRNT titers of the pooled serum samples from each immunized group. The range of individual titers for the eight mice in many of the groups is also shown. In both experiments, the reciprocal titer of the pooled serum from 16007 virus-immunized mice was 80 before boost and 2560 after boost. In both experiments, mice immunized with chimeric DEN-2/1-PP, -EP, or DEN-2/1-VP viruses had a pooled serum titer that was at least as high as those of the

16007 virus-immunized groups before (reciprocal titers of 40-160) and after (reciprocal titers of2560-5210) boost. The immune responses of the mice in these virus groups were nearly equivalent in both Experiment 1 and Experiment 2.

The PDK-13 virus and all three of the chimeras containing the PDK-13 structural genes induced minimal or low reciprocal PRNT titers of 10-20 against DEN2018200081 04 Jan 2018

16007 virus by 20 days after primary immunization in Experiment 1. A somewhat higher reciprocal PRNT titer of 40 was elicited by each of these viruses by 41 days after immunization in Experiment 2. The development of neutralizing antibodies was slower and of lower magnitude following immunization with PDK-13, DEN-2/1-PV, 5 EV, or -VV virus than with 16007, DEN-2/1-PP, -EP, or -VP virus in these mice. One mouse in the DEN-2/ 1-PV group in Experiment 1 and one mouse in each of the DEN2/1-EV groups in both experiments failed to produce a detectable PRNT titer before boost. Boosted titers were also higher for the PDK-13, DEN-2/1-PV, -EV, and -Wimmunized groups in Experiment 2 (pooled reciprocal titers of 160-2560) than in

Experiment 1 (pooled reciprocal titers of 80). Except for the DEN-2/1-PV group in Experiment 2, these boosted titers were lower than the boosted PRNT titers induced by wild-type 16007 virus and chimeric DEN-2/1-PP, -EP, and -VP viruses containing the structural genes of the wild-type DEN-1 16007 virus (Table 7). The high PRNT titer obtained for the pooled serum of the mice boosted with DEN-2/1-PV virus resulted from two mouse sera which had reciprocal titers of 2560 and 10,240. The remaining 6 mice in this group had reciprocal titers of 20 to 640, which were similar to the individual titers of mice in the PDK-13, DEN-2/1-EV, and -VV groups. The PDK-13, DEN-2/1-PV, DEN-2/1-EV, and DEN-2/1-VV viruses appeared to be less immunogenic than the 16007, DEN-2/1-PP, -EP, and -VP viruses in these outbred mice. Pooled serum samples from mice immunized with DEN-2-16681-P48, DEN-2PDK-53-E48, or DEN-2-PDK-53-V48 virus did not contain detectable cross neutralizing antibody against DEN-1 16007 virus.

Inbred AG-129 Mice: To test the immunogenicity of the chimeric viruses, groups of 3.5-4.5-week-old inbred AG-129 mice were immunized intraperitoneally with 10⁴ PFU of wild-type DEN-1 16007, Mahidol candidate vaccine DEN-1 PDK-13, chimeric DEN-2/1-EP, or chimeric DEN-2/1-VP virus. At 26 days after primary immunization, pooled sera from mice immunized with chimeric DEN-2/1-EP or DEN2/1-VP virus had reciprocal 70% serum dilution-plaque reduction neutralizing antibody titers (PRNT₇₀) of 80-160. These titers were equivalent (within 2-fold) of the

2018200081 04 Jan 2018 neutralizing antibody response elicited by the candidate DEN-1 PDK-13 vaccine, but lower than the 640 titer elicited by the wild-type DEN-1 16007 virus. Control mice injected intraperitoneally with phosphate buffered saline had titers of less than 10. All mice were challenged intraperitoneally with 10⁷ PFU of wild-type, virulent DEN-1 virus, strain Mochizuki, at 28 days after primary immunization. All eleven of the control, non-immunized mice died within 21 days (average survival time of 11.5 ± 4.2 days [mean ± standard deviation]) after challenge, whereas all of the DEN-1 (16007, PDK-13, DEN-2/1-EP, DEN-2/1-VP) virus-immunized mice survived challenge with DEN-1 Mochizuki virus. At 34 days after challenge with DEN-1 Mochizuki, all of the virus-immunized mice had reciprocal PRNT₇₀ titers of 1280-2560. The chimeric DEN2/1-EP and DEN-2/1-VP viruses were highly immunogenic and protective for AG-129 mice.

Nucleotide sequence analyses of DEN-1 16007 and PDK-13 viral genomes

We sequenced the genomes of wild-type DEN-1 16007 virus (GenBank accession number AF180817) and its PDK-13 vaccine derivative (accession number AF180818). There were 14 nucleotide and 8 encoded amino acid differences between 16007 and PDK-13 viruses (Table 2). Silent mutations occurred at genome nucleotide positions 1567, 2695, 2782, 7330, and 9445 in the E, NS1, NS4B, andNS5 genes.

Unlike the candidate DEN-2 PDK-53 vaccine virus, which has no amino acid mutations in the E protein, the DEN-1 PDK-13 virus had five amino acid mutations in E, including E-130 Val-to-Ala, E-203 Glu-to-Lys, E-204 Arg-to-Lys, E-225 Ser-to-Leu, and E-447 Met-to-Val. Amino acid mutations in the nonstructural genes included NS3182 Glu-to-Lys, NS3-51O Tyr-to-Phe, and NS4A-144 Met-to-Val. The PDK-13 virus25 specific E-477-Val was incorporated into all of the chimeric constructs.

Immunization of monkeys with chimeric DEN-2/1 viruses

The immunogenicity of the chimeric DEN-2/1-EP and DEN-2/1-VP viruses in adult crab-eating monkeys (Macaca fascicularis) was tested. Immunization of monkeys was accomplished by means of subcutaneous injection with 10⁶ PFU of

2018200081 04 Jan 2018 chimeric DEN-2/1-EP or DEN-2/1-VP virus. Sera obtained from the immunized monkeys were analyzed for the presence of viremia by direct plaque assay of serum aliquots in LLC-MK₂ cell monolayers maintained under agarose overlay in 6-well plates, and by inoculation of serum aliquots into cultures of LLC-MK2 cells maintained in liquid medium. No infectious virus was identified in any of the monkey sera by either of these two classical assay methods. By these two virus assays, no viremia was detectable following immunization with either chimeric DEN-2/1-EP or DEN-2/1-VP virus. Monkey sera were tested for DEN-1 virus-specific neutralizing antibodies. At 30 days after primary immunization, sera from three individual monkeys immunized with chimeric DEN-2/1-EP virus had reciprocal 50% serum dilution-plaque reduction neutralizing antibody titers (PRNT₅₀) of 80,160 and 1280. Sera from three individual monkeys immunized with chimeric DEN-2/1-VP had reciprocal PRNT₅₀ titers of 160, 160 and 640. Monkeys injected with diluent as a control for the experiment had reciprocal PRNT₅₀ titers of less than 10, as did all of the monkeys just prior to immunization. The chimeric DEN-2/1-EP and -VP viruses elicited DEN-1 virusspecific neutralizing antibodies in non-human primates.

Example 2

Construction Of Chimeric DEN-2/3 Infectious Clones

An in vitro ligation strategy was used for the full genome-length DEN-2/3 infectious clones.

(ij 5'-end DEN-2/3 intermediate clones: pD2I/D3-Pl-Asc andpD2I/D3-El-Asc

Intermediate DEN-2 clones, pD2I-P and pD2I-E were used to subclone the DEN-3 16562 virus-specific cDNA fragment. The cDNA fragment containing the prM-E genes of wild-type DEN-3 16562 virus was amplified by reverse transcriptase polymerase chain reaction (RT-PCR) from DEN-3 viral RNA with primers D3435.Mlu:

(5'-TGCTGGCCACTTAACTACGCGTGATGGAGAGCCGCGCA-3' (SEQ ID NO:33); underlined Mlul site followed by DEN-3 virus sequence near the 5' end of the

2018200081 04 Jan 2018 prM gene) and cD3-2394.Ngo:

(5'-TGTAATGATGCCGGCCGCGATGCATGAAAATGA-3' (SEQ ID NO:34); underlined NgoMIV site followed by complementary sequence near the 3' end of the E gene of DEN-3 virus). The Mlul site contained a silent mutation for DEN-2 virus at amino acid prM-5-Thr. This position is Ser in DEN-3 virus, but Thr in chimeric DEN2/3 virus. The NgoMIV site resulted in a Val-to-Ala substitution at E-482 of DEN-2 virus, and an Ile-to-Ala substitution at E-480 of DEN-3 virus. The amplified fragment was cloned into the MluI-NgoMIV sites of the intermediate pD2I-P and pD2I-E clones. A restriction site, Ascl, was introduced downstream of the NgoMIV site by site10 directed mutagenesis to facilitate in vitro ligation. This unique Ascl site was only 16 nts downstream from the NgoMIV site and was excised prior to in vitro ligation of the fulllength DEN-2/3 clones. An additional mutagenesis at nt 1970 (A-to-T) which changed amino acid E-345 from His to Leu, was introduced to permit derivation of viable chimeric viruses in LLC- MK₂ cells, as explained below. These intermediate chimeric

DEN-2/3 clones, pD2I/D3-P-Asc and pD2I/D3-E-Asc, were sequenced to verify the accuracy of the inserted DEN-3 virus-specific cDNA. A silent mutation was incorporated at nt 552 (C-to-T) in both intermediate chimeric clones.

(ii) 3'-end DEN-2 intermediate clones: pD2-Pm^Ab-Asc, pD2-Em^Ab-Asc, and pD220 Vm^Ab- Asc

Intermediate DEN-2 clones containing the truncated DEN-2 virus-specific cDNA sequence from nt 2203-10723 (3'-end) of DEN-2 16681, PDK53-E, or PDK-53V virus were obtained by deletion of the 5'end (including T7 promoter sequence and DEN-2 nts 1-2202) of the virus specific cDNA in the full-length clones, pD2-1668125 P48, pD2-PDK53-E48, and pD2-PDK53- V48, respectively. An Ascl site was also introduced at nt 2358 (22 nts upstream of the NgoMIV site) to facilitate the in vitro ligation. This Ascl site was excised prior to performing the in vitro ligation of the full genome-length, chimeric DEN-2/3 infectious clones.

2018200081 04 Jan 2018 (iii) Full-length chimeric DEN-2/3 cDNA: DEN-2/3-PP1, DEN-2/3-EPL and DEN-2/3VP1

Three to ten mg of the 5'-end pD2I/D3 and 3'-end D2 intermediate clones were digested by Ascl, treated with calf intestine phosphatase (CIP), and then digested with

NgoMIV. The excised small AscI-NgoMIV fragments were removed by passing the digested DNA through Qiagen PCR-purification spin columns. The large 5'- and 3'end, linearized intermediate clones were then ligated together (5': 3' = 1:3 molar ratio) to obtain full genome-length DEN-2/3-PP1 (pD2I/D3-Pl-Asc ligated with pD2- Pm^AbAsc), DEN-2/3-EP1 (pD2I/D3-El-Asc ligated with pD2-Em^Ab-Asc), andDEN-2/310 VP1 (pD2I/D3- El -Asc ligated with pD2-Vm^Ab-Asc). These ligated DNAs were then cut with Xbal to produce the linearized 3'-end of the viral cDNA required for transcription of the recombinant viral RNA.

Recovery of chimeric DEN-2/3 viruses

Recombinant viral RNA was transcribed from Xbal-linearized cDNA and capped with the cap analog m^GpppA. LLC-MK2 or BHK-21 cells (3- 5 x 10^ cells) were transfected by electroporation as described by Kinney et al. (J. Virol 230: 300-308 (1997)). Transfected cells were transferred to 75-cm2 flasks in DMEM medium containing 10% FBS. Viral proteins expressed in the transfected cells were analyzed by indirect immunofluorescence assay (IFA). Virus-infected cells were fixed in icecold acetone for 30 min. DEN-3 and DEN-2 virus-specific monoclonal antibodies 8A1 and 3H5, respectively, were used in the assay, and binding was detected with fluorescein-labeled goat anti-mouse antibody. Viruses were harvested after 5 to 11 days, and were then passaged in LLC-MK₂ cells once to obtain working seeds. Viral genomes extracted from these seeds were sequenced to confirm the genotypes of the progeny viruses. An earlier strategy using 5'-end D2I/D3 intermediate clones containing authentic DEN-3 16562 prM-E genes resulted in mutations at several different positions in the genomes of the viruses recovered from transfected LLC-MK₂ or BHK-21 cells and passaged once in LLC- MK₂ cells. A mutation at nt 1970 from A to T, which changed amino acid E-345 from His to Leu, was found in seven of nine

2018200081 04 Jan 2018 independently recovered recombinant viruses. It was obvious that the original DEN-2/3 chimeric viruses were unstable in LLC-MK₂ and/or BHK-21 cells. The single mutation at E-345 was the only mutation that occurred in the genomes of three recovered viruses, indicating that this mutation might help to stabilize the viruses in culture. We introduced this mutation in all the infectious DEN-2/3 clones and recombinant viruses recovered from such mutagenized clones proved to be stable in cell culture.

Example 3

Construction Of Chimeric DEN-2/4 Infectious Clones pD2-16681-P48, pD2-PDK53-E48, pD2-PDK53-V48 vectors

The three DEN-2 backbone vectors used for construction of the chimeric DEN2/4 clones were modified as described above. The DEN-2 infectious clones have been previously reported in Kinney et al., 1997. Clone pD2-16681-P48 was modified from pD2/IC-30P-A to contain cloning sites Mlul and NgoMIV at nucleotide positions 451 and 2380, respectively. The same cloning sites were introduced into both DEN-2 PDK53 virus-specific clones, pD2/IC-130Vx-4 and -130Vc-K, and the modified clones were designated as pD2-PDK53-E48 and pD2-PDK53-V48, respectively. Two cloning errors were found in the original pD2/IC-130Vx-4 and -130Vc-K at nt-6665 and nt20 8840. These defects were corrected in pD2-PDK53-E48 and -V48. The introduced

NgoMIV cloning site resulted in two nucleotide mutations (nt 2381 and 2382; TG to CC), which encoded a Val-to-Ala substitution at E-482 of DEN-2 virus. The nucleotide changes introduced at the Mlul site were silent for DEN-2 virus and chimeric DEN-2/4 viruses. The Mlul site (near the C/prM junction) and NgoMIV site (close to E/NS1 junction) were used to clone the prM-E genes of heterologous viruses.

Chimeric pDEN-2/4-PPl, -EPI, and -VP1

Two intermediate DEN-2 clones, pD2I-P and pD2I- E, were constructed by deleting the Hpal (nt-2676) to Xbal (3' terminus of viral genomic cDNA) fragments of pD2-16681-P48 and pD2-PDK53-E48, respectively. These intermediate clones were

2018200081 04 Jan 2018 used to subclone DEN-4 1036 virus-specific cDNA fragments. The cDNA fragment containing the prM-E genes of DEN-4 1036 virus was amplified by reverse transcriptase - polymerase chain reaction (RT-PCR) from DEN-4 viral RNA with primers D4-453Mlu:

(5'-GGCGTTTCACTTGTCAACGCGTGATGGCGAACCCCTCA-3’ (SEQ ID

NO:35); underlined Mlul site followed by sequence near the 5' end of the DEN-4 1036 viral genome) and cD4-2394.Ngo:

(5'-AGTGATTCCGCCGGCAGCTATGCACGTCATAGCCAT-3' (SEQ ID NO:36); underlined NgoMIV site followed by complementary sequence near the 3' end of the E gene of DEN-4 virus). Amplified fragments were cloned into the MluI-NgoMIV sites of the intermediate pD2I-P and pD2I-E clones. Intermediate, chimeric DEN-2/4 clones were sequenced to verify the accuracy of the inserted DEN-4 virus-specific cDNA. A silent mutation was incorporated at nt 1401 (A-to-G) in both intermediate clones. Fragments excised from the DEN-2/IC-P48, -VE48, and -VV48 clones with NgoMIV and Seal (downstream of DEN-2 cDNA sequence in these plasmids) were cloned into NgoMIV/Scal-cut chimeric D2/4 intermediate clones to obtain the full-length chimeric D2/4-PP, -EP, and -VP clones. However, transcribed RNA from these chimeric clones only produced viable DEN-2/4 chimeric viruses in transfected C6/36 cells, but not in transfected LLC- MK₂ cells. After passaging the chimeric viruses in C6/36 cells one more time to obtain higher titers, these viruses were passaged in LLC-MK₂ cells five times to obtain stable chimeric DEN-2/4 viruses which replicated efficiently in LLCMK cells. Titers of the virus seeds increased from 200 PFU/ml at the first LLC-MK 2 2 cell passage to over 10^ PFU/ml at the fifth LLC-MK₂ cell passage.

The genomes of viruses from the first, second, third and fifth LLC-MK₂ cell passages of the chimeric DEN-2/4-PP viruses were sequenced. Four mutations, DEN-2 virus-specific, C-100 (Arg-to-Ser), DEN-4 virus-specific E-364 (Ala- to-Ala/Val mix), DEN-4 virus-specific E-447 (Met-to-Leu) and DEN-2 virus-specific NS4B-239 (Ile-toLeu) were identified (amino acid positions based on chimeric DEN-2/4 virus sequences). The three mutations located in the structural genes (C and E) were

2018200081 04 Jan 2018 introduced into the chimeric DEN-2/4-PP, -EP, and -VP infectious cDNA clones to obtain DEN-2/4-PP1, -EPI, and -VP1 clones, respectively. All three of these chimeric DEN-2/4 clones produced viable, high-titered chimeric viruses in LLC-MK₂ cells immediately after transfection indicating that these three mutations helped the viruses to replicate in LLC-MK₂ cells. Chimeric DEN-2/4 clones were also mutagenized to contain different combinations of the four mutations to determine which mutations are needed for replication efficiency of the chimeric DEN-2/4 viruses in LLC-MK₂ cells.

The DEN-4 E-447 (Met-to-Leu) mutation alone or together with the DEN-4 E-364 mutation, in combination with the DEN-2 C-100 (Arg-to-Ser) mutation was adequate to allow derivation of DEN-2/4 virus in LLC-MK cells.

Recovery of recombinant viruses.

Recombinant plasmids pD2/4-PPl, -EPI, and -VP1 all were grown in Escherichia coli XLl-Blue cells. Recombinant viral RNA was transcribed and capped with the cap analog m GpppA from 200-400 ng of Xbal-linearized cDNA, and transfected into 3-5.10⁶ LLC-MK cells. Transfected cells were transferred to 75-cm² 2 flasks in DMEM medium containing 10% FBS. Viral proteins expressed in the transfected cells were analyzed by indirect immunofluorescence assay (IFA). Virusinfected cells were fixed in ice-cold acetone for 30 min. DEN-4 and DEN-2 virus20 specific monoclonal antibodies 1H10 and 3H5, respectively, were used in the assay, and binding was detected with fluorescein-labeled goat anti-mouse antibody. Viruses were harvested after 8 to 10 days, and were then passaged in LLC-MK₂ cells once to obtain working seeds. The genomes of all these three working seeds were fully sequenced, and all the chimeric DEN-2/4 viral genomes contained the expected sequences. The nucleotide and amino acid sequences for the DEN 2/4 chimera are provided herein at SEQ ID NO: 13 and SEQ ID NO:14, respectively.

2018200081 04 Jan 2018

Example 4

Characterization of DEN-2/3 and DEN-2/4 Chimeric Viruses

The viable, infectious chimeric DEN-2/3 and DEN-2/4 viruses, which express 5 the prM/E gene region of wild-type DEN-3 16562 or wild-type DEN-4 1036 virus, respectively, expressed appropriate DEN-3 or DEN-4 virus-specific envelope protein (E) epitopes, as analyzed by indirect immunofluorescence of virus-infected LLC-MK₂ cells with virus-specific anti-E monoclonal antibodies. These chimeric viruses, as well as chimeric DEN-2/1 virus, also expressed appropriate DEN serotype-specific neutralization epitopes when tested against standard polyvalent mouse ascitic fluids or monoclonal antibodies in serum dilution-plaque reduction neutralization tests (Table 8). The chimeric DEN-2/1-EP, DEN-2/3-EP1, and DEN-2/4-EP1 viruses were neutralized by these standard DEN virus-specific antibodies to reciprocal PRNT₅₀ titers that were at least as high as those that occurred for wild-type DEN-1, DEN-3, and DEN-4 viruses, respectively (Table 8). These neutralization data indicated that the chimeric DEN-2/1, DEN-2/3, and DEN-2/4 viruses expressed appropriate DEN serotype-specific neutralization epitopes of DEN-1, DEN-3, and DEN-4 viruses, respectively.

Replication in LLC-MK2 cells

The replication and temperature sensitivity of DEN-2/3 chimeras in LLC-MK2 cells was monitored as the replication and temperature sensitivity of DEN-2/1 chimeras was examined in Example 1. The chimeric DEN-2/3-PP1, -EPI, and -VP1 viruses and chimeric DEN-2/4-PP1, -EPI, and -VP1 viruses, which expressed the prM/E gene region of DEN-3 16562 virus or DEN-4 1036 virus in the genetic background of DEN2 16681 (-PP1), DEN-2 PDK-53-E variant (-EP1), or the DEN-2 PDK-53-V variant (VP1), respectively, all replicated to high peak titers of at least 10⁶·³ PFU/ml in LLCMK₂ cells. As defined in terms of the reduction of virus titers at 38.7°C versus those at 37°C (-, +, 2+, 3+ indicate titer reduction of less than or equal to 60%, 61-90%, 9130 99%, >99%, respectively, calculated from at least 3 experiments). Chimeric DEN-2/32018200081 04 Jan 2018

PP1 and DEN-2/4-PP1 viruses exhibited either borderline temperature sensitivity (DEN-2/3-PP1) or no temperature sensitivity (DEN-2/4-PP1). The chimeric DEN-2/3EP1 and -VP1, as well as the chimeric DEN-2/4-EP1 and -VP1 viruses, all of which were constructed in the genetic background of the DEN-2 PD-53-E or -V variant, retained the temperature-sensitive phenotypes that were exhibited by the two PDK-53 variant viruses (DEN-2-PDK53-E48 and -V48 viruses, respectively). The chimeras constructed in the background of the PDK-53-V variant exhibited a higher degree of temperature sensitivity than did those constructed in the background of the PDK-53-E variant.

Plaque sizes in LLC-MK2 cells

The plaque size resulting from inoculation of LLC-MK2 cells placed under agarose overlay, used as a biological marker to determine attenuation as described in Example 1, was also examined for the chimeric DEN-2/3 and DEN-2/4 viruses.

Average plaque size in mm follows each virus or chimera in brackets: DEN-3-16562 (6.6) , DEN-2/3-PP1 (5.4), DEN-2/3-EP1 (4.5), DEN-2/3-VP1 (2.3), DEN-4-1036 (8.6) , DEN-2/4-PP1 (3), DEN-2/4-EP1 (1.5), DEN-2/4-VP1 (1.2), DEN-2-16681-P48 (4.2), DEN-2-PDK53-E48 (2.5) and DEN-2-PDK-53-V48 (1.8).

The plaque sizes of the DEN-2/3-PP1 and DEN-2/4-PP1 viruses exhibited mean plaque diameters that were larger than those of the DEN-2 16681 or PDK-53 virus (as described in Example 1), but smaller than those of wild-type DEN-3 16562 and DEN-4 1036 viruses, respectively. This indicates that structural genes from the donor DEN-3 and DEN-4 viruses and capsid and/or nonstructural gene regions in the recipient genetic background of DEN-2 16681 virus both affected plaque size. The chimeric DEN-2/3EP1 and -VP1 and DEN-2/4-EP1 and -VP1 viruses exhibited significant reductions in plaque size, relative to wild-type DEN-3 16562 and DEN-4 1036 viruses, respectively. The DEN-2 PDK-53 background-specific effect on plaque size may result from synergistic interaction of the mutations at the NS1-53 and NS3-250 loci of DEN-2

PDK-53 virus. Consequently, -VP1 chimeras exhibited greater reductions in plaque

2018200081 04 Jan 2018 size than did the —EPI chimeras. The chimeric DEN-2/1, DEN-2/3, and DEN-2/4 viruses constructed in the genetic background of the candidate DEN-2 PDK-53 vaccine virus retained the phenotype of decreased plaque size as exhibited by DEN-2 PDK-53 virus.

Replication in C6/36 cells

The ability of the viruses to replicate in mosquito C6/36 cell culture, used as a biological marker to determine attenuation as described in Example 1, was also examined for the chimeric DEN-2/3 and DEN-2/4 viruses. Average peak titers in units of Logi₀ PFU/ml follow each virus or chimera in brackets; D3-16562 (7.3), DEN-2/3PP1 (7.6), DEN-2/3-EP1 (5.2), DEN-2/3-VP1 (5.7), D4-1036 (8.7), DEN-2/4-PP1 (7.8), DEN-2/4-EP1 (4.5), DEN-2/4-VP1 (4.4), DEN-2-16681-P48 (8.3), DEN-2PDK53-E48 (5.4) and DEN-2-PDK-53-V48 (5).

Both of the Mahidol candidate DEN-2 PDK-53 variants exhibit decreased replication efficiency, relative to wild-type DEN-2 16681 virus, in mosquito C6/36 cell culture (DEN-2-PDK-53-E48 and -V48 versus DEN-2-16681-P48 virus). The decreased replication ability in C6/36 cells has been attributed to the mutations at the two 5-NC-57 and NS1-53 loci in the DEN-2 PDK-53 virus; consistent with this view, both variants replicated to equivalently reduced peak titers in these cells. This crippled replication phenotype in C6/36 cells was retained in the chimeric DEN-2/3-EP1 and VP1 and DEN-2/4-EP1 and -VP1 viruses, all of which replicated to lower peak titers than did the wild-type DEN-3 16562 or DEN-4 1036 virus, respectively. The chimeric DEN-2/3-PP1 and DEN-2/4-PP1 viruses, constructed in the genetic background of wild-type DEN-2 16681 virus, replicated to essentially the same extent (DEN-2/3-PP1) as or somewhat lower (DEN-2/4-PP1) than the wild-type DEN-3 16562 and DEN-4 1036 viruses, respectively. These results indicate that the replication-crippling effect of the 5'-NC-57 and NS1-53 loci in the DEN-2 PDK-53 virus-specific background was preserved in those chimeric viruses that were constructed within the DEN-2 PDK-53 genetic background.

2018200081 04 Jan 2018

Neurovirulence for newborn mice

Newborn, outbred, white ICR mice (n=16 for each group) were challenged intracranially with 10⁴ PFU of wild-type DEN-3 and DEN-4 viruses, Mahidol candidate vaccine DEN-3 and DEN-4 viruses, chimeric DEN-2/3-PP1, -EPI, -VP1 viruses, and chimeric DEN-2/4-PP1, -EPI, and -VP1 viruses (Table 9). The wild-type DEN-3 16562 and DEN-4 1036 viruses, which reliably caused 100% fatality in newborn mice, constituted a more sensitive model for attenuation of viral neuro virulence than does the DEN-2 16681 challenge model, which results in 50-100% fatality in newborn mice challenged with this virus. Interestingly, the Mahidol candidate DEN-4 PDK-48 vaccine virus also resulted in 100% fatality in challenged mice, although the average survival time of these mice was about two days longer than for mice challenged intracranially with wild-type DEN-4 1036 virus (Table 9). Like the DEN-2 PDK-53 vaccine virus and both of its variant populations, the chimeric DEN-2/3-EP1 and -VP1 and chimeric DEN-2/4-EP1 and -VP1 viruses were attenuated (no fatalities) for newborn mice. This attenuation may be attributable, at least in part, to the attenuated DEN-2 PDK-53 genetic background of these chimeric viruses, because the chimeric DEN-2/4-PP1 virus exhibited significant neurovirulence (62.5% mortality) in these mice. This latter chimera was constructed in the genetic background of wild-type DEN-2 16681 virus.

Immunization of AG-129 mice with chimeric DEN-2/3 and DEN-2/4 viruses

Inbred AG-129 mice were immunized intraperitoneally with 10⁵ PFU of wildtype or Mahidol vaccine candidate DEN-3 or DEN-4 virus or with 10⁵ PFU of chimeric DEN-2/3-EP1 or DEN-2/4-EP1 virus (Table 10). The chimeric DEN-2/3-EP1 virus elicited reciprocal PRNT₇₀ titers of 80-320 at 4-6 weeks after primary immunization. These titers were essentially equivalent to those elicited by the Mahidol DEN-3 vaccine

2018200081 04 Jan 2018 virus (strain PGMK-30ZFRhL-3). However, the chimeric DEN-2/4-EP1 virus elicited neutralizing antibody titer of 20-40, which was lower than the 80-320 titer elicited by the Mahidol vaccine candidate DEN-4 PDK-48 vaccine virus. Nevertheless, both chimeric DEN-2/3 and DEN-2/4 viruses elicited neutralizing antibody responses in

AG-129 mice.

Example 5

Attenuation of a Dengue-2 Vaccine Virus: Strain 16681 (PDK-53)

Viruses and cell cultures

The parental DEN-2 16681 virus, several intermediate PDK passages (PDK-5, 10, -14, -35, and -45) of 16681 virus, recombinant 16681/PDK-53 viruses, and the genetically characterized LLC-MK₂-1 passage of the candidate PDK-53 vaccine virus were investigated.

Cell cultures of BHK-21 (clone 15), LLC-MK₂, Vero, and C6/36 were grown in

Dulbecco’s modified minimal essential medium (DMEM) supplemented with 10% heat- inactivated (56°C for 30 min) fetal bovine serum (FBS; HyClone Laboratories, Inc., Logan, Utah), 3.7 g/L of sodium bicarbonate (GIBCO-BRL, Life Technologies, Gaithersburg, Md.), 100 units/ml of penicillin G, and 100 mg/ml of streptomycin sulfate (GIBCO-BRL).

Plaque titrations were performed in confluent monolayers of Vero cells in plastic 6-well plates as described previously (Miller et al., Am. J. Trop. Med. & Hyg. 35: 1302-1309 (1986)). A 200- μΐ inoculum of virus was adsorbed for 1.5 h at 37°C, followed by the addition of 4 ml of agarose overlay medium containing 1% SeaKem LE agarose (FMC BioProducts, Rockland, Md.) in nutrient medium (0.165 % lactalbumin hydrolysate [Difco Laboratories, Detroit, Mich.], 0.033% yeast extract [Difco], Earl’s balanced salt solution, 25 mg/L of gentamicin sulfate [Bio Whittaker, Walkersville, Md.], 1.0 mg/L of amphotericin B [Fungizone®, E. R. Squibb & Sons,

Princeton, N.J.], and 2% FBS). Following incubation at 37°C for 7 days, a second 2-ml

2018200081 04 Jan 2018 agarose overlay containing 80 /zg/ml of neutral red vital stain (GIBCO-BRL) was added.

Construction of recombinant DEN-2 16681/PDK-53 viruses 5 During the genetic validation of clone-derived DEN-2 viruses in the present study, two cDNA cloning errors were discovered, nt-6665 A-to-G (NS4A-97 Tyr-toCys) and nt-8840 A-to-G (NS5-424 Glu-to-Gly), in the previously reported PDK-53 virus-specific pD2/IC-130Vc-K (NS3-250-Val variant) clone (Kinney et al., Virology 230: 300-308 (1997)). These defects were corrected in a newly derived PDK-53 virus10 specific (NS3-250-Val variant) clone, pD2/IC-VV45R.

In preliminary studies, recombinant 16681/PDK-53 viruses containing PDK-53 virus-specific gene regions within the genetic background of 16681 virus were used to investigate the genetic loci involved in the attenuation markers of PDK-53 virus.

Analyses of these viruses indicated that the PDK-53 mutation at nt-57 in the 5'NC region and the amino acid mutations at NS 1-53 (analyzed in a linked manner with the NS2A-181 mutation) and NS3-250 were the determinants of the PDK-53 virus-specific phenotype. The prM-29 mutation has little effect on virulence. Based upon sequence analysis and comparison, the 5’NC, NS1 andNS3 mutations were subjected to further mutational analysis. The 5’NC mutation occurred in a possible stem structure. The NS1 and NS3 mutations both occurred at loci conserved in some flaviviruses. 14 recombinant pD2/IC- 16681/PDK-53 plasmids were constructed by exchanging cDNA fragments between pD2/IC-30P-A (16681 clone) and pD2/IC-VV45R (PDK-53 clone) at restriction enzyme sites Sstl (preceding the T7 promoter), Sail (nt-165), SphI (nt25 1380), Spel (nt-2370 and nt-3579), Kpnl (nt-4493), Xhol (nt-5426), and Xbal (3' end of the clone). All recombinant plasmids were grown in Escherichia coli, strain XLI-blue, and were linearized at the unique Xbal site engineered at the 3’ terminus of the cDNA. BHK-21 cells were transfected with transcribed viral RNA by the method of Liljestrom et al. (J. Virology 63: 4107-4113 (1991)).

2018200081 04 Jan 2018

The genotypes of the recombinant D2/IC-Px (where x = 5, 1, and/or 3 to indicate the incorporation of the parental [P in the virus designation] 16681 virusspecific 5'NC-57, NS 1-53, and/or NS3-250 loci into the pD2/IC-VV45R [PDK-53] backbone) and D2/IC-Vx (where x indicates the reciprocal incoiporation of the three candidate PDK-53 vaccine [V in the virus designation] virus-specific loci within the pD2/IC-30P-A [16681] backbone) viruses are shown in Table 11. If the 5'NC, NS1, and NS3 loci are the primary determinants of the PDK-53 virus-specific phenotype, then the D2/IC-P5 and D2/IC-V13 viruses should be equivalent (cognate) because both viruses contain 5'NC-57-C, NSl-53-Asp, and NS3-250-Val. The cognate virus pairs derived from reciprocal mutagenesis of the 16681 and PDK-53 virus- specific infectious clones are indicated in Table 11. To further investigate the prM-29 locus, we moved the prM-29-Asp locus of DEN-2 16681 virus into pD2/IC-VV45R and pD2/ICP5 to derive recombinant D2/IC-Pp and -P5p viruses, respectively. Reciprocal recombinations yielded D2/IC-Vp and -V5p viruses.

Each clone-derived virus (transfected BHK-21 seed) was propagated once in LLC-MK₂ cells. The genotypes of all of the LLC-MK₂-1-passaged, recombinant 16681/PDK-53 viruses were confirmed by complete nucleotide sequence analyses of their genomes. Because all of the viruses had the expected nucleotide sequences, we inferred that their cDNA clones were also correct. All of the clone-derived viruses contained the 16681 virus- specific nt-8571-C locus, which is the site of a silent mutation in PDK-53 virus. Direct sequencing of overlapping cDNA amplicons generated from DEN-2 viral genomic RNA using reverse transcriptase-polymerase chain reaction (RT-PCR) was used to determine the sequence of all but the termini of the cDNA. The sequences of the 5'- and 3'-terminal 30 nucleotides of the genome were detennined by direct sequencing of the infectious clone cDNA in plasmid pBRUC139. The D2/IC- prefix is eliminated in the virus designations in Table 11 and the following text.

2018200081 04 Jan 2018

Characterization of the replication phenotypes of recombinant 16681/PDK-53 viruses.

Viruses were analyzed for plaque size, temperature sensitivity, and replication in LLC-MK₂ and C6/36 cells. Plaque sizes were evaluated after 9 days of incubation under agarose in LLC-MK₂ cell monolayers grown in 6-well plates. Viral growth curves were performed in 75-cm² flasks of LLC-MK₂ or C6/36 cells inoculated at multiplicity of infection (m.o.i.) of approximately 0.001 PFU/cell. After adsorption at 37°C for 2 h, 30 ml of DMEM medium (LLC-MK₂ cells) or overlay nutrient medium (C6/36 cells) containing penicillin/streptomycin and 5% FBS was added, and the cultures were incubated in 5% CO₂ at 37°C or 29°C, respectively. Aliquots of culture medium were removed at 48-h intervals, adjusted to 12.5% FBS, and stored at -80°C prior to virus titration.

Temperature sensitivity assays were performed in LLC-MK₂ cells grown in 75cm² flasks. The cells were inoculated at a m.o.i. of about 0.001 PFU/cell. After adsorption for 2 h at 37°C, 30 ml of DMEM medium containing 5% FBS was added. One set of cultures was incubated for 8 days at 37°C, the other at 38.7°C. The ratio of virus titer at 38.7°C versus the titer at 37°C was calculated.

Mouse neurovirulence assay

Litters of newborn, outbred white ICR mice were inoculated intracranially with

10⁴ PFU of virus in a volume of 30 ml. Mice were individually weighed once a week and were observed for paralysis or death for 35 days.

Plaque phenotypes of recombinant 16681/PDK-53 viruses

Mean diameters of virus plaques (n=12) at 9 days after infection under agarose overlay in LLC-MK₂ cells were measured (FIG. 4). The largest plaques (3.2-3.4 mean diameter) were produced by the wild-type 16681 virus, its clone-derived 30P-A virus,

2018200081 04 Jan 2018 and the recombinant P513 virus, which contained the 5'NC, NS1, and NS3 16681 virusspecific loci in the VV45R (PDK-53) virus genetic background (Table 11). These three 16681-specific loci within the PDK-53 genetic background were sufficient to reconstitute the large plaque phenotype of the 16681 virus.

Individual PDK-53 virus-specific 5-NC-57-T, NSl-53-Asp, andNS3-250-Val mutations incorporated into the 16681 genotype each resulted in significantly (p <

0.00003) decreased plaque sizes of 2.1-2.3 mm in V5, VI, and V3 viruses, respectively, versus those of 16681 virus. The plaque phenotypes of Pl 3 and P51 viruses were similar to those of their cognate V5 and V3 viruses (indicated by graph bars with identical solid or cross-hatching pattern in FIG. 4). The 2.8-mm plaque size of P53 virus differed from 16681 viral plaques to a lesser degree (p < 0.03) than did the 2.1mm plaques of its cognate VI virus. The 1.1 - 1.6-mm plaques of cognate virus pairs V13 (P5) (containing PDK-53 virus-specific NS 1 andNS3 loci), V53 (Pl) (PDK-53 virus-specific 5'NC and NS3 loci), and V51 (P3) virus (PDK-53 virus-specific 5'NC andNSl loci) were essentially equivalent to the 1.3-mm plaques of PDK-53 virus. These results indicate that all pairwise combinations of these three PDK-53 virusspecific loci in the 16681 backbone generated a small-plaque virus similar to PDK-53 virus. Although V51 virus produced a plaque phenotype that was similar to that of

PDK-53 virus, all three 16681 virus-specific 5'NC-C, NSl-53-Gly, and NS3-250-Glu loci were required within the PDK-53 background of P513 virus to reconstitute the plaque phenotype of 16681 virus. The presence of all three PDK-53 loci in the 16681 backbone generated V513 virus, which had a smaller (p < 0.001, Student’s t test) plaque phenotype than that of either PDK-53 or W45R virus. The difference between the plaque size of PDK-53 virus and that of VV45R virus was not significant.

Recombinant Vp virus, which contained the PDK-53 virus-specific prM-29-Val locus in the 16681 background, had a significantly (p < 0.002) reduced plaque size of 2.6 mm. However, the 1.0-mm plaque phenotype of Pp virus (16681 prM-29-Asp locus in the PDK-53 background) was essentially identical to the 1.1-mm and 1.3-mm

2018200081 04 Jan 2018 plaques of W45R and PDK-53 viruses (FIG. 4A), respectively. The prM-29 locus did not affect the plaque phenotypes of P5p (1.0 ± 0.0 mm) and V5p (2.0 ± 0.4 mm) viruses, which produced plaques similar to those of P5 (1.1 ± 0.3 mm) and V5 (2.3 ± 0.4 mm), respectively.

Replication of recombinant 16681/PDK-53 viruses inLLC-MK₂ and C6/36 cells

All of the viruses replicated well in LLC-MK₂ cells, reaching peak titers of 10⁷³ -10⁷·⁹ PFU/ml at 6-8 days after infection. PDK-53 and its clone-derived VV45R virus replicated at a reduced rate during the first four days after infection, relative to the other viruses. To determine temperature sensitivities, virus-infected LLC-MK₂ cells were incubated at 37°C or 38.7°C in 2-5 experiments (FIG. 4B). Temperature sensitivity scores were determined at 8 days after infection. All of the viruses exhibited some degree of temperature sensitivity under these conditions. In individual experiments, wild-type 16681 virus showed 75-80% titer reduction at 38.7°C. Virus VI and cognate viruses P3 (V51), which showed 84-86% average reductions in titer, were slightly more temperature-sensitive than 16681 virus. However, only PDK-53, VV45R, V513, P5p, Pp, and the cognate recombinant viruses V13 and P5, all of which contained both the NSl-53-Asp and NS3-250-Val PDK-53 virus- specific loci, reproducibly showed 90-97% average reduction in titer at 38.7°C.

The 16681 virus and its clone-derived 3 OP-A virus replicated to average peak titers of 10⁸⁶-10⁸·⁸ PFU/ml at 12 days after infection in two independent growth-curve experiments in C6/36 cells (FIG. 4C). The replication of PDK-53 virus (peak titer of IO⁴³ PFU/ml) and its clone- derived VV45R (peak titer of 10⁴·⁶ PFU/ml) virus was approximately 15,000-fold less efficient in C6/36 cells. The 16681 virus-specific 5'NC and NS1 loci within the PDK-53 background of P51 virus fully reconstituted the replication efficacy to that of wild-type 16681 virus. Conversely, the PDK-53 virusspecific 5'NC and NS1 loci within the 16681 background of V51 virus were sufficient to establish the crippled replication phenotype of PDK-53 virus. Recombinant cognate virus pairs V5 (P13) and VI (P53), which contained the PDK-53 virus- specific 5'NC

2018200081 04 Jan 2018 region or NS1 locus, respectively, replicated to average peak titers of 10⁵·⁹ - 10^6,7 PFU/ml. Although the average peak titer of V53 virus was about 40-fold greater than that of V5 virus in C6/36 cells, the peak titers of P513, P13, P53, V3, V13, V513, and P3 viruses were very similar to those of P51, Pl, P5, 30P-A, VI, V51, and W45R viruses, respectively. These data indicated that the NS3-250 locus had little or no observable effect on replication in C6/36 cells (FIG. 4C). Vp and 16681 viruses had nearly equal average peak titers in C6/36 cells, as did P5 and P5p viruses. Pp and V5p viruses produced average peak titers that were slightly higher (8- and 40-fold, respectively) than those of PDK-53 and V5 viruses, respectively. The prM-29 locus appeared to have little or no effect on viral replication in C6/36 cells.

Neurovirulence of recombinant 16681ZPDK-53 viruses in newborn mice

To investigate the neuro virulence of the recombinant viruses, two litters of newborn white ICR mice, eight mice per litter, were infected intracranially with 10⁴ 15 PFU of virus. The DEN-2 16681 virus and its clone-derived 30P-A virus cause 50%100% mortality in these mice. Average survival times (AST) for mice succumbing to challenge with 16681 or 30P-A virus ranged from 15.2 to 16.8 days in various experiments. Mice were weighed individually every 7 days after infection. A single mouse died by day 1 after infection, presumably as a result of inoculation trauma, in each of the P53 and Vp groups (Table 12). These two mice were excluded from the analyses. There were no fatalities and no weight loss in the control, diluent-inoculated group.

Three mouse neurovirulence phenotypes were observed (Table 12). The first phenotype consisted of the mouse-virulent viruses DEN-2 16681, 30P-A, P513, P51, V3, and Vp, which caused at least 50% mortality with AST of 13.2-17.0 days (Table 12). In two other independent experiments, the Vp virus caused 46.67% mortality with AST of 17.4 ±1.4 days (n=16) and 56.25% mortality with AST of 18.3 ±1.3 days (n=16). In an independent experiment, P51 virus caused only 25% mortality with AST of 15.9 ± 5.5 days (n=16). A second phenotype consisted of the mouse-attenuated

2018200081 04 Jan 2018

PDK-53, W45R, V513, Pp, and cognate V51 (P3) viruses, which caused no mortality, and the nearly attenuated VI, cognate VI3 (P5), P5p, and V5p viruses, which killed only 1 of 16 mice (Table 12). The presence of the two PDK-53 virus-specific 5'NC-57T and NSl-53-Asp loci within the 16681 genetic background was sufficient to result in or maintain attenuation in cognate viruses V51 (P3). Except for P53 virus, all of the viruses containing the PDK-53 virus-specific NSl-53-Asp locus were attenuated or nearly attenuated.

The third phenotype, that of intermediate virulence, characterized cognate virus 10 pairs V5 (P13) and V53 (Pl), and P53 virus which caused 18.75%-37.5% mouse mortality and significant weight loss (p < 0.001, Student’s t test, at 3 weeks after infection, relative to diluent-inoculated control mice) in mice that survived virus challenge. Viruses V5 (P13) and V53 (Pl) contained the 5'NC-57-T, but not the NS153-Asp, locus of PDK-53 virus. VI virus (6.25% mortality) was more attenuated than

V5 virus, which produced 18.75% mortality and significant weight loss in the survivors. Conversely, the 16681 virus-specific 5-NC-57-C locus caused little reversion to virulence in P5 virus (6.25% mortality), whereas the NSl-53-Gly moiety in Pl virus resulted in an intermediate level (37.5%) of mortality and significant weight loss in the survivors. Unlike the nearly attenuated cognate VI virus, P53 virus had an intermediate virulence phenotype. The NS 1-53 locus had a more significant effect on the virulence phenotype than did the 5'-NC-57 locus.

The prM-29 locus showed no effect in P5p, Pp, and Vp viruses, relative to P5, PDK-53, and 16681 viruses, respectively. The V5p virus, which contained both PDK25 53 virus-specific 5'NC-57-T and prM-29-Val loci, was nearly attenuated (Table 2). The

NS3-250 locus did not appear to contribute significantly to mouse neurovirulence phenotype in V3, P13, V53, V13, and P3 viruses, which exhibited phenotypes that were

2018200081 04 Jan 2018 equivalent to 16681, Pl, V5, VI, and PDK-53 viruses, respectively. The difference in the level of mortality caused by P53 and P5 viruses suggested that the 16681 virusspecific NS3-250-Glu locus might contribute somewhat to the virulence phenotype within certain genetic contexts.

Evolution of mutations in the DEN-2 PDK-53 vaccine virus

Intermediate passages PDK-5, -10, -14, -35, and -45 of the 16681 virus were analyzed to detennine the accrual of the nine nucleotide mutations in the PDK-53 vaccine strain. Amplicons were amplified directly from genomic mRNA extracted from the viral seed by RT/PCR. Automated sequencing of small genomic regions, which contained the nine relevant loci, was performed by using appropriate primers. The nucleotide residues identified at each of the nine loci for these viruses are shown in Table 13. The NS2A-181 Leu-to-Phe mutation and the silent mutations at E-37, NS3342, and NS5-334 appeared by passage PDK-5 and were the predominant moieties by passage PDK-10 (NS2A-181), PDK-14 (E-373, NS3-342), or PDK-35 (NS5-334). Mutations 5'-NC-57 C-to-T, prM-29 Asp-to-Val, NS1-53 Gly-to-Asp, andNS4A-75 Gly-to-Ala occurred by passage PDK-35. The 5-NC-57-T was predominant at passage PDK-35, while the other listed mutations became predominant by passage PDK-45.

The NS3-250 Glu-to-Val mutation appeared by passage PDK-45 and is not fully mutated to the virus-specific Val in the current PDK-53 vaccine candidate (Table 13). Approximately 29% of the viral population in the PDK-53 vaccine contains NS3-250Glu. The PDK-45 virus was genetically equivalent to the PDK-53 vaccine virus. In the present study, no attempt was made to determine the relative proportions of the two nucleotides at the mixed genetic loci shown in Table 13.

Example 6

Construction of chimeric DEN-2/West Nile clones and virus

Genome-length, chimeric DEN-2/WN infectious cDNA clones containing structural genes of WN virus within the genetic background of DEN-2 virus were

2018200081 04 Jan 2018 constructed using the in vitro ligation strategy used to derive the chimeric DEN-2/3 viruses described earlier.

In a first example, the prM-E encoding cDNA of the 5'-end subclone that was 5 used to derive a chimeric DEN-2/3-PP1 virus clone (see Example 2) was replaced with the prM-E gene region of WN virus, strain NY 99 (New York 1999). The cDNA fragment containing the prM-E gene region of WN virus was amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) from WN virus-specific genomic RNA with forward primer WN-M (5'-GGAGCAGTTACCCTCTCTACGCGTCAAGGGAAGGTGATG-3’ (SEQ ED NO:37); underlined Mlulsite followed by WN virus sequence near the 5' end of the prM gene) and reverse primer cWN-E (5'-GAAGAGCAGAACTCCGCCGGCTGCGAGAAACGTGA GAGCTATGG-3' (SEQ ID NO :3 8); underlined NgoMIV site followed by sequence that was complementary to the WN genomic sequence near the 3' end of the E gene of WN virus). The amplified prM-E cDNA fragment was cloned into the MluI-NgoMIV sites of the intermediate pD2I/D3-Pl-AscI clones, exactly as was done during the derivation of chimeric DEN-2/3 virus (see Example 2, construction of chimeric DEN-2/3 infectious clones), to replace the prM/E region of the DEN-3 16562 virus. In this chimeric DEN-2/WN cDNA, the prM splice site encoded the amino acid sequence (shown as single-letter amino acid abbreviations, and written in amino-to-carboxyl order) SAGMIIMLIPTVMA-FHLTTR0GXWM7V (SEQ ID NO:39). The hyphen in this sequence indicates the polyprotein cleavage site located between the capsid and prM genes; the amino-terminal sequence is DEN-2 virus specific; the carboxyl-terminal sequence in bold, underlined, italicized font indicates the WN virus-specific sequence (QGKVMMTV) (SEQ ID NO :40) near the amino terminus of the prM protein encoded by this chimeric construct. This intermediate DEN-2/WN subclone was ligated in vitro with the 3'-end intermediate DEN-2 subclone, pD2-Pm^Ab-Asc, by the same protocol described in example 2 (construction of chimeric DEN-2/3 infectious clones) to produce the full genome-length, chimeric DEN-2/WN viral cDNA that was used to

2018200081 04 Jan 2018 transcribe chimeric DEN-2/WN virus-specific genomic RNA. Using the same protocol described in example 2, mammalian LLC-MK₂ or mosquito C6/36 cells were transfected with the transcribed chimeric DEN-2/WN RNA. This strategy, which involved using the same Mlul restriction enzyme splice site that was used to derive the chimeric DEN-2/3 and DEN-2/4 viruses, failed to produce viable chimeric virus after transfection of the transcribed chimeric DEN-2/WN RNA in LLC-MK₂ cells, and resulted in only very low titers (< 100 PFU/ml) in C6/36 cells. This failure is probably due to significant gene sequence variation between the carboxyl-terminal ends of the viral capsid proteins and between the amino-terminal ends of the prM protein of DEN-2 and WN viruses. The carboxyl-terminal region of the flavivirus capsid protein serves as a signal peptide sequence for the insertion of prM into intracellular membranes (endoplasmic reticulum) during maturation and cleavage of the prM protein. This DEN-2/WN construct, which contained the capsid-carboxyl-terminal signal sequence, as well as the amino-terminal residues of the prM protein of the DEN-2 backbone, apparently did not permit appropriate maturation of the chimeric virus.

In a second example, the chimeric DEN-2/WN cDNA clone was modified so as to encode the carboxyl-terminal region of the capsid protein, as well as the entire prM protein and most of the E protein, of WN virus. A unique Sstll restriction site was introduced by site-directed mutagenesis near the 3' terminus of the DEN-2 virusspecific capsid gene to serve as a new 5' splice site for the WN capsid-carboxylend/prM/E gene region. This SstH site introduced two silent mutations in the DEN-2 virus-specific sequence encoding the amino acid triad SAG (single-letter abbreviations). The appropriate gene region was amplified from WN viral RNA by using the forward primer WN-452.SAG (5’-AATTCAACGCGTACATCCGCGGGCACCGGAATTGCAGTCA TGATTGGCCTGATGGC-3' (SEQ ID NO:41); underlined Sstll site followed by WN virus-specific sequence) and the same reverse cWN-E primer that was utilized in the previous construct (as described above). This amplified cDNA was cloned to make the intermediate subclone pDEN-27WN-P-SA which contained cDNA encoding the 5'

2018200081 04 Jan 2018 noncoding region and most of the capsid gene from DEN-2 16681 virus and the carboxyl-terminal capsid, entire prM, and most of the E gene from WN virus, as well as a unique Ascl site downstream of the NgoMIV site. In this chimeric DEN-2/WN cDNA, the prM splice site encoded the amino acid sequence (shown as single-letter amino acid abbreviations, and written in amino-to-carboxyl order)

SAGTGIAVM1GLIASVGA-VTLSNFQGKVMMTV (SEQ ID NO:42). The hyphen in this sequence indicates the polyprotein cleavage site located between the capsid and prM genes; the amino-terminal sequence is DEN-2 virus specific; the carboxyl-terminal sequence in bold, underlined, italicized font indicates the WN virus-specific sequence (TGIAVMIGLIASVGA-VTLSNFQGKVMMTV) (SEQ ID NO:43) encoded by this chimeric construct. Following the in vitro ligation protocol of the chimeric DEN-2/3 clones described for chimeric DEN-2/3 virus in example 2, the 5'-end intermediate subclone pDEN-2/WN-P-SA was ligated to the 3'-end pD2-Pm^Ab-Asc subclone to produce the full genome-length cDNA of the chimeric DEN-2/WN-PP1 virus for transcription of the chimeric RNA. The chimeric DEN-2/WN-PP1 construct encoded the indicated WN structural gene region within the genetic background of the wild-type DEN-2 16681 virus. Both LLC-MK₂ and C6/36 cells were transfected with RNA transcribed from this in vziro-ligated, chimeric DEN-2/WN-PP1 clone. Viable, chimeric DEN-2/WN-PP1 virus, at virus titers of 10³-10⁶ PFU/ml of culture medium, was successfully recovered from both transfected cell cultures. Nucleotide sequence analysis of the entire genome of the clone-derived, chimeric DEN-2/WN virus demonstrated the expected genomic sequence. These results demonstrate that the DEN-2 infectious clones of the invention can be used to construct chimeric viruses that express structural genes of heterologous flaviviruses other than DEN-1, DEN-3, and

DEN-4 viruses.

All of the patents, publications and other references mentioned herein are hereby incorporated in their entirety by reference. Modifications and variations of the

2018200081 04 Jan 2018 present methods and compositions will be obvious to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to come within the scope of the appended claims.

In the claims which follow and in the description of the invention, except where the 5 context requires otherwise due to express language or necessary implication, the word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

9845429_1 (GHMatters) P47053.AU.6

2018200081 04 Jan 2018

Table 1

Viral Candidates for Flavivirus Chimeras⁴

Primary Mosquito-	Other Mosquito-Borne:
Borne Species	Species
Dengue-1 **	Alfuy	Jugra
Dengue-3 **	Bagaza	Kokobera
Dengue-4 **	Banzi **	Ntaya
Yellow fever **	Bouboui	Rocio **
Japanese encephalitis **	Bussuquara **	Sepik **
Murray Valley encephalitis **	Edge Hill **	Spondweni **
St. Louis encephalitis **	Ilheus	Stratford
West Nile **	Naranjal	Tembusu
Kunjin *	Israel turkey meningitis	Uganda S Usutu ** Wesselsbron** Zika **
Tick-Borne:	No Arthropod Vector Demonstrated
Absettarov **	Apoi *
Gadgets Gully	Aroa
Hanzalova **	Cacipacore
Hypr **	Carey Island
Kadam	Cowbone Ridge
Karshi	Dakarbat **
Kumlinge **	Entebbe bat
Kyasanur Forest disease **	Jutiapa
Langat	Koutango *
Louping ill **	Modoc *
Meaban	Montana Myotis leukemia
Omsk hemorrhagic fever **	Negishi **
Powassan **	Phnom-Penh bat
Royal Farm	Rio Bravo **
Russian spring	Saboya
summer encephalitis **	Sal Vieja
Saumarez Reef	San Perlita
Tyuleniy	Sokuluk

* = Laboratory infection reported ** = Natural and laboratory infection reported ⁺ = List includes the currently classified members of the Flavivirus genus in the International Catalogue of Arboviruses, Including Certain Other Viruses of Vertebrates, Nick Karabatsos, ed. The American Society of Tropical Medicine and Hygiene. 1985.

2018200081 04 Jan 2018

Table 2

Summary Of Nucleotide And Amino Acid Differences Between The Genomes Of DEN-1 16007 Virus And Its Vaccine Derivative,

Strain PDK-13

Genome Nucleotide Position	Nucleotide	Amino Acid	Protein Position	Polyprotein Position
16007	PDK-13	16007	PDK-13
1323	T	C	Val	Ala	E-130	410
1541)	G	A	Glu	Lys	E-203	483
1543)	A	G
1545	G	A	Arg	Lys	E-204	484
1567	A	G	Gin	Gin	E-211	491
1608	C	T	Ser	Leu	E-225	505
2363	A	G	Met	Val	E-477	757
2695	T	C	Asp	Asp	NS 1-92	867
2782	c	T	Ala	Ala	NS1-121	896
5063	G	A	Glu	Lys	NS3-182	1657
6048	A	T	Tyr	Phe	NS3-510	1985
6806	A	G	Met	Val	NS4A-144	2238
7330	A	G	Gin	Gin	NS4B-168	2412
9445	C	T	Ser	Ser	NS5-624	3117

Table 3

Summary Of Nucleotide And Amino Acid Sequence Differences Between The

Genomes Of DEN-2 16681 Virus And Its

Vaccine Derivative, Strain PDK-53

Genome

2018200081 04 Jan 2018

Nucleotide	Nucleotide	Amino Acid	Protein	Polyprotein
Position	16681	PDK-53	16681	PDK-53	Position	Position
57	C	Ta	-	-
524	A	T	Asp	Val	prM-29
2055	C	T	Phe	Phe	E-373	653
2579	G	A	Gly	Asp	NS1-53	828
4018	C	T	Leu	Phe	NS2A-181	1308
5270	A	T/A	Glu	Glu/Valb	NS3-250	1725
5547	T	C	Arg	Arg	NS3-342	1817
6599	G	c	Gly	Ala	NS4A-75	2168
8571	C	T	Val	Val	NS5-334	2825

^[a] 5' noncoding region.

^[b] The PDK-53 vaccine contains two genetic variants at nt-5270.

2018200081 04 Jan 2018

Table 4

Summary Of Nucleotide And Amino Acid Differences Between The Genomes Of

DEN-3 16562 Virus And Its Vaccine Derivative, Strain PGMK-30/FrhI-3
Genome	Nucleotide	Amino Acid
Nucleotide		PGMK-30	PGMK-30/	Protein	Polvorotein
Position	16562	FRhL-3 16562	FRhL-3	Position	Position
550	C	T	Ala	Ala	prM-38	152
1521	C/T	C	Ser/Leua	Ser	E-196	476
1813	G	A	Lys	Lys	E-293	573
1838	A	G	Ser	Gly	E-302	582
1913	G	A	Glu	Lys	E-327	617
2140	C	T	Ala	Ala	E-402	682
3725	T	C	Phe	Leu	NS2A-86	1211
4781	C	A	Gin	Lys	NS3-90	1563

Two significant genetic variants were located at nt-1521

2018200081 04 Jan 2018

Table 5

Summary Of Nucleotide And Amino Acid Differences Between The Genomes Of DEN-4 1036 Virus And Its Vaccine Derivative, Strain PDK-48

Genome

Nucleotide	Nucleotide	Amino Acid	Protein	Polyprotein
Position	1036	PDK-48	1036	PDK-48	Position	Position
1211	T	C	lie	He	E-91	370
1971	G	A	Glu	Lys	E-345	624
3182	G	C	Gin	His	NS 1-253	1027
6660	C	T	Leu	Phe	NS4A-95	2187
6957	A	A/T	lie	Ile/Phe	NS4B-44	2286
7162	T	c	Leu	Ser	NS4B-112	2354
7546	C	C/T	Ala	Ala/Val	NS4B-240	2366
7623	G	T/G	Asp	Tyr/Asp	NS5-21	2508

2018200081 04 Jan 2018

Table 6

Summary Of Non-Silent Mutations Between The Genomes Of The Parent Vaccine Strains Of DEN-1, DEN-2, DEN-3, And DEN-4 Viruses

Genome

Nucleotide

Position	DEN-1 DEN-2	DEN-3	DEN-4
57	5'NC-57	c-t
524	prM-29	D-V
1323	E-130 V-A
1521		E-196 S/L-S
1541)	E-203 E-K
1543)
1545	E-204 R-K
1608	E-225 S-L
1838		E-302 S-G
1913		E-327 E-K
1971			E-345 E-K
2363	E-477 M-V
2579	NS1-53 <	G-D
3182			NS1-253 Q-H
3725		NS2A-86 F-L
4018	NS2A-181 L-F
4781		NS3-90 Q-K
5063	NS3-182 E-K
5270	NS3-250	E-V/E
6048	NS3-510 Y-F
6599	NS4A-75	G-A
6660			NS4A-95 L-F
6806	NS4A-144 M-V
6957			NS4B-44 I-I/F
7162			NS4B-112 L-S
7546			NS4B-240 A-A/V
7623			NS5-21 D-D/Y

2018200081 04 Jan 2018

Table 7

Immunogenicity of viruses in mice.

Plaque reduction-neutralization titer^a against DEN-1 16007 virus

Experiment lb Primary	Boost	Experiment 2b Primary	Boost
Immunizing Pooled sera virus (Range)	Pooled sera (Range)	Pooled sera (Range)	Pooled sera (Range)

DEN-1 16007	80 (20 - 80)	2560 (80 - 20480)	80 (20 - 160)	2560(160-5120)
D2/1-PP	80	5120	40 (10 - 160)	5120(160-10240)
D2/1-EP	80 (20 - 320)	10240 (640 - 20480)	160 (20 - 320)	5120 (256010240)
D2/1-VP	40(10- 160)	2560(160-5120)	80 (10 - 320)	5120(40-^10240)
DEN-1 PDK-13	10(10-40)	80	40 (20 - 80)	320 (20 - 640)
D2/1-PV	10(<10d-20)	80	40 (10 - 80)	2560(20 - >10240)
D2/1-EV	20 (<10d-20)	80	40 (<10d-40)	160 (10 - 320)
D2/1-W	10(10-40)	80	40(10- 160)	160 (20 - 640)

^a Titers are the reciprocal dilution yielding at least 50% plaque reduction. ^b 3-week-old outbred ICR mice were immunized intraperitoneally with 10⁴PFU of virus, and were boosted with the same virus dose 3 weeks later in experiment 1, or 6 weeks later in experiment 2. Primary = serum taken 20 days (experiment 1) or 41 days (experiment 2) after primary immunization. Boost = serum, taken 21 days after boost in both experiments.

^c Individual titers were not determined.

^d Only one mouse serum titer was less than 10 in these groups.

^e Bold titers indicate the pooled sera titers were 4 fold higher than the titers calculatedwith 70% plaque reduction. All other pooled titers were either no different from or two fold higher than 70% plaque reduction titers.

2018200081 04 Jan 2018

Table 8

Neutralization of chimeric DEN viruses by standard antibodies

Antibody

Virus	Dl-AFa	D2-AFa	D2-H5”	D3-AFa	D3-8Alb	D4-AFa
DEN-1 16007c	1280d	40	20	40	<20	20
DEN-2/1-EP®	2560	9	9	9	5	9
DEN-2 16681c	80	2560>	40960	40	<20	40
DEN-3 16562c	80	160	40	1280	5120	40
DEN-2/3-EP16	9	9	9	2560	20480	9
DEN-4 1036c	20	40	<20	80	<20	1280
DEN-2/4-EP16	5	9	9	9	9	2560

^a AF = DEN-1 (DI), DEN-2 (D2), DEN-3 (D3), and DEN-4 (D4) virus-specific mouse ascitic fluids (polyvalent antisera).

^b DEN-2 and DEN-3 virus-specific, envelope glycoprotein-specific (E-specific) monoclonal antibodies D2-H5 and D3-8A1, respectively. ^c Wild-type DEN virus.

^d Reciprocal serum dilution-plaque reduction neutralization titers (50% endpoint) are shown;

; = not tested ^e Chimeric DEN-2/1-EP, DEN-2/3-EP1, or DEN-2/4-EP1 virus expressing structural genes of DEN-1 16007, DEN-3 16562, or DEN-4 1036 virus, respectively.

2018200081 04 Jan 2018

Table 9

Neuro virulence of chimeric DEN-2/3 and DEN-2/4 viruses in newborn

white ICR mice
Challenge Virus3	Percent Mortalitv b	AST (SD) (davs)6
DEN-3 16562d	100.0	14.1 (2.1)
DEN-3 P30/FRhl-3e	15.0	16.2 (3.2)
DEN-2/3-PPlf	32.5	19.0 (2.1)
DEN-2/3-EPlf	0.0	-
DEN-2/3-VPlf	0.0	-
DEN-4 1036d	100.0	8.6 (0.6)
DEN-4 PDK-486	100.0	10.7 (1.5)
DEN-2/4-PPlf	62.5	17.8 (2.8)
DEN-2/4-EPlf	0.0	-
DEN-2/4-VPlf	0.0	-
DEN-2 16681d	87.5	15.2 (2.6)
DEN-2 PDK53-E486	0.0	-
DEN-2 PDK53-V486	0.0	-
Diluent	0.0	.

³ Newborn mice were challenged intracranially with 10^{4 *} PFU of virus.

^b {Number of fatalities / total number (n=16) of mice challenged} x 100.

⁶ Average survival time (AST) and standard deviation (SD); - = not applicable, becausE there were no fatalities in this group. ^d Wild-type DEN serotype virus ^e Mahidol candidate DEN vaccine virus: DEN-3 = PGMK-30/FRhL-3 (P30/FRhL-3); DEN-4 =-- PDK-48; DEN-2 = PDK-53-E variant (NS3-250-Glu locus) and PDK-53-V variant (NS3-250-Val locus). Both PDK-53-E and -V variant viruses were derived from infectious cDNA clones of the variants.

^f Chimeric DEN-2/3 or DEN-2/4 virus. The prM/E gene region of DEN-3 16562 virus or DEN-4 1036 virus was expressed in the genetic background of wild-type DEN-2 16681 virus (PP1 viruses), Mahidol candidate vaccine DEN-2 PDK-53-E variant (EPI viruses), or Mahidol candidate vaccine DEN-2 PDK-53-V variant (VP1 viruses).

2018200081 04 Jan 2018

Table 10

Protective efficacy of chimeric DEN-2/1 viruses in AG-129 mice³

Reciprocal neutralizing antibody titer against appropriate homologous DEN-3 or DEN4 virus at 4 or 6 weeks after immunization

Immunizing Virus	4 weeks	6 weeks
DEN-3 16562b	320c	640
DEN-3 P30/FRhL-3d	160	320
DEN-2/3-EPle	80	320
DEN-4 1036b	160	1280
DEN-4 PDK-48d	80	320
DEN-2/4-EP16	20	40

^a AG-129 mice are an inbred strain that lack receptors for interferon alpha/beta and interferon gamma. Mice, 3.5-4.5 weeks in age, were immunized intraperitoneally with 10^s PFU of virus.

^b Wild-type DEN virus.

^c Reciprocal dilution of pooled serum that neutralized 70% or greater of the input wildtype DEN-3 16562 virus that was used to test sera from mice immunized with DEN-3 or chimeric DEN-2/3-EP1 virus, or the input wild-type DEN-4 1036 virus that was used to test sera from mice immunized with DEN-4 or chimeric DEN-2/4-EP1 virus.

^d Mahidol candidate vaccine virus, DEN-3 PGMK-30/FRhL-3 (P30/FRhL-3), DEN-4 PD-48.

^e Chimeric DEN-2/3-EP1 or DEN-2/4-EP1 expressing the prM/E gene region of DEN-3 16562 or DEN-4 1036 virus, respectively.

2018200081 04 Jan 2018

Table 11

Genotypes of recombinant DEN-2 16681/PDK-53 viruses

Clone-derived

virus (cognate)1*	5’NC-57	prM-29	NS1-53	NS2A-181	NS3-250	NS4A-75
DEN-2 PDK-53	t	V	D	F	V	A
W45R (V513)
P5 (VI3)	c
Pl (V53)			G
P3 (V51)	.				E
P51 (V3)	c		G
P53 (VI)	c				E
P13 (V5)			G		E
P513 (30P-A)	c		G		E
	Densue-2 PDK-53 determinants in 16681 background”
	5'NC-57	nrM-29	NS1-53	NS2A-181	NS3-250	NS4A-75
DEN-2 16681	c	D	G	L	E	G
30P-A (P513)
V5 (Pl3)	t
VI (P53)			D
V3 (P51)					V
V51 (P3)	t		D
V53 (Pl)	t				V
V13 (P5)			D		V
V513 (VV45R)	t		D		V

^a The genome of the candidate dengue-2 PDK-53 vaccine virus differs from that of its 16681 parent at nine nucleotide loci, including three silent mutations (not shown), a mutation at genome nucleotide position 57 in the 5' noncoding region (5'NC-57; lower case letters), and five nucleotides encoding amino acid mutations (upper case, single-letter abbreviations) at viral polypeptide positions premembrane (prM)-29, nonstructural protein 1 (NSl)-53, NS2A-181, NS3-250, andNS4A-75 (32). Genetic loci from the parental 16681 viras were engineered into the cDNA background of the PDK-53 virus-specific infectious clone, pD2/IC-W45R. Dots indicate sequence identity with PDK-53 virus (NS3-250-Val variant). The candidate PDK-53 vaccine also contains a genetic variant that has Glu at NS3-250 (32).

^b The genotypes of wild-type DEN-2 16681 virus, its attenuated vaccine derivative, DEN-2 PDK-53 virus, infectious clone-derived VV45R (genetically equivalent to the PDK-53 NS3-250- Val variant) and 30P-A (equivalent to wild-type 16681 ) viruses, and recombinant 16681/PDK-53 viruses are shown. The numerical designations for recombinant Px and Vx viruses (where x = _5'NC, NS1, and/or NS3 loci) indicate parental (P in virus designation) 16681 virus-specific loci engineered into the PDK-53 virusspecific infectious cDNA clone (top series) or reciprocal candidate PDK-53 vaccine (V in virus designation) virus-specific loci engineered into the 16681 clone (bottom series), respectively. P5 and VI3 are cognate viruses, assuming that the PDK-53 virus-specific phenotype is determined predominantly by the 5'NC-57, NS 1-53, and NS3-250 loci. Both P5 and V13 viruses contain the 5'NC57-c, NSl-53-Asp, and NS3-250- Val loci within the genetic backgrounds of PDK-53 and 16681 viruses, respectively.

^c Genetic loci from PDK-53 virus were engineered into the cDNA background of the 16681 virusspecific infectious clone, pD2/IC-30P-A. Dots indicate sequence identity with 16681 virus.

2018200081 04 Jan 2018

Table 12

Neuro virulence of DEN-2 16681, PDK-53, and recombinant 16681/PDK-53 viruses in newborn white ICR mice

Mouse challenge¹¹

Virus genotvpe^b

Mortality AST (SD) 5'-NC prM

NS1 NS2A NS3 NS4A

Virus (cognateT	(%)
DEN-2 16681	68.75
30P-A (P513)	81.25
P513 (16681)	100.0
P51 (V3)	50.0d
Pl (V53)	37.5d
P13 (V5)	37.5d
P53 (VI)	20.0d
P5p (VI3)	6.25
P5 (V13)	6.25
Pp (PDK-53)	0
P3 (V51)	0
V3 (P51)	75.0d
Vp (16681)	87.5
V53 (Pl)	18.75d
V5 (P13)	18.75d
V5p (Pl3)	6.25
V13 (P5)	6.25
VI (P53)	6.25
V51 (P3)	0
V513 (PDK-53)	0
VV45R (V513)	0
DEN-2 PDK-53	0

(days) 57_29

15.2(1.2) c D

14.6 (2.3) .

13.2(1.6) . V

15.9 (5.5) . V

19.0 (4.2) t V

13.5(2.1) t V

17.0 (7.8) . V

15.0

27.0 . V t

t V

16.4 (3.2) .

17.0 (0.9) . V

21.3 (6.1) t

21.7 (4.2) t

20.0 t V

17.0 22.0 t

t t V t V

53	181	250	75
G	L	E	G
	F		A
	F	V	A
	F	V	A
	F		A
D	F		A
D	F	V	A
D	F	V	A
D	F	V	A
D	F	V	A
		V
D		V
D
D
D		V
D	F	V	A
D	F	V	A

^a Percent mortality and average survival time (AST) ± standard deviation (SD) of newborn, outbred white ICR mice challenged intracranially with 10⁴ PFU of virus. Sixteen mice per group, except for the P53 and Vp groups in which a single mouse died by day 1 after infection, presumably as a result of inoculation trauma. These two mice were excluded from the study.

^b See text for explanation of virus genotypes. Solid dots indicate sequence identity with 16681 virus. ^c See text for explanation of virus and cognate virus designations. ^d Mean body weight of surviving mice was significantly lower (p < 0.001, Student’s t test) than that of diluent-inoculated control mice (not shown) at 3 weeks after infection. ^e Average survival time is not applicable because there was no mortality in this mouse group.

2018200081 04 Jan 2018

Table 13

Evolution of DEN-2 virus, vaccine strain PDK-53, during passage of the parental 16681 strain in primary dog kidney (PDK) cells

Genome nucleotide position” / Translated polypeptide position^b / Encoded amino acids”

Virus	57“	524 prM-29b D-V”	2055 E-373 F-F	2579 NS1-53 G-D	4018 NS2A-181 L-F	5270 NS3-250 E-V	5547 NS3-342 R-R	6599 NS4A-75 G-A	8571 NS5-334 V-V
16681	Cd	A	C	G	C	A	T	G	C
PDK-5	c	A	C/T=	G	T/C	A	T/C	G	C/T
PDK-10	c	A	T/C	G	T	A	C/T	G	T/C
PDK-14	c	A	T	G	T	A	c	G	T/C
PDK-35	T	T/A	T	A/G	T	A	c	C/G	T
PDK-45	T	T	T	A	T	A/T	c	C	T
PDK-53	T	T	T	A	T	A/T	c	c	T ·

” Genome nucleotide positions of the nine nucleotide sequence differences between 16681 and PDK-53 viruses. Nucleotide position 57 lies within the 5' noncoding region of the viral genome. ^b Protein designations are as follows: prM = premembrane protein; E = envelope glycoprotein; NS = nonstructural protein.

^c The virus-specific amino acid residues (16681 - PDK-53) are shown for each amino acid position. ^d A, C, G, and T (cDNA sense) nucleotides are indicated.

^e Two genetic populations were identified for this locus in the virus. The order of the two nucleotides reflects relative peak heights of the nucleotide signals in sequence chromatograms.

2018200081 04 Jan 2018

Table 14

Conservation of DEN-2 PDK-53 phenotypic attenuation markers in chimeric DEN viruses.

Attenuation phenotype

Attenuation in mice '

DEN virus

DEN-2^a DEN-2/1 DEN-2/3 DEN-2/4

Decreased replication in C6/36 cells +

Small plaques in LLC-MK₂ cells +

Temperature sensitivity in LLC-MK₂ cells + +

+ +

+ +

+ +

+ +

+ +

+ ^a Mahidol candidate DEN-2 PDK-53 vaccine virus. The chimeric DEN-2/1, DEN2/3,and DEN-24 viruses were constructed in the DEN-2 PDK-53 genetic background, NS3-250-Val or -Glu variant. The phenotypes shown for chimeric viruses are representative of chimeric viruses constructed in the background of either variant of DEN-2 PDK-53 virus.

2018200081 04 Jan 2018

Table 15

Diagnostic Genetic Probes and Amplimers for the Candidate Mahidol DEN-1, DEN-2, DEN-3, and DEN-4 Vaccine Viruses.

Genetic Locus: DI V-1323 = Mutated genetic locus for candidate DEN-1 PDK-13 vaccine (V) virus at genome nucleotide position 1323.

Primer designations: p = TaqMan probe sequence, mRNA-sense pc = TaqMan probe sequence, complementary-sense f = forward amplimer, mRNA-sense r = reverse amplimer, complementary-sense SEQ ID = probe or primer sequence.

Genetic Locus	Primer Designation	SEQ ID F
D1V-1323
Probe	pcDlV-1308	44
F	fDlV-1298	45
R	rDlV-1347	46
D1V-1541, 1543, 1545
Probe	pcDlV-1530	47
F	fDlV-1519	48
R	rDlV-1567	43
D1V-1567
Probe	pDlV-1580	50
F	fD IV-1545	51
R	rDlV-1608	52
D1V-1608
Probe	pcDlV-1595	53
F	fD 1V-1567	54
R	rDlV-1626	55
D1V-2363
Probe	pDlV-2374	56
F	fDlV-2334	57
R	rDlV-2386	58
D1V-2695
Probe	pcDlV-2686	59
F	fDlV-2660	60
R	rDlV-2735	61
D1V-2782
Probe	pDlV-2767	62
F	fDlV-2752	63
R	rDlV-2801	64

2018200081 04 Jan 2018

Tablel5 (continued)

Diagnostic Genetic Probes and Amplimers for the Candidate Mahidol DEN-1, DEN-2, DEN-3, and DEN-4 Vaccine Viruses.

Genetic Locus	Primer Designation	SEO ID NO:
D1V-5063
Probe	pcDlV-5052	65
F	fDlV-5040	66
R	rDlV-5095	67
D1V-6048
Probe	pDlV-6059	68
F	fDlV-6030	69
R	rDlV-6069	70
D1V-6806
Probe	pcDlV-6793	71
F	fDlV-6780	72
R	rDlV-6825	73
D1V-7330
Probe	pDlV-7343	74
F	fDlV-7310	75
R	rDlV-7351	76
D1V-9445
Probe	pcDlV-9433	77
F	fDlV-9419	78
R	rDlV-9485	79
D2V-57
Probe	pD2V-69	80
F	fD2V-32	81
R	rD2V-81	82
D2V-524
Probe	pcD2V-513	83
F	fD2V-492	84
R	rD2V-551	85
D2V-2055
Probe	pD2V-2067	86
F	fD2V-2025	87
R	rD2V-2080	88
D2V-2579
Probe	pcD2V-2568	89
F	fD2V-2535	90
R	rD2V-2603	91

2018200081 04 Jan 2018

Tablel5 (continued)

Diagnostic Genetic Probes and Amplimers for the Candidate Mahidol DEN-1, DEN-2, DEN-3, and DEN-4 Vaccine Viruses.

Genetic Locus	Primer Designation	SEO ID NO:
D2V-4018
Probe	pD2V-4030	92
F	fD2V-3993	93
R	rD2V-4043	94
D2V-5270-E
D2V-5270-V
ProbeE	pD2VE-5279	95
ProbeV	pD2VV-5279	96
F	fD2V-5243	97
R	rD2V-5295	98
D2V-5547
Probe	pD2V-5558	99
F	fD2V-5521	100
R	rD2V-5589	101
D2V-6599
Probe	pcD2V-6588	102
F	fD2V-6569	103
R	rD2V-6625	104
D2V-8571
Probe	pD2V-8582	105
F	fD2V-8535	106
R	rD2V-8594	107
D3V-550
Probe	pD3V-562	108
F	fD3V-525	109
R	rD3V-575	110
D3V-1521
Probe	pD3V-1533	111
F	fD3V-1497	112
R	rD3V-1541	113
D3V-1813
Probe	pcD3V-1804	114
F	fD3V-1767	115
R	rD3V-1838	116
D3V-1838
Probe	pcD3V-1827	117
F	fD3V-1813	118
R	rD3V-1913	119

2018200081 04 Jan 2018

Tablel5 (continued)

Diagnostic Genetic Probes and Amplimers for the Candidate Mahidol DEN-1, DEN-2, DEN-3, and DEN-4 Vaccine Viruses.

Genetic Locus	Primer Designation	SEO ID NO:
D3V-1913
Probe	pcD3V-1903	120
F	£D3V-1891	121
R	rD3V-1967	122
D3V-2140
Probe	pcD3V-2127	123
F	fD3V-2116	124
R	rD3V-2188	125
D3V-3725
Probe	pD3V-3738	126
F	fD3V-3698	127
R	rD3V-3745	128
D3V-4781
Probe	pcD3V-4772	129
F	£D3V-4762	130
R	rD3V-4801	131
D4V-1211 (T-C)
Probe	pD4V-1222	132
F	fD4V-1191	133
R	rD4V-1250	134
D4V-1971 (G-A)
Probe	pcD4V-1957	135
F	fD4V-1943	136
R	rD4V-2010	137
D4V-3182 (G-C)
Probe	pD4V-3193	138
F	fD4V-3154	139
R	rD4V-3227	140
D4V-6660 (C-T)
Probe	pcD4V-6648	141
F	fD4V-6638	142
R	rD4V-6688	143
D4V-7162 (T-C)
Probe	pD4V-7174	144
F	fD4V-7141	145
R	rD4V-7188	146

2018200081 04 Jan 2018

Table 16

SEQ ID NO: for TaqMan probes and amplimers.

Underlined residues indicate the positions of the candidate vaccine virus mutation within the primer sequence, or, in the case of SEQID #52, the underlined residue indicates the nt-5270 position of DEN-2 16681 virus.

SEQ ID NO:

5-TTCATATTGAGCTATCTTTCCTTCTA-3'

5'-GTGTGCCAAGTTTAAGTGTG-3'

5'-TGGACGGTGACTATCACTG-3'

5-AAGCCATGATTTCTTTTTCATTGTCA-3'

5'-CAGGGCTAGATTTTAACGAG-3'

5'-AGTGGTAAGTCTAGAAACCAC-3'

5'-TCCACAAACAGTGGTTTCTAGACT-3'

5'-TGTTGCTGACAATGAAAAAGAA-3’

5'-TCCAAGTCTCTTGGGATGTTA-3'

5'-TGGGATGTTAAAGCCCCAGAGGT-3'

5'-TCATGGCTTGTCCACAAACAG-3'

5'-CCAGTAAATCTTGTCTGTTCC-3'

5'-CGTCCCTTTCGGTGATGTGCATC-3'

5'-ATTCTGCTGACATGGCTAGG-3'

5'-TCCTAGGTACAGTGTGACC-3'

5'-AGATTCCACTAACGTCTCCCACG-3'

5--AATTGAACCACATCCTACTTG-3’

5'-TTGTGTTCCATGGGTTGTGG-3'

5'-TATGATTTTAGCTTTTCCCCAGCTT-3'

5-GCCACAACCCATGGAACAC-3'

5'-ATGAAGGTGGTGTTCTGTAC-3'

5'-TCCTAAACACCTTGTCCTCAATCT-3'

5'-GCTAAGGCATCACAAGAAGG-3'

5'-CGATCCTGGATGTAGGTCC-3'

5'-CAGCCCTCTTTGAGCCGGAGA-3'

5'-AATATAAACACACCAGAAGG-3'

5'-TCCCCGTCTATAGCTGCAC-3'

5'-TGTCAATATCACGAATAACAGACCT-3’

5'-CACAGGACAACCAGCTAGC-3'

5'-AATAATCCCATCTCATTGG-3'

5'-ATTTGAAAAACAGCTAGGCCAAATAA-3'

5'-CTTAGATCCCGTGGTTTACG-3'

5'-AATCTGTGATGTGCAAAGTATC-3'

5'-AAAGATTCCCTCAGACTCCATTTGT-3'

5'-CACTTTCACCAACATGGAGG-3'

2018200081 04 Jan 2018

Table 16 (continued)

SEQ ID NO: for TaqMan probes and amplimers.

5'-CGAGAACTCTTCCGGCTAG-3'

5'-AGCTAAGCTCAATGTAGTCTAACA-3'

5'-CGTGGACCGACAAAGACAG-3'

5'-TCATCAGAGATCTGCTCTCT-3'

5'-ATGTTCACGCCAACCTCTGTTTTA-3'

5'-GATCGTCAGCAGACAAGAG-3'

5'-CAATTCACCAAGGTCCATGG-3'

5'-AACCTCCATTTGGAGACAGCTAC-3’

5'-AATTGTGACAGAAAAAGATAGC-3'

5'-TCAGTTGTCCCGGCTCTAC-3'

5'-ATTCCACAAATGTCCTCTTCATGG-3'

5'-TACAAGTTCCAACCAGAATCC-3'

5'-CATCAGATTCTCCAGTCTTG-3

5'-TTTCCCCACTGTTCTTAACATCCT-3'

5'-GAAAGTGAGTTGCACAATATTG-3'

5’-ATGCTAATGGTATCCAATCTG-3’

5'-CATCAGAGCTGAGCACACCGG-3'

5'-CATCAGAGCTGTGCACACCGG-3'

5'-CCTTAGAGGACTTCCAATAAG-3'

5-AATGTGGCATGACACATTAGG-3'

5'-ATCCCTGAACGCTCGTGGAATTC-3'

100 5'-AGAGCAATGCACCAATCATAG-3'

101 5'-GAACGAACCAAACAGTCTTC-3’

102 5'-TATGCCCCTTGCGCTCATCAAG-3'

103 5-CACTTCTGGCTACAGTCAC-3'

104 5'-GTGATTATGCAGCACATTCC-3'

105 5-CTTGGGACGTTGTCCCCATGGT-3'

106 5'-CAGCATCATCCATGGTCAAC-3'

107 5-GGAGTCGTGTCTGTCATTG-3'

108 5-CACTCATAGCTATGGATCTGGGA-3'

109 5'-CTTTTCAAGACAGCCTCTGG-3'

110 5’-CATTTGTAAGTGACCGTGTC-3'

111 5-CAATGAAATGATCTCATTGACAATGAA-3

112 5'-AATGCTCACCACGGACAGG-3'

113 5-TTGTCTATGTACCATCCATGC-3'

114 5'-CATAGCTCATCCCTTTGAGTTCC-3'

115 5'-GAGGCACAAGTATCTTTGC-3'

116 5'-TTTCTTCAACACAAAGCTACC-3'

117 5'-ACACAAAGCTACCCAAGCACATTG-3'

118 5'-GATGGACAAATTGGAACTCAAA-3'

119 5'-ATCTTGCAGGGTGCATCTTT-3'

2018200081 04 Jan 2018

Table 16 (continued)

SEQ ID NO: for TaqMan probes and amplimers.

120 5'-AGGGTGCATCTTTCCCTTTGTAC-3'

121 5'-GCAGCATGGGACAATACTC-3'

122 5'-GTGATCAGTCTGCCATTGTG-3'

123 5'-CCTCTGGCAGTAGCCTCGAACATCT-3'

124 5'-ACTGGTACAAGAAGGGAAGC-3’

125 5'-ACCCACTGATCCAAAGTCC-3'

126 5'-TCAGCCACTCCTGGCTTTGGG-3'

127 5'-GGCGTCACTTACCTAGCTC-3'

128 5'-TAGATGTCAGTTTCCTCAGG-3'

129 5'-CCTCCCCCTTTTTCCATTGTGC-3'

130 5'-TTTCATACGGAGGAGGATGG-3'

131 5'-AGGCTCTACGGCAATAACC-3'

132 5'-CAACAGTACATCTGCCGGAGAGA-3'

133 5'-GAGAGCCTTATCTAAAAGAGG-3'

134 5’-CTTTTCCAAACAAGCCACAG

135 5'-AACCACTTTTTTCTTGTTCACATCTC

136 5'-TGGAGCTCCGTGTAAAGTC-3'

137 5'-GCACTGTTGGTATTCTCAGC-3'

8 5'-CCCTTTTTCAC ACC ACAATTACCG-3'

139 5'-GAAAGCCAGATGCTCATTCC-3'

140 5'-TATCTCTAATTTGCCTAAGTGC-3’

141 5’-CTACCCAGAACAAGCCACTAGC-3’

142 5-ATTGTCAATGGGTTTGATAACC-3'

143 5'-TATGATTGAGGCCGCTATCC-3'

144 5-TAGTCATGCTTTCAGTCCATTATGC-3'

145 5'-AGTGAACCCAACAACTTTGAC-3'

146 5-TGGCTTTTGCCTGCAATCC-3'

2018200081 04 Jan 2018

Claims (59)

1. We claim:

   1. A nucleic acid chimera comprising a first nucleotide sequence encoding nonstructural proteins from an attenuated dengue-2 virus and a second nucleotide sequence encoding a structural protein from a second flavivirus.
2. 2. The nucleic acid chimera of claim 1, wherein the attenuated dengue-2 virus is vaccine strain PDK-53.
3. 3. The nucleic acid chimera of claim 2, wherein the structural protein is selected from the group consisting of a C protein of dengue-1 virus, a prM protein of dengue-1 virus, an E protein of dengue-1 virus or any combination thereof.
4. 4. The nucleic acid chimera of claim 2, wherein the structural protein is selected from the group consisting of a C protein of dengue-2 virus, a prM protein of dengue-2 virus, an E protein of dengue-2 virus or any combination thereof.
5. 5. The nucleic acid chimera of claim 2, wherein the structural protein is selected from the group consisting of a C protein of dengue-3 virus, a prM protein of dengue-3 virus, an E protein of dengue-3 virus or any combination thereof.
6. 6. The nucleic acid chimera of claim 5, wherein the structural protein is an E protein of dengue-3 virus and the E protein contains a leucine at amino acid position 345.
7. 7. The nucleic acid chimera of claim 2, wherein the structural protein is selected from the group consisting of a C protein of dengue-4 virus, a prM protein of dengue-4 virus, an E protein of dengue-4 virus or any combination thereof.

   2018200081 04 Jan 2018
8. 8. The nucleic acid chimera of claim 7, wherein the structural protein is an E protein of dengue-4 virus and the E protein contains a leucine at amino acid position 447, and further comprises a C protein of dengue-2 virus and the C protein contains a serine at position 100.
9. 9. The nucleic acid chimera of claim 8, further comprising a valine at position 364 of the E protein.
10. 10. The nucleic acid chimera of claim 2, wherein the structural protein is selected from the group consisting of a C protein of West Nile virus, a prM protein of West Nile virus, an E protein of West Nile virus or any combination thereof.
11. 11. The nucleic acid chimera of claim 2, wherein the structural protein is selected from the group consisting of a C protein of Japanese encephalitis virus, a prM protein of Japanese encephalitis virus, an E protein of Japanese encephalitis virus or any combination thereof.
12. 12. The nucleic acid chimera of claim 2, wherein the structural protein is selected from the group consisting of a C protein of St. Louis encephalitis virus, a prM protein of St. Louis encephalitis virus, an E protein of St. Louis encephalitis virus or any combination thereof.
13. 13. The nucleic acid chimera of claim 2, wherein the structural protein is selected from the group consisting of a C protein of tick-home encephalitis vims, a prM protein of tick-bome encephalitis vims, an E protein of tick-bome encephalitis vims or any combination thereof.
14. 14. The nucleic acid chimera of claim 2, wherein the structural protein is selected from the group consisting of a C protein of yellow fever vims, a prM protein of yellow fever vims, an E protein of yellow fever vims or any combination thereof.

    2018200081 04 Jan 2018
15. 15. The nucleic acid chimera of claim 2, wherein the second flavivirus is a virulent strain.
16. 16. The nucleic acid chimera of claim 15, wherein the structural protein is selected from the group consisting of a C protein of dengue-1 virus, a prM protein of dengue-1 virus, an E protein of dengue-1 virus or any combination thereof.
17. 17. The nucleic acid chimera of claim 15, wherein the structural protein is selected from the group consisting of a C protein of dengue-2 virus, a prM protein of dengue-2 virus, an E protein of dengue-2 virus or any combination thereof.
18. 18. The nucleic acid chimera of claim 15, wherein the structural protein is selected from the group consisting of a C protein of dengue-3 virus, a prM protein of dengue-3 virus, an E protein of dengue-3 virus or any combination thereof.
19. 19. The nucleic acid chimera of claim 18, wherein the structural protein is an E protein of dengue-3 virus and the E protein contains a leucine at position 345.
20. 20. The nucleic acid chimera of claim 15, wherein the structural protein is selected from the group consisting of a C protein of dengue-4 virus, a prM protein of dengue-4 virus, an E protein of dengue-4 virus or any combination thereof.
21. 21. The nucleic acid chimera of claim 20, wherein the structural protein is an E protein of dengue-4 virus and the E protein contains a leucine at amino acid position 447, and further comprises a C protein of dengue-2 virus and the C protein contains a serine at position 100.
22. 22. The nucleic acid chimera of claim 21, further comprising a valine at position 364 of the E protein.

    2018200081 04 Jan 2018
23. 23. The nucleic acid chimera of claim 15, wherein the structural protein is selected from the group consisting of a C protein of West Nile virus, a prM protein of West Nile virus, an E protein of West Nile virus or any combination thereof.
24. 24. The nucleic acid chimera of claim 15, wherein the structural protein is selected from the group consisting of a C protein of Japanese encephalitis virus, a prM protein of Japanese encephalitis virus, an E protein of Japanese encephalitis virus or any combination thereof.
25. 25. The nucleic acid chimera of claim 15, wherein the structural protein is selected from the group consisting of a C protein of St. Louis encephalitis virus, a prM protein of St. Louis encephalitis virus, an E protein of St; Louis encephalitis virus or any combination thereof.
26. 26. The nucleic acid chimera of claim 15, wherein the structural protein is selected from the group consisting of a C protein of tick-borne encephalitis virus, a prM protein of tick-borne encephalitis virus, an E protein of tick-bome encephalitis virus or any combination thereof.
27. 27. The nucleic acid chimera of claim 15, wherein the structural protein is selected from the group consisting of a C protein of yellow fever virus, a prM protein of yellow fever virus, an E protein of yellow fever virus or any combination thereof.
28. 28. A nucleic acid chimera comprising a first nucleotide sequence encoding nonstructural proteins from an attenuated dengue-2 virus, and at least two different nucleotide sequences, each encoding a structural protein from at least two different flaviviruses.
29. 29. The nucleic acid of claim 28, wherein the attenuated dengue-2 virus is vaccine strain PDK-53.

    2018200081 04 Jan 2018
30. 30. The nucleic acid chimera of claim 28, wherein the structural protein is selected from the group consisting of a C protein of dengue-1 virus, a C protein of dengue-2 virus, a C protein of dengue-3 virus, a C protein of dengue-4 virus, a prM protein of dengue-1 virus, a prM protein of dengue-2 virus, a prM protein of dengue-3 virus, a prM protein of dengue-4 virus, an E protein of dengue-1 virus, an E protein of dengue-2 virus, an E protein of dengue-3 virus, an E protein of dengue-3 virus containing a leucine at amino acid position 345, an E protein of dengue-4 virus, an E protein of dengue-4 virus containing a leucine at amino acid position 447, an E protein of dengue4 virus containing a leucine at amino acid position 447 and a valine at amino acid position 364, a C protein of dengue-2 virus containing a serine at amino acid position 100 or any combination thereof.
31. 31. The nucleic acid chimera of claim 28, wherein the at least two different flaviviruses are selected from the group consisting of the dengue-1 virus, dengue-2 virus, dengue-3 virus, dengue-4 virus, West Nile virus, Japanese encephalitis virus, St. Louis encephalitis virus,tick-borne encephalitis virus, yellow fever virus or any combination thereof.
32. 32. A composition comprising one or more than one nucleic acid chimera of claim 1 and a pharmaceutically acceptable carrier.
33. 33. The composition of claim 32, further comprising an immunizing composition selected from the group consisting of a dengue virus vaccine, a yellow fever virus vaccine, a tick-bome encephalitis virus vaccine, a Japanese encephalitis virus vaccine, a West Nile virus vaccine, a hepatitis C virus vaccine or any combination thereof.
34. 34. A composition comprising one or more than one nucleic acid chimera of claim 28 and a pharmaceutically acceptable carrier.

    2018200081 04 Jan 2018
35. 35. The composition of claim 34, further comprising an immunizing composition selected from the group consisting of a dengue virus vaccine, a yellow fever virus vaccine, a tick-home encephalitis vims vaccine, a Japanese encephalitis vims vaccine, a West Nile vims vaccine, a hepatitis C vims vaccine or any combination thereof.
36. 36. A method of inducing an immune response in a subject comprising administering an effective amount of the composition of claim 32 to the subject.
37. 37. A method of inducing an immune response in a subject comprising administering an effective amount of the composition of claim 33 to the subject.
38. 38. A method of inducing an immune response in a subject comprising administering an effective amount of the composition of claim 34 to the subject.
39. 39. A method of inducing an immune response in'a subject comprising administering an effective amount of the composition of claim 35 to the subject.
40. 40. An isolated nucleic acid consisting essentially of a nucleotide sequence of a genome of a dengue-2 virus, wherein the nucleotide sequence contains a mutation at position 2579 which results in the presence of an aspartate at amino acid residue 53 of the NS1 protein.
41. 41. The nucleic acid of claim 40, wherein the nucleotide sequence further contains a mutation at position 57 which disrupts the function of the 5' noncoding region.
42. 42. The nucleic acid of claim 40, wherein the nucleotide sequence further contains a mutation at position 5270 which results in the presence of a valine at amino acid residue 250 of the NS3 protein.

    2018200081 04 Jan 2018
43. 43. The nucleic acid of claim 42, wherein the nucleotide sequence further contains a mutation at position 57 which disrupts the function of the 5' noncoding region.
44. 44. A nucleic acid chimera comprising the nucleotide sequence of claim 40 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-1 virus, a prM protein of dengue-1 virus, an E protein of dengue-1 virus or any combination thereof.
45. 45. A nucleic acid chimera comprising the nucleotide sequence of claim 40 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-2 virus, a prM protein of dengue-2 vims, an E protein of dengue-2 vims or any combination thereof.
46. 46. A nucleic acid chimera comprising the nucleotide sequence of claim 40 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-3 vims, a prM protein of dengue-3 vims, an E protein of dengue-3 vims or any combination thereof.
47. 47. A nucleic acid chimera comprising the nucleotide sequence of claim 40 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-4 vims, a prM protein of dengue-4 vims, an E protein of dengue-4 vims or any combination thereof.
48. 48. A nucleic acid chimera comprising the nucleotide sequence of claim 41 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-1 vims, a prM protein of dengue-1 vims, an E protein of dengue-1 vims or any combination thereof.

    2018200081 04 Jan 2018
49. 49. A nucleic acid chimera comprising the nucleotide sequence of claim 41 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-2 virus, a prM protein of dengue-2 virus, an E protein of dengue-2 virus or any combination thereof.
50. 50. A nucleic acid chimera comprising the nucleotide sequence of claim 41 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-3 virus, a prM protein of dengue-3 virus, an E protein of dengue-3 virus or any combination thereof.
51. 51. A nucleic acid chimera comprising the nucleotide sequence of claim 41 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-4 virus, a prM protein of dengue-4 virus, an E protein of dengue-4 virus or any combination thereof.
52. 52. A nucleic acid chimera comprising the nucleotide sequence of claim 42 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-1 virus, a prM protein of dengue-1 virus, an E protein of dengue-1 virus or any combination thereof.
53. 53. A nucleic acid chimera comprising the nucleotide sequence of claim 42 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-2 virus, a prM protein of dengue-2 virus, an E protein of dengue-2 virus or any combination thereof.
54. 54. A nucleic acid chimera comprising the nucleotide sequence of claim 42 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-3 virus, a prM protein of dengue-3 virus, an E protein of dengue-3 virus or any combination thereof.

    2018200081 04 Jan 2018
55. 55. A nucleic acid chimera comprising the nucleotide sequence of claim 42 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-4 virus, a prM protein of dengue-4 virus, an E protein of dengue-4 virus or any combination thereof.
56. 56. A nucleic acid chimera comprising the nucleotide sequence of claim 43 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-1 virus, a prM protein of dengue-1 virus, an E protein of dengue-1 virus or any combination thereof.
57. 57. A nucleic acid chimera comprising the nucleotide sequence of claim 43 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-2 virus, a prM protein of dengue-2 virus, an E protein of dengue-2 virus or any combination thereof.
58. 58. A nucleic acid chimera comprising the nucleotide sequence of claim 43 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-3 virus, a prM protein of dengue-3 virus, an E protein of dengue-3 virus or any combination thereof.
59. 59. A nucleic acid chimera comprising the nucleotide sequence of claim 43 and a nucleotide sequence encoding a flavivirus structural protein selected from the group consisting of a C protein of dengue-4 virus, a prM protein of dengue-4 virus, an E protein of dengue-4 virus or any combination thereof.

    1/4

    2018200081 04 Jan 2018

    2/4

    3/4

    2018200081 04 Jan 2018

    - οο β

    ο

    Ό XS Ο

    .«

    - Μ«

    - C4 iraZiUa^0ls°7

    4/4 ο

    (Μ §

    ω •ε xt §

    ω ο

    ο ο

    (Μ ο

    (Μ £>

    Pq

    Virus

    2018200081 04 Jan 2018

    SEQUENCE LISTING .

    <110> The Government of the United States of America, as represented by the Secretary, Department of Health and Human Services, Centers for Disease Control and Prevention <120> AVIRULENT, IMMUNOGENIC FLAVIVIRUS CHIMERAS <130> 14114.0334P1 <140> 60/182,829 <141> 2000-02-16 <160> 148 <170> FastSEQ for Windows Version 4.0 <210> 1 <211> 10735 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <221> CDS <222> (95) . . . (10273) <400> 1 agttgttagt ctacgtggac cgacaagaac agtttcgaat cggaagcttg cttaacgtag 60 ttctaacagt tttttattag agagcagatc tctg atg ate aac caa ega aaa aag 115

    Met lie Asn Gin Arg Lys Lys . 1 5

    aeg ggt Thr Gly ega Arg 10 ccg tet ttc Phe aat Asn atg Met 15 ctg Leu aaa Lys cgc gcg aga Arg 20 aac Asn cgc Arg gtg Val 163 Pro Ser Arg Ala tea act gtt tea cag ttg gcg aag aga ttc tea aaa gga ttg etc tea' 211 Ser Thr Val Ser Gin Leu Ala Lys Arg Phe Ser Lys Gly Leu Leu Ser 25 30 35 ggc caa gga ccc atg aaa ttg gtg atg get ttc ata gca ttc tta aga 259 Gly Gin Gly Pro Met Lys Leu Val Met Ala Phe He Ala Phe Leu Arg 40 45 50 55 ttt eta gcc ata ccc cca aca gca gga att ttg get aga tgg ggc tea 307 Phe Leu Ala He Pro Pro Thr Ala Gly lie Leu Ala Arg Trp Gly Ser 60 65 70

    2018200081 04 Jan 2018

    ttc aag aag aat gga gcg Gly Ala att aaa gtg tta egg ggt ttc Phe aag Lys 85 aga Arg gaa Glu 355 Phe Lys Lys Asn 75 lie Lys Val 80 Leu Arg Gly ate tea aac atg eta aac ata atg aac agg agg aaa aga tee gtg acc 403 lie Ser Asn Met Leu Asn lie Met Asn Arg Arg Lys Arg Ser Val Thr 90 95 100 atg etc ett atg ctg ctg ccc aca gee ctg gcg ttc cat ctg aeg aca 451 Met Leu Leu Met Leu Leu Pro Thr Ala Leu Ala Phe His Leu Thr Thr 105 110 115 ega ggg gga gag ccg cat atg ata gtt age aag cag gaa aga gga aag 499 Arg Gly Gly Glu Pro His Met He Val Ser Lys Gin Glu Arg Gly Lys 120 125 130 135 tea ett ttg ttc aag ace tet gca ggt gtc aac atg tgc acc etc att 547 Ser Leu Leu Phe Lys Thr Ser Ala Gly Val Asn Met Cys Thr Leu He 140 145 150 gcg atg gat ttg gga gag ttg tgt gag gac aeg atg acc tac aaa tgc 595 Ala Met Asp Leu Gly Glu Leu Cys Glu Asp Thr Met Thr Tyr Lys Cys 155 160 165 ccc egg ate act gag gcg gaa cca gat gac gtt gac tgt tgg tgc aat 643 Pro Arg lie Thr Glu Ala Glu Pro Asp Asp Val Asp Cys Trp Cys Asn 170 175 180 gee aeg gac aca tgg gtg acc tat gga aeg tgc tet caa act ggc gaa 691 Ala Thr Asp Thr Trp Val Thr Tyr Gly Thr Cys Ser Gin Thr Gly Glu 185 190 195 cac ega ega gac aaa cgt tee gtc gca ttg gee cca cac gtg ggg ett 739 His Arg Arg Asp Lys Arg Ser Val Ala Leu Ala Pro His Val Gly Leu 200 205 210 215 ggc eta gaa aca aga gee gaa aeg tgg atg tee tet gaa ggt get tgg 787 Gly Leu Glu Thr Arg Ala Glu Thr Trp Met Ser Ser Glu Gly Ala Trp 220 225 230 aaa cag ata caa aaa gta gag act tgg get ctg aga cat cca gga ttc 835 Lys Gin lie Gin Lys Val Glu Thr Trp Ala Leu Arg His Pro Gly Phe 235 240 245 aeg gtg ata gee ett ttt eta gca cat gee ata gga aca tee ate acc 883 Thr Val lie Ala Leu Phe Leu Ala His Ala He Gly Thr Ser He Thr 250 255 260 cag aaa ggg ate att ttc att ttg ctg atg ctg gta aca cca tet atg 931 Gin Lys Gly lie He Phe He Leu Leu Met Leu Val Thr Pro Ser Met 265 270 275 gee atg ega tgc gtg gga ata ggc aac aga gac ttc gtg gaa gga ctg 979 Ala Met Arg Cys Val Gly He Gly Asn Arg Asp Phe Val Glu Gly Leu 280 285 290 295

    2018200081 04 Jan 2018

    tea gga gca aca Ser Gly Ala Thr tgg gtg Trp Val 300 gat Asp gtg gta ctg gag cat His gga Gly agt Ser tgc Cys 310 gtc Val 1027 Val· Val Leu Glu 305 acc acc atg gca aaa aac aaa cca aca ctg gac att gaa etc ttg aag 1075 Thr Thr Met Ala Lys Asn Lys Pro Thr Leu Asp lie Glu Leu Leu Lys 315 320 325 acg gag gtc aca aac cct gca gtt ctg cgt aaa ttg tgc att gaa get 1123 Thr Glu Val Thr Asn Pro Ala Val Leu Arg Lys Leu Cys He Glu Ala 330 335 340 aaa ata tea aac acc acc acc gat teg aga tgt cca aca caa gga gaa 1171 Lys lie Ser Asn Thr Thr Thr Asp Ser Arg Cys Pro Thr Gin Gly Glu 345 350 355 gee aca ctg gtg gaa gaa caa gac gcg aac ttt gtg tgc ega ega acg 1219 Ala Thr Leu Val Glu Glu Gin Asp Ala Asn Phe Val Cys Arg Arg Thr 360 365 370 375 ttc gtg gac aga ggc tgg ggc aat ggc tgt ggg eta ttc gga aaa ggt 1267 Phe Val Asp Arg Gly Trp Gly Asn Gly Cys Gly Leu Phe Gly Lys Gly 380 385 390 agt eta ata acg tgt gcc aag ttt aag tgt gtg aca aaa eta gaa gga 1315 Ser Leu lie Thr Cys Ala Lys Phe Lys Cys Val Thr Lys Leu Glu Gly 395 400 405 aag ata gtt caa tat gaa aac eta aaa tat tea gtg ata gtc acc gtc 1363 Lys lie Val Gin Tyr Glu Asn Leu Lys Tyr Ser Val He Val Thr Val 410 415 420 cac act gga gat cag cac cag gtg gga aat gag act aca gaa cat gga 1411 His Thr Gly Asp Gin His Gin Val Gly Asn Glu Thr Thr Glu His Gly 425 430 435 aca act gca acc ata aca cct caa get cct acg teg gaa ata cag ctg 1459 Thr Thr Ala Thr He Thr Pro Gin Ala Pro Thr Ser Glu He Gin Leu 440 445 450 455 acc gac tac gga acc ett aca tta gat tgt tea cct agg aca ggg eta 1507 Thr Asp Tyr Gly Thr Leu Thr Leu Asp Cys Ser Pro Arg Thr Gly Leu 460 465 470 gat ttt aac gag atg gtg ttg ctg aca atg aaa gaa aga tea tgg ett 1555 Asp Phe Asn Glu Met Val Leu Leu Thr Met Lys Glu Arg Ser Trp Leu 475 480 485 gtc cac aaa caa tgg ttt eta gac tta cca ctg cct tgg acc tet ggg 1603 Val His Lys Gin Trp Phe Leu Asp Leu Pro Leu Pro Trp Thr Ser Gly

    490 495 500

    2018200081 04 Jan 2018

    get Ala tea Ser 505 aca Thr tee Ser caa gag act Gin Glu Thr 510 tgg Trp aac Asn aga Arg caa Gin gat Asp 515 tta Leu ctg Leu gtc Val aca Thr 1651 ttt aag aca get cat gca aag aag cag gaa gta gtc gta eta gga tea 1699 Phe Lys Thr Ala His Ala Lys Lys Gin Glu Val Val Val Leu Gly Ser 520 525 530 535 caa gaa gga gca atg cac act gcg ctg act gga gcg aca gaa ate caa 1747 Gin Glu Gly Ala Met His Thr Ala Leu Thr Gly Ala Thr Glu lie Gin 540 545 550 aeg tea gga aeg aca aca att ttc gca gga cac eta aaa tgc aga eta 1795 Thr Ser Gly Thr Thr Thr lie Phe Ala Gly His Leu Lys Cys Arg Leu 555 560 565 aaa atg gac aaa eta act tta aaa ggg atg tea tat gtg atg tgc aca 1843 Lys Met Asp Lys Leu Thr Leu Lys Gly Met Ser Tyr Val Met Cys Thr 570 575 580 ggc tea ttc aag tta gag aaa gaa gtg get gag acc cag cat gga act 1891 Gly Ser Phe Lys Leu Glu Lys Glu Val Ala Glu Thr Gin His Gly Thr 585 590 595 gtt ctg gtg cag gtt aaa tat gaa gga aca gac gca cca tgc aag att 1939 Val Leu Val Gin Val Lys Tyr Glu Gly Thr Asp Ala Pro Cys Lys He 600 605 610 615 ccc ttt teg acc caa gat gag aaa gga gca acc cag aat ggg aga tta 1987 Pro Phe Ser Thr Gin Asp Glu Lys Gly Ala Thr Gin Asn Gly Arg Leu 620 625 630 ata aca gcc aac ccc ata gtc act gac aaa gaa aaa' cca gtc aat att 2035 lie Thr Ala Asn Pro He Val Thr Asp Lys Glu Lys Pro Val Asn He 635 640 645 gag gca gaa cca ccc ttt ggt gag agc tac ate gtg gta gga gca ggt 2083 Glu Ala Glu Pro Pro Phe Gly Glu Ser Tyr He Val Val Gly Ala Gly 650 655 660 gaa aaa get ttg aaa eta agc tgg ttc aag aaa gga agc agc ata ggg 2131 Glu Lys Ala Leu Lys Leu Ser Trp Phe Lys Lys Gly Ser Ser He Gly · 665 670 675 aaa atg ttt gaa gca act gcc ega gga gca ega agg atg gcc att ctg 2179 Lys Met Phe Glu Ala Thr Ala Arg Gly Ala Arg Arg Met Ala He Leu 680 685 690 695 gga gac acc gca tgg gac ttc ggt tet ata gga gga gtg ttc aeg tet 2227 Gly Asp Thr Ala Trp Asp Phe Gly Ser He Gly Gly Val Phe Thr Ser 700 705 710 atg gga aaa ctg gta cac cag gtt ttt gga act gca tat gga gtt ttg 2275 Met Gly Lys Leu Val His Gin Val Phe Gly Thr Ala Tyr Gly Val Leu 715 720 725

    2018200081 04 Jan 2018

    ttt Phe age Ser gga Gly 730 gtt Val tct Ser tgg acc Trp Thr atg Met 735 aaa Lys ata He gga Gly ata He ggg Gly 740 att He ctg Leu ctg Leu 2323 aca tgg eta gga tta aat tea agg aac aeg tee ett teg atg atg tgc 2371 Thr Trp Leu Gly Leu Asn Ser Arg Asn Thr Ser Leu Ser Met Met Cys 745 750 755 ate gca gtt ggc atg gtc aca ctg tac eta gga gtc atg gtt cag gca 2419 lie Ala Val. Gly Met Val Thr Leu Tyr Leu Gly Val Met Val Gin Ala 760 765 770 775 gat teg gga tgt gta ate aac tgg aaa ggc aga gaa ett aaa tgt gga 2467 Asp Ser Gly Cys Val He Asn Trp Lys Gly Arg Glu Leu Lys Cys Gly 780 785 790 age ggc att ttt gtc act aat gaa gtt cac act tgg aca gag caa tac 2515 Ser Gly lie Phe Val Thr Asn Glu Val His Thr Trp Thr Glu Gin Tyr 795 800 805 aaa ttc cag get gac tee ccc aag aga eta tea gca gcc att ggg aag 2563 Lys Phe Gin Ala Asp Ser Pro Lys Arg Leu Ser Ala Ala He Gly Lys 810 815 820 gca tgg gag gag ggt gtg tgt gga ate cga tea gcc act cgt etc gag 2611 Ala Trp Glu Glu Gly Val Cys Gly He Arg Ser Ala Thr Arg Leu Glu 825 830 835 aac ate atg tgg aaa caa ata tea aat gaa ttg aac cac ate eta ett 2659 Asn He Met Trp Lys Gin He Ser Asn Glu Leu Asn His He Leu Leu 840 845 850 855 gaa aat gac atg aaa ttt aca gtg gtc gtg gga gat gtt agt gga ate 2707 Glu Asn Asp Met Lys Phe Thr Val Val Val Gly Asp Val Ser Gly lie 860 865 870 ttg gee caa ggg aaa aaa atg att agg cca caa ccc atg gaa cac aaa 2755 Leu Ala Gin Gly Lys Lys Met lie Arg Pro Gin Pro Met Glu His Lys 875 880 885 tac teg tgg aaa age tgg gga aaa gcc aaa ate ata gga gcg gat gta 2803 Tyr Ser Trp Lys Ser Trp Gly Lys Ala Lys He He Gly Ala Asp Val 890 895 900 cag aac acc acc ttc ate ate gac ggc cca aac acc cca gaa tgc cct 2851 Gin Asn Thr Thr Phe He He Asp Gly Pro Asn Thr Pro Glu Cys Pro 905 910 915 gac aat caa aga gca tgg aat att tgg gaa gta gag gac tat gga ttt 2899 Asp Asn Gin Arg Ala Trp Asn He Trp Glu Val Glu Asp Tyr Gly Phe 920 925 930 935

    2018200081 04 Jan 2018

    ggg att Gly lie ttc aeg aca aac ata tgg ttg aaa ttg cgt gac tcc tac acc Thr 2947 Phe Thr Thr 940 Asn He Trp Leu Lys 945 Leu Arg Asp Ser Tyr 950 caa gta tgt gac cac egg ctg atg tea get gcc att aag gac age aag 2995 Gin Val Cys Asp 955 His Arg Leu Met Ser 960 Ala Ala He Lys Asp 965 Ser Lys gca gtc cat get gac atg ggg tac tgg ata gaa agt gaa aag aac gag 3043 Ala Val His 970 Ala Asp Met Gly Tyr 975 Trp He Glu Ser Glu 980 Lys Asn Glu aca tgg aag ttg geg aga gcc tcc ttt ata gaa gtt aag aca tgc ate 3091 Thr Trp 98E Lys Leu Ala Arg Ala 99C Ser 1 Phe He Glu Val Lys 995 Thr Cys He tgg cca aaa tcc cac act eta tgg age aat gga gtt ctg gaa agt gaa 3139 Trp Pro 1000 Lys Ser His Thr Leu 1005 Trp Ser Asn Gly Val 1010 Leu Glu Ser Glu 1015 atg ata att cca aag ata tat gga gga cca ata tet cag cac aac tac 3187 Met lie lie Pro Lys He 1020 Tyr Gly Gly Pro He 1025 Ser Gin His Asn Tyr 103 0 aga cca gga tat ttc aca caa aca gca ggg ccg tgg cac eta ggc aag 3235 Arg Pro Gly Tyr Phe 1035 Thr Gin Thr Ala Gly 1040 Pro Trp His Leu Gly 1045 Lys ttg gaa eta gat ttc gat ttt tgt gaa ggt acc aca gtt gtt gtg gat 3283 Leu Glu Leu Asp 1050 Phe Asp Phe Cys Glu 1055 Gly Thr Thr Val Val 1060 Val Asp gaa cat tgt gga aat ega gga cca tet etc aga acc aca aca gtc aca 3331 Glu His Cys 1065 Gly Asn Arg Gly Pro 1070 Ser Leu Arg Thr Thr 1075 Thr Val Thr gga aag ata ate cat gaa tgg tgc tgc aga tet tgt aeg eta ccc ccc 3379 Gly Lys 1080 He He His Glu Trp 1085 Cys Cys Arg Ser Cys 1090 Thr Leu Pro Pro 1095 eta cgt ttc aaa ggg gaa gac ggg tgt tgg tac ggc atg gaa ate aga 3427 Leu Arg Phe Lys Gly Glu 1100 Asp Gly Cys Trp Tyr 1105 Gly Met Glu He Arg 1110 cca gtg aag gac aag gaa gag aac ctg gtc aag tea atg gtc tet gca 3475 Pro Val Lys Asp Lys 1115 Glu Glu Asn Leu Val 1120 Lys Ser Met Val Ser 1125 Ala ggg tea gga gaa gtg gac age ttt tea eta gga ctg eta tgc ata tea 3523 Gly Ser Gly Glu 1130 Val Asp Ser Phe Ser 1135 Leu Gly Leu Leu Cys 1140 lie Ser ata atg att gaa gaa gtg atg aga tcc aga tgg age aaa aaa atg ctg 3571 lie Met He 1145 Glu Glu Val Met Arg 1150 Ser Arg Trp Ser Lys 1155 Lys Met Leu

    2018200081 04 Jan 2018

    atg act gga Met Thr Gly 1160 aca Thr ctg Leu get gtg Ala Val 1165 ttc Phe etc Leu ett Leu ett ata atg Leu He Met 1170 gga Gly caa Gin ttg Leu 1175 3619 aca tgg agt gat ctg ate agg tta tgt att atg gtt gga gcc aac get 3667 Thr Trp Ser Asp Leu 1180 lie Arg 1 Leu Cys lie 1185 Met Val Gly Ala Asn 119C Ala 1 tea gac aag atg ggg atg gga aca aeg tac eta get tta atg gcc act 3715 Ser Asp Lys Met 1195 Gly Met Gly Thr Thr 120C Tyr 1 Leu Ala Leu Met Ala 1205 Thr ttc aaa atg aga cca atg ttc gcc gtc ggg eta tta ttt cgc aga eta 3763 Phe Lys Met Arg 1210 Pro Met Phe Ala 1215 Val Gly Leu Leu Phe Arg 1220 Arg Leu aca tet aga gaa gtt ett ett ett aca att ggc ttg age ctg gtg gca 3811 Thr Ser Arg 1225 Glu Val Leu Leu Leu 1230 Thr He Gly Leu Ser 1235 Leu Val Ala tcc gtg gag eta cca agt tcc eta gag gag ctg ggg gat gga ett gca 3859 Ser Val Glu 1240 Leu Pro Ser Ser 1245 Leu Glu Glu Leu Gly Asp 1250 Gly Leu Ala 1255 ata ggc ate atg atg ttg aaa tta ttg act gat ttt cag tea cac cag 3907 lie Gly lie Met Met Leu Lys 1260 Leu Leu Thr Asp Phe Gin 1265 Ser His Gin 1270 eta tgg get act ctg eta tcc ttg aca ttt att aaa aca act ttt tea 3955 Leu Trp Ala Thr Leu 1275 Leu Ser Leu Thr 128C Phe 1 He Lys Thr Thr Phe 1285 Sex- ttg cac tat gca tgg aag aca atg get atg gta ctg tea att gta tet 4003 Leu His Tyr Ala 1290 Trp Lys Thr Met Ala 1295 Met Val Leu Ser He 1300 Val Ser etc ttc cct tta tgc ctg tcc aeg acc tet caa aaa aca aca tgg ett 4051 Leu Phe Pro 1305 Leu Cys Leu Ser Thr 1310 Thr Ser Gin Lys Thr 1315 Thr Trp Leu ccg gtg ctg ttg gga tet ett gga tgc aaa cca eta ccc atg ttt ett 4099 Pro Val Leu 1320 Leu Gly Ser Leu 1325 Gly Cys Lys Pro Leu Pro 1330 Met Phe Leu 1335 ata aca gaa aac aaa ate tgg gga agg aag agt tgg ccc etc aat gaa 4147 lie Thr Glu Asn Lys lie Trp 1340 Gly Arg Lys Ser Trp Pro 1345 Leu Asn Glu 1350 gga att atg get gtt gga ata gtt agt att eta eta agt tea ett tta 4195 Gly lie Met Ala Val 1355 Gly lie Val Ser He 1360 Leu Leu Ser Ser Leu 1365 Leu

    2018200081 04 Jan 2018

    aaa Lys aat Asn gat gtg Asp Val 1370 ccg Pro eta gcc ggc cca Leu Ala Gly Pro 1375 tta Leu ata He get gga ggc atg Met eta Leu 4243 Ala Gly Gly 1380 ata gca tgt tat gtc ata tee gga agc tea get gat tta tea ctg gag 4291 lie Ala Cys Tyr 1385 Val He Ser Gly Ser 1390 Ser Ala Asp Leu Ser 1395 Leu Glu aaa geg get gag gtc tee tgg gag gaa gaa gca gaa cac tea ggc gcc 4339 Lys 140C Ala 1 Ala Glu Val Ser Trp Glu Glu 1405 Glu Ala Glu 1410 His Ser Gly Ala 1415 tea cac aac ata eta gta gag gtt caa gat gat gga acc atg aag ata 4387 Ser His Asn lie Leu 142C Val Glu Val Gin 1 Asp 142E Asp Gly Thr Met Lys 143 C He 1 aaa gat gaa gag aga gat gac aeg etc acc att etc ett aaa gca act 4435 Lys Asp Glu Glu Arg 1435 Asp Asp Thr Leu Thr 1440 He Leu Leu Lys Ala 1445 Thr ctg ctg gca gtc tea 999 gtg tac cca atg tea ata cca geg acc ett 4483 Leu Leu Ala Val 1450 Ser Gly Val Tyr Pro 1455 Met Ser He Pro Ala 1460 Thr Leu ttt gtg tgg tat ttt tgg cag aaa aag aaa cag aga tea gga gtg eta 4531 Phe Val Trp Tyr 1465 Phe Trp Gin Lys Lys 1470 Lys Gin Arg Ser Gly 1475 Val Leu tgg gac aca ccc agc ccc cca gaa gtg gaa aga gca gtt ett gat gat 4579 Trp Asp 1480 Thr Pro Ser Pro Pro Glu Val 1485 Glu Arg Ala 1490 Val Leu Asp Asp 1495 ggc ate tat aga att ttg caa aga gga ctg ttg ggc agg tee caa gta 4627 Gly He Tyr Arg He 150C Leu Gin Arg Gly 1 Leu 150Ξ Leu Gly Arg Ser Gin 151C Val 1 gga gta gga gtt ttc caa gaa ggc gtg ttc cac aca atg tgg cac gtc 4675 Gly Val Gly Val 1515 Phe Gin Glu Gly Val Phe 1520 His Thr Met Trp His 1525 Val act agg gga get gtc etc atg tat caa gga aaa agg ctg gaa cca agc 4723 Thr Arg Gly Ala 1530 Val Leu Met Tyr Gin 1535 Gly Lys Arg Leu Glu 1540 Pro Ser tgg gcc agt gtc aaa aaa gac ttg ate tea tat gga gga ggt tgg agg 4771 Trp Ala Ser Val 1545 Lys Lys Asp Leu He 1550 Ser Tyr Gly Gly Gly 1555 Trp Arg ttt caa gga tee tgg aac aeg gga gaa gaa gta cag gtg att get gtt 4819 Phe Gin 1560 Gly Ser Trp Asn Thr Gly Glu 1565 Glu Val Gin 1570 Val He Ala Val 1575 gaa ccg gga aaa aac ccc aaa aat gta caa aca aeg ccg ggt acc ttc 4867 Glu Pro Gly Lys Asn Pro Lys Asn Val 1580 Gin Thr 1585 Thr Pro Gly Thr Phe 1590

    2018200081 04 Jan 2018 aag acc cct gaa ggc gaa gtt gga gcc ata gcc tta gac ttt aaa cct 4915

    Lys Thr Pro Glu Gly Glu Val Gly Ala lie Ala Leu Asp Phe Lys Pro

    1595 1600 1605 ggc aca tct gga tct ccc ate gta aac aga gag gga aaa ata gta ggt 4963

    Gly Thr Ser Gly Ser Pro lie Val Asn Arg Glu Gly Lys lie Val Gly

    1610 1615 1620 ett tat gga aat gga gtg gtg aca aca age gga act tac gtt agt gcc 5011

    Leu Tyr Gly Asn Gly Val Val Thr Thr Ser Gly Thr Tyr Val Ser Ala

    1625 1630 1635 ata get caa get aag gca tea caa gaa ggg cct eta cca gag att gag 5059 lie Ala Gin Ala Lys Ala Ser Gin Glu Gly Pro Leu Pro Glu lie Glu

    1640 1645 1650 1655 gac gag gtg ttt agg aaa aga aac tta aca ata atg gac eta cat cca 5107

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

    1660 1665 1670 gga teg gga aaa aca aga aga tac ett cca gcc ata gtc cgt gag gcc 5155

    Gly Ser Gly Lys Thr Arg Arg Tyr Leu Pro Ala lie Val Arg Glu Ala

    1675 1680 1685 ata aaa agg aag ctg ege aeg eta ate eta get ccc aca aga gtt gtc 5203

    He Lys Arg Lys Leu Arg Thr Leu He Leu Ala Pro Thr Arg Val Val

    1690 1695 1700 get tct gaa atg gca gag gca etc aag gga gtg cca ata agg tat cag 5251

    Ala Ser Glu Met Ala Glu Ala Leu Lys Gly Val Pro He Arg Tyr Gin

    1705 1710 1715 aca aca gca gtg aag agt gaa cac aca gga aag gag ata gtt gac ett 5299

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

    1720 1725 1730 1735 atg tgc cac gcc act ttc acc atg ege etc ctg tct ccc gtg aga gtt 5347

    Met Cys His Ala Thr Phe Thr Met Arg Leu Leu Ser Pro Val Arg Val

    1740 1745 1750 ccc aat tat aac atg att ate atg gat gaa gca cac ttc acc gat cca 5395

    Pro Asn Tyr Asn Met He He Met Asp Glu Ala His Phe Thr Asp Pro

    1755 1760 1765 gcc age ata gca gcc aga ggg tac ate tea acc cga gtg ggt atg ggt 5443

    Ala Ser He Ala Ala Arg Gly Tyr He Ser Thr Arg Val Gly Met Gly

    1770 1775 1780 gaa gca get gcg ate ttt atg aca gcc act ccc cca gga teg gtg gag 5491

    Glu Ala Ala Ala He Phe Met Thr Ala Thr Pro Pro Gly Ser Val Glu

    1785 1790 1795

    2018200081 04 Jan 2018

    gcc ttt Ala Phe 1800 cca Pro cag Gin age Ser aat gca Asn Ala 1805 att He ate He caa gat gag gaa aga gac att He 1815 5539 Gin Asp Glu Glu 1810 Arg Asp cct gag aga tea tgg aac tea ggc tat gac tgg ate act gat ttt cca 5587 Pro Glu Arg Ser Trp 182C Asn Ser 1 Gly Tyr Asp Trp He Thr 1825 Asp Phe 183C Pro 1 ggt aaa aca gtc tgg ttt gtt cca age ate aaa tea gga aat gac att 5635 Gly Lys Thr Val 1835 Trp Phe Val Pro Ser 184C He Lys Ser Gly 1 Asn 1845 Asp He gcc aac tgt tta aga aaa aac ggg aaa egg gtg ate caa ttg age aga 5683 Ala Asn Cys Leu 1850 Arg Lys Asn Gly 1855 Lys Arg Val He Gin Leu 1860 Ser Arg aaa acc ttt gac act gag tac cag aaa aca aaa aac aac gac tgg gac 5731 Lys Thr Phe 1865 Asp Thr Glu Tyr Gin 1870 Lys Thr Lys Asn Asn . 1875 Asp Trp Asp tat gtc gtc aca aca gac att tcc gaa atg gga gca aat ttc cgg gcc 5779 Tyr Val 1880 Val Thr Thr Asp lie 1885 Ser Glu Met Gly Ala Asn 1890 Phe Arg Ala 1895 gac agg gta ata gac cca agg cgg tgt ctg aaa ccg gta ata eta aaa 5827 Asp Arg Val lie Asp 190C Pro Arg 1 Arg Cys Leu Lys Pro Val 1905 He Leu Lys 1910 gat ggt cca gag ege gtc att eta gcc gga ccg atg cca gtg act gtg 5875 Asp Gly Pro Glu 1915 Arg Val lie Leu Ala 192C Gly Pro Met Pro 1 Val 1925 Thr Val gcc agt gcc gcc cag agg aga gga aga att gga agg aac caa aac aag 5923 Ala Ser Ala Ala 1930 Gin Arg Arg Gly Arg 1935 He Gly Arg Asn Gin 1940 Asn Lys gaa ggt gat cag tat att tac atg gga cag cct tta aac aat gat gag 5971 Glu Gly Asp 1945 Gin Tyr He Tyr Met 1950 Gly Gin Pro Leu Asn 1955 Asn Asp Glu gac cac get cat tgg aca gaa gca aag atg etc ett gac aat ata aac 6019 Asp His 1960 Ala His Trp Thr Glu 1965 Ala Lys Met Leu Leu Asp 1970 Asn He Asn 1975 aca cca gaa ggg att ate cca gcc etc tat gag ccg gag aga gaa aag 6067 Thr Pro Glu Gly lie He Pro 1980 Ala Leu Tyr Glu Pro Glu 1985 Arg Glu Lys 1990 agt gca get ata gac ggg gaa tac aga ctg cgg ggt gaa gca agg aaa 6115 Ser Ala Ala lie Asp 1995 Gly Glu Tyr Arg 200C Leu Arg Gly Glu 1 Ala Arg 2005 Lys acg ttc gtg gag etc atg aga aga ggg gat eta cca gtc tgg eta tcc 6163 Thr Phe Val Glu 2010 Leu Met Arg Arg Gly Asp Leu Pro Val Trp 2015 2020 Leu Ser

    2018200081 04 Jan 2018

    tac Tyr aaa gtt Lys Val 2025 gcc Ala tea Ser gaa Glu ggc ttc Gly Phe 2030 cag Gin tac Tyr tcc Ser gac aga Asp Arg 2035 agg Arg tgg Trp tgc Cys 6211 ttc gat ggg gaa agg aac aac cag gtg ttg gag gag aac atg gac gtg 6259 Phe 204C Asp Gly I Glu Arg Asn Asn Gin 2045 Val Leu Glu 205C Glu Asn 1 Met Asp Val 2055 gag ate tgg aca aaa gaa gga gaa aga aag aaa eta ega cct ege tgg 6307 Glu lie Trp Thr Lys Glu 2060 Gly Glu Arg Lys 2065 Lys Leu Arg Pro Arg 207C Trp 1 ttg gac gcc aga aca tac tet gac cca ctg get ctg ege gag ttt aaa 6355 Leu Asp Ala Arg Thr 2075 Tyr Ser Asp Pro Leu 2080 Ala Leu Arg Glu Phe 2085 Lys gag ttt gca gca gga aga aga agc gtc tea ggt gac eta ata tta gaa 6403 Glu Phe Ala Ala 2090 Gly Arg Arg Ser Val 2095 Ser Gly Asp Leu He 2100 Leu Glu ata ggg aaa ett cca caa cat ttg aeg caa agg gcc cag aat get ttg 6451 He Gly Lys 2105 Leu Pro Gin His Leu 2110 Thr Gin Arg Ala Gin 2115 Asn Ala Leu gac aac ttg gtc atg ttg cac aat tcc gaa caa gga gga aaa gcc tat 6499 Asp Asn Leu 2120 Val Met Leu His Asn 2125 Ser Glu Gin Gly Gly 2130 Lys Ala Tyr 2135 aga· cat get atg gaa gaa ctg cca gac aca ata gaa aeg ttg atg etc 6547 Arg His Ala Met Glu Glu 2140 Leu Pro Asp Thr 2145 He Glu Thr Leu Met 215C Leu 1 eta gcc ttg ata get gtg ttg act ggt gga gtg aeg ctg ttc ttc eta 6595 Leu Ala Leu He Ala 2155 Val Leu Thr Gly Gly 2160 Val Thr Leu Phe Phe 2165 Leu tea gga alga ggt eta gga aaa aca tet ate ggc tta etc tgc gtg atg 6643 Ser Gly Arg Gly 2170 Leu Gly Lys Thr Ser 2175 He Gly Leu Leu Cys 2180 Val Met gcc tea agc gca ctg tta tgg atg gcc agt gtg gag ccc cat tgg ata 6691 Ala Ser Ser 2185 Ala Leu Leu Trp Met 2190 Ala Ser Val Glu Pro 2195 His Trp He geg gcc tcc ate ata ctg gag ttc ttt ctg atg gta ctg ett att cca 6739 Ala Ala Ser 2200 He He Leu Glu Phe 2205 Phe Leu Met Val Leu 2210 Leu He Pro 2215 gag cca gac aga cag ege act cca cag gac aac cag eta gca tat gtg 6787 Glu Pro Asp Arg Gin Arg 2220 Thr Pro Gin Asp Asn 2225 Gin Leu Ala Tyr Val 2230

    2018200081 04 Jan 2018

    gtg Val ata lie ggt Gly ctg tta Leu Leu 2235 ttc Phe atg Met ata He ttg aca Leu Thr 2240 gtg Val gca Ala gcc Ala aat gag Asn Glu 2245 atg Met 6835 gga tta ttg gaa acc aca aag aaa gac ctg ggg att ggc cat gta get 6883 Gly Leu Leu 225C Glu Thr 1 Thr Lys Lys 225E Asp Leu Gly He Gly 226C His Val 1 Ala get gaa aac cac cac cat get aca atg ctg gac gta gac eta cat cca 6931 Ala Glu Asn 2265 His His His Ala Thr 2270 Met Leu Asp Val Asp 2275 Leu His Pro get tea gcc tgg acc etc tat gca gtg gcc aca aca ate ate act cct 6979 Ala 228C Ser 1 Ala Trp Thr Leu 228E Tyr Ala Val Ala Thr Thr 2290 He He Thr Pro 2295 atg atg aga cac aca att gaa aac aca aeg gca aat att tcc ctg aca 7027 Met Met Arg His Thr He 2300 Glu Asn Thr Thr Ala 2305 Asn He Ser Leu Thr 2310 gcc ate gca aac caa gca get ata ttg atg gga ett gac aag gga tgg 7075 Ala He Ala Asn Gin 2315 Ala Ala He Leu Met 2320 Gly Leu Asp Lys Gly 2325 Trp cca ata teg aag atg gac ata gga gtt cca ett etc gcc ttg ggg tgc 7123 Pro lie Ser Lys Met 2330 Asp He Gly Val Pro 2335 Leu Leu Ala Leu Gly 2340 Cys tat tee caa gtg aat ccg ctg aca ctg ata gcg gca gta ttg atg eta 7171 Tyr Ser Gin 2345 Val Asn Pro Leu Thr 2350 Leu He Ala Ala Val 2355 Leu Met Leu gta get cat tac gcc ata att gga cct gga ctg caa gca aaa get act 7219 Val Ala 2360 His Tyr Ala He lie 2365 Gly Pro Gly Leu Gin 2370 Ala Lys Ala Thr 2375 aga gaa get caa aaa aga aca gcg get gga ata atg aaa aat cca act 7267 Arg Glu Ala Gin Lys Arg 2380 Thr Ala Ala Gly He 2385 Met Lys Asn Pro Thr 2390 gtc gac ggg att gtt gca ata gac tta gat ccc gtg gtt tac gat gca 7315 Val Asp Gly He Val 2395 Ala He Asp Leu Asp 2400 Pro Val Val Tyr Asp 2405 Ala aaa ttt gaa aaa caa eta ggc caa ata atg ttg ttg ata ett tgc aca 7363 Lys Phe Glu Lys Gin 2410 Leu Gly Gin lie Met 2415 Leu Leu He 242C Leu Cys ) Thr tea cag att ett ttg atg egg act aca tgg gcc ttg tgt gaa tcc ate 7411 Ser Gin He 2425 Leu Leu Met Arg Thr 2430 Thr Trp Ala Leu Cys 2435 Glu Ser lie aca ttg get act gga cct ctg acc act ett tgg gag gga tet cca gga 7459 Thr Leu 2440 Ala Thr Gly Pro Leu 2445 Thr Thr Leu Trp Glu 2450 Gly Ser Pro Gly 2455

    2018200081 04 Jan 2018

    aaa ttc tgg aac acc aca ata geg gta tee atg gca aac att ttc agg 7507 Lys Phe Trp Asn Thr 2460 Thr 1 He Ala Val Ser 2465 Met Ala Asn He Phe 247C Arg 1 ggg agt tat eta gca gga gca ggt ctg gee ttc tea tta atg aaa tet 7555 Gly Ser Tyr Leu Ala 2475 Gly Ala Gly Leu Ala 2480 Phe Ser Leu Met Lys 2485 Ser eta gga gga ggt agg aga ggc aeg gga gee caa ggg gaa aca ctg gga 7603 Leu Gly Gly 249C Gly 1 Arg Arg Gly Thr Gly 2495 Ala Gin Gly Glu 250C Thr 1 Leu Gly gaa aaa tgg aaa aga caa eta aac caa ctg agc aag tea gaa ttc aat 7651 Glu Lys Trp 2505 Lys Arg Gin Leu Asn 2510 Gin Leu Ser Lys Ser 2515 Glu Phe Asn act tac aag agg agt ggg att atg gag gtg gat aga tee gaa gee aaa 7699 Thr Tyr 2520 Lys Arg Ser Gly He 2525 Met Glu Val Asp Arg 2530 Ser Glu Ala Lys 2535 gag gga ctg aaa aga gga gaa aca acc aaa cac gca gta teg aga gga 7747 Glu Gly Leu Lys Arg 254C Gly 1 Glu Thr Thr Lys 2545 His Ala Val Ser Arg 255C Gly 1 aeg gee aaa ctg agg tgg ttc gtg gag agg aac ett gtg aaa cca gaa 7795 Thr Ala Lys Leu Arg 2555 Trp Phe Val Glu Arg 2560 Asn Leu Val Lys Pro 2565 Glu ggg aaa gtc ata gac etc ggt tgt gga aga ggt ggc tgg tea tat tat 7843 Gly Lys Val 257C lie 1 Asp Leu Gly Cys Gly 2575 Arg Gly Gly Trp 258C Ser 1 Tyr Tyr tgc get ggg ctg aag aaa gtc aca gaa gtg aaa gga tac aca aaa gga 7891 Cys Ala Gly 2585 Leu Lys Lys Val Thr 2590 Glu Val Lys Gly Tyr 2595 Thr Lys Gly gga cct gga cat gag gaa cca ate cca atg geg acc tat gga tgg aac 7939 Gly Pro 2600 Gly His Glu Glu Pro 2605 He Pro Met Ala Thr 2610 Tyr Gly Trp Asn 2615 eta gta aag ctg cac tee gga aaa gat gta ttt ttt ata cca cct gag 7987 Leu Val Lys Leu His 262C Ser 1 Gly Lys Asp Val 2625 Phe Phe He Pro Pro 263C Glu 1 aaa tgt gac acc ett ttg tgt gat att ggt gag tee tet ccg aac cca 8035 Lys Cys Asp Thr Leu 2635 Leu Cys Asp He Gly 2640 Glu Ser Ser Pro Asn 2645 Pro act ata gag gaa gga aga aeg tta cgt gtt ctg aaa atg gtg gaa cca 8083 Thr He Glu Glu Gly 2650 Arg Thr Leu Arg 2655 Val Leu Lys Met 266C Val 1 Glu Pro

    2018200081 04 Jan 2018

    tgg Trp etc aga gga aac caa ttt tgc Gin Phe Cys 2670 ata He aaa Lys att He eta aat Leu Asn 2675 ccc Pro tat Tyr atg Met 8131 Leu Arg 2665 Gly Asn ccg age gtg ί gta gaa act ctg gaa caa atg caa aga aaa cat gga gga 8179 Pro 268C Ser Val Val Glu Thr Leu Glu 2685 Gin Met Gin 269C Arg Lys 1 His Gly Gly 2695 atg eta gtg ega aac cca etc tea aga aat tcc acc cat gaa atg tac 8227 Met Leu Val Arg Asn 270C Pro Leu Ser 1 Arg Asn 2705 Ser Thr His Glu Met 271C Tyr 1 tgg gtt tea tgt gga aca gga aac att gtg tea gca gta aac atg aca ' 8275 Trp Val Ser Cys Gly 2715 Thr Gly Asn He Val 2720 Ser Ala Val Asn Met 2725 Thr tct aga atg ttg eta aat egg ttc aca atg get cac agg aag cca aca 8323 Ser Arg Met Leu 2730 Leu Asn Arg Phe Thr 2735 Met Ala His Arg Lys 2740 Pro Thr tat gaa aga gac gtg gac tta ggc get gga aca aga cat gtg gca gta 8371 Tyr Glu Arg 2745 Asp Val Asp Leu Gly 2750 Ala Gly Thr Arg His 2755 Val Ala Val gaa cca gag gta gcc aac eta gat ate att ggc cag agg ata gag aat 8419 Glu Pro Glu 2760 Val Ala Asn Leu Asp 2765 He He Gly Gin Arg 2770 He Glu Asn 2775 ata aaa aat gaa cat aag tea aca tgg cat tat gat gag gac aat cca 8467 He Lys Asn Glu His Lys Ser Thr 2780 Trp His Tyr 2785 Asp Glu Asp Asn Pro 2790 tac aaa aca tgg gcc tat cat gga tea tat gag gtt aag cca tea gga 8515 Tyr Lys Thr Trp Ala 2795 Tyr His Gly Ser Tyr 2800 Glu Val Lys Pro Ser 2805 Gly teg gcc tea tcc atg gtc aat ggc gtg gtg aga ttg etc acc aaa cca 8563 Ser Ala Ser Ser 2810 Met Val Asn Gly Val 2 8.15 Val Arg Leu Leu Thr 2820 Lys Pro tgg gat gtt ate ccc atg gtc aca caa ata gcc atg act gat acc aca 8611 Trp Asp Val 2825 lie Pro Met Val Thr 2830 Gin He Ala Met Thr 2835 Asp Thr Thr CCC ttt gga caa cag agg gtg ttt aaa gag aaa gtt gac aeg cgc aca 8659 Pro Phe Gly 2840 Gin Gin Arg Val Phe 2845 Lys Glu Lys Val Asp 2850 Thr Arg Thr 2855 cca aaa gca aaa cgt ggc aca gca caa att atg gaa gtg aca gcc agg 8707 Pro Lys Ala Lys Arg Gly Thr Ala 2860 Gin He Met 2865 Glu Val Thr Ala Arg 2870 tgg tta tgg ggt ttc ett tct aga aac aaa aaa ccc aga att tgc aca 8755 Trp Leu Trp Gly Phe 2875 Leu Ser Arg Asn Lys 2880 Lys Pro Arg He Cys 2885 Thr

    2018200081 04 Jan 2018

    aga Arg gag Glu 1 gag ttt Glu Phe 2890 aca Thr aga Arg aaa Lys gtt agg Val Arg 2895 tea Ser aac Asn gca Ala get att Ala He 2900 gga Gly gca Ala 8803 gtg ttc gtt gat gaa aat caa tgg aac teg gca aaa gaa gca gtg gaa 8851 Val Phe 2905 Val Asp Glu Asn Gin 291C Trp Asn 1 Ser Ala Lys 291Ξ Glu Ala Val Glu gac gaa cgg ttc tgg gaa ett gtc cac aga gag agg gag ett cat aaa 8899 Asp 292C Glu 1 Arg Phe Trp Glu 292E Leu Val His Arg Glu 293C Arg I Glu Leu His Lys 2935 cag ggg aaa tgt gcc aeg tgt gtc tac aat atg atg ggg aag aga gag 8947 Gin Gly Lys Cys Ala Thr 2940 Cys Val Tyr Asn Met 2945 Met Gly Lys Arg Glu 2950 aaa aaa tta gga gag ttc gga aag gca aaa gga agt cgt gca ata tgg 8995 Lys Lys Leu Gly Glu 2955 Phe Gly Lys Ala Lys 2960 Gly Ser Arg Ala He 2965 Trp tac atg tgg ttg gga gca ege ttc eta gag ttt gaa gcc ett ggt ttc 9043 Tyr Met Trp Leu 2970 Gly Ala Arg Phe Leu 2975 Glu Phe Glu Ala Leu 2980 Gly Phe atg aat gaa gat cac tgg ttc agt aga gag aat tea etc agt gga gtg 9091 Met Asn Glu Asp 2985 His Trp Phe Ser Arg 2990 Glu Asn Ser Leu Ser 2995 Gly Val gaa gga gaa gga etc cac aaa ett gga tac ata etc aga gac ata tea 9139 Glu Gly 3000 Glu Gly Leu His Lys 3005 Leu Gly Tyr He Leu 3010 Arg Asp He Ser 3015 agg att cca ggg ggg aac atg tat gca gat gac aca gcc gga tgg gac 9187 Arg He Pro Gly Gly Asn 3020 Met Tyr Ala Asp Asp 3025 Thr Ala Gly Trp Asp 3030 aca aga ata aca gag gat gat etc cag aat gag get aaa ate act gac 9235 Thr Arg He Thr Glu 3035 Asp Asp Leu Gin Asn 3040 Glu Ala Lys He Thr 3045 Asp ate atg gag ccc gaa cat gcc ctg ctg get aeg tea ate ttt aag ctg 9283 lie Met Glu Pro 3050 Glu His Ala Leu Leu 3055 Ala Thr Ser He Phe 3060 Lys Leu acc tac caa aat aag gtg gta agg gtg cag aga cca gca aaa aat gga 9331 Thr Tyr Gin Asn 3065 Lys Val Val Arg Val 3070 Gin Arg Pro Ala Lys 3075 Asn Gly acc gtg atg gat gtt ata tcc aga cgt gac cag aga ggc agt gga cag 9379 Thr Val 3080 Met Asp Val He Ser 3085 Arg Arg Asp Gin Arg Gly Ser 3090 Gly Gin 3095

    2018200081 04 Jan 2018

    gtt Val gga Gly act Thr tat Tyr ggc tta Gly Leu 3100 aac Asn act Thr ttc Phe acc aac Thr Asn 3105 atg Met gag Glu gcc Ala caa ctg Gin Leu 3110 9427 ata aga caa atg gag tcc gag gga ate ttt tta ccc agc gaa ttg gaa 9475 lie Arg Gin Met Glu Ser Glu Gly He Phe Leu Pro Ser Glu Leu Glu 3115 3120 3125 acc cca aat eta gcc gga aga gtt etc gac tgg ttg gaa aaa tat ggt 9523 Thr Pro Asn Leu Ala Gly Arg Val Leu Asp Trp Leu Glu Lys Tyr Gly 3130 3135 3140 gtc gaa agg ctg aaa aga atg gca ate agc gga gat gac tgt gtg gtg 9571 Val Glu Arg Leu Lys Arg Met Ala He Ser Gly Asp Asp Cys Val Val 3145 3150 3155 aaa cca att gat gac agg ttc gca aca gcc tta aca get ttg aat gac 9619 Lys Pro He Asp Asp Arg Phe Ala Thr Ala Leu Thr Ala Leu Asn Asp 3160 3165 3170 3175 atg gga aaa gta aga aaa gac ata cca caa tgg gaa cct tea aaa gga 9667 Met Gly Lys Val Arg Lys Asp He Pro Gin Trp Glu Pro Ser Lys Gly 3180 3185 3190 tgg aat gat tgg caa caa gtg cct ttc tgt tea cac cac ttc cac cag 9715 Trp Asn Asp Trp Gin Gin Val Pro Phe Cys Ser His His Phe His Gin 3195 3200 3205 eta att atg aag gat ggg agg gag ata gtg gtg cca tgc ege aac caa 9763 Leu He Met Lys Asp Gly Arg Glu He Val Val Pro Cys Arg Asn Gin 3210 3215 3220 gat gaa ett gtg ggg agg gcc aga gta tea caa ggc gcc gga tgg agc 9811 Asp Glu Leu Val Gly Arg Ala Arg Val Ser Gin Gly Ala Gly Trp Ser 3225 3230 3235 ctg aga gaa acc gca tgc eta ggc aag tea tat gca caa atg tgg cag 9859 Leu Arg Glu Thr Ala Cys Leu Gly Lys Ser Tyr Ala Gin Met Trp Gin 3240 3245 3250 3255 ctg atg tat ttc cac agg aga gac ctg aga ctg geg get aac get att 9907 Leu Met Tyr Phe His Arg Arg Asp Leu Arg Leu Ala Ala Asn Ala He 3260 3265 3270 tgt tea gee gtt cca gtt gat tgg gtc cca acc agc ege acc acc tgg 9955 Cys Ser Ala Val Pro Val Asp Trp Val Pro Thr Ser Arg Thr Thr Trp 3275 3280 3285 teg ate cat gcc cat cac caa tgg atg aca aca gaa gac atg tta tea 10003 Ser lie His Ala His His Gin Trp Met Thr Thr Glu Asp Met Leu Ser 3290 3295 3300 gta tgg aat agg gtc tgg ata gag gaa aac cca tgg atg gag gat aag 10051 Val Trp Asn Arg Val Trp He Glu Glu Asn Pro Trp Met Glu Asp Lys

    3305 3310 3315

    2018200081 04 Jan 2018

    act cat Thr His 3320 gtg Val tcc Ser agt Ser tgg gaa gaa gtt cca tac eta gga aag agg gaa Pro Tyr Leu Gly Lys Arg Glu 10099 Trp Glu Glu 3325 Val 3330 3335 gat cag tgg tgt gga tcc ctg ata ggc tta aca gca agg gcc acc tgg 10147 Asp Gin Trp Cys Gly Ser Leu lie Gly Leu Thr Ala Arg Ala Thr Trp 3340 3345 3350 gcc act aat ata caa gtg gcc ata aac caa gtg aga agg etc att ggg 10195 Ala- Thr Asn lie Gin Val Ala lie Asn Gin Val Arg Arg Leu He Gly 3355 3360 3365 aat gag aat tat eta gat tac atg aca tea atg aag aga ttc aag aat 10243 Asn Glu Asn Tyr Leu Asp Tyr Met Thr Ser Met Lys Arg Phe Lys Asn 3370 3375 3380 gag agt gat ccc gaa ggg gca etc tgg taa gtcaacacat tcacaaaata 10293 Glu Ser Asp Pro Glu Gly Ala Leu Trp *

    3385 3390 aaggaaaata aaaaatcaaa tgaggcaaga agtcaggcca gattaagcca tagtacggta 10353 agagctatgc tgcctgtgag ccccgtccaa ggacgtaaaa tgaagtcagg ccgaaagcca 10413 cggtttgagc aagccgtgct gcctgtggct ccatcgtggg gatgtaaaaa cccgggaggc 10473 tgcaacccat ggaagctgta cgcatggggt agcagactag tggttagagg agacccctcc 10533 caagacacaa cgcagcagcg gggcccaaca ccaggggaag ctgtaccctg gtggtaagga 10593 ctagaggtta gaggagaccc cccgcgtaac aataaacagc atattgacgc tgggagagac 10653 cagagatcct gctgtctcta cagcatcatt ccaggcacag aacgccagaa aatggaatgg 10713 tgctgttgaa tcaacaggtt ct 10735 <210> 2 <211> 3392 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note =

    synthetic construct <400> 2 Met He Asn Gin Arg Lys Lys Thr Gly Arg Pro Ser Phe Asn Met Leu 1 5 10 15 Lys Arg Ala Arg Asn Arg Val Ser Thr Val Ser Gin Leu Ala Lys Arg 20 25 30 Phe Ser Lys Gly Leu Leu Ser Gly Gin Gly Pro Met Lys Leu Val Met 35 40 45 Ala Phe He Ala Phe Leu Arg Phe Leu Ala lie Pro Pro Thr Ala Gly 50 55 60 lie Leu Ala Arg Trp Gly Ser Phe Lys Lys Asn Gly Ala He Lys Val 65 70 75 80 Leu Arg Gly Phe Lys Arg Glu He Ser Asn Met Leu Asn He Met Asn 85 90 95 Arg Arg Lys Arg Ser Val Thr Met Leu Leu Met Leu Leu Pro Thr Ala 100 105 110

    2018200081 04 Jan 2018

    Leu Ala Phe His 115 Leu Thr Thr Arg Gly Gly Glu Pro His Met He Val 120 125 Ser Lys Gin Glu Arg Gly Lys Ser Leu Leu Phe Lys Thr Ser Ala Gly 130 135 140 Val Asn Met Cys Thr Leu He Ala Met Asp Leu Gly Glu Leu Cys Glu 145 150 155 160 Asp Thr Met Thr Tyr Lys Cys Pro Arg lie Thr Glu Ala Glu Pro Asp 165 170 175 Asp Val Asp Cys Trp Cys Asn Ala Thr Asp Thr Trp Val Thr Tyr Gly 180 185 190 Thr Cys Ser Gin Thr Gly Glu His Arg Arg Asp Lys Arg Ser Val Ala 195 200 205 Leu Ala Pro His Val Gly Leu Gly Leu Glu Thr Arg Ala Glu Thr Trp 210 215 220 Met Ser Ser Glu Gly Ala Trp Lys Gin He Gin Lys Val Glu Thr Trp 225 230 235 240 Ala Leu Arg His Pro Gly Phe Thr Val He Ala Leu Phe Leu Ala His 245 250 255 Ala lie Gly Thr Ser He Thr Gin Lys Gly He He Phe He Leu Leu 260 265 270 Met Leu Val Thr Pro Ser Met Ala Met Arg Cys Val Gly He Qiy Asn 275 280 285 Arg Asp Phe Val Glu Gly Leu Ser Gly Ala Thr Trp Val Asp Val Val 290 295 300 Leu Glu His Gly Ser Cys Val Thr Thr Met Ala Lys Asn Lys Pro Thr 305 310 315 320 Leu Asp lie Glu Leu Leu Lys Thr Glu Val Thr Asn Pro Ala Val Leu 325 330 335 Arg Lys Leu Cys He Glu Ala Lys He Ser Asn Thr Thr Thr Asp Ser 340 345 350 Arg Cys Pro Thr Gin Gly Glu Ala Thr Leu Val Glu Glu Gin Asp Ala 355 360 365 Asn Phe Val Cys Arg Arg Thr Phe Val Asp Arg Gly Trp Gly Asn Gly 370 375 380 Cys Gly Leu Phe Gly Lys Gly Ser Leu He Thr Cys Ala Lys Phe Lys 385 390 395 400 Cys Val Thr Lys Leu Glu Gly Lys He Val Gin Tyr Glu Asn Leu Lys 405 410 415 Tyr Ser Val He Val Thr Val His Thr Gly Asp Gin His Gin Val Gly 420 425 430 Asn Glu Thr Thr Glu His Gly Thr Thr Ala Thr He Thr Pro Gin Ala 435 440 445 Pro Thr Ser Glu He Gin Leu Thr Asp Tyr Gly Thr Leu Thr Leu Asp 450 455 460 Cys Ser Pro Arg Thr Gly Leu Asp Phe Asn Glu Met Val Leu Leu Thr 465 470 475 480 Met Lys Glu Arg Ser Trp Leu Val His Lys Gin Trp Phe Leu Asp Leu 485 490 495 Pro Leu Pro Trp Thr Ser Gly Ala Ser Thr Ser Gin Glu Thr Trp Asn 500 505 510 Arg Gin Asp Leu Leu Val Thr Phe Lys Thr Ala His Ala Lys Lys Gin 515 520 525 Glu Val Val Val Leu Gly Ser Gin Glu Gly Ala Met His Thr Ala Leu 530 535 540

    2018200081 04 Jan 2018

    Thr Gly Ala Thr Glu He Gin Thr Ser Gly Thr Thr Thr lie Phe Ala 545 550 555 560 Gly His Leu Lys Cys Arg Leu Lys Met Asp Lys Leu Thr Leu Lys Gly 565 570 575 Met Ser Tyr Val Met Cys Thr Gly Ser Phe Lys Leu Glu Lys Glu Val 580 585 590 Ala Glu Thr Gin His Gly Thr Val Leu Val Gin Val Lys Tyr Glu Gly 595 600 605 Thr Asp Ala Pro Cys Lys He Pro Phe Ser Thr Gin Asp Glu Lys Gly 610 615 620 Ala Thr Gin Asn Gly Arg Leu He Thr Ala Asn Pro He Val Thr Asp 625 630 635 640 Lys Glu Lys Pro Val Asn He Glu Ala Glu Pro Pro Phe Gly Glu Ser 645 650 655 Tyr lie Val Val Gly Ala' Gly Glu Lys Ala Leu Lys Leu Ser Trp Phe 660 665 670 Lys Lys Gly Ser Ser He Gly Lys Met Phe Glu Ala Thr Ala Arg Gly 675 680 685 Ala Arg Arg Met Ala He Leu Gly Asp Thr Ala Trp Asp Phe Gly Ser 690 695 700 lie Gly Gly Val Phe Thr Ser Met Gly Lys Leu Val His Gin Val Phe 705 710 715 720 Gly Thr Ala Tyr Gly Val Leu Phe Ser Gly Val Ser Trp Thr Met Lys 725 730 735 He Gly He Gly He Leu Leu Thr Trp Leu Gly Leu Asn Ser Arg Asn 740 745 750 Thr Ser Leu Ser Met Met Cys He Ala Val Gly Met Val Thr Leu Tyr 755 760 765 Leu Gly Val Met Val Gin Ala Asp Ser Gly Cys Val He Asn Trp Lys 770 775 780 Gly Arg Glu Leu Lys Cys Gly Ser Gly He Phe Val Thr Asn Glu Val 785 790 795 800 His Thr Trp Thr Glu Gin Tyr Lys Phe Gin Ala Asp Ser Pro Lys Arg 805 810 815 Leu Ser Ala Ala He Gly Lys Ala Trp Glu Glu Gly Val Cys Gly He 820 825 830 Arg Ser Ala Thr Arg Leu Glu Asn He Met Trp Lys Gin lie Ser Asn 835 840 845 Glu Leu Asn His He Leu Leu Glu Asn Asp Met Lys Phe Thr Val Val 850 855 860 Val' Gly Asp Val Ser Gly He Leu Ala Gin Gly Lys Lys Met He Arg 865 870 875 880 Pro Gin Pro Met Glu His Lys Tyr Ser Trp Lys Ser Trp Gly Lys Ala 885 890 895 Lys He He Gly Ala Asp Val Gin Asn Thr Thr Phe He He Asp Gly 900 905 910 Pro Asn Thr Pro Glu Cys Pro Asp Asn Gin Arg Ala Trp Asn He Trp 915 920 925 Glu Val Glu Asp Tyr Gly Phe Gly He Phe Thr Thr Asn He Trp Leu 930 935 940 Lys Leu Arg Asp Ser Tyr Thr Gin Val Cys Asp His Arg Leu Met Ser 945 950 955 960 Ala Ala He Lys Asp Ser Lys Ala Val His Ala Asp Met Gly Tyr Trp 965 970 975

    2018200081 04 Jan 2018

    lie Glu Ser Glu Lys Asn Glu Thr Trp Lys Leu Ala Arg Ala Ser Phe 980 985 990 He Glu Val Lys Thr Cys He Trp Pro Lys Ser His Thr Leu Trp Ser 995 1000 1005 Asn Gly Val Leu Glu Ser Glu Met lie lie Pro Lys He Tyr Gly Gly 1010 1015 1020 Pro He Ser Gin His Asn Tyr Arg Pro Gly Tyr Phe Thr Gin Thr Ala 1025 1030 1035 1040 Gly Pro Trp His Leu Gly Lys Leu Glu Leu Asp Phe Asp Phe Cys Glu 1045 1050 1055 Gly Thr Thr Val Val Val Asp Glu His Cys Gly Asn Arg Gly Pro Ser 1060 1065 i 1070 Leu Arg Thr Thr Thr Val Thr Gly Lys He He His Glu Trp Cys Cys 1075 1080 1085 Arg Ser Cys Thr Leu Pro Pro Leu Arg Phe Lys Gly Glu Asp Gly Cys 1090 1095 1100 Trp Tyr Gly Met Glu He Arg Pro Val Lys Asp Lys Glu Glu Asn Leu 1105 1110 1115 1120 Val Lys Ser Met Val Ser Ala Gly Ser Gly Glu Val Asp Ser Phe Ser 1125 1130 1135 Leu Gly Leu Leu Cys He Ser He Met He Glu Glu Val Met Arg Ser 114C 1 1145 ; 1150 Arg Trp Ser Lys Lys Met Leu Met Thr Gly Thr Leu Ala Val Phe Leu 1155 1160 1165 Leu Leu He Met Gly Gin Leu Thr Trp Ser Asp Leu He Arg Leu Cys 1170 1175 1180 He Met Val Gly Ala Asn Ala Ser Asp Lys Met Gly Met Gly Thr Thr 1185 1190 1195 1200 Tyr Leu Ala Leu Met Ala Thr Phe Lys Met Arg Pro Met Phe Ala Val 1205 1210 1215 Gly Leu Leu Phe Arg Arg Leu Thr Ser Arg Glu Val Leu Leu Leu'Thr 122C I 1225 i 1230 He Gly Leu Ser Leu Val Ala Ser Val Glu Leu Pro Ser Ser Leu Glu 1235 1240 1245 Glu Leu Gly Asp Gly Leu Ala He Gly He Met Met Leu Lys Leu Leu 1250 1255 1260 Thr Asp Phe Gin Ser His Gin Leu Trp Ala Thr Leu Leu Ser Leu Thr 1265 1270 1275 1280 Phe He Lys Thr Thr Phe Ser Leu His Tyr Ala Trp Lys Thr Met Ala 1285 1290 1295 Met Val Leu Ser lie Val Ser Leu Phe Pro Leu Cys Leu Ser Thr Thr 1300 1305 1310 Ser Gin Lys Thr Thr Trp Leu Pro Val Leu Leu Gly Ser Leu Gly Cys 1315 1320 1325 Lys Pro Leu Pro Met Phe Leu He Thr Glu Asn Lys He Trp Gly Arg 1330 1335 1340 Lys Ser Trp Pro Leu Asn Glu Gly He Met Ala Val Gly He Val Ser 1345 1350 1355 1360 He Leu Leu Ser Ser Leu Leu Lys Asn Asp Val Pro Leu Ala Gly Pro 1365 1370 1375 Leu He Ala Gly Gly Met Leu He Ala Cys Tyr Val He Ser Gly Ser 1380 1385 1390 Ser Ala Asp Leu Ser Leu Glu Lys Ala Ala Glu Val Ser Trp Glu Glu 1395 1400 1405

    2018200081 04 Jan 2018

    Glu Ala Glu His Ser Gly Ala Ser His Asn He Leu Val Glu Val Gin 1410 1415 1420 Asp Asp Gly Thr Met Lys He Lys Asp Glu Glu Arg Asp Asp Thr Leu 1425 1430 1435 1440 Thr He Leu Leu Lys Ala Thr Leu Leu Ala Val Ser Gly Val Tyr Pro 1445 1450 1455 Met Ser He Pro Ala Thr Leu Phe Val Trp Tyr Phe Trp Gin Lys Lys 1460 1465 1470 Lys Gin Arg Ser Gly Val Leu Trp Asp Thr Pro Ser Pro Pro Glu Val 1475 148C 1 1485 Glu Arg Ala Val Leu Asp Asp Gly He Tyr Arg He Leu Gin Arg Gly 1490 1495 1500 Leu Leu Gly Arg Ser Gin Val Gly Val Gly Val Phe Gin Glu Gly Val 1505 1510 1515 1520 Phe His Thr Met Trp His Val Thr Arg Gly Ala Val Leu Met Tyr Gin 1525 ’ 1530 1535 Gly Lys Arg Leu Glu Pro Ser Trp Ala Ser Val Lys Lys Asp Leu lie 1540 1545 1550 Ser Tyr Gly Gly Gly Trp Arg Phe Gin Gly Ser Trp Asn Thr Gly Glu 1555 1560 1565 Glu Val Gin Val He Ala Val Glu Pro Gly Lys Asn Pro Lys Asn Val 1570 1575 1580 Gin Thr Thr Pro Gly Thr Phe Lys Thr Pro Glu Gly Glu Val Gly Ala 1585 1590 1595 1600 lie Ala Leu Asp Phe Lys Pro Gly Thr Ser Gly Ser Pro He Val Asn 1605 1610 1615 Arg Glu Gly Lys He Val Gly Leu Tyr Gly Asn Gly Val Val Thr Thr 1620 1625 1630 Ser Gly Thr Tyr Val Ser Ala He Ala Gin Ala Lys Ala Ser Gin Glu 1635 1640 1645 Gly Pro Leu Pro Glu He Glu Asp Glu Val Phe Arg Lys Arg Asn Leu 1650 1655 1660 Thr He Met Asp Leu His Pro Gly Ser Gly Lys Thr Arg Arg Tyr Leu 1665 1670 1675 1680 Pro Ala He Val Arg Glu Ala lie Lys Arg Lys Leu Arg Thr Leu He 1685 1690 1695 Leu Ala Pro Thr Arg Val Val Ala Ser Glu Met Ala Glu Ala Leu Lys 1700 1705 1710 Gly Val Pro He Arg Tyr Gin Thr Thr Ala Val Lys Ser Glu His Thr 1715 1720 1725 Gly Lys Glu He Val Asp Leu Met Cys His Ala Thr Phe Thr Met Arg 1730 1735 1740 Leu Leu Ser Pro Val Arg Val Pro Asn Tyr Asn Met He He Met Asp 1745 1750 1755 1760 Glu Ala His Phe Thr Asp Pro Ala Ser He Ala Ala Arg Gly Tyr He 1765 1770 1775 Ser Thr Arg Val Gly Met Gly Glu Ala Ala Ala He Phe Met Thr Ala 1780 1785 1790 Thr Pro Pro Gly Ser Val Glu Ala Phe Pro Gin Ser Asn Ala He He 1795 1800 1805 Gin Asp Glu Glu Arg Asp He Pro Glu Arg Ser Trp Asn Ser Gly Tyr 1810 1815 1820 Asp Trp He Thr Asp Phe Pro Gly Lys Thr Val Trp Phe Val Pro Ser 1825 1830 1835 1840

    2018200081 04 Jan 2018

    lie Lys Ser Gly Asn Asp 1845 He Ala Asn Cys Leu Arg Lys Asn Gly Lys 1850 1855 Arg Val He. Gin Leu Ser Arg Lys Thr Phe Asp Thr Glu Tyr Gin Lys 1860 1865 1870 Thr Lys Asn Asn Asp Trp Asp Tyr Val Val Thr Thr Asp He Ser Glu 1875 1880 1885 Met Gly Ala Asn Phe Arg Ala Asp Arg Val He Asp Pro Arg Arg Cys 1890 1895 1900 Leu Lys Pro Val He Leu Lys Asp Gly Pro Glu Arg Val He Leu Ala 1905 1910 1915 1 1920 Gly Pro Met Pro Val Thr Val Ala Ser Ala Ala Gin Arg Arg Gly Arg 1925 1930 1935 lie Gly Arg Asn Gin Asn Lys Glu Gly Asp Gin Tyr He Tyr Met Gly 1940 1945 1950 Gin Pro Leu Asn Asn Asp Glu Asp His Ala His Trp Thr Glu Ala Lys 1955 1960 1965 Met Leu Leu Asp Asn He Asn Thr Pro Glu Gly He He Pro Ala Leu 1970 1975 1980 Tyr Glu Pro Glu Arg Glu Lys Ser Ala Ala He Asp Gly Glu Tyr Arg 1985 1990 1995 2000 Leu Arg Gly Glu Ala Arg Lys Thr Phe Val Glu Leu Met Arg Arg Gly 2005 2010 2015 Asp Leu Pro Val Trp Leu Ser Tyr Lys Val Ala Ser Glu Gly Phe Gin 2020 2025 2030 Tyr Ser Asp Arg Arg Trp Cys Phe Asp Gly Glu Arg Asn Asn Gin Val 2035 2040 2045 Leu Glu Glu Asn Met Asp Val Glu He Trp Thr Lys Glu Gly Glu Arg 2050 2055 2060 Lys Lys Leu Arg Pro Arg Trp Leu Asp Ala Arg Thr Tyr Ser Asp Pro 2065 2070 2075 2080 Leu Ala Leu Arg Glu Phe Lys Glu Phe Ala Ala Gly Arg Arg Ser Val 2085 2090 2095 Ser Gly Asp Leu lie Leu Glu He Gly Lys Leu Pro Gin His Leu Thr 2100 2105 2110 Gin Arg Ala Gin Asn Ala Leu Asp Asn Leu Val Met Leu His Asn Ser 2115 2120 2125 Glu Gin Gly Gly Lys Ala Tyr Arg His Ala Met Glu Glu Leu Pro Asp 2130 2135 2140 Thr He Glu Thr Leu Met Leu Leu Ala Leu He Ala Val Leu Thr Gly 2145 2150 2155 2160 Gly Val Thr Leu Phe Phe Leu Ser Gly Arg Gly Leu Gly Lys Thr Ser 2165 2170 2175 He Gly Leu Leu Cys Val Met Ala Ser Ser Ala Leu Leu Trp Met Ala 2180 2185 2190 Ser Val Glu Pro His Trp lie Ala Ala Ser He He Leu Glu Phe Phe 2195 2200 2205 Leu Met Val Leu Leu He Pro Glu Pro Asp Arg Gin Arg Thr Pro Gin 2210 2215 2220 Asp Asn Gin Leu Ala Tyr Val Val He Gly Leu Leu Phe Met He Leu 2225 2230 2235 2240 Thr Val Ala Ala Asn Glu Met Gly Leu Leu Glu Thr Thr Lys Lys Asp 2245 2250 2255 Leu Gly He Gly His Val Ala Ala Glu Asn His His His Ala Thr Met

    2260 2265 2270

    2018200081 04 Jan 2018

    Leu Asp Val Asp Leu His 2275 Pro Ala Ser Ala Trp Thr Leu Tyr Ala Val 2280 2285 Ala Thr Thr He He Thr Pro Met Met Arg His Thr lie Glu Asn Thr 2290 2295 2300 Thr Ala Asn He Ser Leu Thr Ala He Ala Asn Gin Ala Ala He Leu 2305 i 231C ι 2315 i 2320 Met Gly Leu Asp Lys Gly Trp Pro He Ser Lys Met Asp He Gly Val 2325 2330 2335 Pro Leu Leu Ala Leu Gly Cys Tyr Ser Gin Val Asn Pro Leu Thr Leu 2340 2345 2350 lie Ala Ala Val Leu Met Leu Val Ala His Tyr Ala He He Gly Pro 2355 2360 2365 Gly Leu Gin Ala Lys Ala Thr Arg Glu Ala Gin Lys Arg Thr Ala Ala 2370 2375 2380 Gly He Met Lys Asn Pro Thr Val Asp Gly He Val Ala He Asp Leu 2385 i 239C I 2395 i 2400 Asp Pro Val Val Tyr Asp Ala Lys Phe Glu Lys Gin Leu Gly Gin He 2405 2410 2415 Met Leu Leu He Leu Cys Thr Ser Gin He Leu Leu Met Arg Thr Thr 2420 2425 2430 Trp Ala Leu Cys Glu Ser He Thr Leu Ala Thr Gly Pro Leu Thr Thr 2435 2440 2445 Leu Trp Glu Gly Ser Pro Gly Lys Phe Trp Asn Thr Thr He Ala Val 2450 2455 2460 Ser Met Ala Asn He Phe Arg Gly Ser Tyr Leu Ala Gly Ala Gly Leu 2465 2470 2475 2480 Ala Phe Ser Leu Met Lys Ser Leu Gly Gly Gly Arg Arg Gly Thr Gly 2485 2490 2495 Ala Gin Gly Glu Thr Leu Gly Glu Lys Trp Lys Arg Gin Leu Asn Gin 2500 2505 2510 Leu Ser Lys Ser Glu Phe Asn Thr Tyr Lys Arg Ser Gly He Met Glu 2515 2520 2525 Val Asp Arg Ser Glu Ala Lys Glu Gly Leu Lys Arg Gly Glu Thr Thr 2530 2535 2540 Lys His Ala Val Ser Arg Gly Thr Ala Lys Leu Arg Trp Phe Val Glu 2545 2550 2555 2560 Arg Asn Leu Val Lys Pro Glu Gly Lys Val He Asp Leu Gly Cys Gly 2565 2570 2575 Arg Gly Gly Trp Ser Tyr Tyr Cys Ala Gly Leu Lys Lys Val Thr Glu 2580 2585 2590 Val Lys Gly Tyr Thr Lys Gly Gly Pro Gly His Glu Glu Pro He Pro 2595 2600 2605 Met Ala Thr Tyr Gly Trp Asn Leu Val Lys Leu His Ser Gly Lys Asp 2610 2615 2620 Val Phe Phe He Pro Pro Glu Lys Cys Asp Thr Leu Leu Cys Asp He 2625 2630 2635 2640 Gly Glu Ser Ser Pro Asn Pro Thr He Glu Glu Gly Arg Thr Leu Arg 2645 2650 2655 Val Leu Lys Met Val Glu Pro Trp Leu Arg Gly Asn Gin Phe Cys lie 2660 2665 2670 Lys He Leu Asn Pro Tyr Met Pro Ser Val Val Glu Thr Leu Glu Gin 2675 2680 2685 Met Gin Arg Lys His Gly Gly Met Leu Val Arg Asn Pro Leu Ser Arg 2690 2695 2700

    2018200081 04 Jan 2018

    Asn Ser Thr His Glu Met Tyr Trp Val Ser Cys Gly Thr Gly Asn He 2705 2710 2715 2720 Val Ser Ala Val Asn Met Thr Ser Arg Met Leu Leu Asn Arg Phe Thr 2725 2730 2735 Met Ala His Arg Lys Pro Thr Tyr Glu Arg Asp Val Asp Leu Gly Ala 2740 2745 2750 Gly Thr Arg His Val Ala Val Glu Pro Glu Val Ala Asn Leu Asp He 2755 2760 2765 lie Gly Gin Arg He Glu Asn He Lys Asn Glu His Lys Ser Thr Trp 2770 2775 2780 His Tyr Asp Glu Asp Asn Pro Tyr Lys Thr Trp Ala Tyr His Gly Ser 2785 2790 2795 2800 Tyr Glu Val Lys Pro Ser Gly Ser Ala Ser Ser Met Val Asn Gly Val 2805 2810 2815 Val Arg Leu Leu Thr Lys Pro Trp Asp Val He Pro Met Val Thr Gin 2820 2825 2830 He Ala Met Thr Asp Thr Thr Pro Phe Gly Gin Gin Arg Val Phe Lys 2835 2840 2845 Glu Lys Val Asp Thr Arg Thr Pro Lys Ala Lys Arg Gly Thr Ala Gin 2850 2855 2860 He Met Glu Val Thr Ala Arg Trp Leu Trp Gly Phe Leu Ser Arg Asn 2865 2870 2875 2880 Lys Lys Pro Arg He Cys Thr Arg Glu Glu Phe Thr Arg Lys Val Arg 2885 2890 2895 Ser Asn Ala Ala He Gly Ala Val Phe Val Asp Glu Asn Gin Trp Asn 2900 2905 2910 Ser Ala Lys Glu Ala Val Glu Asp Glu Arg Phe Trp Glu Leu Val His 2915 2920 2925 Arg Glu Arg Glu Leu His Lys Gin Gly Lys Cys Ala Thr Cys Val Tyr 2930 2935 2940 Asn Met Met Gly Lys Arg Glu Lys Lys Leu Gly Glu Phe Gly Lys Ala 2945 2950 2955 ' 2960 Lys Gly Ser Arg Ala He Trp Tyr Met Trp Leu Gly Ala Arg Phe Leu 2965 2970 2975 Glu Phe Glu Ala Leu Gly Phe Met Asn Glu Asp His Trp Phe Ser Arg 2980 2985 2990 Glu Asn Ser Leu Ser Gly Val Glu Gly Glu Gly Leu His Lys Leu Gly 2995 3000 3005 Tyr He Leu Arg Asp He Ser Arg He Pro Gly Gly Asn Met Tyr Ala 3010 3015 3020 Asp Asp Thr Ala Gly Trp Asp Thr Arg He Thr Glu Asp Asp Leu Gin 3025 3030 3035 3040 Asn Glu Ala Lys He Thr Asp He Met Glu Pro Glu His Ala Leu Leu 3045 3050 3055 Ala Thr Ser He Phe Lys Leu Thr Tyr Gin Asn Lys Val Val Arg Val 3060 3065 3070 Gin Arg Pro Ala Lys Asn Gly Thr Val Met Asp Val He Ser Arg Arg 3075 3080 3085 Asp Gin Arg Gly Ser Gly Gin Val Gly Thr Tyr Gly Leu Asn Thr Phe 3090 3095 3100 Thr Asn Met Glu Ala Gin Leu He Arg Gin Met Glu Ser Glu Gly He 3105 3110 3115 3120 Phe Leu Pro Ser Glu Leu Glu Thr Pro Asn Leu Ala Gly Arg Val Leu 3125 3130 3135

    2018200081 04 Jan 2018

    Asp Trp Leu Glu Lys Tyr Gly Val Glu Arg Leu Lys Arg Met Ala lie 314 0 i 3145 ; 3150 1 Ser Gly Asp Asp 3155 Cys Val Val Lys Pro 3160 He Asp Asp Arg Phe 3165 Ala Thr Ala Leu Thr Ala 3170 Leu Asn Asp Met Gly 3175 Lys Val Arg Lys Asp 3180 He Pro Gin Trp Glu Pro Ser Lys Gly Trp Asn Asp Trp Gin Gin Val Pro Phe 3185 3190 3195 3200 Cys Ser His His Phe His Gin Leu lie Met Lys Asp Gly Arg Glu He 3205 3210 3215 Val Val Pro Cys Arg Asn Gin Asp Glu Leu Val Gly Arg Ala Arg Val 322C I 3225 ; 3230 Ser Gin Gly Ala 3235 Gly Trp Ser Leu Arg , 3240 Glu Thr Ala Cys Leu 3245 Gly Lys Ser Tyr Ala Gin 3250 Met Trp Gin Leu Met 3255 Tyr Phe His Arg Arg 3260 Asp Leu Arg Leu Ala Ala Asn Ala He Cys Ser Ala Val Pro Val Asp Trp Val 3265 3270 3275 3280 Pro Thr Ser Arg Thr Thr Trp Ser He 3285 His Ala His His Gin 3290 Trp Met 3295 Thr Thr Glu Asp Met Leu Ser Val Trp Asn Arg Val Trp He Glu Glu 3300 3305 3310 Asn Pro Trp Met 3315 Glu Asp Lys Thr His 3320 Val Ser Ser Trp Glu 3325 Glu Val Pro Tyr Leu Gly 3330 Lys Arg Glu Asp Gin 3335 Trp Cys Gly Ser Leu 3340 He Gly Leu Thr Ala Arg Ala Thr Trp Ala Thr Asn He Gin Val Ala He Asn 3345 3350 3355 3360 Gin Val Arg Arg Leu He Gly Asn Glu 3365 Asn Tyr Leu Asp Tyr 3370 Met Thr 3375 Ser Met Lys Arg Phe Lys Asn Glu Ser Asp Pro Glu Gly Ala Leu Trp 3380 3385 3390

    <210> 3 <211> 10735 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <221> CDS <222> (95)...(10273) <400> 3 agttgttagt ctacgtggac cgacaagaac agtttcgaat cggaagcttg cttaacgtag ttctaacagt tttttattag agagcagatc tctg atg ate aac caa ega aaa aag

    Met lie Asn Gin Arg Lys Lys 1 5 aeg ggt ega ccg tet ttc aat atg ctg aaa cgc gcg aga aac cgc gtg Thr Gly Arg Pro Ser Phe Asn Met Leu Lys Arg Ala Arg Asn Arg Val

    10 15 20

    115

    163

    2018200081 04 Jan 2018

    tea act gtt tea cag Ser Gin ttg gcg aag aga ttc tea aaa gga ttg etc tea Ser 211 Ser Thr Val 25 Leu Ala Lys 30 Arg Phe Ser Lys 35 Gly Leu Leu ggc caa gga ccc atg aaa ttg gtg atg get ttc ata gca ttc tta aga 259 Gly Gin Gly Pro Met Lys Leu Val Met Ala Phe He Ala Phe Leu Arg 40 45 50 55 ttt eta gee ata ccc cca aca gca gga att ttg get aga tgg ggc tea 307 Phe Leu Ala He Pro Pro Thr Ala Gly He Leu Ala Arg Trp Gly Ser 60 65 70 ttc aag aag aat gga gcg att aaa gtg tta egg ggt ttc aag aga gaa 355 Phe Lys Lys Asn Gly Ala He Lys Val Leu Arg Gly Phe Lys Arg Glu 75 80 85 ate tea aac atg eta aac ata atg aac agg agg aaa aga tee gtg acc 403 lie Ser Asn Met Leu Asn He Met Asn Arg Arg Lys Arg Ser Val Thr 90 95 100 atg etc ett atg ctg ctg ccc aca gee ctg gcg ttc cat ctg aeg aca 451 Met Leu Leu Met Leu Leu Pro Thr Ala Leu Ala Phe His Leu Thr Thr 105 110 115 ega ggg gga gag ccg cat atg ata gtt age aag cag gaa aga gga aag 499 Arg Gly Gly Glu Pro His Met He Val Ser Lys Gin Glu Arg Gly Lys 120 125 13 0 135 tea ett ttg ttc aag acc tet gca ggt gtc aac atg tgc acc etc att 547 Ser Leu Leu Phe Lys Thr Ser Ala Gly Val Asn Met Cys Thr Leu He 140 145 150 gcg atg gat ttg gga gag ttg tgt gag gac aeg atg acc tac aaa tgc 595 Ala Met Asp Leu Gly Glu Leu Cys Glu Asp Thr Met Thr Tyr Lys Cys 155 160 165 ccc egg ate act gag gcg gaa cca gat gac gtt gac tgt tgg tgc aat 643 Pro Arg lie Thr Glu Ala Glu Pro Asp Asp Val Asp Cys Trp Cys Asn 170 175 180 gee aeg gac aca tgg gtg acc tat gga aeg tgc tet caa act ggc gaa 691 Ala Thr Asp Thr Trp Val Thr Tyr Gly Thr Cys Ser Gin Thr Gly Glu 185 190 195 cac ega ega gac aaa cgt tee gtc gca ttg gee cca cac gtg ggg ett 739 His Arg Arg Asp Lys Arg Ser Val Ala Leu Ala Pro His Val Gly Leu 200 205 210 215 ggc eta gaa aca aga gee gaa aeg tgg atg tee tet gaa ggt get tgg 787 Gly Leu Glu Thr Arg Ala Glu Thr Trp Met Ser Ser Glu Gly Ala Trp 220 225 230

    2018200081 04 Jan 2018

    aaa Lys cag Gin ata He caa Gin 235 aaa gta Lys Val gag Glu act Thr tgg Trp 240 get Ala ctg aga Leu Arg cat His cca Pro 245 gga Gly ttc Phe 835 aeg gtg ata gee ett ttt eta gca cat gee ata gga aca tec ate acc 883 Thr Val He Ala Leu Phe Leu Ala His Ala He Gly Thr Ser He Thr 250 255 260 cag aaa ggg ate att ttc att ttg ctg atg ctg gta aca cca tct atg 931 Gin Lys Gly He He Phe He Leu Leu Met Leu Val Thr Pro Ser Met 265 270 275 gee atg cga tgc gtg gga ata ggc aac aga gac ttc gtg gaa gga ctg 979 Ala Met Arg Cys Val' Gly He Gly Asn Arg Asp Phe Val Glu Gly Leu 280 285 290 295 tea gga gca aca tgg gtg gat gtg gta ctg • gag cat gga agt tgc gtc 1027 Ser Gly Ala Thr Trp Val Asp Val Val Leu Glu His Gly Ser Cys Val 300 305 310 acc acc atg gca aaa aac aaa cca aca ctg gac att gaa etc ttg aag 1075 Thr Thr Met Ala Lys Asn Lys Pro Thr Leu Asp He Glu Leu Leu Lys 315 320 325 aeg gag gtc aca aac cct gca gtt ctg cgt aaa ttg tgc att gaa get 1123 Thr Glu Val Thr Asn Pro Ala Val Leu Arg Lys Leu Cys He Glu Ala 330 335 340 aaa ata tea aac acc acc acc gat teg aga tgt cca aca caa gga gaa 1171 Lys lie Ser Asn Thr Thr Thr Asp Ser Arg Cys Pro Thr Gin Gly Glu 345 350 355 gcc aca ctg gtg gaa gaa caa gac gcg aac ttt gtg tgc cga cga aeg 1219 Ala Thr Leu Val Glu Glu Gin Asp Ala Asn Phe Val Cys Arg Arg Thr 360 365 370 375 ttc gtg gac aga ggc tgg ggc aat ggc tgt ggg eta ttc gga aaa ggt 1267 Phe Val Asp Arg Gly Trp Gly Asn Gly Cys Gly Leu Phe Gly Lys Gly 380 385 390 agt eta ata aeg tgt gee aag ttt aag tgt gtg aca aaa eta gaa gga 1315 Ser Leu He Thr Cys Ala Lys Phe Lys Cys Val Thr Lys Leu Glu Gly 395 400 405 aag ata get caa tat gaa aac eta aaa tat tea gtg ata gtc acc gtc 1363 Lys He Ala Gin Tyr Glu Asn Leu Lys Tyr Ser Val He Val Thr Val 410 415 420 cac act gga gat cag cac cag gtg gga aat gag act aca gaa cat gga 1411 His Thr Gly Asp Gin His Gin Val Gly Asn Glu Thr Thr Glu His Gly 425 430 435 aca act gca acc ata aca cct caa get cct aeg teg gaa ata cag ctg 1459 Thr Thr Ala Thr He Thr Pro Gin Ala Pro Thr Ser Glu He Gin Leu 440 445 450 455

    2018200081 04 Jan 2018

    acc Thr gac Asp tac Tyr gga Gly acc Thr 460 ett Leu aca Thr tta Leu gat Asp tgt Cys 465 tea Ser cct Pro agg aca ggg eta Leu 1507 Arg Thr Gly 470 gat ttt aac gag atg gtg ttg ctg aca atg aaa aag aaa tea tgg ett 1555 Asp Phe Asn Glu 475 Met Val Leu Leu Thr 480 Met Lys Lys Lys Ser 485 Trp Leu gtc cac aaa cag tgg ttt eta gac tta cca ctg cct tgg acc tet ggg 1603 Val His Lys 490 Gin Trp Phe Leu Asp 495 Leu Pro Leu Pro Trp 500 Thr Ser Gly get tta aca tcc caa gag act tgg aac aga caa gat tta ctg gtc aca 1651 Ala Leu 505 Thr Ser Gin Glu Thr 510 Trp Asn Arg Gin Asp 515 Leu Leu Val Thr ttt aag aca get cat gca aag aag cag gaa gta gtc gta eta gga tea 1699 Phe 520 Lys Thr Ala His Ala 525 Lys Lys Gin Glu Val 530 Val Val Leu Gly Ser 535 caa gaa gga gca atg cac act geg ctg act gga geg aca gaa ate caa 1747 Gin Glu Gly Ala Met 540 His Thr Ala Leu Thr 545 Gly Ala Thr Glu He 550 Gin aeg tea gga aeg aca aca att ttc gca gga cac eta aaa tgc aga eta 1795 Thr Ser Gly Thr 555 Thr Thr He Phe Ala 560 Gly His Leu Lys Cys 565 Arg Leu aaa atg gac aaa eta act tta aaa ggg atg tea tat gtg atg tgc aca 1843 Lys Met Asp 570 Lys Leu Thr Leu Lys 575 Gly Met Ser Tyr Val 580 Met Cys Thr ggc tea ttc aag tta gag aaa gaa gtg get gag acc cag cat gga act 1891 Gly Ser 585 Phe Lys Leu Glu Lys 590 Glu Val Ala Glu Thr 595 Gin His Gly Thr gtt ctg gtg cag gtt aaa tat gaa gga aca gac gca cca tgc aag att 1939 Val 600 Leu Val Gin Val Lys 605 Tyr Glu Gly Thr Asp 610 Ala Pro Cys Lys He 615 ccc ttt teg acc caa gat gag aaa gga gca acc cag aat ggg aga tta 1987 Pro Phe Ser Thr Gin 620 Asp Glu Lys Gly Ala 625 Thr Gin Asn Gly Arg 630 Leu ata aca gcc aac ccc ata gtc act gac aaa gaa aaa cca gtc aat att 2035 lie Thr Ala Asn 635 Pro He Val Thr Asp 640 Lys Glu Lys Pro Val 645 Asn lie gag gca gaa cca ccc ttt ggt gag agc tac ate gtg gta gga gca ggt 2083 Glu Ala Glu 650 Pro Pro Phe Gly Glu 655 Ser Tyr He Val Val 660 Gly Ala Gly

    2018200081 04 Jan 2018

    gaa aaa get Ala ttg aaa Leu Lys eta age Leu Ser 670 tgg Trp ttc Phe aag Lys aaa gga age age ata He ggg Gly 2131 Glu Lys 665 Lys Gly 675 Ser Ser aaa atg ttt gaa gca act gcc ega gga gca ega agg atg gcc att ctg 2179 Lys Met Phe Glu Ala Thr Ala Arg Gly Ala Arg Arg Met Ala lie Leu 680 685 690 695 gga gac acc gca tgg gac ttc ggt tet ata gga gga gtg ttc aeg tet 2227 Gly Asp Thr Ala Trp Asp Phe Gly Ser He Gly Gly Val Phe Thr Ser 700 705 710 atg gga aaa ctg gta cac cag gtt ttt gga act gca tat gga gtt ttg 2275 Met Gly Lys Leu Val His Gin Val Phe Gly Thr Ala Tyr Gly Val Leu 715 720 725 ttt age gga gtt tet tgg acc atg aaa ata gga ata ggg att ctg ctg 2323 Phe Ser Gly Val Ser Trp Thr Met Lys He Gly He Gly He Leu Leu 730 735 740 aca tgg eta gga tta aat tea agg aac aeg tcc ett teg gtg atg tgc 2371 Thr Trp Leu Gly Leu Asn Ser Arg Asn Thr Ser Leu Ser Val Met Cys 745 750 755 ate gca gtt ggc atg gtc aca ctg tac eta gga gtc atg gtt cag gca 2419 lie Ala Val Gly Met Val Thr Leu Tyr Leu Gly Val Met Val Gin Ala 760 765 770 775 gat teg gga tgt gta ate aac tgg aaa ggc aga gaa ett aaa tgt gga 2467 Asp Ser Gly Cys Val He Asn Trp Lys Gly Arg Glu Leu Lys Cys Gly 780 785 790 age ggc att ttt gtc act aat gaa gtt cac act tgg aca gag caa tac 2515 Ser Gly He Phe Val Thr Asn Glu Val His Thr Trp Thr Glu Gin Tyr 795 800 805 aaa ttc cag get gac tcc ccc aag aga eta tea gca gee att ggg aag 2563 Lys Phe Gin Ala Asp Ser Pro Lys Arg Leu Ser Ala Ala He Gly Lys 810 815 820 gca tgg gag gag ggt gtg tgt gga ate ega tea gee act cgt etc gag 2611 Ala Trp Glu Glu Gly Val Cys Gly He Arg Ser Ala Thr Arg Leu Glu 825 830 835 aac ate atg tgg aaa caa ata tea aat gaa ttg aac cac ate eta ett 2659 Asn He Met Trp Lys Gin He Ser Asn Glu Leu Asn His He Leu Leu 840 845 850 855 gaa aat gac atg aaa ttt aca gtg gtc gtg gga gac gtt agt gga ate 2707 Glu Asn Asp Met Lys Phe Thr Val Val Val Gly Asp Val Ser Gly He 860 865 870 ttg gcc caa ggg aaa aaa atg att agg cca caa ccc atg gaa cac aaa 2755 Leu Ala Gin Gly Lys Lys Met lie Arg Pro Gin Pro Met Glu His Lys 875 880 885

    2018200081 04 Jan 2018

    tac teg tgg Tyr Ser Trp 890 aaa Lys age Ser tgg gga aaa get aaa ate ata gga gcg gat gta Val 2803 Trp Gly Lys 895 Ala Lys He He Gly 900 Ala Asp cag aac acc acc ttc ate ate gac ggc cca aac acc cca gaa tgc cct 2851 Gin Asn Thr Thr Phe He He Asp Gly Pro Asn Thr Pro Glu Cys Pro 905 910 915 gac aat caa aga gca tgg aat att tgg gaa gta gag gac tat gga ttt 2899 Asp Asn Gin Arg Ala Trp Asn He Trp Glu Val Glu Asp Tyr Gly Phe 920 925 930 935 ggg att ttc aeg aca aac ata tgg ttg aaa ttg cgt gac tcc tac acc 2947 Gly lie Phe Thr Thr Asn He Trp Leu Lys Leu Arg Asp Ser Tyr Thr 940 945 950 caa gta tgt gac cac egg ctg atg tea get gcc att aag gac age aag 2995 Gin Val Cys Asp His Arg Leu Met Ser Ala Ala He Lys Asp Ser Lys 955 960 965 gca gtc cat get gac atg ggg tac tgg ata gaa agt gaa aag aac gag 3043 Ala Val His Ala Asp Met Gly Tyr Trp He Glu Ser Glu Lys Asn Glu 970 975 980 aca tgg aag ttg gcg aga gcc tcc ttt ata gaa gtt aag aca tgc ate 3091 Thr Trp Lys Leu Ala Arg Ala Ser Phe He Glu Val Lys Thr Cys He 985 990 995 tgg cca aaa tcc cac act eta tgg age aat gga gtt ctg gaa agt gaa 3139 Trp Pro Lys Ser His Thr Leu Trp Ser Asn Gly Val Leu Glu Ser Glu ' 1000 1005 1010 1015 atg ata att cca aag ata tat gga gga cca ata tet cag cac aac tac 3187 Met He He Pro Lys He Tyr Gly Gly Pro He Ser Gin His Asn Tyr 1020 1025 1030 aga cca gga tat ttc aca caa aca gca ggg ccg tgg cac eta ggc aag 3235 Arg Pro Gly Tyr Phe Thr Gin Thr Ala Gly Pro Trp His Leu Gly Lys 1035 1040 1045 ttg gaa eta gat ttc gat ttt tgt gaa ggt acc aca gtt gtt gtg gat 3283 Leu Glu Leu Asp Phe Asp Phe Cys Glu Gly Thr Thr Val Val Val Asp 1050 1055 1060 gaa cat tgt gga aat ega gga cca tet etc aga acc aca aca gtc aca 3331 Glu His Cys Gly Asn Arg Gly Pro Ser Leu Arg Thr Thr Thr Val Thr 1065 1070 1075 gga aag ata ate cat gaa tgg tgc tgc aga tet tgt aeg eta ccc ccc 3379 Gly Lys He lie His Glu Trp Cys Cys Arg Ser Cys Thr Leu Pro Pro 1080 1085 1090 1095

    2018200081 04 Jan 2018

    eta Leu cgt Arg ttc Phe aaa Lys ggg gaa Gly Glu 1100 gac Asp ggg Gly tgt Cys tgg tac Trp Tyr 1105 ggc Gly atg Met gaa Glu ate aga He Arg 1110 3427 cca gtg aag gac aag gaa gag aac ctg gtc aag tea atg gtc tet gca 3475 Pro Val Lys Asp 1115 Lys Glu Glu Asn Leu 112C Val Lys 1 Ser Met Val 1125 Ser Ala ggg tea gga gaa gtg gac agc ttt tea eta gga ctg eta tgc ata tea 3523 Gly Ser Gly 113C Glu 1 Val Asp Ser Phe 1135 Ser Leu Gly Leu Leu Cys 1140 He Ser ata atg att gaa gaa gtg atg aga tcc aga tgg agc aaa aaa atg ctg 3571 lie Met He 1145 Glu Glu Val Met Arg 1150 Ser Arg Trp Ser Lys 1155 Lys Met Leu atg act gga aca ctg get gtg ttc etc ett ett ata atg gga caa ttg 3619 Met Thr 1160 Gly Thr Leu Ala Val 1165 Phe Leu Leu Leu lie 1170 Met Gly Gin Leu 1175 aca tgg agt gat ctg ate agg tta tgt att atg gtt gga gcc aac get 3667 Thr Trp Ser Asp Leu He 1180 Arg Leu Cys He Met 1185 Val Gly Ala Asn Ala 1190 tea gac aag atg ggg atg gga aca aeg tac eta get tta atg gcc act 3715 Ser Asp Lys Met Gly Met 1195 Gly Thr Thr Tyr Leu 1200 Ala Leu Met Ala Thr 1205 ttc aaa atg aga cca atg ttc gcc gtc ggg eta tta ttt ege aga eta 3763 Phe Lys Met Arg 1210 Pro Met Phe Ala Val 1215 Gly Leu Leu Phe Arg 1220 Arg Leu aca tet aga gaa gtt ett ett ett aca att ggc ttg age ctg gtg gca 3811 Thr Ser Arg 1225 Glu Val Leu Leu Leu 1230 Thr He Gly Leu Ser 1235 Leu Val Ala tcc gtg gag eta cca agt tcc eta gag gag ctg ggg gat gga ett gca 3859 Ser Val 1240 Glu Leu Pro Ser Ser 1245 Leu Glu Glu Leu Gly 1250 Asp Gly Leu Ala 1255 ata ggc ate atg atg ttg aaa tta ttg act gat ttt cag tea cac cag 3907 He Gly He Met Met Leu 1260 Lys Leu Leu Thr Asp 1265 Phe Gin Ser His Gin 1270 eta tgg get act ctg eta tcc ttg aca ttt att aaa aca act ttt tea 3955 Leu Trp Ala Thr Leu Leu 1275 Ser Leu Thr Phe He 1280 Lys Thr Thr Phe Ser 1285 ttg cac tat gca tgg aag aca atg get atg gta ctg tea att gta tet 4003 Leu His Tyr Ala 1290 Trp Lys Thr Met Ala 1295 Met Val Leu Ser He 1300 Val Ser etc ttc cct tta tgc ctg tcc aeg acc tet caa aaa aca aca tgg ett 4051 Leu Phe Pro 1305 Leu Cys Leu Ser Thr 1310 Thr Ser Gin Lys Thr 1315 Thr Trp Leu

    2018200081 04 Jan 2018

    ccg gtg Pro Val 1320 ctg ttg gga Leu Leu Gly tct ett Ser Leu 1325 gga Gly tgc Cys aaa Lys cca eta Pro Leu 1330 ccc Pro atg Met ttt Phe ett Leu 1335 4099 ata aca gaa aac aaa ate tgg gga agg aag agt tgg ccc etc aat gaa 4147 lie Thr Glu Asn Lys 134C lie Trp 1 Gly Arg Lys 1345 Ser Trp Pro Leu Asn 135C Glu 1 gga att atg get gtt gga ata gtt agt att eta eta agt tea ett tta 4195 Gly lie Met Ala Val 1355 Gly lie Val Ser He 1360 Leu Leu Ser Ser 1365 Leu Leu aaa aat gat gtg ccg eta gcc ggc cca tta ata get gga ggc atg eta 4243 Lys Asn Asp Val Pro 1370 Leu Ala Gly 1375 Pro Leu He Ala Gly Gly 1380 Met Leu ata gca tgt tat gtc ata tcc gga agc tea get gat tta tea ctg gag 4291 He Ala Cys Tyr Val 1385 He Ser Gly 1390 Ser Ser Ala Asp 1395 Leu Ser Leu Glu aaa gcg get gag gtc tcc tgg gag gaa gaa gca gaa cac tea ggc gcc 4339 Lys Ala 1400 Ala Glu Val Ser Trp 1405 Glu Glu Glu Ala Glu 1410 His Ser Gly Ala 1415 tea cac aac ata eta gta gag gtt caa gat gat gga acc atg aag ata 4387 Ser His Asn He Leu 142C Val Glu 1 Val Gin Asp 1425 Asp Gly Thr Met Lys He 1430 aaa gat gaa gag aga gat gac aeg etc acc att etc ett aaa gca act 4435 Lys Asp Glu Glu Arg 1435 Asp Asp Thr Leu Thr 1440 He Leu Leu Lys 1445 Ala Thr ctg ctg gca gtc tea ggg gtg tac cca atg tea ata cca gcg acc ett 4483 Leu Leu Ala Val Ser 1450 Gly Val Tyr Pro 1455 Met Ser He Pro Ala 1460 Thr Leu ttt gtg tgg tat ttt tgg cag aaa aag aaa cag aga tea gga gtg eta 4531 Phe Val Trp Tyr Phe 1465 Trp Gin Lys 1470 Lys Lys Gin Arg Ser 1475 Gly Val Leu tgg gac aca ccc agc ccc cca gaa gtg gaa aga gca gtt ett gat gat 4579 Trp Asp 1480 Thr Pro Ser Pro Pro 1485 Glu Val Glu Arg Ala 1490 Val Leu Asp Asp 1495 ggc ate tat aga att ttg caa aga gga ctg ttg ggc agg tcc caa gta 4627 Gly He Tyr Arg He 150C Leu Gin 1 Arg Gly Leu Leu Gly 1505 Arg Ser Gin Val 1510 gga gta gga gtt ttc caa gaa ggc gtg ttc cac aca atg tgg cac gtc 4675 Gly Val Gly Val Phe 1515 Gin Glu Gly Val Phe 1520 His Thr Met Trp His 1525 Val

    2018200081 04 Jan 2018

    act Thr agg Arg gga get Gly Ala 1530 gtc Val etc Leu atg Met tat caa Tyr Gin 1535 gga Gly aaa Lys agg Arg etg gaa Leu Glu 1540 cca Pro agc Ser 4723 tgg gcc agt gtc aaa aaa gac ttg ate tea tat gga gga ggt tgg agg 4771 Trp Ala 1545 Ser Val Lys Lys Asp 155C Leu He 1 Ser Tyr Gly 1555 Gly Gly Trp Arg ttt caa gga tec tgg aac aeg gga gaa gaa gta cag gtg att get gtt 4819 Phe 156C Gin I Gly Ser Trp Asn Thr 1565 Gly Glu Glu Val 157C Gin 1 Val He Ala Val 1575 gaa ccg gga aaa aac ccc aaa aat gta caa aca aeg ccg ggt acc ttc 4867 Glu Pro Gly Lys Asn 158C Pro i Lys Asn Val Gin Thr 1585 Thr Pro Gly Thr Phe 1590 aag acc cct gaa ggc gaa gtt gga gcc ata gee tta gac ttt aaa cct 4915 Lys Thr Pro Glu Gly 1595 ' Glu Val Gly Ala He 1600 Ala Leu Asp Phe Lys 1605 Pro ggc aca tet gga tet ccc ate gta aac aga gag gga aaa ata gta ggt 4963 Gly Thr Ser Gly 1610 Ser Pro He Val Asn 1615 Arg Glu Gly Lys He 1620 Val Gly ctt tat gga aat gga gtg gtg aca aca agc gga act tac gtt agt gcc 5011 Leu Tyr Gly Asn 1625 Gly Val Val 163C Thr Thr I Ser Gly Thr 1635 Tyr Val Ser Ala ata get caa get aag gca tea caa gaa ggg cct eta cca gag att gag 5059 lie 164C Ala I Gin Ala Lys Ala Ser 1645 Gin Glu Gly Pro 165C Leu 1 Pro Glu He Glu 1655 gac aag gtg ttt agg aaa aga aac tta aca ata atg gac eta cat cca 5107 Asp Lys Val Phe Arg Lys 1660 Arg Asn Leu Thr He 1665 Met Asp Leu His 167C Pro ) gga teg gga aaa aca aga aga tac ctt cca gee ata gtc cgt gag gcc 5155 Gly Ser Gly Lys Thr 1675 Arg Arg Tyr Leu Pro 1680 Ala He Val Arg Glu 1685 Ala ata aaa agg aag ctg ege aeg eta ate eta get ccc aca aga gtt gtc 5203 He Lys Arg Lys 1690 Leu Arg Thr Leu He 1695 Leu Ala Pro Thr Arg 1700 Val Val get tet gaa atg gca gag gca etc aag gga gtg cca ata agg tat cag 5251 Ala Ser Glu Met 1705 Ala Glu Ala Leu Lys 1710 Gly Val Pro 1715 He Arg Tyr Gin aca aca gca gtg aag agt gaa cac aca gga aag gag ata gtt gac ctt 5299 Thr Thr 1720 Ala Val Lys Ser Glu 1725 His Thr Gly Lys 173C Glu I He Val Asp Leu 1735 atg tgc cac gcc act ttc acc atg ege etc ctg tet ccc gtg aga gtt 5347 Met Cys His Ala Thr Phe 1740 Thr Met Arg Leu Leu 1745 Ser Pro Val Arg Val 1750

    2018200081 04 Jan 2018

    ccc Pro aat Asn tat Tyr aac Asn 1755 atg Met att He ate He atg Met gat gaa Asp Glu 1760 gca Ala cac His ttc Phe acc gat Thr Asp 1765 cca Pro 5395 gcc age ata gca gcc aga ggg tac ate tea acc cga gtg ggt atg ggt 5443 Ala Ser lie 177C Ala 1 Ala Arg Gly Tyr 1775 He Ser Thr Arg Val 178C Gly Met 1 Gly gaa gca get gcg ate ttt atg aca gcc act ccc cca gga teg gtg gag 5491 Glu Ala 1785 Ala Ala He Phe Met 179C Thr 1 Ala Thr Pro Pro 1795 Gly Ser Val Glu gcc ttt cca cag age aat gca att ate caa gat gag gaa aga gac att 5539 Ala Phe 1800 Pro Gin Ser Asn Ala 1805 He lie Gin Asp Glu 1810 Glu Arg Asp He •1815 cct gag aga tea tgg aac tea ggc tat gac tgg ate act gat ttt cca 5587 Pro Glu Arg Ser Trp Asn 1820 Ser Gly Tyr Asp Trp 1825 He Thr Asp Phe Pro 1830 ggt aaa aca gtc tgg ttt gtt cca age ate aaa tea gga aat gac att 5635 Gly Lys Thr Val 1835 Trp Phe Val Pro Ser He 1840 Lys Ser Gly Asn Asp 1845 lie gcc aac tgt tta aga aaa aac ggg aaa egg gtg ate caa ttg age aga 5683 Ala Asn Cys Leu 1850 Arg Lys Asn Gly Lys Arg 1855 Val He Gin Leu Ser 1860 Arg aaa acc ttt gac act gag tac cag aaa aca aaa aac aac gac tgg gac 5731 Lys Thr Phe 1865 Asp Thr Glu Tyr Gin 1870 Lys Thr Lys Asn Asn 1875 Asp Trp Asp tat gtc gtc aca aca gac att tcc gaa atg gga gca aat ttc egg gcc 5779 Tyr Val 1880 Val Thr Thr Asp He 1885 Ser Glu Met Gly Ala 1890 Asn Phe Arg Ala 1895 gac agg gta ata gac cca agg egg tgt ctg aaa ccg gta ata eta aaa 5827 Asp Arg Val He Asp Pro 1900 Arg Arg Cys Leu Lys 1905 Pro Val He Leu Lys 1910 gat ggt cca gag cgc gtc att eta gcc gga ecg atg cca gtg act gtg 5875 Asp Gly Pro Glu Arg 1915 Val He Leu Ala Gly 1920 Pro Met Pro Val Thr 1925 Val gcc agt • gcc gcc cag agg aga gga aga att gga agg aac caa aac aag 5923 Ala Ser Ala Ala 1930 Gin Arg Arg Gly Arg He 1935 Gly Arg Asn Gin Asn 1940 Lys gaa ggt gat cag tat att tac atg gga cag cct tta aac aat gat gag 5971 Glu Gly Asp Gin Tyr He Tyr Met Gly Gin Pro Leu Asn Asn Asp Glu

    1945 1950 1955

    2018200081 04 Jan 2018

    gac cac Asp His 1960 get Ala cat His tgg Trp aca gaa Thr Glu 1965 gca Ala aag Lys atg Met etc ett Leu Leu 1970 gac Asp aat Asn ata He aac Asn 1975 6019 aca cca gaa ggg att ate cca gcc etc ttt gag ccg gag aga gaa aag 6067 Thr Pro Glu Gly He 198C He Pro 1 Ala Leu Phe 1985 Glu Pro Glu Arg Glu 1990 Lys 1 agt gca get ata gac ggg gaa tac aga ctg egg ggt gaa gca agg aaa 6115 Ser Ala Ala He 1995 Asp Gly Glu Tyr Arg 200C Leu 1 Arg Gly Glu Ala 2005 Arg Lys aeg ttc gtg gag etc atg aga aga ggg gat eta cca gtc tgg eta tcc 6163 Thr Phe Val Glu 2010 Leu Met Arg Arg Gly 2015 Asp Leu Pro Val Trp 2020 Leu Ser tac aaa gtt gcc tea gaa ggc ttc cag tac tcc gac aga agg tgg tgc 6211 Tyr Lys Val 2025 Ala Ser Glu Gly Phe 2030 Gin Tyr Ser Asp Arg 2035 Arg Trp Cys ttc gat ggg gaa agg aac aac cag gtg ttg gag gag aac atg gac gtg 6259 Phe Asp 2040 Gly Glu Arg Asn Asn 2045 Gin Val Leu Glu Glu 2050 Asn Met Asp Val 2055 gag ate tgg aca aaa gaa gga gaa aga aag aaa eta ega cct ege tgg 6307 Glu lie Trp Thr Lys Glu Gly 2060 Glu Arg Lys Lys Leu 2065 Arg Pro Arg 207C Trp 1 ttg gac gee aga aca tac tet gac cca ctg get ctg ege gag ttt aaa 6355 Leu Asp Ala Arg Thr 2075 Tyr Ser Asp Pro Leu 2080 Ala Leu Arg Glu Phe 2085 Lys gag ttt gca gca gga aga aga agc gtc tea ggt gac eta ata tta gaa 6403 Glu Phe Ala Ala 2090 Gly Arg Arg Ser Val 2095 Ser Gly Asp Leu He 2100 Leu Glu ata ggg aaa ett cca caa cat ttg aeg caa agg gcc cag aat get ttg 6451 He Gly Lys 2105 Leu Pro Gin His Leu 2110 Thr Gin Arg Ala Gin 2115 Asn Ala Leu gac aac ttg gtc atg ttg cac aat tcc gaa caa gga gga aaa gcc tat 6499 Asp Asn 2120 Leu Val Met Leu His 2125 Asn Ser Glu Gin Gly 2130 Gly Lys Ala Tyr 2135 aga cat get atg gaa gaa ctg cca gac aca ata gaa aeg ttg atg etc 6547 Arg His Ala Met Glu Glu Leu 2140 Pro Asp Thr He Glu 2145 Thr Leu Met Leu 2150 eta gcc ttg ata get gtg ttg act ggt gga gtg aeg ctg ttc ttc eta 6595 Leu Ala Leu He Ala 2155 Val Leu Thr Gly Gly 2160 Val Thr Leu Phe Phe 2165 Leu tea gga aga ggt eta gga aaa aca tet ate ggc tta etc tgc gtg atg 6643 Ser Gly Arg Gly Leu Gly Lys Thr Ser He Gly Leu Leu Cys Val Met

    2170 2175 2180

    2018200081 04 Jan 2018

    gcc Ala tea age Ser Ser 2185 gca Ala ctg tta tgg atg gcc agt Ser gtg Val gag ccc Glu Pro 2195 cat His tgg Trp ata He 6691 Leu Leu Trp Met 2190 Ala gcg gcc tee ate ata ctg gag ttc ttt ctg atg gta ctg ett att cca 6739 Ala Ala Ser 2200 He He Leu Glu Phe 2205 Phe Leu Met Val Leu 2210 Leu He Pro 2215 gag cca gac aga cag cgc act cca cag gac aac cag eta gca tat gtg 6787 Glu Pro Asp Arg Gin 222C Arg Thr Pro 1 Gin Asp 2225 Asn Gin Leu Ala Tyr 223C Val 1 gtg ata ggt ctg tta ttc gtg ata ttg aca gtg gca gcc aat gag atg 6835 Val lie Gly Leu Leu 2235 Phe Val He Leu Thr 2240 Val Ala Ala Asn Glu 2245 Met gga tta ttg gaa acc aca aag aaa gac ctg ggg att ggc cat gta get 6883 Gly Leu Leu Glu 2250 Thr Thr Lys Lys Asp 2255 Leu Gly He Gly His 2260 Val Ala get gaa aac cac cac cat get aca atg ctg gac gta gac eta cat cca 6931 Ala Glu Asn 2265 His His His Ala Thr 2270 Met Leu Asp Val Asp 2275 Leu His Pro get tea gcc tgg acc etc tat gca gtg gcc aca aca ate ate act cct 6979 Ala 228C Ser Ala 1 Trp Thr Leu Tyr Ala 2285 Val Ala Thr Thr He 2290 He Thr Pro 2295 atg atg aga cac aca att gaa aac aca aeg gca aat att tcc ctg aca 7027 Met Met Arg His Thr 230C lie Glu Asn 1 Thr Thr 2305 Ala Asn He Ser Leu 231C Thr 1 gcc ate gca aac caa gca get ata ttg atg gga ett gac aag gga tgg 7075 Ala He Ala Asn Gin 2315 Ala Ala He Leu Met 2320 Gly Leu Asp Lys 2325 Gly Trp cca ata teg aag atg gac ata gga gtt cca ett etc gcc ttg ggg tgc 7123 Pro He Ser Lys 2330 Met Asp He Gly Val 2335 Pro Leu Leu Ala Leu 2340 Gly Cys tat tee caa gtg aat ccg ctg aca ctg ata gcg gca gta ttg atg eta 7171 Tyr Ser Gin 2345 Val Asn Pro Leu Thr 2350 Leu lie Ala Ala Val 2355 Leu Met Leu gta get cat tac gcc ata att gga cct gga ctg caa gca aaa get act 7219 Val Ala His 2360 Tyr Ala He He Gly 2365 Pro Gly Leu Gin Ala 2370 Lys Ala Thr 2375 aga gaa get caa aaa aga aca gcg get gga ata atg aaa aat cca act 7267 Arg Glu Ala Gin Lys 238C Arg Thr Ala 1 Ala Gly He 2385 Met Lys Asn Pro 239C Thr I

    2018200081 04 Jan 2018

    gtc Val gac Asp ggg Gly att gtt He Val 2395 gca Ala ata He gac Asp tta gat Leu Asp 2400 ccc Pro gtg Val gtt Val tac gat Tyr Asp 2405 gca Ala 7315 aaa ttt gaa aaa cag eta ggc caa ata atg ttg ttg ata ett tgc aca 7363 Lys Phe Glu 241C Lys Gin 1 Leu Gly Gin 2415 He Met Leu Leu He 242C Leu Cys 1 Thr tea cag att ett ttg atg egg act aca tgg gcc ttg tgt gaa tcc ate 7411 Ser Gin 2425 lie Leu Leu Met Arg Thr 2430 Thr Trp Ala Leu 2435 Cys Glu Ser He aca ttg get act gga cct ctg acc act ett tgg gag gga tet cca gga 7459 Thr Leu 2440 Ala Thr Gly Pro Leu 2445 Thr Thr Leu Trp Glu 2450 Gly Ser Pro Gly 2455 aaa ttc tgg aac acc aca ata gcg gta tcc atg gca aac att ttc agg 7507 Lys Phe Trp Asn Thr Thr 2460 He Ala Val Ser Met 2465 Ala Asn He Phe 247C Arg 1 ggg agt tat eta gca gga gca ggt ctg gcc ttc tea tta atg aaa tet 7555 Gly Ser Tyr Leu Ala 2475 Gly Ala Gly Leu Ala 2480 Phe Ser Leu Met Lys 2485 Ser eta gga gga ggt agg aga ggc aeg gga gcc caa ggg gaa aca ctg gga 7603 Leu Gly Gly Gly Arg 2490 Arg Gly Thr 2495 Gly Ala Gin Gly Glu 250C Thr Leu 1 Gly gaa aaa tgg aaa aga caa eta aac caa ctg age aag tea gaa ttc aat 7651 Glu Lys Trp 2505 Lys Arg Gin Leu Asn 2510 Gin Leu Ser Lys Ser 2515 Glu Phe Asn act tac aag agg agt ggg att atg gag gtg gat aga tcc gaa gcc aaa 7699 Thr Tyr 2520 Lys Arg Ser Gly He 2525 Met Glu Val Asp Arg 2530 Ser Glu Ala Lys 2535 gag gga ctg aaa aga gga gaa aca acc aaa cac gca gta teg aga gga 7747 Glu Gly Leu Lys Arg Gly 2540 Glu Thr Thr Lys His 2545 Ala Val Ser Arg Gly 2550 aeg gcc aaa ctg agg tgg ttc gtg gag agg aac ett gtg aaa cca gaa 7795 Thr Ala Lys Leu Arg 2555 Trp Phe Val Glu Arg 2560 Asn Leu Val Lys Pro 2565 Glu ggg aaa gtc ata gac etc ggt tgt gga aga ggt ggc tgg tea tat tat 7843 Gly Lys Val He Asp 2570 Leu Gly Cys Gly Arg 2575 Gly Gly Trp Ser Tyr 2580 Tyr tgc get ggg ctg aag aaa gtc aca gaa gtg aaa gga tac aca aaa gga 7891 Cys Ala Gly 2585 Leu Lys Lys Val Thr 2590 Glu Val Lys Gly Tyr 2595 Thr Lys Gly gga cct gga cat gag gaa cca ate cca atg gcg acc tat gga tgg aac 7939 Gly Pro Gly His Glu Glu Pro He Pro Met Ala Thr Tyr Gly Trp Asn

    2600 2605 2610 2615

    2018200081 04 Jan 2018

    eta gta aag ctg cac tcc gga aaa gat gta ttt ttt ata cca cct gag 7987 Leu Val Lys Leu His 262C Ser 1 Gly Lys Asp Val 2625 Phe Phe He Pro Pro 263C Glu 1 aaa tgt gac acc ett ttg tgt gat att ggt gag tcc tct ccg aac cca 8035 Lys Cys Asp Thr 2635 Leu Leu Cys Asp He Gly 2640 Glu Ser Ser Pro 2645 Asn Pro act ata gag gaa gga aga aeg tta cgt gtt ctg aaa atg gtg gaa cca 8083 Thr He Glu 265C Glu 1 Gly Arg Thr Leu 2655 Arg Val Leu Lys Met 266C Val 1 Glu Pro tgg etc aga gga aac caa ttt tgc ata aaa att eta aat ccc tat atg 8131 Trp Leu Arg 2665 Gly Asn Gin Phe Cys 2670 He Lys He Leu Asn 2675 Pro Tyr Met ccg age gtg gta gaa act ctg gaa caa atg caa aga aaa cat gga gga 8179 Pro Ser 2680 Val Val Glu Thr Leu 2685 Glu Gin Met Gin Arg 2690 Lys His Gly Gly 2695 atg eta gtg cga aac cca etc tea aga aat tcc acc cat gaa atg tac 8227 Met Leu Val Arg Asn 270C Pro 1 Leu Ser Arg Asn 2705 Ser Thr His Glu Met 271C Tyr 1 tgg gtt tea tgt gga aca gga aac att gtg tea gca gta aac atg aca 8275 Trp Val Ser Cys Gly 2715 Thr Gly Asn He Val 2720 Ser Ala Val Asn Met 2725 Thr tct aga atg ttg eta aat cgg ttc aca atg get cac agg aag cca aca 8323 Ser Arg Met 273C Leu 1 Leu Asn Arg Phe Thr 2735 Met Ala His Arg 274C Lys 1 Pro Thr tat gaa aga gac gtg gac tta ggc get gga aca aga cat gtg gca gta 8371 Tyr Glu Arg 2745 Asp Val Asp Leu Gly 2750 Ala Gly Thr Arg His 2755 Val Ala Val gaa cca gag gta gcc aac eta gat ate att ggc cag agg ata gag aat 8419 Glu Pro 2760 Glu Val Ala Asn Leu 2765 Asp He He Gly Gin 2770 Arg He Glu Asn 2775 ata aaa aat gaa cat aag tea aca tgg cat tat gat gag gac aat cca 8467 lie Lys Asn Glu His 278C Lys 1 Ser Thr Trp His 2785 Tyr Asp Glu Asp Asn 279C Pro 1 tac aaa aca tgg gcc tat cat gga tea tat gag gtt aag cca tea gga 8515 Tyr Lys Thr Trp Ala 2795 Tyr His Gly Ser Tyr 2800 Glu Val Lys Pro Ser 2805 Gly teg gcc tea tcc atg gtc aat ggc gtg gtg aga ttg etc acc aaa cca 8563 Ser Ala Ser Ser 2810 Met Val Asn Gly Val 2815 Val Arg Leu Leu Thr 2820 Lys Pro

    2018200081 04 Jan 2018

    tgg gat gtt Trp Asp Val ate He ccc Pro atg gtc aca Met Val Thr 2830 caa Gin ata He gcc Ala atg act Met Thr 2835 gat Asp acc Thr aca Thr 8611 2825 ccc ttt gga caa cag agg gtg ttt aaa gag aaa gtt gac acg ege aca 8659 Pro Phe Gly 2840 Gin Gin Arg Val Phe 2845 Lys Glu Lys Val Asp 2850 Thr Arg Thr 2855 cca aaa gca aaa cgt ggc aca gca caa att atg gaa gtg aca gcc agg 8707 Pro Lys Ala Lys Arg 286C Gly Thr Ala 1 Gin He 2865 Met Glu Val Thr Ala 287C Arg I tgg tta tgg ggt ttc ett tet aga aac aaa aaa ccc aga att tgc aca 8755 Trp Leu Trp Gly Phe 2875 Leu Ser Arg Asn 288C Lys 1 Lys Pro Arg He Cys 2885 Thr aga gag gag ttt aca aga aaa gtt agg tea aac gca get att gga gca 8803 Arg Glu Glu Phe 2890 Thr Arg Lys Val Arg 2895 Ser Asn Ala Ala He 2900 Gly Ala gtg ttc gtt gat gaa aat caa tgg aac teg gca aaa gaa gca gtg gaa 8851 Val Phe Val 2905 Asp Glu Asn Gin Trp 2910 Asn Ser Ala Lys Glu 2915 Ala Val Glu gac gaa egg ttc tgg gaa ett gtc cac aga gag agg gag ett cat aaa 8899 Asp Glu Arg 2920 Phe Trp Glu Leu Val 2925 His Arg Glu Arg Glu 2930 Leu His Lys 2935 cag ggg aaa tgt gcc acg tgt gtc tac aat atg atg ggg aag aga gag 8947 Gin Gly Lys Cys Ala Thr Cys Val 2940 Tyr Asn Met 2945 Met Gly Lys Arg Glu 2950 aaa aaa tta gga gag ttc gga aag gca aaa gga agt cgt gca ata tgg 8995 Lys Lys Leu Gly 2955 Glu Phe Gly Lys Ala 296C Lys 1 Gly Ser Arg Ala He 2965 Trp tac atg tgg ttg gga gca ege ttc eta gag ttt gaa gcc ett ggt ttc 9043 Tyr Met Trp Leu 2970 Gly Ala Arg Phe Leu 2975 Glu Phe Glu Ala Leu 2980 Gly Phe atg aat gaa gat cac tgg ttc agt aga gag aat tea etc agt gga gtg 9091 Met Asn Glu 2985 Asp His Trp Phe Ser 2990 Arg Glu Asn Ser Leu 2995 Ser Gly Val gaa gga gaa gga etc cac aaa ett gga tac ata etc aga gac ata tea 9139 Glu Gly Glu 3000 Gly Leu His Lys Leu 3005 Gly Tyr He Leu Arg 3010 Asp He Ser 3015 agg att cca ggg ggg aac atg tat gca gat gac aca gcc gga tgg gac 9187 Arg lie Pro Gly Gly Asn Met Tyr 3020 Ala Asp Asp 3025 Thr Ala Gly Trp Asp 3030 aca aga ata aca gag gat gat etc cag aat gag get aaa ate act gac 9235 Thr Arg He Thr Glu Asp Asp Leu Gin Asn Glu Ala Lys He Thr Asp

    3035 3040 3045

    2018200081 04 Jan 2018

    ate lie atg Met gag ccc Glu Pro 3050 gaa Glu cat His gcc Ala ctg ctg Leu Leu 3055 get Ala aeg Thr tea Ser ate ttt He Phe 3060 aag Lys ctg Leu 9283 acc tac caa aat aag gtg gta agg gtg cag aga cca gca aaa aat gga 9331 Thr Tyr 3065 Gin Asn Lys Val Val Arg Val 3070 Gin Arg Pro 3075 Ala Lys Asn Gly acc gtg atg gat gtt ata tcc aga cgt gac cag aga ggc agt gga cag 9379 Thr Val 3080 Met Asp Val He Ser 3085 Arg Arg Asp Gin 309C Arg 1 Gly Ser Gly Gin 3095 gtt gga act tat ggc tta aac act ttc acc aac atg gag gcc caa ctg 9427 Val Gly Thr Tyr Gly Leu 3100 Asn Thr Phe Thr Asn 3105 Met Glu Ala Gin 311C Leu 1 ata aga caa atg gag tet gag gga ate ttt tta ccc age gaa ttg gaa 9475 He Arg Gin Met Glu 3115 Ser Glu Gly He Phe 3120 Leu Pro Ser Glu Leu 3125 Glu acc cca aat eta gec gga aga gtt etc gac tgg ttg gaa aaa tat ggt 9523 Thr Pro Asn Leu 3130 Ala Gly Arg Val Leu 3135 Asp Trp Leu Glu Lys 3140 Tyr Gly gtc gaa agg ctg aaa aga atg gca ate age gga gat gac tgt gtg gtg 9571 Val Glu Arg Leu 3145 Lys Arg Met Ala He 3150 Ser Gly Asp Asp Cys 3155 Val Val aaa cca att gat gac agg ttc gca aca gcc tta aca get ttg aat gac 9619 Lys Pro 3160 He Asp Asp Arg Phe 3165 Ala Thr Ala Leu Thr 3170 Ala Leu Asn Asp 3175 atg gga aaa gta aga aaa gac ata cca caa tgg gaa cct tea aaa gga 9667 Met Gly Lys Val Arg Lys 3180 Asp He Pro Gin Trp 3185 Glu Pro Ser Lys Gly 3190 tgg aat gat tgg caa caa gtg cot ttc tgt tea cac cac ttc cac cag 9715 Trp Asn Asp Trp Gin 3195 Gin Val Pro Phe Cys 3200 Ser His His Phe His 3205 Gin eta att atg aag gat ggg agg gag ata gtg gtg cca tgc ege aac caa 9763 Leu lie Met Lys 3210 Asp Gly Arg Glu He 3215 Val Val Pro Cys Arg 3220 Asn Gin gat gaa ett gtg ggg agg gcc aga gta tea caa ggc gcc gga tgg age 9811 Asp Glu Leu Val 3225 Gly Arg Ala Arg Val 3230 Ser Gin Gly Ala Gly 3235 Trp Ser ctg aga gaa acc gca tgc eta ggc aag tea tat gca caa atg tgg cag 9859 Leu Arg Glu Thr Ala Cys Leu Gly Lys Ser Tyr Ala Gin Met Trp Gin

    3240 3245 3250 3255

    2018200081 04 Jan 2018 ctg atg tat ttc cac agg aga gac ctg aga ctg gcg get aac get att 9907

    Leu Met Tyr Phe His Arg Arg Asp Leu Arg Leu Ala Ala Asn Ala lie

    3260 3265 3270 tgt tea gcc gtt cca gtt gat tgg gtc cca acc age cgc acc acc tgg 9955 Cys Ser Ala Val Pro Val Asp Trp Val 3275 328C Pro Thr Ser 1 Arg Thr Thr Trp 3285 teg ate cat gcc cat cac caa tgg atg aca aca gaa gac atg tta tea 10003 Ser lie His Ala His His Gin Trp Met 3290 3295 Thr Thr Glu Asp Met Leu Ser 3300 gta tgg aat agg gtc tgg ata gag gaa aac cca tgg atg gag gat aag 10051 Val Trp Asn Arg Val Trp lie Glu Glu 3305 3310 Asn Pro Trp Met Glu Asp Lys 3315 act cat gtg tcc agt tgg gaa gaa gtt cca tac eta gga aag agg gaa 10099 Thr His 3320 Val Ser Ser Trp Glu Glu Val 3325 Pro Tyr Leu 3330 Gly Lys Arg Glu 3335 gat cag tgg tgt gga tcc ctg ata ggc tta aca gca agg gcc acc tgg 10147 Asp Gin Trp Cys Gly Ser Leu He Gly 3340 Leu Thr Ala 3345 Arg Ala Thr Trp 3350 gcc act aat ata caa gtg gcc ata aac caa gtg aga agg etc att ggg 10195 Ala Thr Asn lie Gin Val Ala He Asn Gin Val Arg 3355 3360 Arg Leu He Gly 3365 aat gag aat tat eta gat tac atg aca tea atg aag aga ttc aag aat 10243 Asn Glu Asn Tyr Leu Asp Tyr Met Thr 3370 3375 . Ser Met Lys Arg Phe Lys Asn 3380 gag agt gat ccc gaa ggg gca etc tgg Glu Ser Asp Pro Glu Gly Ala Leu Trp 3385 3390 taa gtcaacacat tcacaaaata 10293 *

    aaggaaaata aaaaatcaaa tgaggcaaga agtcaggcca gattaagcca tagtacggta 10353 agagetatge tgcctgtgag ccccgtccaa ggacgtaaaa tgaagteagg ccgaaagcca 10413 cggtttgagc aagccgtgct gcctgtggct ccatcgtggg gatgtaaaaa cccgggaggc 10473 tgcaacccat ggaagctgta cgcatggggt agcagactag tggttagagg agacccctcc 10533 caagacacaa cgcagcagcg gggcccaaca ccaggggaag ctgtaccctg gtggtaagga 10593 ctagaggtta gaggagaccc cccgcgtaac aataaacagc atattgaege tgggagagac 10653 cagagatcct gctgtctcta cagcatcatt ccaggcacag aacgccagaa aatggaatgg 10713 tgctgttgaa tcaacaggtt ct 10735 <210> 4 <211> 3392 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct

    2018200081 04 Jan 2018

    <400> 4 Met He Asn Gin Arg Lys Lys Thr Gly Arg Pro Ser Phe Asn Met Leu 1 5 10 15 Lys Arg Ala Arg Asn Arg Val Ser Thr Val Ser Gin Leu Ala Lys Arg 20 25 30 Phe Ser Lys Gly Leu Leu Ser Gly Gin Gly Pro Met Lys Leu Val Met 35 40 45 Ala Phe He Ala Phe Leu Arg Phe Leu Ala He Pro Pro Thr Ala Gly 50 55 60 lie Leu Ala Arg Trp Gly Ser Phe Lys Lys Asn Gly Ala lie Lys Val 65 70 75 80 Leu Arg Gly Phe Lys Arg Glu He Ser Asn Met Leu Asn He Met Asn 85 90 95 Arg Arg Lys Arg Ser Val Thr Met Leu Leu Met Leu Leu Pro Thr Ala 100 105 110 Leu Ala Phe His Leu Thr Thr Arg Gly Gly Glu Pro His Met He Val 115 120 125 Ser Lys Gin Glu Arg Gly Lys Ser Leu Leu Phe Lys Thr Ser Ala Gly 130 135 140 Val Asn Met Cys Thr Leu He Ala Met Asp Leu Gly Glu Leu Cys Glu 145 150 155 160 Asp Thr Met Thr Tyr Lys Cys Pro Arg He Thr Glu Ala Glu Pro Asp 165 170 175 Asp Val Asp Cys Trp Cys Asn Ala Thr Asp Thr Trp Val Thr Tyr Gly 180 185 190 Thr Cys Ser Gin Thr Gly Glu His Arg Arg Asp Lys Arg Ser Val Ala 195 200 205 Leu Ala Pro His Val Gly Leu Gly Leu Glu Thr Arg Ala Glu Thr Trp 210 215 220 Met Ser Ser Glu Gly Ala Trp Lys Gin He Gin Lys Val Glu Thr Trp 225 230 235 240 Ala Leu Arg His Pro Gly Phe Thr Val He Ala Leu Phe Leu Ala His 245 250 255 Ala He Gly Thr Ser He Thr Gin Lys Gly He He Phe He Leu Leu 260 265 270 Met Leu Val Thr Pro Ser Met Ala Met Arg Cys Val Gly He Gly Asn 275 280 285 Arg Asp Phe Val Glu Gly Leu Ser Gly Ala Thr Trp Val Asp Val Val 290 295 300 Leu Glu His Gly Ser Cys Val Thr Thr Met Ala Lys Asn Lys Pro Thr 305 310 315 320 Leu Asp He Glu Leu Leu Lys Thr Glu Val Thr Asn Pro Ala Val Leu 325 330 335 Arg Lys Leu Cys He Glu Ala Lys He Ser Asn Thr Thr Thr Asp Ser 340 345 350 Arg Cys Pro Thr Gin Gly Glu Ala Thr Leu Val Glu Glu Gin Asp Ala 355 360 365 Asn Phe Val Cys Arg Arg Thr Phe Val Asp Arg Gly Trp Gly Asn Gly 370 375 380 Cys Gly Leu Phe Gly Lys Gly Ser Leu He Thr Cys Ala Lys Phe Lys 385 390 395 400 Cys Val Thr Lys Leu Glu Gly Lys He Ala Gin Tyr Glu Asn Leu Lys 405 410 415 Tyr Ser Val lie Val Thr Val His Thr Gly Asp Gin His Gin Val Gly 420 425 430

    2018200081 04 Jan 2018

    Asn Glu Thr Thr Glu 435 His Gly Thr Thr Ala Thr He Thr Pro Gin Ala 440 445 Pro Thr Ser Glu He Gin Leu Thr Asp Tyr Gly Thr Leu Thr Leu Asp 450 455 460 Cys Ser Pro Arg Thr Gly Leu Asp Phe Asn Glu Met Val Leu Leu Thr 465 470 475 480 Met Lys Lys Lys Ser Trp Leu Val His Lys Gin Trp Phe Leu Asp Leu 485 490 495 Pro Leu Pro Trp Thr Ser Gly Ala Leu Thr Ser Gin Glu Thr Trp Asn 500 505 510 Arg Gin Asp Leu Leu Val Thr Phe Lys Thr Ala His Ala Lys Lys Gin 515 520 525 Glu Val Val Val Leu Gly Ser Gin Glu Gly Ala Met His Thr Ala Leu 530 535 540 Thr Gly Ala Thr Glu He Gin Thr Ser Gly Thr Thr Thr He Phe Ala 545 550 555 ¹ 560 Gly His Leu Lys Cys Arg Leu Lys Met Asp Lys Leu Thr Leu Lys Gly 565 570 575 Met Ser Tyr Val Met Cys Thr Gly Ser Phe Lys Leu Glu Lys Glu Val 580 585 590 Ala Glu Thr Gin His Gly Thr Val Leu Val Gin Val Lys Tyr Glu Gly 595 600 605 Thr Asp Ala Pro Cys Lys He Pro Phe Ser Thr Gin Asp Glu Lys Gly 610 615 620 Ala Thr Gin Asn Gly Arg Leu lie Thr Ala Asn Pro He Val Thr Asp 625 630 635 640 Lys Glu Lys Pro Val Asn He Glu Ala Glu Pro Pro Phe Gly Glu Ser 645 650 655 Tyr He Val Val Gly Ala Gly Glu Lys Ala Leu Lys Leu Ser Trp Phe 660 665 670 Lys Lys Gly Ser Ser He Gly Lys Met Phe Glu Ala Thr Ala Arg Gly 675 680 685 Ala Arg Arg Met Ala He Leu Gly Asp Thr Ala Trp Asp Phe Gly Ser 690 695 700 lie Gly Gly Val Phe Thr Ser Met Gly Lys Leu Val His Gin Val Phe 705 710 715 720 Gly Thr Ala Tyr Gly Val Leu Phe Ser Gly Val Ser Trp Thr Met Lys 725 730 735 He Gly He Gly He Leu Leu Thr Trp Leu Gly Leu Asn Ser Arg Asn 740 745 750 Thr Ser Leu Ser Val Met Cys He Ala Val Gly Met Val Thr Leu Tyr 755 760 765 Leu Gly Val Met Val Gin Ala Asp Ser Gly Cys Val He Asn Trp Lys 770 775 780 Gly Arg Glu Leu Lys Cys Gly Ser Gly He Phe Val Thr Asn Glu Val 785 790 795 800 His Thr Trp Thr Glu Gin Tyr Lys Phe Gin Ala Asp Ser Pro Lys Arg 805 810 815 Leu Ser Ala Ala He Gly Lys Ala Trp Glu Glu Gly Val Cys Gly He 820 825 830 Arg Sex' Ala Thr Arg Leu Glu Asn He Met Trp Lys Gin He Ser Asn 835 840 845 Glu Leu Asn His He Leu Leu Glu Asn Asp Met Lys Phe Thr Val Val 850 855 860

    2018200081 04 Jan 2018

    Val Gly Asp Val Ser Gly He Leu Ala Gin Gly Lys Lys Met He Arg 865 Pro Gin Pro Met Glu 870 His Lys Tyr Ser Trp 875 Lys Ser Trp Gly Lys 880 Ala Lys He He Gly 885 Ala 890 Asp Val Gin Asn Thr Thr Phe He He 895 Asp Gly Pro Asn 900 Thr Pro Glu 905 Cys Pro Asp Asn Gin Arg Ala Trp 910 Asn He Trp Glu Val 915 Glu Asp Tyr 920 Gly Phe Gly He Phe Thr Thr 925 Asn He Trp Leu Lys 930 Leu Arg Asp Ser 935 Tyr Thr Gin Val Cys Asp 940 His Arg Leu Met Ser 945 Ala Ala He Lys Asp 950 Ser Lys Ala Val His 955 Ala Asp Met Gly Tyr 960 Trp lie Glu Ser Glu 965 Lys 970 Asn Glu Thr Trp Lys Leu Ala Arg Ala 975 Ser Phe He Glu 980 Val Lys Thr 985 Cys He Trp Pro Lys Ser His Thr 990 Leu Trp Ser Asn Gly 995 Val Leu Glu 1000 Ser Glu Met He He Pro Lys 1005 He Tyr Gly Gly Pro 1010 He Ser Gin His 1015 Asn Tyr Arg Pro Gly Tyr 1020 Phe Thr Gin Thr Ala 1025 Gly Pro Trp His Leu 1030 Gly Lys Leu Glu Leu 1035 Asp Phe Asp Phe Cys 1040 Glu Gly Thr Thr Val 1045 1050 Val Val Asp Glu His Cys Gly Asn Arg Gly 1055 Pro Ser Leu Arg 1060 Thr Thr Thr 1065 Val Thr Gly Lys He lie His Glu 1070 Trp Cys Cys Arg Ser 1075 Cys Thr Leu 1080 Pro Pro Leu Arg Phe Lys Gly 1085 Glu Asp Gly Cys Trp 1090 Tyr Gly Met Glu 1095 He Arg Pro Val Lys Asp 1100 Lys Glu Glu Asn Leu 1105 Val Lys Ser Met Val 1110 Ser Ala Gly Ser Gly 1115 Glu Val Asp Ser Phe 1120 Ser Leu Gly Leu Leu 1125 1130 Cys He Ser He Met lie Glu Glu Val Met 1135 Arg Ser Arg Trp 1140 Ser Lys Lys 1145 Met Leu Met Thr Gly Thr Leu Ala 1150 Val Phe Leu Leu Leu 1155 He Met Gly 1160 Gin Leu Thr Trp Ser Asp Leu 1165 He Arg Leu Cys He 1170 Met Val Gly Ala 1175 Asn Ala Ser Asp Lys Met 1180 Gly Met Gly Thr Thr 1185 Tyr Leu Ala Leu Met 1190 Ala Thr Phe Lys Met 1195 Arg Pro Met Phe Ala 1200 Val Gly Leu Leu Phe 1205 1210 Arg Arg Leu Thr Ser Arg Glu Val Leu Leu 1215 Leu Thr He Gly 1220 Leu Ser Leu 1225 Val Ala Ser Val Glu Leu Pro Ser 1230 Ser Leu Glu Glu Leu 1235 Gly Asp Gly 1240 Leu Ala He Gly He Met Met 1245 Leu Lys Leu Leu Thr 1250 Asp Phe Gin Ser 1255 His Gin Leu Trp Ala Thr 1260 Leu Leu Ser Leu Thr 1265 Phe He Lys Thr Thr 1270 Phe Ser Leu His Tyr 1275 Ala Trp Lys Thr Met 1280 Ala

    1285 1290 1295

    2018200081 04 Jan 2018

    Met Val Leu Ser 1300 He Val Ser Leu Phe Pro Leu 1305 Cys Leu Ser Thr 1310 Thr Ser Gin Lys Thr Thr Trp Leu Pro Val Leu Leu Gly Ser Leu Gly Cys 1315 1320 1325 Lys Pro Leu Pro Met Phe Leu He Thr Glu Asn Lys He Trp Gly Arg 1330 1335 1340 Lys Ser Trp Pro Leu Asn Glu Gly He Met Ala Val Gly He Val Ser 1345 1350 1355 1360 lie Leu Leu Ser Ser Leu Leu Lys Asn Asp Val Pro Leu Ala Gly Pro 1365 1370 1375 Leu lie Ala Gly Gly Met Leu lie Ala Cys Tyr Val He Ser Gly Ser 1380 1385 1390 Ser Ala Asp Leu Ser Leu Glu Lys Ala Ala Glu Val Ser Trp Glu Glu 1395 1400 1405 Glu Ala Glu His Ser Gly Ala Ser His Asn lie Leu Val Glu Val Gin 1410 1415 1420 Asp Asp Gly Thr Met Lys He Lys Asp Glu Glu Arg Asp Asp Thr Leu 1425 1430 1435 1440 Thr He Leu Leu Lys Ala Thr Leu Leu Ala Val Ser Gly Val Tyr Pro 1445 1450 1455 Met Ser He Pro Ala Thr Leu Phe Val Trp Tyr Phe Trp Gin Lys Lys 1460 1465 1470 Lys Gin Arg Ser Gly Val Leu Trp Asp Thr Pro Ser Pro Pro Glu Val 1475 1480 1485 Glu Arg Ala Val Leu Asp Asp Gly He Tyr Arg He Leu Gin Arg Gly 1490 1495 1500 Leu Leu Gly Arg Ser Gin Val Gly Val Gly Val Phe Gin Glu Gly Val 1505 1510 1515 1520 Phe His Thr Met Trp His Val Thr Arg Gly Ala Val Leu Met Tyr Gin 1525 153 0 1535 Gly Lys Arg Leu Glu Pro Ser Trp Ala Ser Val Lys Lys Asp Leu He 1540 1545 1550 Ser Tyr Gly Gly Gly Trp Arg Phe Gin Gly Ser Trp Asn Thr Gly Glu 1555 1560 1565 Glu Val Gin Val He Ala Val Glu Pro Gly Lys Asn Pro Lys Asn Val 1570 1575 1580 Gin Thr Thr Pro Gly Thr Phe Lys Thr Pro Glu Gly Glu Val Gly Ala 1585 1590 1595 1600 He Ala Leu Asp Phe Lys Pro Gly Thr Ser Gly Ser Pro He Val Asn 1605 1610 1615 Arg Glu Gly Lys lie Val Gly Leu Tyr Gly Asn Gly Val Val Thr Thr 1620 1625 1630 Ser Gly Thr Tyr Val Ser Ala He Ala Gin Ala Lys Ala Ser Gin Glu 1635 1640 1645 Gly Pro Leu Pro Glu He Glu Asp Lys Val Phe Arg Lys Arg Asn Leu 1650 1655 1660 Thr He Met Asp Leu His Pro Gly Ser Gly Lys Thr Arg Arg Tyr Leu 1665 1670 1675 1680 Pro Ala He Val Arg Glu Ala He Lys Arg Lys Leu Arg Thr Leu He 1685 1690 1695 Leu Ala Pro Thr Arg Val Val Ala Ser Glu Met Ala Glu Ala Leu Lys 1700 1705 1710 Gly Val Pro He Arg Tyr Gin Thr Thr Ala Val Lys Ser Glu His Thr

    1715 1720 1725

    2018200081 04 Jan 2018

    Gly Lys Glu He Val Asp Leu Met 1735 Cys His Ala Thr Phe Thr Met 1740 Arg 1730 Leu Leu Ser Pro Val Arg Val Pro Asn Tyr Asn Met He He Met Asp 1745 1750 1755 1760 Glu Ala His Phe Thr Asp Pro Ala Ser He Ala Ala Arg Gly Tyr He 1765 1770 1775 Ser Thr Arg Val Gly Met Gly Glu Ala Ala Ala He Phe Met Thr Ala 1780 1785 1790 Thr Pro Pro Gly Ser Val Glu Ala Phe Pro Gin Ser Asn Ala He He 1795 i 180C I 1805 Gin Asp Glu Glu Arg Asp He Pro Glu Arg Ser Trp Asn Ser Gly Tyr 1810 1815 1820 Asp Trp He Thr Asp Phe Pro Gly Lys Thr Val Trp Phe Val Pro Ser 1825 1830 1835 1840 lie Lys Ser Gly Asn Asp He Ala Asn Cys Leu Arg Lys Asn Gly Lys 1845 1850 1855 Arg Val He Gin Leu Ser Arg Lys Thr Phe Asp Thr Glu Tyr Gin Lys 1860 1865 1870 Thr Lys Asn Asn Asp Trp Asp Tyr Val Val Thr Thr Asp He Ser Glu 1875 1880 1885 Met Gly Ala Asn Phe Arg Ala Asp Arg Val He Asp Pro Arg Arg Cys 1890 1895 1900 Leu Lys Pro Val He Leu Lys Asp Gly Pro Glu Arg Val He Leu Ala 1905 1910 1915 1920 Gly Pro Met Pro Val Thr Val Ala Ser Ala Ala Gin Arg Arg Gly Arg 1925 1930 1935 He Gly Arg Asn Gin Asn Lys Glu Gly Asp Gin Tyr He Tyr Met Gly 1940 1945 1950 Gin Pro Leu Asn Asn Asp Glu Asp His Ala His Trp Thr Glu Ala Lys 1955 1960 1965 Met Leu Leu Asp Asn He Asn Thr Pro Glu Gly He He Pro Ala Leu 1970 1975 1980 Phe Glu Pro Glu Arg Glu Lys Ser Ala Ala He Asp Gly Glu Tyr Arg 1985 1990 1995 2000 Leu Arg Gly Glu Ala Arg Lys Thr Phe Val Glu Leu Met Arg Arg Gly 2005 2010 2015 Asp Leu Pro Val Trp Leu Ser Tyr Lys Val Ala Ser Glu Gly Phe Gin 2020 2025 2030 Tyr Ser Asp Arg Arg Trp Cys Phe Asp Gly Glu Arg Asn Asn Gin Val 2035 2040 2045 Leu Glu Glu Asn Met Asp Val Glu He Trp Thr Lys Glu Gly Glu Arg 2050 2055 2060 Lys Lys Leu Arg Pro Arg Trp Leu Asp Ala Arg Thr Tyr Ser Asp Pro 2065 2070 2075 2080 Leu Ala Leu Arg Glu Phe Lys Glu Phe Ala Ala Gly Arg Arg Ser Val 2085 2090 2095 Ser Gly Asp Leu He Leu Glu He Gly Lys Leu Pro Gin His Leu Thr 2100 2105 2110 Gin Arg Ala Gin Asn Ala Leu Asp Asn Leu Val Met Leu His Asn Ser 2115 2120 2125 Glu Gin Gly Gly Lys Ala Tyr Arg His Ala Met Glu Glu Leu Pro Asp 2130 2135 2140 Thr He Glu Thr Leu Met Leu Leu Ala Leu He Ala Val Leu Thr Gly

    2145 2150 2155 2160

    2018200081 04 Jan 2018

    Gly Val Thr Leu Phe Phe Leu Ser Gly Arg Gly Leu Gly Lys Thr Ser 2175 2165 2170 lie Gly Leu Leu Cys Val Met Ala Ser Ser Ala Leu Leu Trp Met Ala 2180 2185 2190 Ser Val Glu Pro His Trp He Ala Ala Ser He He Leu Glu Phe Phe 2195 : 2200 2205 Leu Met Val Leu Leu He Pro Glu Pro Asp Arg Gin Arg Thr Pro Gin 2210 2215 2220 Asp Asn Gin Leu Ala Tyr Val Val He Gly Leu Leu Phe Val He Leu 2225 2230 2235 2240 Thr Val Ala Ala Asn Glu Met Gly Leu Leu Glu Thr Thr Lys Lys Asp 2245 2250 2255 Leu Gly lie Gly His Val Ala Ala Glu Asn His His His Ala Thr Met 2260 2265 2270 Leu Asp Val Asp Leu His Pro Ala Ser Ala Trp Thr Leu Tyr Ala Val 227Ξ ί 2280 2285 Ala Thr Thr He He Thr Pro Met Met Arg His Thr lie Glu Asn Thr 2290 2295 2300 Thr Ala Asn He Ser Leu Thr Ala He Ala Asn Gin Ala Ala He Leu 2305 2310 2315 2320 Met Gly Leu Asp Lys Gly Trp Pro He Ser Lys Met Asp He Gly Val 2325 2330 2335 Pro Leu Leu Ala Leu Gly Cys Tyr Ser Gin Val Asn Pro Leu Thr Leu 2340 2345 2350 He Ala Ala Val Leu Met Leu Val Ala His Tyr Ala He lie Gly Pro 2355 2360 2365 Gly Leu Gin Ala Lys Ala Thr Arg Glu Ala Gin Lys Arg Thr Ala Ala 2370 2375 2380 Gly lie Met Lys Asn Pro Thr Val Asp Gly He Val Ala He Asp Leu 2385 2390 2395 2400 Asp Pro Val Val Tyr Asp Ala Lys Phe Glu Lys Gin Leu Gly Gin He 2405 2410 2415 Met Leu Leu He Leu Cys Thr Ser Gin He Leu Leu Met Arg Thr Thr 2420 2425 2430 Trp Ala Leu Cys Glu Ser He Thr Leu Ala Thr Gly Pro Leu Thr Thr 2435 2440 2445 Leu Trp Glu Gly Ser Pro Gly Lys Phe Trp Asn Thr Thr He Ala Val 2450 2455 2460 Ser Met Ala Asn He Phe Arg Gly Ser Tyr Leu Ala Gly Ala Gly Leu 2465 2470 2475 2480 Ala Phe Ser Leu Met Lys Ser Leu Gly Gly Gly Arg Arg Gly Thr Gly 2485 2490 2495 Ala Gin Gly Glu Thr Leu Gly Glu Lys Trp Lys Arg Gin Leu Asn Gin 2500 2505 2510 Leu Ser Lys Ser Glu Phe Asn Thr Tyr Lys Arg Ser Gly He Met Glu 2515 2520 2525 Val Asp Arg Ser Glu Ala Lys Glu Gly Leu Lys Arg Gly Glu Thr Thr 2530 2535 2540 Lys His Ala Val Ser Arg Gly Thr Ala Lys Leu Arg Trp Phe Val Glu 2545 2550 2555 2560 Arg Asn Leu Val Lys Pro Glu Gly Lys Val He Asp Leu Gly Cys Gly 2565 2570 2575 Arg Gly Gly Trp Ser Tyr Tyr Cys Ala Gly Leu Lys Lys Val Thr Glu

    2580 2585 2590

    2018200081 04 Jan 2018

    Val Lys Gly Tyr 2595 Thr Lys Gly Gly Pro Gly His 2600 Glu Glu Pro 2605 He Pro Met Ala Thr Tyr Gly Trp Asn Leu Val Lys Leu His Ser Gly Lys Asp 2610 2615 2620 Val Phe Phe He Pro Pro Glu Lys Cys Asp Thr Leu Leu Cys Asp He 2625 2630 2635 2640 Gly Glu Ser Ser Pro Asn Pro Thr He Glu Glu Gly Arg Thr Leu Arg 2645 2650 2655 Val Leu Lys Met Val Glu Pro Trp Leu Arg Gly Asn Gin Phe Cys lie 266C I 2665 2670 Lys He Leu Asn Pro Tyr Met Pro Ser Val Val Glu Thr Leu Glu Gin 2675 2680 2685 Met Gin Arg Lys His Gly Gly Met Leu Val Arg Asn Pro Leu Ser Arg 2690 2695 2700 Asn Ser Thr His Glu Met Tyr Trp Val Ser Cys Gly Thr Gly Asn He 2705 2710 2715 2720 Val Ser Ala Val Asn Met Thr Ser Arg Met Leu Leu Asn Arg Phe Thr 2725 2730 2735 Met Ala His Arg Lys Pro Thr Tyr Glu Arg Asp Val Asp Leu Gly Ala 274C 1 2745 2750 Gly Thr Arg His Val Ala Val Glu Pro Glu Val Ala Asn Leu Asp He 2755 2760 2765 lie Gly Gin Arg lie Glu Asn He Lys Asn Glu His Lys Ser Thr Trp 2770 2775 2780 His Tyr Asp Glu Asp Asn Pro Tyr Lys Thr Trp Ala Tyr His Gly Ser 2785 2790 2795 2800 Tyr Glu Val Lys Pro Ser Gly Ser Ala Ser Ser Met Val Asn Gly Val 2805 2810 2815 Val Arg Leu Leu Thr Lys Pro Trp Asp Val He Pro Met Val Thr Gin 2820 2825 2830 He Ala Met Thr Asp Thr Thr Pro Phe Gly Gin Gin Arg Val Phe Lys 2835 2840 2845 Glu Lys Val Asp Thr Arg Thr Pro Lys Ala Lys Arg Gly Thr Ala Gin 2850 2855 2860 He Met Glu Val Thr Ala Arg Trp Leu Trp Gly Phe Leu Ser Arg Asn 2865 2870 2875 2880 Lys Lys Pro Arg He Cys Thr Arg Glu Glu Phe Thr Arg Lys Val Arg 2885 2890 2895 Ser Asn Ala Ala He Gly Ala Val Phe Val Asp Glu Asn Gin Trp Asn 2900 2905 2910 Ser Ala Lys Glu Ala Val Glu Asp Glu Arg Phe Trp Glu Leu Val His 2915 2920 2925 Arg Glu Arg Glu Leu His Lys Gin Gly Lys Cys Ala Thr Cys Val Tyr 2930 2935 2940 Asn Met Met Gly Lys Arg Glu Lys Lys Leu Gly Glu Phe Gly Lys Ala 2945 2950 2955 2960 Lys Gly Ser Arg Ala He Trp Tyr Met Trp Leu Gly Ala Arg Phe Leu 2965 2970 2975 Glu Phe Glu Ala Leu Gly Phe Met Asn Glu Asp His Trp Phe Ser Arg 2980 2985 2990 Glu Asn Ser Leu Ser Gly Val Glu Gly Glu Gly Leu His Lys Leu Gly 2995 3000 3005 Tyr He Leu Arg Asp He Ser Arg lie Pro Gly Gly Asn Met Tyr Ala 3010 3015 3020

    2018200081 04 Jan 2018

    Asp Asp Thr Ala Gly Trp Asp Thr Arg He Thr Glu Asp Asp Leu Gin 3025 3030 3035 3040 Asn Glu Ala Lys lie Thr Asp He Met Glu Pro Glu His Ala Leu Leu 3045 3050 3055 Ala Thr Ser He Phe Lys Leu Thr Tyr Gin Asn Lys Val Val Arg Val 3060 3065 3070 Gin Arg Pro Ala Lys Asn Gly Thr Val Met Asp Val He Ser Arg Arg 3075 3080 3085 Asp Gin Arg Gly Ser Gly Gin Val Gly Thr Tyr Gly Leu Asn Thr Phe 3090 3095 3100 Thr Asn Met Glu Ala Gin Leu He Arg Gin Met Glu Ser Glu Gly He 3105 311C i 3115 3120 Phe Leu Pro Ser Glu Leu Glu Thr Pro Asn Leu Ala Gly Arg Val Leu 3125 3130 3135 Asp Trp Leu Glu Lys Tyr Gly Val Glu Arg Leu Lys Arg Met Ala He 3140 3145 3150 Ser Gly Asp Asp Cys Val Val Lys Pro He Asp Asp Arg Phe Ala Thr 3155 3160 3165 Ala Leu Thr Ala Leu Asn Asp Met Gly Lys Val Arg Lys Asp lie Pro 3170 3175 3180 Gin Trp Glu Pro Ser Lys Gly Trp Asn Asp Trp Gin Gin Val Pro Phe 3185 319C I 3195 3200 Cys Ser His His Phe His Gin Leu He Met Lys Asp Gly Arg Glu He 3205 3210 3215 Val Val Pro Cys Arg Asn Gin Asp Glu Leu Val Gly Arg Ala Arg Val 3220 3225 3230 Ser Gin Gly Ala Gly Trp Ser Leu Arg Glu Thr Ala Cys Leu Gly Lys 3235 3240 3245 Ser Tyr Ala Gin Met Trp Gin Leu Met Tyr Phe His Arg Arg Asp Leu 3250 3255 3260 Arg Leu Ala Ala Asn Ala He Cys Ser Ala Val Pro Val Asp Trp Val 3265 3270 3275 3280 Pro Thr Ser Arg Thr Thr Trp Ser He His Ala His His Gin Trp Met 3285 3290 3295 Thr Thr Glu Asp Met Leu Ser Val Trp Asn Arg Val Trp He Glu Glu 3300 3305 3310 Asn Pro Trp Met Glu Asp Lys Thr His Val Ser Ser Trp Glu Glu Val 3315 · 3320 3325 Pro Tyr Leu Gly Lys Arg Glu Asp Gin Trp Cys Gly Ser Leu He Gly 3330 3335 3340 Leu Thr Ala Arg Ala Thr Trp Ala Thr Asn He Gin Val Ala He Asn 3345 3350 3355 3360 Gin Val Arg Arg Leu He Gly Asn Glu Asn Tyr Leu Asp Tyr Met Thr 3365 3370 3375 Ser Met Lys Arg Phe Lys Asn Glu Ser Asp Pro'Glu Gly Ala Leu Trp 3380 3385 3390

    <210> 5 <211> 10723 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct

    2018200081 04 Jan 2018 <221> CDS <222> (97)...(10272) <400> 5 agttgttagt ctacgtggac cgacaaagac agattctttg agggagctaa gctcaatgta 60 gttctaacag ttttttaatt agagagcaga tctctg atg ate aac caa ega aaa 114

    Met lie Asn Gin Arg Lys 1 5

    aag aeg ggt ega Arg 10 ccg Pro tet Ser ttc Phe aat Asn atg Met 15 ctg Leu aaa Lys ege Arg gcg Ala aga Arg 20 aac Asn ege Arg 162 Lys Thr Gly gtg tea act gtt tea cag ttg gcg aag aga ttc tea aaa gga ttg etc 210 Val Ser Thr 25 Val Ser Gin Leu Ala 30 Lys Arg Phe Ser Lys 35 Gly Leu Leu tea ggc caa gga ccc atg aaa ttg gtg atg get ttc ata gca ttc tta 258 Ser Gly 40 Gin Gly Pro Met Lys 45 Leu Val Met Ala Phe 50 He Ala Phe Leu aga ttt eta gcc ata ccc cca aca gca gga att ttg gcc aga tgg ggc 306 Arg 55 Phe Leu Ala lie Pro 60 Pro Thr Ala Gly lie 65 Leu Ala Arg Trp Gly 70 tea ttc aag aag aat gga gcg att aaa gtg tta egg ggt ttc aag aga 354 Ser Phe Lys Lys Asn 75 Gly Ala He Lys Val 80 Leu Arg Gly Phe Lys 85 Arg gaa ate tea aac atg eta aac ata atg aac agg agg aaa aga tcc gtg 402 Glu lie Ser Asn 90 Met Leu Asn He Met 95 Asn Arg Arg Lys Arg 100 Ser Val acc atg etc ett atg ctg ctg ccc aca gcc ctg gcg ttc cat ctg aeg 450 Thr Met Leu 105 Leu Met Leu Leu Pro 110 Thr Ala Leu Ala Phe 115 His Leu Thr aca ega ggg gga gag ccg cat atg ata gtt agc aag cag gaa aga gga 498 Thr Arg 120 Gly Gly Glu Pro His 125 Met lie Val Ser Lys 130 Gin Glu Arg Gly aag tea ett ttg ttc aag ate tet gca ggt gtc aac atg tgc acc etc 546 Lys 135 Ser Leu Leu Phe Lys 140 Thr Ser Ala Gly Val 145 Asn Met Cys Thr Leu 150 att gcg atg gat ttg gga gag ttg tgt gag gac aeg atg acc tac aaa 594 lie Ala Met Asp Leu 155 Gly Glu Leu Cys Glu 160 Asp Thr Met Thr Tyr 165 Lys tgc ccc egg ate act gag gcg gaa cca gat gac gtt gac tgt tgg tgc 642 Cys Pro Arg He 170 Thr Glu Ala Glu Pro 175 Asp Asp Val Asp Cys 180 Trp Cys

    2018200081 04 Jan 2018

    aat Asn gcc Ala acg gac aca Thr tgg Trp gtg acc tat Tyr gga Gly acg Thr tgc Cys tet Ser 195 caa Gin act Thr ggc Gly 690 Thr 185 Asp Val Thr 190 gaa cac ega ega gac aaa cgt tcc gtc gca ttg gcc cca cac gtg ggg 738 Glu His Arg Arg Asp Lys Arg Ser Val Ala Leu Ala Pro His Val Gly 200 205 210 ett ggc eta gaa aca aga gcc gaa acg tgg atg tcc tet gaa ggt get 786 Leu Gly Leu Glu Thr Arg Ala Glu Thr Trp Met Ser Ser Glu Gly Ala 215 220 225 230 tgg aaa cag ata caa aaa gta gag act tgg get ctg aga cat cca gga 834 Trp Lys Gin He Gin Lys Val Glu Thr Trp Ala Leu Arg His Pro Gly 235 240 245 ttc acg gtg ata gcc ett ttt eta gca cat gcc ata gga aca tcc ate 882 Phe Thr Val He Ala Leu Phe Leu Ala His Ala He Gly Thr Ser He 250 255 260 acc cag aaa ggg ate att ttc att ttg ctg atg ctg gta aca cca tet 930 Thr Gin Lys Gly He He Phe lie Leu Leu Met Leu Val Thr Pro Ser 265 270 275 atg gcc atg ega tgc gtg gga ata ggc aac aga gac ttc gtg gaa gga 978 Met Ala Met Arg Cys Val Gly He Gly Asn Arg Asp Phe Val Glu Gly 280 285 290 ctg tea gga gca aca tgg gtg gat gtg gta ctg gag cat gga agt tgc 1026 Leu Ser Gly Ala Thr Trp Val Asp Val Val Leu Glu His Gly Ser Cys 295 300 305 310 gtc acc acc atg gca aaa aac aaa cca aca ctg gac att gaa etc ttg 1074 Val Thr Thr Met Ala Lys Asn Lys Pro Thr Leu Asp He Glu Leu Leu 315 320 325 aag acg gag gtc aca aac cct gca gtt ctg cgt aaa ttg tgc att gaa 1122 Lys Thr Glu Val Thr Asn Pro Ala Val Leu Arg Lys Leu Cys He Glu 330 335 340 get aaa ata tea aac acc acc acc gat teg aga tgt cca aca caa gga 1170 Ala Lys lie Ser Asn Thr Thr Thr Asp Ser Arg Cys Pro Thr Gin Gly 345 350 355 gaa gcc aca ctg gtg gaa gaa caa gac gcg aac ttt gtg tgc ega ega 1218 Glu Ala Thr Leu Val Glu Glu Gin Asp Ala Asn Phe Val Cys Arg Arg 360 365 370 acg ttc gtg gac aga ggc tgg ggc aat ggc tgt ggg eta ttc gga aaa 1266 Thr Phe Val Asp Arg Gly Trp Gly Asn Gly Cys Gly Leu Phe Gly Lys 375 380 385 390 ggt agt eta ata acg tgt gcc aag ttt aag tgt gtg aca aaa eta gaa 1314 Gly Ser Leu He Thr Cys Ala Lys Phe Lys Cys Val Thr Lys Leu Glu 395 400 405

    2018200081 04 Jan 2018

    gga Gly aag ata gtt Val 410 caa Gin tat Tyr gaa aac Glu Asn eta Leu 415 aaa Lys tat Tyr tea Ser gtg Val ata He 420 gtc Val acc Thr 1362 Lys lie gtc cac act gga gat cag cac cag gtg gga aat gag act aca gaa cat 1410 Val His Thr Gly Asp Gin His Gin Val Gly Asn Glu Thr Thr Glu His 425 430 435 gga aca act gca acc ata aca cct caa get cct aeg teg gaa ata cag 1458 Gly Thr Thr Ala Thr He Thr Pro Gin Ala Pro Thr Ser Glu He Gin 440 445 450 ctg acc gac tac gga acc ett aca tta gat tgt tea cct agg aca ggg 1506 Leu Thr Asp Tyr Gly Thr Leu Thr Leu Asp Cys Ser Pro Arg Thr Gly· 455 460 465 470 eta gat ttt aac gag atg gtg ttg ctg aca atg aaa gaa aga tea tgg 1554 Leu Asp Phe Asn Glu Met Val Leu Leu Thr Met Lys Glu Arg Ser Trp 475 480 485 ett gtc cac aaa caa tgg ttc eta gac tta cca ctg cct tgg acc tct 1602 Leu Val His Lys Gin Trp Phe Leu Asp Leu Pro Leu Pro Trp Thr Ser 490 495 500 ggg get tea aca tcc caa gag act tgg aac aga caa gat tta ctg gtc 1650 Gly Ala Ser Thr Ser Gin Glu Thr Trp Asn Arg Gin Asp Leu Leu Val 505 510 515 aca ttt aag aca get cat gca aag aag cag gaa gta gtc gta eta gga 1698 Thr Phe Lys Thr Ala His Ala Lys Lys Gin Glu Val Val Val Leu Gly 520 525 530 tea caa gaa gga gca atg cac act gcg ctg act gga gcg aca gaa ate 1746 Ser Gin Glu Gly Ala Met His Thr Ala Leu Thr Gly Ala Thr Glu He 535 540 545 550 caa aeg tea gga aeg aca aca att ttc gca gga cac eta aaa tgc aga 1794 Gin Thr Ser Gly Thr Thr Thr lie Phe Ala Gly His Leu Lys Cys Arg 555 560 565 eta aaa atg gac aaa eta act tta aaa ggg atg tea tat gtg atg tgc 1842 Leu Lys Met Asp Lys Leu Thr Leu Lys Gly Met Ser Tyr Val Met Cys 570 575 580 aca ggc tea ttc aag tta gag aaa gaa gtg get gag acc cag cat gga 1890 Thr Gly Ser Phe Lys Leu Glu Lys Glu Val Ala Glu Thr Gin His Gly 585 590 595 act gtt ctg gtg cag gtt aaa tat gaa gga aca gac gca cca tgc aag 1938 Thr Val Leu Val Gin Val Lys Tyr Glu Gly Thr Asp Ala Pro Cys Lys

    600 605 610

    2018200081 04 Jan 2018

    att lie 615 ccc Pro ttt Phe teg acc caa gat gag Glu aaa Lys gga Gly gca Ala 625 acc Thr cag aat ggg Gly aga Arg 630 1986 Ser Thr Gin 620 Asp Gin Asn tta ata aca gcc aac ccc ata gtc act gac aaa gaa aaa cca gtc aat 2034 Leu He Thr Ala Asn 635 Pro He Val Thr Asp 640 Lys Glu Lys Pro Val 645 Asn att gag gca gaa cca ccc ttt ggt gag age tac ate gtg gta gga gca 2082 He Glu Ala Glu 650 Pro Pro Phe Gly Glu 655 Ser Tyr He Val Val 660 Gly Ala ggt gaa aaa get ttg aaa eta agc tgg ttc aag aaa gga age agc ata 2130 Gly Glu Lys 665 Ala Leu Lys Leu Ser 670 Trp Phe Lys Lys Gly 675 Ser Ser He ggg aaa atg ttt gaa gca act gcc cga gga gca cga agg atg gcc att 2178 Gly Lys 680 Met Phe Glu Ala Thr 685 Ala Arg Gly Ala Arg 690 Arg Met Ala lie ctg gga gac acc gca tgg gac ttc ggt tet ata gga gga gtg ttc aeg 2226 Leu 695 Gly Asp Thr Ala Trp 700 Asp Phe Gly Ser He 705 Gly Gly Val Phe Thr 710 tet atg gga aaa ctg gta cac cag gtt ttt gga act gca tat gga gtt 2274 Ser Met Gly Lys Leu 715 Val His Gin Val Phe 720 Gly Thr Ala Tyr Gly 725 Val ttg ttt age gga gtt tet tgg acc atg aaa ata gga ata ggg att ctg 2322 Leu Phe Ser Gly 730 Val Ser Trp Thr Met 735 Lys He Gly He Gly 740 He Leu ctg aca tgg eta gga tta aat tea agg aac aeg tcc ctt teg gtg atg 2370 Leu Thr Trp 745 Leu Gly Leu Asn Ser 750 Arg Asn Thr Ser Leu 755 Ser Val Met tgc ate gca gcc ggc att gtg aca ctg tat ttg gga gtc atg gtg cag 2418 Cys He 760 Ala Ala Gly He Val 765 Thr Leu Tyr Leu Gly 770 Val Met Val Gin gcc gat agt ggt tgc gtt gtg agc tgg aaa aac aaa gaa ctg aaa tgt 2466 Ala 775 Asp Ser Gly Cys Val 780 Val Ser Trp Lys Asn 785 Lys Glu Leu Lys Cys 790 ggc agt ggg att ttc ate aca gac aac gtg cac aca tgg aca gaa caa 2514 Gly Ser Gly lie Phe 795 lie Thr Asp Asn Val 800 His Thr Trp Thr Glu 805 Gin tac aag ttc caa cca gaa tcc cct tea aaa eta get tea get ate cag 2562 Tyr Lys Phe Gin 810 Pro Glu Ser Pro Ser 815 Lys Leu Ala Ser Ala 820 He Gin aaa gcc cat gaa gag gac att tgt gga ate ege tea gta aca aga ctg 2610 Lys Ala His 825 Glu Glu Asp lie Cys 830 Gly He Arg Ser Val 835 Thr Arg Leu

    2018200081 04 Jan 2018

    gag aat ctg Leu atg Met tgg Trp aaa Lys caa ata aca cca gaa Pro Glu ttg Leu 850 aat Asn cac His att He eta Leu 2658 Glu Asn 840 Gin 845 He Thr tea gaa aat gag gtg aag tta act att atg aca gga gac ate aaa gga 2706 Ser Glu Asn Glu Val Lys Leu Thr He Met Thr Gly Asp He Lys Gly 855 860 865 870 ate atg cag gca gga aaa cga tct ctg egg cct cag ccc act gag ctg 2754 lie Met Gin Ala Gly Lys Arg Ser Leu Arg Pro Gin Pro Thr Glu Leu 875 880 885 aag tat tea tgg aaa aca tgg ggc aaa gca aaa atg etc tct aca gag 2802 Lys Tyr Ser Trp Lys Thr Trp Gly Lys Ala Lys Met Leu Ser Thr Glu 890 895 900 tct cat aac cag acc ttt etc att gat ggc ccc gaa aca gca gaa tgc 2850 Ser His Asn Gin Thr Phe Leu He Asp Gly Pro Glu Thr Ala Glu Cys 905 910 915 ccc aac aca aat aga get tgg aat teg ttg gaa gtt gaa gac tat ggc 2898 Pro Asn Thr Asn Arg Ala Trp Asn Ser Leu Glu Val Glu Asp Tyr Gly 920 925 930 ttt gga gta ttc acc acc aat ata tgg eta aaa ttg aaa gaa aaa cag 2946 Phe Gly Val Phe Thr Thr Asn He Trp Leu Lys Leu Lys Glu Lys Gin 935 940 945 950 gat gta ttc tgc gac tea aaa etc atg tea gcg gcc ata aaa gac aac 2994 Asp Val Phe Cys Asp Ser Lys Leu Met Ser Ala Ala He Lys Asp Asn 955 960 965 aga gcc gtc cat gcc gat atg ggt tat tgg ata gaa agt gca etc aat 3042 Arg Ala Val His Ala Asp Met Gly Tyr Trp He Glu Ser Ala Leu Asn 970 975 980 gac aca tgg aag ata gag aaa gcc tct ttc att gaa gtt aaa aac tgc 3090 Asp Thr Trp Lys He Glu Lys Ala Ser Phe He Glu Val Lys Asn Cys 985 990 995 cac tgg cca aaa tea cac acc etc tgg age aat gga gtg eta gaa agt 3138 His Trp Pro Lys Ser His Thr Leu Trp Ser Asn Gly Val Leu Glu Ser 1000 1005 1010 gag atg ata att cca aag aat etc get gga cca gtg tct caa cac aac 3186 Glu Met lie lie Pro Lys Asn Leu Ala Gly Pro Val Ser Gin His Asn 1015 1020 1025 1030 tat aga cca ggc tac cat aca caa ata aca gga cca tgg cat eta ggt 3234 Tyr Arg Pro Gly Tyr His Thr Gin He Thr Gly Pro Trp His Leu Gly

    1035 1040 1045

    2018200081 04 Jan 2018

    aag Lys ett gag atg gac Met Asp 1050 ttt Phe gat Asp ttc Phe tgt gat gga aca aca gtg gta gtg 3282 Leu Glu Cys Asp Gly Thr Thr Val Val Val 1055 1060 act gag gac tgc gga aat aga gga ccc tct ttg aga aca acc act gcc 3330 Thr Glu Asp 1065 Cys Gly Asn Arg Gly 107C Pro Ser Leu 1 Arg Thr Thr Thr 1075 Ala tct gga aaa etc ata aca gaa tgg tgc tgc ega tct tgc aca tta cca 3378 Ser Gly 108C Lys 1 Leu He Thr Glu 1085 Trp Cys Cys Arg Ser Cys Thr Leu 1090 Pro ccg eta aga tac aga ggt gag gat ggg tgc tgg tac ggg atg gaa ate 3426 Pro 1095 Leu Arg Tyr Arg Gly Glu 1100 Asp Gly Cys Trp 1105 Tyr Gly Met Glu He 1110 aga cca ttg aag gag aaa gaa gag aat ttg gtc aac tcc ttg gtc aca 3474 Arg Pro Leu Lys Glu Lys 1115 Glu Glu Asn Leu Val 1120 Asn Ser Leu Val Thr 1125 get gga cat ggg cag gtc gac aac ttt tea eta gga gtc ttg gga atg 3522 Ala Gly His Gly Gin 1130 Val Asp Asn Phe Ser Leu 1135 Gly Val Leu Gly 1140 Met gca ttg ttc ctg gag gaa atg ett agg acc ega gta gga aeg aaa cat 3570 Ala Leu Phe Leu Glu 1145 Glu Met Leu Arg Thr Arg 1150 Val Gly Thr Lys 1155 His gca ata eta eta gtt gca gtt tct ttt gtg aca ttg ate aca ggg aac 3618 Ala lie Leu 1160 Leu Val Ala Val Ser 1165 Phe Val Thr Leu He Thr Gly 1170 Asn atg tcc ttt aga gac ctg gga aga gtg atg gtt atg gta ggc gcc act 3666 Met 1175 Ser Phe Arg Asp Leu Gly 1180 Arg Val Met Val 1185 Met Val Gly Ala Thr 1190 atg aeg gat gac ata ggt atg ggc gtg act tat ett gcc eta eta gca 3714 Met Thr Asp Asp lie Gly 1195 Met Gly Val Thr Tyr 1200 Leu Ala Leu Leu Ala 1205 gcc ttc aaa gtc aga cca act ttt gca get gga eta etc ttg aga aag 3762 Ala Phe Lys Val Arg 1210 Pro Thr Phe Ala Ala Gly 1215 Leu Leu Leu Arg 1220 Lys ctg acc tcc aag gaa ttg atg atg act act ata gga att gta etc etc 3810 Leu Thr Ser Lys Glu 1225 Leu Met Met Thr Thr lie 1230 Gly He Val Leu 1235 Leu tcc cag age acc ata cca gag acc att ett gag ttg act gat gcg tta 3858 Ser Gin Ser 1240 Thr He Pro Glu Thr 1245 He Leu Glu Leu Thr Asp Ala 1250 Leu gcc tta ggc atg atg gtc etc aaa atg gtg aga aat atg gaa aag tat 3906 Ala 1255 Leu Gly Met Met Val Leu 1260 Lys Met Val Arg Asn Met Glu Lys 1265 Tyr 1270

    2018200081 04 Jan 2018

    caa Gin ttg Leu gca Ala gtg Val act ate Thr He 1275 atg Met get Ala ate He ttg tgc Leu Cys 1280 gtc Val cca Pro aac Asn gca gtg Ala Val 1285 3954 ata tta caa aac gca tgg aaa gtg agt tgc aca ata ttg gca gtg gtg 4002 lie Leu Gin Asn 129C Ala Trp 1 Lys Val Ser 1295 Cys Thr He Leu Ala 130C Val Val 1 tcc gtt tcc cca ctg ttc tta aca tcc tea cag caa aaa aca gat tgg 4050 Ser Val Ser Pro 1305 Leu Phe Leu Thr Ser 1310 Ser Gin Gin Lys Thr 1315 Asp Trp ata cca tta gca ttg aeg ate aaa ggt etc aat cca aca get att ttt 4098 lie Pro 132C Leu 1 Ala Leu Thr He Lys 1325 Gly Leu Asn Pro Thr 1330 Ala He Phe eta aca acc etc tea aga acc age aag aaa agg age tgg cca tta aat 4146 Leu 1335 Thr Thr Leu Ser Arg 134C Thr 1 Ser Lys Lys Arg Ser 1345 Trp Pro Leu Asn 1350 gag get ate atg gca gtc ggg atg gtg agc att tta gcc agt tet etc 4194 Glu Ala He Met Ala Val 1355 Gly Met Val Ser He 1360 Leu Ala Ser Ser Leu 1365 eta aaa aat gat att ccc atg aca gga cca tta gtg get gga ggg etc 4242 Leu Lys Asn Asp 137C lie Pro 1 Met Thr Gly 1375 Pro Leu Val Ala Gly Gly Leu 1380 etc act gtg tgc tac gtg etc act gga ega teg gcc gat ttg gaa ctg 4290 Leu Thr Val Cys 1385 Tyr Val Leu Thr Gly 1390 Arg Ser Ala Asp Leu 1395 Glu Leu gag aga gca gcc gat gtc aaa tgg gaa gac cag gca gag ata tea gga 4338 Glu Arg Ala 1400 Ala Asp Val Lys Trp 1405 Glu Asp Gin Ala Glu 1410 He Ser Gly agc agt cca ate ctg tea ata aca ata tea gaa gat ggt agc atg teg 4386 Ser Ser 1415 Pro lie Leu Ser 142C lie 1 Thr lie Ser Glu Asp 1425 Gly Ser Met Ser 1430 ata aaa aat gaa gag gaa gaa caa aca ctg acc ata etc att aga aca 4434 He Lys Asn Glu Glu Glu 1435 Glu Gin Thr Leu Thr 1440 He Leu He Arg Thr 1445 gga ttg ctg gtg ate tea gga ett ttt cct gta tea ata cca ate aeg 4482 Gly Leu Leu Val He Ser 1450 Gly Leu Phe Pro Val 1455 Ser He Pro He Thr 1460 gca gca gca tgg tac ctg tgg gaa gtg aag aaa caa cgg gcc gga gta 4530 Ala Ala Ala Trp Tyr Leu Trp Glu Val Lys Lys Gin Arg Ala Gly Val

    1465 1470 1475

    2018200081 04 Jan 2018

    ttg tgg gat gtt Val cct Pro tea ccc cca ccc atg Met gga aag get Gly Lys Ala 1490 gaa Glu ctg Leu gaa Glu 4578 Leu Trp Asp 1480 Ser Pro Pro 1485 Pro gat gga gcc tat aga att aag caa aaa ggg att ctt gga tat tee cag 4626 Asp 1495 Gly Ala Tyr Arg He Lys Gin 1500 Lys Gly He Leu Gly 1505 Tyr Ser Gin 1510 ate gga gcc gga gtt tac aaa gaa gga aca ttc cat aca atg tgg cat 4674 lie Gly Ala Gly Val 1515 Tyr Lys Glu Gly Thr 152C Phe His Thr I Met Trp 1525 His gtc aca cgt ggc get gtt eta atg cat aaa gga aag agg att gaa cca 4722 Val Thr Arg Gly Ala 1530 Val Leu Met His Lys 1535 Gly Lys Arg lie Glu 1540 Pro tea tgg geg gac gtc aag aaa gac eta ata tea tat gga gga. ggc tgg 4770 Ser Trp Ala Asp 1545 Val Lys Lys Asp 155C Leu I He Ser Tyr Gly Gly 1555 Gly Trp aag tta gaa gga gaa tgg aag gaa gga gaa gaa gtc cag gta ttg gca 4818 Lys Leu Glu 1560 Gly Glu Trp Lys Glu 1565 Gly Glu Glu Val Gin 1570 Val Leu Ala ctg gag cct gga aaa aat cca aga gee gtc caa aeg aaa cct ggt ctt 4866 Leu Glu Pro 1575 Gly Lys Asn Pro Arg 1580 Ala Val Gin Thr Lys 1585 Pro Gly Leu 1590 ttc aaa acc aac gee gga aca ata ggt get gta tet ctg gac ttt tet 4914 Phe Lys Thr Asn Ala Gly Thr lie 1595 Gly Ala Val Ser Leu 1600 Asp Phe Ser 1605 cct gga aeg tea gga tet cca att ate gac aaa aaa gga aaa gtt gtg 4962 Pro Gly Thr Ser Gly 1610 Ser Pro He He Asp 1615 Lys Lys Gly Lys Val 1620 Val ggt ctt tat ggt aat ggt gtt gtt aca agg agt gga gca tat gtg agt 5010 Gly Leu Tyr Gly 1625 Asn Gly Val Val Thr 1630 Arg Ser Gly Ala Tyr 1635 Val Ser get ata gcc cag act gaa aaa age att gaa gac aac cca gag ate gaa 5058 Ala He Ala 1640 Gin Thr Glu Lys Ser 1645 He Glu Asp Asn Pro 1650 Glu He Glu gat gac att ttc ega aag aga aga ctg acc ate atg gac etc cac cca 5106 Asp Asp lie 1655 Phe Arg Lys Arg Arg 1660 Leu Thr He Met Asp 1665 Leu His Pro 1670 gga geg gga aag aeg aag aga tac ctt ccg gcc ata gtc aga gaa get 5154 Gly Ala Gly Lys Thr Lys Arg Tyr 1675 Leu Pro Ala lie Val 1680 Arg Glu Ala 1685 ata aaa egg ggt ttg aga aca tta ate ttg gcc ccc act aga gtt gtg 5202 lie Lys Arg Gly Leu Arg Thr Leu He Leu Ala Pro Thr Arg Val Val

    1690 1695 1700

    2018200081 04 Jan 2018

    gca Ala get Ala gaa atg Glu Met 1705 gag Glu gaa Glu gcc Ala ett aga Leu Arg 1710 gga Gly ett Leu cca Pro ata aga He Arg 1715 tac Tyr cag Gin 5250 acc cca gcc ate aga get gtg cac acc ggg egg gag att gtg gac eta 5298 Thr Pro 172C Ala lie 1 Arg Ala Val 1725 His Thr Gly Arg Glu 1730 He Val Asp Leu atg tgt cat gcc aca ttt acc atg agg ctg eta tea cca gtt aga gtg 5346 Met Cys 1735 His Ala Thr Phe Thr 1740 Met Arg Leu Leu 1745 Ser Pro Val Arg Val 1750 cca aac tac aac ctg att ate atg gac gaa gee cat ttc aca gac cca 5394 Pro Asn Tyr Asn Leu He 1755 He Met Asp Glu Ala 1760 His Phe Thr Asp Pro 1765 gca agt ata gca get aga gga tac ate tea act ega gtg gag atg ggt 5442 Ala Ser He Ala Ala 1770 Arg Gly Tyr He Ser 1775 Thr Arg Val Glu Met 1780 Gly gag gca get ggg att ttt atg aca gcc act ccc ccg gga age aga gac 5490 Glu Ala Ala Gly 1785 He Phe Met Thr Ala 1790 Thr Pro Pro Gly Ser 1795 Arg Asp cca ttt cct cag age aat gca cca ate ata gat gaa gaa aga gaa ate 5538 Pro Phe 180C Pro Gin 1 Ser Asn Ala 1805 Pro He lie Asp Glu 181C Glu Arg 1 Glu He cct gaa ege teg tgg aat tcc gga cat gaa tgg gtc aeg gat ttt aaa 5586 Pro Glu 1815 Arg Ser Trp Asn Ser 1820 Gly His Glu Trp Val 1825 Thr Asp Phe Lys 1830 ggg aag act gtt tgg ttc gtt cca agt ata aaa gca gga aat gat ata 5634 Gly Lys Thr Val Trp Phe 1835 Val Pro Ser He Lys 1840 Ala Gly Asn Asp He 1845 gca get tgc ctg agg aaa aat gga aag aaa gtg ata caa etc agt agg 5682 Ala Ala Cys Leu Arg 1850 Lys Asn Gly Lys Lys 1855 Val He Gin Leu Ser 1860 Arg aag acc ttt gat tet gag tat gtc aag act aga acc aat gat tgg gac 5730 Lys Thr Phe Asp 1865 Ser Glu Tyr Val Lys 1870 Thr Arg Thr Asn Asp 1875 Trp Asp ttc gtg gtt aca act gac att tea gaa atg ggt gcc aat ttc aag get 5778 Phe Val Val Thr 1880 Thr Asp He Ser Glu 1885 Met Gly Ala Asn Phe 1890 Lys Ala gag agg gtt ata gac ccc aga ege tgc atg aaa cca gtc ata eta aca 5826 Glu Arg 1895 Val He Asp Pro Arg 1900 Arg Cys Met Lys Pro 1905 Val He Leu Thr 1910

    2018200081 04 Jan 2018

    gat Asp ggt Gly gaa Glu gag Glu egg gtg Arg Val 1915 att He ctg Leu gca Ala gga cct Gly Pro 1920 atg Met cca Pro gtg Val acc cac Thr His 1925 5874 tet agt gca gca caa aga aga ggg aga ata gga aga aat cca aaa aat 5922 Ser Ser Ala Ala 193C Gin Arg I Arg Gly Arg 1935 lie Gly Arg Asn Pro 194C Lys Asn 1 gag aat gac cag tac ata tac atg ggg gaa cct ctg gaa aat gat gaa 5970 Glu Asn Asp Gin 1945 Tyr He Tyr Met Gly 1950 Glu Pro Leu Glu Asn 1955 Asp Glu gac tgt gca cac tgg aaa gaa get aaa atg etc eta gat aac ate aac 6018 Asp Cys Ala 1960 His Trp Lys Glu Ala 1965 Lys Met Leu Leu Asp 1970 Asn He Asn aeg cca gaa gga ate att cct agc atg ttc gaa cca gag cgt gaa aag 6066 Thr Pro 1975 Glu Gly He He Pro 1980 Ser Met Phe Glu Pro 1985 Glu Arg Glu Lys 1990 gtg gat gec att gat ggc gaa tac ege ttg aga gga gaa gca agg aaa 6114 Val Asp Ala lie Asp Gly 1995 Glu Tyr Arg Leu Arg 2000 Gly Glu Ala Arg Lys 2005 acc ttt gta gac tta atg aga aga gga gac eta cca gtc tgg ttg gee 6162 Thr Phe Val Asp 201C Leu Met I Arg Arg Gly 2015 Asp Leu Pro Val Trp 202C Leu Ala I tac aga gtg gca get gaa ggc ate aac tac gca gac aga agg tgg tgt 6210 Tyr Arg Val Ala 2025 Ala Glu Gly He Asn 2030 Tyr Ala Asp Arg Arg 2035 Trp Cys ttt gat gga gtc aag aac aac caa ate eta gaa gaa aac gtg gaa gtt 6258 Phe Asp Gly 2040 Val Lys Asn Asn Gin 2045 He Leu Glu Glu Asn 2050 Val Glu Val gaa ate tgg aca aaa gaa ggg gaa agg aag aaa ttg aaa ccc aga tgg 6306 Glu lie 2055 Trp Thr Lys Glu Gly 2060 Glu Arg Lys Lys Leu 2065 Lys Pro Arg Trp 2070 ttg gat get agg ate tat tet gac cca ctg geg eta aaa gaa ttt aag 6354 Leu Asp Ala Arg He Tyr 2075 Ser Asp Pro Leu Ala 2080 Leu Lys Glu Phe Lys 2085 gaa ttt gca gec gga aga aag tet ctg acc ctg aac eta ate aca gaa 6402 Glu Phe Ala Ala Gly Arg 2090 Lys Ser Leu Thr Leu 2095 Asn Leu He Thr Glu 2100 atg ggt agg etc cca acc ttc atg act cag aag gca aga gac gca ctg 6450 Met Gly Arg Leu 2105 Pro Thr Phe Met Thr 2110 Gin Lys Ala Arg Asp 2115 Ala Leu gac aac tta gca gtg ctg cac aeg get gag gca ggt gga agg geg tac 6498 Asp Asn Leu 2120 Ala Val Leu His Thr 2125 Ala Glu Ala Gly Gly Arg 2130 Ala Tyr

    2018200081 04 Jan 2018

    aac cat Asn His 2135 get Ala etc Leu agt Ser gaa ctg Glu Leu 2140 ccg gag Pro Glu acc Thr ctg gag aca ttg Leu Glu Thr Leu 2145 ett Leu tta Leu 2150 6546 ctg aca ett ctg get aca gtc aeg gga ggg ate ttt tta ttc ttg atg 6594 Leu Thr Leu Leu Ala 2155 Thr Val Thr Gly Gly 216C He Phe Leu Phe 1 Leu 2165 Met age gca agg ggc ata ggg aag atg acc ctg gga atg tgc tgc ata ate 6642 Ser Ala Arg Gly 217C He 1 Gly Lys Met Thr 2175 Leu Gly Met Cys Cys 2180 He 1 He aeg get age ate etc eta tgg tac gca caa ata cag cca cac tgg ata 6690 Thr Ala Ser 2185 He Leu Leu Trp Tyr Ala 2190 Gin He Gin Pro His 2195 Trp He gca get tea ata ata ctg gag ttt ttt etc ata gtt ttg ett att cca 6738 Ala Ala Ser 2200 He He Leu Glu 2205 Phe Phe Leu He Val Leu Leu 2210 He Pro gaa cct gaa aaa cag aga aca ccc caa gac aac caa ctg acc tac gtt 6786 Glu Pro 2215 Glu Lys Gin Arg Thr 2220 Pro Gin Asp Asn Gin Leu Thr 2225 Tyr Val 2230 gtc ata gcc ate etc aca gtg gtg gcc gca acc atg gca aac gag atg 6834 Val lie Ala He Leu Thr Val 2235 Val Ala Ala Thr Met Ala Asn 2240 Glu 2245 Met ggt ttc eta gaa aaa aeg aag aaa gat etc gga ttg gga age att gca 6882 Gly Phe Leu Glu Lys 2250 Thr Lys Lys Asp Leu 2255 Gly Leu Gly Ser 226C He 1 Ala acc cag caa ccc gag age aac ate ctg gac ata gat eta cgt cct gca 6930 Thr Gin Gin 2265 Pro Glu Ser Asn He Leu 2270 Asp He Asp Leu Arg 2275 Pro Ala tea gca tgg aeg ctg tat gcc gtg gcc aca aca ttt gtt aca cca atg 6978 Ser Ala Trp 2280 Thr Leu Tyr Ala Val Ala 2285 Thr Thr Phe Val Thr 2290 Pro Met ttg aga cat age att gaa aat tcc tea gtg aat gtg tcc eta aca get 7026 Leu Arg 2295 His Ser He Glu Asn 2300 Ser Ser Val Asn Val Ser Leu 2305 Thr Ala 2310 ata gcc aac caa gcc aca gtg tta atg ggt etc ggg aaa gga tgg cca 7074 He Ala Asn Gin Ala Thr Val 2.315 Leu Met Gly Leu Gly Lys Gly 2320 Trp Pro 2325 ttg tea aag atg gac ate gga gtt ccc ett etc gcc att gga tgc tac 7122 Leu Ser Lys Met Asp 2330 He Gly Val Pro Leu 2335 Leu Ala He Gly Cys 2340 Tyr

    2018200081 04 Jan 2018

    tea Ser caa Gin gtc aac Val Asn 2345 ccc Pro ata He act Thr etc aca Leu Thr 2350 gca Ala get Ala ett Leu ttc tta Phe Leu 2355 ttg Leu gta Val 7170 gca cat tat gcc ate ata ggg cca gga etc caa gca aaa gca acc aga 7218 Ala His 236C Tyr Ala 1 He He Gly 236Ξ Pro Gly Leu Gin Ala 237C Lys Ala 1 Thr Arg gaa get cag aaa aga gca geg geg ggc ate atg aaa aac cca act gtc 7266 Glu Ala 2375 Gin Lys Arg Ala Ala 2380 Ala Gly He Met Lys 2385 Asn Pro Thr Val 2390 gat gga ata aca gtg att gac eta gat cca ata cct tat gat cca aag 7314 Asp Gly He Thr Val 2395 He Asp Leu Asp Pro 240C He I Pro Tyr Asp Pro 240Ξ Lys ttt gaa aag cag ttg gga caa gta atg etc eta gtc. etc tgc gtg act 7362 Phe Glu Lys Gin Leu 2410 Gly Gin Val Met Leu 2415 Leu Val Leu Cys Val 2420 Thr caa gta ttg atg atg agg act aca tgg get ctg tgt gag get tta acc 7410 Gin Val Leu Met 2425 Met Arg Thr Thr Trp 2430 Ala Leu Cys Glu Ala 2435 Leu Thr tta get acc ggg ccc ate tcc aca ttg tgg gaa gga aat cca ggg agg 7458 Leu Ala 244C Thr Gly 1 Pro He Ser Thr Leu 2445 Trp Glu Gly Asn Pro 2450 Gly Arg ttt tgg aac act acc att geg gtg tea atg get aac att ttt aga ggg 7506 Phe Trp 2455 Asn Thr Thr He Ala 2460 Val Ser Met Ala Asn 2465 lie Phe Arg Gly 2470 agt tac ttg gcc gga get gga ett etc ttt tet att atg aag aac aca 7554 Ser Tyr Leu Ala Gly Ala 2475 Gly Leu Leu Phe Ser 2480 He Met Lys Asn Thr 2485 acc aac aca aga agg gga act ggc aac ata gga gag aeg ett gga gag 7602 Thr Asn Thr Arg Arg 2490 Gly Thr Gly Asn He 2495 Gly Glu Thr Leu Gly 2500 Glu aaa tgg aaa agc ega ttg aac gca ttg gga aaa agt gaa ttc cag ate 7650 Lys Trp Lys Ser 2505 Arg Leu Asn Ala Leu 2510 Gly Lys Ser Glu Phe 2515 Gin He tac aag aaa agt gga ate cag gaa gtg gat aga acc tta gca aaa gaa 7698 Tyr Lys Lys Ser 2520 Gly He Gin Glu Val 2525 Asp Arg Thr Leu Ala 2530 Lys Glu ggc att aaa aga gga gaa aeg gac cat cac get gtg teg ega ggc tea 7746 Gly lie 2535 Lys Arg Gly Glu Thr 2540 Asp His His Ala Val 2545 Ser Arg Gly Ser 2550 gca aaa ctg aga tgg ttc gtt gag aga aac atg gtc aca cca gaa ggg 7794 Ala Lys Leu Arg Trp Phe 2555 Val Glu Arg Asn Met 2560 Val Thr Pro Glu Gly 2565

    2018200081 04 Jan 2018

    aaa Lys gta Val gtg Val gac etc Asp Leu 2570 ggt Gly tgt Cys ggc Gly aga gga Arg Gly 2575 ggc Gly tgg Trp tea Ser tac tat Tyr Tyr 2580 tgt Cys 7842 gga gga eta aag aat gta aga gaa gtc aaa ggc eta aca aaa gga gga 7890 Gly Gly Leu 2585 Lys Asn Val Arg Glu 259C Val Lys 1 Gly Leu Thr 2595 Lys Gly Gly cca gga cac gaa gaa ccc ate ccc atg tea aca tat ggg tgg aat eta 7938 Pro Gly 260C His 1 Glu Glu Pro He 2605 Pro Met Ser Thr Tyr 261C Gly Trp Asn I Leu gtg cgt ett caa agt gga gtt gac gtt ttc ttc ate ccg cca gaa aag 7986 Val Arg 2615 Leu Gin Ser Gly Val 2620 Asp Val Phe Phe 2625 lie Pro Pro Glu Lys 2630 tgt gac aca tta ttg tgt gac ata ggg gag tea tea cca aat ccc aca 8034 Cys Asp Thr Leu Leu Cys 2635 · Asp He Gly Glu Ser 2640 Ser Pro Asn Pro 2645 Thr gtg gaa gca gga ega aca etc aga gtc ett aac tta gta gaa aat tgg 8082 Val Glu Ala Gly Arg 2650 Thr Leu Arg Val Leu 2655 Asn Leu Val Glu Asn 2660 Trp ttg aac aac aac act caa ttt tgc ata aag gtt etc aac cca tat atg 8130 Leu Asn Asn Asn Thr 2665 Gin Phe Cys lie Lys 2670 Val Leu Asn 2675 Pro Tyr Met ccc tea gtc ata gaa aaa atg gaa gca eta caa agg aaa tat gga gga 8178 Pro Ser Val 2680 lie Glu Lys Met Glu 2685 Ala Leu Gin Arg Lys 2690 Tyr Gly Gly gcc tta gtg agg aat cca etc tea ega aac tcc aca cat gag atg tac 8226 Ala Leu 2695 Val Arg Asn Pro Leu 2700 Ser Arg Asn Ser Thr 2705 His Glu Met Tyr 2710 tgg gta tcc aat get tcc ggg aac ata gtg tea tea gtg aac atg att 8274 Trp Val Ser Asn Ala Ser 2715 Gly Asn He Val Ser 2720 Ser Val Asn Met He 2725 tea agg atg ttg ate aac aga ttt aca atg aga tac aag aaa gcc act 8322 Ser Arg Met Leu He 2730 Asn Arg Phe Thr Met 2735 Arg Tyr Lys Lys Ala 2740 Thr tac gag ccg gat gtt gac etc gga age gga acc cgt aac ate ggg att 8370 Tyr Glu Pro Asp Val 2745 Asp Leu Gly Ser Gly 2750 Thr Arg Asn 2755 He Gly He gaa agt gag ata cca aac eta gat ata att ggg aaa aga ata gaa aaa 8418 Glu Ser Glu 2760 He Pro Asn Leu Asp 2765 He He Gly Lys Arg 2770 He Glu Lys

    2018200081 04 Jan 2018

    63 ata aag caa gag cat gaa aca tea tgg cac tat gac caa gac cac cca 8466 lie Lys Gin Glu His Glu Thr Ser Trp His Tyr Asp Gin Asp His Pro 2775 2780 2785 2790 tac aaa acg tgg gca tac cat ggt age tat gaa aca aaa cag act gga 8514 Tyr Lys Thr Trp Ala Tyr His Gly Ser Tyr Glu Thr Lys Gin Thr Gly 2795 i 2800 2805 tea gca tea tec atg gtc aac gga gtg gtc agg ctg ctg aca aaa cct 8562 Ser Ala Ser Ser Met Val Asn Gly Val Val Arg Leu Leu Thr Lys Pro 2810 2815 2820 tgg gac gtc gtc ccc atg gtg aca cag atg gca atg aca gac acg act 8610 Trp Asp Val Val Pro Met Val Thr Gin Met Ala Met Thr Asp Thr Thr 2825 2830 2835 cca ttt gga caa cag ege gtt ttt aaa gag aaa gtg gac acg aga acc 8658 Pro Phe Gly Gin Gin Arg Val Phe Lys Glu Lys Val Asp Thr Arg Thr 2840 2845 2850 caa gaa ccg aaa gaa ggc acg aag aaa eta atg aaa ata aca gca gag 8706 Gin Glu Pro Lys Glu Gly Thr Lys Lys Leu Met Lys He Thr Ala Glu 2855 2860 2865 2870 tgg ett tgg aaa gaa tta ggg aag aaa aag aca ccc agg atg tgc acc 8754 Trp Leu Trp Lys Glu Leu Gly Lys Lys Lys Thr Pro Arg Met Cys Thr 2875 2880 2885 aga gaa gaa ttc aca aga aag gtg aga age aat gca gcc ttg ggg gcc 8802 Arg Glu Glu Phe Thr Arg Lys Val Arg Ser Asn Ala Ala Leu Gly Ala 2890 2895 2900 ata ttc act gat gag aac aag tgg aag teg gca cgt gag get gtt gaa 8850 He Phe Thr Asp Glu Asn Lys Trp Lys Ser Ala Arg Glu Ala Val Glu 2905 2910 2915 gat agt agg ttt tgg gag ctg gtt gac aag gaa agg aat etc cat ett 8898 Asp Ser Arg Phe Trp Glu Leu Val Asp Lys Glu Arg Asn Leu His Leu 2920 2925 2930 gaa gga aag tgt gaa aca tgt gtg tac aac atg atg gga aaa aga gag 8946 Glu Gly Lys Cys Glu Thr Cys Val Tyr Asn Met Met Gly Lys Arg Glu 2935 2940 2945 2950 aag aag eta ggg gaa ttc ggc aag gca aaa ggc age aga gcc ata tgg 8994 Lys Lys Leu Gly Glu Phe Gly Lys Ala Lys Gly Ser Arg Ala He Trp 2955 2960 2965 tac atg tgg ett gga gca ege ttc tta gag ttt gaa gcc eta gga ttc 9042 Tyr Met Trp Leu Gly Ala Arg Phe Leu Glu Phe Glu Ala Leu Gly Phe 2970 2975 2980 tta aat gaa gat cac tgg ttc tcc aga gag aac tcc ctg agt gga gtg 9090 Leu Asn Glu Asp His Trp Phe Ser Arg Glu Asn Ser Leu Ser Gly Val

    2985 2990 2995

    2018200081 04 Jan 2018

    gaa gga gaa ggg ctg cac aag eta Lys Leu 3005 ggt Gly tac Tyr att He eta aga gac Leu Arg Asp 3010 gtg Val age Ser 9138 Glu Gly Glu 3000 Gly Leu His aag aaa gag gga gga gca atg tat gcc gat gac acc gca gga tgg gat 9186 Lys Lys Glu 3015 Gly Gly Ala Met Tyr 3020 Ala Asp Asp 3025 Thr Ala Gly Trp Asp 3030 aca aga ate aca eta gaa gac eta aaa aat gaa gaa atg gta aca aac 9234 Thr Arg He Thr Leu Glu 3035 Asp Leu Lys Asn 304C Glu 1 Glu Met Val Thr 3045 Asn cac atg gaa gga gaa cac aag aaa eta gcc gag gcc att ttc aaa eta 9282 His Met Glu Gly 305C Glu 1 His Lys Lys Leu Ala 3055 Glu Ala He Phe 306C Lys 1 Leu acg tac caa aac aag gtg gtg cgt gtg caa aga cca aca cca aga ggc 9330 Thr Tyr Gin Asn 3065 Lys Val Val Arg Val 3070 Gin Arg Pro Thr Pro 3075 Arg Gly aca gta atg gac ate ata teg aga aga gac caa aga ggt agt gga caa 9378 Thr Val Met 3080 Asp He He Ser Arg 3085 Arg Asp Gin Arg Gly Ser 3090 Gly Gin gtt ggc acc tat gga etc aat act ttc acc aat atg gaa gcc caa eta 9426 Val Gly Thr 3095 Tyr Gly Leu Asn Thr 3100 Phe Thr Asn Met Glu' Ala 3105 Gin Leu 3110 ate aga cag atg gag gga gaa gga gtc ttt aaa age att cag cac eta 9474 lie Arg Gin Met Glu Gly 3115 Glu Gly Val Phe Lys 3120 Ser He Gin His 3125 Leu aca ate aca gaa gaa ate get gtg caa aac tgg tta gca aga gtg ggg 9522 Thr He Thr Glu Glu 3130 He Ala Val Gin Asn 3135 Trp Leu Ala Arg Val 3140 Gly ege gaa agg tta tea aga atg gcc ate agt gga gat gat tgt gtt gtg 9570 Arg Glu Arg Leu 3145 Ser Arg Met Ala He 3150 Ser Gly Asp Asp Cys 3155 Val Val aaa cct tta gat gac agg ttc gca age get tta aca get eta aat gac 9618 Lys Pro Leu 3160 Asp Asp Arg Phe Ala 3165 Ser Ala Leu Thr Ala Leu 3170 Asn Asp atg gga aag att agg aaa gac ata caa caa tgg gaa cct tea aga gga 9666 Met Gly Lys 3175 lie Arg Lys Asp He 3180 Gin Gin Trp Glu Pro Ser 3185 Arg Gly 3190 tgg aat gat tgg aca caa gtg ccc ttc tgt tea cac cat ttc cat gag 9714 Trp Asn Asp Trp Thr Gin 3195 Val Pro Phe Cys Ser 3200 His His Phe His Glu 3205

    2018200081 04 Jan 2018

    tta Leu ate lie atg aaa gac Met Lys Asp 3210 ggt Gly cgc gta Arg Val etc gtt gtt Leu Val Val 3215 cca Pro tgt Cys aga aac Arg Asn 3220 caa Gin 9762 gat gaa ctg att ggc aga gcc ega ate tcc caa gga gca ggg tgg tet 9810 Asp Glu Leu lie Gly Arg Ala Arg He Ser Gin Gly Ala Gly Trp Ser 3225 3230 3235 ttg egg gag aeg gcc tgt ttg ggg aag tet tac gcc caa atg tgg age 9858 Leu Arg Glu Thr Ala Cys Leu Gly Lys Ser Tyr Ala Gin Met Trp Ser 3240 3245 3250 ttg atg tac ttc cac aga cgc gac etc agg ctg gcg gca aat get att 9906 Leu Met Tyr Phe His Arg Arg Asp Leu Arg Leu Ala Ala Asn Ala lie 3255 3260 3265 3270 tgc teg gca gta cca tea cat tgg gtt cca aca agt ega aca acc tgg 9954 Cys Ser Ala Val Pro Ser His Trp Val Pro Thr Ser Arg Thr Thr Trp 3275 3280 3285 tcc ata cat get aaa cat gaa tgg atg aca aeg gaa gac atg ctg aca 10002 Ser He His Ala Lys His Glu Trp Met Thr Thr Glu Asp Met Leu Thr 3290 3295 3300 gtc tgg aac agg gtg tgg att caa gaa aac cca tgg atg gaa gac aaa 10050 Val Trp Asn Arg Val Trp He Gin Glu Asn Pro Trp Met Glu Asp Lys 3305 3310 3315 act cca gtg gaa tea tgg gag gaa ate cca tac ttg ggg aaa aga gaa 10098 Thr Pro Val Glu Ser Trp Glu Glu lie Pro Tyr Leu Gly Lys Arg Glu 3320 3325 3330 gac caa tgg tgc ggc tea ttg att ggg tta aca agc agg gcc acc tgg 10146 Asp Gin Trp Cys Gly Ser Leu He Gly Leu Thr Ser Arg Ala Thr Trp 3335 3340 3345 3350 gca aag aac ate caa gca gca ata aat caa gtt aga tcc ett ata ggc 10194 Ala Lys Asn He Gin Ala Ala He Asn Gin Val Arg Ser Leu He Gly 3355 3360 3365 aat gaa gaa tac aca gat tac atg cca tcc atg aaa aga ttc aga aga 10242 Asn Glu Glu Tyr Thr Asp Tyr Met Pro Ser Met Lys Arg Phe Arg Arg 3370 3375 3380 gaa gag gaa gaa gca gga gtt ctg tgg tag aaagcaaaac taacatgaaa 10292 Glu Glu Glu Glu Ala Gly Val Leu Trp 3385 3390

    caaggctaga ccccgtccaa atgcagcctg agctgtacgc gcaacaatgg gaggagaccc ctgtctcctc agtcaggtcg ggacgttaaa tagctccacc atggcgtagt gggcccaagg ccccgaaaca agcatcattc gattaagcca agaagtcagg tgagaaggtg ggactagcgg cgagatgaag aaaaacagca caggcacaga tagtacggaa ccatcataaa taaaaaatcc ttagaggaga ctgtagtctc tattgacgct acgccagaaa aaaactatgc tgccatagct gggaggccac cccctccctt gctggaagga gggaaagacc atggaatggt

    10352

    10412

    10472

    10532

    10592

    10652

    10712 tacctgtgag tgagtaaact aaaccatgga acaaatcgca ctagaggtta agagatcctg gctgttgaat

    2018200081 04 Jan 2018 caacaggttc t <210> 6 <211> 3391 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct

    <400> 6 Met He Asn Gin Arg Lys Lys Thr Gly Arg Pro Ser Phe Asn Met Leu 1 5 10 15 Lys Arg Ala Arg Asn Arg Val Ser Thr Val Ser Gin Leu Ala Lys Arg 20 25 30 Phe Ser Lys Gly Leu Leu Ser Gly Gin Gly Pro Met Lys Leu Val Met 35 40 45 Ala Phe lie Ala Phe Leu Arg Phe Leu Ala He Pro Pro Thr Ala Gly 50 55 60 lie Leu Ala Arg Trp Gly Ser Phe Lys Lys Asn Gly Ala He Lys Val 65 70 75 80 Leu Arg Gly Phe Lys Arg Glu He Ser Asn Met Leu Asn He Met Asn 85 90 95 Arg Arg Lys Arg Ser Val Thr Met Leu Leu Met Leu Leu Pro Thr Ala 100 105 110 Leu Ala Phe His Leu Thr Thr Arg Gly Gly Glu Pro His Met He Val 115 120 125 Ser Lys Gin Glu Arg Gly Lys Ser Leu Leu Phe Lys Thr Ser Ala Gly 130 135 140 Val Asn Met Cys Thr Leu He Ala Met Asp Leu Gly Glu Leu Cys Glu 145 150 155 160 Asp Thr Met Thr Tyr Lys Cys Pro Arg He Thr Glu Ala Glu Pro Asp 165 170 175 Asp Val Asp Cys Trp Cys Asn Ala Thr Asp Thr Trp Val Thr Tyr Gly 180 185 190 Thr Cys Ser Gin Thr Gly Glu His Arg Arg Asp Lys Arg Ser Val Ala 195 200 205 Leu Ala Pro His Val Gly Leu Gly Leu Glu Thr Arg Ala Glu Thr Trp 210 215 220 Met Ser Ser Glu Gly Ala Trp Lys Gin He Gin Lys Val Glu Thr Trp 225 230 235 240 Ala Leu Arg His Pro Gly Phe Thr Val He Ala Leu Phe Leu Ala His 245 250 255 Ala He Gly Thr Ser He Thr Gin Lys Gly He He Phe He Leu Leu 260 265 270 Met Leu Val Thr Pro Ser Met Ala Met Arg Cys Val Gly He Gly Asn 275 280 285 Arg Asp Phe Val Glu Gly Leu Ser Gly Ala Thr Trp Val Asp Val Val 290 295 3 00 Leu Glu His Gly Ser Cys Val Thr Thr Met Ala Lys Asn Lys Pro Thr 305 310 315 320

    10723

    2018200081 04 Jan 2018

    Leu Asp He Glu Leu Leu Lys 325 Thr Glu Val Thr Asn Pro Ala Val Leu 330 335 Arg Lys Leu Cys He Glu Ala Lys He Ser Asn Thr Thr Thr Asp Ser 340 345 350 Arg Cys Pro Thr Gin Gly Glu Ala Thr Leu Val Glu Glu Gin Asp Ala 355 360 365 Asn Phe Val Cys Arg Arg Thr Phe Val Asp Arg Gly Trp Gly Asn Gly 370 375 380 Cys Gly Leu Phe Gly Lys Gly Ser Leu He Thr Cys Ala Lys Phe Lys 385 390 395 400 Cys Val Thr Lys Leu Glu Gly Lys He Val Gin Tyr Glu Asn Leu Lys 405 410 415 Tyr Ser Val He Val Thr Val His Thr Gly Asp Gin His Gin Val Gly 420 425 430 Asn Glu Thr Thr Glu His Gly Thr Thr Ala Thr He Thr Pro Gin Ala 435 440 445 Pro Thr Ser Glu He Gin Leu Thr Asp Tyr Gly Thr Leu Thr Leu Asp 450 455 460 Cys Ser Pro Arg Thr Gly Leu Asp Phe Asn Glu Met Val Leu Leu Thr 465 470 475 480 Met Lys Glu Arg Ser Trp Leu Val His Lys Gin Trp Phe Leu Asp Leu 485 490 495 Pro Leu Pro Trp Thr Ser Gly Ala Ser Thr Ser Gin Glu Thr Trp Asn 500 505 510 Arg Gin Asp Leu Leu Val Thr Phe Lys Thr Ala His Ala Lys Lys Gin 515 520 525 Glu Val Val Val Leu Gly Ser Gin Glu Gly Ala Met His Thr Ala Leu 530 535 540 Thr Gly Ala Thr Glu He Gin Thr Ser Gly Thr Thr Thr He Phe Ala 545 550 555 560 Gly His Leu Lys Cys Arg Leu Lys Met Asp Lys Leu Thr Leu Lys Gly 565 570 575 Met Ser Tyr Val Met Cys Thr Gly Ser Phe Lys Leu Glu Lys Glu Val 580 585 590 Ala Glu Thr Gin His Gly Thr Val Leu Val Gin Val Lys Tyr Glu Gly 595 600 605 Thr Asp Ala Pro Cys Lys He Pro Phe Ser Thr Gin Asp Glu Lys Gly 610 615 620 Ala Thr Gin Asn Gly Arg Leu He Thr Ala Asn Pro He Val Thr Asp 625 630 635 640 Lys Glu Lys Pro Val Asn He Glu Ala Glu Pro Pro Phe Gly Glu Ser 645 650 655 Tyr He Val Val Gly Ala Gly Glu Lys Ala Leu Lys Leu Ser Trp Phe 660 665 670 Lys Lys Gly Ser Ser He Gly Lys Met Phe Glu Ala Thr Ala Arg Gly 675 680 685 Ala Arg Arg Met Ala He Leu Gly Asp Thr Ala Trp Asp Phe Gly Ser 690 695 700 lie Gly Gly Val Phe Thr Ser Met Gly Lys Leu Val His Gin Val Phe 705 710 715 720 Gly Thr Ala Tyr Gly Val Leu Phe Ser Gly Val Ser Trp Thr Met Lys 725 730 735 He Gly He Gly He Leu Leu Thr Trp Leu Gly Leu Asn Ser Arg Asn 740 745 750

    2018200081 04 Jan 2018

    Thr Ser Leu Ser 755 Val Met Cys He Ala Ala Gly He Val Thr Leu Tyr 760 765 Leu Gly 770 Val Met Val Gin Ala 775 Asp Ser Gly Cys Val Val Ser Trp Lys 780 Asn 785 Lys Glu Leu Lys Cys Gly 790 Ser Gly He Phe He Thr Asp Asn Val 795 800 His Thr Trp Thr Glu Gin Tyr 805 Lys Phe Gin Pro Glu Ser Pro Ser Lys 810 815 Leu Ala Ser Ala 820 He Gin Lys Ala His Glu Glu Asp He Cys Gly He 825 830 Arg Ser Val Thr 835 Arg Leu Glu Asn 840 Leu Met Trp Lys Gin He Thr Pro 845 Glu Leu 850 Asn His He Leu Ser 855 Glu Asn Glu Val Lys Leu Thr He Met 860 Thr 865 Gly Asp He Lys Gly He 870 Met Gin Ala Gly Lys Arg Ser Leu Arg 875 880 Pro Gin Pro Thr Glu Leu Lys 885 Tyr Ser Trp Lys Thr Trp Gly Lys Ala 890 895 Lys Met Leu Ser 900 Thr Glu Ser His Asn Gin Thr Phe Leu He Asp Gly 905 910 Pro Glu Thr Ala 915 Glu Cys Pro Asn 920 Thr Asn Arg Ala Trp Asn Ser Leu 925 Glu Val 930 Glu Asp Tyr Gly Phe 935 Gly Val Phe Thr Thr Asn lie Trp Leu 940 Lys 945 Leu Lys Glu Lys Gin Asp 950 Val Phe Cys Asp Ser Lys Leu Met Ser 955 960 Ala Ala He Lys Asp Asn Arg 965 Ala Val His Ala Asp Met Gly Tyr Trp 970 975 lie Glu Ser Ala 980 Leu Asn Asp Thr Trp Lys lie Glu Lys Ala Ser Phe 985 990 He Glu Val Lys 995 Asn Cys His Trp Pro Lys Ser His Thr Leu Trp Ser 1000 1005 Asn Gly Val Leu 1010 Glu Ser Glu Met 1015 He He Pro Lys Asn Leu Ala Gly 1020 Pro Val 1025 Ser Gin His Asn Tyr 1030 Arg Pro Gly Tyr His Thr Gin He Thr 1035 1040 Gly Pro Trp His Leu Gly Lys 1045 Leu Glu Met Asp Phe Asp Phe Cys Asp 1050 1055 Gly Thr Thr Val Val Val Thr 1060 Glu Asp Cys Gly Asn Arg Gly Pro Ser 1065 1070 Leu Arg Thr Thr 1075 Thr Ala Ser Gly Lys Leu He Thr Glu Trp Cys Cys 1080 1085 Arg Ser Cys Thr 1090 Leu Pro Pro Leu 1095 Arg ,Tyr Arg Gly Glu Asp Gly Cys 1100 Trp Tyr 1105 Gly Met Glu He Arg 1110 Pro Leu Lys Glu Lys Glu Glu Asn Leu 1115. 1120 Val Asn Ser Leu Val Thr Ala 1125 Gly His Gly Gin Val Asp Asn Phe Ser 1130 1135 Leu Gly Val Leu Gly Met Ala 1140 Leu Phe Leu Glu Glu Met Leu Arg Thr 1145 1150 Arg Val Gly Thr 1155 Lys His Ala He Leu Leu Val Ala Val Ser Phe Val 1160 1165 Thr Leu He Thr 1170 Gly Asn Met Ser 1175 Phe Arg Asp Leu Gly Arg Val Met 1180

    2018200081 04 Jan 2018

    Val Met Val Gly Ala Thr Met Thr Asp Asp He Gly Met Gly Val Thr 1185 1190 1195 1200 Tyr Leu Ala Leu Leu Ala Ala Phe Lys Val Arg Pro Thr Phe Ala Ala 1205 i 1210 1215 Gly Leu Leu Leu Arg Lys Leu Thr Ser Lys Glu Leu Met Met Thr Thr 1220 1225 1230 lie Gly He Val Leu Leu Ser Gin Ser Thr He Pro Glu Thr He Leu 1235 1240 1245 Glu Leu Thr Asp Ala Leu Ala Leu Gly Met Met Val Leu Lys Met Val 1250 1255 1260 Arg Asn Met Glu Lys Tyr Gin Leu Ala Val Thr He Met Ala He Leu 1265 1270 1275 1280 Cys Val Pro Asn Ala Val He Leu Gin Asn Ala Trp Lys Val Ser Cys 1285 i 1290 1295 Thr He Leu Ala Val Val Ser Val Ser Pro Leu Phe Leu Thr Ser Ser 1300 1305 1310 Gin Gin Lys Thr Asp Trp He Pro Leu Ala Leu Thr He Lys Gly Leu 1315 1320 1325 Asn Pro Thr Ala He Phe Leu Thr Thr Leu Ser Arg Thr Ser Lys Lys 133C ) 1335 1340 Arg Ser Trp Pro Leu Asn Glu Ala He Met Ala Val Gly Met Val Ser 1345 1350 1355 1360 He Leu Ala Ser Ser Leu Leu Lys Asn Asp He Pro Met Thr Gly Pro 1365 i 1370 1375 Leu Val Ala Gly Gly Leu Leu Thr Val Cys Tyr Val Leu Thr Gly Arg 1380 1385 1390 Ser Ala Asp Leu Glu Leu Glu Arg Ala Ala Asp Val Lys Trp Glu Asp 1395 1400 1405 Gin Ala Glu He Ser Gly Ser Ser Pro He Leu Ser He Thr He Ser 1410 1415 1420 Glu Asp Gly Ser Met Ser He Lys Asn Glu Glu Glu Glu Gin Thr Leu 1425 1430 1435 1440 Thr He Leu lie Arg Thr Gly Leu Leu Val He Ser Gly Leu Phe Pro 1445 1450 1455 Val Ser He Pro He Thr Ala Ala Ala Trp Tyr Leu Trp Glu Val Lys 1460 1465 1470 Lys Gin Arg Ala Gly Val Leu Trp Asp Val Pro Ser Pro Pro Pro Met 1475 1480 1485 Gly Lys Ala Glu Leu Glu Asp Gly Ala Tyr Arg He Lys Gin Lys Gly 1490 1495 1500 He Leu Gly Tyr Ser Gin He Gly Ala Gly Val Tyr Lys Glu Gly Thr 1505 1510 1515 1520 Phe His Thr Met Trp His Val Thr Arg Gly Ala Val Leu Met His Lys 1525 1530 1535 Gly Lys Arg He Glu Pro Ser Trp Ala Asp Val Lys Lys Asp Leu He 1540 1545 1550 Ser Tyr Gly Gly Gly Trp Lys Leu Glu Gly Glu Trp Lys Glu Gly Glu 1555 1560 1565 Glu Val Gin Val Leu Ala Leu Glu Pro Gly Lys Asn Pro Arg Ala Val 1570 1575 ' 1580 Gin Thr Lys Pro Gly Leu Phe Lys Thr Asn Ala Gly Thr lie Gly Ala 1585 1590 1595 1600 Val Ser Leu Asp Phe Ser Pro Gly Thr Ser Gly Ser Pro He He Asp 1605- 1610 1615

    2018200081 04 Jan 2018

    Lys Lys Gly Lys Val Val Gly Leu Tyr Gly Asn Gly Val Val Thr Arg 1620 1625 1630 Ser Gly Ala Tyr Val Ser Ala He Ala Gin Thr Glu Lys Ser He Glu 1635 1640 1645 Asp Asn Pro Glu He Glu Asp Asp He Phe Arg Lys Arg Arg Leu Thr 1650 1655 1660 lie Met Asp Leu His Pro Gly Ala Gly Lys Thr Lys Arg Tyr Leu Pro 1665 1670 1675 1680 Ala He Val Arg Glu Ala He Lys Arg Gly Leu Arg Thr Leu He Leu 1685 1690 1695 Ala Pro Thr Arg Val Val Ala Ala Glu Met Glu Glu Ala Leu Arg Gly 1700 1705 1710 Leu Pro He Arg Tyr Gin Thr Pro Ala He Arg Ala Val His Thr Gly 1715 1720 1725 Arg Glu lie Val Asp Leu Met Cys His Ala Thr Phe Thr Met Arg Leu 1730 1735 1740 Leu Ser Pro Val Arg Val Pro Asn Tyr Asn Leu He He Met Asp Glu 1745 1750 1755 1760 Ala His Phe Thr Asp Pro Ala Ser He Ala Ala Arg Gly Tyr He Ser 1765 1770 1775 Thr Arg Val Glu Met Gly Glu Ala Ala Gly He Phe Met Thr Ala Thr 1780 1785 1790 Pro Pro Gly Ser Arg Asp Pro Phe Pro Gin Ser Asn Ala Pro He He 1795 1800 1805 Asp Glu Glu Arg Glu He Pro Glu Arg Ser Trp Asn Ser Gly His Glu 1810 1815 1820 Trp Val Thr Asp Phe Lys Gly Lys Thr Val Trp Phe Val Pro Ser He 1825 1830 1835 1840 Lys Ala Gly Asn Asp He Ala Ala Cys Leu Arg Lys Asn Gly Lys Lys 1845 1850 1855 Val He Gin Leu Ser Arg Lys Thr Phe Asp Ser Glu Tyr Val Lys Thr 1860 1865 1870 Arg Thr Asn Asp Trp Asp Phe Val Val Thr Thr Asp He Ser Glu Met 1875 1880 1885 Gly Ala Asn Phe Lys Ala Glu Arg Val He Asp Pro Arg Arg Cys Met 1890 1895 1900 Lys Pro Val He Leu Thr Asp Gly Glu Glu Arg Val He Leu Ala Gly 1905 1910 1915 1920 Pro Met Pro Val Thr His Ser Ser Ala Ala Gin Arg Arg Gly Arg He 1925 1930 1935 Gly Arg Asn Pro Lys Asn Glu Asn Asp Gin Tyr He Tyr Met Gly Glu 1940 1945 1950 Pro Leu Glu Asn Asp Glu Asp Cys Ala His Trp Lys Glu Ala Lys Met 1955 1960 1965 Leu Leu Asp Asn He Asn Thr Pro Glu Gly He He Pro Ser Met Phe 1970 1975 1980 Glu Pro Glu Arg Glu Lys Val Asp Ala He Asp Gly Glu Tyr Arg Leu 1985 1990 1995 2000 Arg Gly Glu Ala Arg Lys Thr Phe Val Asp Leu Met Arg Arg Gly Asp 2005 2010 2015 Leu Pro Val Trp Leu Ala Tyr Arg Val Ala Ala Glu Gly He Asn Tyr 2020 2025 2030 Ala Asp Arg Arg Trp Cys Phe Asp Gly Val Lys Asn Asn Gin He Leu

    2035 2040 2045

    2018200081 04 Jan 2018

    Glu Glu Asn Val Glu Val Glu He 2055 Trp Thr Lys Glu Gly Glu Arg 2060 Lys 2050 Lys Leu Lys Pro Arg Trp Leu Asp Ala Arg He Tyr Ser Asp Pro Leu 2065 2070 2075 2080 Ala Leu Lys Glu Phe Lys Glu Phe Ala Ala Gly Arg Lys Ser Leu Thr 2085 2090 2095 Leu Asn Leu He Thr Glu Met Gly Arg Leu Pro Thr Phe Met Thr Gin 2100 2105 2110 Lys Ala Arg Asp Ala Leu Asp Asn Leu Ala Val Leu His Thr Ala Glu 2115 2120 2125 Ala Gly Gly Arg Ala Tyr Asn His Ala Leu Ser Glu Leu Pro Glu Thr 2130 2135 2140 Leu Glu Thr Leu Leu Leu Leu Thr Leu Leu Ala Thr Val Thr Gly Gly 2145 2150 2155 2160 lie Phe Leu Phe Leu Met Ser Ala Arg Gly He Gly Lys Met Thr Leu 2165 2170 2175 Gly Met Cys Cys lie He Thr Ala Ser He Leu Leu Trp Tyr Ala Gin 2180 2185 2190 He Gin Pro His Trp He Ala Ala Ser He He Leu Glu Phe Phe Leu 2195 2200 2205 He Val Leu Leu He Pro Glu Pro Glu Lys Gin Arg Thr Pro Gin Asp 2210 2215 2220 Asn Gin Leu Thr Tyr Val Val He Ala He Leu Thr Val Val Ala Ala 2225 2230 2235 2240 Thr Met Ala Asn Glu Met Gly Phe Leu Glu Lys Thr Lys Lys Asp Leu 2245 2250 2255 Gly Leu Gly Ser He Ala Thr Gin Gin Pro Glu Ser Asn He Leu Asp 2260 2265 2270 He Asp Leu Arg Pro Ala Ser Ala Trp Thr Leu Tyr Ala Val Ala Thr 2275 2280 2285 Thr Phe Val Thr Pro Met Leu Arg His Ser He Glu Asn Ser Ser Val 2290 2295 2300 Asn Val Ser Leu Thr Ala He Ala Asn Gin Ala Thr Val Leu Met Gly 2305 2310 2315 2320 Leu Gly Lys Gly Trp Pro Leu Ser Lys Met Asp He Gly Val Pro Leu 2325 2330 2335 Leu Ala He Gly Cys Tyr Ser Gin Val Asn Pro He Thr Leu Thr Ala 2340 2345 2350 Ala Leu Phe Leu Leu Val Ala His Tyr Ala He lie Gly Pro Gly Leu 2355 2360 2365 Gin Ala Lys Ala Thr Arg Glu Ala Gin Lys Arg Ala Ala Ala Gly He 2370 2375 2380 Met Lys Asn Pro Thr Val Asp Gly He Thr Val He Asp Leu Asp Pro 2385 2390 2395 2400 He Pro Tyr Asp Pro Lys Phe Glu Lys Gin Leu Gly Gin Val Met Leu 2405 2410 2415 Leu Val Leu Cys Val Thr Gin Val Leu Met Met Arg Thr Thr Trp Ala 2420 · 2425 2430 Leu Cys Glu Ala Leu Thr Leu Ala Thr Gly Pro He Ser Thr Leu Trp 2435 2440 2445 Glu Gly Asn Pro Gly Arg Phe Trp Asn Thr Thr He Ala Val Ser Met 2450 2455 2460 Ala Asn He Phe Arg Gly Ser Tyr Leu Ala Gly Ala Gly Leu Leu Phe 2465 2470 2475 2480

    2018200081 04 Jan 2018

    Ser lie Met Lys Asn Thr Thr Asn Thr Arg Arg Gly Thr Gly Asn lie 2485 2490 2495 Gly Glu Thr Leu Gly Glu Lys Trp Lys Ser Arg Leu Asn Ala Leu Gly 2500 2505 2510 Lys Ser Glu Phe Gin lie Tyr Lys Lys Ser Gly He Gin Glu Val Asp 2515 2520 2525 Arg Thr Leu Ala Lys Glu Gly He Lys Arg Gly Glu Thr Asp His His 2530 2535 2540 Ala Val Ser Arg Gly Ser Ala Lys Leu Arg Trp Phe Val Glu Arg Asn 2545 2550 2555 2560 Met Val Thr Pro Glu Gly Lys Val Val Asp Leu Gly Cys Gly Arg Gly 2565 2570 2575 Gly Trp Ser Tyr Tyr Cys Gly Gly Leu Lys Asn Val Arg Glu Val Lys 2580 2585 2590 Gly Leu Thr Lys Gly Gly Pro Gly His Glu Glu Pro He Pro Met Ser 2595 2600 2605 Thr Tyr Gly Trp Asn Leu Val Arg Leu Gin Ser Gly Val Asp Val Phe 2610 2615 2620 Phe lie Pro Pro Glu Lys Cys Asp Thr Leu Leu Cys Asp lie Gly Glu 2625 2630 2635 2640 Ser Ser Pro Asn Pro Thr Val Glu Ala Gly Arg Thr Leu Arg Val Leu 2645 2650 2655 Asn Leu Val Glu Asn Trp Leu Asn Asn Asn Thr Gin Phe Cys He Lys 2660 2665 2670 Val Leu Asn Pro Tyr Met Pro Ser Val He Glu Lys Met Glu Ala Leu 2675 2680 2685 Gin Arg Lys Tyr Gly Gly Ala Leu Val Arg Asn Pro Leu Ser Arg Asn 2690 2695 2700 Ser Thr His Glu Met Tyr Trp Val Ser Asn Ala Ser Gly Asn He Val 2705 2710 2715 2720 Ser Ser Val Asn Met He Ser Arg Met Leu He Asn Arg Phe Thr Met 2725 2730 2735 Arg Tyr Lys Lys Ala Thr Tyr Glu Pro Asp Val Asp Leu Gly Ser Gly 2740 2745 2750 Thr Arg Asn lie Gly He Glu Ser Glu He Pro Asn Leu Asp lie He 2755 2760 2765 Gly Lys Arg lie Glu Lys He Lys Gin Glu His Glu Thr Ser Trp His 2770 2775 2780 Tyr Asp Gin Asp His Pro Tyr Lys Thr Trp Ala Tyr His Gly Ser Tyr 2785 2790 2795 2800 Glu Thr Lys Gin Thr Gly Ser Ala Ser Ser Met Val Asn Gly Val Val 2805 2810 2815 Arg Leu Leu Thr Lys Pro Trp Asp Val Val Pro Met Val Thr Gin Met 2820 2825 2830 Ala Met Thr Asp Thr Thr Pro Phe Gly Gin Gin Arg Val Phe Lys Glu 2835 2840 2845 Lys Val Asp Thr Arg Thr Gin Glu Pro Lys Glu Gly Thr Lys Lys Leu 2850 2855 2860 Met Lys He Thr Ala Glu Trp Leu Trp Lys Glu Leu Gly Lys Lys Lys 2865 2870 2875 2880 Thr Pro Arg Met Cys Thr Arg Glu Glu Phe Thr Arg Lys Val Arg Ser 2885 2890 2895 Asn Ala Ala Leu Gly Ala He Phe Thr Asp Glu Asn Lys Trp Lys Ser 2900 2905 2910

    2018200081 04 Jan 2018

    Ala Arg Glu Ala Val Glu Asp Ser Arg Phe Trp Glu Leu Val Asp Lys 2915 2920 2925 Glu Arg Asn Leu His Leu Glu Gly Lys Cys Glu Thr Cys Val Tyr Asn 2930 2935 2940 Met Met Gly Lys Arg Glu Lys Lys Leu Gly Glu Phe Gly Lys Ala Lys 2945 2950 2955 2960 Gly Ser Arg Ala lie Trp Tyr Met Trp Leu Gly Ala Arg Phe Leu Glu 2965 297C I 2975 Phe Glu Ala Leu Gly Phe Leu Asn Glu Asp His Trp Phe Ser Arg Glu 2980 2985 2990 Asn Ser Leu Ser Gly Val Glu Gly Glu Gly Leu His Lys Leu Gly Tyr 2995 3000 3005 lie Leu Arg Asp Val Ser Lys Lys Glu Gly Gly Ala Met Tyr Ala Asp 3010 3015 3020 Asp Thr Ala Gly Trp Asp Thr Arg He Thr Leu Glu Asp Leu Lys Asn 3025 3030 3035 3040 Glu Glu Met Val Thr Asn His Met Glu Gly Glu His Lys Lys Leu Ala 3045 305C I 3055 Glu Ala He Phe Lys Leu Thr Tyr Gin Asn Lys Val Val Arg Val Gin 3060 3065 3070 Arg Pro Thr Pro Arg Gly Thr Val Met Asp He He Ser Arg Arg Asp 3075 3080 3085 Gin Arg Gly Ser Gly Gin Val Gly Thr Tyr Gly Leu Asn Thr Phe Thr 3090 3095 3100 Asn Met Glu Ala Gin Leu He Arg Gin Met Glu Gly Glu Gly Val Phe 3105 3110 3115 3120 Lys Ser He Gin His Leu Thr He Thr Glu Glu lie Ala Val Gin Asn 3125 3130 3135 Trp Leu Ala Arg Val Gly Arg Glu Arg Leu Ser Arg Met Ala He Ser 3140 3145 3150 Gly Asp Asp Cys Val Val Lys Pro Leu Asp Asp Arg Phe Ala Ser Ala 3155 3160 3165 Leu Thr Ala Leu Asn Asp Met Gly Lys He Arg Lys Asp He Gin Gin 3170 3175 3180 Trp Glu Pro Ser Arg Gly Trp Asn Asp Trp Thr Gin Val Pro Phe Cys 3185 3190 3195 3200 Ser His His Phe His Glu Leu He Met Lys Asp Gly Arg Val Leu Val 3205 3210 3215 Val Pro Cys Arg Asn Gin Asp Glu Leu He Gly Arg Ala Arg He Ser 3220 3225 3230 Gin Gly Ala Gly Trp Ser Leu Arg Glu Thr Ala Cys Leu Gly Lys Ser 3235 3240 3245 Tyr Ala Gin Met Trp Ser Leu Met Tyr Phe His Arg Arg Asp Leu Arg 3250 3255 3260 Leu Ala Ala Asn Ala He Cys Ser Ala Val Pro Ser His Trp Val Pro 3265 3270 3275 3280 Thr Ser Arg Thr Thr Trp Ser He His Ala Lys His Glu Trp Met Thr 3285 3290 3295 Thr Glu Asp Met Leu Thr Val Trp Asn Arg Val Trp He Gin Glu Asn 3300 3305 3310 Pro Trp Met Glu Asp Lys Thr Pro Val Glu Ser Trp Glu Glu He Pro 3315 3320 3325 Tyr Leu Gly Lys Arg Glu Asp Gin Trp Cys Gly Ser Leu He Gly Leu 3330 3335 3340

    2018200081 04 Jan 2018

    Thr Ser Arg Ala Thr Trp Ala Lys Asn He Gin Ala Ala He Asn Gin 3345 3350 3355 3360 Val Arg Ser Leu lie Gly Asn Glu Glu Tyr Thr Asp Tyr Met Pro Ser 3365 3370 3375 Met Lys Arg Phe Arg Arg Glu Glu Glu Glu Ala Gly Val Leu Trp 3380 3385 3390

    <210> 7 <211> 10723 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <221> CDS <222> (97)...(10272) <400> 7 agttgttagt ctacgtggac cgacaaagac agattctttg agggagctaa gctcaatgta 60 gttctaacag ttttttaatt agagagcaga tctctg atg ate aac caa ega aaa 114

    Met 1 He Asn Gin Arg 5 Lys aag acg ggt ega ccg tot ttc aat atg ctg aaa ege geg aga aac ege 162 Lys Thr Gly Arg 10 Pro Ser Phe Asn Met 15 Leu Lys Arg Ala Arg 20 Asn Arg gtg tea act gtt tea cag ttg geg aag aga ttc tea aaa gga ttg etc 210 Val Ser Thr 25 Val Ser Gin Leu Ala 30 Lys Arg Phe Ser Lys 35 Gly Leu Leu tea ggc caa gga ccc atg aaa ttg gtg atg get ttc ata gca ttc tta 258 Ser Gly 40 Gin Gly Pro Met Lys 45 Leu Val Met Ala Phe 50 He Ala Phe Leu aga ttt eta gcc ata ccc cca aca gca gga att ttg get aga tgg ggc 306 Arg 55 Phe Leu Ala lie Pro 60 Pro Thr Ala Gly He 65 Leu Ala Arg Trp Gly 70 tea ttc aag aag aat gga geg att aaa gtg tta cgg ggt ttc aag aga 354 Ser Phe Lys Lys Asn 75 Gly Ala He Lys Val 80 Leu Arg Gly Phe Lys 85 Arg gaa ate tea aac atg eta aac ata atg aac agg agg aaa aga tcc gtg 402 Glu He Ser Asn 90 Met Leu Asn He Met 95 Asn Arg Arg Lys Arg 100 Ser Val acc atg etc ett atg ctg ctg ccc aca gcc ctg geg ttc cat ctg acg 450 Thr Met Leu 105 Leu Met Leu Leu Pro 110 Thr Ala Leu Ala Phe 115 His Leu Thr

    2018200081 04 Jan 2018

    aca cga ggg Thr Arg Gly 120 gga Gly gag ccg cat atg Met ata gtt age Ser aag cag gaa aga gga 498 Glu Pro His 125 He Val Lys 130 Gin Glu Arg Gly aag tea ett ttg ttc aag acc tct gca ggt gtc aac atg tgc acc etc 546 Lys Ser Leu Leu Phe Lys Thr Ser Ala Gly Val Asn Met Cys Thr Leu 135 140 145 150 att gcg atg gat ttg gga gag ttg tgt gag gac aeg atg acc tac aaa 594 lie Ala Met Asp Leu Gly Glu Leu Cys Glu Asp Thr Met Thr Tyr Lys 155 160 165 tgc ccc cgg ate act gag gcg gaa cca gat gac gtt gac tgt tgg tgc 642 Cys Pro Arg He Thr Glu Ala Glu Pro Asp Asp Val Asp Cys Trp Cys 170 175 180 aat gcc aeg gac aca tgg gtg acc tat gga aeg tgc tct caa act ggc 690 Asn Ala Thr Asp Thr Trp Val Thr Tyr Gly Thr Cys Ser Gin Thr Gly 185 190 195 gaa cac cga cga gac aaa cgt tcc gtc gca ttg gcc cca cac gtg ggg 738 Glu His Arg Arg Asp Lys Arg Ser Val Ala Leu Ala Pro His Val Gly 200 205 210 ett ggc eta gaa aca aga gcc gaa aeg tgg atg tcc tct gaa ggt get 786 Leu Gly Leu Glu Thr Arg Ala Glu Thr Trp Met Ser Ser Glu Gly Ala 215 220 225 230 tgg aaa cag ata caa aaa gta gag act tgg get ctg aga cat cca gga 834 Trp Lys Gin He Gin Lys Val Glu Thr Trp Ala Leu Arg His Pro Gly 235 240 245 ttc aeg gtg ata gcc ett ttt eta gca cat gcc ata gga aca tcc ate 882 Phe Thr Val He Ala Leu Phe Leu Ala His Ala He Gly Thr Ser He 250 255 260 acc cag aaa ggg ate att ttc att ttg ctg atg ctg gta aca cca tct 930 Thr Gin Lys Gly He He Phe He Leu Leu Met Leu Val Thr Pro Ser 265 270 275 atg gcc atg cga tgc gtg gga ata ggc aac aga gac ttc gtg gaa gga 978 Met Ala Met Arg Cys Val Gly He Gly Asn Arg Asp Phe Val Glu Gly 280 285 290 ctg tea gga gca aca tgg gtg gat gtg gta ctg gag cat gga agt tgc 1026 Leu Ser Gly Ala Thr Trp Val Asp Val Val Leu Glu His Gly Ser Cys 295 300 305 310 gtc acc acc atg gca aaa aac aaa cca aca ctg gac att gaa etc ttg 1074 Val Thr Thr Met Ala Lys Asn Lys Pro Thr Leu Asp He Glu Leu Leu 315 320 325 aag aeg gag gtc aca aac cct gca gtt ctg cgt aaa ttg tgc att gaa 1122 Lys Thr Glu Val Thr Asn Pro Ala Val Leu Arg Lys Leu Cys He Glu 330 335 340

    2018200081 04 Jan 2018

    get Ala aaa Lys ata tea aac Asn acc Thr acc Thr acc Thr 350 gat Asp teg aga tgt Cys cca Pro 355 aca Thr caa Gin gga Gly 1170 lie 345 Ser Ser Arg gaa gcc aca ctg gtg gaa gaa caa gac gcg aac ttt gtg tgc ega ega 1218 Glu Ala Thr Leu Val Glu Glu Gin Asp Ala Asn Phe Val Cys Arg Arg 360 365 370 acg ttc gtg gac aga ggc tgg ggc aat ggc tgt ggg eta ttc gga aaa 1266 Thr Phe Val Asp Arg Gly Trp Gly Asn Gly Cys Gly Leu Phe Gly Lys 375 380 385 390 ggt agt eta ata acg tgt gcc aag ttt aag tgt gtg aca aaa eta gaa 1314 Gly Ser Leu He Thr Cys Ala Lys Phe Lys Cys Val Thr Lys Leu Glu 395 400 405 gga aag ata get caa tat gaa aac eta aaa tat tea gtg ata gtc acc 1362 Gly Lys He Ala Gin Tyr Glu Asn Leu Lys Tyr Ser Val He Val Thr 410 415 420 gtc cac act gga gat cag cac cag gtg gga aat gag act aca gaa cat 1410 Val His Thr Gly Asp Gin His Gin Val Gly Asn Glu Thr Thr Glu His 425 430 435 gga aca act gca acc ata aca cct caa get cct acg teg gaa ata cag 1458 Gly Thr Thr Ala Thr lie Thr Pro Gin Ala Pro Thr Ser Glu He Gin 440 445 450 ctg acc gac tac gga acc ett aca tta gat tgt tea cct agg aca ggg 1506 Leu Thr Asp Tyr Gly Thr Leu Thr Leu Asp Cys Ser Pro Arg Thr Gly 455 460 465 470 eta gat ttt aac gag atg gtg ttg ctg aca atg aaa aag aaa tea tgg 1554 Leu Asp Phe Asn Glu Met Val Leu Leu Thr Met Lys Lys Lys Ser Trp 475 480 485 ett gtc cac aaa cag tgg ttc eta gac tta cca ctg cct tgg acc tet 1602 Leu Val His Lys Gin Trp Phe Leu Asp Leu Pro Leu Pro Trp Thr Ser 490 495 500 ggg get tta aca tcc caa gag act tgg aac aga caa gat tta ctg gtc 1650 Gly Ala Leu Thr Ser Gin Glu Thr Trp Asn Arg Gin Asp Leu Leu Val 505 510 515 aca ttt aag aca get cat gca aag aag cag gaa gta gtc gta eta gga 1698 Thr Phe Lys Thr Ala His Ala Lys Lys Gin Glu Val Val Val Leu Gly 520 525 530 tea caa gaa gga gca atg cac act gcg ctg act gga gcg aca gaa ate 1746 Ser Gin Glu Gly Ala Met His Thr Ala Leu Thr Gly Ala Thr Glu He 535 540 545 550

    2018200081 04 Jan 2018

    caa Gin aeg tea gga aeg Thr 555 aca Thr aca Thr att He ttc Phe gca Ala 560 gga Gly cac His eta Leu aaa Lys tgc Cys 565 aga Arg 1794 Thr Ser Gly eta aaa atg gac aaa eta act tta aaa ggg atg tea tat gtg atg tgc 1842 Leu Lys Met Asp 570 Lys Leu Thr Leu Lys 575 Gly Met Ser Tyr Val 580 Met Cys aca ggc tea ttc aag tta gag aaa gaa gtg get gag acc cag cat gga 1890 Thr Gly Ser 585 Phe Lys Leu Glu Lys 590 Glu Val Ala Glu Thr 595 Gin His Gly act gtt ctg gtg cag gtt aaa tat gaa gga aca gac gca cca tgc aag 1938 Thr Val 600 Leu Val Gin Val Lys 605 Tyr Glu Gly Thr Asp 610 Ala Pro Cys Lys att ccc ttt teg acc caa gat gag aaa gga gca acc cag aat ggg aga 1986 lie 615 Pro Phe Ser Thr Gin 620 Asp Glu Lys Gly Ala 625 Thr Gin Asn Gly Arg 630 tta ata aca gcc aac ccc ata gtc act gac aaa gaa aaa cca gtc aat 2034 Leu He Thr Ala Asn 635 Pro He Val Thr Asp 640 Lys Glu Lys Pro Val 645 Asn att gag gca gaa cca ccc ttt ggt gag agc tac ate gtg gta gga gca 2082 He Glu Ala Glu 650 Pro Pro Phe Gly Glu 655 Ser Tyr He Val Val 660 Gly Ala . ggt gaa aaa get ttg aaa eta age tgg ttc aag aaa gga age agc ata 2130 Gly Glu Lys 665 Ala Leu Lys Leu Ser 670 Trp Phe Lys Lys Gly 675 Ser Ser He ggg aaa atg ttt gaa gca act gcc cga gga gca cga agg atg gcc att 2178 Gly Lys 680 Met Phe Glu Ala Thr 685 Ala Arg Gly Ala Arg 690 Arg Met Ala He ctg gga gac acc gca tgg gac ttc ggt tet ata gga gga gtg ttc aeg 2226 Leu 695 Gly Asp Thr Ala Trp 700 Asp Phe Gly Ser He 705 Gly Gly Val Phe Thr 710 tet atg gga aaa ctg gta cac cag gtt ttt gga act gca tat gga gtt 2274 Ser Met Gly Lys Leu 715 Val His Gin Val Phe 720 Gly Thr Ala Tyr Gly 725 Val ttg ttt agc gga gtt tet tgg acc atg aaa ata gga ata ggg att ctg 2322 Leu Phe Ser Gly 730 Val Ser Trp Thr Met 735 Lys He Gly He Gly 740 He Leu ctg aca tgg eta gga tta aat tea agg aac aeg tcc ctt teg gtg atg 2370 Leu Thr Trp 745 Leu Gly Leu Asn Ser 750 Arg Asn Thr Ser Leu 755 Ser Val Met tgc ate gca gcc ggc att gtg aca ctg tat ttg gga gtc atg gtg cag 2418 Cys He 760 Ala Ala Gly He Val 765 Thr Leu Tyr Leu Gly 770 Val Met Val Gin

    2018200081 04 Jan 2018

    gcc gat Ala Asp 775 agt Ser ggt Gly tgc gtt gtg Val age Ser tgg Trp aaa Lys aac Asn 785 aaa Lys gaa Glu ctg aaa tgt Cys 790 2466 Cys Val 780 Leu Lys ggc agt ggg att ttc ate aca gac aac gtg cac aca tgg aca gaa caa 2514 Gly Ser Gly He Phe He Thr Asp Asn Val His Thr Trp Thr Glu Gin 795 800 805 tac aag ttc caa cca gaa tcc cct tea aaa eta get tea get ate cag 2562 Tyr Lys Phe Gin Pro Glu Ser Pro Ser Lys Leu Ala Ser Ala He Gin 810 815 820 aaa gcc cat gaa gag gac att tgt gga ate cgc tea gta aca aga ctg 2610 Lys Ala His Glu Glu Asp He Cys Gly He Arg Ser Val Thr Arg Leu 825 830 835 gag aat ctg atg tgg aaa caa ata aca cca gaa ttg aat cac att eta 2658 Glu Asn Leu Met Trp Lys Gin He Thr Pro Glu Leu Asn His He Leu 840 845 850 tea gaa aat gag gtg aag tta act att atg aca gga gac ate aaa gga 2706 Ser Glu Asn Glu Val Lys Leu Thr lie Met Thr Gly Asp He Lys Gly 855 860 865 870 ate atg cag gca gga aaa ega tct ctg cgg cct cag ccc act gag ctg 2754 He Met Gin Ala Gly Lys Arg Ser Leu Arg Pro Gin Pro Thr Glu Leu 875 880 885 aag tat tea tgg aaa aca tgg ggc aaa gca aaa atg etc tct aca gag 2802 Lys Tyr Ser Trp Lys Thr Trp Gly Lys Ala Lys Met Leu Ser Thr Glu 890 895 900 tct cat aac cag acc ttt etc att gat ggc ccc gaa aca gca gaa tgc 2850 Ser His Asn Gin Thr Phe Leu He Asp Gly Pro Glu Thr Ala Glu Cys 905 910 915 ccc aac aca aat aga get tgg aat teg ttg gaa gtt gaa gac tat ggc 2898 Pro Asn Thr Asn Arg Ala Trp Asn Ser Leu Glu Val Glu Asp Tyr Gly 920 925 930 ttt gga gta ttc acc acc aat ata tgg eta aaa ttg aaa gaa aaa cag 2946 Phe Gly Val Phe Thr Thr Asn He Trp Leu Lys Leu Lys Glu Lys Gin 935 940 945 950 gat gta ttc tgc gac tea aaa etc atg tea gcg gcc ata aaa gac aac 2994 Asp Val Phe Cys Asp Ser Lys Leu Met Ser Ala Ala He Lys Asp Asn 955 960 965

    aga gcc gtc cat gcc gat atg ggt tat tgg ata gaa agt gca etc aat Arg Ala Val His Ala Asp Met Gly Tyr Trp lie Glu Ser Ala Leu Asn

    970 975 980

    3042

    2018200081 04 Jan 2018

    gac Asp aca Thr tgg aag Trp Lys 985 ata He gag Glu aaa Lys gcc tct Ala Ser 990 ttc Phe att He gaa Glu gtt aaa Val Lys 995 aac Asn tgc Cys 3090 cac tgg cca aaa tea cac acc etc tgg age aat gga gtg eta gaa agt 3138 His Trp 100C Pro Lys 1 Ser His Thr Leu Trp 1005 Ser Asn Gly 101C Val Leu 1 Glu Ser gag atg ata att cca aag aat etc get gga cca gtg tct caa cac aac 3186 Glu 1015 Met He lie Pro Lys Asn 1020 Leu Ala Gly Pro Val 1025 Ser Gin His Asn 1030 tat aga cca ggc tac cat aca caa ata aca gga cca tgg cat eta ggt 3234 Tyr Arg Pro Gly Tyr 1035 His Thr Gin He Thr 104C Gly 1 Pro Trp His Leu 1045 Gly aag ett gag atg gac ttt gat ttc tgt gat gga aca aca gtg gta gtg 3282 Lys Leu Glu Met Asp 1050 Phe Asp Phe Cys Asp 1055 Gly Thr Thr Val Val 1060 Val act gag gac tgc gga aat aga gga ccc tct ttg aga aca acc act gcc 3330 Thr Glu Asp Cys 1065 Gly Asn Arg Gly Pro 1070 Ser Leu Arg Thr Thr 1075 Thr Ala tct gga aaa etc ata aca gaa tgg tgc tgc cga tct tgc aca tta cca 3378 Ser Gly Lys Leu 1080 He Thr Glu Trp Cys 1085 Cys Arg Ser Cys Thr 1090 Leu Pro ccg eta aga tac aga ggt gag gat ggg tgc tgg tac ggg atg gaa ate 3426 Pro Leu 1095 Arg Tyr Arg Gly Glu 1100 Asp Gly Cys Trp Tyr 1105 Gly Met Glu He 1110 aga cca ttg aag gag aaa gaa gag aat ttg gtc aac tcc ttg gtc aca 3474 Arg Pro Leu Lys Glu Lys 1115 Glu Glu Asn Leu Val 1120 Asn Ser Leu Val Thr 1125 get gga cat ggg cag gtc gac aac ttt tea eta gga gtc ttg gga atg 3522 Ala Gly His Gly Gin 1130 Val Asp Asn Phe Ser 1135 Leu Gly Val Leu Gly 1140 Met gca ttg ttc ctg gag gaa atg ett agg acc cga gta gga aeg aaa cat 3570 Ala Leu Phe Leu 1145 Glu Glu Met Leu Arg 1150 Thr Arg Val Gly Thr 1155 Lys His gca ata eta eta gtt gca gtt tct ttt gtg aca ttg ate aca ggg aac 3618 Ala lie Leu Leu 1160 Val Ala Val Ser Phe 1165 Val Thr Leu He Thr 1170 Gly Asn atg tcc ttt aga gac ctg gga aga gtg atg gtt atg gta ggc gcc act 3666 Met Ser 1175 Phe Arg Asp Leu Gly 1180 Arg Val Met Val Met 1185 Val Gly Ala Thr 1190 atg aeg gat gac ata ggt atg ggc gtg act tat ett gcc eta eta gca 3714 Met Thr Asp Asp He Gly Met 1195 Gly Val Thr Tyr 1200 Leu Ala Leu Leu Ala 1205

    3762

    2018200081 04 Jan 2018

    gcc Ala ttc Phe aaa Lys gtc Val 121C aga Arg 1 cca Pro act Thr ttt Phe gca get Ala Ala 1215 gga Gly eta Leu etc Leu ttg aga Leu Arg 1220 aag Lys ctg acc tcc aag gaa ttg atg atg act act ata gga att gta etc etc Leu Thr Ser Lys 1225 Glu Leu Met Met 123C Thr Thr 1 He Gly He Val Leu 1235 Leu tcc cag age acc ata cca gag acc att ctt gag ttg act gat geg tta Ser Gin 124C Ser 1 Thr He Pro Glu 1245 Thr He Leu Glu Leu 125C Thr 1 Asp Ala Leu gcc tta ggc atg atg gtc etc aaa atg gtg aga aat atg gaa aag tat Ala Leu 1255 Gly Met Met Val Leu 1260 Lys Met Val Arg Asn 1265 Met Glu Lys Tyr 1270 caa ttg gca gtg act ate atg get ate ttg tgc gtc cca aac gca gtg Gin Leu Ala Val Thr He 1275 Met Ala lie Leu Cys 1280 Val Pro Asn Ala Val 1285 ata tta caa aac gca tgg aaa gtg agt tgc aca ata ttg gca gtg gtg lie Leu Gin Asn 129C Ala 1 Trp Lys Val Ser Cys 1295 Thr He Leu Ala Val 1300 Val tcc gtt tcc cca ctg ttc tta aca tcc tea cag caa aaa aca gat tgg Ser Val Ser Pro 1305 Leu Phe Leu Thr Ser Ser 1310 Gin Gin Lys Thr Asp 1315 Trp ata cca tta gca ttg aeg ate aaa ggt etc aat cca aca get att ttt He Pro Leu 1320 Ala Leu Thr He Lys 1325 Gly Leu Asn Pro Thr 1330 Ala He Phe eta aca acc etc tea aga acc age aag aaa agg age tgg cca tta aat Leu Thr 1335 Thr Leu Ser Arg Thr 1340 Ser Lys Lys Arg Ser 1345 Trp Pro Leu Asn 1350 gag get ate atg gca gtc ggg atg gtg age att tta gcc agt tet etc Glu Ala He Met Ala Val 1355 Gly Met Val Ser He 1360 Leu Ala Ser Ser Leu 1365 eta aaa aat gat att ccc atg aca gga cca tta gtg get gga ggg etc Leu Lys Asn Asp He 1370 Pro Met Thr Gly Pro 1375 Leu Val Ala Gly Gly 1380 Leu etc act gtg tgc tac gtg etc act gga ega teg gcc gat ttg gaa ctg Leu Thr Val Cys 1385 Tyr Val Leu Thr Gly Arg 1390 Ser Ala Asp Leu Glu 1395 Leu gag aga gca gcc gat gtc aaa tgg gaa gac cag gca gag ata tea gga Glu Arg Ala 1400 Ala Asp Val Lys Trp 1405 Glu Asp Gin Ala Glu 1410 He Ser Gly

    3810

    3858

    3906

    3954

    4002

    4050

    4098

    4146

    4194

    4242

    4290

    4338

    2018200081 04 Jan 2018

    age agt Ser Ser 1415 cca ate Pro He ctg tea ata aca ata tea gaa gat ggt age Ser atg Met teg Ser 1430 4386 Leu Ser He 1420 Thr He Ser Glu Asp 1425 Gly ata aaa aat gaa gag gaa gaa caa aca ctg acc ata etc att aga aca 4434 lie Lys Asn Glu Glu Glu Glu 1435 Gin Thr Leu 144C Thr He 1 Leu He Arg 1445 Thr gga ttg ctg gtg ate tea gga ett ttt cct gta tea ata cca ate aeg 4482 Gly Leu Leu Val 145C He Ser Gly 1 Leu Phe 1455 Pro Val Ser He Pro 146C He 1 Thr gca gca gca tgg tac ctg tgg gaa gtg aag aaa caa egg gcc gga gta 4530 Ala Ala Ala Trp 1465 Tyr Leu Trp Glu 147C Val I Lys Lys Gin Arg Ala 1475 Gly Val ttg tgg gat gtt cct tea ccc cca ccc atg gga aag get gaa ctg gaa 4578 Leu Trp Asp Val 1480 Pro Ser Pro Pro 1485 Pro Met Gly Lys Ala 1490 Glu Leu Glu gat gga gcc tat aga att aag caa aaa ggg att ett gga tat tcc cag 4626 Asp Gly 1495 Ala Tyr Arg He Lys 1500 Gin Lys Gly lie Leu 1505 Gly Tyr Ser Gin 1510 ate gga gcc gga gtt tac aaa gaa gga aca ttc cat aca atg tgg cat 4674 He Gly Ala Gly Val Tyr Lys 1515 Glu Gly Thr 152C Phe His I Thr Met Trp 1525 His gtc aca cgt ggc get gtt eta atg cat aaa gga aag agg att gaa cca 4722 Val Thr Arg Gly Ala Val Leu 1530 Met His 1535 Lys Gly Lys Arg He 154C Glu 1 Pro tea tgg gcg gac gtc aag aaa gac eta ata tea tat gga gga ggc tgg 4770 Ser Trp Ala Asp 1545 Val Lys Lys Asp Leu 1550 He Ser Tyr Gly Gly 1555 Gly Trp aag tta gaa gga gaa tgg aag gaa gga gaa gaa gtc cag gta ttg gca 4818 Lys Leu Glu Gly 1560 Glu Trp Lys Glu 1565 Gly Glu Glu Val Gin 1570 Val Leu Ala ctg gag cct gga aaa aat cca aga gcc gtc caa aeg aaa cct ggt ett 4866 Leu Glu 1575 Pro Gly Lys Asn Pro 1580 Arg Ala Val Gin Thr 1585 Lys Pro Gly Leu 1590 ttc aaa acc aac gcc gga aca ata ggt get gta tet ctg gac ttt tet 4914 Phe Lys Thr Asn Ala Gly Thr 1595 He Gly Ala Val Ser 1600 Leu Asp Phe Ser 1605 cct gga aeg tea gga tet cca att ate gac aaa aaa gga aaa gtt gtg 4962 Pro Gly Thr Ser Gly Ser Pro 1610 He He Asp 1615 Lys Lys Gly Lys Val 1620 Val ggt ett tat ggt aat ggt gtt gtt aca agg agt gga gca tat gtg agt 5010 Gly Leu Tyr Gly Asn Gly Val Val Thr Arg Ser Gly Ala Tyr Val Ser

    1625 1630 1635

    2018200081 04 Jan 2018

    get Ala ata gcc He Ala 1640 cag Gin act Thr gaa aaa agc Glu Lys Ser 1645 att He gaa Glu gac Asp aac cca Asn Pro 1650 gag Glu ate He gaa Glu 5058 gat gac att ttc ega aag aga aga ctg acc ate atg gac etc cac cca 5106 Asp 1655 Asp He Phe Arg Lys Arg Arg 1660 Leu Thr lie 1665 Met Asp Leu His Pro 1670 gga geg gga aag aeg aag aga tac ett ccg gee ata gtc aga gaa get 5154 Gly Ala Gly Lys Thr Lys Arg Tyr 1675 Leu Pro Ala 1680 He Val Arg Glu Ala 1685 ata aaa egg ggt ttg aga aca tta ate ttg gee ccc act aga gtt gtg 5202 lie Lys Arg Gly 169C Leu 1 Arg Thr Leu He 1695 Leu Ala Pro Thr Arg Val 1700 Val gca get gaa atg gag gaa gcc ett aga gga ett cca ata aga tac cag 5250 Ala Ala Glu Met 1705 Glu Glu Ala Leu Arg 1710 Gly Leu Pro He Arg 1715 Tyr Gin acc cca gcc ate aga get gtg cac acc ggg egg gag att gtg gac eta 5298 Thr Pro Ala 1720 He Arg Ala Val His 1725 Thr Gly Arg Glu He 1730 Val Asp Leu atg tgt cat gee aca ttt acc atg agg ctg eta tea cca gtt aga gtg 5346 Met Cys His 1735 Ala Thr Phe Thr Met 1740 Arg Leu Leu Ser Pro 1745 Val Arg Val 1750 cca aac tac aac ctg att ate atg gac gaa gee cat ttc aca gac cca 5394 Pro Asn Tyr Asn Leu He lie Met 1755 Asp Glu Ala 1760 His Phe Thr Asp Pro 1765 gca agt ata gca get aga gga tac ate tea act ega gtg gag atg ggt 5442 Ala Ser lie Ala Ala 1770 Arg Gly Tyr He Ser 1775 Thr Arg Val Glu Met 1780 Gly gag gca get ggg att ttt atg aca gee act ccc ccg gga agc aga gac 5490 Glu Ala Ala Gly 1785 lie Phe Met Thr Ala 1790 Thr Pro Pro Gly Ser 1795 Arg Asp cca ttt cct cag agc aat gca cca ate ata gat gaa gaa aga gaa ate 5538 Pro Phe Pro 1800 Gin Ser Asn Ala Pro 1805 He He Asp Glu Glu 1810 Arg Glu He cct gaa cgc teg tgg aat tec gga cat gaa tgg gtc aeg gat ttt aaa 5586 Pro Glu Arg 1815 Ser Trp Asn Ser Gly 1820 His Glu Trp Val Thr 1825 Asp Phe Lys 1830 ggg aag act gtt tgg ttc gtt cca agt ata aaa gca gga aat gat ata 5634 Gly Lys Thr Val Trp Phe Val Pro 1835 Ser He Lys 1840 Ala Gly Asn Asp He 1845

    2018200081 04 Jan 2018

    gca Ala get Ala tgc Cys ctg agg Leu Arg 1850 aaa Lys aat Asn gga Gly aag aaa Lys Lys 1855 gtg Val ata He caa Gin etc agt Leu Ser 1860 agg Arg 5682 aag acc ttt gat tet gag tat gtc aag act aga acc aat gat tgg gac 5730 Lys Thr Phe 1865 Asp Ser Glu Tyr Val 187C Lys Thr 1 Arg Thr Asn 1875 Asp Trp Asp ttc gtg gtt aca act gac att tea gaa atg ggt gcc aat ttc aag get 5778 Phe Val 188C Val I Thr Thr Asp lie Ser 1885 Glu Met Gly Ala Asn 1890 Phe Lys Ala gag agg gtt ata gac ccc aga cgc tgc atg aaa cca gtc ata eta aca 5826 Glu Arg 1895 Val He Asp Pro Arg 1900 Arg Cys Met Lys Pro 1905 Val He Leu Thr 1910 gat ggt gaa gag egg gtg att ctg gca gga cct atg cca gtg acc cac 5874 Asp Gly Glu Glu Arg Val 1915 He Leu Ala Gly Pro 1920 Met Pro Val Thr His 1925 tet agt gca gca caa aga aga ggg aga ata gga aga aat cca aaa aat 5922 Ser Ser Ala Ala Gin 1930 Arg Arg Gly Arg He 1935 Gly Arg Asn Pro Lys 1940 Asn gag aat gac cag tac ata tac atg ggg gaa cct ctg gaa aat gat gaa 5970 Glu Asn Asp Gin Tyr 1945 He Tyr Met Gly Glu 1950 Pro Leu Glu Asn Asp 1955 Glu gac tgt gca cac tgg aaa gaa get aaa atg etc eta gat aac ate aac 6018 Asp Cys Ala 1960 His Trp Lys Glu Ala 1965 Lys Met Leu Leu Asp 1970 Asn He Asn aeg cca gaa gga ate att cct agc atg ttc gaa cca gag cgt gaa aag 6066 Thr Pro 1975 Glu Gly He He Pro 1980 Ser Met Phe Glu Pro 1985 Glu Arg Glu Lys 1990 gtg gat gcc att gat ggc gaa tac cgc ttg aga gga gaa gca agg aaa 6114 Val Asp Ala He Asp Gly 1995 Glu Tyr Arg Leu Arg 2000 Gly Glu Ala Arg Lys 2005 acc ttt gta gac tta atg aga aga gga gac eta cca gtc tgg ttg gcc 6162 Thr Phe Val Asp Leu 2010 Met Arg Arg Gly Asp 2015 Leu Pro Val Trp Leu 2020 Ala tac aga gtg gca get gaa ggc ate aac tac gca gac aga agg tgg tgt 6210 Tyr Arg Val Ala Ala 2025 Glu Gly He Asn Tyr 2030 Ala Asp Arg Arg Trp 2035 Cys ttt gat gga gtc aag aac aac caa ate eta gaa gaa aac gtg gaa gtt 6258 Phe Asp Gly 2040 Val Lys Asn Asn Gin 2045 He Leu Glu Glu Asn 2050 Val Glu Val gaa ate tgg aca aaa gaa ggg gaa agg aag aaa ttg aaa ccc aga tgg 6306 Glu lie 2055 Trp Thr Lys Glu Gly Glu 2060 Arg Lys Lys Leu 2065 Lys Pro Arg Trp 2070

    2018200081 04 Jan 2018

    ttg Leu gat Asp get Ala agg Arg ate tat He Tyr 2075 tet Ser gac Asp cca Pro ctg geg Leu Ala 2080 eta Leu aaa Lys gaa Glu ttt Phe 2085 aag Lys 6354 gaa ttt gca gee gga aga aag tet ctg acc ctg aac eta ate aca gaa 6402 Glu Phe Ala Ala 2090 Gly Arg 1 . Lys Ser Leu 2095 Thr Leu Asn Leu He 2100 Thr 1 Glu atg ggt agg etc cca acc ttc atg act cag aag gca aga gac gca ctg 6450 Met Gly Arg Leu 2105 Pro Thr Phe Met Thr 2110 Gin Lys Ala Arg Asp 2115 Ala Leu gac aac tta gca gtg ctg cac aeg get gag gca ggt gga agg geg tac 6498 Asp Asn Leu 2120 Ala Val Leu His Thr 2125 Ala Glu Ala Gly Gly 2130 Arg Ala Tyr aac cat get etc agt gaa ctg ccg gag acc ctg gag aca ttg ett tta 6546 Asn His 2135 Ala Leu Ser Glu Leu 2140 Pro Glu Thr Leu Glu 2145 Thr Leu Leu Leu 2150 ctg aca ett ctg get aca gtc aeg gga ggg ate ttt tta ttc ttg atg 6594 Leu Thr Leu Leu Ala Thr 2155 Val Thr Gly Gly He 2160 Phe Leu Phe Leu 2165 Met age gca agg ggc ata ggg aag atg acc ctg gga atg tgc tgc ata ate 6642 Ser Ala Arg Gly 217C He Gly 1 Lys Met Thr 2175 Leu Gly Met Cys Cys He 2180 He aeg get age ate etc eta tgg tac gca caa ata cag cca cac tgg ata 6690 Thr Ala Ser He 2185 Leu Leu Trp Tyr Ala 2190 Gin He Gin Pro His 2195 Trp He gca get tea ata ata ctg gag ttt ttt etc ata gtt ttg ett att cca 6738 Ala Ala Ser 2200 He He Leu Glu Phe 2205 Phe Leu lie Val Leu 2210 Leu He Pro gaa cct gaa aaa cag aga aca ccc caa gac aac caa ctg acc tac gtt 6786 Glu Pro 2215 Glu Lys Gin Arg Thr 2220 Pro Gin Asp Asn Gin 2225 Leu Thr Tyr Val 2230 gtc ata gcc ate etc aca gtg gtg gee gca acc atg gca aac gag atg 6834 Val lie Ala lie Leu Thr 2235 Val Val Ala Ala Thr 2240 Met Ala Asn Glu Met 2245 ggt ttc eta gaa aaa aeg aag aaa gat etc gga ttg gga age att gca 6882 Gly Phe Leu Glu Lys Thr 2250 Lys Lys Asp Leu Gly 2255 Leu Gly Ser He 2260 Ala acc cag caa CCC gag age aac ate ctg gac ata gat eta cgt cct gca 6930 Thr Gin Gin Pro Glu Ser Asn He Leu Asp He Asp Leu Arg Pro Ala

    2265 2270 2275

    2018200081 04 Jan 2018

    tea Ser gca tgg Ala Trp 2280 aeg Thr ctg Leu tat gcc gtg Tyr Ala Val 2285 gcc Ala aca Thr aca Thr ttt gtt Phe Val 2290 aca Thr cca Pro atg Met 6978 ttg aga cat age att gaa aat tcc tea gtg aat gtg tcc eta aca get 7026 Leu 2295 Arg His Ser He Glu Asn Ser 2300 Ser Val Asn 2305 Val Ser Leu Thr Ala 2310 ata gcc aac caa gcc aca gtg tta atg ggt etc ggg aaa gga tgg cca 7074 lie Ala Asn Gin Ala 2315 Thr Val Leu Met Gly Leu 2320 Gly Lys Gly Trp 2325 Pro ttg tea aag atg gac ate gga gtt ccc ett etc gcc att gga tgc tac 7122 Leu Ser Lys Met Asp 2330 He Gly Val Pro Leu 2335 Leu Ala He Gly 234C Cys I Tyr tea caa gtc aac ccc ata act etc aca gca get ett ttc tta ttg gta 7170 Ser Gin Val Asn 2345 Pro He Thr Leu 235C Thr 1 Ala Ala Leu Phe Leu 2355 Leu Val gca cat tat gcc ate ata ggg cca gga etc caa gca aaa gca acc aga 7218 Ala His Tyr 2360 Ala He He Gly Pro 2365 Gly Leu Gin Ala Lys 2370 Ala Thr Arg gaa get cag aaa aga gca gcg gcg ggc ate atg aaa aac cca act gtc 7266 Glu Ala Gin 2375 Lys Arg Ala Ala Ala 2380 Gly He Met 2385 Lys Asn Pro Thr Val 2390 gat gga ata aca gtg att gac eta gat cca ata cct tat gat cca aag 7314 Asp Gly He Thr Val 2395 He Asp Leu Asp Pro He 2400 Pro Tyr Asp Pro 2405 Lys ttt gaa aag cag ttg gga caa gta atg etc eta gtc etc tgc gtg act 7362 Phe Glu Lys Gin Leu 2410 Gly Gin Val Met Leu 2415 Leu Val Leu Cys Val 2420 Thr caa gta ttg atg atg agg act aca tgg get ctg tgt gag get tta acc 7410 Gin Val Leu Met 2425 Met Arg Thr Thr Trp 2430 Ala Leu Cys Glu Ala 2435 Leu Thr tta get acc ggg ccc ate tcc aca ttg tgg gaa gga aat cca ggg agg 7458 Leu Ala Thr 2440 Gly Pro He Ser Thr 2445 Leu Trp Glu Gly Asn 2450 Pro Gly Arg ttt tgg aac act acc att gcg gtg tea atg get aac att ttt aga ggg 7506 Phe Trp Asn 2455' Thr Thr He Ala Val 2460 Ser Met Ala Asn He 2465 Phe Arg Gly 2470 agt tac ttg gcc gga get gga ett etc ttt tet att atg aag aac aca 7554 Ser Tyr Leu Ala Gly Ala Gly Leu 2475 Leu Phe Ser 2480 He Met Lys Asn Thr 2485 acc aac aca aga agg gga act ggc aac ata gga gag aeg ett gga gag 7602 Thr Asn Thr Arg Arg Gly Thr Gly Asn lie Gly Glu Thr Leu Gly Glu

    2490 2495 2500

    2018200081 04 Jan 2018

    aaa Lys tgg Trp aaa age Lys Ser 2505 ega Arg ttg aac gca ttg Ala Leu 2510 gga Gly aaa Lys agt gaa ttc Ser Glu Phe 2515 cag Gin ate He 7650 Leu Asn tac aag aaa agt gga ate cag gaa gtg gat aga acc tta gca aaa gaa 7698 Tyr Lys 252C Lys Ser I Gly He Gin Glu Val 2525 Asp Arg Thr Leu Ala 2530 Lys Glu ggc att aaa aga gga gaa aeg gac cat cac get gtg teg ega ggc tea 7746 Gly 2535 Xie Lys Arg Gly Glu Thr 2540 Asp His His Ala 2545 Val Ser Arg Gly Ser 2550 gca aaa ctg aga tgg ttc gtt gag aga aac atg gtc aca cca gaa ggg 7794 Ala Lys Leu Arg Trp Phe 2555 Val Glu Arg Asn Met 2560 Val Thr Pro Glu 2565 Gly aaa gta gtg gac etc ggt tgt ggc aga gga ggc tgg tea tac tat tgt 7842 Lys Val Val Asp Leu 2570 Gly Cys Gly Arg Gly 2575 Gly Trp Ser Tyr Tyr 2580 Cys gga gga eta aag aat gta aga gaa gtc aaa ggc eta aca aaa gga gga 7890 Gly Gly Leu Lys 2585 Asn Val Arg Glu Val 2590 Lys Gly Leu Thr Lys 2595 Gly Gly cca gga cac gaa gaa ccc ate ccc atg tea aca tat ggg tgg aat eta 7938 Pro Gly His Glu 2600 Glu Pro He Pro Met 2605 Ser Thr Tyr Gly Trp 2610 Asn Leu gtg cgt ett caa agt gga gtt gac gtt ttc ttc ate ccg cca gaa aag 7986 Val Arg 2615 Leu Gin Ser Gly Val 2620 Asp Val Phe Phe He Pro Pro 2625 Glu Lys 2630 tgt gac aca tta ttg tgt gac ata ggg gag tea tea cca aat ccc aca 8034 Cys Asp Thr Leu Leu Cys 2635 Asp He Gly Glu Ser 2640 Ser Pro Asn Pro Thr 2645 gtg gaa gca gga ega aca etc aga gtc ett aac tta gta gaa aat tgg 8082 Val Glu Ala Gly Arg 2650 Thr Leu Arg Val Leu 2655 Asn Leu Val Glu Asn 2660 Trp ttg aac aac aac act caa ttt tgc ata aag gtt etc aac cca tat atg 8130 Leu Asn Asn Asn 2665 Thr Gin Phe Cys He 2670 Lys Val Leu Asn Pro 2675 Tyr Met ccc tea gtc ata gaa aaa atg gaa gca eta caa agg aaa tat gga gga 8178 Pro Ser Val lie 2680 Glu Lys Met Glu Ala 2685 Leu Gin Arg Lys Tyr 2690 Gly Gly gcc tta gtg agg aat cca etc tea ega aac tcc aca cat gag atg tac 8226 Ala Leu 2695 Val Arg Asn Pro Leu 2700 Ser Arg Asn Ser Thr His Glu 2705 Met Tyr 2710

    2018200081 04 Jan 2018

    tgg Trp gta Val tcc Ser aat Asn get tcc Ala Ser 2715 ggg Gly aac Asn ata gtg tea tea He Val Ser Ser 2720 ' gtg Val aac Asn atg Met 2725 att He 8274 tea agg atg ttg ate aac aga ttt aca atg aga tac aag aaa gcc act 8322 Ser Arg Met Leu 273C He Asn 1 Arg Phe Thr Met Arg Tyr 2735 Lys Lys 274C Ala 1 Thr tac gag ccg gat gtt gac etc gga age gga acc cgt aac ate ggg att 8370 Tyr Glu Pro Asp 2745 Val Asp Leu Gly 275C Ser Gly Thr Arg 1 Asn He 2755 Gly He gaa agt gag ata cca aac eta gat ata att ggg aaa aga ata gaa aaa 8418 Glu Ser Glu 2760 He Pro Asn Leu Asp 2765 He He Gly Lys Arg 2770 He Glu Lys ata aag caa gag cat gaa aca tea tgg cac tat gac caa gac cac cca 8466 lie Lys 2775 Gin Glu His Glu Thr 2780 Ser Trp His-Tyr Asp 2785 Gin Asp His Pro 2790 tac aaa acg tgg gca tac cat ggt age tat gaa aca aaa cag act gga 8514 Tyr Lys Thr Trp Ala Tyr 2795 His Gly Ser Tyr Glu Thr 2800 Lys Gin Thr 2805 Gly tea gca tea tcc atg gtc aac gga gtg gtc agg ctg ctg aca aaa cct 8562 Ser Ala Ser Ser Met Val 2810 Asn Gly Val Val Arg Leu 2815 Leu Thr Lys 2820 Pro tgg gac gtc gtc ccc atg gtg aca cag atg gca atg aca gac acg act 8610 Trp Asp Val Val 2825 Pro Met Val Thr Gin Met Ala Met 2830 Thr Asp 2835 Thr Thr cca ttt gga caa cag ege gtt ttt aaa gag aaa gtg gac acg aga acc 8658 Pro Phe Gly 2840 Gin Gin Arg Val Phe 2845 Lys Glu Lys Val Asp 2850 Thr Arg Thr caa gaa ccg aaa gaa ggc acg aag aaa eta atg aaa ata aca gca gag 8706 Gin Glu 2855 Pro Lys Glu Gly Thr 2860 Lys Lys Leu Met Lys 2865 He Thr Ala Glu 2870 tgg ett tgg aaa gaa tta ggg aag aaa aag aca ccc agg atg tgc acc 8754 Trp Leu Trp Lys Glu Leu 2875 Gly Lys Lys Lys Thr Pro 2880 Arg Met Cys Thr 2885 aga gaa gaa ttc aca aga aag gtg aga age aat gca gcc ttg ggg gcc 8802 Arg Glu Glu Phe Thr Arg 2890 Lys Val Arg Ser Asn Ala 2895 Ala Leu Gly 2900 Ala ata ttc act gat gag aac aag tgg aag teg gca cgt gag get gtt gaa 8850 He Phe Thr Asp 2905 Glu Asn Lys Trp Lys Ser Ala Arg 2910 Glu Ala 2915 Val Glu gat agt agg ttt tgg gag ctg gtt gac aag gaa agg aat etc cat ett 8898 Asp Ser Arg 2920 Phe Trp Glu Leu Val 2925 Asp Lys Glu Arg Asn 2930 Leu His Leu

    2018200081 04 Jan 2018

    gaa gga aag tgt gaa Cys Glu aca tgt gtg Thr Cys Val 2940 tac Tyr aac Asn atg atg gga aaa aga gag 8946 Glu Gly 2935 Lys Met Met 2945 Gly Lys Arg Glu 2950 aag aag eta ggg gaa ttc ggc aag gca aaa ggc age aga gcc ata tgg 8994 Lys Lys Leu Gly Glu 2955 Phe Gly Lys Ala Lys Gly Ser 2960 Arg Ala He 2965 Trp tac atg tgg ett gga gca ege ttc tta gag ttt gaa gee eta gga ttc 9042 Tyr Met Trp Leu Gly 2970 Ala Arg Phe Leu Glu 2975 Phe Glu Ala Leu 298C Gly I Phe tta aat gaa gat cac tgg ttc tcc aga gag aac tcc ctg agt gga gtg 9090 Leu Asn Glu Asp His 2985 Trp Phe Ser Arg 2990 Glu Asn Ser Leu Ser 2995 Gly Val gaa gga gaa ggg ctg cac aag eta ggt tac att eta aga gac gtg age 9138 Glu Gly Glu 3000 Gly Leu His Lys Leu 3005 Gly Tyr He Leu Arg 3010 Asp Val Ser aag aaa gag gga gga gca atg tat gcc gat gac acc gca gga tgg gat 9186 Lys Lys 3015 Glu Gly Gly Ala Met Tyr 3020 Ala Asp Asp Thr 3025 Ala Gly Trp Asp 3030 aca aga ate aca eta gaa gac eta aaa aat gaa gaa atg gta aca aac 9234 Thr Arg He Thr Leu Glu Asp Leu 3035 Lys Asn Glu Glu 3040 Met Val Thr Asn 3045 cac atg gaa gga gaa cac aag aaa eta gee gag gcc att ttc aaa eta 9282 His Met Glu Gly Glu 3050 His Lys Lys Leu Ala 3055 Glu Ala He Phe Lys 3060 Leu acg tac caa aac aag gtg gtg cgt gtg caa aga cca aca cca aga ggc 9330 Thr Tyr Gin Asn Lys 3065 Val Val Arg Val 3070 Gin Arg Pro Thr Pro 3075 Arg Gly aca gta atg gac ate ata teg aga aga gac caa aga ggt agt gga caa 9378 Thr Val Met 3080 Asp He He Ser Arg 3085 Arg Asp Gin Arg Gly 3090 Ser Gly Gin gtt ggc acc tat gga etc aat act ttc acc aat atg gaa gcc caa eta 9426 Val Gly 3095 Thr Tyr Gly Leu Asn Thr 3100 Phe Thr Asn Met 3105 Glu Ala Gin Leu 3110 ate aga cag atg gag gga gaa gga gtc ttt aaa age att cag cac eta 9474 lie Arg Gin Met Glu Gly Glu Gly 3115 Val Phe Lys Ser 3120 He Gin His Leu 3125 aca ate aca gaa gaa ate get gtg caa aac tgg tta gca aga gtg ggg 9522 Thr He Thr Glu Glu He Ala Val Gin Asn Trp Leu Ala Arg Val Gly

    3130 3135 3140

    2018200081 04 Jan 2018

    cgc Arg gaa Glu agg tta Arg Leu 3145 tea Ser aga Arg atg Met gcc ate Ala He 3150 agt Ser gga Gly gat Asp gat tgt Asp Cys 3155 gtt Val gtg Val 9570 aaa cct tta gat gac agg ttc gca age get tta aca get eta aat gac 9618 Lys Pro 316C Leu Asp 1 Asp Arg Phe 3165 Ala Ser Ala Leu Thr Ala Leu 3170 Asn Asp atg gga aag att agg aaa gac ata caa caa tgg gaa cct tea aga gga- 9666 Met 3175 Gly Lys He Arg Lys Asp 3180 He Gin Gin Trp 3185 Glu Pro Ser Arg Gly 3190 tgg aat gat tgg aca caa gtg ccc ttc tgt tea cac cat ttc cat gag 9714 Trp Asn Asp Trp Thr 3195 Gin Val Pro Phe Cys 320C Ser 1 His His Phe His 3205 Glu tta ate atg aaa gac ggt cgc gta etc gtt gtt cca tgt aga aac caa 9762 Leu lie Met Lys Asp 3210 Gly Arg Val Leu Val 3215 Val Pro Cys Arg Asn 3220 Gin gat gaa ctg att ggc aga gcc ega ate tcc caa gga gca ggg tgg tct 9810 Asp Glu Leu He 3225 Gly Arg Ala Arg He 3230 Ser Gin Gly Ala Gly. 3235 Trp Ser ttg egg gag aeg gcc tgt ttg ggg aag tct tac gcc caa atg tgg age 9858 Leu Arg Glu Thr 3240 Ala Cys Leu Gly Lys 3245 Ser Tyr Ala Gin Met 3250 Trp Ser ttg atg tac ttc cac aga cgc gac etc agg ctg gcg gca aat get att 9906 Leu Met 3255 Tyr Phe His Arg Arg 3260 Asp Leu Arg Leu Ala 3265 Ala Asn Ala He 3270 tgc teg gca gta cca tea cat tgg gtt cca aca agt ega aca acc tgg 9954 Cys Ser Ala Val Pro Ser 3275 His Trp Val Pro 328C Thr 1 Ser Arg Thr Thr 3285 Trp tcc ata cat get aaa cat gaa tgg atg aca aeg gaa gac atg ctg aca 10002 Ser He His Ala Lys 3290 His Glu Trp Met Thr 3295 Thr Glu Asp Met Leu 3300 Thr gtc tgg aac agg gtg tgg att caa gaa aac cca tgg atg gaa gac aaa 10050 Val Trp Asn Arg 3305 Val Trp He Gin Glu 3310 Asn Pro Trp Met Glu 3315 Asp Lys act cca gtg gaa tea tgg gag gaa ate cca tac ttg ggg aaa aga gaa 10098 Thr Pro Val Glu 3320 Ser Trp Glu Glu He 3325 Pro Tyr Leu Gly Lys 3330 Arg Glu gac caa tgg tgc ggc tea ttg att ggg tta aca age agg gcc acc tgg 10146 Asp Gin 3335 Trp Cys Gly Ser Leu 3340 He Gly Leu Thr Ser 3345 Arg Ala Thr Trp 3350 gca aag aac ate caa gca gca ata aat caa gtt aga tcc ett ata ggc 10194 Ala Lys Asn He Gin Ala 3355 Ala He Asn Gin Val 3360 Arg Ser Leu He 3365 Gly

    2018200081 04 Jan 2018 aat gaa gaa tac aca gat tac atg cca tcc atg aaa aga ttc aga aga

    Asn Glu Glu Tyr Thr Asp Tyr Met Pro Ser Met Lys Arg Phe Arg Arg

    3370 3375 3380 gaa gag gaa gaa gca gga gtt ctg tgg tag aaagcaaaac taacatgaaa

    Glu Glu Glu Glu Ala Gly Val Leu Trp *

    3385 3390 caaggctaga agtcaggtcg gattaagcca tagtacggaa aaaactatgc tacctgtgag ccccgtccaa ggacgttaaa.agaagtcagg ccatcataaa tgccatagct tgagtaaact atgcagcctg tagctccacc tgagaaggtg taaaaaatcc gggaggccac aaaccatgga agctgtacgc atggcgtagt ggactagcgg ttagaggaga cccctccctt acaaatcgca gcaacaatgg gggcccaagg cgagatgaag ctgtagtctc gctggaagga ctagaggtta gaggagaccc ccccgaaaca aaaaacagca tattgacgct gggaaagacc agagatcctg ctgtctcctc agcatcattc caggcacaga acgccagaaa atggaatggt gctgttgaat caacaggttc t <210> 8 <211> 3391 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct

    10242

    10292

    10352

    10412

    10472

    10532

    10592

    10652

    10712

    10723

    <400> 8 Met He Asn Gin Arg Lys Lys Thr Gly Arg Pro Ser Phe Asn Met Leu 1 5 10 15 Lys Arg Ala Arg Asn Arg Val Ser Thr Val Ser Gin Leu Ala Lys Arg 20 25 30 Phe Ser Lys Gly Leu Leu Ser Gly Gin Gly Pro Met Lys Leu Val Met 35 40 45 Ala Phe He Ala Phe Leu Arg Phe Leu Ala He Pro Pro Thr Ala Gly 50 55 60 lie Leu Ala Arg Trp Gly Ser Phe Lys Lys Asn Gly Ala He Lys Val 65 70 75 80 Leu Arg Gly Phe Lys Arg Glu He Ser Asn Met Leu Asn He Met Asn 85 90 95 Arg Arg Lys Arg Ser Val Thr Met Leu Leu Met Leu Leu Pro Thr Ala 100 105 110 Leu Ala Phe His Leu Thr Thr Arg Gly Gly Glu Pro His Met He Val 115 120 125 Ser Lys Gin Glu Arg Gly Lys Ser Leu Leu Phe Lys Thr Ser Ala Gly 130 135 140 Val Asn Met Cys Thr Leu He Ala Met Asp Leu Gly Glu Leu Cys Glu 145 150 155 160 Asp Thr Met Thr Tyr Lys Cys Pro Arg He Thr Glu Ala Glu Pro Asp 165 170 175 Asp Val Asp Cys Trp Cys Asn Ala Thr Asp Thr Trp Val Thr Tyr Gly 180 185 190 Thr Cys Ser Gin Thr Gly Glu His Arg Arg Asp Lys Arg Ser Val Ala 195 200 205

    2018200081 04 Jan 2018

    Leu Ala 210 Pro His Val Gly Leu Gly Leu Glu Thr Arg Ala Glu Thr Trp 215 220 Met Ser Ser Glu Gly Ala Trp Lys Gin He Gin Lys Val Glu Thr Trp 225 230 235 240 Ala Leu Arg His Pro Gly Phe Thr Val He Ala Leu Phe Leu Ala His 245 250 255 Ala lie Gly Thr Ser He Thr Gin Lys Gly He He Phe He Leu Leu 260 265 270 Met Leu Val Thr Pro Ser Met Ala Met Arg Cys Val Gly He Gly Asn 275 280 285 Arg Asp Phe Val Glu Gly Leu Ser Gly Ala Thr Trp Val Asp Val Val 290 295 300 Leu Glu His Gly Ser Cys Val Thr Thr Met Ala Lys Asn Lys Pro Thr 305 310 315 320 Leu Asp He Glu Leu Leu Lys Thr Glu Val Thr Asn Pro Ala Val Leu 325 330 335 Arg Lys Leu Cys He Glu Ala Lys lie Ser Asn Thr Thr Thr Asp Ser 340 345 350 Arg Cys Pro Thr Gin Gly Glu Ala Thr Leu Val Glu Glu Gin Asp Ala 355 360 365 Asn Phe Val Cys Arg Arg Thr Phe Val Asp Arg Gly Trp Gly Asn Gly 370 375 380 Cys Gly Leu Phe Gly Lys Gly Ser Leu He Thr Cys Ala Lys Phe Lys 385 390 395 400 Cys Val Thr Lys Leu Glu Gly Lys He Ala Gin Tyr Glu Asn Leu Lys 405 410 415 Tyr Ser Val He Val Thr Val His Thr Gly Asp Gin His Gin Val Gly 420 425 430 Asn Glu Thr Thr Glu His Gly Thr Thr Ala Thr He Thr Pro Gin Ala 435 440 445 Pro Thr Ser Glu lie Gin Leu Thr Asp Tyr Gly Thr Leu Thr Leu Asp 450 455 460 Cys Ser Pro Arg Thr Gly Leu Asp Phe Asn Glu Met Val Leu Leu Thr 465 470 475 480 Met Lys Lys Lys Ser Trp Leu Val His Lys Gin Trp Phe Leu Asp Leu 485 490 495 Pro Leu Pro Trp Thr Ser Gly Ala Leu Thr Ser Gin Glu Thr Trp Asn 500 505 510 Arg Gin Asp Leu Leu Val Thr Phe Lys Thr Ala His Ala Lys Lys Gin 515 520 525 Glu Val Val Val Leu Gly Ser Gin Glu Gly Ala Met His Thr Ala Leu 530 535 540 Thr Gly Ala Thr Glu lie Gin Thr Ser Gly Thr Thr Thr He Phe Ala 545 550 555 560 Gly His Leu Lys Cys Arg Leu Lys Met Asp Lys Leu Thr Leu Lys Gly 565 570 575 Met Ser Tyr Val Met Cys Thr Gly Ser Phe Lys Leu Glu Lys Glu Val 580 585 590 Ala Glu Thr Gin His Gly Thr Val Leu Val Gin Val Lys Tyr Glu Gly 595 600 605 Thr Asp Ala Pro Cys Lys lie Pro Phe Ser Thr Gin Asp Glu Lys Gly 610 615 620 Ala Thr Gin Asn Gly Arg Leu lie Thr Ala Asn Pro He Val Thr Asp 625 630 635 640

    2018200081 04 Jan 2018

    Lys Glu Lys Pro Val Asn He Glu Ala Glu Pro Pro Phe Gly Glu Ser 645 650 655 Tyr He Val Val Gly Ala 660 Gly Glu Lys Ala Leu 665 Lys Leu Ser Trp Phe 670 Lys Lys Gly Ser Ser He 675 Gly Lys Met Phe Glu 680 Ala Thr Ala Arg Gly 685 Ala Arg 690 Arg Met Ala He Leu Gly Asp Thr Ala 695 Trp Asp Phe Gly Ser 700 lie 705 Gly Gly Val Phe Thr 710 Ser Met Gly Lys Leu 715 Val His Gin Val Phe 720 Gly Thr Ala Tyr Gly Val 725 Leu Phe Ser Gly Val 730 Ser Trp Thr Met Lys 735 lie Gly lie Gly He Leu 740 Leu Thr Trp Leu Gly 745 Leu Asn Ser Arg Asn 750 Thr Ser Leu Ser Val Met 755 Cys He Ala Ala Gly 760 He Val Thr Leu Tyr 765 Leu Gly 770 Val Met Val Gin Ala Asp Ser Gly Cys 775 Val Val Ser Trp Lys 780 Asn 785 Lys Glu Leu Lys Cys 790 Gly Ser Gly He Phe 795 He Thr Asp Asn Val 800 His Thr Trp Thr Glu Gin 805 Tyr Lys Phe Gin Pro 810 Glu Ser Pro Ser Lys 815 Leu Ala Ser Ala He Gin 820 Lys Ala His Glu Glu 825 Asp He Cys Gly He 830 Arg Ser Val Thr Arg Leu 835 Glu Asn Leu Met Trp 840 Lys Gin He Thr Pro 845 Glu Leu 850 Asn His He Leu Ser Glu Asn Glu Val 855 Lys Leu Thr lie Met 860 Thr 865 Gly Asp He Lys Gly 870 He Met Gin Ala Gly 875 Lys Arg Ser Leu Arg 880 Pro Gin Pro Thr Glu Leu 885 Lys Tyr Ser Trp Lys 890 Thr Trp Gly Lys Ala 895 Lys Met Leu Ser Thr Glu 900 Ser His Asn Gin Thr 905 Phe Leu He Asp Gly 910 Pro Glu Thr Ala Glu Cys 915 Pro Asn Thr Asn Arg 920 Ala Trp Asn Ser Leu 925 Glu Val 930 Glu Asp Tyr Gly Phe Gly Val Phe Thr 935 Thr Asn He Trp Leu 940 Lys 945 Leu Lys Glu Lys Gin 950 Asp Val Phe Cys Asp ' 955 Ser Lys Leu Met Ser 960 Ala Ala He Lys Asp Asn 965 Arg Ala Val His Ala 970 Asp Met Gly Tyr Trp 975 He Glu Ser Ala Leu Asn 980 Asp Thr Trp Lys lie 985 Glu Lys Ala Ser Phe 990 He Glu Val Lys Asn Cys 995 His Trp Pro Lys Ser 1000 His Thr Leu Trp Ser 1005 Asn Gly Val Leu Glu Ser 1010 Glu Met He He Pro 1015 Lys Asn Leu Ala Gly 1020 Pro Val 1025 Ser Gin His Asn Tyr Arg Pro Gly Tyr His Thr Gin He Thr 1030 1035 1040 Gly Pro Trp His Leu Gly Lys Leu Glu Met Asp 1045 1050 Phe Asp Phe Cys Asp 1055 Gly Thr Thr Val Val Val 1060 Thr Glu Asp Cys Gly Asn Arg Gly Pro Ser 1065 1070

    2018200081 04 Jan 2018

    Leu Arg Thr Thr Thr Ala Ser Gly Lys Leu He Thr Glu Trp 1085 Cys Cys 1075 1080 Arg Ser Cys Thr Leu Pro Pro Leu Arg Tyr Arg Gly Glu Asp Gly Cys 1090 1095 1100 Trp Tyr Gly Met Glu He Arg Pro Leu Lys Glu Lys Glu Glu Asn Leu 1105 1110 1115 1120 Val Asn Ser Leu Val Thr Ala Gly His Gly Gin Val Asp Asn Phe Ser 1125 1130 ' . 1135 Leu Gly Val Leu Gly Met Ala Leu Phe Leu Glu Glu Met Leu Arg Thr 1140 1145 i 1150 Arg Val Gly Thr Lys His Ala He Leu Leu Val Ala Val Ser Phe Val 1155 1160 1165 Thr Leu He Thr Gly Asn Met Ser Phe Arg Asp Leu Gly Arg Val Met 1170 1175 1180 Val Met Val Gly Ala Thr Met Thr Asp Asp He Gly Met Gly Val Thr 1185 1190 1195 1200 Tyr Leu Ala Leu Leu Ala Ala Phe Lys Val Arg Pro Thr Phe Ala Ala 1205 1210 1215 Gly Leu Leu Leu Arg Lys Leu Thr Ser Lys Glu Leu Met Met Thr Thr 122C I 1225 i 1230 lie Gly He Val Leu Leu Ser Gin Ser Thr He Pro Glu Thr He Leu 1235 1240 1245 Glu Leu Thr Asp Ala Leu Ala Leu Gly Met Met Val Leu Lys Met Val 1250 1255 1260 Arg Asn Met Glu Lys Tyr Gin Leu Ala Val Thr He Met Ala He Leu 1265 1270 1275 1280 Cys Val Pro Asn Ala Val He Leu Gin Asn Ala Trp Lys Val Ser Cys 1285 12 90 1295 Thr lie Leu Ala Val Val Ser Val Ser Pro Leu Phe Leu Thr Ser Ser 1300 1305 i ' 1310 Gin Gin Lys Thr Asp Trp He Pro Leu Ala Leu Thr He Lys Gly Leu 1315 1320 . 1325 Asn Pro Thr Ala He Phe Leu Thr Thr Leu Ser Arg Thr Ser Lys Lys 1330 1335 1340 Arg Ser Trp Pro Leu Asn Glu Ala He Met Ala Val Gly Met Val Ser 1345 1350 1355 1360 He Leu Ala Ser Ser Leu Leu Lys Asn Asp He Pro Met Thr Gly Pro 1365 1370 1375 Leu Val Ala Gly Gly Leu Leu Thr Val Cys Tyr Val Leu Thr Gly Arg 1380 1385 ; 1390 Ser Ala Asp Leu Glu Leu Glu Arg Ala Ala Asp Val Lys Trp Glu Asp 1395 1400 1405 Gin Ala Glu He Ser Gly Ser Ser Pro He Leu Ser He Thr He Ser 1410 1415 1420 Glu Asp Gly Ser Met Ser He Lys Asn Glu Glu Glu Glu Gin Thr Leu 1425 1430 1435 1440 Thr He Leu lie Arg Thr Gly Leu Leu Val He Ser Gly Leu Phe Pro 1445 1450 1455 Val Ser He Pro He Thr Ala Ala Ala Trp Tyr Leu Trp Glu Val Lys 1460 1465 1470 Lys Gin Arg Ala Gly Val Leu Trp Asp Val Pro Ser Pro Pro Pro Met 1475 14 8 0 1485 Gly Lys Ala Glu Leu Glu Asp Gly Ala Tyr Arg lie Lys Gin Lys Gly 1490 1495 1500

    2018200081 04 Jan 2018

    lie Leu Gly Tyr Ser Gin He Gly Ala Gly Val Tyr Lys Glu Gly Thr 1505 1510 1515 1520 Phe His Thr Met Trp His Val Thr Arg Gly Ala Val Leu Met His Lys 1525 1530 1535 Gly Lys Arg He Glu Pro Ser Trp Ala Asp Val Lys Lys Asp Leu He 1540 1545 1550 Ser Tyr Gly Gly Gly Trp Lys Leu Glu Gly Glu Trp Lys Glu Gly Glu 1555 1560 1565 Glu Val Gin Val Leu Ala Leu Glu Pro Gly Lys Asn Pro Arg Ala Val 1570 1575 1580 Gin Thr Lys Pro Gly Leu Phe Lys Thr Asn Ala Gly Thr He Gly Ala 1585 159C i 1595 1600 Val Ser Leu Asp Phe Ser Pro Gly Thr Ser Gly Ser Pro He He Asp 1605 1610 1615 Lys Lys Gly Lys Val Val Gly Leu Tyr Gly Asn Gly Val Val Thr Arg 1620 1625 1630 Ser Gly Ala Tyr Val Ser Ala He Ala Gin Thr Glu Lys Ser He Glu 1635 1640 1645 Asp Asn Pro Glu lie Glu Asp Asp He Phe Arg Lys Arg Arg Leu Thr 1650 1655 1660 He Met Asp Leu His Pro Gly Ala Gly Lys Thr Lys Arg Tyr Leu Pro 1665 167C I 1675 1680 Ala He Val Arg Glu Ala He Lys Arg Gly Leu Arg Thr Leu He Leu 1685 1690 1695 Ala Pro Thr Arg Val Val Ala Ala Glu Met Glu Glu Ala Leu Arg Gly . 1700 1705 1710 Leu Pro He Arg Tyr Gin Thr Pro Ala He Arg Ala Val His Thr Gly 1715 1720 1725 Arg Glu He Val Asp Leu Met Cys His Ala Thr Phe Thr Met Arg Leu 1730 1735 1740 Leu Ser Pro Val Arg Val Pro Asn Tyr Asn Leu He He Met Asp Glu 1745 1750 1755 1760 Ala His Phe Thr Asp Pro Ala Ser He Ala Ala Arg Gly Tyr He Ser 1765 1770 1775 Thr Arg Val Glu Met Gly Glu Ala Ala Gly He Phe Met Thr Ala Thr 1780 1785 1790 Pro Pro Gly Ser Arg Asp Pro Phe Pro Gin Ser Asn Ala Pro He He 1795 1800 1805 Asp Glu Glu Arg Glu He Pro Glu Arg Ser Trp Asn Ser Gly His Glu 1810 1815 1820 Trp Val Thr Asp Phe Lys Gly Lys Thr Val Trp Phe Val Pro Ser He 1825 1830 1835 1840 Lys Ala Gly Asn Asp He Ala Ala Cys Leu Arg Lys Asn Gly Lys Lys 1845 1850 1855 Val He Gin Leu Ser Arg Lys Thr Phe Asp Ser Glu Tyr Val Lys Thr 1860 1865 1870 Arg Thr Asn Asp Trp Asp Phe Val Val Thr Thr Asp He Ser Glu Met 1875 1880 1885 Gly Ala Asn Phe Lys Ala Glu Arg Val He Asp Pro Arg Arg Cys Met 1890 1895 1900 Lys Pro Val He Leu Thr Asp Gly Glu Glu Arg Val He Leu Ala Gly 1905 1910 1915 1920 Pro Met Pro Val Thr His Ser Ser Ala Ala Gin Arg Arg Gly Arg He 1925 1930 1935

    2018200081 04 Jan 2018

    Gly Arg Asn Pro Lys Asn Glu Asn Asp Gin Tyr He Tyr Met Gly Glu 1950 1940 1945 Pro Leu Glu Asn Asp Glu Asp Cys Ala His Trp Lys Glu Ala Lys Met 1955 1960 1965 Leu Leu Asp Asn He Asn Thr Pro Glu Gly He He Pro Ser Met Phe 1970 1975 1980 Glu Pro Glu Arg Glu Lys Val Asp Ala He Asp Gly Glu Tyr Arg Leu 1985 1990 1995 2000 Arg Gly Glu Ala Arg Lys Thr Phe Val Asp Leu Met Arg Arg Gly Asp 200E i 2010 2015 Leu Pro Val Trp Leu Ala Tyr Arg Val Ala Ala Glu Gly He Asn Tyr 2020 2025 2030 Ala Asp Arg Arg Trp Cys Phe Asp Gly Val Lys Asn Asn Gin He Leu 2035 2040 2045 Glu Glu Asn Val Glu Val Glu He Trp Thr Lys Glu Gly Glu Arg Lys 2050 2055 2060 Lys Leu Lys Pro Arg Trp Leu Asp Ala Arg lie Tyr Ser Asp Pro Leu 2065 2070 2075 i 2080 Ala Leu Lys Glu Phe Lys Glu Phe Ala Ala Gly Arg Lys Ser Leu Thr 2085 2090 2095 Leu Asn Leu He Thr Glu Met Gly Arg Leu Pro Thr Phe Met Thr Gin 2100 2105 2110 Lys Ala Arg Asp Ala Leu Asp Asn Leu Ala Val Leu His Thr Ala Glu 2115 2120 2125 Ala Gly Gly Arg Ala Tyr Asn His Ala Leu Ser Glu Leu Pro Glu Thr 2130 2135 2140 Leu Glu Thr Leu Leu Leu Leu Thr Leu Leu Ala Thr Val Thr Gly Gly 2145 2150 215E ί 2160 lie Phe Leu Phe Leu Met Ser Ala Arg Gly He Gly Lys Met Thr Leu 2165 2170 2175 Gly Met Cys Cys lie He Thr Ala Ser lie Leu Leu Trp Tyr Ala Gin 2180 2185 2190 He Gin Pro His Trp He Ala Ala Ser He He Leu Glu Phe Phe Leu 2195 2200 . 2205 He Val Leu Leu He Pro Glu Pro Glu Lys Gin Arg Thr Pro Gin Asp 2210 2215 2220 Asn Gin Leu Thr Tyr Val Val He Ala He Leu Thr Val Val Ala Ala 2225 2230 2235 2240 Thr Met Ala Asn Glu Met Gly Phe Leu Glu Lys Thr Lys Lys Asp Leu 2245 2250 2255 Gly Leu Gly Ser He Ala Thr Gin Gin Pro Glu Ser Asn He Leu Asp 2260 2265 2270 He Asp Leu Arg Pro Ala Ser Ala Trp Thr Leu Tyr Ala Val Ala Thr 2275 2280 2285 Thr Phe Val Thr Pro Met Leu Arg His Ser He Glu Asn Ser Ser Val 2290 2295 2300 Asn Val Ser Leu Thr Ala He Ala Asn Gin Ala Thr Val Leu Met Gly 2305 2310 2315 2320 Leu Gly Lys Gly Trp Pro Leu Ser Lys Met Asp He Gly Val Pro Leu 2325 2330 2335 Leu Ala lie Gly Cys Tyr Ser Gin Val Asn Pro He Thr Leu Thr Ala 2340 2345 2350 Ala Leu Phe Leu Leu Val Ala His Tyr Ala He He Gly Pro Gly Leu 2355 2360 2365

    2018200081 04 Jan 2018

    Gin Ala Lys Ala Thr Arg Glu Ala Gin Lys Arg Ala Ala Ala Gly He 2370 2375 2380 Met Lys Asn Pro Thr Val Asp Gly He Thr Val He Asp Leu Asp Pro 2385 2390 2395 2400 lie Pro Tyr Asp Pro Lys Phe Glu Lys Gin Leu Gly Gin Val Met Leu 2405 2410 . 2415 Leu Val Leu Cys Val Thr Gin Val Leu Met Met Arg Thr Thr Trp Ala 2420 2425 2430 Leu Cys Glu Ala Leu Thr Leu Ala Thr Gly Pro He Ser Thr Leu Trp 2435 1 2440 2445 Glu Gly Asn Pro Gly Arg Phe Trp Asn Thr Thr He Ala Val Ser Met 2450 2455 2460 Ala Asn He Phe Arg Gly Ser Tyr Leu Ala Gly Ala Gly Leu Leu Phe 2465 2470 2475 2480 Ser lie Met Lys Asn Thr Thr Asn Thr Arg Arg Gly Thr Gly Asn He 2485 2490 2495 Gly Glu Thr Leu Gly Glu Lys Trp Lys Ser Arg Leu Asn Ala Leu Gly 2500 2505 2510 Lys Ser Glu Phe Gin He Tyr Lys Lys Ser Gly He Gin Glu Val Asp 2515 i 2520 2525 Arg Thr Leu Ala Lys Glu Gly He Lys Arg Gly Glu Thr Asp His His 2530 2535 2540 Ala Val Ser Arg Gly Ser Ala Lys Leu Arg Trp Phe Val Glu Arg Asn 2545 2550 2555 2560 Met Val Thr Pro Glu Gly Lys Val Val Asp Leu Gly Cys Gly Arg Gly 2565 2570 2575 Gly Trp Ser Tyr Tyr Cys Gly Gly Leu Lys Asn Val Arg Glu Val Lys 2580 2585 2590 Gly Leu Thr Lys Gly Gly Pro Gly His Glu Glu Pro He Pro Met Ser 2595 ; 2600 2605 Thr Tyr Gly Trp Asn Leu Val Arg Leu Gin Ser Gly Val Asp Val Phe 2610 2615 2620 Phe He Pro Pro Glu Lys Cys Asp Thr Leu Leu Cys Asp He Gly Glu 2625 2630 2635 2640 Ser Ser Pro Asn Pro Thr Val Glu Ala Gly Arg Thr Leu Arg Val Leu 2645 2650 2655 Asn Leu Val Glu Asn Trp Leu Asn Asn Asn Thr Gin Phe Cys He Lys 2660 2665 2670 Val Leu Asn Pro Tyr Met Pro Ser Val He Glu Lys Met Glu Ala Leu 2 675 ; 2680 2685 Gin Arg Lys Tyr Gly Gly Ala Leu Val Arg Asn Pro Leu Ser Arg Asn 2690 2695 2700 Ser Thr His Glu Met Tyr Trp Val Ser Asn Ala Ser Gly Asn He Val 2705 2710 2715 2720 Ser Ser Val Asn Met He Ser Arg Met Leu He Asn Arg Phe Thr Met 2725 2730 2735 Arg Tyr Lys Lys Ala Thr Tyr Glu Pro Asp Val Asp Leu Gly Ser Gly 2740 2745 2750 Thr Arg Asn He Gly He Glu Ser Glu He Pro Asn Leu Asp lie lie 2755 i 2760 2765 Gly Lys Arg He Glu Lys lie Lys Gin Glu His Glu Thr Ser Trp His 2770 2775 2780 Tyr Asp Gin Asp His Pro Tyr Lys Thr Trp Ala Tyr His Gly Ser Tyr 2785 2790 2795 2800

    2018200081 04 Jan 2018

    Glu Thr Lys Gin Thr Gly Ser Ala Ser Ser Met Val Asn Gly Val Val 2805 2810 2815 Arg Leu Leu Thr Lys Pro Trp Asp Val Val Pro Met Val Thr Gin Met 282C i 2825 2830 Ala Met Thr Asp Thr Thr Pro Phe Gly Gin Gin Arg Val Phe Lys Glu 2835 2840 2845 Lys Val Asp Thr Arg Thr Gin Glu Pro Lys Glu Gly Thr Lys Lys Leu 2850 2855 2860 Met Lys lie Thr Ala Glu Trp Leu Trp Lys Glu Leu Gly Lys Lys Lys 2865 2870 2875 2880 Thr Pro Arg Met Cys Thr Arg Glu Glu Phe Thr Arg Lys Val Arg Ser 2885 2890 2895 Asn Ala Ala Leu Gly Ala He Phe Thr Asp Glu Asn Lys Trp Lys Ser 290C 1 2905 2910 Ala Arg Glu Ala Val Glu Asp Ser Arg Phe Trp Glu Leu Val Asp Lys 2915 2920 2925 Glu Arg Asn Leu His Leu Glu Gly Lys Cys Glu Thr Cys Val Tyr Asn 2930 2935 2940 Met Met Gly Lys Arg Glu Lys Lys Leu Gly Glu Phe Gly Lys Ala Lys 2945 2950 2955 2960 Gly Ser Arg Ala He Trp Tyr Met Trp Leu Gly Ala Arg Phe Leu Glu 2965 2970 2975 Phe Glu Ala Leu Gly Phe Leu Asn Glu Asp His Trp Phe Ser Arg Glu 2980 2985 2990 Asn Ser Leu Ser Gly Val Glu Gly Glu Gly Leu His Lys Leu Gly Tyr 2995 3000 3005 He Leu Arg Asp Val Ser Lys Lys Glu Gly Gly Ala Met Tyr Ala Asp 3010 3015 3020 ' Asp Thr Ala Gly Trp Asp Thr Arg He Thr Leu Glu Asp Leu Lys Asn 3025 3030 3035 3040 Glu Glu Met Val Thr Asn His Met Glu Gly Glu His Lys Lys Leu Ala 3045 3050 3055 Glu Ala He Phe Lys Leu Thr Tyr Gin Asn Lys Val Val Arg Val Gin 3060 3065 3070 Arg Pro Thr Pro Arg Gly Thr Val Met Asp He He Ser Arg Arg Asp 3075 3080 3085 Gin Arg Gly Ser Gly Gin Val Gly Thr Tyr Gly Leu Asn Thr Phe Thr 3090 3095 3100 Asn Met Glu Ala Gin Leu He Arg Gin Met Glu Gly Glu Gly Val Phe 3105 3110 3115 3120 Lys Ser He Gin His Leu Thr He Thr Glu Glu He Ala Val Gin Asn 3125 3130 3135 Trp Leu Ala Arg Val Gly Arg Glu Arg Leu Ser Arg Met Ala He Ser 3140 3145 3150 Gly Asp Asp Cys Val Val Lys Pro Leu Asp Asp Arg Phe Ala Ser Ala 3155 3160 3165 Leu Thr Ala Leu Asn Asp Met Gly Lys He Arg Lys Asp He Gin Gin 3170 3175 3180 Trp Glu Pro Ser Arg Gly Trp Asn Asp Trp Thr Gin Val Pro Phe Cys 3185 3190 3195 3200 Ser His His Phe His Glu Leu He Met Lys Asp Gly Arg Val Leu Val 3205 3210 3215 Val Pro Cys Arg Asn Gin Asp Glu Leu lie Gly Arg Ala Arg He Ser 3220 3225 3230

    2018200081 04 Jan 2018

    Gin Gly Ala Gly 3235 Trp Ser Leu Arg Glu Thr Ala Cys Leu Gly Lys Ser 3240 3245 Tyr Ala Gin Met Trp Ser Leu Met Tyr Phe His Arg Arg Asp Leu Arg 3250 3255 3260 Leu Ala Ala Asn Ala He Cys Ser Ala Val Pro Ser His Trp Val Pro 3265 327C I 3275 3280 Thr Ser Arg Thr Thr Trp Ser He His Ala Lys His Glu Trp Met Thr 3285 3290 3295 Thr Glu Asp Met Leu Thr Val Trp Asn Arg Val Trp He Gin Glu Asn 3300 3305 3310 Pro Trp Met Glu Asp Lys Thr Pro Val Glu Ser Trp Glu Glu He Pro 3315 3320 3325 Tyr Leu Gly Lys Arg Glu Asp Gin Trp Cys Gly Ser Leu He Gly Leu 3330 3335 3340 Thr Ser Arg Ala Thr Trp Ala Lys Asn He Gin Ala Ala He Asn Gin 3345 3350 3355 3360 Val Arg Ser Leu lie Gly Asn Glu Glu Tyr Thr Asp Tyr Met Pro Ser 3365 3370 3375 Met Lys Arg Phe Arg Arg Glu Glu Glu Glu Ala Gly Val Leu Trp 3380 3385 3390

    <210> 9 <211> 10717 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <221> CDS <222> (97)...(10266) <400> 9 agttgttagt ctacgtggac cgacaaagac agattctttg agggagctaa gctcaatgta 60 gttctaacag ttttttaatt agagagcaga tctctg atg aat aac caa egg aaa 114

    Met Asn Asn Gin Arg Lys 1 5

    aag Lys gcg aaa aac acg Thr cct Pro ttc Phe aat Asn atg Met 15 ctg Leu aaa Lys ege gag aga Arg 20 aac Asn ege Arg 162 Ala Lys Asn 10 Arg Glu gtg teg act gtg caa cag ctg aca aag •aga ttc tea ett gga atg ctg 210 Val Ser Thr 25 Val Gin Gin Leu Thr 30 Lys Arg Phe Ser Leu 35 Gly Met Leu cag gga ega gga cca tta aaa ctg ttc atg gcc ctg gtg gcg ttc ett 258 Gin Gly 40 Arg Gly Pro Leu Lys 45 Leu Phe Met Ala Leu 50 Val Ala Phe Leu cgt ttc eta aca ate cca cca aca gca ggg ata ttg- aag aga tgg gga 306

    2018200081 04 Jan 2018

    Arg 55 Phe Leu Thr He Pro 60 Pro Thr Ala Gly He 65 Leu Lys Arg Trp Gly 70 aca att aaa aaa tea aaa get att aat gtt ttg' aga ggg ttc agg aaa 354 Thr He Lys Lys Ser 75 Lys Ala lie Asn Val 80 Leu Arg Gly Phe Arg 85 Lys gag att gga agg atg ctg aac ate ttg aat agg aga ege aga tet gca 402 Glu He Gly Arg 90 Met Leu Asn He Leu 95 Asn Arg Arg Arg Arg 100 Ser Ala ggc atg ate att atg ctg att cca aca gtg atg gcg ttc cat tta acc 450 Gly Met He 105 He Met Leu He Pro 110 Thr Val Met Ala Phe 115 His Leu Thr aeg cgt gat gga gag ccg ege atg att gtg ggg aag aat gaa aga gga 498 Thr Arg 120 Asp Gly Glu Pro Arg 125 Met He Val Gly Lys 130 Asn Glu Arg Gly aaa tcc eta ett ttc aag aca gcc tet gga ate aac atg tgc aca etc 546 Lys 135 Ser Leu Leu Phe Lys 140 Thr Ala Ser Gly He 145 Asn Met Cys Thr Leu 150 ata get atg gat ctg gga gag atg tgt gat gac aeg gtc act tac aaa 594 lie Ala Met Asp Leu 155 Gly Glu Met Cys Asp 160 Asp Thr Val Thr Tyr 165 Lys tgc ccc cac att acc gaa gtg gag cct gaa gac att gac tgc tgg tgc 642 Cys Pro His He 170 Thr Glu Val Glu Pro 175 Glu Asp He Asp Cys 180 Trp Cys aac ett aca teg aca tgg gtg act tat gga aca tgc aat caa get gga 690 Asn Leu Thr 185 Ser Thr Trp Val Thr 190 Tyr Gly Thr Cys Asn 195 Gin Ala Gly gag cat aga ege gat aag aga tea gtg gcg tta get ccc cat gtt ggc 738 Glu His 200 Arg Arg Asp Lys Arg 205 Ser Val Ala Leu Ala 210 Pro His Val Gly atg gga ctg gac aca ege act caa acc tgg atg teg get gaa gga get 786 Met 215 Gly Leu Asp Thr Arg 220 Thr Gin Thr Trp Met 225 Ser Ala Glu Gly Ala 230 tgg aga caa gtc gag aag gta gag aca tgg gcc ett agg cac cca ggg 834 Trp Arg Gin Val Glu 235 Lys Val Glu Thr Trp 240 Ala Leu Arg His Pro 245 Gly ttt acc ata eta gcc eta ttt ett gcc cat tac ata ggc act tcc ttg 882 Phe Thr He Leu 250 Ala Leu Phe Leu Ala 255 His Tyr He Gly Thr 260 Ser Leu acc cag aaa gtg gtt att ttt ata eta tta atg ctg gtt acc cca tcc 930 Thr Gin Lys Val Val He Phe He Leu Leu Met Leu Val Thr Pro Ser

    265 270 275

    100

    2018200081 04 Jan 2018

    atg Met aca' atg aga Arg tgt Cys gta gga gta gga aac Asn aga Arg gat Asp 290 ttt Phe gtg Val gaa Glu ggc Gly 978 Thr 280 Met Val Gly 285 Val Gly eta teg gga get aeg tgg gtt gac gtg gtg etc gag cac ggt ggg tgt 1026 Leu Ser Gly Ala Thr Trp Val Asp Val Val Leu Glu His Gly Gly Cys 295 300 305 310 gtg act acc atg get aag aac aag ccc aeg ctg gac ata gag ett cag 1074 Val Thr Thr Met Ala Lys Asn Lys Pro Thr Leu Asp He Glu Leu Gin 315 320 325 aag acc gag gcc acc caa ctg gcg acc eta agg aag eta tgc att gag 1122 Lys Thr Glu Ala Thr Gin Leu Ala Thr Leu Arg Lys Leu Cys He Glu 330 335 340 gga aaa att acc aac ata aca acc gac tea aga tgt ccc acc caa ggg 1170 Gly Lys lie Thr Asn He Thr Thr Asp Ser Arg Cys Pro Thr Gin Gly 345 350 355 gaa gcg att tta cct gag gag cag gac cag aac tac gtg tgt aag cat 1218 Glu Ala He Leu Pro Glu Glu Gin Asp Gin Asn Tyr Val Cys Lys His 360 365 370 aca tac gtg gac aga ggc tgg gga aac ggt tgt ggt ttg ttt ggc aag 1266 Thr Tyr Val Asp Arg Gly Trp Gly Asn Gly Cys Gly Leu Phe Gly Lys 375 380 385 390 gga age ttg gtg aca tgc gcg aaa ttt caa tgt tta gaa tea ata gag 1314 Gly Ser Leu Val Thr Cys Ala Lys Phe Gin Cys Leu Glu Ser He Glu 395 400 405 gga aaa gtg gtg caa cat gag aac etc aaa tac acc gtc ate ate aca 1362 Gly Lys Val Val Gin His Glu Asn Leu Lys Tyr Thr Val He He Thr 410 415 420 gtg cac aca gga gac caa cac cag gtg gga aat gaa aeg cag gga gtc 1410 Val His Thr Gly Asp Gin His Gin Val Gly Asn Glu Thr Gin Gly Val 425 430 435 aeg get gag ata aca ccc cag gca tea acc get gaa gcc att tta cct 1458 Thr Ala Glu He Thr Pro Gin Ala Ser Thr Ala Glu Ala He Leu Pro 440 445 450 gaa tat gga acc etc ggg eta gaa tgc tea cca egg aca ggt ttg gat 1506 Glu Tyr Gly Thr Leu Gly Leu Glu Cys Ser Pro Arg Thr Gly Leu Asp 455 460 465 470 ttc aat gaa atg ate tea ttg aca atg aag aac aaa gca tgg atg gta 1554 Phe Asn Glu Met He Ser Leu Thr Met Lys Asn Lys Ala Trp Met Val 475 480 485

    1602 cat aga caa tgg ttc ttt gac tta ccc eta cca tgg aca tea gga get His Arg Gin Trp Phe Phe Asp Leu Pro Leu Pro Trp Thr Ser Gly Ala

    490 495 500

    101

    2018200081 04 Jan 2018

    aca gca Thr Ala gaa Glu 505 aca cca act tgg aac Trp Asn 510 agg aaa gag ett ( Leu ett gtg aca ttt 1650 Thr Pro Thr Arg Lys Glu Leu 515 Val Thr Phe aaa aat gca cat gca aaa aag caa gaa gta gtt gtt ett gga tea caa 1698 Lys Asn Ala His Ala Lys Lys Gin Glu Val Val Val Leu Gly Ser Gin 520 525 530 gag gga gca atg cat aca gca ctg aca gga get aca gag ate caa acc 1746 Glu Gly Ala Met His Thr Ala Leu Thr Gly Ala Thr Glu He Gin Thr 535 540 545 550 tea gga ggc aca agt ate ttt gcg ggg cac tta aaa tgt aga etc aag 1794 Ser Gly Gly Thr Ser He Phe Ala Gly His Leu Lys Cys Arg Leu Lys 555 560 565 atg gac, aaa ttg gaa etc aag ggg atg age tat gca atg tgc ttg agt 1842 Met Asp Lys Leu Glu Leu Lys Gly Met Ser Tyr Ala Met Cys Leu Ser 570 575 580 age ttt gtg ttg aag aaa gaa gtc tcc gaa aeg cag cat ggg aca ata 1890 Ser Phe Val Leu Lys Lys Glu Val Ser Glu Thr Gin His Gly Thr He 585 590 595 etc att aag gtt gag tac aaa ggg gaa gat gca ccc tgc aag att cct 1938 Leu lie Lys Val Glu Tyr Lys Gly Glu Asp Ala Pro Cys Lys He Pro 600 605 610 ttc tcc aeg gag gat gga caa gga aaa get etc aat ggc aga ctg ate 1986 Phe Ser Thr Glu Asp Gly Gin Gly Lys Ala Leu Asn Gly Arg Leu He 615 620 625 630 aca gcc aat cca gtg gtg acc aag aag gag gag cct gtc aac att gag 2034 Thr Ala Asn Pro Val Val Thr Lys Lys Glu Glu Pro Val Asn He Glu 635 640 645 gcc gaa cct cct ttt gga gaa agt aac ata gta att gga att gga gac 2082 Ala Glu Pro Pro Phe Gly Glu Ser Asn He Val He Gly He Gly Asp 650 655 660 aaa gcc ctg aaa ate aac tgg tac aag aag gga age teg att ggg aag 2130 Lys Ala Leu Lys He Asn Trp Tyr Lys Lys Gly Ser Ser He Gly Lys 665 670 675 atg ttc gag gcc act gcc aga ggt gca agg cgc atg gcc ate ttg gga 2178 Met Phe Glu Ala Thr Ala Arg Gly Ala Arg Arg Met Ala He Leu Gly 680 685 690 gac aca gcc tgg gac ttt gga tea gtg ggt ggt gtt ttg aat tea tta 2226 Asp Thr Ala Trp Asp Phe Gly Ser Val Gly Gly Val Leu Asn Ser Leu 695 700 705 710

    102

    2018200081 04 Jan 2018

    ggg aaa Gly Lys atg Met gtc Val cac His 715 caa Gin ata lie ttt Phe ggg agt get tac Tyr aca Thr gcc Ala eta Leu 725 ttt Phe 2274 Gly Ser Ala 720 ggt gga gtc tcc tgg atg atg aaa att gga ata ggt gtc etc tta acc 2322 Gly Gly Val Ser Trp Met Met Lys He Gly He Gly Val Leu Leu Thr 730 735 740 tgg ata ggg ttg aac tea aaa aat act tet atg tea ttt tea tgc ate 2370 Trp lie Gly Leu Asn Ser Lys Asn Thr Ser Met Ser Phe Ser Cys He 745 750 755 geg gcc ggc att gtg aca ctg tat ttg gga gtc atg gtg cag gcc gat 2418 Ala Ala Gly He Val Thr Leu Tyr Leu Gly Val Met Val Gin Ala Asp 760 765 770 agt ggt tgc gtt gtg agc tgg aaa aac aaa gaa ctg aaa tgt ggc agt 2466 Ser Gly Cys Val Val Ser Trp Lys Asn Lys Glu Leu Lys Cys Gly Ser 775 780 785 790 ggg att ttc ate aca gac aac gtg cac aca tgg aca gaa caa tac aag 2514 Gly He Phe He Thr Asp Asn Val His Thr Trp Thr Glu Gin Tyr Lys 795 800 805 ttc caa cca gaa tcc cct tea aaa eta get tea get ate cag aaa gcc 2562 Phe Gin Pro Glu Ser Pro Ser Lys Leu Ala Ser Ala He Gin Lys Ala 810 815 820 cat gaa gag gac att tgt gga ate cgc tea gta aca aga ctg gag aat 2610 His Glu Glu Asp He Cys Gly lie Arg Ser Val Thr Arg Leu Glu Asn 825 830 835 ctg atg tgg aaa caa ata aca cca gaa ttg aat cac att eta tea gaa 2658 Leu Met Trp Lys Gin He Thr Pro Glu Leu Asn His He Leu Ser Glu 840 845 850 aat gag gtg aag tta act att atg aca gga gac ate aaa gga ate atg 2706 Asn Glu Val Lys Leu Thr He Met Thr Gly Asp He Lys Gly He Met 855 860 865 870 cag gca gga aaa ega tet ctg egg cct cag ccc act gag ctg aag tat 2754 Gin Ala Gly Lys Arg Ser Leu Arg Pro Gin Pro Thr Glu Leu Lys Tyr 875 880 885 tea tgg aaa aca tgg ggc aaa gca aaa atg etc tet aca gag tet cat 2802 Ser Trp Lys Thr Trp Gly Lys Ala Lys Met Leu Ser Thr Glu Ser His 890 895 900 aac cag acc ttt etc att gat ggc ccc gaa aca gca gaa tgc ccc aac 2850 Asn Gin Thr Phe Leu He Asp Gly Pro Glu Thr Ala Glu Cys Pro Asn 905 910 915 aca aat aga get tgg aat teg ttg gaa gtt gaa gac tat ggc ttt gga 2898 Thr Asn Arg Ala Trp Asn Ser Leu Glu Val Glu Asp Tyr Gly Phe Gly 920 925 930

    103

    2018200081 04 Jan 2018

    gta ttc acc Thr acc Thr aat Asn ata He 940 tgg Trp eta Leu aaa ttg aaa gaa aaa Lys cag Gin gat Asp gta Val 950' 2946 Val 935 Phe Lys Leu Lys 945 Glu ttc tgc gac tea aaa etc atg tea gcg gcc ata aaa gac aac aga gcc 2994 Phe Cys Asp Ser Lys 955 Leu Met Ser Ala Ala 960 He Lys Asp Asn Arg 965 Ala gtc cat gcc gat atg ggt tat tgg ata gaa agt gca etc aat gac aca 3042 Val His Ala Asp 970 Met Gly Tyr Trp He 975 Glu Ser Ala Leu Asn 980 Asp Thr tgg aag ata gag aaa gcc tet ttc att gaa gtt aaa aac tgc cac tgg 3090 Trp Lys He Glu 985 Lys Ala Ser Phe He 990 Glu Val Lys Asn Cys 995 His Trp cca aaa tea cac acc etc tgg agc aat gga gtg eta gaa agt gag atg 3138 Pro Lys Ser 1000 His Thr Leu Trp Ser 1005 Asn Gly Val Leu Glu 1010 Ser Glu Met ata att cca aag aat etc get gga cca gtg tet caa cac aac tat aga 3186 lie He 1015 Pro Lys Asn Leu Ala 1020 Gly Pro Val Ser Gin 1025 His Asn Tyr Arg 1030 cca ggc tac cat aca caa ata aca gga cca tgg cat eta ggt aag ett 3234 Pro Gly Tyr His Thr Gin 1035 He Thr Gly Pro Trp 1040 His Leu Gly Lys Leu 1045 gag atg gac ttt gat ttc tgt gat gga aca aca gtg gta gtg act gag 3282 Glu Met Asp Phe Asp 1050 Phe Cys Asp Gly Thr 1055 Thr Val Val Val Thr 1060 Glu gac tgc gga aat aga gga ccc tet ttg aga aca acc act gcc tet gga 3330 Asp Cys Gly Asn 1065 Arg Gly Pro Ser Leu 1070 Arg Thr Thr Thr Ala 1075 Ser Gly aaa etc ata aca gaa tgg tgc tgc ega tet tgc aca tta cca ccg eta 3378 Lys Leu He 1080 Thr Glu Trp Cys Cys 1085 Arg Ser Cys Thr Leu 1090 Pro Pro Leu aga tac aga ggt gag gat ggg tgc tgg tac ggg atg gaa ate aga cca 3426 Arg Tyr 1095 Arg Gly Glu Asp Gly 1100 Cys Trp Tyr Gly Met 1105 Glu He Arg Pro 1110 ttg aag gag aaa gaa gag aat ttg gtc aac tcc ttg gtc aca get gga 3474 Leu Lys Glu Lys Glu Glu 1115 Asn Leu Val Asn Ser 112 0 Leu Val Thr Ala Gly 1125 cat ggg cag gtc gac aac ttt tea eta gga gtc ttg gga atg gca ttg 3522 His Gly Gin Val Asp 1130 Asn Phe Ser Leu Gly Val 1135 Leu Gly Met Ala 1140 Leu

    104

    2018200081 04 Jan 2018

    ttc Phe ctg Leu gag gaa Glu Glu 1145 atg Met ett Leu agg Arg acc ega Thr Arg 1150 gta Val gga Gly aeg Thr aaa cat Lys His 1155 gca Ala ata lie 3570 eta eta gtt gca gtt tet ttt gtg aca ttg ate aca ggg aac atg tcc 3618 Leu Leu Val Ala 1160 Val Ser Phe Val Thr 1165 Leu He Thr 117C Gly Asn 1 Met Ser ttt aga gac ctg gga aga gtg atg gtt atg gta ggc gcc act atg aeg 3666 Phe Arg 1175 Asp Leu Gly Arg Val 1180 Met Val Met Val Gly 1185 Ala Thr Met Thr 1190 gat gac ata ggt atg ggc gtg act tat ett gcc eta eta gca gcc ttc 3714 Asp Asp He Gly Met Gly 1195 Val Thr Tyr Leu 120C Ala 1 Leu Leu Ala Ala, 1205 Phe aaa gtc aga cca act ttt gca get gga eta etc ttg aga aag ctg acc 3762 Lys Val Arg Pro Thr 1210 Phe Ala Ala Gly Leu 1215 Leu Leu Arg Lys Leu 1220 Thr tcc aag gaa ttg atg atg act act ata gga att gta etc etc tcc cag 3810 Ser Lys Glu Leu 1225 Met Met Thr Thr He 1230 Gly He Val Leu Leu 1235 Ser Gin age acc ata cca gag acc att ett gag ttg act gat geg tta gcc tta 3858 Ser Thr lie Pro 1240 Glu Thr He Leu Glu 1245 Leu Thr Asp Ala Leu 1250 Ala Leu ggc atg atg gtc etc aaa atg gtg aga aat atg gaa aag tat caa ttg 3906 Gly Met 1255 Met Val Leu Lys Met 1260 Val Arg Asn Met Glu 1265 Lys Tyr Gin Leu 1270 gca gtg act ate atg get ate ttg tgc gtc cca aac gca gtg ata tta 3954 Ala Val Thr lie Met Ala 1275 He Leu Cys Val Pro 1280 Asn Ala Val He 1285 Leu caa aac gca tgg aaa gtg agt tgc aca ata ttg gca gtg gtg tcc gtt 4002 Gin Asn Ala Trp Lys 1290 Val Ser Cys Thr He 1295 Leu Ala Val Val Ser 1300 Val tcc cca ctg ttc tta aca tcc tea cag caa aaa aca gat tgg ata cca 4050 Ser Pro Leu Phe 1305 Leu Thr Ser Ser Gin 1310 Gin Lys Thr Asp Trp 1315 He Pro tta gca ttg aeg ate aaa ggt etc aat cca aca get att ttt eta aca 4098 Leu Ala Leu Thr 1320 lie Lys Gly Leu Asn 1325 Pro Thr Ala lie Phe 1330 Leu Thr acc etc tea aga acc age aag aaa agg age tgg cca tta aat gag get 4146 Thr Leu 1335 Ser Arg Thr Ser Lys 1340 Lys Arg Ser Trp Pro 1345 Leu Asn Glu Ala 1350 ate atg gca gtc ggg atg gtg age att tta gcc agt tet etc eta aaa 4194 lie Met Ala Val Gly Met Val Ser He Leu Ala Ser Ser Leu Leu Lys

    1355 1360 1365

    105

    2018200081 04 Jan 2018

    aat Asn gat Asp att He ccc atg Pro Met 1370 aca Thr gga Gly cca Pro tta gtg Leu Val 1375 get Ala gga Gly ggg Gly etc etc Leu Leu 1380 act Thr 4242 gtg tgc tac gtg etc act gga ega teg gcc gat ttg gaa ctg gag aga 4290 Val Cys Tyr 1385 Val Leu Thr Gly Arg 1390 Ser Ala 1 Asp Leu Glu 1395 Leu Glu Arg gca gcc gat gtc aaa tgg gaa gac cag gca gag ata tea gga age agt 4338 Ala Ala Asp 14 0 0 Val Lys Trp Glu Asp 1405 Gin Ala Glu He Ser 1410 Gly Ser Ser cca ate ctg tea ata aca ata tea gaa gat ggt age atg teg ata aaa 4386 Pro lie 1415 Leu Ser He Thr He 1420 Ser Glu Asp Gly Ser 1425 Met Ser He Lys 1430 aat gaa gag gaa gaa caa aca ctg acc ata etc att aga aca gga ttg 4434 Asn Glu Glu Glu Glu 1435 Gin Thr Leu Thr He Leu 1440 He Arg Thr Gly Leu 1445 ctg gtg ate tea gga ett ttt cct gta tea ata cca ate aeg gca gca 4482 Leu Val He Ser Gly 1450 Leu Phe Pro Val Ser 1455 lie Pro He Thr Ala 1460 Ala gca tgg tac ctg tgg gaa gtg aag aaa caa egg gcc gga gta ttg tgg 4530 Ala Trp Tyr 1465 Leu Trp Glu Val Lys 147C Lys Gin 1 Arg Ala Gly 1475 Val Leu Trp gat gtt cct tea ccc cca ccc atg gga aag get gaa ctg gaa gat gga 4578 Asp Val Pro 1480 Ser Pro Pro Pro Met 1485 Gly Lys Ala Glu Leu 1490 Glu Asp Gly gcc tat aga att aag caa aaa ggg att ett gga tat tcc cag ate gga 4626 Ala Tyr 1495 Arg He Lys Gin Lys 1500 Gly He Leu Gly Tyr 1505 Ser Gin He Gly 1510 gcc gga gtt tac aaa gaa gga aca ttc cat aca atg tgg cat gtc aca 4674 Ala Gly Val Tyr Lys Glu 1515 Gly Thr Phe His Thr 1520 Met Trp His Val Thr 1525 cgt ggc get gtt eta atg cat aaa gga aag agg att gaa cca tea tgg 4722 Arg Gly Ala Val Leu 1530 Met His Lys Gly Lys 1535 Arg He Glu Pro Ser 1540 Trp gcg gac gtc aag aaa gac eta ata tea tat gga gga ggc tgg aag tta 4770 Ala Asp Val Lys Lys 1545 Asp Leu He Ser Tyr 1550 Gly Gly Gly Trp Lys 1555 Leu gaa gga gaa tgg aag gaa gga gaa gaa gtc cag gta ttg gca ctg gag 4818 Glu Gly Glu Trp Lys Glu Gly Glu Glu Val Gin Val Leu Ala Leu Glu

    1560 1565 1570

    106

    2018200081 04 Jan 2018

    cct gga Pro Gly 1575 aaa Lys aat Asn cca Pro aga gcc gtc Arg Ala Val 1580 caa Gin aeg aaa cct Thr Lys Pro 1585 ggt Gly ett Leu ttc Phe aaa Lys 1590 4866 acc aac gee gga aca ata ggt get gta tct ctg gac ttt tct cct gga 4914 Thr Asn Ala Gly Thr He Gly Ala 1595 Val Ser Leu Asp 1600 Phe Ser Pro 1605 Gly aeg tea gga tct cca att ate gac aaa aaa gga aaa gtt gtg ggt ett 4962 Thr Ser Gly Ser 161C Pro 1 He He Asp Lys 1615 Lys Gly Lys Val Val 162C Gly 1 Leu tat ggt aat ggt gtt gtt aca agg agt gga gca tat gtg agt get ata 5010 Tyr Gly Asn Gly 1625 Val Val Thr Arg Ser 1630 Gly Ala Tyr Val Ser 1635 Ala lie gcc cag act gaa aaa age att gaa gac aac cca gag ate gaa gat gac 5058 Ala Gin Thr 1640 Glu Lys Ser He Glu 1645 Asp Asn Pro Glu He 1650 Glu Asp Asp att ttc cga aag aga aga ctg acc ate atg gac etc cac cca gga gcg 5106 lie Phe 1655 Arg Lys Arg Arg Leu Thr 1660 He Met Asp Leu 1665 His Pro Gly Ala 1670 gga aag aeg aag aga tac ett ccg gee ata gtc aga gaa get ata aaa 5154 Gly Lys Thr Lys Arg Tyr Leu Pro 1675 Ala He Val Arg 1680 Glu Ala He 1685 Lys egg ggt ttg aga aca tta ate ttg gcc ccc act aga gtt gtg gca get 5202 Arg Gly Leu Arg Thr 1690 Leu He Leu Ala Pro Thr Arg 1695 Val Val Ala 1700 Ala gaa atg gag gaa gee ett aga gga ett cca ata aga tac cag acc cca 5250 Glu Met Glu Glu 1705 Ala Leu Arg Gly Leu 1710 Pro He Arg Tyr Gin 1715 Thr Pro gcc ate aga get gtg cac acc ggg egg gag att gtg gac eta atg tgt 5298 Ala He Arg 1720 Ala Val His Thr Gly 1725 Arg Glu He Val Asp 1730 Leu Met Cys cat gcc aca ttt acc atg agg ctg eta tea cca gtt aga gtg cca aac 5346 His Ala 1735 Thr Phe Thr Met Arg Leu 1740 Leu Ser Pro Val 1745 Arg Val Pro Asn 1750 tac aac ctg att ate atg gac gaa gcc cat ttc aca gac cca gca agt 5394 Tyr Asn Leu He He Met Asp Glu 1755 Ala His Phe Thr 1760 Asp Pro Ala Ser 1765 ata gca get aga gga tac ate tea act cga gtg gag atg ggt gag gca 5442 He Ala Ala Arg Gly 1770 Tyr He Ser Thr Arg Val Glu 1775 Met Gly Glu 1780 Ala get ggg att ttt atg aca gcc act ccc ccg gga age aga gac cca ttt 5490 Ala Gly He Phe Met Thr Ala Thr Pro Pro Gly Ser Arg Asp Pro Phe

    1785 1790 1795

    107

    2018200081 04 Jan 2018

    cct Pro cag age aat gca Ala cca Pro ate ata gat gaa He lie Asp Glu 1805 gaa Glu aga gaa Arg Glu 1810 ate He cct Pro gaa Glu 5538 Gin. Ser 1800 Asn cgc teg tgg aat tcc gga cat gaa tgg gtc aeg gat ttt aaa ggg aag 5586 Arg 1815 Ser Trp Asn Ser Gly 182C His Glu Trp Val 1 Thr 1825 Asp Phe Lys Gly Lys 1830 act gtt tgg ttc gtt cca agt ata aaa gca gga aat gat ata gca get 5634 Thr Val Trp Phe Val 1835 Pro Ser He Lys Ala Gly 1840 Asn Asp He Ala 1845 Ala tgc ctg agg aaa aat gga aag aaa gtg ata caa etc agt agg aag acc 5682 Cys Leu Arg Lys Asn 1850 Gly Lys Lys Val He 1855 Gin Leu Ser Arg Lys 1860 Thr ttt gat tet gag tat gtc aag act aga acc aat gat tgg gac ttc gtg 5730 Phe Asp Ser Glu 1865 Tyr Val Lys Thr Arg Thr 1870 Asn Asp Trp Asp 1875 Phe Val gtt aca act gac att tea gaa atg ggt gcc aat ttc aag get gag agg 5778 Val Thr Thr 1880 Asp He Ser Glu Met Gly Ala 1885 Asn Phe Lys 1890 Ala Glu Arg gtt ata gac ccc aga cgc tgc atg aaa cca gtc ata eta aca gat ggt 5826 Val lie Asp 1895 Pro Arg Arg Cys Met Lys Pro 1900 Val He Leu 1905 Thr Asp Gly 1910 gaa gag egg gtg att ctg gca gga cct atg cca gtg acc cac tet agt 5874 Glu Glu Arg Val He Leu 1915 Ala Gly Pro Met Pro 1920 Val Thr His Ser Ser 1925 gca gca caa aga aga ggg aga ata gga aga aat cca aaa aat gag aat 5922 Ala Ala Gin Arg Arg 1930 Gly Arg He Gly Arg 1935 Asn Pro Lys Asn Glu 1940 Asn gac cag tac ata tac atg ggg gaa cct ctg gaa aat gat gaa gac tgt 5970 Asp Gin Tyr He 1945 Tyr Met Gly Glu Pro Leu 1950 Glu Asn Asp Glu 1955 Asp Cys gca cac tgg aaa gaa get aaa atg etc eta gat aac ate aac aeg cca 6018 Ala His Trp 1960 Lys Glu Ala Lys Met Leu Leu 1965 Asp Asn He 1970 Asn Thr Pro gaa gga ate att cct age atg ttc gaa cca gag cgt gaa aag gtg gat 6066 Glu Gly He 1975 He Pro Ser Met Phe Glu Pro 1980 Glu Arg Glu 1985 Lys Val Asp 1990 gcc att gat ggc gaa tac cgc ttg aga gga gaa gca agg aaa acc ttt 6114 Ala He Asp Gly Glu Tyr 1995 Arg Leu Arg Gly Glu 2000 Ala Arg Lys Thr Phe 2005

    2018200081 04 Jan 2018

    108 gta gac tta atg aga aga gga gac eta cca gtc tgg ttg gcc tac aga 6162

    Val Asp Leu Met Arg Arg Gly Asp Leu Pro Val Trp Leu Ala Tyr Arg

    2010 2015 2020 gtg gca get gaa ggc ate aac tac gca gac aga agg tgg tgt ttt gat 6210

    Val Ala Ala Glu Gly lie Asn Tyr Ala Asp Arg Arg Trp Cys Phe Asp

    2025 2030 2035

    gga Gly gtc aag Val Lys 2040 aac Asn aac Asn caa Gin ate eta He Leu 2045 gaa Glu gaa Glu aac Asn gtg gaa Val Glu 2050 gtt Val gaa Glu ate He 6258 tgg aca aaa gaa ggg gaa agg aag aaa ttg aaa ccc aga tgg ttg gat 6306 Trp 2055 Thr Lys Glu Gly Glu 206C Arg Lys 1 Lys Leu Lys 2065 Pro Arg Trp Leu Asp 2070 get agg ate tat tet gac cca ctg geg eta aaa gaa ttt aag gaa ttt 6354 Ala Arg He Tyr Ser Asp 2075 Pro Leu Ala Leu 208C Lys 1 Glu Phe Lys Glu 2085 Phe gca gcc gga aga aag tet ctg acc ctg aac eta ate aca gaa atg ggt 6402 Ala Ala Gly Arg Lys 2090 Ser Leu Thr Leu Asn 2095 Leu He Thr Glu Met 2100 Gly agg etc cca acc ttc atg act cag aag gca aga gac gca ctg gac aac 6450 Arg Leu Pro 2105 Thr Phe Met Thr Gin 211C Lys 1 Ala Arg Asp Ala 2115 Leu Asp Asn tta gca gtg ctg cac acg get gag gca ggt gga agg geg tac aac cat 6498 Leu Ala Val 2120 Leu His Thr Ala Glu 2125 Ala Gly Gly Arg Ala 2130 Tyr Asn His get etc agt gaa ctg ccg gag acc ctg gag aca ttg ett tta ctg aca 6546 Ala Leu Ser 2135 Glu Leu Pro Glu Thr 2140 Leu Glu Thr Leu Leu 2145 Leu Leu Thr 2150 ett ctg get aca gtc acg gga ggg ate ttt tta ttc ttg atg age gca 6594 Leu Leu Ala Thr Val Thr 2155 Gly Gly He Phe Leu 2160 Phe Leu Met Ser Ala 2165 agg ggc ata ggg aag atg acc ctg gga atg tgc tgc ata ate acg get 6642 Arg Gly He Gly Lys 2170 Met Thr Leu Gly Met 2175 Cys Cys He He Thr 2180 Ala age ate etc eta tgg tac gca caa ata cag cca cac tgg ata gca get 6690 Ser lie Leu Leu 2185 Trp Tyr Ala Gin He 2190 Gin Pro His Trp He 2195 Ala Ala tea ata ata ctg gag ttt ttt etc ata gtt ttg ett att cca gaa cct 6738 Ser He He 2200 Leu Glu Phe Phe Leu 2205 He Val Leu Leu He 2210 Pro Glu Pro gaa aaa cag aga aca ccc caa gac aac caa ctg acc tac gtt gtc ata 6786 Glu Lys Gin 2215 Arg Thr Pro Gin Asp 2220 Asn Gin Leu Thr Tyr 2225 Val Val lie 2230

    109

    2018200081 04 Jan 2018

    gcc Ala ate lie etc aca gtg gtg gcc gca acc atg gca Met Ala 2240 aac Asn gag Glu atg Met ggt Gly 2245 ttc Phe 6834 Leu Thr Val Val 2235 Ala Ala Thr eta gaa aaa acg aag aaa gat etc gga ttg gga age att gca acc cag 6882 Leu Glu Lys Thr Lys Lys 2250 Asp Leu Gly 2255 Leu Gly Ser He Ala 226C Thr 1 Gin caa ccc gag age aac ate ctg gac ata gat eta cgt cct gca tea gca 6930 Gin Pro Glu 2265 Ser Asn He Leu Asp He 2270 Asp Leu Arg Pro Ala 2275 Ser Ala tgg acg ctg tat gcc gtg gcc aca aca ttt gtt aca cca atg ttg aga 6978 Trp Thr Leu 2280 Tyr Ala Val Ala Thr 2285 Thr Phe Val Thr Pro 2290 Met Leu Arg cat age att gaa aat tcc tea gtg aat gtg tcc eta aca get ata gcc 7026 His Ser 2295 He Glu Asn Ser Ser 2300 Val Asn Val Ser Leu 2305 Thr Ala He Ala 2310 aac caa gcc aca gtg tta atg ggt etc ggg aaa gga tgg cca ttg tea ' 7074 Asn Gin Ala Thr Val Leu 2315 Met Gly Leu Gly Lys 2320 Gly Trp Pro Leu Ser 2325 aag atg gac ate gga gtt ccc ett etc gcc att gga tgc tac tea caa 7122 Lys Met Asp He Gly Val 2330 Pro Leu Leu Ala He 2335 Gly Cys Tyr Ser 2340 Gin gtc aac ccc ata act etc aca gca get ett ttc tta ttg gta gca cat 7170 Val Asn Pro He Thr Leu 2345 Thr Ala Ala 2350 Leu Phe Leu Leu Val 2355 Ala His tat gcc ate ata ggg cca gga etc caa gca aaa gca acc aga gaa get 7218 Tyr Ala He 2360 He Gly Pro Gly Leu 2365 Gin Ala Lys Ala Thr 2370 Arg Glu Ala cag aaa aga gca gcg gcg ggc ate atg aaa aac cca act gtc gat gga 7266 Gin Lys 2375 Arg Ala Ala Ala Gly 2380 He Met Lys Asn Pro 2385 Thr Val Asp Gly 2390 ata aca gtg att gac eta gat cca ata cct tat gat cca aag ttt gaa 7314 lie Thr Val He Asp Leu 2395 Asp Pro He Pro Tyr 2400 Asp Pro Lys Phe Glu 2405 aag cag ttg gga caa gta atg etc eta gtc etc tgc gtg act caa gta 7362 Lys Gin Leu Gly Gin Val 2410 Met Leu Leu Val Leu 2415 Cys Val Thr Gin 2420 Val ttg atg atg agg act aca tgg get ctg tgt gag get tta acc tta get 7410 Leu Met Met Arg Thr Thr Trp Ala Leu Cys Glu Ala Leu Thr Leu Ala

    2425 2430 2435

    110

    2018200081 04 Jan 2018

    acc ggg ccc Thr Gly Pro ate lie tcc Ser aca Thr ttg tgg gaa gga aat Asn cca ggg Pro Gly 2450 agg Arg ttt Phe tgg Trp 7458 Leu Trp 2445 Glu Gly 2440 aac act acc att gcg gtg tea atg get aac att ttt aga ggg agt tac 7506 Asn 2455 Thr Thr He Ala Val 246C Ser Met 1 Ala Asn He 2465 Phe Arg Gly Ser Tyr 2470 ttg gcc gga get gga ett etc ttt tct att atg aag aac aca acc aac 7554 Leu Ala Gly Ala Gly 2475 Leu Leu Phe Ser He 248C Met 1 Lys Asn Thr Thr 2485 Asn aca aga agg gga act ggc aac ata gga gag aeg ett gga gag aaa tgg 7602 Thr Arg Arg Gly Thr 2490 Gly Asn He Gly Glu 2495 Thr' Leu Gly Glu Lys 2500 Trp aaa agc ega ttg aac gca ttg gga aaa agt gaa ttc cag ate tac aag 7650 Lys Ser Arg Leu 2505 Asn Ala Leu Gly Lys 2510 Ser Glu Phe Gin He 2515 Tyr Lys aaa agt gga ate cag gaa gtg gat aga acc tta gca aaa gaa ggc att 7698 Lys Ser Gly 2520 He Gin Glu Val Asp 2525 Arg Thr Leu Ala Lys 2530 Glu Gly He aaa aga gga gaa aeg gac cat cac get gtg teg ega ggc tea gca aaa 7746 Lys Arg Gly 2535 Glu Thr Asp His His 2540 Ala Val Ser Arg Gly 2545 Ser Ala Lys 2550 ctg aga tgg ttc gtt gag aga aac atg gtc aca cca gaa ggg aaa gta 7794 Leu Arg Trp Phe Val Glu 2555 Arg Asn Met Val Thr 2560 Pro Glu Gly Lys Val 2565 gtg gac etc ggt tgt ggc aga gga ggc tgg tea tac tat tgt gga gga 7842 Val Asp Leu Gly Cys 2570 Gly Arg Gly Gly Trp 2575 Ser Tyr Tyr Cys Gly 2580 Gly eta aag aat gta aga gaa gtc aaa ggc eta aca aaa gga gga cca gga 7890 Leu Lys Asn Val 2585 Arg Glu Val Lys Gly 2590 Leu Thr Lys Gly Gly 2595 Pro Gly cac gaa gaa ccc ate ccc atg tea aca tat ggg tgg aat eta gtg cgt 7938 His Glu Glu 2600 Pro He Pro Met Ser 2605 Thr Tyr Gly Trp Asn 2610 Leu Val Arg ett caa agt gga gtt gac gtt ttc ttc ate ccg cca gaa aag tgt gac 7986 Leu Gin Ser 2615 Gly Val Asp Val Phe 2620 Phe lie Pro Pro Glu 2625 Lys Cys Asp 2630 aca tta ttg tgt gac ata ggg gag tea tea cca aat ccc aca gtg gaa 8034 Thr Leu Leu Cys Asp He 2635 Gly Glu Ser Ser Pro 2640 Asn Pro Thr Val Glu 2645 gca gga ega aca etc aga gtc ett aac tta gta gaa aat tgg ttg aac 8082 Ala Gly Arg Thr Leu Arg Val Leu Asn Leu Val Glu Asn Trp Leu Asn

    2650 2655 2660

    111

    2018200081 04 Jan 2018

    aac Asn aac Asn act caa ttt Thr Gin Phe 2665 tgc Cys ata He aag gtt Lys Val 2670 etc Leu aac Asn cca Pro tat atg Tyr Met 2675 ccc Pro tea Ser 8130 gtc ata gaa aaa atg gaa gca eta caa agg aaa tat gga gga gcc tta 8178 Val lie 268C Glu Lys Met 1 Glu Ala 2685 Leu Gin Arg Lys Tyr 269C Gly Gly 1 Ala Leu gtg agg aat cca etc tea ega aac tcc aca cat gag atg tac tgg gta 8226 Val Arg 2695 Asn Pro Leu Ser 270C Arg 1 Asn Ser Thr His 2705 Glu Met Tyr Trp Val 2710 tcc aat get tcc ggg aac ata gtg tea tea gtg aac atg att tea agg 8274 Ser Asn Ala Ser Gly Asn 2715 He Val Ser Ser Val 2720 Asn Met He Ser Arg 2725 atg ttg ate aac aga ttt aca atg aga tac aag aaa gcc act tac gag 8322 Met Leu He Asn Arg 2730 Phe Thr Met Arg Tyr 2735 Lys Lys Ala Thr 274C Tyr 1 Glu ccg gat gtt gac etc gga agc gga acc cgt aac ate ggg att gaa agt 8370 Pro Asp Val Asp Leu 2745 Gly Ser Gly Thr 2750 Arg Asn He Gly He 2755 Glu Ser gag ata cca aac eta gat ata att ggg aaa aga ata gaa aaa ata aag 8418 Glu He Pro Asn Leu 2760 Asp lie He Gly 2765 Lys Arg He Glu Lys 2770 He Lys caa gag cat gaa aca tea tgg cac tat gac caa gac cac cca tac aaa 8466 Gin Glu 2775 His Glu Thr Ser Trp 2780 His Tyr Asp Gin Asp 2785 His Pro Tyr Lys 2790 aeg tgg gca tac cat ggt agc tat gaa aca aaa cag act gga tea gca 8514 Thr Trp Ala Tyr His Gly 2795 Ser Tyr Glu Thr Lys 2800 Gin Thr Gly Ser Ala 2805 tea tcc atg gtc aac gga gtg gtc agg ctg ctg aca aaa cct tgg gac 8562 Ser Ser Met Val Asn 2810 Gly Val Val Arg Leu 2815 Leu Thr Lys Pro Trp 2820 Asp gtc gtc ccc atg gtg aca cag atg gca atg aca gac aeg act cca ttt 8610 Val Val Pro Met Val 2825 Thr Gin Met Ala 2830 Met Thr Asp Thr Thr 2835 Pro Phe gga caa cag ege gtt ttt aaa gag aaa gtg gac aeg aga acc caa gaa 8658 Gly Gin Gin Arg Val 2840 Phe Lys Glu Lys 2845 Val Asp Thr Arg Thr 2850 Gin Glu ccg aaa gaa ggc aeg aag aaa eta atg aaa ata aca gca gag tgg ett 8706 Pro Lys 2855 Glu Gly Thr Lys Lys 2860 Leu Met Lys He Thr 2865 Ala Glu Trp Leu 2870

    112

    2018200081 04 Jan 2018

    tgg Trp aaa Lys gaa Glu tta Leu ggg aag Gly Lys 2875 aaa Lys aag Lys aca Thr ccc agg Pro Arg 2880 atg Met tgc Cys acc Thr aga gaa Arg Glu 2 885 8754 gaa ttc aca aga aag gtg aga age aat gca gcc ttg ggg gcc ata ttc 8802 Glu Phe Thr Arg Lys Val 2890 Arg Ser Asn Ala Ala 2895 Leu Gly Ala He Phe 2900 act gat gag aac aag tgg aag teg gca cgt gag get gtt gaa gat agt 8850 Thr Asp Glu Asn 2905 Lys Trp Lys Ser Ala 2910 Arg Glu Ala Val Glu 2915 Asp Ser agg ttt tgg gag ctg gtt gac aag gaa agg aat etc cat ett gaa gga 8898 Arg Phe 292C Trp 1 Glu Leu Val Asp Lys 2925 Glu Arg Asn Leu His 2930 Leu Glu Gly aag tgt gaa aca tgt gtg tac aac atg atg gga aaa aga gag aag aag 8946 Lys Cys 2935 Glu Thr Cys Val Tyr 2940 Asn Met Met Gly Lys 2945 Arg Glu Lys Lys 2950 eta ggg gaa ttc ggc aag gca aaa ggc age aga gcc ata tgg tac atg 8994 Leu Gly Glu Phe Gly Lys 2955 Ala Lys Gly Ser Arg 2960 Ala He Trp Tyr Met 2965 tgg ett gga gca cgc ttc tta gag ttt gaa gcc eta gga ttc tta aat 9042 Trp Leu Gly Ala Arg Phe 2970 Leu Glu Phe Glu Ala 2975 Leu Gly Phe Leu Asn 2980 gaa gat cac tgg ttc tcc aga gag aac tcc ctg agt gga gtg gaa gga 9090 Glu Asp His 2985 Trp Phe Ser Arg Glu Asn 2990 Ser Leu Ser Gly Val 2995 Glu Gly gaa ggg ctg cac aag eta ggt tac att eta aga gac gtg age aag aaa 9138 Glu Gly 300C Leu 1 His Lys Leu Gly Tyr 3005 He Leu Arg Asp Val 3010 Ser Lys Lys gag gga gga gca atg tat gcc gat gac acc gca gga tgg gat aca aga 9186 Glu Gly 3015 Gly Ala Met Tyr Ala 3020 Asp Asp Thr Ala Gly 3025 Trp Asp Thr Arg 3030 ate aca eta gaa gac eta aaa aat gaa gaa atg gta aca aac cac atg 9234 lie Thr Leu Glu Asp Leu 3035 Lys Asn Glu Glu Met 3040 Val Thr Asn His Met 3045 gaa gga gaa cac aag aaa eta gcc gag gcc att ttc aaa eta aeg tac 9282 Glu Gly Glu His 305C Lys Lys 1 Leu Ala Glu Ala He 3055 Phe Lys Leu 306C Thr Tyr 1 caa aac aag gtg gtg cgt gtg caa aga cca aca cca aga ggc aca gta 9330 Gin Asn Lys 3065 Val Val Arg Val Gin 307C Arg I Pro Thr Pro Arg 3075 Gly Thr Val atg gac ate ata teg aga aga gac caa aga ggt agt gga caa gtt ggc 9378 Met Asp 308C He 1 He Ser Arg Arg 3085 Asp Gin Arg Gly Ser Gly Gin 3090 Val Gly

    113

    2018200081 04 Jan 2018

    acc tat Thr Tyr 3095 gga Gly etc Leu aat Asn act ttc Thr Phe 3100 acc Thr aat Asn atg gaa gcc Met Glu Ala 3105 caa Gin eta Leu ate He aga Arg 3110 9426 cag atg gag gga gaa gga gtc ttt aaa age att cag cac eta aca ate 9474 Gin Met Glu Gly Glu Gly Val 3115 Phe Lys Ser He Gin 3120 His Leu Thr 3125 He aca gaa gaa ate get gtg caa aac tgg tta gca aga gtg ggg ege gaa 9522 Thr Glu Glu He Ala 3130 Val Gin Asn Trp Leu Ala Arg 3135 Val Gly 314C Arg 1 Glu agg tta tea aga atg gcc ate agt gga gat gat tgt gtt gtg aaa cct 9570 Arg Leu Ser Arg 3145 Met Ala He Ser Gly 3150 Asp Asp Cys Val Val 3155 Lys Pro tta gat gac agg ttc gca age get tta aca get eta aat gac atg gga 9618 Leu Asp Asp 3160 Arg Phe Ala Ser Ala 3165 Leu Thr Ala Leu Asn 3170 Asp Met Gly aag att agg aaa gac ata caa caa tgg gaa cct tea aga gga tgg aat 9666 Lys lie 3175 Arg Lys Asp He Gin 3180 Gin Trp Glu Pro Ser 3185 Arg Gly Trp Asn 3190 gat tgg aca caa gtg ccc ttc tgt tea cac cat ttc cat gag tta ate 9714 Asp Trp Thr Gin Val Pro Phe 3195 Cys Ser His His Phe 3200 His Glu Leu 3205 He atg aaa gac ggt ege gta etc gtt gtt cca tgt aga aac caa gat gaa 9762 Met Lys Asp Gly Arg 3210 Val Leu Val Val Pro Cys Arg 3215 Asn Gin Asp 3220 Glu ctg att ggc aga gee ega ate tcc caa gga gca ggg tgg tet ttg egg 9810 Leu He Gly Arg 3225 Ala Arg He Ser Gin 3230 Gly Ala Gly Trp Ser 3235 Leu Arg gag aeg gcc tgt ttg ggg aag tet tac gcc caa atg tgg age ttg atg 9858 Glu Thr Ala 3240 Cys Leu Gly Lys Ser 3245 Tyr Ala Gin Met Trp 3250 Ser Leu Met tac ttc cac aga ege gac etc agg ctg geg gca aat get att tgc teg 9906 Tyr Phe 3255 His Arg Arg Asp Leu 3260 Arg Leu Ala Ala Asn 3265 Ala He Cys Ser 3270 gca gta cca tea cat tgg gtt cca aca agt ega aca acc tgg tcc ata 9954 Ala Val Pro Ser His Trp Val 3275 Pro Thr Ser Arg Thr 3280 Thr Trp Ser lie 3285 cat get aaa cat gaa tgg atg aca aeg gaa gac atg ctg aca gtc tgg 10002 His Ala Lys His Glu Trp Met Thr Thr Glu Asp Met Leu Thr Val Trp

    3290 3295 3300

    114

    2018200081 04 Jan 2018

    aac Asn agg Arg gtg tgg Val Trp 3305 att He caa Gin gaa Glu aac cca Asn Pro 3310 tgg Trp atg Met gaa Glu gac aaa Asp Lys 3315 act Thr cca Pro 10050 gtg gaa tea tgg gag gaa ate cca tac ttg ggg aaa aga gaa gac caa 10098 Val Glu Ser Trp 3320 Glu Glu He Pro Tyr 3325 Leu Gly Lys Arg Glu 3330 Asp Gin tgg tgc ggc tea ttg att ggg tta aca agc agg gcc acc tgg gca aag 10146 Trp 3335 Cys Gly Ser Leu He Gly 3340 Leu Thr Ser Arg Ala 3345 Thr Trp Ala Lys 3350 aac ate caa gca gca ata aat caa gtt aga tcc ett ata ggc aat gaa 10194 Asn lie Gin Ala Ala 3355 lie Asn Gin Val Arg 336C Ser 1 Leu He Gly Asn 3365 Glu gaa tac aca gat tac atg cca tcc atg aaa aga ttc aga aga gaa gag 10242 Glu Tyr Thr Asp Tyr Met Pro Ser Met Lys Arg Phe Arg Arg Glu Glu

    3370 3375 3380 gaa gaa gca gga gtt ctg tgg tag aaagcaaaac taacatgaaa caaggctaga 10296 Glu Glu Ala Gly Val Leu Trp *

    3385 agtcaggtcg gattaagcca tagtacggaa aaaactatgc tacctgtgag ccccgtccaa 10356 ggacgttaaa agaagtcagg ccatcataaa tgccatagct tgagtaaact atgcagcctg 10416 tagctccacc tgagaaggtg taaaaaatcc gggaggccac aaaccatgga agctgtacgc 10476 atggcgtagt ggactagcgg ttagaggaga cccctccctt acaaatcgca gcaacaatgg 10536 gggcccaagg cgagatgaag ctgtagtctc gctggaagga ctagaggtta gaggagaccc 10596 ccccgaaaca aaaaacagca tattgacgct gggaaagacc agagatcctg ctgtctcctc 10656 agcatcattc caggcacaga acgccagaaa atggaatggt gctgttgaat caacaggttc 10716 t 10717 <210> 10 <211> 3389 <212> PRT <213> Artificial Sequence <220> .

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 10

    Met Asn Asn Gin Arg Lys Lys Ala Lys Asn Thr Pro Phe Asn Met Leu 1 5 10 15 Lys Arg Glu Arg Asn Arg Val Ser Thr Val Gin Gin Leu Thr Lys Arg 20 25 30 Phe Ser Leu Gly Met Leu Gin Gly Arg Gly Pro Leu Lys Leu Phe Met 35 40 45 Ala Leu Val Ala Phe Leu Arg Phe Leu Thr He Pro Pro Thr Ala Gly 50 55 60 He Leu Lys Arg Trp Gly Thr He Lys Lys Ser Lys Ala He Asn Val 65 70 75 80

    115

    2018200081 04 Jan 2018

    Leu Arg Gly Phe Arg Lys Glu lie Gly Arg Met Leu Asn. He Leu Asn 85 90 95 Arg Arg Arg Arg Ser Ala Gly Met He He Met Leu He Pro Thr Val 100 105 110 Met Ala Phe His Leu Thr Thr Arg Asp Gly Glu Pro Arg Met He Val 115 120 125 Gly Lys Asn Glu Arg Gly Lys Ser Leu Leu Phe Lys Thr Ala Ser Gly 130 135 140 He Asn Met Cys Thr Leu He Ala Met Asp Leu Gly Glu Met Cys Asp 145 150 155 160 Asp Thr Val Thr Tyr Lys Cys Pro His He Thr Glu Val Glu Pro Glu 165 170 175 Asp He Asp Cys Trp Cys Asn Leu Thr Ser Thr Trp Val Thr Tyr Gly 180 185 190 Thr Cys Asn Gin Ala Gly Glu His Arg Arg Asp Lys Arg Ser Val Ala 195 200 205 Leu Ala Pro His Val Gly Met Gly Leu Asp Thr Arg Thr Gin Thr Trp 210 215 220 Met Ser Ala Glu Gly Ala Trp Arg Gin Val Glu Lys Val Glu Thr Trp 225 230 235 240 Ala Leu Arg His Pro Gly Phe Thr lie Leu Ala Leu Phe Leu Ala His 245 250 255 Tyr He Gly Thr Ser Leu Thr Gin Lys Val Val He Phe He Leu Leu 260 265 270 Met Leu Val Thr Pro Ser Met Thr Met Arg Cys Val Gly Val Gly Asn 275 280 285 Arg Asp Phe Val Glu Gly Leu Ser Gly Ala Thr Trp Val Asp Val Val 290 295 300 Leu Glu His Gly Gly Cys Val Thr Thr Met Ala Lys Asn Lys Pro Thr 305 310 315 320 Leu Asp He Glu Leu Gin Lys Thr Glu Ala Thr Gin Leu Ala Thr Leu 325 330 335 Arg Lys Leu Cys He Glu Gly Lys He Thr Asn He Thr Thr Asp Ser 340 345 350 Arg Cys Pro Thr Gin Gly Glu Ala He Leu Pro Glu Glu Gin Asp Gin 355 360 365 Asn Tyr Val Cys Lys His Thr Tyr Val Asp Arg Gly Trp Gly Asn Gly 370 375 380 Cys Gly Leu Phe Gly Lys Gly Ser Leu Val Thr Cys Ala Lys Phe Gin 385 390 395 400 Cys Leu Glu Ser He Glu Gly Lys Val Val Gin His Glu Asn Leu Lys 405 410 415 Tyr Thr Val He He Thr Val His Thr Gly Asp Gin His Gin Val Gly 420 425 430 Asn Glu Thr Gin Gly Val Thr Ala Glu He Thr Pro Gin Ala Ser Thr 435 440 445 Ala Glu Ala He Leu Pro Glu Tyr Gly Thr Leu Gly Leu Glu Cys Ser 450 455 460 Pro Arg Thr Gly Leu Asp Phe Asn Glu Met He Ser Leu Thr Met Lys 465 470 475 480 Asn Lys Ala Trp Met Val His Arg Gin Trp Phe Phe Asp Leu Pro Leu 485 490 495 Pro Trp Thr Ser Gly Ala Thr Ala Glu Thr Pro Thr Trp Asn Arg Lys 500 505 510

    116

    2018200081 04 Jan 2018

    Glu Leu Leu 515 Val Thr Phe Lys Asn Ala His Ala Lys Lys Gin Glu Val 520 525 Val Val Leu Gly Ser Gin Glu Gly Ala Met His Thr Ala Leu Thr Gly 530 535 540 Ala Thr Glu He Gin Thr Ser Gly Gly Thr Ser He Phe Ala Gly His 545 550 555 560 Leu Lys Cys Arg Leu Lys Met Asp Lys Leu Glu Leu Lys Gly Met Ser 565 570 575 Tyr Ala Met Cys Leu Ser Ser Phe Val Leu Lys Lys Glu Val Ser Glu 580 585 590 Thr Gin His Gly Thr He Leu He Lys Val Glu Tyr Lys Gly Glu Asp 595 600 605 Ala Pro Cys Lys lie Pro Phe Ser Thr Glu Asp Gly Gin Gly Lys Ala 610 615 620 Leu Asn Gly Arg Leu He Thr Ala Asn Pro Val Val Thr Lys Lys Glu 625 630 635 640 Glu Pro Val Asn He Glu Ala Glu Pro Pro Phe Gly Glu Ser Asn He 645 650 655 Val He Gly He Gly Asp Lys Ala Leu Lys He Asn Trp Tyr Lys Lys 660 665 670 Gly Ser Ser He Gly Lys Met Phe Glu Ala Thr Ala Arg Gly Ala Arg 675 680 685 Arg Met Ala He Leu Gly Asp Thr Ala Trp Asp Phe Gly Ser Val Gly 690 695 700 Gly Val Leu Asn Ser Leu Gly Lys Met Val His Gin He Phe Gly Ser 705 710 715 720 Ala Tyr Thr Ala Leu Phe Gly Gly Val Ser Trp Met Met Lys He Gly 725 730 735 lie Gly Val Leu Leu Thr Trp He Gly Leu Asn Ser Lys Asn Thr Ser 740 745 750 Met Ser Phe Ser Cys He Ala Ala Gly He Val Thr Leu Tyr Leu Gly 755 760 765 Val Met Val Gin Ala Asp Ser Gly Cys Val Val Ser Trp Lys Asn Lys 770 775 780 Glu Leu Lys Cys Gly Ser Gly He Phe He Thr Asp Asn Val His Thr 785 790 795 800 Trp Thr Glu Gin Tyr Lys Phe Gin Pro Glu Ser Pro Ser Lys Leu Ala 805 810 815 Ser Ala lie Gin Lys Ala His Glu Glu Asp He Cys Gly He Arg Ser 820 825 830 Val Thr Arg Leu Glu Asn Leu Met Trp Lys Gin He Thr Pro Glu Leu 835 840 845 Asn His He Leu Ser Glu Asn Glu Val Lys Leu Thr He Met Thr Gly 850 855 860 Asp He Lys Gly He Met Gin Ala Gly Lys Arg Ser Leu Arg Pro Gin 865 870 875 880 Pro Thr Glu Leu Lys Tyr Ser Trp Lys Thr Trp Gly Lys Ala Lys Met 885 890 895 Leu Ser Thr Glu Ser His Asn Gin Thr Phe Leu He Asp Gly Pro Glu 900 905 910 Thr Ala Glu Cys Pro Asn Thr Asn Arg Ala Trp Asn Ser Leu Glu Val 915 920 925 Glu Asp Tyr Gly Phe Gly Val Phe Thr Thr Asn He Trp Leu Lys Leu 930 935 940

    117

    2018200081 04 Jan 2018

    Lys Glu Lys Gin Asp Val Phe Cys Asp Ser Lys Leu Met Ser Ala Ala 945 950 955 960 lie Lys Asp Asn Arg Ala Val His Ala Asp Met Gly Tyr Trp He Glu 965 970 975 Ser Ala Leu Asn Asp Thr Trp Lys He Glu Lys Ala Ser Phe He Glu 980 985 990 Val Lys Asn Cys His Trp Pro Lys Ser His Thr Leu Trp Ser Asn Gly 995 1000 1005 Val Leu Glu Ser Glu Met He He Pro Lys Asn Leu Ala Gly Pro Val 1010 1015 1020 Ser Gin His Asn Tyr Arg Pro Gly Tyr His Thr Gin He Thr Gly Pro 1025 1030 1035 1040 Trp His Leu Gly Lys Leu Glu Met Asp Phe Asp Phe Cys Asp Gly Thr 1045 1050 1055 Thr Val Val Val Thr Glu Asp Cys Gly Asn Arg Gly Pro Ser Leu Arg 1060 1065 1070 Thr Thr Thr Ala Ser Gly Lys Leu He Thr Glu Trp Cys Cys Arg Ser 1075 1080 1085 Cys Thr Leu Pro Pro Leu Arg Tyr Arg Gly Glu Asp Gly Cys Trp Tyr 1090 1095 1100 Gly Met Glu He Arg Pro Leu Lys Glu Lys Glu Glu Asn Leu Val Asn 1105 1110 1115 1120 Ser Leu Val Thr Ala Gly His Gly Gin Val Asp Asn Phe Ser Leu Gly 1125 1130 1135 Val Leu Gly Met Ala Leu Phe Leu Glu Glu Met Leu Arg Thr Arg Val 1140 1145 1150 Gly Thr Lys His Ala He Leu Leu Val Ala Val Ser Phe Val Thr Leu 1155 1160 1165 He Thr Gly Asn Met Ser Phe Arg Asp Leu Gly Arg Val Met Val Met 1170 1175 1180 Val Gly Ala Thr Met Thr Asp Asp He Gly Met Gly Val Thr Tyr Leu 1185 1190 1195 1200 Ala Leu Leu Ala Ala Phe Lys Val Arg Pro Thr Phe Ala Ala Gly Leu 1205 1210 1215 Leu Leu Arg Lys Leu Thr Ser Lys Glu Leu Met Met Thr Thr He Gly 1220 1225 1230 He Val Leu Leu Ser Gin Ser Thr He Pro Glu Thr He Leu Glu Leu 1235 1240 1245 Thr Asp Ala Leu Ala Leu Gly Met Met Val Leu Lys Met Val Arg Asn 1250 1255 1260 Met Glu Lys Tyr Gin Leu Ala Val Thr He Met Ala He Leu Cys Val 1265 1270 1275 1280 Pro Asn Ala Val He Leu Gin Asn Ala Trp Lys Val Ser Cys Thr He 1285 1290 1295 Leu Ala Val Val Ser Val Ser Pro Leu Phe Leu Thr Ser Ser Gin Gin 1300 1305 1310 Lys Thr Asp Trp He Pro Leu Ala Leu Thr He Lys Gly Leu Asn Pro 1315 1320 1325 Thr Ala He Phe Leu Thr Thr Leu Ser Arg Thr Ser Lys Lys Arg Ser 1330 1335 1340 Trp Pro Leu Asn Glu Ala He Met Ala Val Gly Met Val Ser He Leu 1345 1350 1355 1360 Ala Ser Ser Leu Leu Lys Asn Asp lie Pro Met Thr Gly Pro Leu Val 1365 1370 1375

    118

    2018200081 04 Jan 2018

    Ala Gly Gly Leu Leu Thr Val Cys Tyr Val Leu Thr Gly Arg Ser Ala 1380 1385 1390 Asp Leu Glu Leu Glu Arg Ala Ala Asp Val Lys Trp Glu Asp Gin Ala 1395 1400 1405 Glu He Ser Gly Ser Ser Pro lie Leu Ser lie Thr lie Ser Glu Asp 1410 1415 1420 Gly Ser Met Ser He Lys Asn Glu Glu Glu Glu Gin Thr Leu Thr He 1425 1430 1435 1440 Leu He Arg Thr Gly Leu Leu Val He Ser Gly Leu Phe Pro Val Ser 1445 145C 1 1455 lie Pro He Thr Ala Ala Ala Trp Tyr Leu Trp Glu Val Lys Lys Gin 1460 1465 1470 Arg Ala Gly Val Leu Trp Asp Val Pro Ser Pro Pro Pro Met Gly Lys 1475 1480 1485 Ala Glu Leu Glu Asp Gly Ala Tyr Arg He Lys Gin Lys Gly He Leu 1490 1495 1500 Gly Tyr Ser Gin He Gly Ala Gly Val Tyr Lys Glu Gly Thr Phe His 1505 1510 1515 1520 Thr Met Trp His Val Thr Arg Gly Ala Val Leu Met His Lys Gly Lys 1525 153C 1 1535 Arg He Glu Pro Ser Trp Ala Asp Val Lys Lys Asp Leu He Ser Tyr 1540 1545 1550 Gly Gly Gly Trp Lys Leu Glu Gly Glu Trp Lys Glu Gly Glu Glu Val 1555 1560 1565 Gin Val Leu Ala Leu Glu Pro Gly Lys Asn Pro Arg Ala Val Gin Thr 1570 1575 1580 Lys Pro Gly Leu Phe Lys Thr Asn Ala Gly Thr He Gly Ala Val Ser 1585 1590 1595 1600 Leu Asp Phe Ser Pro Gly Thr Ser Gly Ser Pro He He Asp Lys Lys 1605 1610 1615 Gly Lys Val Val Gly Leu Tyr Gly Asn Gly Val Val Thr Arg Ser Gly 1620 1625 1630 Ala Tyr Val Ser Ala He Ala Gin Thr Glu Lys Ser He Glu Asp Asn 1635 1640 1645 Pro Glu He Glu Asp Asp He Phe Arg Lys Arg Arg Leu Thr He Met 1650 1655 1660 Asp Leu His Pro Gly Ala Gly Lys Thr Lys Arg Tyr Leu Pro Ala He 1665 1670 1675 1680 Val Arg Glu Ala He Lys Arg Gly Leu Arg Thr Leu He Leu Ala Pro 1685 1690 1695 Thr Arg Val Val Ala Ala Glu Met Glu Glu Ala Leu Arg Gly Leu Pro 1700 1705 1710 He Arg Tyr Gin Thr Pro Ala He Arg Ala Val His Thr Gly Arg Glu 1715 1720 1725 He Val Asp Leu Met Cys His Ala Thr Phe Thr Met Arg Leu Leu Ser 1730 1735 1740 Pro Val Arg Val Pro Asn Tyr Asn Leu He He Met Asp Glu Ala His 1745 1750 1755 1760 Phe Thr Asp Pro Ala Ser He Ala Ala Arg Gly Tyr He Ser Thr Arg 1765 1770 1775 Val Glu Met Gly Glu Ala Ala Gly He Phe Met Thr Ala Thr Pro Pro 1780 1785 1790 Gly Ser Arg Asp Pro Phe Pro Gin Ser Asn Ala Pro He He Asp Glu

    1795 1800 1805

    119

    2018200081 04 Jan 2018

    Glu Arg Glu lie 1810 Pro Glu Arg Ser Trp Asn Ser Gly His Glu Trp Val 1815 1820 Thr Asp Phe Lys Gly Lys Thr Val Trp Phe Val Pro Ser He Lys Ala 1825 1830 1835 1840 Gly Asn Asp He Ala Ala Cys Leu Arg Lys Asn Gly Lys Lys Val He 1845 1850 1855 Gin Leu Ser Arg Lys Thr Phe Asp Ser Glu Tyr Val Lys Thr Arg Thr 1860 1865 1870 Asn Asp Trp Asp Phe Val Val Thr Thr Asp He Ser Glu Met Gly Ala 1875 1880 1885 Asn Phe Lys Ala Glu Arg Val He Asp Pro Arg Arg Cys Met Lys Pro 1890 1895 1900 Val He Leu Thr Asp Gly Glu Glu Arg Val He Leu Ala Gly Pro Met 1905 1910 1915 1920 Pro Val Thr His Ser Ser Ala Ala Gin Arg Arg Gly Arg He Gly Arg 1925 1930 1935 Asn Pro Lys Asn Glu Asn Asp Gin Tyr He Tyr Met Gly Glu Pro Leu 1940 1945 1950 Glu Asn Asp Glu Asp Cys Ala His Trp Lys Glu Ala Lys Met Leu Leu 1955 • 1960 1965 Asp Asn He Asn Thr Pro Glu Gly He He Pro Ser Met Phe Glu Pro 1970 1975 1980 Glu Arg Glu Lys Val Asp Ala He Asp Gly Glu Tyr Arg Leu Arg Gly 1985 1990 1995 2000 Glu Ala Arg Lys Thr Phe Val Asp Leu Met Arg Arg Gly Asp Leu Pro 2005 2010 2015 Val Trp Leu Ala Tyr Arg Val Ala Ala Glu Gly He Asn Tyr Ala Asp 2020 2025 2030 Arg Arg Trp Cys Phe Asp Gly Val Lys Asn Asn Gin He Leu Glu Glu 2035 2040 2045 Asn Val Glu Val Glu He Trp Thr Lys Glu Gly Glu Arg Lys Lys Leu 2050 2055 2060 Lys Pro Arg Trp Leu Asp Ala Arg He Tyr Ser Asp Pro Leu Ala Leu 2065 2070 2075 2080 Lys Glu Phe Lys Glu Phe Ala Ala Gly Arg Lys Ser Leu Thr Leu Asn 2085 2090 2095 Leu He Thr Glu Met Gly Arg Leu Pro Thr Phe Met Thr Gin Lys Ala 2100 2105 2110 Arg Asp Ala Leu Asp Asn Leu Ala Val Leu His Thr Ala Glu Ala Gly 2115 2120 2125 Gly Arg Ala Tyr Asn His Ala Leu Ser Glu Leu Pro Glu Thr Leu Glu 2130 2135 2140 Thr Leu Leu Leu Leu Thr Leu Leu Ala Thr Val Thr Gly Gly He Phe 2145 2150 2155 2160 Leu Phe Leu Met Ser Ala Arg Gly He Gly Lys Met Thr Leu Gly Met 2165 2170 2175 Cys Cys He He Thr Ala Ser He Leu Leu Trp Tyr Ala Gin He Gin 2180 2185 2190 Pro His Trp He Ala Ala Ser He He Leu Glu Phe Phe Leu He Val 2195 2200 2205 Leu Leu He Pro Glu Pro Glu Lys Gin Arg Thr Pro Gin Asp Asn Gin 2210 2215 2220 Leu Thr Tyr Val Val He Ala He Leu Thr Val Val Ala Ala Thr Met 2225 2230 2235 2240

    120

    2018200081 04 Jan 2018

    Ala Asn Glu Met Gly Phe Leu Glu Lys 2245 Thr Lys 2250 Lys Asp Leu Gly Leu 2255 Gly Ser lie Ala Thr Gin Gin Pro Glu Ser Asn He Leu Asp He Asp 2260 i 2265 2270 Leu Arg Pro Ala Ser Ala Trp Thr Leu Tyr Ala Val Ala Thr Thr Phe 2275 2280 2285 Val Thr Pro Met Leu Arg His Ser He Glu Asn Ser Ser Val Asn Val 2290 2295 2300 Ser Leu Thr Ala He Ala Asn Gin Ala Thr Val Leu Met Gly Leu Gly 2305 2310 2315 2320 Lys Gly Trp Pro Leu Ser Lys Met Asp He Gly Val Pro Leu Leu Ala 2325 2330 2335 lie Gly Cys Tyr Ser Gin Val Asn Pro He Thr Leu Thr Ala Ala Leu 2340 i 2345 2350 Phe Leu Leu Val Ala His Tyr Ala He He Gly Pro Gly Leu Gin Ala 2355 2360 2365 Lys Ala Thr Arg Glu Ala Gin Lys Arg Ala Ala Ala Gly lie Met Lys 2370 2375 2380 Asn Pro Thr Val Asp Gly He Thr Val lie Asp Leu Asp Pro He Pro 2385 2390 2395 2400 Tyr Asp Pro Lys Phe Glu Lys Gin Leu Gly Gin Val Met Leu Leu Val 2405 2410 2415 Leu Cys Val Thr Gin Val Leu Met Met Arg Thr Thr Trp Ala Leu Cys 2420 i 2425 2430 Glu Ala Leu Thr Leu Ala Thr Gly Pro He Ser Thr Leu Trp Glu Gly 2435 2440 2445 Asn Pro Gly Arg Phe Trp Asn Thr Thr He Ala Val Ser Met Ala Asn 2450 2455 2460 He Phe Arg Gly Ser Tyr Leu Ala Gly Ala Gly Leu Leu Phe Ser He 2465 2470 2475 2480 Met Lys Asn Thr Thr Asn Thr Arg Arg Gly Thr Gly Asn He Gly Glu 2485 2490 2495 Thr Leu Gly Glu Lys Trp Lys Ser Arg Leu Asn Ala Leu Gly Lys Ser 250C I 2505 2510 Glu Phe Gin He Tyr Lys Lys Ser Gly He Gin Glu Val Asp Arg Thr 2515 2520 2525 Leu Ala Lys Glu Gly He Lys Arg Gly Glu Thr Asp His His Ala Val 2530 2535 2540 Ser Arg Gly Ser Ala Lys Leu Arg Trp Phe Val Glu Arg Asn Met Val 2545 2550 2555 2560 Thr Pro Glu Gly Lys Val Val Asp Leu Gly Cys Gly Arg Gly Gly Trp 2565 2570 2575 Ser Tyr Tyr Cys Gly Gly Leu Lys Asn Val Arg Glu Val Lys Gly Leu 2580 2585 2590 Thr Lys Gly Gly Pro Gly His Glu Glu Pro He Pro Met Ser Thr Tyr 2595 2600 2605 Gly Trp Asn Leu Val Arg Leu Gin Ser Gly Val Asp Val Phe Phe He 2610 2615 2620 Pro Pro Glu Lys Cys Asp Thr Leu Leu Cys Asp He Gly Glu Ser Ser 2625 2630 2635 2640 Pro Asn Pro Thr Val Glu Ala Gly Arg Thr Leu Arg Val Leu Asn Leu 2645 2650 2655 Val Glu Asn Trp Leu Asn Asn Asn Thr Gin Phe Cys He Lys Val Leu 2660 2665 2670

    121

    2018200081 04 Jan 2018

    Asn Pro Tyr Met 2675 Pro Ser Val He Glu Lys Met Glu Ala Leu Gin Arg 2680 2685 Lys Tyr Gly Gly Ala Leu Val Arg Asn Pro Leu Ser Arg Asn Ser Thr 2690 2695 i 2700 His Glu Met Tyr Trp Val Ser Asn Ala Ser Gly Asn He Val Ser Ser 2705 2710 2715 2720 Val Asn Met He Ser Arg Met Leu He Asn Arg Phe Thr Met Arg Tyr 2725 2730 2735 Lys Lys Ala Thr Tyr Glu Pro Asp Val Asp Leu Gly Ser Gly Thr Arg 2740 2745 2750 Asn lie Gly He Glu Ser Glu He Pro Asn Leu Asp He He Gly Lys 2755 2760 2765 Arg He Glu Lys He Lys Gin Glu His Glu Thr Ser Trp His Tyr Asp 2770 2775 ; 2780 Gin Asp His Pro Tyr Lys Thr Trp Ala Tyr His Gly Ser Tyr Glu Thr 2785 2790 2795 2800 Lys Gin Thr Gly Ser Ala Ser Ser Met Val Asn Gly Val Val Arg Leu 2805 2810 2815 Leu Thr Lys Pro Trp Asp Val Val Pro Met Val Thr Gin Met Ala Met 2820 2825 2830 Thr Asp Thr Thr Pro Phe Gly Gin Gin Arg Val Phe Lys Glu Lys Val 2835 2840 2845 Asp Thr Arg Thr Gin Glu Pro Lys Glu Gly Thr Lys Lys Leu Met Lys 2850 2855 i 2860 lie Thr Ala Glu Trp Leu Trp Lys Glu Leu Gly Lys Lys Lys Thr Pro 2865 2870 2875 2880 Arg Met Cys Thr Arg Glu Glu Phe Thr Arg Lys Val Arg Ser Asn Ala 2885 2890 2895 Ala Leu Gly Ala He Phe Thr Asp Glu Asn Lys Trp Lys Ser Ala Arg 2900 2905 2910 Glu Ala Val Glu Asp Ser Arg Phe Trp Glu Leu Val Asp Lys Glu Arg 2915 2920 2925 Asn Leu His Leu Glu Gly Lys Cys Glu Thr Cys Val Tyr Asn Met Met 2930 2935 i 2940 Gly Lys Arg Glu Lys Lys Leu Gly Glu Phe Gly Lys Ala Lys Gly Ser 2945 2950 2955 2960 Arg Ala He Trp Tyr Met Trp Leu Gly Ala Arg Phe Leu Glu Phe Glu 2965 2970 2975 Ala Leu Gly Phe Leu Asn Glu Asp His Trp Phe Ser Arg Glu Asn Ser 2980 2985 2990 Leu Ser Gly Val Glu Gly Glu Gly Leu His Lys Leu Gly Tyr He Leu 2995 3000 3005 Arg Asp Val Ser Lys Lys Glu Gly Gly Ala Met Tyr Ala Asp Asp Thr 3010 3015 3020 Ala Gly Trp Asp Thr Arg He Thr Leu Glu Asp Leu Lys Asn Glu Glu 3025 3030 3035 3040 Met Val Thr Asn His Met Glu Gly Glu His Lys Lys Leu Ala Glu Ala 3045 3050 3055 He Phe Lys Leu Thr Tyr Gin Asn Lys Val Val Arg Val Gin Arg Pro 3060 3065 3070 Thr Pro Arg Gly Thr Val Met Asp He He Ser Arg Arg Asp Gin Arg 3075 3080 3085 Gly Ser Gly Gin Val Gly Thr Tyr Gly Leu Asn Thr Phe Thr Asn Met

    3090 3095 3100

    122

    2018200081 04 Jan 2018

    Glu Ala Gin Leu He Arg Gin Met Glu Gly Glu Gly Val Phe Lys Ser 3105 3110 3115 3120 lie Gin His Leu Thr He Thr Glu Glu He Ala Val Gin Asn Trp Leu 3125 3130 3135 Ala Arg Val Gly Arg Glu Arg Leu Ser Arg Met Ala He Ser Gly Asp 3140 3145 3150 Asp Cys Val Val Lys Pro Leu Asp Asp Arg Phe Ala Ser Ala Leu Thr 3155 3160 3165 Ala Leu Asn Asp Met Gly Lys He Arg Lys Asp He Gin Gin Trp Glu 3170 3175 3180 Pro Ser Arg Gly Trp Asn Asp Trp Thr Gin Val Pro Phe Cys Ser His 3185 3190 3195 3200 His Phe His Glu Leu He Met Lys Asp Gly Arg Val Leu Val Val Pro 3205 3210 3215 Cys Arg Asn Gin Asp Glu Leu He Gly Arg Ala Arg He Ser Gin Gly 3220 3225 3230 Ala Gly Trp Ser Leu Arg Glu Thr Ala Cys Leu Gly Lys Ser Tyr Ala 3235 3240 3245 Gin Met Trp Ser Leu Met Tyr Phe His Arg Arg Asp Leu Arg Leu Ala 3250 3255 3260 Ala Asn Ala He Cys Ser Ala Val Pro Ser His Trp Val Pro Thr Ser 3265 3270 3275 3280 Arg Thr Thr Trp Ser He His Ala Lys His Glu Trp Met Thr Thr Glu 3285 3290 3295 Asp Met Leu Thr Val Trp Asn Arg Val Trp lie Gin Glu Asn Pro Trp 3300 3305 3310 Met Glu Asp Lys Thr Pro Val Glu Ser Trp Glu Glu He Pro Tyr Leu 3315 3320 3325 Gly Lys Arg Glu Asp Gin Trp Cys Gly Ser Leu He Gly Leu Thr Ser 3330 3335 3340 Arg Ala Thr Trp Ala Lys Asn He Gin Ala Ala He Asn Gin Val Arg 3345 3350 3355 3360 Ser Leu He Gly Asn Glu Glu Tyr Thr Asp Tyr Met Pro Ser Met Lys 3365 3370 3375 Arg Phe Arg Arg Glu Glu Glu Glu Ala Gly Val Leu Trp 3380 3385

    <210> 11 <211> 10723 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <221> CDS ' <222> (97)...(10272) <400> 11 agttgttagt ctacgtggac cgacaaagac agattctttg agggagctaa gctcaatgta

    SO ·

    123

    2018200081 04 Jan 2018 gttctaacag ttttttaatt agagagcaga tctctg atg aat aac caa cgg aaa 114

    Met Asn Asn Gin Arg Lys

    1 5

    aag Lys geg Ala aaa aac Lys Asn 10 acg Thr cct Pro ttc Phe aat Asn atg Met 15 ctg Leu aaa Lys ege Arg gag Glu aga Arg 20 aac Asn ege Arg 162 gtg teg act gtg caa cag ctg aca aag aga ttc tea ett gga atg ctg 210 Val Ser Thr Val Gin Gin Leu Thr Lys Arg Phe Ser Leu Gly Met Leu 25 30 35 cag gga ega gga cca tta aaa ctg ttc atg gcc ctg gtg geg ttc ett 258 Gin Gly Arg Gly Pro Leu Lys Leu Phe Met Ala Leu Val Ala Phe Leu 40 45 50 cgt ttc eta aca ate cca cca aca gca ggg ata ttg aag aga tgg gga 306 Arg Phe Leu Thr He Pro Pro Thr Ala Gly He Leu Lys Arg Trp Gly 55 60 65 70 aca att aaa aaa tea aaa get att aat gtt ttg aga ggg ttc agg aaa 354 Thr He Lys Lys Ser Lys Ala He Asn Val Leu Arg Gly Phe Arg Lys 75 80 85 gag att gga agg atg ctg aac ate ttg aat agg aga ege age tet gca 402 Glu He Gly Arg Met Leu Asn He Leu Asn Arg Arg Arg Ser Ser Ala 90 95 100 ggc atg ate att atg ctg att cca aca gtg atg geg ttc cat tta acc 450 Gly Met He He Met Leu He Pro Thr Val Met Ala Phe His Leu Thr 105 110 115 acg cgt gat ggc gaa ccc etc atg ata gtg gca aaa cat gaa agg ggg 498 Thr Arg Asp Gly Glu Pro Leu Met He Val Ala Lys His Glu Arg Gly 120 125 130 aga cct etc ttg ttt aag aca aca gag ggg ate aac aaa tgc act etc 546 Arg Pro Leu Leu Phe Lys Thr Thr Glu Gly He Asn Lys Cys Thr Leu 135 140 145 150 att gcc atg gac ttg ggt gaa atg tgt gag gac act gtc acg tat aaa 594 lie Ala Met Asp Leu Gly Glu Met Cys Glu Asp Thr Val Thr Tyr Lys 155 160 165 tgc ccc tta ctg gtc aat acc gaa cct gaa gac att gat tgc tgg tgc 642 Cys Pro Leu Leu Val Asn Thr Glu Pro Glu Asp He Asp Cys Trp Cys 170 175 180 aat etc acg tet acc tgg gtc atg tat ggg aca tgc acc cag age gga 690 Asn Leu Thr Ser Thr Trp Val Met Tyr Gly Thr Cys Thr Gin Ser Gly 185 190 195 gaa egg aga ega gag aag ege tea gta get tta aca cca cat tea gga 738 Glu Arg Arg Arg Glu Lys Arg Ser Val Ala Leu Thr Pro His Ser Gly 200 205 210

    124

    2018200081 04 Jan 2018

    atg gga Met Gly 215 ttg gaa aca Thr aga get gag aca tgg atg tea teg gaa ggg get 786 Leu Glu Arg Ala 220 Glu Thr Trp Met 225 Ser Ser Glu Gly Ala 230 tgg aag cat get cag aga gta gag age tgg ata etc aga aac cca gga 834 Trp Lys His Ala Gin Arg Val Glu Ser Trp lie Leu Arg Asn Pro Gly 235 240 245 ttc gcg etc ttg gca gga ttt atg get tat atg att ggg caa aca gga 882 Phe Ala Leu Leu Ala Gly Phe Met Ala Tyr Met He Gly Gin Thr Gly 250 255 260 ate cag ega act gtc ttc ttt gtc eta atg atg ctg gtc gcc cca tcc 930 lie Gin Arg Thr Val Phe Phe Val Leu Met Met Leu Val Ala Pro Ser 265 270 275 tac gga atg ega tgc gta gga gta gga aac aga gac ttt gtg gaa gga 978 Tyr Gly Met Arg Cys Val Gly Val Gly Asn Arg Asp Phe Val Glu Gly 280 285 290 gtc tea ggt gga gca tgg gtc gat ctg gtg eta gaa cat gga gga tgc 1026 Val Ser Gly Gly Ala Trp Val Asp Leu Val Leu Glu His Gly Gly Cys 295 300 305 310 gtc aca acc atg gee cag gga aaa cca acc ttg gat ttt gaa ctg act 1074 Val Thr Thr Met Ala Gin Gly Lys Pro Thr Leu Asp Phe Glu Leu Thr 315 320 325 aag aca aca gcc aag gaa gtg get ctg tta aga acc tat tgc att gaa 1122 Lys Thr Thr Ala Lys Glu Val Ala Leu Leu Arg Thr Tyr Cys He Glu 330 335 340 gcc tea ata tea aac ata acc aeg gca aca aga tgt cca aeg caa gga 1170 Ala Ser He Ser Asn He Thr Thr Ala Thr Arg Cys Pro Thr Gin Gly 345 350 355 gag cct tat eta aaa gag gaa caa gac caa cag tac att tgc egg aga 1218 Glu Pro Tyr Leu Lys Glu Glu Gin Asp Gin Gin Tyr He Cys Arg Arg 360 365 370 gat gtg gta gac aga ggg tgg ggc aat ggc tgt ggc ttg ttt gga aaa 1266 Asp Val Val Asp Arg Gly Trp Gly Asn Gly Cys Gly Leu Phe Gly Lys 375 380 385 390 gga gga gtt gtg aca tgt gcg aag ttt tea tgt teg ggg aag ata aca 1314 Gly Gly Val Val Thr Cys Ala Lys Phe Ser Cys Ser Gly Lys He Thr 395 400 405 ggc aat ttg gtc caa att gag aac ett gaa tac aca gtg gtt gta aca 1362 Gly Asn Leu Val Gin He Glu Asn Leu Glu Tyr Thr Val Val Val Thr 410 415 420

    125

    2018200081 04 Jan 2018

    gtc Val cac His aat gga gac acc Thr cat His gca Ala 430 gta gga aat gac aeg Thr 435 tcc Ser aat Asn cat His 1410 Asn 425 Gly Asp Val Gly Asn Asp gga gtt aca gcc aeg ata act ccc agg tea cca teg gtg gaa gtc aaa 1458 Gly Val Thr Ala Thr He Thr Pro Arg Ser Pro Ser Val Glu Val Lys 440 445 450 ttg ccg gac tat gga gaa eta aca etc gat tgt gaa ccc agg tet gga 1506 Leu Pro Asp Tyr Gly Glu Leu Thr Leu Asp Cys Glu Pro Arg Ser Gly 455 460 465 470 att gac ttt aat gag atg att ctg atg aaa atg aaa aag aaa aca tgg 1554 lie Asp Phe Asn Glu Met He Leu Met Lys Met Lys Lys Lys Thr Trp 475 480 485 ett gtg cat aag caa tgg ttt ttg gat eta cct eta cca tgg aca gca 1602 Leu Val His Lys Gin Trp Phe Leu Asp Leu Pro Leu Pro Trp Thr Ala 490 495 500 gga gca gac aca tea gag gtt cac tgg aat tac aaa gag aga atg gtg 1650 Gly Ala Asp Thr Ser Glu Val His Trp Asn Tyr Lys Glu Arg Met Val 505 510 515 aca ttt aag gtt cct cat gcc aag aga cag gat gtg aca gtg ctg gga 1698 Thr Phe Lys Val Pro His Ala Lys Arg Gin Asp Val Thr Val Leu Gly 520 525 530 tet cag gaa gga gcc atg cat tet gcc etc get gga gcc aca gaa gtg 1746 Ser Gin Glu Gly Ala Met His Ser Ala Leu Ala Gly Ala Thr Glu Val 535 540 545 550 gac tcc ggt gat gga aat cac atg ttt gca gga cat etc aag tgc aaa 1794 Asp Ser Gly Asp Gly Asn His Met Phe Ala Gly His Leu Lys Cys Lys 555 560 565 gtc cgt atg gag aaa ttg aga ate aag gga atg tea tac aeg atg tgt 1842 Val Arg Met Glu Lys Leu Arg He Lys Gly Met Ser Tyr Thr Met Cys 570 575 580 tea gga aag ttc tea att gac aaa gag atg gca gaa aca cag cat ggg 1890 Ser Gly Lys Phe Ser He Asp Lys Glu Met Ala Glu Thr Gin His Gly 585 590 595 aca aca gtg gtg aaa gtc aag tat gaa ggt get gga get ccg tgt aaa 1938 Thr Thr Val Val Lys Val Lys Tyr Glu Gly Ala Gly Ala Pro Cys Lys 600 605 610 gtc ccc ata gag ata aga gat gtg aac aag gaa aaa gtg gtt ggg cgt 1986 Val Pro He Glu He Arg Asp Val Asn Lys Glu Lys Val Val Gly Arg 615 620 625 630 ate ate tea tcc acc cct ttg get gag aat acc aac agt gta acc aac 2034 He He Ser Ser Thr Pro Leu Ala Glu Asn Thr Asn Ser Val Thr Asn

    635 640 645

    126

    2018200081 04 Jan 2018

    ata gag lie Glu tta Leu gaa ccc Glu Pro 650 ccc Pro ttt ggg gac agc tac ata gtg ata ggt Gly gtt Val 2082 Phe Gly Asp 655 Ser Tyr He Val He 660 gga aac agt gca tta aca etc cat tgg ttc agg aaa ggg agt tcc att 2130 Gly Asn Ser Ala Leu Thr Leu His Trp Phe Arg Lys Gly Ser Ser He 665 670 675 ggc aag atg ttt gag tcc aca tac aga ggt gca aaa ega atg gcc att 2178 Gly Lys Met Phe Glu Ser Thr Tyr Arg Gly Ala Lys Arg Met Ala He 680 685 690 eta ggt gaa aca get tgg gat ttt ggt tcc gtt ggt gga ctg ttc aca 2226 Leu Gly Glu Thr Ala Trp Asp Phe Gly Ser Val Gly Gly Leu Phe Thr 695 700 705 710 tea ttg gga aag get gtg cac cag gtt ttt gga agt gtg tat aca acc 2274 Ser Leu Gly Lys Ala Val His Gin Val Phe Gly Ser Val Tyr Thr Thr 715 720 725 ctg ttt gga gga gtc tea tgg atg att aga ate eta att ggg ttc eta 2322 Leu Phe Gly Gly Val Ser Trp Met He Arg He Leu He Gly Phe Leu 730 735 740 gtg ttg tgg att ggc aeg aac tea agg aac act tea atg get atg aeg 2370 Val Leu Trp lie Gly Thr Asn Ser Arg Asn Thr Ser Met Ala Met Thr 745 750 755 tgc ata get gcc ggc att gtg aca ctg tat ttg gga gtc atg gtg cag 2418 Cys He Ala Ala Gly lie Val Thr Leu Tyr Leu Gly Val Met Val Gin 760 765 770 gcc gat agt ggt tgc gtt gtg agc tgg aaa aac aaa gaa ctg aaa tgt 2466 Ala Asp Ser Gly Cys Val Val Ser Trp Lys Asn Lys Glu Leu Lys Cys 775 780 785 790 ggc agt ggg att ttc ate aca gac aac gtg cac aca tgg aca gaa • caa 2514 Gly Ser Gly He Phe He Thr Asp Asn Val His Thr Trp Thr Glu Gin 795 800 805 tac aag ttc caa cca gaa tcc cct tea aaa eta get tea get ate cag 2562 Tyr Lys Phe Gin Pro Glu Ser Pro Ser Lys Leu Ala Ser Ala lie Gin 810 815 820 aaa gcc cat gaa gag gac att tgt gga ate ege tea gta aca aga ctg 2610 Lys Ala His Glu Glu Asp He Cys Gly He Arg Ser Val Thr Arg Leu 825 830 835 gag aat ctg atg tgg aaa caa ata aca cca gaa ttg aat cac att eta 2658 Glu Asn Leu Met Trp Lys Gin He Thr Pro Glu Leu Asn His He Leu 840 845 850

    127

    2018200081 04 Jan 2018

    tea Ser 855 gaa aat Glu Asn gag Glu gtg Val aag Lys 860 tta Leu act Thr att He atg aca gga gac Asp ate He aaa Lys gga Gly 870 2706 Met Thr 865 Gly ate atg cag gca gga aaa ega tet ctg egg cct cag ccc act gag ctg 2754 He Met Gin Ala Gly 875 Lys Arg Ser Leu Arg 880 Pro Gin Pro Thr Glu 885 Leu aag tat tea tgg aaa aca tgg ggc aaa gca aaa atg etc tet aca gag 2802 Lys Tyr Ser Trp 890 Lys Thr Trp Gly Lys 895 Ala Lys Met Leu Ser 900 Thr Glu tet cat aac cag acc ttt etc att gat ggc ccc gaa aca gca gaa tgc 2850 Ser His Asn 905 Gin Thr Phe Leu He 910 Asp Gly Pro Glu Thr 915 Ala Glu Cys ccc aac aca aat aga get tgg aat teg ttg gaa gtt gaa gac tat ggc 2898 Pro Asn Thr 920 Asn Arg Ala Trp 925 Asn Ser Leu Glu Val 930 Glu Asp Tyr Gly ttt gga gta ttc acc acc aat ata tgg eta aaa ttg aaa gaa aaa cag 2946 Phe 935 Gly Val Phe Thr Thr 940 Asn He Trp Leu Lys 945 Leu Lys Glu Lys Gin 950 gat gta ttc tgc gac tea aaa etc atg tea gcg gcc ata aaa gac aac 2994 Asp Val Phe Cys Asp 955 Ser Lys Leu Met Ser 960 Ala Ala He Lys Asp 965 Asn aga gcc gtc cat gcc gat atg ggt tat tgg ata gaa agt gca etc aat 3042 Arg Ala Val His 970 Ala Asp Met Gly Tyr 975 Trp He Glu Ser Ala 980 Leu Asn gac aca tgg aag ata gag aaa gcc tet ttc att gaa gtt aaa aac tgc 3090 Asp Thr Trp Lys 985 He Glu Lys Ala Ser 990 Phe He Glu Val Lys 995 Asn Cys cac tgg cca aaa tea cac acc etc tgg age aat gga gtg eta gaa agt 3138 His Trp Pro 1000 Lys Ser His Thr Leu 1005 Trp Ser Asn Gly Val 1010 Leu Glu Ser gag atg ata att cca aag aat etc get gga cca gtg tet caa cac aac 3186 Glu Met He 1015 He Pro Lys Asn 1020 Leu Ala Gly Pro Val 1025 Ser Gin His Asn 1030 tat aga cca ggc tac cat aca caa ata aca gga cca tgg cat eta ggt 3234 Tyr Arg Pro Gly Tyr His 1035 Thr Gin He Thr Gly 1040 Pro Trp His Leu Gly 1045 aag ett gag atg gac ttt gat ttc tgt gat gga aca aca gtg gta gtg 3282 Lys Leu Glu Met Asp 1050 Phe Asp Phe Cys Asp 1055 Gly Thr Thr Val Val 1060 Val act gag gac tgc gga aat aga gga CCC tet ttg aga aca acc act gcc 3330 Thr Glu Asp Cys 1065 Gly Asn Arg Gly Pro 1070 Ser Leu Arg Thr Thr 1075 Thr Ala

    128

    2018200081 04 Jan 2018

    tct gga aaa Ser Gly Lys etc Leu ata aca gaa tgg tgc tgc Cys cga Arg tct tgc Ser Cys 1090 aca Thr tta Leu cca Pro 3378 lie Thr Glu Trp Cys 1085 1080 ccg eta aga tac aga ggt gag gat ggg tgc tgg tac ggg atg gaa ate 3426 Pro 1095 Leu Arg Tyr Arg Gly Glu Asp Gly 1100 Cys Trp 1105 Tyr Gly Met Glu He 1110 aga cca ttg aag gag aaa gaa gag aat ttg gtc aac tcc ttg gtc aca 3474 Arg Pro Leu Lys Glu Lys 1115 Glu Glu Asn Leu Val 1120 Asn Ser Leu Val 1125 Thr get gga cat ggg cag gtc gac aac ttt tea eta gga gtc ttg gga atg ’ 3522 Ala Gly His Gly Gin 1130 Val Asp Asn Phe 1135 Ser Leu Gly Val Leu Gly 1140 Met gca ttg ttc ctg gag gaa atg ett agg acc cga gta gga aeg aaa cat 3570 Ala Leu Phe 1145 Leu Glu Glu Met Leu Arg 1150 Thr Arg Val Gly Thr 1155 Lys His gca ata eta eta gtt gca gtt tct ttt gtg aca ttg ate aca ggg aac 3618 Ala lie Leu 1160 Leu Val Ala Val Ser Phe 1165 Val Thr Leu lie 1170 Thr Gly Asn atg tcc ttt aga gac ctg gga aga gtg atg gtt atg gta ggc gcc act 3666 Met 1175 Ser Phe Arg Asp Leu Gly Arg Val 1180 Met Val Met Val 1185 Gly Ala Thr 1190 atg aeg gat gac ata ggt atg ggc gtg act tat ett gcc eta eta gca 3714 Met Thr Asp Asp He Gly 1195 Met Gly Val Thr Tyr 1200 Leu Ala Leu Leu Ala 1205 gcc ttc aaa gtc aga cca act ttt gca get gga eta etc ttg aga aag 3762 Ala Phe Lys Val Arg 1210 Pro Thr Phe Ala Ala 1215 Gly Leu Leu Leu Arg 1220 •Lys ctg acc tcc aag gaa ttg atg atg act act ata gga att gta etc etc 3810 Leu Thr Ser Lys 1225 Glu Leu Met Met Thr 1230 Thr He Gly He Val 1235 Leu Leu tcc cag age acc ata cca gag acc att ett gag ttg act gat gcg tta 3858 Ser Gin Ser 1240 Thr He Pro Glu Thr He 1245 Leu Glu Leu Thr 1250 Asp Ala Leu gcc tta ggc atg atg gtc etc aaa atg gtg aga aat atg gaa aag tat 3906 Ala Leu Gly 1255 Met Met Val Leu Lys Met 1260 Val Arg Asn Met 1265 Glu Lys Tyr 1270 caa ttg gca gtg act ate atg get ate ttg tgc gtc cca aac gca gtg 3954 Gin Leu Ala Val Thr He 1275 Met Ala He Leu Cys 1280 Val Pro Asn Ala Val 1285

    129

    2018200081 04 Jan 2018

    ata lie tta Leu caa Gin aac gca Asn Ala 1290 tgg Trp aaa Lys gtg Val agt tgc Ser Cys 1295 aca Thr ata He ttg Leu gca gtg Ala Val 1300 gtg Val 4002 tcc gtt tcc cca ctg ttc tta aca tcc tea cag caa aaa aca gat tgg 4050 Ser Val Ser Pro Leu Phe Leu Thr Ser Ser Gin Gin Lys Thr Asp Trp 1305 1310 1315 ata cca tta gca ttg acg ate aaa ggt etc aat cca aca get att ttt 4098 He Pro Leu Ala Leu Thr He Lys Gly Leu Asn Pro Thr Ala He Phe 1320 1325 1330 eta aca acc etc tea aga acc age aag aaa agg age tgg cca tta aat 4146 Leu Thr Thr Leu Ser Arg Thr Ser Lys Lys Arg Ser Trp Pro Leu Asn 1335 1340 1345 1350 gag get ate atg gca gtc ggg atg gtg age att tta gcc agt tet etc 4194 Glu Ala He Met Ala Val Gly Met Val Ser He Leu Ala Ser Ser Leu 1355 1360 1365 eta aaa aat gat att ccc atg aca gga cca tta gtg get gga ggg etc 4242 Leu Lys Asn Asp He Pro Met Thr Gly Pro Leu Val Ala Gly Gly Leu 1370 1375 1380 etc act gtg tgc tac gtg etc act gga ega teg gcc gat ttg gaa ctg 4290 Leu Thr Val Cys Tyr Val Leu Thr Gly Arg Ser Ala Asp Leu Glu Leu 1385 1390 1395 gag aga gca gcc gat gtc aaa tgg gaa gac cag gca gag ata tea gga 4338 Glu Arg Ala Ala Asp Val Lys Trp Glu Asp Gin Ala Glu He Ser Gly 1400 1405 1410 age agt cca ate ctg tea ata aca ata tea gaa gat ggt age atg teg 4386 Ser Ser Pro He Leu Ser He Thr He Ser Glu Asp Gly Ser Met Ser 1415 1420 1425 1430 ata aaa aat gaa gag gaa gaa caa aca ctg acc ata etc att aga aca 4434 He Lys Asn Glu Glu Glu Glu Gin Thr Leu Thr He Leu He Arg Thr 1435 1440 1445 gga ttg ctg gtg ate tea gga ett ttt cct gta tea ata cca ate acg 4482 Gly Leu Leu Val He Ser Gly Leu Phe Pro Val Ser He Pro He Thr 1450 1455 1460 gca gca gca tgg tac ctg tgg gaa gtg aag aaa caa egg gcc gga gta 4530 Ala Ala Ala Trp Tyr Leu Trp Glu Val Lys Lys Gin Arg Ala Gly Val 1465 1470 1475 ttg tgg gat gtt cct tea ccc cca ccc atg gga aag get gaa ctg gaa 4578 Leu Trp Asp Val Pro Ser Pro Pro Pro Met Gly Lys Ala Glu Leu Glu 14 8 0 1485 1490 gat gga gcc tat aga att aag caa aaa ggg att Ctt gga tat tcc cag 4626 Asp Gly Ala Tyr Arg He Lys Gin Lys Gly He Leu Gly Tyr Ser Gin

    1495

    1500

    1505

    1510

    130

    2018200081 04 Jan 2018

    ate lie gga Gly gcc Ala gga Gly gtt tac Val Tyr 1515 aaa Lys gaa Glu gga Gly aca ttc Thr Phe 1520 cat His aca Thr atg Met tgg cat Trp His 1525 4674 gtc aca cgt ggc get gtt eta atg cat aaa gga aag agg att gaa cca 4722 Val Thr Arg Gly Ala Val 1530 Leu Met His 1535 Lys Gly Lys Arg He 1540 Glu Pro 1 tea tgg gcg gac gtc aag aaa gac eta ata tea tat gga gga ggc tgg 4770 Ser Trp Ala 1545 Asp Val Lys Lys Asp 155C Leu I He Ser Tyr Gly 1555 Gly Gly Trp aag tta gaa gga gaa tgg aag gaa gga gaa gaa gtc cag gta ttg gca 4818 Lys Leu Glu 1560 Gly Glu Trp Lys Glu 1565 Gly Glu Glu Val Gin 1570 Val Leu Ala ctg gag cct gga aaa aat cca aga gee gtc caa aeg aaa cct ggt ett 4866 Leu Glu 1575 Pro Gly Lys Asn Pro 1580 Arg Ala Val Gin Thr 1585 Lys Pro Gly Leu 1590 ttc aaa acc aac gcc gga aca ata ggt get gta tct ctg gac ttt tct 4914 Phe Lys Thr Asn Ala Gly 1595 Thr He Gly Ala Val 1600 Ser Leu Asp Phe Ser 1605 cct gga aeg tea gga tct cca att ate gac aaa aaa gga aaa gtt gtg 4962 Pro Gly Thr Ser Gly Ser 1610 Pro He He Asp Lys 1615 Lys Gly Lys 162C Val Val 1 ggt ett tat ggt aat ggt gtt gtt aca agg agt gga gca tat gtg agt 5010 Gly Leu Tyr Gly 1625 Asn Gly Val Val Thr 1630 Arg Ser Gly Ala Tyr 1635 Val Ser get ata gcc cag act gaa aaa agc att gaa gac aac cca gag ate gaa 5058 Ala He Ala 1640 Gin Thr Glu Lys Ser 1645 He Glu Asp Asn Pro 1650 Glu He Glu gat gac att ttc ega aag aga aga ctg acc ate atg gac etc cac cca 5106 Asp Asp 1655 He Phe Arg Lys Arg 1660 Arg Leu Thr He Met 1665 Asp Leu His Pro 1670 gga gcg gga aag aeg aag aga tac ett ccg gcc ata gtc aga gaa get 5154 Gly Ala Gly Lys Thr Lys 1675 Arg Tyr Leu Pro Ala 1680 He Val Arg Glu Ala 1685 ata aaa egg ggt ttg aga aca tta ate ttg gcc ccc act aga gtt gtg 5202 He Lys Arg Gly Leu Arg 1690 Thr Leu He Leu Ala 1695 Pro Thr Arg Val Val 1700 gca get gaa atg gag gaa gee ett aga gga ett cca ata aga tac cag 5250 Ala Ala Glu Met Glu Glu Ala Leu Arg Gly Leu Pro He Arg Tyr Gin

    1705 1710 1715

    2018200081 04 Jan 2018

    131 acc cca gcc ate aga get gtg cac acc ggg egg gag att gtg gac eta 5298 Thr Pro Ala He 1720 Arg Ala Val His Thr Gly Arg Glu He Val Asp Leu 1725 1730 atg tgt cat gcc aca ttt acc atg agg ctg eta tea cca gtt aga gtg 5346 Met Cys His Ala 1735 Thr Phe Thr Met Arg Leu Leu Ser Pro Val Arg Val 1740 1745 1750 cca aac tac aac ctg att ate atg gac gaa gcc cat ttc aca gac cca 5394 Pro Asn Tyr Asn Leu He He Met Asp Glu Ala His Phe Thr Asp Pro 1755 1760 1765 gca agt ata gca get aga gga tac ate tea act ega gtg gag atg ggt 5442 Ala Ser He Ala 177C Ala Arg Gly Tyr He Ser Thr Arg Val Glu Met Gly 1 1775 1780 gag gca get ggg att ttt atg aca gcc act ccc ccg gga age aga gac 5490 Glu Ala Ala Gly 1785 He Phe Met Thr Ala Thr Pro Pro Gly Ser Arg Asp 1790 1795 cca ttt cct cag age aat gca cca ate ata gat gaa gaa aga gaa ate 5538 Pro Phe Pro Gin 1800 Ser Asn Ala Pro He He Asp Glu Glu Arg Glu He 1805 1810 cct gaa ege teg tgg aat tcc gga cat gaa tgg gtc acg gat ttt aaa 5586 Pro Glu Arg Ser 1815 Trp Asn Ser Gly His Glu Trp Val Thr Asp Phe Lys 1820 1825 1830 ggg aag act gtt tgg ttc gtt cca agt ata aaa gca gga aat gat ata 5634 Gly Lys Thr Val Trp Phe Val Pro Ser He Lys Ala Gly Asn Asp He 1835 1840 1845 gca get tgc ctg agg aaa aat gga aag aaa gtg ata caa etc agt agg 5682 Ala Ala Cys Leu Arg Lys Asn Gly Lys Lys Val He Gin Leu Ser Arg 1850 1855 1860 aag acc ttt gat tet gag tat gtc aag act aga acc aat gat tgg gac 5730 Lys Thr Phe Asp 1865 Ser Glu Tyr Val Lys Thr Arg Thr Asn Asp Trp Asp 1870 '1875 ttc gtg gtt aca act gac att tea gaa atg ggt gcc aat ttc aag get 5778 Phe Val Val Thr 1880 Thr Asp He Ser Glu Met Gly Ala Asn Phe Lys Ala 1885 1890 gag agg gtt ata gac ccc aga ege tgc atg aaa cca gtc ata eta aca 5826 Glu Arg Val He 1895 Asp Pro Arg Arg Cys Met Lys Pro Val He Leu Thr 1900 1905 1910 gat ggt gaa gag egg gtg att ctg gca gga cct atg cca gtg acc cac 5874 Asp Gly Glu Glu Arg Val lie Leu Ala Gly Pro Met Pro Val Thr His

    1915 1920 1925 tet agt gca gca caa aga aga ggg aga ata gga aga aat cca aaa aat Ser Ser Ala Ala Gin Arg Arg Gly Arg lie Gly Arg Asn Pro Lys Asn

    1930 1935 1940

    5922

    132

    2018200081 04 Jan 2018

    gag Glu aat Asn gac cag tac ata He tac Tyr atg ggg gaa Met Gly Glu 1950 cct Pro ctg gaa aat Leu Glu Asn 1955 gat Asp gaa Glu 5970 Asp Gin 1945 Tyr gac tgt gca cac tgg aaa gaa get aaa atg etc eta gat aac ate aac 6018 Asp Cys 196C Ala His 1 Trp Lys Glu 1965 Ala Lys Met Leu Leu Asp Asn 1970 He Asn aeg cca gaa gga ate att cct age atg ttc gaa cca gag cgt gaa aag 6066 Thr Pro 1975 Glu Gly He He 198C Pro 1 Ser Met Phe Glu 1985 Pro Glu Arg Glu Lys 1990 gtg gat gcc att gat ggc gaa tac ege ttg aga gga gaa gca agg aaa 6114 Val Asp Ala He Asp Gly 1995 Glu Tyr Arg Leu Arg 2000 Gly Glu Ala Arg Lys 2005 acc ttt gta gac tta atg aga aga gga gac eta cca gtc tgg ttg gcc 6162 Thr Phe Val Asp Leu 2010 Met Arg Arg Gly Asp 2015 Leu Pro Val Trp Leu 2020 Ala tac aga gtg gca get gaa ggc ate aac tac gca gac aga agg tgg tgt 6210 Tyr Arg Val Ala 2025 Ala Glu Gly He Asn Tyr 2030 Ala Asp Arg Arg 2035 Trp Cys ttt gat gga gtc aag aac aac caa ate eta gaa gaa aac gtg gaa gtt 6258 Phe Asp Gly Val 2040 Lys Asn Asn Gin He Leu 2045 Glu Glu Asn Val 2050 Glu Val gaa ate tgg aca aaa gaa ggg gaa agg aag aaa ttg aaa ccc aga tgg 6306 Glu lie 2055 Trp Thr Lys Glu Gly 2060 Glu Arg Lys Lys Leu Lys Pro 2065 Arg Trp 2070 ttg gat get agg ate tat tet gac cca ctg geg eta aaa gaa ttt aag 6354 Leu Asp Ala Arg He Tyr 2075 Ser Asp Pro Leu Ala 2080 Leu Lys Glu Phe Lys 2085 gaa ttt gca gcc gga aga aag tet ctg acc ctg aac eta ate aca gaa 6402 Glu Phe Ala Ala Gly 2090 Arg Lys Ser Leu Thr 2095 Leu Asn Leu He Thr 2100 Glu atg ggt agg etc cca acc ttc atg act cag aag gca aga gac gca ctg 6450 Met Gly Arg Leu 2105 Pro Thr Phe Met Thr Gin 2110 Lys Ala Arg Asp 2115 Ala Leu gac aac tta gca gtg ctg cac aeg get gag gca ggt gga agg geg tac 6498 Asp Asn Leu Ala 2120 Val Leu His Thr Ala Glu 2125 Ala Gly Gly Arg 2130 Ala Tyr aac cat get etc agt gaa ctg ccg gag acc ctg gag aca ttg ctt tta 6546 Asn His 2135 Ala Leu Ser Glu Leu 2140 Pro Glu Thr Leu Glu Thr Leu 2145 Leu Leu 2150

    133

    2018200081 04 Jan 2018

    ctg aca Leu Thr ett Leu ctg get aca Leu Ala Thr 2155 gtc Val aeg gga ggg ate Gly He 2160 ttt Phe tta Leu ttc Phe ttg atg Leu Met 2165 6594 Thr Gly age gca agg ggc ata ggg aag atg acc ctg gga atg tgc tgc ata ate 6642 Ser Ala Arg Gly lie Gly 2170 Lys Met Thr Leu Gly 2175 Met Cys Cys 218C He He 1 aeg get age ate etc eta tgg tac gca caa ata cag cca cac tgg ata 6690 Thr Ala Ser 2185 He Leu Leu Trp Tyr Ala 2190 Gin He Gin Pro His 2195 Trp lie gca get tea ata ata ctg gag ttt ttt etc ata gtt ttg ett att cca 6738 Ala Ala Ser 2200 He He Leu Glu Phe 2205 Phe Leu He Val Leu 2210 Leu He Pro gaa cct gaa aaa cag aga aca ccc caa gac aac caa ctg acc tac gtt 6786 Glu Pro 2215 Glu Lys Gin Arg Thr 2220 Pro Gin Asp Asn Gin 2225 Leu Thr Tyr Val 2230 gtc ata gcc ate etc aca gtg gtg gcc gca acc atg gca aac gag atg 6834 Val lie Ala He Leu Thr 2235 Val Val Ala Ala Thr 2240 Met Ala Asn Glu Met 2245 ggt ttc eta gaa aaa aeg aag aaa gat etc gga ttg gga age att gca 6882 Gly Phe Leu Glu Lys Thr 2250 Lys Lys Asp Leu Gly 2255 Leu Gly Ser 226C lie Ala acc cag caa ccc gag age aac ate ctg gac ata gat eta cgt cct gca 6930 Thr Gin Gin 2265 Pro Glu Ser Asn He 227C Leu 1 Asp He Asp Leu 2275 Arg Pro Ala tea gca tgg aeg ctg tat gee gtg gcc aca aca ttt gtt aca cca atg 6978 Ser Ala Trp 2280 Thr Leu Tyr Ala Val 2285 Ala Thr Thr Phe Val 2290 Thr Pro Met ttg aga cat age att gaa aat tcc tea gtg aat gtg tcc eta aca get 7026 Leu Arg 2295 His Ser He Glu Asn 2300 Ser Ser Val Asn Val 2305 Ser Leu Thr Ala 2310 ata gcc aac caa gcc aca gtg tta atg ggt etc ggg aaa gga tgg cca 7074 He Ala Asn Gin Ala Thr 2315 Val Leu Met Gly Leu 2320 Gly Lys Gly Trp Pro 2325 ttg tea aag atg gac ate gga gtt ccc ett etc gcc att gga tgc tac 7122 Leu Ser Lys Met Asp He 2330 Gly Val Pro Leu Leu 2335 Ala He Gly 2340 Cys Tyr 1 tea caa gtc aac ccc ata act etc aca gca get ett ttc tta ttg gta 7170 Ser Gin Val 2345 Asn Pro He Thr Leu Thr 2350 Ala Ala Leu Phe 2355 Leu Leu Val gca cat tat gcc ate ata ggg cca gga etc caa gca aaa gca acc aga 7218 Ala His Tyr Ala He He Gly Pro Gly Leu Gin Ala Lys Ala Thr Arg

    2360 2365 2370

    134

    2018200081 04 Jan 2018

    gaa get Glu Ala 2375 cag aaa aga gca geg geg ggc ate He atg aaa aac cca Pro act Thr gtc Val 2390 7266 Gin Lys Arg Ala Ala 2380 Ala Gly Met Lys 2385 Asn gat gga ata aca gtg att gac eta gat cca ata cct tat gat cca aag 7314 Asp Gly He Thr Val He Asp 2395 Leu Asp Pro 2400 He Pro 1 Tyr Asp Pro 2405 Lys ttt gaa aag cag ttg gga caa gta atg etc eta gtc etc tgc gtg act 7362 Phe Glu Lys Gin Leu Gly Gin 2410 Val Met 2415 Leu Leu Val Leu Cys Val 2420 Thr caa gta ttg atg atg agg act aca tgg get ctg tgt gag get tta acc 7410 Gin Val Leu Met 2425 Met Arg Thr Thr Trp 2430 Ala Leu Cys Glu Ala 2435 Leu Thr tta get acc ggg ccc ate tcc aca ttg tgg gaa gga aat cca ggg agg 7458 Leu Ala Thr 2440 Gly Pro He Ser Thr 2445 Leu Trp Glu Gly Asn 2450 Pro Gly Arg ttt tgg aac act acc att geg gtg tea atg get aac att ttt aga ggg 7506 Phe Trp 2455 Asn Thr Thr lie Ala 2460 Val Ser Met Ala Asn 2465 He Phe Arg Gly 2470 agt tac ttg gcc gga get gga ett etc ttt tet att atg aag aac aca 7554 Ser Tyr Leu Ala Gly Ala Gly 2475 Leu Leu Phe 248C Ser He 1 Met Lys Asn 2485 Thr acc aac aca aga agg gga act ggc aac ata gga gag aeg ett gga gag 7602 Thr Asn Thr Arg Arg Gly Thr 2490 Gly Asn He 2495 Gly Glu Thr Leu Gly 2500 Glu aaa tgg aaa age ega ttg aac gca ttg gga aaa agt gaa ttc cag ate 7650 Lys Trp Lys Ser 2505 Arg Leu Asn Ala Leu 2510 Gly Lys Ser Glu Phe 2515 Gin He tac aag aaa agt gga ate cag gaa gtg gat aga acc tta gca aaa gaa 7698 Tyr Lys 252C Lys 1 Ser Gly lie Gin Glu 2525 Val Asp Arg Thr Leu 2530 Ala Lys Glu ggc att aaa aga gga gaa aeg gac cat cac get gtg teg ega ggc tea 7746 Gly lie 2535 Lys Arg Gly Glu Thr 2540 Asp His His Ala Val 2545 Ser Arg Gly Ser 2550 gca aaa ctg aga tgg ttc gtt gag aga aac atg gtc aca cca gaa ggg 7794 Ala Lys Leu Arg Trp Phe Val 2555 Glu Arg Asn Met Val 2560 Thr Pro Glu Gly 2565 aaa gta gtg gac etc ggt tgt ggc aga gga ggc tgg tea tac tat tgt 7842 Lys Val Val Asp Leu Gly Cys 2570 Gly Arg Gly Gly Trp 2575 Ser Tyr Tyr 2580 Cys

    135

    2018200081 04 Jan 2018

    gga Gly gga Gly eta aag Leu Lys 2585 aat Asn gta Val aga Arg gaa gtc Glu Val 2590 aaa Lys ggc Gly eta Leu aca aaa Thr Lys 2595 gga Gly gga Gly 7890 cca gga cac gaa gaa ccc ate ccc atg tea aca tat ggg tgg aat eta 7938 Pro Gly 260C His Glu 1 Glu Pro He 2605 Pro Met Ser Thr Tyr 261C Gly Trp 1 Asn Leu gtg cgt ett caa agt gga gtt gac gtt ttc ttc ate ccg cca gaa aag 7986 Val Arg 2615 Leu Gin Ser Gly 262C Val 1 Asp Val Phe Phe 2625 He Pro Pro Glu Lys 2630 tgt gac aca tta ttg tgt gac ata ggg gag tea tea cca aat ccc aca 8034 Cys Asp Thr Leu Leu 2635 Cys Asp He Gly Glu Ser 2640 Ser Pro Asn Pro Thr 2645 gtg gaa gca gga ega aca etc aga gtc ett aac tta gta gaa aat tgg 8082 Val Glu Ala Gly Arg 2650 Thr Leu Arg Val Leu 2655 Asn Leu Val Glu Asn 2660 Trp ttg aac aac aac act caa ttt tgc ata aag gtt etc aac cca tat atg 8130 Leu Asn Asn Asn 2665 Thr Gin Phe Cys He 2670 Lys Val Leu Asn Pro 2675 Tyr Met ccc tea gtc ata gaa aaa atg gaa gca eta caa agg aaa tat gga gga 8178 Pro Ser 268C Val He I Glu Lys Met Glu Ala 2685 Leu Gin Arg Lys Tyr 2690 Gly Gly gcc tta gtg agg aat cca etc tea ega aac tcc aca cat gag atg tac 8226 Ala Leu 2695 Val Arg Asn Pro Leu 2700 Ser Arg Asn Ser Thr 2705 His Glu Met Tyr 2710 tgg gta tcc aat get tcc ggg aac ata gtg tea tea gtg aac atg att 8274 Trp Val Ser Asn Ala Ser 2715 Gly Asn He Val Ser 2720 Ser Val Asn Met He 2725 tea agg atg ttg ate aac aga ttt aca atg aga tac aag aaa gcc act 8322 Ser Arg Met Leu He 2730 Asn Arg Phe Thr Met 2735 Arg Tyr Lys Lys Ala 2740 Thr tac gag ccg gat gtt gac etc gga age gga acc cgt aac ate ggg att 8370 Tyr Glu Pro Asp 2745 Val Asp Leu Gly Ser 2750 Gly Thr Arg Asn He 2755 Gly He gaa agt gag ata cca aac eta gat ata att ggg aaa aga ata gaa aaa 8418 Glu Ser Glu He 2760 Pro Asn Leu Asp He 2765 He Gly Lys Arg He 2770 Glu Lys ata aag caa gag cat gaa aca tea tgg cac tat gac caa gac cac cca 8466 lie Lys 2775 Gin Glu His Glu Thr 2780 Ser Trp His Tyr Asp 2785 Gin Asp His Pro 2790 tac aaa aeg tgg gca tac cat ggt age tat' gaa aca aaa cag act gga 8514 Tyr Lys Thr Trp Ala Tyr His Gly Ser Tyr Glu Thr Lys Gin Thr Gly

    2795 2800 2805

    136

    2018200081 04 Jan 2018

    tea Ser gca tea tcc atg gtc aac Asn gga gtg gtc agg ctg ctg aca aaa cct 8562 Ala Ser Ser Met 2810 Val Gly Val Val Arg Leu Leu Thr Lys Pro 2815 2820 tgg gac gtc gtc ccc atg gtg aca cag atg gca atg aca gac aeg act 8610 Trp Asp Val Val Pro 2825 Met Val Thr 283C Gin Met 1 Ala Met Thr Asp Thr 2835 Thr cca ttt gga caa cag cgc gtt ttt aaa gag aaa gtg gac aeg aga acc 8658 Pro Phe Gly Gin Gin 2840 Arg Val Phe 2845 Lys Glu Lys Val Asp Thr Arg 2850 Thr caa gaa ccg aaa gaa ggc aeg aag aaa eta atg aaa ata aca gca gag 8706 Gin Glu 2855 Pro Lys Glu Gly Thr 2860 Lys Lys Leu Met Lys lie Thr Ala 2865 Glu 2870 tgg ett tgg aaa gaa tta ggg aag aaa aag aca ccc agg atg tgc acc 8754 Trp Leu Trp Lys Glu Leu 2875 Gly Lys Lys Lys Thr Pro Arg Met Cys Thr 2880 2885 aga gaa gaa ttc aca aga aag gtg aga agc aat gca gcc ttg ggg gcc 8802 Arg Glu Glu Phe Thr 2890 Arg Lys Val Arg Ser 2895 Asn Ala Ala Leu Gly 2900 Ala ata ttc act gat gag aac aag tgg aag teg gca cgt gag get gtt gaa 8850 lie Phe Thr Asp Glu 2905 Asn Lys Trp Lys Ser 2910 Ala Arg Glu Ala Val 2915 Glu gat agt agg ttt tgg gag ctg gtt gac aag gaa agg aat etc cat ett 8898 Asp Ser 292C Arg Phe Trp 1 Glu Leu Val 2925 Asp Lys Glu Arg Asn Leu His 2930 Leu gaa gga aag tgt gaa aca tgt gtg tac aac atg atg gga aaa aga gag 8946 Glu Gly 2935 Lys Cys Glu Thr Cys 2940 Val Tyr Asn Met Met Gly Lys Arg 2945 Glu 2950 aag aag eta ggg gaa ttc ggc aag gca aaa ggc agc aga gcc ata tgg 8994 Lys Lys Leu Gly Glu Phe 2955 Gly Lys Ala Lys Gly Ser Arg Ala He Trp 2960 2965 tac atg tgg ett gga gca cgc ttc tta gag ttt gaa gcc eta gga ttc 9042 Tyr Met Trp Leu Gly 2970 Ala Arg Phe Leu Glu 2 975 Phe Glu Ala Leu Gly 2980 Phe tta aat gaa gat cac tgg ttc tcc aga gag aac tcc ctg agt gga gtg 9090 Leu Asn Glu Asp His 2985 Trp Phe Ser 299C Arg Glu 1 Asn Ser Leu Ser Gly 2995 Val gaa gga gaa ggg ctg cac aag eta ggt tac att eta aga gac gtg agc 9138 Glu Gly Glu Gly Leu 3000 His Lys Leu Gly Tyr 3005 He Leu Arg Asp Val 3010 Ser

    137

    2018200081 04 Jan 2018

    aag aaa Lys Lys 3015 gag Glu gga Gly gga Gly gca atg Ala Met 3020 tat Tyr gcc Ala gat Asp gac acc Asp Thr 3025 gca Ala gga Gly tgg Trp gat Asp 3030 9186 aca aga ate aca eta gaa gac eta aaa aat gaa gaa atg gta aca aac 9234 Thr Arg He Thr Leu 3035 Glu Asp Leu Lys Asn Glu Glu 3040 Met Val Thr 3045 Asn cac atg gaa gga gaa cac aag aaa eta gcc gag gcc att ttc aaa eta 9282 His Met Glu Gly Glu 3050 His Lys Lys Leu Ala 3055 Glu Ala He Phe Lys 3060 Leu aeg tac caa aac aag gtg gtg cgt gtg caa aga cca aca cca aga ggc 9330 Thr Tyr Gin Asn 3065 Lys Val Val Arg Val 3070 Gin Arg Pro Thr Pro 3075 Arg Gly aca gta atg gac ate ata teg aga aga gac caa aga ggt agt gga caa 9378 Thr Val Met 3080 Asp He lie Ser Arg 3085 Arg Asp Gin Arg Gly 3090 Ser Gly Gin gtt ggc acc tat gga etc aat act ttc acc aat atg gaa gee caa eta 9426 Val Gly 3095 Thr Tyr Gly Leu Asn 3100 Thr Phe Thr Asn Met 3105 Glu Ala Gin Leu 3110 ate aga cag atg gag gga gaa gga gtc ttt aaa age att cag cac eta 9474 lie Arg Gin Met Glu Gly Glu 3115 Gly Val Phe Lys Ser 3120 He Gin His Leu 3125 aca ate aca gaa gaa ate get gtg caa aac tgg tta gca aga gtg ggg 9522 Thr He Thr Glu 313C Glu 1 He Ala Val Gin Asn 3135 Trp Leu Ala Arg Val 3140 Gly ege gaa agg tta tea aga atg gcc ate agt gga gat gat tgt gtt gtg 9570 Arg Glu Arg Leu 3145 Ser Arg Met Ala He 3150 Ser Gly Asp Asp Cys 3155 Val Val aaa cct tta gat gac agg ttc gca age get tta aca get eta aat gac 9618 Lys Pro Leu 3160 Asp Asp Arg Phe Ala 3165 Ser Ala Leu Thr Ala 3170 Leu Asn Asp atg gga aag att agg aaa gac ata caa caa tgg gaa cct tea aga gga 9666 Met Gly 3175 Lys He Arg Lys Asp 3180 He Gin Gin Trp Glu 3185 Pro Ser Arg Gly 3190 tgg aat gat tgg aca caa gtg ccc ttc tgt tea cac cat ttc cat gag 9714 Trp Asn Asp Trp Thr Gin Val 3195 Pro Phe Cys Ser His 3200 His Phe His Glu 3205 tta ate atg aaa gac ggt ege gta etc gtt gtt cca tgt aga aac caa 9762 Leu lie Met Lys Asp 3210 Gly Arg Val Leu Val 3215 Val Pro Cys Arg Asn 3220 Gin gat gaa ctg att ggc aga gcc ega ate tcc caa gga gca ggg tgg tet 9810 Asp Glu Leu lie Gly Arg Ala Arg He Ser Gin Gly Ala Gly Trp Ser

    3225 3230 3235

    138

    2018200081 04 Jan 2018

    ttg Leu egg gag Arg Glu 3240 aeg Thr gcc Ala tgt Cys ttg ggg Leu Gly 3245 aag Lys tot Ser tac Tyr gcc caa Ala Gin 3250 atg Met tgg Trp age Ser 9858 ttg atg tac ttc cac aga ege gac etc agg ctg gcg gca aat get att 9906 Leu 3255 Met Tyr Phe His Arg 326C Arg Asp 1 Leu Arg Leu 3265 Ala Ala Asn Ala He 3270 tgc teg gca gta cca tea cat tgg gtt cca aca agt ega aca acc tgg 9954 Cys Ser Ala Val Pro 3275 Ser His Trp Val Pro 328C Thr 1 Ser Arg Thr Thr 3285 Trp tcc ata cat get aaa cat gaa tgg atg aca aeg gaa gac atg ctg aca 10002 Ser lie His Ala Lys 3290 His Glu Trp Met 3295 Thr Thr Glu Asp Met Leu 3300 Thr gtc tgg aac agg gtg tgg att caa gaa aac cca tgg atg gaa gac aaa 10050 Val Trp Asn 3305 Arg Val Trp He Gin Glu 3310 Asn Pro Trp Met Glu 3315 Asp Lys act cca gtg gaa tea tgg gag gaa ate cca tac ttg ggg aaa aga gaa 10098 Thr Pro Val 3320 Glu Ser Trp Glu Glu 3325 lie Pro Tyr Leu Gly 3330 Lys Arg Glu gac caa tgg tgc ggc tea ttg att ggg tta aca age agg gcc acc tgg 10146 Asp Gin Trp 3335 Cys Gly Ser Leu He 3340 Gly Leu Thr Ser Arg 3345 Ala Thr Trp 3350 gca aag aac ate caa gca gca ata aat caa gtt aga tcc ett ata ggc 10194 Ala Lys Asn He Gin Ala 3355 Ala He Asn Gin Val 3360 Arg Ser Leu He Gly 3365 aat gaa gaa tac aca gat tac atg cca tcc atg aaa aga ttc aga aga 10242 Asn Glu Glu Tyr Thr 3370 Asp Tyr Met Pro Ser 3375 Met Lys Arg Phe Arg 3380 Arg gaa Glu gag gaa gaa Glu Glu Glu 3385 gca Ala gga Gly gtt ctg tgg Val Leu Trp 3390 tag * aaagcaaaac taacatgaaa 10292

    caaggctaga agtcaggtcg gattaagcca tagtacggaa aaaactatgc tacctgtgag 10352 ccccgtccaa ggacgttaaa agaagtcagg ccatcataaa tgccatagct tgagtaaact 10412 atgcagcctg tagctccacc tgagaaggtg taaaaaatcc gggaggccac aaaccatgga 10472 agctgtacgc atggcgtagt ggactagcgg ttagaggaga cccctccctt acaaatcgca 10532 gcaacaatgg gggcccaagg cgagatgaag ctgtagtctc gctggaagga ctagaggtta 10592 gaggagaccc ccccgaaaca aaaaacagca tattgacgct gggaaagacc agagatcctg 10652 ctgtctcctc agcatcattc caggcacaga acgccagaaa atggaatggt gctgttgaat 10712 caacaggttc t 10723 <210> 12 <211> 3391 <212> PRT <213> Artificial Sequence

    2018200081 04 Jan 2018

    139 <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 12

    Met Asn Asn Gin Arg Lys Lys Ala Lys Asn Thr Pro Phe Asn Met Leu 1 5 10 15 Lys Arg Glu Arg Asn Arg Val Ser Thr Val Gin Gin Leu Thr Lys Arg 20 25 30 Phe Ser Leu Gly Met Leu Gin Gly Arg Gly Pro Leu Lys Leu Phe Met 35 40 45 Ala Leu Val Ala Phe Leu Arg Phe Leu Thr lie Pro Pro Thr Ala Gly 50 55 60 lie Leu Lys Arg Trp Gly Thr He Lys Lys Ser Lys Ala He Asn Val 65 70 75 80 Leu Arg Gly Phe Arg Lys Glu He Gly Arg Met Leu Asn He Leu Asn 85 90 95 Arg Arg Arg Ser Ser Ala Gly Met He lie Met Leu He Pro Thr Val 100 105 110 Met Ala Phe His Leu Thr Thr Arg Asp Gly Glu Pro Leu Met He Val 115 120 125 Ala Lys His Glu Arg Gly Arg Pro Leu Leu Phe Lys Thr Thr Glu Gly 130 135 140 He Asn Lys Cys Thr Leu lie Ala Met Asp Leu Gly Glu Met Cys Glu 145 150 155 160 Asp Thr Val Thr Tyr Lys Cys Pro Leu Leu Val Asn Thr Glu Pro Glu 165 170 175 Asp He Asp Cys Trp Cys Asn Leu Thr Ser Thr Trp Val Met Tyr Gly 180 185 190 Thr Cys Thr Gin Ser Gly Glu Arg Arg Arg Glu Lys Arg Ser Val Ala 195 200 205 Leu Thr Pro His Ser Gly Met Gly Leu Glu Thr Arg Ala Glu Thr Trp 210 215 220 Met Ser Ser Glu Gly Ala Trp Lys His Ala Gin Arg Val Glu Ser Trp 225 230 235 240 He Leu Arg Asn Pro Gly Phe Ala Leu Leu Ala Gly Phe Met Ala Tyr 245 250 255 Met He Gly Gin Thr Gly He Gin Arg Thr Val Phe Phe Val Leu Met 260 265 270 Met Leu Val Ala Pro Ser Tyr Gly Met Arg Cys Val Gly Val Gly Asn 275 280 285 Arg Asp Phe Val Glu Gly Val Ser Gly Gly Ala Trp Val Asp Leu Val 290 295 300 Leu Glu His Gly Gly Cys Val Thr Thr Met Ala Gin Gly Lys Pro Thr 305 310 315 320 Leu Asp Phe Glu Leu Thr Lys Thr Thr Ala Lys Glu Val Ala Leu Leu 325 330 335 Arg Thr Tyr Cys He Glu Ala Ser He Ser Asn lie Thr Thr Ala Thr 340 345 350 Arg Cys Pro Thr Gin Gly Glu Pro Tyr Leu Lys Glu Glu Gin Asp Gin 355 360 365 Gin Tyr He Cys Arg Arg Asp Val Val Asp Arg Gly Trp Gly Asn Gly 370 375 380

    140

    2018200081 04 Jan 2018

    Cys Gly Leu Phe Gly Lys Gly Gly Val Val Thr Cys Ala Lys Phe Ser 385 390 395 400 Cys Ser Gly Lys He Thr Gly Asn Leu Val Gin He Glu Asn Leu Glu 405 410 415 Tyr Thr Val Val Val Thr Val His Asn Gly Asp Thr His Ala Val Gly 420 ⁴²⁵ 430 Asn Asp Thr Ser Asn His Gly Val Thr Ala Thr He Thr Pro Arg Ser 435 440 445 Pro Ser Val Glu Val Lys Leu Pro Asp Tyr Gly Glu Leu Thr Leu Asp 450 455 460 Cys Glu Pro Arg Ser Gly He Asp Phe Asn Glu Met He Leu Met Lys 465 - 470 475 480 Met Lys Lys Lys Thr Trp Leu Val His Lys Gin Trp Phe Leu Asp Leu 485 490 495 Pro Leu Pro Trp Thr Ala Gly Ala Asp Thr Ser Glu Val His Trp Asn 500 505 510 Tyr Lys Glu Arg Met Val Thr Phe Lys Val Pro His Ala Lys Arg Gin 515 520 525 Asp Val Thr Val Leu Gly Ser Gin Glu Gly Ala Met His Ser Ala Leu 530 535 540 Ala Gly Ala Thr Glu Val Asp Ser Gly Asp Gly Asn His Met Phe Ala 545 550 555 560 Gly His Leu Lys Cys Lys Val Arg Met Glu Lys Leu Arg He Lys Gly 565 570 575 Met Ser Tyr Thr Met Cys Ser Gly Lys Phe Ser He Asp Lys Glu Met 580 585 590 Ala Glu Thr Gin His Gly Thr Thr Val Val Lys Val Lys Tyr Glu Gly 595 600 605 Ala Gly Ala Pro Cys Lys Val Pro He Glu He Arg Asp Val Asn Lys 610 615 620 Glu Lys Val Val Gly Arg He He Ser Ser Thr Pro Leu Ala Glu Asn 625 630 635 640 Thr Asn Ser Val Thr Asn He Glu Leu Glu Pro Pro Phe Gly Asp Ser 645 650 655 Tyr lie Val He Gly Val Gly Asn Ser Ala Leu Thr Leu His Trp Phe 660 665 670 Arg Lys Gly Ser Ser He Gly Lys Met Phe Glu Ser Thr Tyr Arg Gly 675 680 685 Ala Lys Arg Met Ala He Leu Gly Glu Thr Ala Trp Asp Phe Gly Ser 690 695 700 Val Gly Gly Leu Phe Thr Ser Leu Gly Lys Ala Val His Gin Val Phe 705 710 715 720 Gly Ser Val Tyr Thr Thr Leu Phe Gly Gly Val Ser Trp Met He Arg 725 730 735 lie Leu He Gly Phe Leu Val Leu Trp He Gly Thr Asn Ser Arg Asn 740 745 750 Thr Ser Met Ala Met Thr Cys He Ala Ala Gly lie Val Thr Leu Tyr 755 760 765 Leu Gly Val Met Val Gin Ala Asp Ser Gly Cys Val Val Ser Trp Lys 770 775 780 Asn Lys Glu Leu Lys Cys Gly Ser Gly He Phe He Thr Asp Asn Val 785 790 795 800 His Thr Trp Thr Glu Gin Tyr Lys Phe Gin Pro Glu Ser Pro Ser Lys 805 810 815

    141

    2018200081 04 Jan 2018

    Leu Ala Ser Ala 820 He Gin Lys Ala His 825 Glu Glu Asp He Cys 830 Gly He Arg Ser Val 835 Thr Arg Leu Glu Asn Leu 840 Met Trp Lys Gin 845 He Thr Pro Glu Leu 850 Asn His lie Leu Ser Glu Asn 855 Glu Val Lys 860 Leu Thr He Met Thr 865 Gly Asp He Lys Gly He Met Gin 870 Ala Gly Lys 875 Arg Ser Leu Arg 880 Pro Gin Pro Thr Glu Leu Lys Tyr Ser 885 Trp Lys Thr 890 Trp Gly Lys 895 Ala Lys Met Leu Ser 900 Thr Glu Ser His Asn 905 Gin Thr Phe Leu He 910 Asp Gly Pro Glu Thr 915 Ala Glu Cys Pro Asn Thr 920 Asn Arg Ala Trp 925 Asn Ser Leu Glu Val 930 Glu Asp Tyr Gly Phe Gly Val 935 Phe Thr Thr 940 Asn He Trp Leu Lys 945 Leu Lys Glu Lys Gin Asp Val Phe' 950 Cys Asp Ser 955 Lys Leu Met Ser 960 Ala Ala He Lys Asp Asn Arg Ala Val 965 His Ala Asp 970 Met Gly Tyr 975 Trp lie Glu Ser Ala 980 Leu Asn Asp Thr Trp 985 Lys He Glu Lys Ala 990 Ser Phe He Glu Val 995 Lys Asn Cys His Trp Pro 1000 Lys Ser His Thr Leu 1005 Trp Ser Asn Gly Val 1010 Leu Glu Ser Glu Met He 1015 He Pro Lys Asn 1020 Leu Ala Gly Pro Val 1025 Ser Gin His Asn Tyr Arg Pro 1030 Gly Tyr His 1035 Thr Gin He Thr 1040 Gly Pro Trp His Leu Gly Lys Leu Glu 1045 Met Asp Phe 1050 Asp Phe Cys Asp 1055 Gly Thr Thr Val Val Val Thr Glu Asp Cys Gly Asn 1060 1065 Arg Gly Pro 1070 Ser Leu Arg Thr Thr 1075 Thr Ala Ser Gly Lys 1080 Leu He Thr Glu Trp 1085 Cys Cys Arg Ser Cys 1090 Thr Leu Pro Pro Leu Arg 1095 Tyr Arg Gly Glu 1100 Asp Gly Cys Trp Tyr 1105 Gly Met Glu He Arg Pro Leu 1110 Lys Glu Lys 1115 Glu Glu Asn Leu 1120 Val Asn Ser Leu Val Thr Ala Gly His 1125 Gly Gin Val 1130 Asp Asn Phe Ser 1135 Leu Gly Val Leu Gly Met Ala Leu Phe Leu Glu Glu 1140 1145 Met Leu Arg 1150 Thr Arg Val Gly Thr 1155 Lys His Ala He Leu 1160 Leu Val Ala Val Ser 1165 Phe Val Thr Leu He 1170 Thr Gly Asn Met Ser Phe 1175 Arg Asp Leu Gly 1180 Arg Val Met Val Met 1185 Val Gly Ala Thr Met Thr Asp 1190 Asp He Gly 1195 Met Gly Val Thr 1200 Tyr Leu Ala Leu Leu Ala Ala Phe Lys 1205 Val Arg Pro 1210 Thr Phe Ala Ala 1215 Gly Leu Leu Leu Arg Lys Leu Thr Ser Lys Glu Leu 1220 1225 Met Met Thr 1230 Thr He Gly He Val Leu Leu Ser Gin Ser Thr He Pro Glu Thr He Leu

    1235 1240 1245

    142

    2018200081 04 Jan 2018

    Glu Leu Thr Asp Ala Leu Ala Leu Gly Met Met Val Leu Lys Met Val 1250 1255 1260 Arg Asn Met Glu Lys Tyr Gin Leu Ala Val Thr He Met Ala He Leu 1265 1270 1275 1280 Cys Val Pro Asn Ala Val He Leu Gin Asn Ala Trp Lys Val Ser Cys 1285 129C i 1295 Thr He Leu Ala Val Val Ser Val Ser Pro Leu Phe Leu Thr Ser Ser 1300 1305 1310 Gin Gin Lys Thr Asp Trp He Pro Leu Ala Leu Thr He Lys Gly Leu 131Ξ 1 1320 1325 Asn Pro Thr Ala He Phe Leu Thr Thr Leu Ser Arg Thr Ser Lys Lys 1330 1335 , 1340 Arg Ser Trp Pro Leu Asn Glu Ala He Met Ala Val Gly Met Val Ser 1345 1350 1355 1360 lie Leu Ala Ser Ser Leu Leu Lys Asn Asp He Pro Met Thr Gly Pro 1365 137C I 1375 Leu Val Ala Gly Gly Leu Leu Thr Val Cys Tyr Val Leu Thr Gly Arg 1380 1385 1390 Ser Ala Asp Leu Glu Leu Glu Arg Ala Ala Asp Val Lys Trp Glu Asp 1395 1400 1405 Gin Ala Glu He Ser Gly Ser Ser Pro He Leu Ser He Thr He Ser 1410 1415 1420 Glu Asp Gly Ser Met Ser He Lys Asn Glu Glu Glu Glu Gin Thr Leu 1425 1430 1435 1440 Thr lie Leu He Arg Thr Gly Leu Leu Val lie Ser Gly Leu Phe Pro 1445 1450 1455 Val Ser He Pro He Thr Ala Ala Ala Trp Tyr Leu Trp Glu Val Lys 1460 1465 1470 Lys Gin Arg Ala Gly Val Leu Trp Asp Val Pro Ser Pro Pro Pro Met 1475 1480 1485 Gly Lys Ala Glu Leu Glu Asp Gly Ala Tyr Arg He Lys Gin Lys Gly 1490 1495 1500 He Leu Gly Tyr Ser Gin He Gly Ala Gly Val Tyr Lys Glu Gly Thr 1505 1510 1515 1520 Phe His Thr Met Trp His Val Thr Arg Gly Ala Val Leu Met His Lys 1525 1530 1535 Gly Lys Arg lie Glu Pro Ser Trp Ala Asp Val Lys Lys Asp Leu He 1540 1545 1550 . Ser Tyr Gly Gly Gly Trp Lys Leu Glu Gly Glu Trp Lys Glu Gly Glu 1555 1560 1565 Glu Val Gin Val Leu Ala Leu Glu Pro Gly Lys Asn Pro Arg Ala Val 1570 1575 1580 Gin Thr Lys Pro Gly Leu Phe Lys Thr Asn Ala Gly Thr lie Gly Ala 1585 1590 1595 1600 Val Ser Leu Asp Phe Ser Pro Gly Thr Ser Gly Ser Pro lie He Asp 1605 1610 1615 Lys Lys Gly Lys Val Val Gly Leu Tyr Gly Asn Gly Val Val Thr Arg 1620 1625 1630 Ser Gly Ala Tyr Val Ser Ala He Ala Gin Thr Glu Lys Ser He Glu 1635 1640 1645 Asp Asn Pro Glu He Glu Asp Asp He Phe Arg Lys Arg Arg Leu Thr 1650 1655 1660 He Met Asp Leu His Pro Gly Ala Gly Lys Thr Lys Arg Tyr Leu Pro 1665 1670 1675 1680

    143

    2018200081 04 Jan 2018

    Ala He Val Arg Glu Ala He Lys Arg Gly Leu Arg Thr Leu He Leu 1695 1685 1690 Ala Pro Thr Arg Val Val Ala Ala Glu Met Glu Glu Ala Leu Arg Gly 1700 1705 1710 Leu Pro He Arg Tyr Gin Thr Pro Ala He Arg Ala Val His Thr Gly 1715 1720 1725 Arg Glu lie Val Asp Leu Met Cys His Ala Thr Phe Thr Met Arg Leu 1730 1735 1740 Leu Ser Pro Val Arg Val Pro Asn Tyr Asn Leu He He Met Asp Glu 1745 i 1750 1755 1760 Ala His Phe Thr Asp Pro Ala Ser He Ala Ala Arg Gly Tyr He Ser 1765 1770 1775 Thr Arg Val Glu Met Gly Glu Ala Ala Gly He Phe Met Thr Ala Thr 1780 1785 1790 Pro Pro Gly Ser Arg Asp Pro Phe Pro Gin Ser Asn Ala Pro lie He 1795 1800 1805 Asp Glu Glu Arg Glu He Pro Glu Arg Ser Trp Asn Ser Gly His Glu 1810 1815 1820 Trp Val Thr Asp Phe Lys Gly Lys Thr Val Trp Phe Val Pro Ser He 182E ; 1830 1835 1840 Lys Ala Gly Asn Asp He Ala Ala Cys Leu Arg Lys Asn Gly Lys Lys 1845 1850 1855 Val He Gin Leu Ser Arg Lys Thr Phe Asp Ser Glu Tyr Val Lys Thr 1860 1865 1870 Arg Thr Asn Asp Trp Asp Phe Val Val Thr Thr Asp He Ser Glu Met 1875 1880 1885 Gly Ala Asn Phe Lys Ala Glu Arg Val He Asp Pro Arg Arg Cys Met 1890 1895 ' 1900 Lys Pro Val lie Leu Thr Asp Gly Glu Glu Arg Val lie Leu Ala Gly 1905 ί 1910 1915 1920 Pro Met Pro Val Thr His Ser Ser Ala Ala Gin Arg Arg Gly Arg He 1925 1930 1935 Gly Arg Asn Pro Lys Asn Glu Asn Asp Gin Tyr He Tyr Met Gly Glu 1940 1945 1950 Pro Leu Glu Asn Asp Glu Asp Cys Ala His Trp Lys Glu Ala Lys Met 1955 1960 1965 Leu Leu Asp Asn He Asn Thr Pro Glu Gly lie lie Pro Ser Met Phe 1970 1975 1980 Glu Pro Glu Arg Glu Lys Val Asp Ala He Asp Gly Glu Tyr Arg Leu 1985 1990 1995 2000 Arg Gly Glu Ala Arg Lys Thr Phe Val Asp Leu Met Arg Arg Gly Asp 2005 2010 2015 Leu Pro Val Trp Leu Ala Tyr Arg Val Ala Ala Glu Gly He Asn Tyr 2020 2025 2030 Ala Asp Arg Arg Trp Cys Phe Asp Gly Val Lys Asn Asn Gin He Leu 2035 2040 2045 Glu Glu Asn Val Glu Val Glu He Trp Thr Lys Glu Gly Glu Arg Lys 2050 2055 2060 Lys Leu Lys Pro Arg Trp Leu Asp Ala Arg lie Tyr Ser Asp Pro Leu 2065 2070 2075 2080 Ala Leu Lys Glu Phe Lys Glu Phe Ala Ala Gly Arg Lys Ser Leu Thr 2085 2090 2095 Leu Asn Leu He Thr Glu Met Gly Arg Leu Pro Thr Phe Met Thr Gin 2100 2105 2110

    144

    2018200081 04 Jan 2018

    Lys Ala Arg Asp Ala Leu Asp Asn Leu Ala Val Leu His Thr Ala Glu 2115 2120 2125 Ala Gly Gly Arg Ala Tyr Asn His Ala Leu Ser Glu Leu Pro Glu Thr 2130 2135 2140 Leu Glu Thr Leu Leu Leu Leu Thr Leu Leu Ala Thr Val Thr Gly Gly 2145 2150 2155 2160 lie Phe Leu Phe Leu Met Ser Ala Arg Gly He Gly Lys Met Thr Leu 2165 2170 2175 Gly Met Cys Cys He He Thr Ala Ser He Leu Leu Trp Tyr Ala Gin 2180 2185 2190 He Gin Pro His Trp lie Ala Ala Ser He He Leu Glu Phe Phe Leu 2195 ' 2200 2205 He Val Leu Leu He Pro Glu Pro Glu Lys Gin Arg Thr Pro Gin Asp 2210 2215 2220 Asn Gin Leu Thr Tyr Val Val He Ala He Leu Thr Val Val Ala Ala 2225 2230 2235 2240 Thr Met Ala Asn Glu Met Gly Phe Leu Glu Lys Thr Lys Lys Asp Leu 2245 2250 2255 Gly Leu Gly Ser He Ala Thr Gin Gin Pro Glu Ser Asn He Leu Asp 2260 2265 2270 He Asp Leu Arg Pro Ala Ser Ala Trp Thr Leu Tyr Ala Val Ala Thr 2275 2280 2285 Thr Phe Val Thr Pro Met Leu Arg His Ser He Glu Asn Ser Ser Val 2290 2295 2300 Asn Val Ser Leu Thr Ala He Ala Asn Gin Ala Thr Val Leu Met Gly 2305 2310 2315 2320 Leu Gly Lys Gly Trp Pro Leu Ser Lys Met Asp He Gly Val Pro Leu 2325 2330 2335 Leu Ala He Gly cys Tyr Ser Gin Val Asn Pro He Thr Leu Thr Ala 2340 2345 2350 Ala Leu Phe Leu Leu Val Ala His Tyr Ala lie He Gly Pro Gly Leu 2355 2360 2365 Gin Ala Lys Ala Thr Arg Glu Ala Gin Lys Arg Ala Ala Ala Gly He 2370 2375 2380 Met Lys Asn Pro Thr Val Asp Gly He Thr Val He Asp Leu Asp Pro 2385 2390 2395 2400 He Pro Tyr Asp Pro Lys Phe Glu Lys Gin Leu Gly Gin Val Met Leu 2405 2410 2415 Leu Val Leu Cys Val Thr Gin Val Leu Met Met Arg Thr Thr Trp Ala 2420 2425 2430 Leu Cys Glu Ala Leu Thr Leu Ala Thr Gly Pro He Ser Thr Leu Trp 2435 2440 2445 Glu Gly Asn Pro Gly Arg Phe Trp Asn Thr Thr He Ala Val Ser Met 2450 2455 2460 Ala Asn He Phe Arg Gly Ser Tyr Leu Ala Gly Ala Gly Leu Leu Phe 2465 2470 2475 2480 Ser He Met Lys Asn Thr Thr Asn Thr Arg Arg Gly Thr Gly Asn He 2485 2490 2495 Gly Glu Thr Leu Gly Glu Lys Trp Lys Ser Arg Leu Asn Ala Leu Gly 2500 2505 2510 Lys Ser Glu Phe Gin He Tyr Lys Lys Ser Gly He Gin Glu Val Asp 2515 2520 2525 Arg Thr Leu Ala Lys Glu Gly He Lys Arg Gly Glu Thr Asp His His 2530 2535 2540

    145

    2018200081 04 Jan 2018

    Ala Val Ser Arg Gly Ser Ala Lys Leu Arg Trp Phe Val Glu Arg Asn 2545 2550 2555 1 2560 Met Val Thr Pro Glu Gly Lys Val Val Asp Leu Gly Cys Gly Arg Gly 2565 2570 2575 Gly Trp Ser Tyr Tyr Cys Gly Gly Leu Lys Asn Val Arg Glu Val Lys 258C ι 2585 2590 Gly Leu Thr Lys Gly Gly Pro Gly His Glu Glu Pro He Pro Met Ser 2595 2600 2605 Thr Tyr Gly Trp Asn Leu Val Arg Leu Gin Ser Gly Val Asp Val Phe 2610 2615 2620 Phe lie Pro Pro Glu Lys Cys Asp Thr Leu Leu Cys Asp He Gly Glu 2625 2630 2635 l 2640 Ser Ser Pro Asn Pro Thr Val Glu Ala Gly Arg Thr Leu Arg Val Leu 2645 2650 2655 Asn Leu Val Glu Asn Trp Leu Asn Asn Asn Thr Gin Phe Cys He Lys 266C 1 2665 2670 Val Leu Asn Pro Tyr Met Pro Ser Val He Glu Lys Met Glu Ala Leu 2675 2680 2685 Gin Arg Lys Tyr Gly Gly Ala Leu Val Arg Asn Pro Leu Ser Arg Asn 2690 2695 2700 Ser Thr His Glu Met Tyr Trp Val Ser Asn Ala Ser Gly Asn He Val 2705 2710 2715 2720 Ser Ser Val Asn Met He Ser Arg Met Leu He Asn Arg Phe Thr Met 2725 2730 2735 Arg Tyr Lys Lys Ala Thr Tyr Glu Pro Asp Val Asp Leu Gly Ser Gly 2740 2745 2750 Thr Arg Asn lie Gly He Glu Ser Glu He Pro Asn Leu Asp He He 2755 2760 2765 Gly Lys Arg He Glu Lys He Lys Gin Glu His Glu Thr Ser Trp His 2770 2775 2780 Tyr Asp Gin Asp His Pro Tyr Lys Thr Trp Ala Tyr His Gly Ser Tyr 2785 2790 2795 2800 Glu Thr Lys Gin Thr Gly Ser Ala Ser Ser Met Val Asn Gly Val Val 2805 2810 2815 Arg Leu Leu Thr Lys Pro Trp Asp Val Val Pro Met Val Thr Gin Met 2820 2825 2830 Ala Met Thr Asp Thr Thr Pro Phe Gly Gin Gin Arg Val Phe Lys Glu 2835 2840 2845 Lys Val Asp Thr Arg Thr Gin Glu Pro Lys Glu Gly Thr Lys Lys Leu 2850 2855 2860 Met Lys He Thr Ala Glu Trp Leu Trp Lys Glu Leu Gly Lys Lys Lys 2865 2870 2875 2880 Thr Pro Arg Met Cys Thr Arg Glu Glu Phe Thr Arg Lys Val Arg Ser 2885 2890 2895 Asn Ala Ala Leu Gly Ala He Phe Thr Asp Glu Asn Lys Trp Lys Ser 2900 2905 2910 Ala Arg Glu Ala Val Glu Asp Ser Arg Phe Trp Glu Leu Val Asp Lys 2915 2920 2925 Glu Arg Asn Leu His Leu Glu Gly Lys Cys Glu Thr Cys Val Tyr Asn 2930 2935 2940 Met Met Gly Lys Arg Glu Lys Lys Leu Gly Glu Phe Gly Lys Ala Lys 2945 2950 2955 2960 Gly Ser Arg Ala He Trp Tyr Met Trp Leu Gly Ala Arg Phe Leu Glu

    2965 2970 2975

    146

    2018200081 04 Jan 2018

    Phe Glu Ala Leu Gly Phe Leu Asn Glu Asp His Trp Phe Ser Arg 2990 Glu 2980 2985 Asn Ser Leu Ser Gly Val Glu Gly Glu Gly Leu His Lys Leu Gly Tyr 2995 3000 3005 lie Leu Arg Asp Val Ser Lys Lys Glu Gly Gly Ala Met Tyr Ala Asp 3010 3015 3020 Asp Thr Ala Gly Trp Asp Thr Arg lie Thr Leu Glu Asp Leu Lys Asn 3025 3030 3035 3040 Glu Glu Met Val Thr Asn His Met Glu Gly Glu His Lys Lys Leu Ala 3045 3050 3055 Glu Ala He Phe Lys Leu Thr Tyr Gin Asn Lys Val Val Arg Val Gin 3060 3065 3070 Arg Pro Thr Pro Arg Gly Thr Val Met Asp He He Ser Arg Arg Asp 3075 3080 3085 Gin Arg Gly Ser Gly Gin Val Gly Thr Tyr Gly Leu Asn Thr Phe Thr 3090 3095 3100 Asn Met Glu Ala Gin Leu He Arg Gin Met Glu Gly Glu Gly Val Phe 3105 3110 3115 3120 Lys Ser He Gin His Leu Thr He Thr Glu Glu He Ala Val Gin Asn 3125 3130 3135 Trp Leu Ala Arg Val Gly Arg Glu Arg Leu Ser Arg Met Ala lie Ser 3140 3145 3150 Gly Asp Asp Cys Val Val Lys Pro Leu Asp Asp Arg Phe Ala Ser Ala 3155 3160 3165 Leu Thr Ala Leu Asn Asp Met Gly Lys He Arg Lys Asp He Gin Gin 3170 3175 3180 Trp Glu Pro Ser Arg Gly Trp Asn Asp Trp Thr Gin Val Pro Phe Cys 3185 3190 3195 3200 Ser His His Phe His Glu Leu He Met Lys Asp Gly Arg Val Leu Val 3205 3210 3215 Val Pro Cys Arg Asn Gin Asp Glu Leu He Gly Arg Ala Arg He Ser 3220 3225 3230 Gin Gly Ala Gly Trp Ser Leu Arg Glu Thr Ala Cys Leu Gly Lys Ser 3235 3240 3245 Tyr Ala Gin Met Trp Ser Leu Met Tyr Phe His Arg Arg Asp Leu Arg 3250 3255 3260 Leu Ala Ala Asn Ala He Cys Ser Ala Val Pro Ser His Trp Val Pro 3265 3270 3275 3280 Thr Ser Arg Thr Thr Trp Ser He His Ala Lys His Glu Trp Met Thr 3285 3290 3295 Thr Glu Asp Met Leu Thr Val Trp Asn Arg Val Trp lie Gin Glu Asn 3300 3305 3310 Pro Trp Met Glu Asp Lys Thr Pro Val Glu Ser Trp Glu Glu He Pro 3315 3320 3325 Tyr Leu Gly Lys Arg Glu Asp Gin Trp Cys Gly Ser Leu lie Gly Leu 3330 3335 3340 Thr Ser Arg Ala Thr Trp Ala Lys Asn He Gin Ala Ala He Asn Gin 3345 3350 3355 3360 Val Arg Ser Leu lie Gly Asn Glu Glu Tyr Thr Asp Tyr Met Pro Ser 3365 3370 3375 Met Lys Arg Phe Arg Arg Glu Glu Glu Glu Ala Gly Val Leu Trp 3380 3385 3390

    <210> 13 <211> 10723

    147

    2018200081 04 Jan 2018 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <221> CDS <222> (97)...(10272) <400> 13 agttgttagt ctacgtggac cgacaaagac agattctttg agggagctaa gctcaacgta 60 gttctaacag ttttttaatt agagagcaga tctctg atg aat aac caa cgg aaa 114

    Met Asn Asn Gin Arg Lys 1 5

    aag gcg aaa Lys aac Asn 10 aeg Thr cct Pro ttc Phe aat Asn atg Met 15 ctg Leu aaa Lys ege gag aga aac Asn ege Arg 162 Lys Ala Arg Glu Arg 20 gtg teg act gtg caa cag ctg aca aag aga ttc tea ett gga atg ctg 210 Val Ser Thr 25 Val Gin Gin Leu Thr 30 Lys Arg Phe Ser Leu 35 Gly Met Leu cag gga cga gga cca tta aaa ctg ttc atg gcc ctg gtg gcg ttc ett 258 Gin Gly 40 Arg Gly Pro Leu Lys 45 Leu Phe Met Ala Leu 50 Val Ala Phe Leu cgt ttc eta aca ate cca cca aca gca ggg ata ttg aag aga tgg gga 306 Arg 55 Phe Leu Thr He Pro 60 Pro Thr Ala Gly He 65 Leu Lys Arg Trp Gly 70 aca att aaa aaa tea aaa get att aat gtt ttg aga ggg ttc agg aaa 354 Thr lie Lys Lys Ser 75 Lys Ala He Asn Val 80 Leu Arg Gly Phe Arg 85 Lys gag att gga agg atg ctg aac ate ttg aat agg aga ege aga tct gca 402 Glu He Gly Arg 90 Met Leu Asn lie Leu 95 Asn Arg Arg Arg Arg 100 Ser Ala ggc atg ate att atg ctg att cca aca gtg atg gcg ttc cat tta acc 450 Gly Met He 105 He Met Leu He Pro 110 Thr Val Met Ala Phe 115 His Leu Thr aca cgt aac gga gaa cca cac atg ate gtc age aga caa gag aaa ggg 498 Thr Arg 120 Asn Gly Glu Pro His 125 Met He Val Ser Arg 130 Gin Glu Lys Gly aaa agt ett ctg ttt aaa aca gag gat ggc gtg aac atg tgt acc etc 546 Lys 135 Ser Leu Leu Phe Lys 140 Thr Glu Asp Gly Val 145 Asn Met Cys Thr Leu 150

    148

    2018200081 04 Jan 2018

    atg gcc atg gac ett ggt Met Ala Met Asp Leu 155 Gly tgt ccc ett etc agg cag Cys Pro Leu Leu 170 Arg Gin aac tet aeg tcc aeg tgg Asn Ser Thr 185 Ser Thr Trp gaa cat aga aga gaa aaa Glu His 200 Arg Arg Glu Lys atg gga ctg gag aca ega Met 215 Gly Leu Glu Thr Arg 220 tgg aaa cat gtc cag aga Trp Lys His Val Gin 235 Arg ttc acc atg atg gca gca Phe Thr Met Met 250 Ala Ala ttc caa aga gcc ctg att Phe Gin Arg 265 Ala Leu He atg aca atg cgt tgc ata Met Thr 280 Met Arg Cys lie gtt tea gga gga age tgg Val 295 Ser Gly Gly Ser Trp 300 gtg aeg aeg atg gca aaa Val Thr Thr Met Ala 315 Lys aaa aca gaa gcc aaa cag Lys Thr Glu Ala 330 Lys Gin gca aag eta acc aac aca Ala Lys Leu 345 Thr Asn Thr gaa ccc agc eta aat gaa Glu Pro Ser Leu Asn Glu

    360

    gaa ttg tgt gaa gac aca Glu Leu Cys Glu 160 Asp Thr aat gag cca gaa gac ata Asn Glu Pro 175 Glu Asp He gta act tat ggg aeg tgt Val Thr 190 Tyr Gly Thr Cys aga tea gtg gca etc gtt Arg 205 Ser Val Ala Leu Val 210 act gaa aca tgg atg tea Thr Glu Thr Trp Met 225 Ser att gaa act tgg ate ttg lie Glu Thr Trp 240 lie Leu ate ctg gca tac acc ata He Leu Ala 255 Tyr Thr He ttc ate tta ctg aca get Phe lie 270 Leu Leu Thr Ala gga atg tea aat aga gac Gly 285 Met Ser Asn Arg Asp 290 gtt gac ata gtc tta gaa Val Asp lie Val Leu 305 Glu aac aaa cca aca ttg gat Asn Lys Pro Thr 320 Leu Asp cct gcc acc eta agg aag Pro Ala Thr 335 Leu Arg Lys aca aca gaa tet ege tgc Thr Thr 350 Glu Ser Arg Cys gag cag gac aaa agg ttc Glu 365 Gin Asp Lys Arg Phe 370

    ate aeg tac aag 594 lie Thr Tyr Lys

    165 gac tgt tgg tgc 642

    Asp Cys Trp Cys

    180 acc acc atg gga 690

    Thr Thr Met Gly

    195 cca cat gtg gga 738

    Pro His Val Gly tea gaa ggg gcc 786

    Ser Glu Gly Ala

    230 aga cat cca ggc 834

    Arg His Pro Gly

    245 gga aeg aca cat 882

    Gly Thr Thr His

    260 gtc act cct tea 930

    Val Thr Pro Ser

    275 ttt gtg gaa ggg 978

    Phe Val Glu Gly cat gga agc tgt 1026

    His Gly Ser Cys

    310 ttt gaa ctg ata 1074

    Phe Glu Leu He

    325 tac tgt ata gag 1122

    Tyr Cys lie Glu

    340 cca aca caa ggg 1170

    Pro Thr Gin Gly

    355 gtc tgc aaa cac 1218

    Val Cys Lys His

    149

    2018200081 04 Jan 2018

    tcc Ser 375 atg Met gta gac Val Asp aga gga tgg gga aat gga tgt gga Gly eta Leu ttt Phe gga Gly aag Lys 390 1266 Arg Gly 380 Trp Gly Asn Gly Cys 385 gga ggc att gtg acc tgt get atg ttc aga tgc aaa aag aac atg gaa 1314 Gly Gly He Val Thr Cys Ala Met Phe Arg Cys Lys Lys Asn Met Glu 395 400 405 gga aaa gtt gtg caa cca gaa aac ttg gaa tac acc att gtg ata aca 1362 Gly Lys Val Val Gin Pro Glu Asn Leu Glu Tyr Thr He Val He Thr 410 415 420 cct cac tea ggg gaa gag cat gca gtc gga aat gac aca gga aaa cat 1410 Pro His Ser Gly Glu Glu His Ala Val Gly Asn Asp Thr Gly Lys His 425 430 435 ggc aag gaa ate aaa ata aca cca cag agt tcc ate aca gaa gca gaa 1458 Gly Lys Glu He Lys He Thr Pro Gin Ser Ser He Thr Glu Ala Glu 440 445 450 ttg aca ggt tat ggc act gtc aca atg gag tgc tet cca aga aeg ggc 1506 Leu Thr Gly Tyr Gly Thr Val Thr Met Glu Cys Ser Pro Arg Thr Gly 455 460 465 470 etc gac ttc aat gag atg gtg ttg ctg cag atg gaa aat aaa get tgg 1554 Leu Asp Phe Asn Glu Met Val Leu Leu Gin Met Glu Asn Lys Ala Trp 475 480 485 ctg gtg cac agg caa tgg ttc eta gac ctg ccg tta cca tgg ttg ccc 1602 Leu Val His Arg Gin Trp Phe Leu Asp Leu Pro Leu Pro Trp Leu Pro 490 495 500 gga geg gac aca caa ggg tea aat tgg ata cag aaa gag aca ttg gtc 1650 Gly Ala Asp Thr Gin Gly Ser Asn Trp He Gin Lys Glu Thr Leu Val 505 510 515 act ttc aaa aat ccc cat geg aag aaa cag gat gtt gtt gtt tta gga 1698 Thr Phe Lys Asn Pro His Ala Lys Lys Gin Asp Val Val Val Leu Gly

    520 525 530 tcc caa gaa ggg gcc atg cac aca gca ett aca ggg gcc aca gaa ate 1746

    Ser Gin Glu Gly Ala Met His Thr Ala Leu Thr Gly Ala Thr Glu lie

    535 540 545 550 caa atg tea tea gga aac tta etc ttc aca gga cat etc aag tgc agg 1794

    Gin Met Ser Ser Gly Asn Leu Leu Phe Thr Gly His Leu Lys Cys Arg

    555 560 565 ctg aga atg gac aag eta cag etc aaa gga atg tea tac tet atg tgc 1842

    Leu Arg Met Asp Lys Leu Gin Leu Lys Gly Met Ser Tyr Ser Met Cys

    570 575 580

    150

    2018200081 04 Jan 2018

    aca gga aag Thr Gly Lys ttt Phe aaa gtt gtg aag gaa ata gca gaa aca caa cat gga 1890 Lys Val Val Lys 590 Glu He Ala Glu Thr Gin His 595 Gly 585 aca ata gtt ate aga gtg caa tat gaa ggg gac ggc tet cca tgc aag 1938 Thr He Val lie Arg Val Gin Tyr Glu Gly Asp Gly Ser Pro Cys Lys 600 605 610 ate cct ttt gag ata atg gat ttg gaa aaa aga cat gtc tta ggt ege 1986 lie Pro Phe Glu lie Met Asp Leu Glu Lys Arg His Val Leu Gly Arg 615 620 625 630 ctg att aca gtc aac cca att gtg aca gaa aaa gat age cca gtc aac 2034 Leu He Thr Val Asn Pro He Val Thr Glu Lys Asp Ser Pro Val Asn 635 640 645 ata gaa gca gaa cct cca ttc gga gac age tac ate ate ata gga gta 2082 He Glu Ala Glu Pro Pro Phe Gly Asp Ser Tyr He He He Gly Val 650 655 660 gag ccg gga caa ctg aag etc aac tgg ttt aag aaa gga agt tet ate 2130 Glu Pro Gly Gin Leu Lys Leu Asn Trp Phe Lys Lys Gly Ser Ser He 665 670 675 ggc caa atg ttt gag aca aca atg agg ggg gcg aag aga atg gcc att 2178 Gly Gin Met Phe Glu Thr Thr Met Arg Gly Ala Lys Arg Met Ala He 680 685 690 tta ggt gac aca gcc tgg gat ttt gga tcc ttg gga gga gtg ttt aca 2226 Leu Gly Asp Thr Ala Trp Asp Phe Gly Ser Leu Gly Gly Val Phe Thr 695 700 705 710 tet ata gga aag get etc cac caa gtc ttt gga gca ate tat gga get 2274 Ser He Gly Lys Ala Leu His Gin Val Phe Gly Ala He Tyr Gly Ala 715 720 725 gcc ttc agt ggg gtt tea tgg act atg aaa ate etc ata gga gtc att 2322 Ala Phe Ser Gly Val Ser Trp Thr Met Lys He Leu He Gly Val He 730 735 740 ate aca tgg ata gga atg aat tea ege age acc tea ctg tet gtg aca 2370 He Thr Trp lie Gly Met Asn Ser Arg Ser Thr Ser Leu Ser Val Thr 745 750 755 eta gta ttg gtg gga att gtg aca ctg tat ttg gga gtc atg gtg cag 2418 Leu Val Leu Val Gly He Val Thr Leu Tyr Leu Gly Val Met Val Gin 760 765 770 gcc gat agt ggt tgc gtt gtg age tgg aaa aac aaa gaa ctg aaa tgt 2466 Ala Asp Ser Gly Cys Val val Ser Trp Lys Asn Lys Glu Leu Lys Cys 775 780 785 790 ggc agt ggg att ttc ate aca gac aac gtg cac aca tgg aca gaa caa 2514 Gly Ser Gly He Phe He Thr Asp Asn Val His Thr Trp Thr Glu Gin 795 800 805

    151

    2018200081 04 Jan 2018

    tac Tyr aag Lys ttc Phe caa Gin 810 cca Pro gaa Glu tcc. Ser cct Pro tea Ser 815 aaa Lys eta Leu get Ala tea Ser get Ala 820 ate He cag Gin 2562 aaa gcc cat gaa gag ggc att tgt gga ate cgc tea gta aca aga ctg 2610 Lys Ala His 825 Glu Glu Gly lie Cys 830 Gly He Arg Ser Val 835 Thr Arg Leu gag aat ctg atg tgg aaa caa ata aca cca gaa ttg aat cac att eta 2658 Glu Asn 840 Leu Met Trp Lys Gin 845 He Thr Pro Glu Leu 850 Asn His He Leu tea gaa aat gag gtg aag tta act att atg aca gga gac ate aaa gga 2706 Ser 855 Glu Asn Glu Val Lys 860 Leu Thr He Met Thr 865 Gly Asp He Lys Gly 870 ate atg cag gca gga aaa ega tet ctg egg cct cag ccc act gag ctg 2754 lie Met Gin Ala Gly 875 Lys Arg Ser Leu Arg 880 Pro Gin Pro Thr Glu 885 Leu aag tat tea tgg aaa aca tgg ggc aaa gca aaa atg etc tet aca gag 2802 Lys Tyr Ser Trp 890 Lys Thr Trp Gly Lys 895 Ala Lys Met Leu Ser 900 Thr Glu tet cat aac cag acc ttt etc att gat ggc ccc gaa aca gca gaa tgc 2850 Ser His Asn 905 Gin Thr Phe Leu He 910 Asp Gly Pro Glu Thr 915 Ala Glu Cys ccc aac aca aat aga get tgg aat teg ttg gaa gtt gaa gac tat ggc 2898 Pro Asn 920 Thr Asn Arg Ala Trp 925 Asn Ser Leu Glu Val 930 Glu Asp Tyr Gly ttt gga gta ttc acc acc aat ata tgg eta aaa ttg aaa gaa aaa cag 2946 Phe 935 Gly Val Phe Thr Thr 940 Asn He Trp Leu Lys 945 Leu Lys Glu Lys Gin 950 gat gta ttc tgc gac tea aaa etc atg tea gcg gcc ata aaa gac aac 2994 Asp Val Phe Cys Asp 955 Ser Lys Leu Met Ser 960 Ala Ala He Lys Asp 965 Asn aga gcc gtc cat gcc gat atg ggt tat tgg ata gaa agt gca etc aat 3042 Arg Ala Val His 970 Ala Asp Met Gly Tyr 975 Trp He Glu Ser Ala 980 Leu Asn gac aca tgg aag ata gag aaa gcc tet ttc att gaa gtt aaa aac tgc 3090 Asp Thr Trp Lys 985 He Glu Lys Ala Ser 990 Phe He Glu Val Lys 995 Asn Cys cac tgg cca aaa tea cac acc etc tgg age aat gga gtg eta gaa agt 3138 His Trp Pro 1000 Lys Ser His Thr Leu 1005 Trp Ser Asn Gly Val 1010 Leu Glu Ser

    2018200081 04 Jan 2018

    152 gag atg ata att cca aag aat etc get gga cca gtg tet caa cac aac 3186 Glu Met lie He Pro Lys Asn Leu Ala Gly Pro Val Ser Gin His Asn 1015 . 1020 1025 1030 ' tat aga cca ggc tac cat aca caa ata aca gga cca tgg cat eta ggt 3234 Tyr Arg Pro Gly Tyr His Thr Gin He Thr Gly Pro Trp His Leu Gly 1035 1040 1045 aag ctt gag atg gac ttt gat ttc tgt gat gga aca aca gtg gta gtg 3282 Lys Leu Glu Met Asp Phe Asp Phe Cys Asp Gly Thr Thr Val Val Val 1050 1055 1060 act gag gac tgc gga aat aga gga ccc tet ttg aga aca acc act gcc 3330 Thr Glu Asp Cys Gly Asn Arg Gly Pro Ser Leu Arg Thr Thr Thr Ala 1065 107C I 1075 tet gga aaa etc ata aca gaa tgg tgc tgc ega tet tgc aca tta cca 3378 Ser Gly Lys Leu He Thr Glu Trp Cys Cys Arg Ser Cys Thr Leu Pro 1080 1085 1090 ccg eta aga tac aga ggt gag gat ggg tgc tgg tac ggg atg gaa ate 3426 Pro Leu Arg Tyr Arg Gly Glu Asp Gly Cys Trp Tyr Gly Met Glu He 1095 1100 1105 1110 aga cca ttg aag gag aaa gaa gag aat ttg gtc aac tcc ttg gtc aca 3474 Arg Pro Leu Lys Glu Lys Glu Glu Asn Leu Val Asn Ser Leu Val Thr 1115 1120 1125 get gga cat ggg cag gtc gac aac ttt tea eta gga gtc ttg gga atg 3522 Ala Gly His Gly Gin Val Asp Asn Phe Ser Leu Gly Val Leu Gly Met 1130 1135 1140 gca ttg ttc ctg gag gaa atg ctt agg acc ega gta gga aeg aaa cat 3570 Ala Leu Phe Leu Glu Glu Met Leu Arg Thr Arg Val Gly Thr Lys His 1145 1150 1155 gca ata eta eta gtt gca gtt tet ttt gtg aca ttg ate aca ggg aac 3618 Ala He Leu Leu Val Ala Val Ser Phe Val Thr Leu He Thr Gly Asn 1160 1165 1170 atg tcc ttt aga gac ctg gga aga gtg atg gtt atg gta ggc gcc act 3'666 Met Ser Phe Arg Asp Leu Gly Arg Val Met Val Met Val Gly Ala Thr 1175 1180 1185 1190 atg aeg gat gac ata ggt atg ggc gtg act tat ctt gcc eta eta gca 3714 Met Thr Asp Asp He Gly Met Gly Val Thr Tyr Leu Ala Leu Leu Ala 1195 1200 1205 gcc ttc aaa gtc aga cca act ttt gca get gga eta etc ttg aga aag 3762 Ala Phe Lys Val Arg Pro Thr Phe Ala Ala Gly Leu Leu Leu Arg Lys 1210 1215 1220 ctg acc tcc aag gaa ttg atg atg act act ata gga att gta etc etc 3810 Leu Thr Ser Lys Glu Leu Met Met Thr Thr He Gly He Val Leu Leu

    1225 1230 1235

    153

    2018200081 04 Jan 2018

    tcc Ser cag age Gin Ser 1240 acc Thr ata He cca gag acc Pro Glu Thr 1245 att He ett Leu gag Glu ttg act gat Leu Thr Asp 1250 gcg Ala tta Leu 3858 gcc tta ggc atg atg gtc etc aaa atg gtg aga aat atg gaa aag tat 3906 Ala 1255 Leu Gly Met Met Val Leu Lys 1260 Met Val Arg 1265 Asn Met Glu Lys Tyr 1270 caa ttg gca gtg act ate atg get ate ttg tgc gtc cca aac gca gtg 3954 Gin Leu Ala Val Thr lie Met Ala 1275 He Leu Cys 1280 Val Pro Asn Ala Val 1285 ata tta caa aac gca tgg aaa gtg agt tgc aca ata ttg gca gtg gtg 4002 lie Leu Gin Asn 129C Ala I Trp Lys Val Ser 1295 Cys Thr He Leu Ala Val 1300 Val tcc gtt tcc cca ctg etc tta aca tcc tea cag caa aaa aca gat tgg 4050 Ser Val Ser Pro 1305 Leu Leu Leu Thr Ser 1310 Ser Gin Gin Lys Thr 1315 Asp Trp ata cca tta gca ttg aeg ate aaa ggt etc aat cca aca get att ttt 4098 He Pro Leu 1320 Ala Leu Thr He Lys 1325 Gly Leu Asn Pro Thr Ala 1330 He Phe eta aca acc etc tea aga acc age aag aaa agg age tgg cca tta aat 4146 Leu 1335 Thr Thr Leu Ser Arg Thr Ser 1340 Lys Lys Arg Ser Trp Pro 1345 Leu Asn 1350 gag get ate atg gca gtc ggg atg gtg age att tta gcc agt tct etc 4194 Glu Ala He Met Ala Val Gly Met 1355 Val Ser He 1360 Leu Ala Ser Ser Leu 1365 eta aaa aat gat att ccc atg aca gga cca tta gtg get gga ggg etc 4242 Leu Lys Asn Asp He 1370 Pro Met Thr Gly Pro 1375 Leu Val Ala Gly Gly 1380 Leu etc act gtg tgc tac gtg etc act gga cga teg gcc gat ttg gaa ctg 4290 Leu Thr Val Cys 1385 Tyr Val Leu Thr Gly 1390 Arg Ser Ala Asp Leu 1395 Glu Leu gag aga gca gcc gat gtc aaa tgg gaa gac cag gca gag ata tea gga 4338 Glu Arg Ala 1400 Ala Asp Val Lys Trp 1405 Glu Asp Gin Ala Glu He 1410 Ser Gly age agt cca ate ctg tea ata aca ata tea gaa gat ggt age atg teg 4386 Ser Ser Pro 1415 He Leu Ser He Thr 1420 lie Ser Glu Asp Gly Ser 1425 Met Ser 1430 ata aaa aat gaa gag gaa gaa caa aca ctg acc ata etc att aga aca 4434 He Lys Asn Glu Glu Glu Glu Gin 1435 Thr Leu Thr 1440 He Leu He Arg Thr 1445

    154

    2018200081 04 Jan 2018

    gga Gly ttg Leu ctg Leu gtg ate Val He 1450 tea Ser gga Gly ett Leu ttt cct Phe Pro 1455 gta Val tea Ser ata He cca ate Pro He 1460 aeg Thr 4482 gca gca gca tgg tac ctg tgg gaa gtg aag aaa caa egg gcc gga gta 4530 Ala Ala Ala 1465 Trp Tyr Leu Trp Glu 147C Val Lys 1 Lys Gin Arg 1475 Ala Gly Val ttg tgg gat gtt cct tea ccc cca ccc atg gga aag get gaa ctg gaa 4578 Leu Trp Asp 1480 Val Pro Ser Pro 148Ξ Pro Pro Met Gly Lys Ala 1490 Glu Leu Glu gat gga gcc tat aga att aag caa aaa ggg att ett gga tat tcc cag 4626 Asp Gly 1495 Ala Tyr Arg He Lys 1500 Gin Lys Gly He Leu 1505 Gly Tyr Ser Gin 1510 ate gga gcc gga gtt tac aaa gaa gga aca ttc cat aca atg tgg cat 4674 lie Gly Ala Gly Val Tyr 1515 Lys Glu Gly Thr Phe 1520 His Thr Met Trp His 1525 gtc aca cgt ggc get gtt eta atg cat aaa gga aag agg att gaa cca 4722 Val Thr Arg Gly Ala 1530 Val Leu Met His Lys 1535 Gly Lys Arg He Glu 1540 Pro tea tgg geg gac gtc aag aaa gac eta ata tea tat gga gga ggc tgg 4770 Ser Trp Ala Asp Val 1545 Lys Lys Asp Leu lie 1550 Ser Tyr Gly Gly Gly 1555 Trp aag tta gaa gga gaa tgg aag gaa gga gaa gaa gtc cag gta ttg gca 4818 Lys Leu Glu 1560 Gly Glu Trp Lys Glu 1565 Gly Glu Glu Val Gin 1570 Val Leu Ala ctg gag cct gga aaa aat cca aga gcc gtc caa aeg aaa cct ggt ett 4866 Leu Glu 1575 Pro Gly Lys Asn Pro 1580 Arg Ala Val Gin Thr 1585 Lys Pro Gly Leu 1590 ttc aaa acc aac gcc gga aca ata ggt get gta tet ctg gac ttt tet 4914 Phe Lys Thr Asn Ala Gly 1595 Thr He Gly Ala Val 1600 Ser Leu Asp Phe Ser 1605 cct gga aeg tea gga tet cca att ate gac aaa aaa gga aaa gtt gtg 4962 Pro Gly Thr Ser Gly 1610 Ser Pro He He Asp 1615 Lys Lys Gly Lys Val 1620 Val ggt ett tat ggt aat ggt gtt gtt aca agg agt gga gca tat gtg agt 5010 Gly Leu Tyr Gly Asn 1625 Gly Val Val Thr Arg 1630 Ser Gly Ala Tyr Val 1635 Ser get ata gcc cag act gaa aaa age att gaa gac aac cca gag ate gaa 5058 Ala He Ala 1640 Gin Thr Glu Lys Ser 1645 He Glu Asp Asn Pro 1650 Glu He Glu gat gac att ttc ega aag aga aga ctg acc ate atg gac etc cac cca 5106 Asp Asp 1655 He Phe Arg Lys Arg Arg 1660 Leu Thr lie Met 1665 Asp Leu His Pro 1670

    155

    2018200081 04 Jan 2018

    gga gcg gga aag Lys aeg aag Thr Lys 1675 aga tac ctt Leu ccg gcc Pro Ala 1680 ata lie gtc Val aga gaa get Arg Glu Ala 1685 5154 Gly Ala Gly Arg Tyr ata aaa egg ggt ttg aga aca tta ate ttg gcc ccc act aga gtt gtg 5202 lie Lys Arg Gly 169C Leu Arg 1 Thr Leu He 1695 Leu Ala Pro Thr Arg Val Val 1700 gca get gaa atg gag gaa gcc ctt aga gga ctt cca ata aga tac cag 5250 Ala Ala Glu 170S Met Glu Glu Ala Leu Arg 1710 Gly Leu Pro He Arg Tyr Gin 1715 acc cca gcc ate aga get gag cac acc ggg egg gag att gtg gac eta 5298 Thr Pro Ala 1720 He Arg Ala Glu His 1725 Thr Gly Arg Glu He 1730 Val Asp Leu atg tgt cat gee aca ttt acc atg agg ctg eta tea cca gtt aga gtg . 5346 Met Cys 1735 His Ala Thr Phe Thr 1740 Met Arg Leu Leu Ser 1745 Pro Val Arg Val 1750 cca aac tac aac ctg att ate atg gac gaa gcc cat ttc aca gac cca 5394 Pro Asn Tyr Asn Leu He 1755 He Met Asp Glu Ala 1760 His Phe Thr Asp Pro 1765 gca agt ata gca get aga gga tac ate tea act cga gtg gag atg ggt 5442 Ala Ser He Ala Ala Arg 1770 Gly Tyr He Ser Thr 1775 Arg Val Glu Met Gly 1780 gag gca get ggg att ttt atg aca gcc act ccc ccg gga agc aga gac 5490 Glu Ala Ala Gly 1785 He Phe Met Thr Ala 1790 Thr Pro Pro Gly Ser Arg Asp 1795 cca ttt cct cag agc aat gca cca ate ata gat gaa gaa aga gaa ate 5538 Pro Phe Pro 1800 Gin Ser Asn Ala Pro 1805 He He Asp Glu Glu 1810 Arg Glu He cct gaa cgt teg tgg aat tcc gga cat gaa tgg gtc aeg gat ttt aaa 5586 Pro Glu 1815 Arg Ser Trp Asn Ser 1820 Gly His Glu Trp Val 1825 Thr Asp Phe Lys 1830 ggg aag act gtt tgg ttc gtt cca agt ata aaa gca gga aat gat ata 5634 Gly Lys Thr Val Trp Phe 1835 Val Pro Ser He Lys 1840 Ala Gly Asn Asp He 1845 gca get tgc ctg agg aaa aat gga aag aaa gtg ata caa etc agt agg 5682 Ala Ala Cys Leu Arg Lys 1850 Asn Gly Lys Lys Val 1855 He Gin Leu Ser Arg 1860 aag acc ttt gat tet gag tat gtc aag act aga acc aat gat tgg gac 5730 Lys Thr Phe Asp 1865 Ser Glu Tyr Val Lys 1870 Thr Arg Thr Asn Asp Trp Asp 1875 ’

    156

    2018200081 04 Jan 2018

    ttc gtg gtt Phe Val Val 1880 aca act gac att tea gaa atg ggt gcc aat He Ser Glu Met Gly Ala Asn ttc Phe aag Lys get Ala 5778 Thr Thr Asp 1885 1890 gag agg gtt ata gac ccc aga ege tgc atg aaa cca gtc ata eta aca 5826 Glu Arg Val 1895 He Asp Pro Arg Arg Cys Met 1900 Lys Pro Val 1905 He Leu Thr 1910 gat ggt gaa gag cgg gtg att ctg gca gga cct atg cca gtg acc cac 5874 Asp Gly Glu Glu Arg Val 1915 He Leu Ala Gly Pro Met Pro 1920 Val Thr His 1925 tet agt gca gca caa aga aga ggg aga ata gga aga aat cca aaa aat 5922 Ser Ser Ala Ala Gin Arg 1930 Arg Gly Arg He 1935 Gly Arg Asn Pro 194C Lys I Asn gag aat gac cag tac ata tac atg ggg gaa cct ctg gaa aat gat gaa 5970 Glu Asn Asp Gin 1945 Tyr He Tyr Met Gly Glu 1950 Pro Leu Glu Asn 1955 Asp Glu gac tgt gca cac tgg aaa gaa get aaa atg etc eta gat aac ate aac 6018 Asp Cys Ala 1960 His Trp Lys Glu Ala Lys Met 1965 Leu Leu Asp 1970 Asn lie Asn acg cca gaa gga ate att cct age atg ttc gaa cca gag cgt gaa aag 6066 Thr Pro Glu 1975 Gly He He Pro Ser Met Phe 1980 Glu Pro Glu 1985 Arg Glu Lys 1990 gtg gat gcc att gat ggc gaa tac ege ttg aga gga gaa gca agg aaa 6114 Val Asp Ala He Asp Gly 1995 Glu Tyr Arg Leu Arg Gly Glu 2000 Ala Arg Lys 2005 acc ttt gta gac tta atg aga aga gga gac eta cca gtc tgg ttg gcc 6162 Thr Phe Val Asp Leu Met 2010 Arg Arg Gly Asp 2015 Leu Pro Val Trp Leu 2020 Ala tac aga gtg gca get gaa ggc ate aac tac gca gac aga agg tgg tgt 6210 Tyr Arg Val Ala 2025 Ala Glu Gly lie Asn Tyr 2030 Ala Asp Arg Arg 2035 Trp Cys ttt gat gga gtc aag aac aac caa ate eta gaa gaa aac gtg gaa gtt 6258 Phe Asp Gly 2040 Val Lys Asn Asn Gin He Leu 2045 Glu Glu Asn 2050 Val Glu Val gaa ate tgg aca aaa gaa ggg gaa agg aag aaa ttg aaa ccc aga tgg 6306 Glu lie Trp 2055 Thr Lys Glu Gly Glu Arg Lys 2060 Lys Leu Lys 2065 Pro Arg Trp 2070 ttg gat get agg ate tat tet gac cca ctg geg eta aaa gaa ttt aag 6354 Leu Asp Ala Arg lie Tyr 2075 Ser Asp Pro Leu Ala Leu Lys 2080 Glu Phe Lys 2085 gaa ttt gca gcc gga aga aag tet ctg acc ctg aac eta ate aca gaa 6402 Glu Phe Ala Ala Gly Arg Lys Ser Leu Thr Leu Asn Leu He Thr Glu

    2090 2095 2100

    157

    2018200081 04 Jan 2018

    atg Met ggt Gly agg etc Arg Leu 2105 cca acc ttc Phe atg act Met Thr 2110 cag Gin aag gca aga gac Arg Asp 2115 gca Ala ctg Leu 6450 Pro Thr Lys Ala gac aac tta gca gtg ctg cac aeg get gag gca ggt gga agg gcg tac 6498 Asp Asn 212C Leu Ala 1 Val Leu His 2125 Thr Ala Glu Ala Gly 213C Gly Arg 1 Ala Tyr aac cat get etc agt gaa ctg ccg gag acc ctg gag aca ttg ett tta 6546 Asn His 2135 Ala Leu Ser Glu 214C Leu 1 Pro Glu Thr Leu Glu 2145 Thr Leu Leu Leu 2150 ctg aca ett ctg get aca gtc aeg gga ggg ate ttt tta ttc ttg atg 6594 Leu Thr Leu Leu Ala Thr 2155 Val Thr Gly Gly He 2160 Phe Leu Phe Leu Met 2165 age gga agg ggc ata ggg aag atg acc ctg gga atg tgc tgc ata ate 6642 Ser Gly Arg Gly He 2170 Gly Lys Met Thr Leu 2175 Gly Met Cys Cys He 2180 He aeg get age ate etc eta tgg tac gca caa ata cag cca cac tgg ata 6690 Thr Ala Ser He 2185 Leu Leu Trp Tyr Ala 2190 Gin He Gin Pro His 2195 Trp He gca get tea ata ata ctg gag ttt ttt etc ata gtt ttg ett att cca 6738 Ala Ala 220C Ser He 1 He Leu Glu 220E Phe Phe Leu He Val 221C Leu Leu 1 He Pro gaa cct gaa aaa cag aga aca ccc caa gac aac caa ctg acc tac gtt 6786 Glu Pro 2215 Glu Lys Gin Arg 222C Thr 1 Pro Gin Asp Asn Gin 2225 Leu Thr Tyr Val 2230 gtc ata gcc ate etc aca gtg gtg gcc gca acc atg gca aac gag atg 6834 Val lie Ala He Leu Thr 2235 Val Val Ala Ala Thr 2240 Met Ala Asn Glu Met 2245 ggt ttc eta gaa aaa aeg aag aaa gat etc gga ttg gga age att gca 6882 Gly Phe Leu Glu 225C Lys I Thr Lys Lys Asp Leu 2255 Gly Leu Gly Ser 226C He 1 Ala acc cag caa ccc gag age aac ate ctg gac ata gat eta cgt cct gca 6930 Thr Gin Gin Pro 2265 Glu Ser Asn He Leu 2270 Asp He Asp Leu Arg 2275 Pro Ala tea gca tgg aeg ctg tat gcc gtg gcc aca aca ttt gtt aca cca atg 6978 Ser Ala Trp Thr 2280 Leu Tyr Ala 228E Val Ala Thr Thr Phe 229C Val Thr 1 Pro Met ttg aga cat age att gaa aat tcc tea gtg aat gtg tcc eta aca get 7026 Leu Arg 2295 His Ser He Glu Asn 2300 Ser Ser Val Asn Val 2305 Ser Leu Thr Ala 2310

    158

    2018200081 04 Jan 2018

    ata lie gcc Ala aac Asn caa Gin gcc aca Ala Thr 2315 gtg Val tta Leu atg Met ggt etc Gly Leu 2320 ggg Gly aaa Lys gga Gly tgg cca Trp Pro 2325 7074 ttg tea aag atg gac ate gga gtt ccc ett etc gee att gga tgc tac 7122 Leu Ser Lys Met Asp He 2330 Gly Val Pro 2335 Leu Leu Ala He Gly 234C Cys Tyr 1 tea caa gtc aac ccc ata act etc aca gca get ett ttc tta ttg gta 7170 Ser Gin Val 2345 Asn Pro He Thr Leu 235C Thr 1 Ala Ala Leu Phe 2355 Leu Leu Val gca cat tat gcc ate ata ggg cca gga etc caa gca aaa gca acc aga 7218 Ala His 236C Tyr 1 Ala He He Gly Pro 2365 Gly Leu Gin Ala Lys 2370 Ala Thr Arg gaa get cag aaa aga gca gcg gcg ggc ate atg aaa aac cca act gtc 7266 Glu Ala 2375 Gin Lys Arg Ala Ala 2380 Ala Gly He Met Lys 2385 Asn Pro Thr Val 2390 gat gga ata aca gtg att gac eta gat •cca ata cct tat gat cca aag 7314 Asp Gly He Thr Val He 2395 Asp Leu Asp Pro He 2400 Pro Tyr Asp Pro Lys 2405 ttt gaa aag cag ttg gga caa gta atg etc eta gtc etc tgc gtg act 7362 Phe Glu Lys Gin Leu Gly 2410 Gin Val Met Leu Leu 2415 Val Leu Cys Val Thr 2420 caa gta ttg atg atg agg act aca tgg get ctg tgt gag get tta acc 7410 Gin Val Leu Met 2425 Met Arg Thr Thr Trp 2430 Ala Leu Cys Glu 2435 Ala Leu Thr tta get acc ggg ccc ate tcc aca ttg tgg gaa gga aat cca ggg agg 7458 Leu Ala Thr 2440 Gly Pro He Ser Thr 2445 Leu Trp Glu Gly Asn 2450 Pro Gly Arg ttt tgg aac act acc att gcg gtg tea atg get aac att ttt aga ggg 7506 Phe Trp 2455 Asn Thr Thr He Ala 2460 Val Ser Met Ala Asn 2465 He Phe Arg Gly 2470 agt tac ttg gcc gga get gga ett etc ttt tct att atg aag aac aca 7554 Ser Tyr Leu Ala Gly Ala 2475 Gly Leu Leu Phe Ser 2480 He Met Lys Asn Thr 2485 acc aac aca aga agg gga act ggc aac ata gga gag aeg ett gga gag 7602 Thr Asn Thr Arg Arg Gly 2490 Thr Gly Asn He Gly 2495 Glu Thr Leu Gly Glu 2500 aaa tgg aaa age ega ttg aac gca ttg gga aaa agt gaa ttc cag ate 7650 Lys Trp Lys Ser 2505 Arg Leu Asn Ala Leu 2510 Gly Lys Ser Glu Phe 2515 Gin He tac aag aaa agt gga ate cag gaa gtg gat aga acc tta gca aaa gaa 7698 Tyr Lys Lys Ser Gly lie Gin Glu Val Asp Arg Thr Leu Ala Lys Glu

    2520 2525 2530

    159

    2018200081 04 Jan 2018

    ggc att Gly lie 2535 aaa aga gga gaa aeg Lys Arg Gly Glu Thr 2540 gac Asp cat His cac His get gtg Ala Val 2545 teg Ser ega Arg ggc Gly tea Ser 2550 7746 gca aaa ctg aga tgg ttc gtt gag aga aac atg gtc aca cca gaa ggg 7794 Ala Lys Leu Arg Trp Phe Val 2555 Glu Arg Asn Met Val 2560 Thr Pro Glu 256Ξ Gly aaa gta gtg gac etc ggt tgt ggc aga gga ggc tgg tea tac tat tgt 7842 Lys Val Val Asp Leu Gly Cys 2570 Gly Arg Gly 2575 Gly Trp Ser Tyr 258C Tyr 1 Cys gga gga eta aag aat gta aga gaa gtc aaa ggc eta aca aaa gga gga 7890 Gly Gly Leu Lys Asn Val Arg 2585 Glu Val 2590 Lys Gly Leu Thr Lys 2595 Gly Gly cca gga cac gaa gaa ccc ate ccc atg tea aca tat ggg tgg aat eta 7938 Pro Gly His Glu Glu Pro He Pro 2600 2605 Met Ser Thr Tyr Gly 2610 Trp Asn Leu gtg cgt ett caa agt gga gtt gac gtt ttc ttc ate ccg cca gaa aag 7986 Val Arg 2615 Leu Gin Ser Gly Val 2620 Asp Val Phe Phe He 2625 Pro Pro Glu Lys 2630 tgt gac aca tta ttg tgt gac ata ggg gag tea tea cca aat ccc aca 8034 Cys Asp Thr Leu Leu Cys Asp 2635 He Gly Glu Ser Ser 2640 Pro Asn Pro Thr 2645 gtg gaa gca gga ega aca etc aga gtc ett aac tta gta gaa' aat tgg 8082 Val Glu Ala Gly Arg Thr Leu 2650 Arg Val Leu 2655 Asn Leu Val Glu Asn 2660 Trp ttg aac aac aac act caa ttt tgc ata aag gtt etc aac cca tat atg 8130 Leu Asn Asn Asn Thr Gin Phe 2665 Cys He 2670 Lys Val Leu Asn Pro 2675 Tyr Met ccc tea gtc ata gaa aaa atg gaa gca eta caa agg aaa tat gga gga 8178 Pro Ser Val He Glu Lys Met Glu 2680 2685 Ala Leu Gin Arg Lys 2690 Tyr Gly Gly gcc tta gtg agg aat cca etc tea ega aac tcc aca cat gag atg tac 8226 Ala Leu 2695 Val Arg Asn Pro Leu 2700 Ser Arg Asn Ser Thr 2705 His Glu Met Tyr 2710 tgg gta tee aat get tcc ggg aac ata gtg tea tea gtg aac atg att 8274 Trp Val Ser Asn Ala Ser Gly 2715 Asn He Val Ser Ser 2720 Val Asn Met He 2725 tea agg atg ttg ate aac aga ttt aca atg aga tac aag aaa gcc act 8322 Ser Arg Met Leu He Asn Arg Phe Thr Met Arg Tyr Lys Lys Ala Thr

    2730 2735 2740

    160

    2018200081 04 Jan 2018

    tac Tyr gag Glu ccg gat Pro Asp 2745 gtt Val gac Asp etc Leu gga age Gly Ser 2750 gga Gly acc Thr cgt Arg aac ate Asn He 2755 ggg Gly att He 8370 gaa agt gag ata cca aac eta gat ata att ggg aaa aga ata gaa aaa 8418 Glu Ser 276C Glu He 1 Pro Asn Leu Asp He 2765 He Gly Lys Arg He 2770 Glu Lys ata aag caa gag cat gaa aca tea tgg cac tat gac caa gac cac cca 8466 lie Lys 2775 Gin Glu His Glu Thr 2780 Ser Trp His Tyr Asp 2785 Gin Asp His Pro 2790 tac aaa aeg tgg gca tac cat ggt age tat gaa aca aaa cag act gga 8514 Tyr Lys Thr Trp Ala Tyr 2795 His Gly Ser Tyr Glu 2800 Thr Lys Gin Thr 2805 Gly tea gca tea tcc atg gtc aac gga gtg gtc agg ctg ctg aca aaa cct 8562 Ser Ala Ser Ser Met 2810 Val Asn Gly Val Val 2815 Arg Leu Leu Thr Lys 2820 Pro tgg gac gtc gtc ccc atg gtg aca cag atg gca atg aca gac aeg act 8610 Trp Asp Val Val 2825 Pro Met Val Thr Gin 2830 Met Ala Met Thr Asp 2835 Thr Thr cca ttt gga caa cag ege gtt ttt aaa gag aaa gtg gac aeg aga acc 8658 Pro Phe 284C Gly Gin 1 Gin Arg Val Phe Lys 2845 Glu Lys Val Asp Thr 2850 Arg Thr caa gaa ccg aaa gaa ggc aeg aag aaa eta atg aaa ata aca gca gag 8706 Gin Glu 2855 Pro Lys Glu Gly Thr 2860 Lys Lys Leu Met Lys 2865 He Thr Ala Glu 2870 tgg ett tgg aaa gaa tta ggg aag aaa aag aca ccc agg atg tgc acc 8754 Trp Leu Trp Lys Glu Leu 2875 Gly Lys Lys Lys Thr 2880 Pro Arg Met Cys Thr 2885 aga gaa gaa ttc aca aga aag gtg aga age aat gca gcc ttg ggg gcc 8802 Arg Glu Glu Phe Thr 2890 Arg Lys Val Arg Ser 2895 Asn Ala Ala Leu Gly 2900 Ala ata ttc act gat gag aac aag tgg aag teg gca cgt gag get gtt gaa 8850 He Phe Thr Asp 2905 Glu Asn Lys Trp Lys 2910 Ser Ala Arg Glu Ala 2915 Val Glu gat agt agg ttt tgg gag ctg gtt gac aag gaa agg aat etc cat ett 8898 Asp Ser Arg Phe 2920 Trp Glu Leu Val Asp 2925 Lys Glu Arg Asn Leu 2930 His Leu gaa gga aag tgt gaa aca tgt gtg tac aac atg atg gga aaa aga gag 8946 Glu Gly 2935 Lys Cys Glu Thr Cys 2940 Val Tyr Asn Met Met 2945 Gly Lys Arg Glu 2950 aag aag eta ggg gaa ttc ggc aag gca aaa ggc age aga gcc ata tgg 8994 Lys Lys Leu Gly Glu Phe 2955 Gly Lys Ala Lys Gly 2960 Ser Arg Ala He Trp 2965

    161

    2018200081 04 Jan 2018

    tac Tyr atg Met tgg Trp ett gga gca Leu Gly Ala 2970 cgc Arg ttc Phe tta gag Leu Glu 2975 ttt Phe gaa Glu gcc Ala eta gga Leu Gly 2980 ttc Phe 9042 tta aat gaa gat cac tgg ttc tcc aga gag aac tcc ctg agt gga gtg 9090 Leu Asn Glu 2985 Asp His Trp Phe Ser 299C Arg Glu 1 Asn Ser Leu 2995 Ser Gly Val gaa gga gaa ggg Ctg cac aag eta ggt tac att eta aga gac gtg age 9138 Glu Gly 3000 Glu 1 Gly Leu His Lys 3005 Leu Gly Tyr He Leu Arg 3010 Asp Val Ser aag aaa gag gga gga gca atg tat gcc gat gac acc gca gga tgg gat 9186 Lys Lys 3015 Glu Gly Gly Ala Met 3020 Tyr Ala Asp Asp Thr 3025 Ala Gly Trp Asp 3030 aca aga ate aca eta gaa gac eta aaa aat gaa gaa atg gta aca aac 9234 Thr Arg He Thr Leu Glu 3035 Asp Leu Lys Asn Glu 3040 Glu Met Val Thr Asn 3045 cac atg gaa gga gaa cac aag aaa eta gcc gag gcc att ttc aaa eta 9282 His Met Glu Gly Glu His 3050 Lys Lys Leu Ala 3055 Glu Ala He Phe Lys 3060 Leu aeg tac caa aac aag gtg gtg cgt gtg caa aga cca aca cca aga ggc 9330 Thr Tyr Gin Asn Lys Val 3065 Val Arg 307C Val Gin I Arg Pro Thr Pro Arg 3075 Gly aca gta atg gac ate ata teg aga aga gac caa aga ggt agt gga caa 9378 Thr Val 308C Met 1 Asp He He Ser Arg 3085 Arg Asp Gin Arg Gly 3090 Ser Gly Gin gtt ggc acc tat gga etc aat act ttc acc aat atg gaa gcc caa eta 9426 Val Gly 3095 Thr Tyr Gly Leu Asn 3100 Thr Phe Thr Asn Met 3105 Glu Ala Gin Leu 3110 ate aga cag atg gag gga gaa gga gtc ttt aaa age att cag cac eta 9474 lie Arg Gin Met Glu Gly 3115 Glu Gly Val Phe Lys 3120 Ser He Gin His Leu 3125 aca ate aca gaa gaa ate get gtg caa aac tgg tta gca aga gtg ggg 9522 Thr He Thr Glu Glu He 3130 Ala Val Gin Asn 3135 Trp Leu Ala Arg Val 3140 Gly cgc gaa agg tta tea aga atg gcc ate agt gga gat gat tgt gtt gtg 9570 Arg Glu Arg Leu Ser Arg 3145 Met Ala lie Ser 3150 Gly Asp Asp Cys Val 3155 Val aaa cct tta gat gac agg ttc gca age get tta aca get eta aat gac 9618 Lys Pro Leu 3160 Asp Asp Arg Phe Ala 3165 Ser Ala Leu Thr Ala 3170 Leu Asn Asp

    162

    9666

    2018200081 04 Jan 2018

    atg gga Met Gly 3175 aag Lys att He agg aaa gac ata caa caa tgg gaa cct tea Ser aga Arg gga Gly 3190 Arg Lys Asp 3180 He Gin Gin Trp Glu 3185 Pro tgg aat gat tgg aca caa gtg ccc ttc tgt tea cac cat ttc cat gag Trp Asn Asp Trp Thr 3195 Gin Val Pro Phe Cys 320C Ser His 1 His Phe His 3205 Glu tta ate atg aaa gac ggt ege gta etc gtt gtt cca tgt aga aac caa Leu lie Met Lys Asp 3210 Gly Arg Val Leu 3215 Val Val Pro Cys Arg 322C Asn 1 Gin gat gaa ctg att ggc aga gcc ega ate tcc caa gga gca ggg tgg tet Asp Glu Leu 3225 He Gly Arg Ala Arg 323C He 1 Ser Gin Gly Ala 3235 Gly Trp Ser ttg egg gag aeg gcc tgt ttg ggg aag tet tac gcc caa atg tgg age Leu Arg Glu 3240 Thr Ala Cys Leu Gly 3245 Lys Ser Tyr Ala Gin 3250 Met Trp Ser ttg atg tac ttc cac aga ege gac etc agg ctg gcg gca aat get att Leu Met 3255 Tyr Phe His Arg Arg 3260 Asp Leu Arg Leu Ala 3265 Ala Asn Ala lie 3270 tgc teg gca gta cca tea cat tgg gtt cca aca agt ega aca acc tgg Cys Ser Ala Val Pro Ser His 3275 Trp Val Pro Thr Ser 3280 Arg Thr Thr Trp 3285 tcc ata cat get aaa cat gaa tgg atg aca aeg gaa gac atg ctg aca Ser He His Ala Lys 3290 His Glu Trp Met Thr 3295 Thr Glu Asp Met Leu 3300 Thr gtc tgg aac agg gtg tgg att caa gaa aac cca tgg atg gaa gac aaa Val Trp Asn Arg 3305 Val Trp He Gin Glu 3310 Asn Pro Trp Met Glu 3315 Asp Lys act cca gtg gaa tea tgg gag gaa ate cca tac ttg ggg aaa aga gaa Thr Pro Val 3320 Glu Ser Trp Glu Glu 3325 He Pro Tyr Leu Gly 3330 Lys Arg Glu gac caa tgg tgc ggc tea ttg att ggg tta aca age agg gcc acc tgg Asp Gin 3335 Trp Cys Gly Ser Leu 3340 He Gly Leu Thr Ser 3345 Arg Ala Thr Trp 3350 gca aag aac ate caa gca gca ata aat caa gtt aga tcc ett ata ggc Ala Lys Asn He Gin Ala Ala 3355 He Asn Gin Val Arg 3360 Ser Leu He Gly 3365 aat gaa gaa tac aca gat tac atg cca tcc atg aaa aga ttc aga aga Asn Glu Glu Tyr Thr 3370 Asp Tyr Met Pro Ser 3375 Met Lys Arg Phe Arg 3380 Arg gaa gag Glu Glu gaa Glu gaa Glu gca Ala gga gtt Gly Val ctg Leu tgg Trp tag * aaagcaaaac taacatgaaa

    3385 3390

    9714

    9762

    9810

    9858

    9906

    9954

    10002

    10050

    10098

    10146

    10194

    10242

    10292

    163

    2018200081 04 Jan 2018 caaggctaga agtcaggtcg gattaagcca tagtacggaa aaaactatgc tacctgtgag ccccgtccaa ggacgttaaa agaagtcagg ccatcataaa tgccatagct tgagtaaact atgcagcctg tagctccacc tgagaaggtg taaaaaatcc gggaggccac aaaccatgga agctgtacgc atggcgtagt ggactagcgg ttagaggaga cccctccctt acaaatcgca gcaacaatgg gggcccaagg cgagatgaag ctgtagtctc gctggaagga ctagaggtta gaggagaccc ccccgaaaca aaaaacagca tattgacgct gggaaagacc agagatcctg ctgtctcctc agcatcattc caggcacaga acgccagaaa atggaatggt gctgttgaat caacaggttc t <210> 14 <211> 3391 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct

    10352

    10412

    10472

    10532

    10592

    10652

    10712

    10723

    <400> 14 Met Asn Asn Gin Arg Lys Lys Ala Lys Asn Thr Pro Phe Asn Met Leu 1 5 10 15 Lys Arg Glu Arg Asn Arg Val Ser Thr Val Gin Gin Leu Thr Lys Arg 20 25 30 Phe Ser Leu Gly Met Leu Gin Gly Arg Gly Pro Leu Lys Leu Phe Met 35 40 45 Ala Leu Val Ala Phe Leu Arg Phe Leu Thr lie Pro Pro Thr Ala Gly 50 55 60 lie Leu Lys Arg Trp Gly Thr He Lys Lys Ser Lys Ala He Asn Val 65 70 75 80 Leu Arg Gly Phe Arg Lys Glu He Gly Arg Met Leu Asn He Leu Asn 85 90 95 Arg Arg Arg Arg Ser Ala Gly Met He He Met Leu He Pro Thr Val 100 105 110 Met Ala Phe His Leu Thr Thr Arg Asn Gly Glu Pro His Met He Val 115 120 125 Ser Arg Gin Glu Lys Gly Lys Ser Leu Leu Phe Lys Thr Glu Asp Gly 130 135 140 Val Asn Met Cys Thr Leu Met Ala Met Asp Leu Gly Glu Leu Cys Glu 145 150 155 160 Asp Thr He Thr Tyr Lys Cys Pro Leu Leu Arg Gin Asn Glu Pro Glu 165 170 175 Asp He Asp Cys Trp Cys Asn Ser Thr Ser Thr Trp Val Thr Tyr Gly 180 185 190 Thr Cys Thr Thr Met Gly Glu His Arg Arg Glu Lys Arg Ser Val Ala 195 200 205 Leu Val Pro His Val Gly Met Gly Leu Glu Thr Arg Thr Glu Thr Trp 210 215 220 Met Ser Ser Glu Gly Ala Trp Lys His Val Gin Arg He Glu Thr Trp 225 230 235 240 He Leu Arg His Pro Gly Phe Thr Met Met Ala Ala He Leu Ala Tyr 245 250 255 Thr lie Gly Thr Thr His Phe Gin Arg Ala Leu He Phe lie Leu Leu 260 265 270

    164

    2018200081 04 Jan 2018

    Thr Ala Val 275 Thr Pro Ser Met Thr 280 Met Arg Cys He Gly Met 285 Ser Asn Arg Asp Phe Val Glu Gly Val Ser Gly Gly Ser Trp Val Asp He Val 290 295 300 Leu Glu His Gly Ser Cys Val Thr Thr Met Ala Lys Asn Lys Pro Thr 305 310 315 320 Leu Asp Phe Glu Leu He Lys Thr Glu Ala Lys Gin Pro Ala Thr Leu 325 330 335 Arg Lys Tyr Cys He Glu Ala Lys Leu Thr Asn Thr Thr Thr Glu Ser 340 345 350 Arg Cys Pro Thr Gin Gly Glu Pro Ser Leu Asn Glu Glu Gin Asp Lys 355 360 365 Arg Phe Val Cys Lys His Ser Met Val Asp Arg Gly Trp Gly Asn Gly 370 375 380 Cys Gly Leu Phe Gly Lys Gly Gly He Val Thr Cys Ala Met Phe Arg 385 390 395 400 Cys Lys Lys Asn Met Glu Gly Lys Val Val Gin Pro Glu Asn Leu Glu 405 410 415 Tyr Thr He Val He Thr Pro His Ser Gly Glu Glu His Ala Val Gly 420 425 430 Asn Asp Thr Gly Lys His Gly Lys Glu He Lys lie Thr Pro Gin Ser 435 440 445 Ser lie Thr Glu Ala Glu Leu Thr Gly Tyr Gly Thr Val Thr Met Glu 450 455 460 Cys Ser Pro Arg Thr Gly Leu Asp Phe Asn Glu Met Val Leu Leu Gin 465 470 475 480 Met Glu Asn Lys Ala Trp Leu Val His Arg Gin Trp Phe Leu Asp Leu 485 490 495 Pro Leu Pro Trp Leu Pro Gly Ala Asp Thr Gin Gly Ser Asn Trp He 500 505 510 Gin Lys Glu Thr Leu Val Thr Phe Lys Asn Pro His Ala Lys Lys Gin 515 520 525 Asp Val Val Val Leu Gly Ser Gin Glu Gly Ala Met His Thr Ala Leu 530 535 540 Thr Gly Ala Thr Glu He Gin Met Ser Ser Gly Asn Leu Leu Phe Thr 545 550 555 560 Gly His Leu Lys Cys Arg Leu Arg Met Asp Lys Leu Gin Leu Lys Gly 565 570 575 Met Ser Tyr Ser Met Cys Thr Gly Lys Phe Lys Val Val Lys Glu lie 580 585 590 Ala Glu Thr Gin His Gly Thr lie Val He Arg Val Gin Tyr Glu Gly 595 600 605 Asp Gly Ser Pro Cys Lys He Pro Phe Glu lie Met Asp Leu Glu Lys 610 615 620 Arg His Val Leu Gly Arg Leu He Thr Val Asn Pro He Val Thr Glu 625 630 635 640 Lys Asp Ser Pro Val Asn He Glu Ala Glu Pro Pro Phe Gly Asp Ser 645 650 655 Tyr He He He Gly Val Glu Pro Gly Gin Leu Lys Leu Asn Trp Phe 660 665 670 Lys Lys Gly Ser Ser He Gly Gin Met Phe Glu Thr Thr Met Arg Gly 675 680 685 Ala Lys Arg Met Ala He Leu Gly Asp Thr Ala Trp Asp Phe Gly Ser 690 695 700

    165

    2018200081 04 Jan 2018

    Leu Gly Gly Val Phe Thr Ser He Gly Lys Ala Leu His Gin Val Phe 705 710 715 720 Gly Ala lie Tyr Gly Ala Ala Phe Ser Gly Val Ser Trp Thr Met Lys 725 730 735 He Leu He Gly Val He lie Thr Trp He Gly Met Asn Ser Arg Ser 740 745 750 Thr Ser Leu Ser Val Thr Leu Val Leu Val Gly He Val Thr Leu Tyr 755 760 765 Leu Gly Val Met Val Gin Ala Asp Ser Gly Cys Val Val Ser Trp Lys 770 775 780 Asn Lys Glu Leu Lys Cys Gly Ser Gly He Phe He Thr Asp Asn Val 785 790 795 800 His Thr Trp Thr Glu Gin Tyr Lys Phe Gin Pro Glu Ser Pro Ser Lys 805 810 815 Leu Ala Ser Ala lie Gin Lys Ala His Glu Glu Gly He Cys Gly lie 820 825 830 Arg Ser Val Thr Arg Leu Glu Asn Leu Met Trp Lys Gin He Thr Pro 835 840 845 Glu Leu Asn His He Leu Ser Glu Asn Glu Val Lys Leu Thr He Met 850 855 860 Thr Gly Asp lie Lys Gly He Met Gin Ala Gly Lys Arg Ser Leu Arg 865 870 875 880 Pro Gin Pro Thr Glu Leu Lys Tyr Ser Trp Lys Thr Trp Gly Lys Ala 885 890 895 Lys Met Leu Ser Thr Glu Ser His Asn Gin Thr Phe Leu He Asp Gly 900 905 910 Pro Glu Thr Ala Glu Cys Pro Asn Thr Asn Arg Ala Trp Asn Ser Leu 915 920 925 Glu Val Glu Asp Tyr Gly Phe Gly Val Phe Thr Thr Asn He Trp Leu 930 935 940 Lys Leu Lys Glu Lys Gin Asp Val Phe Cys Asp Ser Lys Leu Met Ser 945 950 955 960 Ala Ala He Lys Asp Asn Arg Ala Val His Ala Asp Met Gly Tyr Trp 965 970 975 He Glu Ser Ala Leu Asn Asp Thr Trp Lys lie Glu Lys Ala Ser Phe 980 985 990 He Glu Val Lys Asn Cys His Trp Pro Lys Ser His Thr Leu Trp Ser 995 1000 1005 Asn Gly Val Leu Glu Ser Glu Met He He Pro Lys Asn Leu Ala Gly 1010 1015 1020 Pro Val Ser Gin His Asn Tyr Arg Pro Gly Tyr His Thr Gin lie Thr 1025 1030 1035 1040 Gly Pro Trp His Leu Gly Lys Leu Glu Met Asp Phe Asp Phe Cys Asp 1045 1050 1055 Gly Thr Thr Val Val Val Thr Glu Asp Cys Gly Asn Arg Gly Pro Ser 1060 1065 1070 Leu Arg Thr Thr Thr Ala Ser Gly Lys Leu He Thr Glu Trp Cys Cys 1075 1080 1085 Arg Ser Cys Thr Leu Pro Pro Leu Arg Tyr Arg Gly Glu Asp Gly Cys 1090 1095 1100 Trp Tyr Gly Met Glu He Arg Pro Leu Lys Glu Lys Glu Glu Asn Leu 1105 1110 1115 1120 Val Asn Ser Leu Val Thr Ala Gly His Gly Gin Val Asp Asn Phe Ser 1125 1130 1135

    166

    2018200081 04 Jan 2018

    Leu Gly Val Leu Gly Met Ala Leu Phe Leu Glu Glu Met Leu Arg Thr 1140 1145 1150 Arg Val Gly Thr Lys His Ala He Leu Leu Val Ala Val Ser Phe Val 1155 1160 1165 Thr Leu lie Thr Gly Asn Met Ser Phe Arg Asp Leu Gly Arg Val Met 1170 1175 1180 Val Met Val Gly Ala Thr Met Thr Asp Asp He Gly Met Gly Val Thr 1185 1190 1195 1200 Tyr Leu Ala Leu Leu Ala Ala Phe Lys Val Arg Pro Thr Phe Ala Ala 1205 i 1210 1215 Gly Leu Leu Leu Arg Lys Leu Thr Ser Lys Glu Leu Met Met Thr Thr 1220 1225 1230 lie Gly He Val Leu Leu Ser Gin Ser Thr He Pro Glu Thr He Leu 1235 1240 1245 Glu Leu Thr Asp Ala Leu Ala Leu Gly Met Met Val Leu Lys Met Val 1250 1255 1260 Arg Asn Met Glu Lys Tyr Gin Leu Ala Val Thr He Met Ala He Leu 1265 1270 1275 1280 Cys Val Pro Asn Ala Val He Leu Gin Asn Ala Trp Lys Val Ser Cys 1285 1290 1295 Thr He Leu Ala Val Val Ser Val Ser Pro Leu Leu Leu Thr Ser Ser 1300 1305 1310 Gin Gin Lys Thr Asp Trp He Pro Leu Ala Leu Thr He Lys Gly Leu 1315 1320 1325 Asn Pro Thr Ala He Phe Leu Thr Thr Leu Ser Arg Thr Ser Lys Lys 1330 1335 1340 Arg Ser Trp Pro Leu Asn Glu Ala He Met Ala Val Gly Met Val Ser 1345 1350 1355 1360 He Leu Ala Ser Ser Leu Leu Lys Asn Asp He Pro Met Thr Gly Pro 1365 1370 1375 Leu Val Ala Gly Gly Leu Leu Thr Val Cys Tyr Val Leu Thr Gly Arg 1380 1385 1390 Ser Ala Asp Leu Glu Leu Glu Arg Ala Ala Asp Val Lys Trp Glu Asp 1395 1400 1405 Gin Ala Glu He Ser Gly Ser Ser Pro He Leu Ser He Thr He Ser 1410 1415 1420 Glu Asp Gly Ser Met Ser He Lys Asn Glu Glu Glu Glu Gin Thr Leu 1425 1430 1435 1440 Thr He Leu He Arg Thr Gly Leu Leu Val He Ser Gly Leu Phe Pro 1445 1450 1455 Val Ser He Pro He Thr Ala Ala Ala Trp Tyr Leu Trp Glu Val Lys 1460 1465 1470 Lys Gin Arg Ala Gly Val Leu Trp Asp Val Pro Ser Pro Pro Pro Met 1475 1480 1485 Gly Lys Ala Glu Leu Glu Asp Gly Ala Tyr Arg He Lys Gin Lys Gly 1490 1495 1500 He Leu Gly Tyr Ser Gin He Gly Ala Gly Val Tyr Lys Glu Gly Thr 1505 1510 1515 1520 Phe His Thr Met Trp His Val Thr Arg Gly Ala Val Leu Met His Lys 1525 1530 1535 Gly Lys Arg He Glu Pro Ser Trp Ala Asp Val Lys Lys Asp Leu He 1540 1545 1550 Ser Tyr Gly Gly Gly Trp Lys Leu Glu Gly Glu Trp Lys Glu Gly Glu

    1555 1560 1565

    167

    2018200081 04 Jan 2018

    Glu Val 1570 Gin Val Leu Ala Leu Glu Pro Gly Lys Asn Pro Arg Ala Val 1575 1580 Gin Thr Lys Pro Gly Leu Phe Lys Thr Asn Ala Gly Thr lie Gly Ala 1585 1590 1595 1600 Val Ser Leu Asp Phe Ser Pro Gly Thr Ser Gly Ser Pro He lie Asp 1605 161C i 1615 Lys Lys Gly Lys Val Val Gly Leu Tyr Gly Asn Gly Val Val Thr Arg 1620 • 1625 1630 Ser Gly Ala Tyr Val Ser Ala lie Ala Gin Thr Glu Lys Ser He Glu 1635 1640 1645 Asp Asn Pro Glu He Glu Asp Asp He Phe Arg Lys Arg Arg Leu Thr 1650 1655 1660 lie Met Asp Leu His Pro Gly Ala Gly Lys Thr Lys Arg Tyr Leu Pro 1665 1670 1675 1680 Ala He Val Arg Glu Ala He Lys Arg Gly Leu Arg Thr Leu lie Leu 1685 1690 1695 Ala Pro Thr Arg Val Val Ala Ala Glu Met Glu Glu Ala Leu Arg Gly 1700 1705 1710 Leu Pro He Arg Tyr Gin Thr Pro Ala He Arg Ala Glu His Thr Gly 1715 1720 1725 Arg Glu He Val Asp Leu Met Cys His Ala Thr Phe Thr Met Arg Leu 1730 1735 1740 Leu Ser Pro Val Arg Val Pro Asn Tyr Asn Leu He He Met Asp Glu 1745 1750 1755 1760 Ala His Phe Thr Asp Pro Ala Ser He Ala Ala Arg Gly Tyr He Ser 1765 1770 1775 Thr Arg Val Glu Met Gly Glu Ala Ala Gly He Phe Met Thr Ala Thr 1780 1785 1790 Pro Pro Gly Ser Arg Asp Pro Phe Pro Gin Ser Asn Ala Pro He He 1795 1800 1805 Asp Glu Glu Arg Glu He Pro Glu Arg Ser Trp Asn Ser Gly His Glu 1810 1815 1820 Trp Val Thr Asp Phe Lys Gly Lys Thr Val Trp Phe Val Pro Ser He 1825 1830 1835 1840 Lys Ala Gly Asn Asp He Ala Ala Cys Leu Arg Lys Asn Gly Lys Lys 1845 1850 1855 Val He Gin Leu Ser Arg Lys Thr Phe Asp Ser Glu Tyr Val Lys Thr 1860 1865 1870 Arg Thr Asn Asp Trp Asp Phe Val Val Thr Thr Asp He Ser Glu Met 1875 1880 1885 Gly Ala Asn Phe Lys Ala Glu Arg Val He Asp Pro Arg Arg Cys Met 1890 1895 1900 Lys Pro Val He Leu Thr Asp Gly Glu Glu Arg Val He Leu Ala Gly 1905 1910 1915 1920 Pro Met Pro Val Thr His Ser Ser Ala Ala Gin Arg Arg Gly Arg He 1925 1930 1935 Gly Arg Asn Pro Lys Asn Glu Asn Asp Gin Tyr He Tyr Met Gly Glu 1940 1945 1950 Pro Leu Glu Asn Asp Glu Asp Cys Ala His Trp Lys Glu Ala Lys Met 1955 1960 1965 Leu Leu Asp Asn He Asn Thr Pro Glu Gly He He Pro Ser Met Phe 1970 1975 1980 Glu Pro Glu Arg Glu Lys Val Asp Ala He Asp Gly Glu Tyr Arg Leu 1985 1990 1995 2000

    168

    2018200081 04 Jan 2018

    Arg Gly Glu Ala Arg Lys Thr Phe Val Asp Leu Met Arg Arg Gly Asp 2005 2010 2015 Leu Pro Val Trp Leu Ala Tyr Arg Val Ala Ala Glu Gly He Asn Tyr 2020 2025 2030 Ala Asp Arg Arg Trp Cys Phe Asp Gly Val Lys Asn Asn Gin He Leu 2035 204C 1 2045 Glu Glu Asn Val Glu Val Glu He Trp Thr Lys Glu Gly Glu Arg Lys 2050 2055 2060 Lys Leu Lys Pro Arg Trp Leu Asp Ala Arg He Tyr Ser Asp Pro Leu 2065 1 2070 . 2075 2080 Ala Leu Lys Glu Phe Lys Glu Phe Ala Ala Gly Arg Lys Ser Leu Thr 2085 2090 2095 Leu Asn Leu He Thr Glu Met Gly Arg Leu Pro Thr Phe Met Thr Gin 2100 2105 ' 2110 Lys Ala Arg Asp Ala Leu Asp Asn Leu Ala Val Leu His Thr Ala Glu 2115 2120 2125 Ala Gly Gly Arg Ala Tyr Asn His Ala Leu Ser Glu Leu Pro Glu Thr 2130 2135 2140 Leu Glu Thr Leu Leu Leu Leu Thr Leu Leu Ala Thr Val Thr Gly Gly 2145 ί 2150 2155 2160 lie Phe Leu Phe Leu Met Ser Gly Arg Gly He Gly Lys Met Thr Leu 2165 2170 2175 Gly Met Cys Cys lie He Thr Ala Ser He Leu Leu Trp Tyr Ala Gin 2180 2185 2190 lie Gin Pro His Trp He Ala Ala Ser He lie Leu Glu Phe Phe Leu 2195 2200 2205 He Val Leu Leu He Pro Glu Pro Glu Lys Gin Arg Thr Pro Gin Asp 2210 2215 2220 Asn Gin Leu Thr Tyr Val Val He Ala He Leu Thr Val Val Ala Ala 2225 1 2230 2235 2240 Thr Met Ala Asn Glu Met Gly Phe Leu Glu Lys Thr Lys Lys Asp Leu 2245 2250 2255 Gly Leu Gly Ser lie Ala Thr Gin Gin Pro Glu Ser Asn He Leu Asp 2260 2265 2270 He Asp Leu Arg Pro Ala Ser Ala Trp Thr Leu Tyr Ala Val Ala Thr 2275 2280 2285 Thr Phe Val Thr Pro Met Leu Arg His Ser He Glu Asn Ser Ser Val 2290 2295 2300 Asn Val Ser Leu Thr Ala lie Ala Asn Gin Ala Thr Val Leu Met Gly 2305 2310 2315 2320 Leu Gly Lys Gly Trp Pro Leu Ser Lys Met Asp lie Gly Val Pro Leu 2325 2330 2335 Leu Ala He Gly Cys Tyr Ser Gin Val Asn Pro lie Thr Leu Thr Ala 2340 2345 2350 Ala Leu Phe Leu Leu Val Ala His Tyr Ala He He Gly Pro Gly Leu 2355 2360 2365 Gin Ala Lys Ala Thr Arg Glu Ala Gin Lys Arg Ala Ala Ala Gly lie 2370 2375 2380 Met Lys Asn Pro Thr Val Asp Gly He Thr Val He Asp Leu Asp Pro 2385 2390 2395 2400 lie Pro Tyr Asp Pro Lys Phe Glu Lys Gin Leu Gly Gin Val Met Leu 2405 2410 2415 Leu Val Leu Cys Val Thr Gin Val Leu Met Met Arg Thr Thr Trp Ala 2420 2425 2430

    169

    2018200081 04 Jan 2018

    Leu Cys Glu Ala Leu Thr Leu 2435 Ala Thr Gly 2440 Pro He Ser Thr Leu Trp 2445 Glu Gly Asn Pro Gly Arg Phe Trp Asn Thr Thr lie Ala Val Ser Met 2450 2455 2460 Ala Asn lie Phe Arg Gly Ser Tyr Leu Ala Gly Ala Gly Leu Leu Phe 2465 i 2470 2475 2480 Ser He Met Lys Asn Thr Thr Asn Thr Arg Arg Gly Thr Gly Asn He 2485 2490 2495 Gly Glu Thr Leu Gly Glu Lys Trp Lys Ser Arg Leu Asn Ala Leu Gly 2500 2505 . 2510 Lys Ser Glu Phe Gin He Tyr Lys Lys Ser Gly He Gin Glu Val Asp 2515 2520 2525 Arg Thr Leu Ala Lys Glu Gly He Lys Arg Gly Glu Thr Asp His His 2530 2535 2540 Ala Val Ser Arg Gly Ser Ala Lys Leu Arg Trp Phe Val Glu Arg Asn 2545 ; 2550 2555 2560 Met Val Thr Pro Glu Gly Lys Val Val Asp Leu Gly Cys Gly Arg Gly 2565 2570 2575 Gly Trp Ser Tyr Tyr Cys Gly Gly Leu Lys Asn Val Arg Glu Val Lys 2580 2585 2590 Gly Leu Thr Lys Gly Gly Pro Gly His Glu Glu Pro He Pro Met Ser 2595 2600 2605 Thr Tyr Gly Trp Asn Leu Val Arg Leu Gin Ser Gly Val Asp Val Phe 2610 2615 2620 Phe He Pro Pro Glu Lys Cys Asp Thr Leu Leu Cys Asp He Gly Glu 2625 i 2630 2635 2640 Ser Ser Pro Asn Pro Thr Val Glu Ala Gly Arg Thr Leu Arg Val Leu 2645 2650 2655 Asn Leu Val Glu Asn Trp Leu Asn Asn Asn Thr Gin Phe Cys He Lys 2660 2665 2670 Val Leu Asn Pro Tyr Met Pro Ser Val He Glu Lys Met Glu Ala Leu 2675 2680 2685 Gin Arg Lys Tyr Gly Gly Ala Leu Val Arg Asn Pro Leu Ser Arg Asn 2690 2695 2700 Ser Thr His Glu Met Tyr Trp Val Ser Asn Ala Ser Gly Asn He Val 2705 i 2710 2715 2720 Ser Ser Val Asn Met He Ser Arg Met Leu He Asn Arg Phe Thr Met 2725 2730 2735 Arg Tyr Lys Lys Ala Thr Tyr Glu Pro Asp Val Asp Leu Gly Ser Gly 2740 2745 2750 Thr Arg Asn He Gly He Glu Ser Glu He Pro Asn Leu Asp He He 2755 2760 2765 Gly Lys Arg He Glu Lys He Lys Gin Glu His Glu Thr Ser Trp His 2770 2775 2780 Tyr Asp Gin Asp His Pro Tyr Lys Thr Trp Ala Tyr His Gly Ser Tyr 2785 2790 2795 2800 Glu Thr Lys Gin Thr Gly Ser Ala Ser Ser Met Val Asn Gly Val Val 2805 2810 2815 Arg Leu Leu Thr Lys Pro Trp Asp Val Val Pro Met Val Thr Gin Met 2820 2825 2830 Ala Met Thr Asp Thr Thr Pro Phe Gly Gin Gin Arg Val Phe Lys Glu 2835 2840 2845 Lys Val Asp Thr Arg Thr Gin Glu Pro Lys Glu Gly Thr Lys Lys Leu 2850 2855 2860

    170

    2018200081 04 Jan 2018

    Met Lys He Thr Ala Glu Trp Leu Trp Lys Glu Leu Gly Lys Lys Lys 2865 2870 2875 2880 Thr Pro Arg Met Cys Thr Arg Glu Glu Phe Thr Arg Lys Val Arg Ser 2885 2890 2895 Asn Ala Ala Leu Gly Ala He Phe Thr Asp Glu Asn Lys Trp Lys Ser 2900 2905 2910 Ala Arg Glu Ala Val Glu Asp Ser Arg Phe Trp Glu Leu Val Asp Lys 2915 2920 2925 Glu Arg Asn Leu His Leu Glu Gly Lys Cys Glu Thr, Cys Val Tyr Asn 2930 2935 2940 Met Met Gly Lys Arg Glu Lys Lys Leu Gly Glu Phe Gly Lys Ala Lys 2945 2950 2955 2960 Gly Ser Arg Ala lie Trp Tyr Met Trp Leu Gly Ala Arg Phe Leu Glu 2965 2970 2975 Phe Glu Ala Leu Gly Phe Leu Asn Glu Asp His Trp Phe Ser Arg Glu 2980 2985 2990 Asn Ser Leu Ser Gly Val Glu Gly Glu Gly Leu His Lys Leu Gly Tyr 2995 3000 3005 lie Leu Arg Asp Val Ser Lys Lys Glu Gly Gly Ala Met Tyr Ala Asp 3010 3015 3020 Asp Thr Ala Gly Trp Asp Thr Arg lie Thr Leu Glu Asp Leu Lys Asn 3025 3030 3035 3040 Glu Glu Met Val Thr Asn His Met Glu Gly Glu His Lys Lys Leu Ala 3045 3050 3055 Glu Ala lie Phe Lys Leu Thr Tyr Gin Asn Lys Val Val Arg Val Gin 3060 3065 3070 Arg Pro Thr Pro Arg Gly Thr Val Met Asp He He Ser Arg Arg Asp 3075 3080 3085 Gin Arg Gly Ser Gly Gin Val Gly Thr Tyr Gly Leu Asn Thr Phe Thr 3090 3095 3100 Asn Met Glu Ala Gin Leu He Arg Gin Met Glu Gly Glu Gly Val Phe 3105 3110 3115 3120 Lys Ser He Gin His Leu Thr He Thr Glu Glu He Ala Val Gin Asn 3125 3130 3135 Trp Leu Ala Arg Val Gly Arg Glu Arg Leu Ser Arg Met Ala He Ser 3140 3145 3150 Gly Asp Asp Cys Val Val Lys Pro Leu Asp Asp Arg Phe Ala Ser Ala 3155 3160 3165 Leu Thr Ala Leu Asn Asp Met Gly Lys He Arg Lys Asp He Gin Gin 3170 3175 3180 Trp Glu Pro Ser Arg Gly Trp Asn Asp Trp Thr Gin Val Pro Phe Cys 3185 3190 3195 3200 Ser His His Phe His Glu Leu He Met Lys Asp Gly Arg Val Leu Val 3205 3210 3215 Val Pro Cys Arg Asn Gin Asp Glu Leu He Gly Arg Ala Arg He Ser 3220 3225 3230 Gin Gly Ala Gly Trp Ser Leu Arg Glu Thr Ala Cys Leu Gly Lys Ser 3235 3240 3245 Tyr Ala Gin Met Trp Ser Leu Met Tyr Phe His Arg Arg Asp Leu Arg 3250 3255 3260 Leu Ala Ala Asn Ala He Cys Ser Ala Val Pro Ser His Trp Val Pro 3265 3270 3275 3280 Thr Ser Arg Thr Thr Trp Ser He His Ala Lys His Glu Trp Met Thr 3285 3290 3295

    171

    2018200081 04 Jan 2018

    Thr Glu Asp Met Leu Thr Val Trp Asn Arg Val Trp He Gin Glu 3310 Asn 3300 3305 Pro Trp Met Glu Asp Lys Thr Pro Val Glu Ser Trp Glu Glu He Pro 331E ί 3320 3325 Tyr Leu Gly Lys Arg Glu Asp Gin Trp Cys Gly Ser Leu He Gly Leu 3330 3335 ' 3340 Thr Ser Arg Ala Thr Trp Ala Lys Asn He Gin Ala Ala He Asn Gin 3345 3350 3355 3360 Val Arg Ser Leu lie Gly Asn Glu Glu Tyr Thr Asp Tyr Met Pro Ser 3365 3370 3375 Met Lys Arg Phe Arg Arg Glu Glu Glu Glu Ala Gly Val Leu Trp

    3380 3385 3390 <210> 15 <211> 10723 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <221> CDS <222> (97)...(10272) <400> 15 agttgttagt ctacgtggac cgacaaagac agattctttg agggagctaa gctcaatgta 60 gttctaacag ttttttaatt agagagcaga tctctg atg aat aac caa egg aaa 114

    Met Asn Asn Gin Arg Lys 1 5

    aag gcg aaa aac acg cct Thr Pro ttc aat Phe Asn atg ctg aaa ege gag aga Arg 20 aac Asn ege Arg 162 Lys Ala Lys Asn 10 Met 15 Leu Lys Arg Glu gtg teg act gtg caa cag ctg aca aag aga ttc tea ctt gga atg ctg 210 Val Ser Thr Val Gin Gin Leu Thr Lys Arg Phe Ser Leu Gly Met Leu 25 30 35 cag gga ega gga cca tta aaa ctg ttc atg gcc ctg gtg gcg ttc ctt 258 Gin Gly Arg Gly Pro Leu Lys Leu Phe Met Ala Leu Val Ala Phe Leu 40 45 50 cgt ttc eta aca ate cca cca aca gca ggg ata ttg aag aga tgg gga 306 Arg Phe Leu Thr lie Pro Pro Thr Ala Gly He Leu Lys Arg Trp Gly 55 60 65 70 aca att aaa aaa tea aaa get att aat gtt ttg aga ggg ttc agg aaa 354 Thr He Lys Lys Ser Lys Ala lie Asn Val Leu Arg Gly Phe Arg Lys 75 80 85 gag att gga agg atg ctg aac ate ttg aat agg aga ege aga tet gca 402 Glu He Gly Arg Met Leu Asn He Leu Asn Arg Arg Arg Arg Ser Ala

    90 95 100

    172

    2018200081 04 Jan 2018

    ggc Gly atg ate att lie atg ctg Met Leu att He cca Pro 110 aca gtg atg gcg ttc cat His tta Leu acc Thr 450 Met lie 105 Thr Val Met Ala Phe 115 aca cgt aac gga gaa cca cac atg ate gtc age aga caa gag aaa ggg 498 Thr Arg Asn Gly Glu Pro His Met lie Val Ser Arg Gin Glu Lys Gly 120 125 130 aaa agt ett ctg ttt aaa aca gag gtt ggc gtg aac atg tgt acc etc 546 Lys Ser Leu Leu Phe Lys Thr Glu Val Gly Val Asn Met Cys Thr Leu 135 140 145 150 atg gcc atg gac ett ggt gaa ttg tgt gaa gac aca ate aeg tac aag 594 Met Ala Met Asp Leu Gly Glu Leu Cys Glu Asp Thr He Thr Tyr Lys 155 160 165 tgt ccc ett etc agg cag aat gag cca gaa gac ata gac tgt tgg tgc 642 Cys Pro Leu Leu Arg Gin Asn Glu Pro Glu Asp He Asp Cys Trp Cys 170 175 180 aac tct aeg tcc aeg tgg gta act tat ggg aeg tgt acc acc atg gga 690 Asn Ser Thr Ser Thr Trp Val Thr Tyr Gly Thr Cys Thr Thr Met Gly 185 190 195 gaa cat aga aga gaa aaa aga tea gtg gca etc gtt cca cat gtg gga 738 Glu His Arg Arg Glu Lys Arg Ser Val Ala Leu Val Pro His Val Gly 200 205 210 atg gga ctg gag aca ega act gaa aca tgg atg tea tea gaa ggg gcc 786 Met Gly Leu Glu Thr Arg Thr Glu Thr Trp Met Ser Ser Glu Gly Ala 215 220 225 230 tgg aaa cat gtc cag aga att gaa act tgg ate ttg aga cat cca ggc 834 Trp Lys His Val Gin Arg He Glu Thr Trp He Leu Arg His Pro Gly 235 240 245 ttc acc atg atg gca gca ate ctg gca tac acc ata gga aeg aca cat 882 Phe Thr Met Met Ala Ala He Leu Ala Tyr Thr He Gly Thr Thr His 250 255 260 ttc caa aga gcc ctg att ttc ate tta ctg aca get gtc act cct tea 930 Phe Gin Arg Ala Leu He Phe He Leu Leu Thr Ala Val Thr Pro Ser 265 270 275 atg aca atg cgt tgc ata gga atg tea aat aga gac ttt gtg gaa ggg 978 Met Thr Met Arg Cys He Gly Met Ser Asn Arg Asp Phe Val Glu Gly 280 285 290 gtt tea gga gga age tgg gtt gac ata gtc tta gaa cat gga age tgt 1026 Val Ser Gly Gly Ser Trp Val Asp He Val Leu Glu His Gly Ser Cys 295 300 305 310

    173

    2018200081 04 Jan 2018

    gtg Val aeg' aeg atg gca aaa Lys aac Asn aaa Lys cca Pro aca ttg gat Asp ttt Phe gaa Glu ctg Leu 325 ata lie 1074 Thr Thr Met Ala 315 Thr 320 Leu aaa aca gaa gcc aaa cag cct gcc acc eta agg aag tac tgt ata gag 1122 Lys Thr Glu Ala 330 Lys Gin Pro Ala Thr 335 Leu Arg Lys Tyr Cys 340 He Glu gca aag eta acc aac aca aca aca gaa tct cgc tgc cca aca caa ggg 1170 Ala Lys Leu 345 Thr Asn Thr Thr Thr 350 Glu Ser Arg Cys Pro 355 Thr Gin Gly gaa ccc age eta aat gaa gag cag gac aaa agg ttc gtc tgc aaa cac 1218 Glu Pro 360 Ser Leu Asn Glu Glu 365 Gin Asp Lys Arg Phe 370 Val Cys Lys His tcc atg gta gac aga gga tgg gga aat gga tgt gga eta ttt gga aag 1266 Ser 375 Met Val Asp Arg Gly 380 Trp Gly Asn Gly Cys 385 Gly Leu Phe Gly Lys 390 gga ggc att gtg acc tgt get atg ttc aga tgc aaa aag aac atg gaa 1314 Gly Gly lie Val Thr 395 Cys Ala Met Phe Arg 400 Cys Lys Lys Asn Met 405 Glu gga aaa gtt gtg caa cca gaa aac ttg gaa tac acc att gtg ata aca 1362 Gly Lys Val Val 410 Gin Pro Glu Asn Leu 415 Glu Tyr Thr He Val 420 He Thr cct cac tea ggg gaa gag cat gca gtc gga aat gac aca gga aaa cat 1410 Pro His Ser 425 Gly Glu Glu His Ala 430 Val Gly Asn Asp Thr 435 Gly Lys His ggc aag gaa ate aaa ata aca cca cag agt tcc ate aca gaa gca gaa 1458 Gly Lys 440 Glu He Lys He Thr 445 Pro Gin Ser Ser He 450 Thr Glu Ala Glu ttg aca ggt tat ggc act gtc aca atg gag tgc tct cca aga aeg ggc 1506 Leu 455 Thr Gly Tyr Gly Thr 460 Val Thr Met Glu Cys 465 Ser Pro Arg Thr Gly 470 etc gac ttc aat gag atg gtg ttg ctg cag atg gaa aat aaa get tgg 1554 Leu Asp Phe Asn Glu 475 Met Val Leu Leu Gin 480 Met Glu Asn Lys Ala 485 Trp ctg gtg cac agg caa tgg ttc eta gac ctg ccg tta cca tgg ttg ccc 1602 Leu Val His Arg 490 Gin Trp Phe Leu Asp 495 Leu Pro Leu Pro Trp 500 Leu Pro gga gcg gac aca caa ggg tea aat tgg ata cag aaa gag aca ttg gtc 1650 Gly Ala Asp 505 Thr Gin Gly Ser Asn 510 Trp He Gin Lys Glu 515 Thr Leu Val act ttc aaa aat ccc cat gcg aag aaa cag gat gtt gtt gtt tta gga 1698 Thr Phe 520 Lys Asn Pro His Ala 525 Lys Lys Gin Asp Val 530 Val Val Leu Gly

    174

    2018200081 04 Jan 2018

    tcc Ser 535 caa Gin gaa Glu ggg Gly gcc Ala atg cac aca gca Thr Ala ett Leu aca ggg gcc Thr Gly Ala 545 aca Thr gaa Glu ate He 550 1746 Met 540 His caa atg tea tea gga aac tta etc ttc aca gga cat etc aag tgc agg 1794 Gin Met Ser Ser Gly Asn Leu Leu Phe Thr Gly His Leu Lys Cys Arg 555 560 565 ctg aga atg gac aag eta cag etc aaa gga atg tea tac tet atg tgc 1842 Leu Arg Met Asp Lys Leu Gin Leu Lys Gly Met Ser Tyr Ser Met Cys 570 575 580 aca gga aag ttt aaa gtt gtg aag gaa ata gca gaa aca caa cat gga 1890 Thr Gly Lys Phe Lys Val Val Lys Glu He Ala Glu Thr Gin His Gly 585 590 595 aca ata gtt ate aga gtg caa tat gaa ggg gac ggc tet cca tgc aag 1938 Thr lie Val He Arg Val Gin Tyr Glu Gly Asp Gly Ser Pro Cys Lys 600 605 610 ate cct ttt gag ata atg gat ttg gaa aaa aga cat gtc tta ggt ege 1986 lie Pro Phe Glu He Met Asp Leu Glu Lys Arg His Val Leu Gly Arg 615 620 625 630 ctg att aca gtc aac cca att gtg aca gaa aaa gat age cca gtc aac 2034 Leu He Thr Val Asn Pro He Val Thr Glu Lys Asp Ser Pro Val Asn 635 640 645 ata gaa gca gaa cct cca ttt gga gac age tac ate ate ata gga gta 2082 He Glu Ala Glu Pro Pro Phe Gly Asp Ser Tyr He He He Gly Val 650 655 660 gag ccg gga caa ctg aag etc aac tgg ttt aag aaa gga agt tet ate 2130 Glu Pro Gly Gin Leu Lys Leu Asn Trp Phe Lys Lys Gly Ser Ser He 665 670 675 ggc caa atg ttt gag aca aca atg agg ggg geg aag aga atg gcc att 2178 Gly Gin Met Phe Glu Thr Thr Met Arg Gly Ala Lys Arg Met Ala He ' 680 685 690 tta ggt gac aca gcc tgg gat ttt gga tcc ttg gga gga gtg ttt aca 2226 Leu Gly Asp Thr Ala Trp Asp Phe Gly Ser Leu Gly Gly Val Phe Thr 695 700 705 710 tet ata gga aag get etc cac caa gtc ttt gga gca ate tat gga get 2274 Ser He Gly Lys Ala Leu His Gin Val Phe Gly Ala lie Tyr Gly Ala 715 720 725 gcc ttc agt ggg gtt tea tgg act atg aaa ate etc ata gga gtc att 2322 Ala Phe Ser Gly Val Ser Trp Thr Met Lys lie Leu He Gly Val He 730 735 740

    175

    2370

    2018200081 04 Jan 2018

    ate aca tgg ata gga atg aat tea ege age acc tea ctg tet gtg aca lie Thr Trp 745 He Gly Met Asn Ser 750 Arg Ser Thr Ser Leu 755 Ser Val Thr eta gta ttg gtg gga att gtg aca ctg tat ttg gga gtc atg gtg cag Leu Val 760 Leu Val Gly He Val 765 Thr Leu Tyr Leu Gly 770 Val Met Val Gin gee gat agt ggt tgc gtt gtg age tgg aaa aac aaa gaa ctg aaa tgt Ala 775 Asp Ser Gly Cys Val 780 Val Ser Trp Lys Asn 785 Lys Glu Leu Lys Cys 790 ggc agt ggg att ttc ate aca gac aac gtg cac aca tgg aca gaa caa Gly Ser Gly lie Phe 795 He Thr Asp Asn Val 800 His Thr Trp Thr Glu 805 Gin tac aag ttc caa cca gaa tcc cct tea aaa eta get tea get ate cag Tyr Lys Phe Gin 810 Pro Glu Ser Pro Ser 815 Lys Leu Ala Ser Ala 820 He Gin aaa gcc cat gaa gag gac att tgt gga ate ege tea gta aca aga ctg Lys Ala His 825 Glu Glu Asp He Cys 830 Gly He Arg Ser Val 835 Thr Arg Leu gag aat ctg atg tgg aaa caa ata aca cca gaa ttg aat cac att eta Glu Asn 840 Leu Met Trp Lys Gin 845 He Thr Pro Glu Leu 850 Asn His He Leu tea gaa aat gag gtg aag tta act att atg aca gga gac ate aaa gga Ser 855 Glu Asn Glu Val Lys 860 Leu Thr He Met Thr 865 Gly Asp He Lys Gly 870 ate atg cag gca gga aaa ega tet ctg egg cct cag ccc act gag ctg lie Met Gin Ala Gly 875 Lys Arg Ser Leu Arg 880 Pro Gin Pro Thr Glu 885 Leu aag tat tea tgg aaa aca tgg ggc aaa gca aaa atg etc tet aca gag Lys Tyr Ser Trp 890 Lys Thr Trp Gly Lys 895 Ala Lys Met Leu Ser 900 Thr Glu tet cat aac cag acc ttt etc att gat ggc ccc gaa aca gca gaa tgc Ser His Asn 905 Gin Thr Phe Leu He 910 Asp Gly Pro Glu Thr 915 Ala Glu Cys ccc aac aca aat aga get tgg aat teg ttg gaa gtt gaa gac tat ggc Pro Asn 920 Thr Asn Arg Ala Trp 925 Asn Ser Leu Glu Val 930 Glu Asp Tyr Gly ttt gga gta ttc acc acc aat ata tgg eta aaa ttg aaa gaa aaa cag Phe 935 Gly Val Phe Thr Thr 940 Asn He Trp Leu Lys 945 Leu Lys Glu Lys Gin 950 gat gta ttc tgc gac tea aaa etc atg tea geg gcc ata aaa gac aac Asp Val Phe Cys Asp 955 Ser Lys Leu Met Ser 960 Ala Ala He Lys Asp 965 Asn

    2418

    2466

    2514

    2562

    2610

    2658

    2706

    2754

    2802

    2850

    2898

    2946

    2994

    176

    2018200081 04 Jan 2018

    aga Arg gcc gtc Ala Val cat His 970 gcc gat Ala Asp atg ggt tat Tyr 975 tgg ata gaa agt gca etc aat Asn 3042 Met Gly Trp He Glu Ser Ala 980 Leu gac aca tgg aag ata gag aaa gcc tet ttc att gaa gtt aaa aac tgc 3090 Asp Thr Trp 985 Lys He Glu Lys Ala 990 Ser 1 Phe He Glu Val 995 Lys Asn Cys cac tgg cca aaa tea cac acc etc tgg agc aat gga gtg eta gaa agt 3138 His Trp Pro 1000 Lys Ser His Thr Leu 1005 Trp Ser Asn Gly Val 1010 Leu Glu Ser gag atg ata att cca aag aat etc get gga cca gtg tet caa cac aac 3186 Glu 1015 Met lie He Pro Lys Asn 1020 Leu Ala Gly Pro Val 1025 Ser Gin His Asn 1030 tat aga cca ggc tac cat aca caa ata aca gga cca tgg cat eta ggt 3234 Tyr Arg Pro Gly Tyr His 1035 Thr Gin He Thr Gly 1040 Pro Trp His Leu Gly 1045 aag ctt gag atg gac ttt gat ttc tgt gat gga aca aca gtg gta gtg 3282 Lys Leu Glu Met Asp Phe 1050 Asp Phe Cys Asp 1055 Gly Thr Thr Val Val 1060 Val act gag gac tgc gga aat aga gga ccc tet ttg aga aca acc act gcc 3330 Thr Glu Asp Cys 1065 Gly Asn Arg Gly Pro 1070 Ser Leu Arg Thr Thr 1075 Thr Ala tet gga aaa etc ata aca gaa tgg tgc tgc cga tet tgc aca tta cca 3378 Ser Gly Lys 1080 Leu He Thr Glu Trp 1085 Cys Cys Arg Ser Cys 1090 Thr Leu Pro ccg eta aga tac aga ggt gag gat ggg tgc tgg tac ggg atg gaa ate 3426 Pro Leu Arg 1095 Tyr Arg Gly Glu 1100 Asp Gly Cys Trp Tyr 1105 Gly Met Glu He 1110 aga cca ttg aag gag aaa gaa gag aat ttg gtc aac tcc ttg gtc aca 3474 Arg Pro Leu Lys Glu Lys 1115 Glu Glu Asn Leu Val 1120 Asn Ser Leu Val Thr 1125 get gga cat ggg cag gtc gac aac ttt tea eta gga gtc ttg gga atg 3522 Ala Gly His Gly Gin Val 1130 Asp Asn Phe Ser 1135 Leu Gly Val Leu Gly 1140 Met gca ttg ttc ctg gag gaa atg ctt agg acc cga gta gga aeg aaa cat 3570 Ala Leu Phe Leu 1145 Glu Glu Met Leu Arg 1150 Thr Arg Val Gly Thr 1155 Lys His gca ata eta eta gtt gca gtt tet ttt gtg aca ttg ate aca ggg aac 3618 Ala He Leu Leu Val Ala Val Ser Phe Val Thr Leu lie Thr Gly Asn

    1160 1165 1170

    177

    2018200081 04 Jan 2018

    atg tcc Met Ser 1175 ttt Phe aga Arg gac Asp ctg gga Leu Gly 1180 aga Arg gtg Val atg Met gtt atg Val Met 1185 gta Val ggc Gly gcc Ala act Thr 1190 3666 atg aeg gat gac ata ggt atg ggc gtg act tat ett gcc eta eta gca 3714 Met Thr Asp Asp He 1195 Gly Met Gly Val Thr 120C Tyr Leu 1 Ala Leu Leu 1205 Ala gcc ttc aaa gtc aga cca act ttt gca get gga eta etc ttg aga aag 3762 Ala Phe Lys Val Arg 1210 Pro Thr Phe Ala Ala 1215 Gly Leu Leu Leu Arg 1220 Lys ctg acc tcc aag gaa ttg atg atg act act ata gga att gta etc etc 3810 Leu Thr Ser Lys 1225 Glu Leu Met Met Thr 1230 Thr He Gly He Val 1235 Leu Leu tcc cag age acc ata cca gag acc att ett gag ttg act gat geg tta 3858 Ser Gin Ser 1240 Thr He Pro Glu Thr 1245 He Leu Glu Leu Thr 1250 Asp Ala Leu gcc tta ggc atg atg gtc etc aaa atg gtg aga aat atg gaa aag tat 3906 Ala Leu 1255 Gly Met Met Val Leu 1260 Lys Met Val Arg Asn 1265 Met Glu Lys Tyr 1270 caa ttg gca gtg act ate atg get ate ttg tgc gtc cca aac gca gtg 3954 Gin Leu Ala Val Thr He Met 1275 Ala He Leu Cys Val 1280 Pro Asn Ala Val 1285 ata tta caa aac gca tgg aaa gtg agt tgc aca ata ttg gca gtg gtg 4002 lie Leu Gin Asn Ala 1290 Trp Lys Val Ser Cys 1295 Thr He Leu Ala Val 1300 Val tcc gtt tcc cca ctg ttc tta aca tcc tea cag caa aaa aca gat tgg 4050 Ser Val Ser Pro 1305 Leu Phe Leu Thr Ser 1310 Ser Gin Gin Lys Thr 1315 Asp Trp ata cca tta gca ttg aeg ate aaa ggt etc aat cca aca get att ttt 4098 He Pro Leu 1320 Ala Leu Thr He Lys 1325 Gly Leu Asn Pro Thr 1330 Ala He Phe eta aca acc etc tea aga acc age aag aaa agg agc tgg cca tta aat 4146 Leu Thr 1335 Thr Leu Ser Arg Thr 1340 Ser Lys Lys Arg Ser 1345 Trp Pro Leu Asn 1350 gag get ate atg gca gtc ggg atg gtg age att tta gcc agt tet etc 4194 Glu Ala He Met Ala Val Gly 1355 Met Val Ser He Leu 1360 Ala Ser Ser Leu 1365 eta aaa aat gat att ccc atg aca gga cca tta gtg get gga ggg etc 4242 Leu Lys Asn Asp He 1370 Pro Met Thr Gly Pro 1375 Leu Val Ala Gly Gly 1380 Leu etc act gtg tgc tac gtg etc act gga ega teg gcc gat ttg gaa ctg 4290 Leu Thr Val Cys Tyr Val Leu Thr Gly Arg Ser Ala Asp Leu Glu Leu

    1385 1390 1395

    178

    2018200081 04 Jan 2018

    gag aga gca gcc Ala gat Asp gtc Val aaa tgg Lys Trp 1405 gaa Glu gac Asp cag gca gag Gin Ala Glu 1410 ata He tea gga 4338 Glu Arg Ala 1400 Ser Gly agc agt cca ate ctg tea ata aca ata tea gaa gat ggt agc atg teg 4386 Ser 1415 Ser Pro He Leu Ser 1420 He Thr 1 He Ser Glu Asp Gly 1425 Ser Met Ser 1430 ata aaa aat gaa gag gaa gaa caa aca ctg acc ata etc att aga aca 4434 lie Lys Asn. Glu Glu 1435 Glu Glu Gin Thr Leu 144C Thr He Leu I He Arg 1445 Thr gga ttg ctg gtg ate tea gga ett ttt cct gta tea ata cca ate aeg 4482 Gly Leu Leu Val He 1450 Ser Gly Leu Phe Pro 1455 Val Ser He Pro He 1460 Thr gca gca gca tgg tac ctg tgg gaa gtg aag aaa caa cgg gcc gga gta 4530 Ala Ala Ala Trp 1465 Tyr Leu Trp Glu Val 1470 Lys Lys Gin Arg Ala 1475 Gly Val ttg tgg gat gtt cct tea ccc cca ccc atg gga aag get gaa ctg gaa 4578 Leu Trp Asp 1480 Val Pro Ser Pro Pro 1485 Pro Met Gly Lys Ala 1490 Glu Leu Glu gat gga gcc tat aga att aag caa aaa ggg att ett gga tat tcc cag 4626 Asp Gly Ala 1495 Tyr Arg He 150C Lys Gin I Lys Gly He Leu Gly 1505 Tyr Ser Gin 1510 ate gga gcc gga gtt tac aaa gaa gga aca ttc cat aca atg tgg cat 4674 He Gly Ala Gly Val Tyr 1515 Lys Glu Gly Thr Phe His Thr 1520 Met Trp His 1525 gtc aca cgt ggc get gtt eta atg cat aaa gga aag agg att gaa cca 4722 Val Thr Arg Gly Ala 1530 Val Leu Met His Lys 1535 Gly Lys Arg He Glu 1540 Pro tea tgg geg gac gtc aag aaa gac eta ata tea tat gga gga ggc tgg 4770 Ser Trp Ala Asp 1545 Val Lys Lys Asp Leu 1550 He Ser Tyr Gly Gly 1555 Gly Trp aag tta gaa gga gaa tgg aag gaa gga gaa gaa gtc cag gta ttg gca 4818 Lys Leu Glu 1560 Gly Glu Trp Lys Glu 1565 Gly Glu Glu Val Gin 1570 Val Leu Ala ctg gag cct gga aaa aat cca aga gcc gtc caa aeg aaa cct ggt ett 4866 Leu Glu Pro 1575 Gly Lys Asn Pro Arg 1580 Ala Val Gin Thr Lys 1585 Pro Gly Leu 1590 ttc aaa acc aac gcc gga aca ata ggt get gta tet ctg gac ttt tet 4914 Phe Lys Thr Asn Ala Gly Thr He 1595 Gly Ala Val Ser Leu 1600 Asp Phe Ser 1605

    179

    2018200081 04 Jan 2018

    cct Pro gga Gly aeg Thr tea gga tet Ser Gly Ser 1610 cca Pro att He ate gac He Asp 1615 aaa Lys aaa Lys gga Gly aaa gtt Lys Val 1620 gtg Val 4962 ggt ett tat ggt aat ggt gtt gtt aca agg agt gga gca tat gtg agt 5010 Gly Leu Tyr Gly Asn Gly 1625 Val Val 163C Thr Arg I Ser Gly Ala Tyr Val 1635 Ser get ata gee cag act gaa aaa age att gaa gac aac cca gag ate gaa 5058 Ala He 164C Ala 1 Gin Thr Glu Lys 1645 Ser He Glu Asp Asn Pro 1650 Glu He Glu gat gac att ttc ega aag aga aga ctg acc ate atg gac etc cac cca 5106 Asp 1655 Asp He Phe Arg Lys 166C Arg 1 Arg Leu Thr He 1665 Met Asp Leu His Pro 1670 gga gcg gga aag aeg aag aga tac ett ccg gcc ata gtc aga gaa get 5154 Gly Ala Gly Lys Thr Lys 1675 Arg Tyr Leu Pro Ala 1680 He Val Arg Glu Ala 1685 ata aaa egg ggt ttg aga aca tta ate ttg gcc ccc act aga gtt gtg 5202 lie Lys Arg Gly Leu Arg 1690 Thr Leu He Leu 1695 Ala Pro Thr Arg Val 1700 Val gca get gaa atg gag gaa gee ett aga gga ett cca ata aga tac cag 5250 Ala Ala Glu Met Glu Glu 1705 Ala Leu Arg Gly 1710 Leu Pro He Arg Tyr 1715 Gin acc cca gcc ate aga get gtg cac acc ggg egg gag att gtg gac eta 5298 Thr Pro Ala 1720 He Arg Ala Val His 1725 Thr Gly Arg Glu lie 1730 Val Asp Leu atg tgt cat gcc aca ttt acc atg agg Ctg eta tea cca gtt aga gtg 5346 Met 1735 Cys His Ala Thr Phe Thr 1740 Met Arg Leu Leu Ser 1745 Pro Val Arg Val 1750 cca aac tac aac ctg att ate atg gac gaa gee cat ttc aca gac cca 5394 Pro Asn Tyr Asn Leu lie 1755 He Met Asp Glu Ala 1760 His Phe Thr Asp Pro 1765 gca agt ata gca get aga gga tac ate tea act ega gtg gag atg ggt 5442 Ala Ser He Ala Ala Arg 1770 Gly Tyr He Ser 1775 Thr Arg Val Glu Met 1780 Gly gag gca get 999 att ttt atg aca gcc act ccc ccg gga age aga gac 5490 Glu Ala Ala Gly He Phe 1785 Met Thr Ala Thr 1790 Pro Pro Gly Ser Arg 1795 Asp cca ttt cct cag age aat gca cca ate ata gat gaa gaa aga gaa ate 5538 Pro Phe Pro 1800 Gin Ser Asn Ala Pro 1805 He He Asp Glu Glu 1810 Arg Glu He cct gaa ege teg tgg aat tcc gga cat gaa tgg gtc aeg gat ttt aaa 5586 Pro Glu Arg 1815 Ser Trp Asn Ser 1820 Gly His Glu Trp Val 1825 Thr Asp Phe Lys 1830

    2018200081 04 Jan 2018

    180 ggg aag act gtt tgg ttc gtt cca agt ata aaa gca gga aat gat ata 5634 Gly Lys Thr Val Trp Phe Val Pro Ser He Lys Ala Gly Asn Asp He 1835 1840 1845 gca get tgc ctg agg aaa aat gga aag aaa gtg ata caa etc agt agg 5682 Ala Ala Cys Leu Arg Lys Asn Gly Lys Lys Val lie Gin Leu Ser Arg 1850 1855 1860 aag acc ttt gat tet gag tat gtc aag act aga acc aat gat tgg gac 5730 Lys Thr Phe Asp Ser Glu Tyr Val Lys Thr Arg Thr Asn Asp Trp Asp 1865 1870 1875 ttc gtg gtt aca act gac att tea gaa atg ggt gcc aat ttc aag get 5778 Phe Val Val Thr Thr Asp lie Ser Glu Met Gly Ala Asn Phe Lys Ala 1880 1885 1890 gag agg gtt ata gac ccc aga cgc tgc atg aaa cca gtc ata eta aca 5826 Glu Arg Val He Asp Pro Arg Arg Cys Met Lys Pro Val He Leu Thr 1895 1900 1905 1910 gat ggt gaa gag egg gtg att ctg gca gga cct atg cca gtg acc cac 5874 Asp Gly Glu Glu Arg Val He Leu Ala Gly Pro Met Pro Val Thr His 1915 1920 1925 tet agt gca gca caa aga aga ggg aga ata gga aga aat cca aaa aat 5922 Ser Ser Ala Ala Gin Arg Arg Gly Arg He Gly Arg Asn Pro Lys Asn 1930 1935 1940 gag aat gac cag tac ata tac atg ggg gaa cct ctg gaa aat gat gaa 5970 Glu Asn Asp Gin Tyr He Tyr Met Gly Glu Pro Leu Glu Asn Asp Glu 1945 1950 1955 gac tgt gca cac tgg aaa gaa get aaa atg etc eta gat aac ate aac 6018 Asp Cys Ala His Trp Lys Glu Ala Lys Met Leu Leu Asp Asn He Asn 1960 1965 1970 aeg cca gaa gga ate att cct agc atg ttc gaa cca gag cgt gaa aag 6066 Thr Pro Glu Gly He He Pro Ser Met Phe Glu Pro Glu Arg Glu Lys 1975 1980 1985 1990 gtg gat gcc att gat ggc gaa tac cgc ttg aga gga gaa gca agg aaa 6114 Val Asp Ala He Asp Gly Glu Tyr Arg Leu Arg Gly Glu Ala Arg Lys 1995 2000 2005 acc ttt gta gac tta atg aga aga gga gac eta cca gtc tgg ttg gcc 6162 Thr Phe Val Asp Leu Met Arg Arg Gly Asp Leu Pro Val Trp Leu Ala 2010 2015 2020 tac aga gtg gca get gaa ggc ate aac tac gca gac aga agg tgg tgt 6210 Tyr Arg Val Ala Ala Glu Gly He Asn Tyr Ala Asp Arg Arg Trp Cys

    2025 2030 2035

    181

    2018200081 04 Jan 2018

    ttt Phe gat gga Asp Gly 2040 gtc Val aag Lys aac Asn aac caa Asn Gin 2045 ate He eta Leu gaa Glu gaa aac Glu Asn 2050 gtg Val gaa Glu gtt Val 6258 gaa ate tgg aca aaa gaa ggg gaa agg aag aaa ttg aaa ccc aga tgg 6306 Glu 2055 lie Trp Thr Lys Glu 2060 Gly Glu 1 Arg Lys Lys 2065 Leu Lys Pro Arg Trp 2070 ttg gat get agg ate tat tct gac cca ctg gcg eta aaa gaa ttt aag 6354 Leu Asp Ala Arg He Tyr 2075 Ser Asp Pro Leu Ala 2080 Leu Lys Glu Phe 2085 Lys gaa ttt gca gcc gga aga aag tct ctg acc ctg aac eta ate aca gaa 6402 Glu Phe Ala Ala Gly 2090 Arg Lys Ser Leu 2095 Thr Leu Asn Leu He Thr 2100 Glu atg ggt agg etc cca acc ttc atg act cag aag gca aga gac gca ctg 6450 Met Gly Arg Leu 2105 Pro Thr Phe Met Thr 2110 Gin Lys Ala Arg Asp 2115 Ala Leu gac aac tta gca gtg ctg cac aeg get gag gca ggt gga agg gcg tac 6498 Asp Asn Leu 2120 Ala Val Leu His Thr 2125 Ala Glu Ala Gly Gly 2130 Arg Ala Tyr aac cat get etc agt gaa ctg ccg gag acc ctg gag aca ttg ett tta 6546 Asn His Ala 2135 Leu Ser Glu 214C Leu Pro I Glu Thr Leu Glu Thr 2145 Leu Leu Leu 2150 ctg aca ett ctg get aca gtc aeg gga ggg ate ttt tta ttc ttg atg 6594 Leu Thr Leu Leu Ala Thr 2155 Val Thr Gly Gly lie 2160 Phe Leu Phe Leu Met 2165 age gca agg ggc ata ggg aag atg acc ctg gga atg tgc tgc ata ate 6642 Ser Ala Arg Gly He 2170 Gly Lys Met Thr Leu 2175 Gly Met Cys Cys lie 2180 He aeg get age ate etc eta tgg tac gca caa ata cag cca cac tgg ata 6690 Thr Ala Ser He 2185 Leu Leu Trp Tyr Ala 2190 Gin He Gin Pro His 2195 Trp He gca get tea ata ata ctg gag ttt ttt etc ata gtt ttg ett att cca 6738 Ala Ala Ser 2200 He He Leu Glu Phe 2205 Phe Leu lie Val Leu 2210 Leu lie Pro gaa cct gaa aaa cag aga aca ccc caa gac aac caa ctg acc tac gtt 6786 Glu Pro Glu 2215 Lys Gin Arg Thr Pro 2220 Gin Asp Asn Gin Leu 2225 Thr Tyr Val 2230 gtc ata gcc ate etc aca gtg gtg gcc gca acc atg gca aac gag atg 6834 Val He Ala He Leu Thr 2235 Val Val Ala Ala Thr 2240 Met Ala Asn Glu Met 2245 ggt ttc eta gaa aaa aeg aag aaa gat etc gga ttg gga age att gca 6882 Gly Phe Leu Glu Lys 2250 Thr Lys Lys Asp Leu 2255 Gly Leu Gly Ser He 2260 Ala

    2018200081 04 Jan 2018

    182 acc cag caa ccc gag age aac ate ctg gac ata gat eta cgt cct gca 6930

    Thr Gin Gin Pro Glu Ser Asn lie Leu Asp He Asp Leu Arg Pro Ala

    2265 2270 2275 tea gca tgg aeg ctg tat gcc gtg gcc aca aca ttt gtt aca cca atg 6978

    Ser Ala Trp Thr Leu Tyr Ala Val Ala Thr Thr Phe Val Thr Pro Met

    2280 2285 2290 ttg aga cat age att gaa aat tcc tea gtg aat gtg tcc eta aca get 7026

    Leu Arg His Ser lie Glu Asn Ser Ser Val Asn Val Ser Leu Thr Ala

    2295 2300 2305 2310 ata gcc aac caa gcc aca gtg tta atg ggt etc ggg aaa gga tgg cca 7074

    He Ala Asn Gin Ala Thr Val Leu Met Gly Leu Gly Lys Gly Trp Pro

    2315 2320 2325 ttg tea aag atg gaC ate gga gtt ccc ett etc gcc att gga tgc tac 7122

    Leu Ser Lys Met Asp He Gly Val Pro Leu Leu Ala He Gly Cys Tyr

    2330 2335 2340 tea caa gtc aac ccc ata act etc aca gca get ett ttc tta ttg gta 7170

    Ser Gin Val Asn Pro He Thr Leu Thr Ala Ala Leu Phe Leu Leu Val

    2345 2350 2355 gca cat tat gcc ate ata ggg cca gga etc caa gca aaa gca acc aga 7218

    Ala His Tyr Ala He He Gly Pro Gly Leu Gin Ala Lys Ala Thr Arg

    2360 2365 2370 gaa get cag aaa aga gca gcg gcg ggc ate atg aaa aac cca act gtc 7266

    Glu Ala Gin Lys Arg Ala Ala Ala Gly He Met Lys Asn Pro Thr Val

    2375 2380 2385 2390 gat gga ata aca gtg att gac eta gat cca ata cct tat gat cca aag 7314

    Asp Gly He Thr Val He Asp Leu Asp Pro He Pro Tyr Asp Pro Lys

    2395 2400 2405 ttt gaa aag cag ttg gga caa gta atg etc eta gtc etc tgc gtg act 7362

    Phe Glu Lys Gin Leu Gly Gin Val Met Leu Leu Val Leu Cys Val Thr

    2410 2415 2420 caa gta ttg atg atg agg act aca tgg get ctg tgt gag get tta acc 7410

    Gin Val Leu Met Met Arg Thr Thr Trp Ala Leu Cys Glu Ala Leu Thr

    2425 2430 2435 tta get acc ggg ccc ate tcc aca ttg tgg gaa gga aat cca ggg agg 7458

    Leu Ala Thr Gly Pro He Ser Thr Leu Trp Glu Gly Asn Pro Gly Arg

    2440 2445 2450 ttt tgg aac act acc att gcg gtg tea atg get aac att ttt aga ggg 7506

    Phe Trp Asn Thr Thr He Ala Val Ser Met Ala Asn He Phe Arg Gly

    2455 2460 2465 2470

    183

    2018200081 04 Jan 2018

    agt Ser tac Tyr ttg Leu gcc Ala gga get Gly Ala 2475 gga Gly ett Leu etc Leu ttt tet Phe Ser 2480 att He atg Met aag Lys aac Asn 2485 aca Thr 7554 acc aac aca aga agg gga act ggc aac ata gga gag aeg ett gga gag 7602 Thr Asn Thr Arg 249C Arg Gly I Thr Gly Asn 2495 He Gly Glu Thr Leu 250C Gly 1 Glu aaa tgg aaa age ega ttg aac gca ttg gga aaa agt gaa ttc cag ate 7650 Lys Trp Lys Ser 2505 Arg Leu Asn Ala Leu 2510 Gly Lys Ser Glu Phe 2515 Gin lie tac aag aaa agt gga ate cag gaa gtg gat aga acc tta gca aaa gaa 7698 Tyr Lys Lys 2520 Ser Gly lie Gin Glu 2525 Val Asp Arg Thr Leu 2530 Ala Lys Glu ggc att aaa aga gga gaa aeg gac cat cac get gtg teg ega ggc tea 7746 Gly 2535 lie Lys Arg Gly Glu Thr 2540 Asp His His Ala 2545 Val Ser Arg Gly Ser 2550 gca aaa ctg aga tgg ttc gtt gag aga aac atg gtc aca cca gaa ggg 7794 Ala Lys Leu Arg Trp Phe 2555 Val Glu Arg Asn Met 2560 Val Thr Pro Glu 2565 Gly aaa gta gtg gac etc ggt tgt ggc aga gga ggc tgg tea tac tat tgt 7842 Lys Val Val Asp Leu Gly 2570 Cys Gly Arg Gly Gly 2575 Trp Ser Tyr Tyr 2580 Cys gga gga eta aag aat gta aga gaa gtc aaa ggc eta aca aaa gga gga 7890 Gly Gly Leu Lys 2585 Asn Val Arg Glu Val 2590 Lys Gly Leu Thr Lys 2595 Gly Gly cca gga cac gaa gaa ccc ate ccc atg tea aca tat ggg tgg aat eta 7938 Pro Gly His 2600 Glu Glu Pro He Pro 2605 Met Ser Thr Tyr Gly 2610 Trp Asn Leu gtg cgt ett caa agt gga gtt gac gtt ttc ttc ate ccg cca gaa aag 7986 Val Arg 2615 Leu Gin Ser Gly Val 2620 Asp Val Phe Phe He 2625 Pro Pro Glu Lys 2630 tgt gac aca tta ttg tgt gac ata ggg gag tea tea cca aat ccc aca 8034 Cys Asp Thr Leu Leu Cys 2635 Asp He Gly Glu Ser 2640 Ser Pro Asn Pro Thr 2645 gtg gaa gca gga ega aca etc aga gtc ett aac tta gta gaa aat tgg 8082 Val Glu Ala Gly Arg Thr 2650 Leu Arg Val Leu Asn 2655 Leu Val Glu Asn 2660 Trp ttg aac aac aac act caa ttt tgc ata aag gtt etc aac cca tat atg 8130 Leu Asn Asn Asn 2665 Thr Gin Phe Cys He 2670 Lys Val Leu Asn Pro 2675 Tyr Met ccc tea gtc ata gaa aaa atg gaa gca eta caa agg aaa tat gga gga 8178 Pro Ser Val He Glu Lys Met Glu Ala Leu Gin Arg Lys Tyr Gly Gly

    2680 2685 2690

    184

    2018200081 04 Jan 2018

    gcc tta gtg agg Ala Leu Val Arg 2695 aat Asn cca etc Pro Leu 2700 tea Ser ega Arg aac Asn tcc aca Ser Thr 2705 cat His gag Glu atg Met tac Tyr 2710 8226 tgg gta tcc aat get tcc ggg aac ata gtg tea tea gtg aac atg att 8274 Trp Val Ser Asn Ala 2715 Ser Gly Asn He Val Ser Ser 2720 Val Asn Met 2725 He tea agg atg ttg ate aac aga ttt aca atg aga tac aag aaa gcc act 8322 Ser Arg Met Leu lie 2730 Asn Arg Phe Thr Met 2735 Arg Tyr Lys Lys Ala 2740 Thr tac gag ccg gat gtt gac etc gga agc gga acc cgt aac ate ggg att 8370 Tyr Glu Pro Asp 2745 Val Asp Leu Gly Ser 2750 Gly Thr Arg Asn He 2755 Gly He gaa agt gag ata cca aac eta gat ata att ggg aaa aga ata gaa aaa 8418 Glu Ser Glu He 2760 Pro Asn Leu Asp 2765 He He Gly Lys Arg 2770 He Glu Lys ata aag caa gag cat gaa aca tea tgg cac tat gac caa gac cac cca 8466 lie Lys Gin Glu 2775 His Glu Thr 2780 Ser Trp His Tyr Asp 2785 Gin Asp His Pro 2790 tac aaa aeg tgg gca tac cat ggt agc tat gaa aca aaa cag act gga 8514 Tyr Lys Thr Trp Ala 2795 Tyr His Gly Ser Tyr Glu Thr 2800 Lys Gin Thr 2805 Gly tea gca tea tcc atg gtc aac gga gtg gtc agg ctg ctg aca aaa cct 8562 Ser Ala Ser Ser Met 2810 Val Asn Gly Val Val 2815 Arg Leu Leu Thr Lys 2820 Pro tgg gac gtt gtc ccc atg gtg aca cag atg gca atg aca gac aeg act 8610 Trp Asp Val Val 2825 Pro Met Val Thr Gin 2830 Met Ala Met Thr Asp 2835 Thr Thr cca ttt gga caa cag cgc gtt ttt aaa gag aaa gtg gac aeg aga acc 8658 Pro Phe Gly Gin 2840 Gin Arg Val Phe 2845 Lys Glu Lys Val Asp 2850 Thr Arg Thr caa gaa ccg aaa gaa ggc aeg aag aaa eta atg aaa ata aca gca gag 8706 Gin Glu Pro Lys 2855 Glu Gly Thr 2860 Lys Lys Leu Met Lys 2865 He Thr Ala Glu 2870 tgg ett tgg aaa gaa tta ggg aag aaa aag aca ccc agg atg tgc acc 8754 Trp Leu Trp Lys Glu Leu Gly 2875 Lys Lys Lys Thr Pro 2880 Arg Met Cys Thr 2885 aga gaa gaa ttc aca aga aag gtg aga age aat gca gcc ttg ggg gcc 8802 Arg Glu Glu Phe Thr Arg Lys Val Arg Ser Asn Ala Ala Leu Gly Ala

    2890 2895 2900

    185

    2018200081 04 Jan 2018

    ata ttc act gat Thr Asp 2905 gag Glu aac Asn aag Lys tgg aag teg gca cgt gag get gtt gaa 8850 lie Phe Trp Lys 2910 Ser Ala Arg Glu Ala 2915 Val Glu gat agt agg ttt tgg gag ctg gtt gac aag gaa agg aat etc cat ett 8898 Asp Ser 292C Arg Phe 1 Trp Glu Leu 292E Val Asp Lys Glu Arg 293C Asn Leu' 1 His Leu gaa gga aag tgt gaa aca tgt gtg tac aac atg atg gga aaa aga gag 8946 Glu Gly 2935 Lys Cys Glu Thr 294C Cys 1 Val Tyr Asn Met Met 2945 Gly Lys Arg Glu 2950 aag aag eta ggg gaa ttc ggc aag gca aaa ggc age aga gcc ata tgg 8994 Lys Lys Leu Gly Glu 295E Phe Gly Lys Ala Lys Gly Ser 2960 Arg Ala He Trp 2965 tac atg tgg ett gga' gca ege ttc tta gag ttt gaa gcc eta gga ttc 9042 Tyr Met Trp Leu Gly 2970 Ala Arg Phe Leu Glu Phe Glu 2975 Ala Leu Gly 2980 Phe tta aat gaa gat cac tgg ttc tcc aga gag aac tcc ctg agt gga gtg 9090 Leu Asn Glu Asp 2985 His Trp Phe Ser Arg 2990 Glu Asn Ser Leu Ser 2995 Gly Val gaa gga gaa ggg ctg cac aag eta ggt tac att eta aga gac gtg age 9138 Glu Gly Glu Gly 3000 Leu His Lys Leu Gly 3005 Tyr lie Leu Arg Asp 3010 Val Ser aag aaa gag gga gga gca atg tat gcc gat gac acc gca gga tgg gat 9186 Lys Lys 3015 Glu Gly Gly Ala Met 3020 Tyr Ala Asp Asp Thr 3025 Ala Gly Trp Asp 3030 aca aga ate aca eta gaa gac eta aaa aat gaa gaa atg gta aca aac 9234 Thr Arg He Thr Leu Glu 3035 Asp Leu Lys Asn Glu Glu 3040 Met Val Thr Asn 3045 cac atg gaa gga gaa cac aag aaa eta gcc gag gcc att ttc aaa eta 9282 His Met Glu Gly Glu 3050 His Lys Lys Leu Ala Glu Ala 3055 He Phe Lys 3060 Leu aeg tac caa aac aag gtg gtg cgt gtg caa aga cca aca cca aga ggc 9330 Thr Tyr Gin Asn 3065 Lys Val Val Arg Val 3070 Gin Arg Pro Thr Pro 3075 Arg Gly aca gta atg gac ate ata teg aga aga gac caa aga ggt agt gga caa 9378 Thr Val Met Asp 3080 He He Ser Arg Arg 3085 Asp Gin Arg Gly Ser 3090 Gly Gin gtt ggc acc tat gga etc aat act ttc acc aat atg gaa gcc caa eta 9426 Val Gly 3095 Thr Tyr Gly Leu Asn 3100 Thr Phe Thr Asn Met 3105 Glu Ala Gin Leu 3110 ate aga cag atg gag gga gaa gga gtc ttt aaa age att cag cac eta 9474 He Arg Gin Met Glu Gly Glu 3115 Gly Val Phe Lys Ser 3120 lie Gin His Leu 3125

    186

    2018200081 04 Jan 2018

    aca ate aca gaa gaa ate get gtg caa aac tgg tta gca aga gtg ggg 9522 Thr lie Thr Glu Glu He 3130 Ala Val Gin Asn Trp Leu Ala Arg Val Gly 3135 314 0 ege gaa agg tta tea aga atg gcc ate agt gga gat gat tgt gtt gtg 9570 Arg Glu Arg 3145 Leu Ser Arg Met Ala 3150 He Ser Gly 1 Asp Asp Cys Val 3155 Val aaa cct tta gat gac agg ttc gca agc get tta aca get eta aat gac 9618 Lys Pro Leu 3160 Asp Asp Arg Phe Ala 3165 Ser Ala Leu Thr Ala Leu Asn 3170 Asp atg gga aag att agg aaa gac ata caa caa tgg gaa cct tea aga gga 9666 Met 317E Gly Lys He Arg Lys Asp 3180 He Gin Gin Trp Glu Pro Ser Arg 3185 Gly 3190 tgg aat gat tgg aca caa gtg ccc ttc tgt tea cac cat ttc cat gag 9714 Trp Asn Asp Trp Thr Gin 3195 Val Pro Phe Cys Ser 3200 His His Phe His Glu 3205 tta ate atg aaa gac ggt ege gta etc gtt gtt cca tgt aga aac caa 9762 Leu He Met Lys Asp Gly 3210 Arg Val Leu Val Val 3215 Pro Cys Arg Asn 3220 Gin gat gaa ctg att ggc aga gcc ega ate tcc caa gga gca ggg tgg tet 9810 Asp Glu Leu He Gly Arg 3225 Ala Arg He Ser Gin 3230 Gly Ala Gly Trp 3235 Ser ttg egg gag aeg gcc tgt ttg ggg aag tet tac gcc caa atg tgg agc 9858 Leu Arg Glu 3240 Thr Ala Cys Leu Gly 3245 Lys Ser Tyr Ala Gin Met Trp 3250 Ser ttg atg tac ttc cac aga ege gac etc agg ctg geg gca aat get att 9906 Leu Met 3255 Tyr Phe His Arg Arg 3260 Asp Leu Arg Leu Ala Ala Asn Ala 3265 He 3270 tgc teg gca gta cca tea cat tgg gtt cca aca agt ega aca acc tgg 9954 Cys Ser Ala Val Pro Ser 3275 His Trp Val Pro Thr 3280 Ser Arg Thr Thr Trp 3285 tcc ata cat get aaa cat gaa tgg atg aca aeg gaa gac atg ctg aca 10002 Ser He His Ala Lys His 3290 Glu Trp Met Thr Thr 3295 Glu Asp Met Leu 3300 Thr gtc tgg aac agg gtg tgg att caa gaa aac cca tgg atg gaa gac aaa 10050 Val Trp Asn Arg Val Trp 3305 He Gin Glu Asn Pro 3310 Trp Met Glu Asp 3315 Lys act cca gtg gaa tea tgg gag gaa ate cca tac ttg ggg aaa aga gaa 10098 Thr Pro Val 3320 Glu Ser Trp Glu Glu 3325 He Pro Tyr Leu Gly Lys Arg 3330 Glu

    187

    2018200081 04 Jan 2018

    gac caa Asp Gin 3335 tgg Trp tgc Cys ggc Gly tea ttg att ggg Gly tta Leu aca age Thr Ser 3345 agg Arg gcc Ala acc Thr tgg Trp 3350 10146 Ser Leu 3340 He gca aag aac ate caa gca gca ata aat caa gtt aga tcc ett ata ggc 10194 Ala Lys Asn lie Gin Ala Ala He Asn Gin Val Arg Ser Leu He Gly 3355 3360 3365 aat gaa gaa tac aca gat tac atg cca tcc atg aaa aga ttc aga aga 10242 Asn Glu Glu Tyr Thr Asp Tyr Met Pro Ser Met Lys Arg Phe Arg Arg 3370 3375 3380 gaa gag gaa gaa gca gga gtt ctg tgg tag aaagcaaaac taacatgaaa 10292 Glu Glu Glu Glu Ala Gly Val Leu Trp * 3385 3390

    caaggctaga agtcaggtcg gattaagcca tagtacggaa aaaactatgc tacctgtgag 10352 ccccgtccaa ggacgttaaa agaagtcagg ccatcataaa tgccatagct tgagtaaact 10412 atgcagcctg tagctccacc tgagaaggtg taaaaaatcc gggaggccac aaaccatgga 10472 agctgtacgc atggcgtagt ggactagcgg ttagaggaga cccctccctt acaaatcgca 10532 gcaacaatgg gggcccaagg cgagatgaag ctgtagtctc gctggaagga ctagaggtta 10592 gaggagaccc ccccgaaaca aaaaacagca tattgacgct gggaaagacc agagatcctg 10652 ctgtctcctc agcatcattc caggcacaga acgccagaaa atggaatggt gctgttgaat 10712 caacaggttc t 10723 <210> 16 <211> 3391 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence :/Note =

    synthetic construct <400> 16 Met Asn Asn Gin Arg Lys Lys Ala Lys Asn Thr Pro Phe Asn Met Leu 1 5 10 15 Lys Arg Glu Arg Asn Arg Val Ser Thr Val Gin Gin Leu Thr Lys Arg 20 25 30 Phe Ser Leu Gly Met Leu Gin Gly Arg Gly Pro Leu Lys Leu Phe Met 35 40 45 Ala Leu Val Ala Phe Leu Arg Phe Leu Thr He Pro Pro Thr Ala Gly 50 55 60 He Leu Lys Arg Trp Gly Thr He Lys Lys Ser Lys Ala He Asn Val 65 70 75 80 Leu Arg Gly Phe Arg Lys Glu He Gly Arg Met Leu Asn He Leu Asn 85 90 95 Arg Arg Arg Arg Ser Ala Gly Met He He Met Leu He Pro Thr Val 100 105 110 Met Ala Phe His Leu Thr Thr Arg Asn Gly Glu Pro His Met He Val 115 120 125 Ser Arg Gin Glu Lys Gly Lys Ser Leu Leu Phe Lys Thr Glu Val Gly 130 135 140

    188

    2018200081 04 Jan 2018

    Val Asn Met Cys Thr Leu Met Ala Met Asp Leu Gly Glu Leu Cys Glu 145 150 155 160 Asp Thr He Thr Tyr Lys Cys Pro Leu Leu Arg Gin Asn Glu Pro Glu 165 170 175 Asp He Asp Cys Trp Cys Asn Ser Thr Ser Thr Trp Val Thr Tyr Gly 180 185 190 Thr Cys Thr Thr Met Gly Glu His Arg Arg Glu Lys Arg Ser Val Ala 195 200 205 Leu Val Pro His Val Gly Met Gly Leu Glu Thr Arg Thr Glu Thr Trp 210 215 220 Met Ser Ser Glu Gly Ala Trp Lys His Val Gin Arg He Glu Thr Trp 225 230 235 240 lie Leu Arg His Pro Gly Phe Thr Met Met Ala Ala He Leu Ala Tyr 245 250 255 Thr He Gly Thr Thr His Phe Gin Arg Ala Leu He Phe He Leu Leu 260 265 270 Thr Ala Val Thr Pro Ser Met Thr Met Arg Cys He Gly Met Ser Asn 275 280 285 Arg Asp Phe Val Glu Gly Val Ser Gly Gly Ser Trp Val Asp He Val 290 295 300 Leu Glu His Gly Ser Cys Val Thr Thr Met Ala Lys Asn Lys Pro Thr 305 310 315 320 Leu Asp Phe Glu Leu lie Lys Thr Glu Ala Lys Gin Pro Ala Thr Leu 325 330 335 Arg Lys Tyr Cys He Glu Ala Lys Leu Thr Asn Thr Thr Thr Glu Ser 340 345 350 Arg Cys Pro Thr Gin Gly Glu Pro Ser Leu Asn Glu Glu Gin Asp Lys 355 360 365 Arg Phe Val Cys Lys His Ser Met Val Asp Arg Gly Trp Gly Asn Gly 370 375 380 Cys Gly Leu Phe Gly Lys Gly Gly He Val Thr Cys Ala Met Phe Arg 385 390 395 400 Cys Lys Lys Asn Met Glu Gly Lys Val Val Gin Pro Glu Asn Leu Glu 405 410 415 Tyr Thr lie Val He Thr Pro His Ser Gly Glu Glu His Ala Val Gly 420 425 430 Asn Asp Thr Gly Lys His Gly Lys Glu He Lys He Thr Pro Gin Ser 435 440 445 Ser He Thr Glu Ala Glu Leu Thr Gly Tyr Gly Thr Val Thr Met Glu 450 455 460 Cys Ser Pro Arg Thr Gly Leu Asp Phe Asn Glu Met Val Leu Leu Gin 465 470 475 480 Met Glu Asn Lys Ala Trp Leu Val His Arg Gin Trp Phe Leu Asp Leu 485 490 495 Pro Leu Pro Trp Leu Pro Gly Ala Asp Thr Gin Gly Ser Asn Trp He 500 505 510 Gin Lys Glu Thr Leu Val Thr Phe Lys Asn Pro His Ala Lys Lys Gin 515 520 525 Asp Val Val Val Leu Gly Ser Gin Glu Gly Ala Met His Thr Ala Leu 530 535 540 Thr Gly Ala Thr Glu He Gin Met Ser Ser Gly Asn Leu Leu Phe Thr 545 550 555 560 Gly His Leu Lys Cys Arg Leu Arg Met Asp Lys Leu Gin Leu Lys Gly 565 570 575

    189

    2018200081 04 Jan 2018

    Met Ser Tyr Ser 580 Met Cys Thr Gly Lys 585 Phe Lys Val Val Lys 590 Glu He Ala Glu Thr Gin His Gly Thr He Val He Arg Val Gin Tyr Glu Gly 595 600 605 Asp Gly Ser Pro Cys Lys He Pro Phe Glu He Met Asp Leu Glu Lys 610 615 . 620 Arg His Val Leu Gly Arg Leu He Thr Val Asn Pro He Val Thr Glu 625 630 635 640 Lys Asp Ser Pro Val Asn He Glu Ala Glu Pro Pro Phe Gly Asp Ser 645 650 655 Tyr He He He Gly Val Glu Pro Gly Gin Leu Lys Leu Asn Trp Phe 660 665 670 Lys Lys Gly Ser Ser He Gly Gin Met Phe Glu Thr Thr Met Arg Gly 675 680 ' 685 Ala Lys Arg Met Ala He Leu Gly Asp Thr Ala Trp Asp Phe Gly Ser 690 695 700 Leu Gly Gly Val Phe Thr Ser He Gly Lys Ala Leu His Gin Val Phe 705 710 715 720 Gly Ala He Tyr Gly Ala Ala Phe Ser Gly Val Ser Trp Thr Met Lys 725 730 735 lie Leu lie Gly Val He He Thr Trp He Gly Met Asn Ser Arg Ser 740 745 750 Thr Ser Leu Ser Val Thr Leu Val Leu Val Gly lie Val Thr Leu Tyr 755 760 765 Leu Gly Val Met Val Gin Ala Asp Ser Gly Cys Val Val Ser Trp Lys 770 775 780 Asn Lys Glu Leu Lys Cys Gly Ser Gly He Phe He Thr Asp Asn Val 785 790 795 800 His Thr Trp Thr Glu Gin Tyr Lys Phe Gin Pro Glu Ser Pro Ser Lys 805 810 815 Leu Ala Ser Ala He Gin Lys Ala His Glu Glu Asp lie Cys Gly He 820 825 830 Arg Ser Val Thr Arg Leu Glu Asn Leu Met Trp Lys Gin He Thr Pro 835 840 845 Glu Leu Asn His He Leu Ser Glu Asn Glu Val Lys Leu Thr lie Met 850 855 860 Thr Gly Asp lie Lys Gly He Met Gin Ala Gly Lys Arg Ser Leu Arg 865 870 875 880 Pro Gin Pro Thr Glu Leu Lys Tyr Ser Trp Lys Thr Trp Gly Lys Ala 885 890 895 Lys Met Leu Ser Thr Glu Ser His Asn Gin Thr Phe Leu He Asp Gly 900 905 910 Pro Glu Thr Ala Glu Cys Pro Asn Thr Asn Arg Ala Trp Asn Ser Leu 915 92 0 925 Glu Val Glu Asp Tyr Gly Phe Gly Val Phe Thr Thr Asn He Trp Leu 930 935 940 Lys Leu Lys Glu Lys Gin Asp Val Phe Cys Asp Ser Lys Leu Met Ser 945 950 955 960 Ala Ala He Lys Asp Asn Arg Ala Val His Ala Asp Met Gly Tyr Trp 965 970 975 He Glu Ser Ala Leu Asn Asp Thr Trp Lys He Glu Lys Ala Ser Phe 980 985 990 He Glu Val Lys Asn Cys His Trp Pro Lys Ser His Thr Leu Trp Ser 995 1000 1005

    190

    2018200081 04 Jan 2018

    Asn Gly Val Leu Glu Ser Glu Met 1015 He He Pro Lys Asn Leu Ala 1020 Gly 1010 Pro Val Ser Gin His Asn Tyr Arg Pro Gly Tyr His Thr Gin He Thr 1025 1030 1035 1040 Gly Pro Trp His Leu Gly Lys Leu Glu Met Asp Phe Asp Phe Cys Asp 1045 1050 1055 Gly Thr Thr Val Val Val Thr Glu Asp Cys Gly Asn Arg Gly Pro Ser 1060 1065 1070 Leu Arg Thr Thr Thr Ala Ser Gly Lys Leu He Thr Glu Trp Cys Cys 1075 1080 1085 Arg Ser Cys Thr Leu Pro Pro Leu Arg Tyr Arg Gly Glu Asp Gly Cys 1090 1095 1100 Trp Tyr Gly Met Glu He Arg Pro Leu Lys Glu Lys Glu Glu Asn Leu 1105 1110 1115 1120 Val Asn Ser Leu Val Thr Ala Gly His Gly Gin Val Asp Asn Phe Ser 1125 1130 1135 Leu Gly Val Leu Gly Met Ala Leu Phe Leu Glu Glu Met Leu Arg Thr 1140 1145 1150 Arg Val Gly Thr Lys His Ala He Leu Leu Val Ala Val Ser Phe Val 1155 1160 1165 Thr Leu He Thr Gly Asn Met Ser Phe Arg Asp Leu Gly Arg Val Met 1170 1175 1180 Val Met Val Gly Ala Thr Met Thr Asp Asp He Gly Met Gly Val Thr 1185 1190 1195 1200 Tyr Leu Ala Leu Leu Ala Ala Phe Lys Val Arg Pro Thr Phe Ala Ala 1205 1210 1215 Gly Leu Leu Leu Arg Lys Leu Thr Ser Lys Glu Leu Met Met Thr Thr 1220 1225 1230 lie Gly He Val Leu Leu Ser Gin Ser Thr He Pro Glu Thr He Leu 1235 1240 1245 Glu Leu Thr Asp Ala Leu Ala Leu Gly Met Met Val Leu Lys Met Val 1250 1255 1260 Arg Asn Met Glu Lys Tyr Gin Leu Ala Val Thr He Met Ala He Leu 1265 1270 1275 1280 Cys Val Pro Asn Ala Val He Leu Gin Asn Ala Trp Lys Val Ser Cys 1285 1290 1295 Thr He Leu Ala Val Val Ser Val Ser Pro Leu Phe Leu Thr Ser Ser 1300 1305 1310 Gin Gin Lys Thr Asp Trp He Pro Leu Ala Leu Thr He Lys Gly Leu 1315 1320 1325 Asn Pro Thr Ala He Phe Leu Thr Thr Leu Ser Arg Thr Ser Lys Lys 1330 1335 1340 Arg Ser Trp Pro Leu Asn Glu Ala He Met Ala Val Gly Met Val Ser 1345 1350 1355 1360 He Leu Ala Ser Ser Leu Leu Lys Asn Asp He Pro Met Thr Gly Pro 1365 1370 1375 Leu Val Ala Gly Gly Leu Leu Thr Val Cys Tyr Val Leu Thr Gly Arg 1380 1385 1390 Ser Ala Asp Leu Glu Leu Glu Arg Ala Ala Asp Val Lys Trp Glu Asp 1395 1400 1405 Gin Ala Glu He Ser Gly Ser Ser Pro He Leu Ser He Thr He Ser 1410 1415 1420 Glu Asp Gly Ser Met Ser He Lys Asn Glu Glu Glu Glu Gin Thr Leu 1425 1430 1435 1440

    191

    2018200081 04 Jan 2018

    Thr lie Leu He Arg Thr Gly Leu Leu Val lie Ser Gly Leu Phe Pro 1445 1450 1455 Val Ser He Pro lie Thr Ala Ala Ala Trp Tyr Leu Trp Glu Val Lys 1460 1465 1470 Lys Gin Arg Ala Gly Val Leu Trp Asp Val Pro Ser Pro Pro Pro Met 1475 1480 1485 Gly Lys Ala Glu Leu Glu Asp Gly Ala Tyr Arg He Lys Gin Lys Gly 1490 1495 1500 lie Leu Gly Tyr Ser Gin He Gly Ala Gly Val Tyr Lys Glu Gly Thr 1505 1510 1515 1520 Phe His Thr Met Trp His Val Thr Arg Gly Ala Val Leu Met His Lys 1525 1530 1535 Gly Lys Arg He Glu Pro Ser Trp Ala Asp Val Lys Lys Asp Leu He 1540 1545 1550 Ser Tyr Gly Gly Gly Trp Lys Leu Glu Gly Glu Trp Lys Glu Gly Glu 1555 1560 1565 Glu Val Gin Val Leu Ala Leu Glu Pro Gly Lys Asn Pro Arg Ala Val 1570 1575 1580 Gin Thr Lys Pro Gly Leu Phe Lys Thr Asn Ala Gly Thr He Gly Ala 1585 1590 1595 1600 Val Ser Leu Asp Phe Ser Pro Gly Thr Ser Gly Ser Pro lie He Asp 1605 1610 1615 Lys Lys Gly Lys Val Val Gly Leu Tyr Gly Asn Gly Val Val Thr Arg 1620 1625 1630 Ser Gly Ala Tyr Val Ser Ala lie Ala Gin Thr Glu Lys Ser He Glu 1635 1640 1645 Asp Asn Pro Glu He Glu Asp Asp He Phe Arg Lys Arg Arg Leu Thr 1650 1655 1660 He Met Asp Leu His Pro Gly Ala Gly Lys Thr Lys Arg Tyr Leu Pro 1665 1670 1675 1680 Ala He Val Arg Glu Ala He Lys Arg Gly Leu Arg Thr Leu He Leu 1685 1690 1695 Ala Pro Thr Arg Val Val Ala Ala Glu Met Glu Glu Ala Leu Arg Gly 1700 1705 1710 Leu Pro He Arg Tyr Gin Thr Pro Ala He Arg Ala Val His Thr Gly 1715 1720 1725 Arg Glu He Val Asp Leu Met Cys His Ala Thr Phe Thr Met Arg Leu 1730 1735 1740 Leu Ser Pro Val Arg Val Pro Asn Tyr Asn Leu He He Met Asp Glu 1745 1750 1755 1760 Ala His Phe Thr Asp Pro Ala Ser He Ala Ala Arg Gly Tyr He Ser 1765 1770 1775 Thr Arg Val Glu Met Gly Glu Ala Ala Gly He Phe Met Thr Ala Thr 1780 1785 1790 Pro Pro Gly Ser Arg Asp Pro Phe Pro Gin Ser Asn Ala Pro He He 1795 1800 1805 Asp Glu Glu Arg Glu He Pro Glu Arg Ser Trp Asn Ser Gly His Glu 1810 1815 1820 Trp Val Thr Asp Phe Lys Gly Lys Thr Val Trp Phe Val Pro Ser He 1825 1830 1835 1840 Lys Ala Gly Asn Asp He Ala Ala Cys Leu Arg Lys Asn Gly Lys Lys 1845 1850 1855 Val He Gin Leu Ser Arg Lys Thr Phe Asp Ser Glu Tyr Val Lys Thr 1860 1865 1870

    192

    2018200081 04 Jan 2018

    Arg Thr Asn Asp Trp Asp Phe Val Val Thr Thr Asp He Ser Glu Met 1875 1880 1885 Gly Ala Asn Phe Lys Ala Glu Arg Val He Asp Pro Arg Arg Cys Met 1890 1895 1900 Lys Pro Val He Leu Thr Asp Gly Glu Glu Arg Val He Leu Ala Gly 1905 1910 1915 1920 Pro Met Pro Val Thr His Ser Ser Ala Ala Gin Arg Arg Gly Arg lie 1925 1930 1935 Gly Arg Asn Pro Lys Asn Glu Asn Asp Gin Tyr He Tyr Met Gly Glu 1940 1945 1950 Pro Leu Glu Asn Asp Glu Asp Cys Ala His Trp Lys Glu Ala Lys Met 1955 1960 1965 Leu Leu Asp Asn lie Asn Thr Pro Glu Gly He lie Pro Ser Met Phe 1970 1975 1980 Glu Pro Glu Arg Glu Lys Val Asp Ala lie Asp Gly Glu Tyr Arg Leu 1985 1990 1995 2000 Arg Gly Glu Ala Arg Lys Thr Phe Val Asp Leu Met Arg Arg Gly Asp 2005 2010 2015 Leu Pro Val Trp Leu Ala Tyr Arg Val Ala Ala Glu Gly He Asn Tyr 2020 2025 2030 Ala Asp Arg Arg Trp Cys Phe Asp Gly Val Lys Asn Asn Gin He Leu 2035 2040 2045 Glu Glu Asn Val Glu Val Glu He Trp Thr Lys Glu Gly Glu Arg Lys 2050 2055 2060 Lys Leu Lys Pro Arg Trp Leu Asp Ala Arg He Tyr Ser Asp Pro Leu 2065 2070 2075 2080 Ala Leu Lys Glu Phe Lys Glu Phe Ala Ala Gly Arg Lys Ser Leu Thr 2085 2090 2095 Leu Asn Leu He Thr Glu Met Gly Arg Leu Pro Thr Phe Met Thr Gin 2100 2105 2110 Lys Ala Arg Asp Ala Leu Asp Asn Leu Ala Val Leu His Thr Ala Glu 2115 2120 2125 Ala Gly Gly Arg Ala Tyr Asn His Ala Leu Ser Glu Leu Pro Glu Thr 2130 2135 2140 Leu Glu Thr Leu Leu Leu Leu Thr Leu Leu Ala Thr Val Thr Gly Gly 2145 2150 2155 2160 lie Phe Leu Phe Leu Met Ser Ala Arg Gly He Gly Lys Met Thr Leu 2165 2170 2175 Gly Met Cys Cys He He Thr Ala Ser lie Leu Leu Trp Tyr Ala Gin 2180 2185 2190 He Gin Pro His Trp lie Ala Ala Ser He He Leu Glu Phe Phe Leu 2195 2200 2205 He Val Leu Leu He Pro Glu Pro Glu Lys Gin Arg Thr Pro Gin Asp 2210 2215 2220 Asn Gin Leu Thr Tyr Val Val He Ala He Leu Thr Val Val Ala Ala 2225 2230 2235 2240 Thr Met Ala Asn Glu Met Gly Phe Leu Glu Lys Thr Lys Lys Asp Leu 2245 2250 2255 Gly Leu Gly Ser He Ala Thr Gin Gin Pro Glu Ser Asn He Leu Asp 2260 2265 2270 He Asp Leu Arg Pro Ala Ser Ala Trp Thr Leu Tyr Ala Val Ala Thr 2275 2280 2285 Thr Phe Val Thr Pro Met Leu Arg His Ser He Glu Asn Ser Ser Val

    2290 2295 2300

    193

    2018200081 04 Jan 2018

    Asn Val Ser Leu Thr Ala He Ala Asn Gin Ala Thr Val Leu Met Gly 2305 2310 2315 2320 Leu Gly Lys Gly Trp Pro Leu Ser Lys Met Asp He Gly Val Pro Leu 2325 2330 2335 Leu Ala lie Gly Cys Tyr Ser Gin Val Asn Pro He Thr Leu Thr Ala 2340 2345 2350 Ala Leu Phe Leu Leu Val Ala His Tyr Ala He He Gly Pro Gly Leu 2355 2360 2365 Gin Ala Lys Ala Thr Arg Glu Ala Gin Lys Arg Ala Ala Ala Gly He 2370 2375 2380 Met Lys Asn Pro Thr Val Asp Gly He Thr Val He Asp Leu Asp Pro 2385 2390 2395 2400 lie Pro Tyr Asp Pro Lys Phe Glu Lys Gin Leu Gly Gin Val Met Leu 2405 2410 2415 Leu Val Leu Cys Val Thr Gin Val Leu Met Met Arg Thr Thr Trp Ala 2420 2425 2430 Leu Cys Glu Ala Leu Thr Leu Ala Thr Gly Pro He Ser Thr Leu Trp 2435 2440 2445 Glu Gly Asn Pro Gly Arg Phe Trp Asn Thr Thr He Ala Val Ser Met 2450 2455 2460 Ala Asn He Phe Arg Gly Ser Tyr Leu Ala Gly Ala Gly Leu Leu Phe 2465 2470 2475 2480 Ser He Met Lys Asn Thr Thr Asn Thr Arg Arg Gly Thr Gly Asn He 2485 2490 2495 Gly Glu Thr Leu Gly Glu Lys Trp Lys Ser Arg Leu Asn Ala Leu Gly 2500 2505 2510 Lys Ser Glu Phe Gin He Tyr Lys Lys Ser Gly He Gin Glu Val Asp 2515 2520 2525 Arg Thr Leu Ala Lys Glu Gly He Lys Arg Gly Glu Thr Asp His His 2530 2535 2540 Ala Val Ser Arg Gly Ser Ala Lys Leu Arg Trp Phe Val Glu Arg Asn 2545 2550 2555 2560 Met Val Thr Pro Glu Gly Lys Val Val Asp Leu Gly Cys Gly Arg Gly 2565 2570 2575 Gly Trp Ser Tyr Tyr Cys Gly Gly Leu Lys Asn Val Arg Glu Val Lys. 2580 2585 2590 Gly Leu Thr Lys Gly Gly Pro Gly His Glu Glu Pro He Pro Met Ser 2595 2600 2605 Thr Tyr Gly Trp Asn Leu Val Arg Leu Gin Ser Gly Val Asp Val Phe 2610 2615 2620 Phe He Pro Pro Glu Lys Cys Asp Thr Leu Leu Cys Asp He Gly Glu 2625 2630 2635 2640 Ser Ser Pro Asn Pro Thr Val Glu Ala Gly Arg Thr Leu Arg Val Leu 2645 2650 2655 Asn Leu Val Glu Asn Trp Leu Asn Asn Asn Thr Gin Phe Cys He Lys 2660 2665 2670 Val Leu Asn Pro Tyr Met Pro Ser Val He Glu Lys Met Glu Ala Leu 2675 2680 2685 Gin Arg Lys Tyr Gly Gly Ala Leu Val Arg Asn Pro Leu Ser Arg Asn 2690 2695 2700 Ser Thr His Glu Met Tyr Trp Val Ser Asn Ala Ser Gly Asn He Val 2705 2710 2715 2720 Ser Ser Val Asn Met He Ser Arg Met Leu He Asn Arg Phe Thr Met

    2725 2730 2735

    194

    2018200081 04 Jan 2018

    Arg Tyr Lys Lys Ala Thr Tyr Glu Pro Asp Val Asp Leu Gly Ser Gly 2740 2745 2750 Thr Arg Asn He Gly He Glu Ser Glu He Pro Asn Leu Asp He He 2755 2760 2765 Gly Lys Arg lie Glu Lys He Lys Gin Glu His Glu Thr Ser Trp His 2770 2775 2780 Tyr Asp Gin Asp His Pro Tyr Lys Thr Trp Ala Tyr His Gly Ser Tyr 2785 2790 2795 2800 Glu Thr Lys Gin Thr Gly Ser Ala Ser Ser Met Val Asn Gly Val Val 2805 2810 2815 Arg Leu Leu Thr Lys Pro Trp Asp Val Val Pro Met Val Thr Gin Met 2820 2825 2830 Ala Met Thr Asp Thr Thr Pro Phe Gly Gin Gin Arg Val Phe Lys Glu 2835 2840 2845 Lys Val Asp Thr Arg Thr Gin Glu Pro Lys Glu Gly Thr Lys Lys Leu 2850 2855 2860 Met Lys lie Thr Ala Glu Trp Leu Trp Lys Glu Leu Gly Lys Lys Lys 2865 2870 2875 2880 Thr Pro Arg Met Cys Thr Arg Glu Glu Phe Thr Arg Lys Val Arg Ser 2885 2890 2895 Asn Ala Ala Leu Gly Ala He Phe Thr Asp Glu Asn Lys Trp Lys Ser 2900 2905 2910 Ala Arg Glu Ala Val Glu Asp Ser Arg Phe Trp Glu Leu Val Asp Lys 2915 2920 2925 Glu Arg Asn Leu His Leu Glu Gly Lys Cys Glu Thr Cys Val Tyr Asn 2930 2935 2940 Met Met Gly Lys Arg Glu Lys Lys Leu Gly Glu Phe Gly Lys Ala Lys 2945 2950 2955 2960 Gly Ser Arg Ala He Trp Tyr Met Trp Leu Gly Ala Arg Phe Leu Glu 2965 2970 2975 Phe Glu Ala Leu Gly Phe Leu Asn Glu Asp His Trp Phe Ser Arg Glu 2980 2985 2990 Asn Ser Leu Ser Gly Val Glu Gly Glu Gly Leu His Lys Leu Gly Tyr 2995 3000 3005 He Leu Arg Asp Val Ser Lys Lys Glu Gly Gly Ala Met Tyr Ala Asp 3010 3015 3020 Asp Thr Ala Gly Trp Asp Thr Arg He Thr Leu Glu Asp Leu Lys Asn 3025 3030 3035 3040 Glu Glu Met Val Thr Asn His Met Glu Gly Glu His Lys Lys Leu Ala 3045 3050 3055 Glu Ala He Phe Lys Leu Thr Tyr Gin Asn Lys Val Val Arg Val Gin 3060 3065 3070 Arg Pro Thr Pro Arg Gly Thr Val Met Asp He He Ser Arg Arg Asp 3075 3080 3085 Gin Arg Gly Ser Gly Gin Val Gly Thr Tyr Gly Leu Asn Thr Phe Thr 3090 3095 3100 Asn Met Glu Ala Gin Leu He Arg Gin Met Glu Gly Glu Gly Val Phe 3105 3110 3115 3120 Lys Ser lie Gin His Leu Thr He Thr Glu Glu He Ala Val Gin Asn 3125 3130 3135 Trp Leu Ala Arg Val Gly Arg Glu Arg Leu Ser Arg Met Ala He Ser 3140 3145 3150 Gly Asp Asp Cys Val Val Lys Pro Leu Asp Asp Arg Phe Ala Ser Ala 3155 3160 3165

    195

    2018200081 04 Jan 2018

    Leu Thr Ala 3170 Leu Asn Asp Met Gly Lys 3175 He Arg Lys Asp 3180 He Gin Gin Trp Glu Pro Ser Arg Gly Trp Asn Asp Trp Thr Gin Val Pro Phe Cys 3185 3190 3195 3200 Ser His His Phe His Glu Leu lie Met Lys Asp Gly Arg Val Leu Val 3205 3210 3215 Val Pro Cys Arg Asn Gin Asp Glu Leu He Gly Arg Ala Arg He Ser 3220 3225 3230 Gin Gly Ala Gly Trp Ser Leu Arg Glu Thr Ala Cys Leu Gly Lys Ser 3235 3240 3245 Tyr Ala Gin Met Trp Ser Leu Met Tyr Phe His Arg Arg Asp Leu Arg 3250 3255 3260 Leu Ala Ala Asn Ala He Cys Ser Ala Val Pro Ser His Trp Val Pro 3265 3270 3275 3280 Thr Ser Arg Thr Thr Trp Ser He His Ala Lys His Glu Trp Met Thr 3285 3290 3295 Thr Glu Asp Met Leu Thr Val Trp Asn Arg Val Trp He Gin Glu Asn 3300 3305 3310 Pro Trp Met Glu Asp Lys Thr Pro Val Glu Ser Trp Glu Glu He Pro 3315 3320 3325 Tyr Leu Gly Lys Arg Glu Asp Gin Trp Cys Gly Ser Leu He Gly Leu 3330 3335 3340 Thr Ser Arg Ala Thr Trp Ala Lys Asn He Gin Ala Ala He Asn Gin 3345 3350 3355 3360 Val Arg Ser Leu He Gly Asn Glu Glu Tyr Thr Asp Tyr Met Pro Ser 3365 3370 3375 Met Lys Arg Phe Arg Arg Glu Glu Glu Glu Ala Gly Val Leu Trp 3380 3385 3390

    <210> 17 <211> 10756 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence :/Note = synthetic construct <221> CDS <222> (97) . . . (10305) <400> 17 agttgttagt ctacgtggac cgacaaagac agattctttg agggagctaa gctcaacgta 60 gttctaacag ttttttaatt agagagcaga tctctg atg aat aac caa egg aaa 114

    Met Asn Asn Gin Arg Lys 1 5

    aag gcg aaa Lys Ala Lys aac Asn 10 aeg Thr cct Pro ttc Phe aat Asn atg Met 15 ctg Leu aaa Lys cgc Arg gag Glu aga Arg 20 aac Asn cgc Arg 162 gtg teg act gtg caa cag ctg aca aag aga ttc tea ett gga atg ctg 210 Val Ser Thr Val Gin Gin Leu Thr Lys Arg Phe Ser Leu Gly Met Leu 25 30 35

    196

    2018200081 04 Jan 2018

    cag gga ega gga cca Pro tta aaa ctg, ttc atg Met gcc Ala ctg gtg gcg ttc Leu Val Ala Phe 50 ett Leu 258 Gin Gly 40 Arg Gly Leu Lys 45 Leu Phe cgt ttc eta aca ate cca cca aca gca ggg ata ttg aag aga tgg gga 306 Arg Phe Leu Thr He Pro Pro Thr Ala Gly He Leu Lys Arg Trp Gly 55 60 65 70 aca att aaa aaa tea aaa get att aat gtt ttg aga ggg ttc agg aaa 354 Thr He Lys Lys Ser Lys Ala He Asn Val Leu Arg Gly Phe Arg Lys 75 80 85 gag att gga agg atg ctg aac ate ttg aat agg aga cgc aga tcc gcg 402 Glu He Gly Arg Met Leu Asn He Leu Asn Arg Arg Arg Arg Ser Ala 90 95 100 ggc acc gga att gca gtc atg att ggc ctg ate gcc age gta gga gca 450 Gly Thr Gly He Ala Val Met He Gly Leu lie Ala Ser Val Gly Ala 105 110 115 gtt acc etc tct aac ttc caa ggg aag gtg atg atg aeg gta aat get 498 Val Thr Leu Ser Asn Phe Gin Gly Lys Val ' Met Met Thr Val Asn Ala 120 125 13 0 act gac gtc aca gat gtc ate aeg att cca aca get get gga aag aac 546 Thr Asp Val Thr Asp Val lie Thr lie Pro Thr Ala Ala Gly Lys Asn 135 140 145 150 eta tgc att gtc aga gca atg gat gtg gga tac atg tgc gat gat act 594 Leu Cys He Val Arg Ala Met Asp Val Gly Tyr Met Cys Asp Asp Thr 155 160 165 ate act tat gaa tgc cca gtg ctg teg get ggt aat gat cca gaa gac 642 lie Thr Tyr Glu Cys Pro Val Leu Ser Ala Gly Asn Asp Pro Glu Asp 170 175 180 ate gac tgt tgg tgc aca aag tea gca gtc tac gtc agg tat gga aga 690 He Asp Cys Trp Cys Thr Lys Ser Ala Val Tyr Val Arg Tyr Gly Arg 185 190 195 tgc acc aag aca cgc cac tea aga cgc agt cgg agg tea ctg aca gtg 738 Cys Thr Lys Thr Arg His Ser Arg Arg Ser Arg Arg Ser Leu Thr Val 200 205 • 210 cag aca cac gga gaa age act eta gcg aac aag aag ggg get tgg atg 786 Gin Thr His Gly Glu Ser Thr Leu Ala Asn Lys Lys Gly Ala Trp Met ' 215 220 225 230 gac age acc aag gcc aca agg tat ttg gta aaa aca gaa tea tgg ate 834 Asp Ser Thr Lys Ala Thr Arg Tyr Leu Val Lys Thr Glu Ser Trp He 235 240 245

    197

    2018200081 04 Jan 2018

    ttg agg aac Asn cct gga tat gcc ctg gtg gca gcc gtc att ggt tgg Trp atg Met 882 Leu Arg Pro 250 Gly Tyr Ala Leu Val Ala 255 Ala Val He Gly 260 ett ggg age aac acc atg cag aga gtt gtg ttt gtc gtg eta ttg ett 930 Leu Gly Ser Asn Thr Met Gin Arg Val Val Phe Val Val Leu Leu Leu 265 270 275 ttg gtg gcc cca get tac age ttc aac tgc ett gga atg age aac aga 978 Leu Val Ala Pro Ala Tyr Ser Phe Asn Cys Leu Gly Met Ser Asn Arg 280 285 290 gac ttc ttg gaa gga gtg tet gga gca aca tgg gtg gat ttg gtt etc 1026 Asp Phe Leu Glu Gly Val Ser Gly Ala Thr Trp Val Asp Leu Val Leu 295 300 305 310 gaa ggc gac age tgc gtg act ate atg tet aag gac aag cct acc ate 1074 Glu Gly Asp Ser Cys Val Thr He Met Ser Lys Asp Lys Pro Thr He 315 320 325 gat gtg aag atg atg aat atg gag geg gcc aac ctg gca gag gtc ege 1122 Asp Val Lys Met Met Asn Met Glu Ala Ala Asn Leu Ala Glu Val Arg 330 335 340 agt tat tgc tat ttg get acc gtc age gat etc tcc acc aaa get geg 1170 Ser Tyr Cys Tyr Leu Ala Thr Val Ser Asp Leu Ser Thr Lys Ala Ala 345 350 355 tgc ccg acc atg gga gaa get cac aat gac aaa cgt get gac cca get 1218 Cys Pro Thr Met Gly Glu Ala His Asn Asp Lys Arg Ala Asp Pro Ala 360 365 370 ttt gtg tgc aga caa gga gtg gtg gac agg ggc tgg ggc aac ggc tgc 1266 Phe Val Cys Arg Gin Gly Val Val Asp Arg Gly Trp Gly Asn Gly Cys 375 380 385 390 gga eta ttt ggc aaa gga age att gac aca tgc gcc aaa ttt gcc tgc 1314 Gly Leu Phe Gly Lys Gly Ser He Asp Thr Cys Ala Lys Phe Ala Cys 395 400 405 tet acc aag gca ata gga aga acc ate ttg aaa gag aat ate aag tac 1362 Ser Thr Lys Ala He Gly Arg Thr He Leu Lys Glu Asn He Lys Tyr 410 415 420 gaa gtg gcc att ttt gtc cat gga cca act act gtg gag teg cac gga 1410 Glu Val Ala lie Phe Val His Gly Pro Thr Thr Val Glu Ser His Gly 425 430 435 aat tac tcc aca cag gtt gga gcc act cag gca ggg aga ttc age ate 1458 Asn Tyr Ser Thr Gin Val Gly Ala Thr Gin Ala Gly Arg Phe Ser He 440 445 450 act cct geg geg cct tea tac aca eta aag ett gga gaa tat gga gag 1506 Thr Pro Ala Ala Pro Ser Tyr Thr Leu Lys Leu Gly Glu Tyr Gly Glu 455 460 465 470

    198

    2018200081 04 Jan 2018

    gtg aca gtg gac Asp tgt Cys 475 gaa cca Glu Pro egg tea ggg att gac acc aat gca tac 1554 Val Thr Val Arg Ser Gly 480 He Asp Thr Asn Ala 485 Tyr tac gtg atg act gtt gga aca aag aeg ttc ttg gtc cat cgt gag tgg 1602 Tyr Val Met Thr Val Gly Thr Lys Thr Phe Leu Val His Arg Glu Trp 490 495 500 ttc atg gac etc aac etc cct tgg age agt get gga agt act gtg tgg 1650 Phe Met Asp Leu Asn Leu Pro Trp Ser Ser Ala Gly Ser Thr Val Trp 505 510 515 agg aac aga gag aeg tta atg gag ttt gag gaa cca cac gcc aeg aag 1698 Arg Asn Arg Glu Thr Leu Met Glu Phe Glu Glu Pro His Ala Thr Lys 520 525 530 cag tet gtg ata gca ttg ggc tea caa gag gga get ctg cat caa get 1746 Gin Ser Val lie Ala Leu Gly Ser Gin Glu Gly Ala Leu His Gin Ala 535 540 545 550 ttg get gga gcc att cct gtg gaa ttt tea agc aac act gtc aag ttg 1794 Leu Ala Gly Ala He Pro Val Glu Phe Ser Ser Asn Thr Val Lys Leu 555 560 565 aeg teg ggt cat ttg aag tgt aga gtg aag atg gaa aaa ttg cag ttg 1842 Thr Ser Gly His Leu Lys Cys Arg Val Lys Met Glu Lys Leu Gin Leu 570 575 580 aag gga aca acc tat ggc gtc tgt tea aag get ttc aag ttt ctt ggg 1890 Lys Gly Thr Thr Tyr Gly Val Cys Ser Lys Ala Phe Lys Phe Leu Gly 585 590 595 act ccc gca gac aca ggt cac ggc act gtg gtg ttg gaa ttg cag tac 1938 Thr Pro Ala Asp Thr Gly His Gly Thr Val Val Leu Glu Leu Gin Tyr 600 605 610 act ggc aeg gat gga cct tgc aaa gtt cct ate teg tea gtg get tea 1986 Thr Gly Thr Asp Gly Pro Cys Lys Val Pro He Ser Ser Val Ala Ser 615 620 625 630 ttg aac gac eta aeg cca gtg ggc aga ttg gtc act gtc aac cct ttt 2034 Leu Asn Asp Leu Thr Pro Val Gly Arg Leu Val Thr Val Asn Pro Phe 635 640 645 gtt tea gtg gee aeg gcc aac get aag gtc ctg att gaa ttg gaa cca 2082 Val Ser Val Ala Thr Ala Asn Ala Lys Val Leu He Glu Leu Glu Pro 650 655 660 ccc ttt gga gac tea tac ata gtg gtg ggc aga gga gaa caa cag ate 2130 Pro Phe Gly Asp Ser Tyr He Val Val Gly Arg Gly Glu Gin Gin He 665 670 675

    199

    2018200081 04 Jan 2018

    aat Asn cac His 680 cat His tgg Trp cac His aag Lys tet Ser 685 gga Gly agc Ser agc Ser att He ggc Gly 690 aaa Lys gcc Ala ttt Phe aca Thr 2178 acc acc etc aaa gga geg cag aga eta gcc get eta gga gac aca get 2226 Thr Thr Leu Lys Gly Ala Gin Arg Leu Ala Ala Leu Gly Asp Thr Ala 695 700 705 710 tgg gac ttt gga tea gtt gga ggg gtg ttc acc tea gtt ggg aag get 2274 Trp Asp Phe Gly Ser Val Gly Gly Val Phe Thr Ser Val Gly Lys Ala 715 720 725 gtc cat caa gtg ttc gga gga gca ttc ege tea ctg ttc gga ggc atg 2322 Val His Gin Val Phe Gly Gly Ala Phe Arg Ser Leu Phe Gly Gly Met 730 735 740 tcc tgg ata aeg caa gga ttg ctg ggg get etc ctg ttg tgg atg ggc 2370 Ser Trp He Thr Gin Gly Leu Leu Gly Ala Leu Leu Leu Trp Met Gly 745 750 755 ate aat get cgt gat agg tcc ata get etc aeg ttt etc gca gee ggc 2418 lie Asn Ala Arg Asp Arg Ser He Ala Leu Thr Phe Leu Ala Ala Gly 760 765 770 att gtg aca ctg tat ttg ggg gtc atg gtg. cag gee gat agt ggt tgc 2466 He Val Thr Leu Tyr Leu Gly Val Met Val Gin Ala Asp Ser Gly Cys 775 780 785 790 gtt gtg agc tgg aaa aac aaa gaa ctg aaa tgt ggc agt ggg att ttc 2514 Val Val Ser Trp Lys Asn Lys Glu Leu Lys Cys Gly Ser Gly He Phe 795 800 805 ate aca gac aac gtg cac aca tgg aca gaa caa tac aag ttc caa cca 2562 He Thr Asp Asn Val His Thr Trp Thr Glu Gin Tyr Lys Phe Gin Pro 810 815 820 gaa tcc cct tea aaa eta get tea get ate cag aaa gcc cat gaa gag 2610 Glu Ser Pro Ser Lys Leu Ala Ser Ala He Gin Lys Ala His Glu Glu 825 830 835 ggc att tgt gga ate ege tea gta aca aga ctg gag aat ctg atg tgg 2658 Gly He Cys Gly He Arg Ser Val Thr Arg Leu Glu Asn Leu Met Trp 840 845 850 aaa caa ata aca cca gaa ttg aat cac att eta tea gaa aat gag gtg 2706 Lys Gin He Thr Pro Glu Leu Asn His He Leu Ser Glu Asn Glu Val 855 860 865 870 aag tta act att atg aca gga gac ate aaa gga ate atg cag gca gga 2754 Lys Leu Thr He Met Thr Gly Asp He Lys Gly He Met Gin Ala Gly 875 880 885 aaa ega tet ctg cgg cct cag ccc act- gag ctg aag tat tea tgg aaa 2802 Lys Arg Ser Leu Arg Pro Gin Pro Thr Glu Leu Lys Tyr Ser Trp Lys 890 895 900

    200

    2018200081 04 Jan 2018

    aca tgg Thr Trp ggc Gly 905 aaa Lys gca aaa atg Met etc Leu 910 tet Ser aca gag tet Thr Glu Ser cat His 915 aac Asn cag Gin acc Thr 2850 Ala Lys ttt etc att gat ggc ccc gaa aca gca gaa tgc ccc aac aca aat aga 2898 Phe Leu 920 lie Asp Gly Pro Glu 925 Thr Ala Glu Cys Pro 930 Asn Thr Asn Arg get tgg aat teg ttg gaa gtt gaa gac tat ggc ttt gga gta ttc acc 2946 Ala Trp 935 Asn Ser Leu Glu 940 Val Glu Asp Tyr Gly Phe 945 Gly Val Phe Thr 950 acc aat ata tgg eta aaa ttg aaa gaa aaa cag gat gta ttc tgc gac 2994 Thr Asn He Trp Leu 955 Lys Leu Lys Glu Lys Gin Asp 960 Val Phe Cys 965 Asp tea aaa etc atg tea geg gcc ata aaa gac aac aga gee gtc cat gee 3042 Ser Lys Leu Met 970 Ser Ala Ala He Lys 975 Asp Asn Arg Ala Val 980 His Ala gat atg ggt tat tgg ata gaa agt gca etc aat gac aca tgg aag ata 3090 Asp Met Gly Tyr 985 Trp He Glu Ser Ala 990 Leu Asn Asp Thr Trp 995 Lys He gag aaa gcc tet ttc att gaa gtt aaa aac tgc cac tgg cca aaa tea 3138 Glu Lys Ala 1000 Ser Phe He Glu Val 1005 Lys Asn Cys His Trp 1010 Pro Lys Ser cac acc etc tgg age aat gga gtg eta gaa agt gag atg ata att cca 3186 His Thr 1015 Leu Trp Ser Asn Gly 1020 Val Leu Glu Ser Glu 1025 Met He He Pro 1030 aag aat etc get gga cca gtg tet caa cac aac tat aga cca ggc tac 3234 Lys Asn Leu Ala Gly Pro 1035 Val Ser Gin His Asn Tyr 1040 Arg Pro Gly Tyr 1045 cat aca caa ata aca gga cca tgg cat eta ggt aag ett gag atg gac 3282 His Thr Gin He Thr 1050 Gly Pro Trp His Leu Gly Lys 1055 Leu Glu Met 1060 Asp ttt gat ttc tgt gat gga aca aca gtg gta gtg act gag gac tgc gga 3330 Phe Asp Phe Cys 1065 Asp Gly Thr Thr Val 1070 Val Val Thr Glu Asp 1075 Cys Gly aat aga gga ccc tet ttg aga aca acc act gcc tet gga aaa etc ata 3378 Asn Arg Gly 1080 Pro Ser Leu Arg Thr 1085 Thr Thr Ala Ser Gly 1090 Lys Leu lie aca gaa tgg tgc tgc ega tet tgc aca tta cca ccg eta aga tac aga 3426 Thr Glu 1095 Trp Cys Cys Arg Ser 1100 Cys Thr Leu Pro Pro 1105 Leu Arg Tyr Arg 1110

    201

    2018200081 04 Jan 2018

    ggt Gly gag Glu gat Asp ggg Gly tgc tgg Cys Trp 1115 . tac Tyr ggg Gly atg Met gaa ate Glu He 1120 aga Arg cca Pro ttg Leu aag gag Lys Glu 1125 3474 aaa gaa gag aat ttg gtc aac tcc ttg gtc aca get gga cat ggg cag 3522 Lys Glu Glu Asn, 1130 Leu Val Asn Ser Leu 1135 Val Thr Ala Gly His 114C Gly Gin 1 gtc gac aac ttt tea eta gga gtc ttg gga atg gca ttg ttc ctg gag 3570 Val Asp Asn Phe 1145 Ser Leu Gly Val Leu 1150 Gly Met Ala Leu Phe 1155 Leu Glu gaa atg ett agg acc ega gta gga aeg aaa cat gca ata eta eta gtt 3618 Glu Met Leu 1160 Arg Thr Arg Val Gly 1165 Thr Lys His Ala 117C He 1 Leu Leu Val gca gtt tet ttt gtg aca ttg ate aca ggg aac atg tcc ttt aga gac 3666 Ala Val 1175 Ser Phe Val Thr Leu 1180 He Thr Gly Asn Met 1185 Ser Phe Arg Asp 1190 ctg gga aga gtg atg gtt atg gta ggc gcc act atg aeg gat gac ata 3714 Leu Gly Arg Val Met Val 1195 Met Val Gly Ala Thr 1200 Met Thr Asp Asp He 1205 ggt atg ggc gtg act tat ett gcc eta eta gca gcc ttc aaa gtc aga 3762 Gly Met Gly Val Thr Tyr 1210 Leu Ala Leu Leu Ala 1215 Ala Phe Lys Val Arg 1220 cca act ttt gca get gga eta etc ttg aga aag ctg acc tcc aag gaa 3810 Pro Thr Phe Ala 1225 Ala Gly Leu Leu Leu 1230 Arg Lys Leu Thr Ser 1235 Lys Glu ttg atg atg act act ata gga att gta etc etc tcc cag agc acc ata 3858 Leu Met Met 1240 Thr Thr He Gly He 1245 Val Leu Leu Ser Gin 1250 Ser Thr He cca gag acc att ett gag ttg act gat gcg tta gcc tta ggc atg atg 3906 Pro Glu 1255 Thr lie Leu Glu Leu 1260 Thr Asp Ala Leu Ala 1265 Leu Gly Met Met 1270 gtc etc. aaa atg gtg aga aat atg gaa aag tat caa ttg gca gtg act 3954 Val Leu Lys Met Val Arg 1275 Asn Met Glu Lys Tyr 1280 Gin Leu Ala Val Thr 1285 ate atg get ate ttg tgc gtc cca aac gca gtg ata tta caa aac gca 4002 lie Met Ala He Leu Cys 1290 Val Pro Asn Ala Val 1295 lie Leu Gin Asn Ala 1300 tgg aaa gtg agt tgc aca ata ttg gca gtg gtg tcc gtt tcc cca ctg 4050 Trp Lys Val Ser 1305 Cys Thr He Leu Ala 1310 Val Val Ser Val Ser 1315 Pro Leu etc tta aca tcc tea cag caa aaa aca gat tgg ata cca tta gca ttg 4098 Leu Leu Thr 1320 Ser Ser Gin Gin Lys 1325 Thr Asp Trp He Pro 1330 Leu Ala Leu

    202

    2018200081 04 Jan 2018

    aeg Thr 1335 ate He aaa Lys ggt Gly etc Leu aat cca aca get Ala att He ttt eta aca Phe Leu Thr 1345 acc Thr etc Leu tea Ser 1350 4146 Asn Pro 1340 Thr aga acc age aag aaa agg age tgg cca tta aat gag get ate atg gca 4194 Arg Thr Ser Lys Lys 1355 Arg Ser Trp Pro Leu 136C Asn Glu Ala 1 He Met 1365 Ala gtc ggg atg gtg age att tta gcc agt tct etc eta aaa aat gat att 4242 Val Gly Met Val 137C Ser 1 He Leu Ala Ser 1375 Ser Leu Leu Lys Asn Asp 1380 He ccc atg aca gga cca tta gtg get gga ggg etc etc act gtg tgc tac 4290 Pro Met Thr Gly 1385 Pro Leu Val Ala Gly 1390 Gly Leu Leu Thr Val 1395 Cys Tyr gtg etc act gga cga teg gcc gat ttg gaa ctg gag aga gca gcc gat 4338 Val Leu Thr 1400 Gly Arg Ser Ala Asp 1405 Leu Glu Leu Glu Arg 1410 Ala Ala Asp gtc aaa tgg gaa gac cag gca gag ata tea gga age agt cca ate ctg 4386 Val Lys 1415 Trp Glu Asp Gin Ala 1420 Glu He Ser Gly Ser Ser 1425 Pro He Leu 1430 tea ata aca ata tea gaa gat ggt age atg teg ata aaa aat gaa gag 4434 Ser lie Thr He Ser Glu Asp 1435 Gly Ser Met Ser He Lys 1440 Asn Glu Glu 1445 gaa gaa caa aca ctg acc ata etc att aga aca gga ttg ctg gtg ate 4482 Glu Glu Gin Thr Leu 1450 Thr He Leu He Arg 1455 Thr Gly Leu Leu Val 1460 He tea gga ett ttt cct gta tea ata cca ate aeg gca gca gca tgg tac 4530 Ser Gly Leu Phe 1465 Pro Val Ser He Pro 1470 He Thr Ala Ala Ala 1475 Trp Tyr ctg tgg gaa gtg aag aaa caa egg gee gga gta ttg tgg gat gtt cct 4578 Leu Trp Glu 1480 Val Lys Lys Gin Arg 1485 Ala Gly Val Leu Trp 1490 Asp Val Pro tea ccc cca ccc atg gga aag get gaa ctg gaa gat gga gee tat aga 4626 Ser Pro 1495 Pro Pro Met Gly Lys 1500 Ala Glu Leu Glu Asp Gly 1505 Ala Tyr Arg 1510 att aag caa aaa ggg att ett gga tat tcc cag ate gga gee gga gtt 4674 lie Lys Gin Lys Gly He Leu 1515 Gly Tyr Ser Gin He Gly 1520 Ala Gly Val 1525 tac aaa gaa gga aca ttc cat aca atg tgg cat gtc aca cgt ggc get 4722 Tyr Lys Glu Gly Thr Phe His Thr Met Trp His .Val Thr Arg Gly Ala

    1530 1535 1540

    203

    2018200081 04 Jan 2018

    gtt Val eta Leu atg cat Met His 1545 aaa Lys gga Gly aag Lys agg att Arg He 1550 gaa Glu cca Pro tea Ser tgg gcg Trp Ala 1555 gac Asp gtc Val 4770 aag aaa gac eta ata tea tat gga gga ggc tgg aag tta gaa gga gaa 4818 Lys Lys 156C Asp Leu 1 He Ser Tyr 1565 Gly Gly Gly Trp Lys 1570 Leu Glu 1 Gly Glu tgg aag gaa gga gaa gaa gtc cag gta ttg gca ctg gag cct gga aaa 4866 Trp 157Ξ Lys Glu Gly Glu Glu 158C Val 1 Gin Val Leu Ala 1585 Leu Glu Pro Gly Lys 1590 aat cca aga gcc gtc caa aeg aaa cct ggt ett ttc aaa acc aac gcc 4914 Asn Pro Arg Ala Val Gin 1595 Thr Lys Pro Gly Leu 1600 Phe Lys Thr Asn Ala 1605 gga aca ata ggt get gta tct ctg gac ttt tct cct gga aeg tea gga 4962 Gly Thr lie Gly Ala 1610 Val Ser Leu Asp Phe 1615 Ser Pro Gly Thr Ser 1620 Gly tct cca att ate gac aaa aaa gga aaa gtt gtg ggt ett tat ggt aat 5010 Ser Pro He He 1625 Asp Lys Lys Gly Lys 1630 Val Val Gly Leu Tyr 1635 Gly Asn ggt gtt gtt aca agg agt gga gca tat gtg agt get ata gcc cag act 5058 Gly Val Val Thr 1640 Arg Ser Gly Ala Tyr 1645 Val Ser Ala He Ala 1650 Gin Thr gaa aaa age att gaa gac aac cca gag ate gaa gat gac att ttc ega 5106 Glu Lys 1655 Ser He Glu Asp Asn 1660 Pro Glu He Glu Asp 1665 Asp He Phe Arg 1670 aag aga aga ctg acc ate atg gac etc cac cca gga gcg gga aag aeg 5154 Lys Arg Arg Leu Thr He 1675 Met Asp Leu His Pro 1680 Gly Ala Gly Lys Thr 1685 aag aga tac ett ccg gcc ata gtc aga gaa get ata aaa egg ggt ttg 5202 Lys Arg Tyr Leu Pro 1690 Ala He Val Arg Glu 1695 Ala He Lys Arg Gly 1700 Leu aga aca tta ate ttg gcc ccc act aga gtt gtg gca get gaa atg gag 5250 Arg Thr Leu He 1705 Leu Ala Pro Thr Arg 1710 Val Val Ala Ala Glu 1715 Met Glu gaa gcc ett aga gga ett cca ata aga tac cag acc cca gcc ate aga 5298 Glu Ala Leu Arg 1720 Gly Leu Pro He Arg 1725 Tyr Gin Thr Pro Ala 1730 He Arg get gag cac acc ggg egg gag att gtg gac eta atg tgt cat gcc aca 5346 Ala Glu 1735 His Thr Gly Arg Glu 1740 He Val Asp Leu Met 1745 Cys His Ala Thr 1750 ttt acc atg agg ctg eta tea cca gtt aga gtg cca aac tac aac ctg 5394 Phe Thr Met Arg Leu Leu 1755 Ser Pro Val Arg Val 1760 Pro Asn Tyr Asn Leu 1765

    204

    2018200081 04 Jan 2018

    att lie ate He atg gac gaa Met Asp Glu 1770 gcc Ala cat His ttc aca gac cca Pro gca Ala agt Ser ata gca get He Ala Ala 1780 5442 Phe Thr Asp 1775 aga gga tac ate tea act ega gtg gag atg ggt gag gca get ggg att 5490 Arg Gly Tyr He Ser 1785 Thr Arg Val Glu Met 1790 Gly Glu Ala 1795 Ala Gly He ttt atg aca gcc act ccc ccg gga age aga gac cca ttt cct cag age 5538 Phe Met 180C Thr Ala Thr 1 Pro Pro 1805 Gly Ser Arg Asp Pro Phe 1810 Pro Gin Ser aat gca cca ate ata gat gaa gaa aga gaa ate cct gaa cgt teg tgg 5586 Asn Ala 1815 Pro lie He Asp Glu 1820 Glu Arg Glu He Pro 1825 Glu Arg Ser Trp 1830 aat tcc gga cat gaa tgg gtc aeg gat ttt aaa ggg aag act gtt tgg 5634 Asn Ser Gly His Glu Trp 1835 Val Thr Asp Phe Lys 1840 Gly Lys Thr Val Trp 1845 ttc gtt cca agt ata aaa gca gga aat gat ata gca get tgc ctg agg 5682 Phe Val Pro Ser He 1850 Lys Ala Gly Asn Asp 1855 He Ala Ala Cys Leu Arg 1860 aaa aat gga aag aaa gtg ata caa etc agt agg aag acc ttt gat tet 5730 Lys Asn Gly Lys Lys 1865 Val lie Gin Leu Ser 1870 Arg Lys Thr Phe Asp Ser 1875 gag tat gtc aag act aga acc aat gat tgg gac ttc gtg gtt aca act 5778 Glu Tyr Val Lys Thr 1880 Arg Thr Asn 1885 Asp Trp Asp Phe Val 1890 Val Thr Thr gac att tea gaa atg ggt gcc aat ttc aag get gag agg gtt ata gac 5826 Asp He 1895 Ser Glu Met Gly Ala 1900 Asn Phe Lys Ala Glu 1905 Arg Val He Asp 1910 ccc aga ege tgc atg aaa cca gtc ata eta aca gat ggt gaa gag egg 5874 Pro Arg Arg Cys Met Lys 1915 Pro Val He Leu Thr 1920 Asp Gly Glu Glu Arg 1925 gtg att ctg gca gga cct atg cca gtg acc cac tet agt gca gca caa 5922 Val He Leu Ala Gly 1930 Pro Met Pro Val Thr 1935 His Ser Ser Ala Ala Gin 1940 aga aga ggg aga ata gga aga aat cca aaa aat gag aat gac cag tac 5970 Arg Arg Gly Arg He 1945 Gly Arg Asn Pro Lys 1950 Asn Glu Asn Asp Gin Tyr 1955 ata tac atg ggg gaa cct ctg gaa aat gat gaa gac tgt gca cac tgg 6018 He Tyr Met Gly Glu 1960 Pro Leu Glu 1965 Asn Asp Glu Asp Cys 1970 Ala His Trp

    205

    2018200081 04 Jan 2018

    aaa gaa Lys Glu 1975 get Ala aaa atg etc eta gat Leu Leu Asp 1980 aac Asn ate He aac aeg Asn Thr 1985 cca Pro gaa Glu gga Gly ate He 1990 6066 Lys Met att cct agc atg ttc gaa cca gag cgt gaa aag gtg gat gcc att gat 6114 lie Pro Ser Met Phe 1995 Glu Pro Glu Arg Glu 2000 Lys Val 1 Asp Ala He 2005 Asp ggc gaa tac cgc ttg aga gga gaa gca agg aaa acc ttt gta gac tta 6162 Gly Glu Tyr Arg Leu 2010 Arg Gly Glu Ala Arg 2015 Lys Thr Phe Val Asp 2020 Leu atg aga aga gga gac eta cca gtc tgg ttg gcc tac aga gtg gca get 6210 Met Arg Arg Gly 2025 Asp Leu Pro Val Trp 2030 Leu Ala Tyr Arg Val 2035 Ala Ala gaa ggc ate aac tac gca gac aga agg tgg tgt ttt gat gga gtc aag 6258 Glu Gly He 2040 Asn Tyr Ala Asp Arg 2045 Arg Trp Cys Phe Asp 2050 Gly Val Lys aac aac caa ate eta gaa gaa aac gtg gaa gtt gaa ate tgg aca aaa 6306 Asn Asn 2055 Gin He Leu Glu Glu Asn 2060 Val Glu Val Glu 2065 He Trp Thr Lys 2070 gaa ggg gaa agg aag aaa ttg aaa ccc aga tgg ttg gat get agg ate 6354 Glu Gly Glu Arg Lys Lys Leu Lys 2075 Pro Arg Trp Leu 2080 Asp Ala Arg He 2085 tat tct gac cca ctg gcg eta aaa gaa ttt aag gaa ttt gca gcc gga 6402 Tyr Ser Asp Pro Leu 2090 Ala Leu Lys Glu Phe 2095 Lys Glu Phe Ala Ala 2100 Gly aga aag tct ctg acc ctg aac eta ate aca gaa atg ggt agg etc cca 6450 Arg Lys Ser Leu 2105 Thr Leu Asn Leu He 2110 Thr Glu Met Gly Arg 2115 Leu Pro acc ttc atg act cag aag gca aga gac gca ctg gac aac tta gca gtg 6498 Thr Phe Met 2120 Thr Gin Lys Ala Arg 2125 Asp Ala Leu Asp Asn 2130 Leu Ala Val ctg cac aeg get gag gca ggt gga agg gcg tac aac cat get etc agt 6546 Leu His 2135 Thr Ala Glu Ala Gly Gly 2140 Arg Ala Tyr Asn 2145 His Ala Leu Ser 2150 gaa ctg ccg gag acc ctg gag aca ttg ett tta ctg aca ett ctg get 6594 Glu Leu Pro Glu Thr Leu Glu Thr 2155 Leu Leu Leu Leu 2160 Thr Leu Leu Ala 2165 aca gtc aeg gga ggg ate ttt tta ttc ttg atg agc gga agg ggc ata 6642 Thr Val Thr Gly Gly 2170 He Phe Leu Phe Leu 2175 Met Ser Gly Arg Gly 2180 He ggg aag atg acc ctg gga atg tgc tgc ata ate aeg get agc ate etc 6690 Gly Lys Met Thr 2185 Leu Gly Met Cys Cys 2190 He He Thr Ala Ser 2195 He Leu

    206

    2018200081 04 Jan 2018

    eta Leu tgg tac gca caa Trp Tyr Ala Gin 2200 ata He cag cca cac Gin Pro His 2205 tgg Trp ata gca get He Ala Ala 2210 tea Ser ata He ata He 6738 ctg gag ttt ttt etc ata gtt ttg ett att cca gaa cct gaa aaa cag 6786 Leu 2215 Glu Phe Phe Leu He 222C Val Leu Leu 1 He Pro Glu Pro 2225 Glu Lys Gin 2230 aga aca ccc caa gac aac caa ctg acc tac gtt gtc ata gcc ate etc 6834 Arg Thr Pro Gin Asp 2235 Asn Gin Leu Thr Tyr 224C Val Val He 1 Ala He 2245 Leu aca gtg gtg gcc gca acc atg gca aac gag atg ggt ttc eta gaa aaa 6882 Thr Val Val Ala Ala 2250 Thr Met Ala Asn 2255 Glu Met Gly Phe Leu 226C Glu 1 Lys aeg aag aaa gat etc gga ttg gga agc att gca acc cag caa ccc gag 6930 Thr Lys Lys Asp Leu 2265 Gly Leu Gly Ser 2270 He Ala Thr Gin Gin 2275 Pro Glu agc aac ate ctg gac ata gat eta cgt cct gca tea gca tgg aeg ctg 6978 Ser Asn He Leu Asp 2280 He Asp Leu Arg 2285 Pro Ala Ser Ala 2290 Trp Thr Leu tat gcc gtg gcc aca aca ttt gtt aca cca atg ttg aga cat agc att 7026 Tyr 2295 Ala Val Ala Thr Thr Phe Val Thr 2300 Pro Met Leu Arg 2305 His Ser He 2310 gaa aat tcc tea gtg aat gtg tcc eta aca get ata gcc aac caa gcc 7074 Glu Asn Ser Ser Val 2315 Asn Val Ser Leu Thr Ala He Ala 2320 Asn Gin Ala 2325 aca gtg tta atg ggt etc ggg aaa gga tgg cca ttg tea aag atg gac 7122 Thr Val Leu Met Gly 2330 Leu Gly Lys Gly Trp 2335 Pro Leu Ser Lys Met 2340 Asp ate gga gtt ccc ett etc gcc att gga tgc tac tea caa gtc aac ccc 7170 lie Gly Val Pro Leu 2345 Leu Ala lie Gly 2350 Cys Tyr Ser Gin Val 2355 Asn Pro ata act etc aca gca get ett ttc tta ttg gta gca cat tat gcc ate 7218 He Thr Leu Thr Ala 2360 Ala Leu Phe Leu 2365 Leu Val Ala His 2370 Tyr Ala He ata ggg cca gga etc caa gca aaa gca acc aga gaa get cag aaa aga 7266 He Gly Pro Gly Leu 2375 Gin Ala Lys Ala 2380 Thr Arg Glu Ala 2385 Gin Lys Arg 2390 gca geg geg ggc ate atg aaa aac cca act gtc gat gga ata aca gtg 7314 Ala Ala Ala Gly He Met 2395 Lys Asn Pro Thr Val Asp Gly 2400 He Thr Val 2405

    207

    2018200081 04 Jan 2018

    att lie gac Asp eta Leu gat cca Asp Pro 2410 ata He cct Pro tat Tyr gat cca Asp Pro 2415 aag Lys ttt Phe gaa Glu aag cag Lys Gin 2420 ttg Leu 7362 gga caa gta atg etc eta gtc etc tgc gtg act caa gta ttg atg atg 7410 Gly Gin Val 2425 Met Leu Leu Val Leu 243C Cys Val 1 Thr Gin Val 2435 Leu Met Met agg act aca tgg get ctg tgt gag get tta acc tta get acc ggg ccc 7458 Arg Thr Thr 2440 Trp Ala Leu Cys Glu 2445 Ala Leu Thr Leu Ala 2450 Thr Gly Pro ate tcc aca ttg tgg gaa gga aat cca ggg agg ttt tgg aac act acc 7506 He Ser 2455 Thr Leu Trp Glu Gly 2460 Asn Pro Gly Arg 2465 Phe Trp Asn Thr Thr 2470 att 9cg gtg tea atg get aac att ttt aga ggg agt tac ttg gcc gga 7554 lie Ala Val Ser Met Ala 2475 Asn He Phe Arg Gly 2480 Ser Tyr Leu Ala Gly 2485 get gga ett etc ttt tet att atg aag aac aca acc aac aca aga agg 7602 Ala Gly Leu Leu Phe 2490 Ser He Met Lys Asn 2495 Thr Thr Asn Thr Arg 2500 Arg gga act ggc aac ata gga gag aeg ett gga gag aaa tgg aaa agc ega 7650 Gly Thr Gly Asn He 2505 Gly Glu Thr Leu Gly 2510 Glu Lys Trp Lys Ser 2515 Arg ttg aac gca ttg gga aaa agt gaa ttc cag ate tac aag aaa agt gga 7698 Leu Asn Ala 2520 Leu Gly Lys Ser Glu 2525 Phe Gin He Tyr Lys 2530 Lys Ser Gly ate cag gaa gtg gat aga' acc tta gca aaa gaa ggc att aaa aga gga 7746 He Gin 2535 Glu Val Asp Arg Thr 2540 Leu Ala Lys Glu Gly 2545 He Lys Arg Gly 2550 gaa aeg gac cat cac get gtg teg ega ggc tea gca aaa ctg aga tgg 7794 Glu Thr Asp His His Ala 2555 Val Ser Arg Gly Ser 2560 Ala Lys Leu Arg Trp 2565 ttc gtt gag aga aac atg gtc aca cca gaa ggg aaa gta gtg gac etc 7842 Phe Val Glu Arg Asn 2570 Met Val Thr Pro Glu 2575 Gly Lys Val Val Asp 2580 Leu ggt tgt ggc aga gga ggc tgg tea tac tat tgt gga gga eta aag aat 7890 Gly Cys Gly Arg Gly 2585 Gly Trp Ser Tyr Tyr 2590 Cys Gly Gly Leu Lys 2595 Asn gta aga gaa gtc aaa ggc eta aca aaa gga gga cca gga cac gaa gaa 7938 Val Arg Glu 2600 Val Lys Gly Leu Thr 2605 Lys Gly Gly Pro Gly 2610 His Glu Glu ccc ate ccc atg tea aca tat ggg tgg aat eta gtg cgt ett caa agt 7986 Pro He Pro Met Ser Thr Tyr Gly Trp Asn Leu Val Arg Leu Gin Ser

    2615 2620 2625 2630

    208

    2018200081 04 Jan 2018

    gga gtt gac Asp gtt Val ttc Phe 2635 ttc Phe ate He ccg Pro cca Pro gaa aag Glu Lys 2640 tgt Cys gac Asp aca Thr tta ttg Leu Leu 2645 8034 Gly Val tgt gac ata ggg gag tea tea cca aat ccc aca gtg gaa gca gga ega 8082 Cys Asp lie Gly 265C Glu 1 Ser Ser Pro Asn 2655 Pro Thr Val Glu Ala Gly Arg 2660 aca etc aga gtc ett aac tta gta gaa aat tgg ttg aac aac aac act 8130 Thr Leu Arg Val 2665 Leu Asn Leu Val 267C Glu 1 Asn Trp' Leu Asn Asn 2675 Asn Thr caa ttt tgc ata aag gtt etc aac cca tat atg ccc tea gtc ata gaa 8178 Gin Phe Cys 2680 He Lys Val Leu Asn 2685 Pro Tyr Met Pro Ser 2690 Val He Glu aaa atg gaa gca eta caa agg aaa tat gga gga gcc tta gtg agg aat 8226 Lys Met 2695 Glu Ala Leu Gin Arg 2700 Lys Tyr Gly Gly Ala 2705 Leu Val Arg Asn 2710 cca etc tea ega aac tcc aca cat gag atg tac tgg gta tcc aat get 8274 Pro Leu Ser Arg Asn 2715 Ser Thr His Glu Met Tyr 2720 Trp Val Ser Asn Ala 2725 tcc ggg aac ata gtg tea tea gtg aac atg att tea agg atg ttg ate 8322 Ser Gly Asn lie Val 2730 Ser Ser Val Asn Met He 2735 Ser Arg Met Leu He 2740 aac aga ttt aca atg aga tac aag aaa gcc act tac gag ccg gat gtt 8370 Asn Arg Phe Thr 2745 Met Arg Tyr Lys Lys 2750 Ala Thr Tyr Glu Pro 2755 Asp Val gac etc gga age gga acc cgt aac ate ggg att gaa agt gag ata cca 8418 Asp Leu Gly 2760 Ser Gly Thr Arg Asn 2765 He Gly He Glu Ser 2770 Glu He Pro aac eta gat ata att ggg aaa aga ata gaa aaa ata aag caa gag cat 8466 Asn Leu 2775 Asp He He Gly Lys 2780 Arg He Glu Lys He 2785 Lys Gin Glu His 2790 gaa aca tea tgg cac tat gac caa gac cac cca tac aaa aeg tgg gca 8514 Glu Thr Ser Trp His Tyr 2795 Asp Gin Asp His Pro 2800 Tyr Lys Thr Trp Ala 2805 tac cat ggt age tat gaa aca aaa cag act gga tea gca tea tcc atg 8562 Tyr His Gly Ser Tyr 2810 Glu Thr Lys Gin Thr Gly 2815 Ser Ala Ser Ser Met 2820 gtc aac gga gtg gtc agg ctg ctg aca aaa cct tgg gac gtc gtc ccc 8610 Val Asn Gly Val Val Arg Leu Leu Thr Lys Pro Trp Asp Val Val Pro

    2825 2830 2835

    209

    2018200081 04 Jan 2018

    atg Met gtg aca cag atg gca atg aca gac Val Thr Gin Met Ala Met Thr Asp acg act cca ttt Pro Phe 2850 gga Gly caa Gin cag Gin 8658 Thr Thr 2840 2845 cgc gtt ttt aaa gag aaa gtg gac acg aga acc caa gaa ccg aaa gaa 8706 Arg 2855 Val Phe Lys Glu Lys Val Asp Thr 2860 Arg Thr 2865 Gin Glu Pro Lys Glu 2870 ggc acg aag aaa eta atg aaa ata aca gca gag tgg ett tgg aaa gaa 8754 Gly Thr Lys Lys Leu 2875 Met Lys lie Thr Ala 288C Glu 1 Trp Leu Trp Lys 2885 Glu tta ggg aag aaa aag aca ccc agg atg tgc acc aga gaa gaa ttc aca 8802 Leu Gly Lys Lys Lys 2890 Thr Pro Arg Met Cys 2895 Thr Arg Glu Glu Phe 2900 Thr aga aag gtg aga age aat gca gcc ttg ggg gcc ata ttc act gat gag 8850 Arg Lys Val Arg Ser 2905 Asn Ala Ala Leu 2910 Gly Ala He Phe Thr 2915 Asp Glu aac aag tgg aag teg gca cgt gag get gtt gaa gat agt agg ttt tgg 8898 Asn Lys Trp Lys Ser 2920 Ala Arg Glu Ala 2925 Val Glu Asp Ser 2930 Arg Phe Trp gag ctg gtt gac aag gaa agg aat etc cat ett gaa gga aag tgt gaa 8946 Glu 2935 Leu Val Asp Lys Glu Arg Asn Leu 2940 His Leu 2945 Glu Gly Lys Cys Glu 2950 aca tgt gtg tac aac atg atg gga aaa aga gag aag aag eta ggg gaa 8994 Thr Cys Val Tyr Asn 2955 Met Met Gly Lys Arg Glu 2960 Lys Lys Leu Gly 2965 Glu ttc ggc aag gca aaa ggc age aga gcc ata tgg tac atg tgg ett gga 9042 Phe Gly Lys Ala Lys 2970 Gly Ser Arg Ala He 2975 Trp Tyr Met Trp Leu 2980 Gly gca cgc ttc tta gag ttt gaa gcc eta gga ttc tta aat gaa gat cac 9090 Ala Arg Phe Leu Glu 2985 Phe Glu Ala Leu 2990 Gly Phe Leu Asn Glu 2995 Asp His tgg ttc tcc aga gag aac tcc ctg agt gga gtg gaa gga gaa ggg ctg 9138 Trp Phe Ser Arg Glu 3000 Asn Ser Leu Ser 3005 Gly Val Glu Gly 3010 Glu Gly Leu cac aag eta ggt tac att eta aga gac gtg age aag aaa gag gga gga 9186 His Lys Leu Gly Tyr 3015 He Leu Arg Asp 3020 Val Ser Lys Lys 3025 Glu Gly Gly 3030 gca atg tat gcc gat gac acc gca gga tgg gat aca aga ate aca eta 9234 Ala Met Tyr Ala Asp Asp Thr Ala Gly 3035 Trp Asp 3040 Thr Arg He Thr Leu 3045 gaa gac eta aaa aat gaa gaa atg gta aca aac cac atg gaa gga gaa 9282 Glu Asp Leu Lys Asn Glu Glu Met Val Thr Asn His Met Glu Gly Glu

    3050 3055 3060

    210

    2018200081 04 Jan 2018

    cac His aag Lys aaa eta gcc Lys Leu Ala 3065 gag Glu gee Ala att ttc He Phe 3070 aaa Lys eta Leu acg Thr tac Tyr 3075 caa Gin aac Asn aag Lys 9330 gtg gtg cgt gtg caa aga cca aca cca aga ggc aca gta atg gac ate 9378 Val Val 308C Arg Val Gin 1 Arg Pro 3085 Thr Pro Arg Gly Thr Val 3090 Met Asp He ata teg aga aga gac caa aga ggt agt gga caa gtt ggc acc tat gga 9426 lie 3095 Ser Arg Arg Asp Gin 310C Arg 1 Gly Ser Gly Gin 3105 Val Gly Thr Tyr Gly 3110 etc aat act ttc acc aat atg gaa gcc caa eta ate aga cag atg gag 9474 Leu Asn Thr Phe Thr 3115 Asn Met Glu Ala Gin 312C Leu I He Arg Gin Met 3125 Glu gga gaa gga gtc ttt aaa age att cag cac eta aca ate aca gaa gaa 9522 Gly Glu Gly Val Phe 3130 Lys Ser lie Gin His 3135 Leu Thr lie Thr Glu 3140 Glu ate get gtg caa aac tgg tta gca aga gtg ggg ege gaa agg tta tea 9570 He Ala Val Gin Asn 3145 Trp Leu Ala Arg 3150 Val Gly Arg Glu 3155 Arg Leu Ser aga atg gcc ate agt gga gat gat tgt gtt gtg aaa cct tta gat gac 9618 Arg Met Ala He Ser 3160 Gly Asp Asp Cys 3165 Val Val Lys Pro 3170 Leu Asp Asp agg ttc gca age get tta aca get eta aat gac atg gga aag att agg 9666 Arg Phe 3175 Ala Ser Ala Leu Thr 3180 Ala Leu Asn Asp Met 3185 Gly Lys He Arg 3190 aaa gac ata caa caa tgg gaa cct tea aga gga tgg aat gat tgg aca 9714 Lys Asp He Gin Gin Trp 3195 Glu Pro Ser Arg Gly 3200 Trp Asn Asp Trp Thr 3205 caa gtg ccc ttc tgt tea cac cat ttc cat gag tta ate atg aaa gac 9762 Gin Val Pro Phe Cys 3210 Ser His His Phe His 3215 Glu Leu He Met Lys 3220 Asp ggt ege gta etc gtt gtt cca tgt aga aac caa gat gaa ctg att ggc 9810 Gly Arg Val Leu Val 3225 Val Pro Cys Arg 3230 Asn Gin Asp Glu Leu 3235 He Gly aga gcc ega ate tcc caa gga gca ggg tgg tet ttg egg gag acg gcc 9858 Arg Ala Arg He Ser 3240 Gin Gly Ala Gly 3245 Trp Ser Leu Arg 3250 Glu Thr Ala tgt ttg ggg aag tet tac gee caa atg tgg age ttg atg tac ttc cac 9906 Cys Leu 3255 Gly Lys Ser Tyr Ala 3260 Gin Met Trp Ser Leu 3265 Met Tyr Phe His 3270

    211

    2018200081 04 Jan 2018

    aga Arg ege Arg gac Asp etc Leu agg ctg Arg Leu 3275 gcg Ala gca Ala aat Asn get att Ala He 3280 tgc Cys teg Ser gca Ala gta cca Val Pro 3285 9954 tea cat tgg gtt cca aca agt ega aca acc tgg tcc ata cat get aaa 10002 Ser His Trp Val Pro Thr Ser Arg Thr Thr Trp Ser He His Ala Lys 3290 3295 3300 cat gaa tgg atg aca aeg gaa gac atg ctg aca gtc tgg aac agg gtg 10050 His Glu Trp Met Thr Thr Glu Asp Met Leu Thr Val Trp Asn Arg Val 3305 3310 3315 tgg att caa gaa aac cca tgg atg gaa gac aaa act cca gtg gaa tea 10098 Trp lie Gin Glu Asn Pro Trp Met Glu Asp Lys Thr Pro Val Glu Ser 3320 3325 3330 tgg gag gaa ate cca tac ttg ggg aaa aga gaa gac caa tgg tgc ggc 10146 Trp Glu Glu He Pro Tyr Leu Gly Lys Arg Glu Asp Gin Trp Cys Gly 3335 3340 3345 3350 tea ttg att ggg tta aca age agg gcc acc tgg gca aag aac ate caa 10194 Ser Leu He Gly Leu Thr Ser Arg Ala Thr Trp Ala Lys Asn He Gin 3355 3360 3365 gca gca ata aat caa gtt aga tcc ett ata ggc aat gaa gaa tac aca 10242 Ala Ala He Asn Gin Val Arg Ser Leu He Gly Asn Glu Glu Tyr Thr 3370 3375 3380 gat tac atg cca tcc atg aaa aga ttc aga aga gaa gag gaa gaa gca 10290 Asp Tyr Met Pro Ser Met Lys Arg Phe Arg Arg Glu Glu Glu Glu Ala 3385 3390 3395 gga gtt ctg tgg tag aaagcaaaac taacatgaaa caaggctaga agtcaggtcg 10345 Gly Val Leu Trp * 3400

    gattaagcca tagtacggaa aaaactatgc tacctgtgag ccccgtccaa ggacgttaaa 10405 agaagtcagg ccatcataaa tgccatagct tgagtaaact atgcagcctg tagctccacc 10465 tgagaaggtg taaaaaatcc gggaggccac aaaccatgga agctgtacgc atggcgtagt 10525 ggactagcgg ttagaggaga cccctccctt acaaatcgca gcaacaatgg gggcccaagg 10585 cgagatgaag ctgtagtctc gctggaagga ctagaggtta gaggagaccc ccccgaaaca 10645 aaaaacagca tattgacgct gggaaagacc agagatcctg ctgtctcctc agcatcattc 10705 caggcacaga acgccagaaa atggaatggt gctgttgaat caacaggttc t 10756 <210> 18 <211> 3402 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence :/Note = synthetic construct <400> 18

    212

    2018200081 04 Jan 2018

    Met 1 Asn Asn Gin Arg 5 Lys Lys Ala Lys Asn Thr Pro Phe Asn Met Leu 10 15 Lys Arg Glu Arg Asn Arg Val Ser Thr Val Gin Gin Leu Thr Lys Arg •20 25 30 Phe Ser Leu Gly Met Leu Gin Gly Arg Gly Pro Leu Lys Leu Phe Met 35 40 45 Ala Leu Val Ala Phe Leu Arg Phe Leu Thr He Pro Pro Thr Ala Gly 50 55 60 lie Leu Lys Arg Trp Gly Thr He Lys Lys Ser Lys Ala He Asn Val 65 70 75 80 Leu Arg Gly Phe Arg Lys Glu He Gly Arg Met Leu Asn He Leu Asn 85 90 95 Arg Arg Arg Arg Ser Ala Gly Thr Gly He Ala Val Met He Gly Leu 100 105 110 He Ala Ser Val Gly Ala Val Thr Leu Ser Asn Phe Gin Gly Lys Val 115 120 125 Met Met Thr Val Asn Ala Thr Asp Val Thr Asp Val He Thr He Pro 13 0 135 14 0 Thr Ala Ala Gly Lys Asn Leu Cys He Val Arg Ala Met Asp Val Gly 145 150 155 160 Tyr Met Cys Asp Asp Thr He Thr Tyr Glu Cys Pro Val Leu Ser Ala 165 170 175 Gly Asn Asp Pro Glu Asp He Asp Cys Trp Cys Thr Lys Ser Ala Val 180 185 190 Tyr Val Arg Tyr Gly Arg Cys Thr Lys Thr Arg His Ser Arg Arg Ser 195 200 205 Arg Arg Ser Leu Thr Val Gin Thr His Gly Glu Ser Thr Leu Ala Asn 210 215 220 Lys Lys Gly Ala Trp Met Asp Ser Thr Lys Ala Thr Arg Tyr Leu Val 225 230 235 240 Lys Thr Glu Ser Trp lie Leu Arg Asn Pro Gly Tyr Ala Leu Val Ala 245 250 255 Ala Val He Gly Trp Met Leu Gly Ser Asn Thr Met Gin Arg Val Val 260 265 270 Phe Val Val Leu Leu Leu Leu Val Ala Pro Ala Tyr Ser Phe Asn Cys 275 280 285 Leu Gly Met Ser Asn Arg Asp Phe Leu Glu Gly Val Ser Gly Ala Thr 290 295 300 Trp Val Asp Leu Val Leu Glu Gly Asp Ser Cys Val Thr He Met Ser 305 310 315 320 Lys Asp Lys Pro Thr He Asp Val Lys Met Met Asn Met Glu Ala Ala 325 330 335 Asn Leu Ala Glu Val Arg Ser Tyr Cys Tyr Leu Ala Thr Val Ser Asp 340 345 350 Leu Ser Thr Lys Ala Ala Cys Pro Thr Met Gly Glu Ala His Asn Asp 355 360 365 Lys Arg Ala Asp Pro Ala Phe Val Cys Arg Gin Gly Val Val Asp Arg 370 375 380 Gly Trp Gly Asn Gly Cys Gly Leu Phe Gly Lys Gly Ser He Asp Thr 385 390 395 400 Cys Ala Lys Phe Ala Cys Ser Thr Lys Ala lie Gly Arg Thr He Leu 405 410 415 Lys Glu Asn He Lys Tyr Glu Val Ala He Phe Val His Gly Pro Thr 420 425 430

    213

    2018200081 04 Jan 2018

    Thr Val Glu 435 Ser His Gly Asn Tyr Ser Thr Gin Val Gly Ala Thr Gin 440 445 Ala Gly Arg Phe Ser He Thr Pro Ala Ala Pro Ser Tyr Thr Leu Lys 450 455 460 Leu Gly Glu Tyr Gly Glu Val Thr Val Asp Cys Glu Pro Arg Ser Gly 465 470 475 480 lie Asp Thr Asn Ala Tyr Tyr Val Met Thr Val Gly Thr Lys Thr Phe 485 490 495 Leu Val His Arg Glu Trp Phe Met Asp Leu Asn Leu Pro Trp Ser Ser 500 505 510 Ala Gly Ser Thr Val Trp Arg Asn Arg Glu Thr Leu Met Glu Phe Glu 515 520 525 Glu Pro His Ala Thr Lys Gin Ser Val He Ala Leu Gly Ser Gin Glu 530 535 540 Gly Ala Leu His Gin Ala Leu Ala Gly Ala He Pro Val Glu Phe Ser 545 550 555 560 Ser Asn Thr Val Lys Leu Thr Ser Gly His Leu Lys Cys Arg Val Lys 565 570 575 Met Glu Lys Leu Gin Leu Lys Gly Thr Thr Tyr Gly Val Cys Ser Lys 580 585 590 Ala Phe Lys Phe Leu Gly Thr Pro Ala Asp Thr Gly His Gly Thr Val 595 600 605 Val Leu Glu Leu Gin Tyr Thr Gly Thr Asp Gly Pro Cys Lys Val Pro 610 615 620 He Ser Ser Val Ala Ser Leu Asn Asp Leu Thr Pro Val Gly Arg Leu 625 630 635 640 Val Thr Val Asn Pro Phe Val Ser Val Ala Thr Ala Asn Ala Lys Val 645 650 655 Leu He Glu Leu Glu Pro Pro Phe Gly Asp Ser Tyr He Val Val Gly 660 665 670 Arg Gly Glu Gin Gin He Asn His His Trp His Lys Ser Gly Ser Ser 675 680 685 He Gly Lys Ala Phe Thr Thr Thr Leu Lys Gly Ala Gin Arg Leu Ala 690 695 700 Ala Leu Gly Asp Thr Ala Trp Asp Phe Gly Ser Val Gly Gly Val Phe 705 710 715 720 Thr Ser Val Gly Lys Ala Val His Gin Val Phe Gly Gly Ala Phe Arg 725 730 735 Ser Leu Phe Gly Gly Met Ser Trp He Thr Gin Gly Leu Leu Gly Ala 740 745 750 Leu Leu Leu Trp Met Gly He Asn Ala Arg Asp Arg Ser He Ala Leu 755 760 765 Thr Phe Leu Ala Ala Gly He Val Thr Leu Tyr Leu Gly Val Met Val 770 775 780 Gin Ala Asp Ser Gly Cys Val Val Ser Trp Lys Asn Lys Glu Leu Lys 785 790 795 800 Cys Gly Ser Gly He Phe He Thr Asp Asn Val His Thr Trp Thr Glu 805 810 815 Gin Tyr Lys Phe Gin Pro Glu Ser Pro Ser Lys Leu Ala Ser Ala He 820 825 830 Gin Lys Ala His Glu Glu Gly He Cys Gly He Arg Ser Val Thr Arg 835 840 845 Leu Glu Asn Leu Met Trp Lys Gin He Thr Pro Glu Leu Asn His He 850 855 860

    214

    2018200081 04 Jan 2018

    Leu Ser Glu Asn Glu Val Lys Leu Thr He Met Thr Gly Asp He Lys 865 Gly He 870 Met Gin Ala Gly Lys Arg Ser Leu 875 Arg Pro Gin Pro Thr 880 Glu Leu Lys 885 Tyr Ser Trp Lys Thr 890 Trp Gly Lys Ala Lys Met Leu 895 Ser Thr Glu Ser 900 His Asn Gin Thr Phe 905 Leu He Asp Gly Pro Glu 910 Thr Ala Glu Cys Pro 915 Asn Thr Asn Arg Ala 920 Trp Asn Ser Leu Glu 925 Val Glu Asp Tyr Gly 930 Phe ‘ 935 Gly Val Phe Thr Thr Asn He Trp Leu 940 Lys Leu Lys Glu Lys 945 Gin Asp 950 Val Phe Cys Asp Ser Lys Leu Met 955 Ser Ala Ala He Lys 960 Asp Asn Arg 965 Ala Val His Ala Asp 970 Met Gly Tyr Trp lie Glu Ser 975 Ala Leu Asn Asp 980 Thr Trp Lys He Glu 985 Lys Ala Ser Phe He Glu 990 Val Lys Asn Cys His 995 Trp Pro Lys Ser His 1000 Thr Leu Trp Ser Asn 100E Gly Val Leu Glu Ser 1010 1015 Glu Met He He Pro Lys Asn Leu Ala Gly 1020 Pro Val Ser Gin His 1025 Asn Tyr 1030 Arg Pro Gly Tyr His Thr Gin He 103E Thr Gly Pro Trp His 1040 Leu Gly Lys 1045 Leu Glu Met Asp Phe 1050 Asp Phe Cys Asp Gly Thr Thr 1055 Val Val Val Thr 1060 Glu Asp Cys Gly Asn 1065 Arg Gly Pro Ser Leu Arg 1070 Thr Thr Thr Ala Ser 1075 Gly Lys Leu He Thr 1080 Glu Trp Cys Cys Arg 1085 Ser Cys Thr Leu Pro 1090 1095 Pro Leu Arg Tyr Arg Gly Glu Asp Gly Cys 1100 Trp Tyr Gly Met Glu 1105 lie Arg 1110 Pro Leu Lys Glu Lys Glu Glu Asn 1115 Leu Val Asn Ser Leu 1120 Val Thr Ala 1125 Gly His Gly Gin Val 1130 Asp Asn Phe Ser Leu Gly Val 1135 Leu Gly Met Ala 1140 Leu Phe Leu Glu Glu 1145 Met Leu Arg Thr Arg Val 1150 Gly Thr Lys His Ala 1155 He Leu Leu Val Ala 1160 Val Ser Phe Val Thr 1165 Leu He Thr Gly Asn 1170 1175 Met Ser Phe Arg Asp Leu Gly Arg Val Met 1180 Val Met Val Gly Ala 1185 Thr Met 1190 Thr Asp Asp He Gly Met Gly Val 1195 Thr Tyr Leu Ala Leu 1200 Leu Ala Ala 1205 Phe Lys Val Arg Pro 1210 Thr Phe Ala Ala Gly Leu Leu 1215 Leu Arg Lys Leu 1220 Thr Ser Lys Glu Leu 1225 Met Met Thr Thr He Gly 1230 He Val Leu Leu Ser 1235 Gin Ser Thr He Pro 1240 Glu Thr He Leu Glu 1245 Leu Thr Asp Ala Leu 1250 1255 Ala Leu Gly Met Met Val Leu Lys Met Val 1260 Arg Asn Met Glu Lys 1265 Tyr Gin 1270 Leu Ala Val Thr He Met Ala He 1275 Leu Cys Val Pro Asn 1280 Ala 1285 1290 1295

    215

    2018200081 04 Jan 2018

    Val lie Leu Gin Asn Ala 1300 Trp Lys Val 1305 Ser Cys Thr He Leu Ala 1310 Val Val Ser Val Ser Pro Leu Leu Leu Thr Ser Ser Gin Gin Lys Thr Asp 1315 1320 1325 Trp He Pro Leu Ala Leu Thr He Lys Gly Leu Asn Pro Thr Ala He 1330 1335 1340 Phe Leu Thr Thr Leu Ser Arg Thr Ser Lys Lys Arg Ser Trp Pro Leu 1345 ; 1350 1355 1360 Asn Glu Ala He Met Ala Val Gly Met Val Ser He Leu Ala Ser Ser 1365 1370 1375 Leu Leu Lys Asn Asp He Pro Met Thr Gly Pro Leu Val Ala Gly Gly 1380 1385 1390 Leu Leu Thr Val Cys Tyr Val Leu Thr Gly Arg Ser Ala Asp Leu Glu 1395 1400 1405 Leu Glu Arg Ala Ala Asp Val Lys Trp Glu Asp Gin Ala Glu He Ser 1410 1415 1420 Gly Ser Ser Pro He Leu Ser He Thr He Ser Glu Asp Gly Ser Met 1425 i 1430 1435 1440 Ser lie Lys Asn Glu Glu Glu Glu Gin Thr Leu Thr He Leu He Arg 1445 1450 1455 Thr Gly Leu Leu Val He Ser Gly Leu Phe Pro Val Ser He Pro He 1460 1465 1470 Thr Ala Ala Ala Trp Tyr Leu Trp Glu Val Lys Lys Gin Arg Ala Gly 1475 1480 1485 Val Leu Trp Asp Val Pro Ser Pro Pro Pro Met Gly Lys Ala Glu Leu 1490 1495 1500 Glu Asp Gly Ala Tyr Arg He Lys Gin Lys Gly He Leu Gly Tyr Ser 1505 i 1510 1515 1520 Gin He Gly Ala Gly Val Tyr Lys Glu Gly Thr Phe His Thr Met Trp 1525 1530 1535 His Val Thr Arg Gly Ala Val Leu Met His Lys Gly Lys Arg He Glu 1540 1545 1550 Pro Ser Trp Ala Asp Val Lys Lys Asp Leu He Ser Tyr Gly Gly Gly 1555 1560 1565 Trp Lys Leu Glu Gly Glu Trp Lys Glu Gly Glu Glu Val Gin Val Leu 1570 1575 1580 Ala Leu Glu Pro Gly Lys Asn Pro Arg Ala Val Gin Thr Lys Pro Gly 1585 1590 1595 1600 Leu Phe Lys Thr Asn Ala Gly Thr He Gly Ala Val Ser Leu Asp Phe 1605 1610 1615 Ser Pro Gly Thr Ser Gly Ser Pro He He Asp Lys Lys Gly Lys Val 1620 1625 1630 Val Gly Leu Tyr Gly Asn Gly Val Val Thr Arg Ser Gly Ala Tyr Val 1635 1640 1645 Ser Ala He Ala Gin Thr Glu Lys Ser He Glu Asp Asn Pro Glu He 1650 1655 1660 Glu Asp Asp He Phe Arg Lys Arg Arg Leu Thr He Met Asp Leu His 1665 1670 1675 1680 Pro Gly Ala Gly Lys Thr Lys Arg Tyr Leu Pro Ala He Val Arg Glu 1685 1690 1695 Ala He Lys Arg Gly Leu Arg Thr Leu He Leu Ala Pro Thr Arg Val 1700 1705 1710 Val Ala Ala Glu Met Glu Glu Ala Leu Arg Gly Leu Pro He Arg Tyr 1715 1720 1725

    216

    2018200081 04 Jan 2018

    Gin Thr Pro Ala He Arg Ala Glu His 1735 Thr Gly Arg Glu 1740 He Val Asp 1730 Leu Met Cys His Ala Thr Phe Thr Met Arg Leu Leu Ser Pro Val Arg 1745 1750 1755 1760 Val Pro Asn Tyr Asn Leu He lie Met Asp Glu Ala His Phe Thr Asp 1765 1770 1775 Pro Ala Ser He Ala Ala Arg Gly Tyr He Ser Thr Arg Val Glu Met 178C i 1785 1790 Gly Glu Ala Ala Gly He Phe Met Thr Ala Thr Pro Pro Gly Ser Arg 1795 1800 1805 Asp Pro Phe Pro Gin Ser Asn Ala Pro He He Asp Glu Glu Arg Glu 1810 1815 1820 lie Pro Glu Arg Ser Trp Asn Ser Gly His Glu Trp Val Thr Asp Phe 1825 1830 1835 1840 Lys Gly Lys Thr Val Trp Phe Val Pro Ser He Lys Ala Gly Asn Asp 1845 1850 1855 He Ala Ala Cys Leu Arg Lys Asn Gly Lys Lys Val He Gin Leu Ser 1860 1865 1870 Arg Lys Thr Phe Asp Ser Glu Tyr Val Lys Thr Arg Thr Asn Asp Trp 1875 1880 1885 Asp Phe Val Val Thr Thr Asp He Ser Glu Met Gly Ala Asn Phe Lys 1890 1895 1900 Ala Glu Arg Val He Asp Pro Arg Arg Cys Met Lys Pro Val He Leu 1905 1910 1915 1920 Thr Asp Gly Glu Glu Arg Val He Leu Ala Gly Pro Met Pro Val Thr 1925 1930 1935 His Ser Ser Ala Ala Gin Arg Arg Gly Arg lie Gly Arg Asn Pro Lys 1940 1945 1950 Asn Glu Asn Asp Gin Tyr He Tyr Met Gly Glu Pro Leu Glu Asn Asp 1955 1960 1965 Glu Asp Cys Ala His Trp Lys Glu Ala Lys Met Leu Leu Asp Asn He 1970 1975 1980 Asn Thr Pro Glu Gly lie He Pro Ser Met Phe Glu Pro Glu Arg Glu 1985 1990 1995 2000 Lys Val Asp Ala lie Asp Gly Glu Tyr Arg Leu Arg Gly Glu Ala Arg 2005 2010 2015 Lys Thr Phe Val Asp Leu Met Arg Arg Gly Asp Leu Pro Val Trp Leu 2020 2025 2030 Ala Tyr Arg Val Ala Ala Glu Gly He Asn Tyr Ala Asp Arg Arg Trp 2035 2040 2045 Cys Phe Asp Gly Val Lys Asn Asn Gin He Leu Glu Glu Asn Val Glu 2050 2055 2060 Val Glu He Trp Thr Lys Glu Gly Glu Arg Lys Lys Leu Lys Pro Arg 2065 2070 2075 2080 Trp Leu Asp Ala Arg He Tyr Ser Asp Pro Leu Ala Leu Lys Glu Phe 2085 2090 2095 Lys Glu Phe Ala Ala Gly Arg Lys Ser Leu Thr Leu Asn Leu He Thr 2100 2105 2110 Glu Met Gly Arg Leu Pro Thr Phe Met Thr Gin Lys Ala Arg Asp Ala 2115 2120 2125 Leu Asp Asn Leu Ala Val Leu His Thr Ala Glu Ala Gly Gly Arg Ala 2130 2135 2140 Tyr Asn His Ala Leu Ser Glu Leu Pro Glu Thr Leu Glu Thr Leu Leu 2145 2150 2155 2160

    217

    2018200081 04 Jan 2018

    Leu Leu Thr Leu Leu Ala 2165 Thr Val Thr Gly Gly He Phe Leu Phe Leu 2170 2175 Met Ser Gly Arg Gly He Gly Lys Met Thr Leu Gly Met Cys Cys He 2180 2185 2190 lie Thr Ala Ser He Leu Leu Trp Tyr Ala Gin He Gin Pro His Trp 2195 2200 2205 He Ala Ala Ser He He Leu Glu Phe Phe Leu He Val Leu Leu He 2210 2215 2220 Pro Glu Pro Glu Lys Gin Arg Thr Pro Gin Asp Asn Gin Leu Thr Tyr 2225 2230 2235 2240 Val Val He Ala He Leu Thr Val Val Ala Ala Thr Met Ala Asn Glu 2245 2250 2255 Met Gly Phe Leu Glu Lys Thr Lys Lys Asp Leu Gly Leu Gly Ser He 2260 2265 2270 Ala Thr Gin Gin Pro Glu Ser Asn He Leu Asp He Asp Leu Arg Pro 2275 2280 2285 Ala Ser Ala Trp Thr Leu Tyr Ala Val Ala Thr Thr Phe Val Thr Pro 2290 2295 2300 Met Leu Arg His Ser He Glu Asn Ser Ser Val Asn Val Ser Leu Thr 2305 2310 2315 2320 Ala He Ala Asn Gin Ala Thr Val Leu Met Gly Leu Gly Lys Gly Trp 2325 2330 2335 Pro Leu Ser Lys Met Asp He Gly Val Pro Leu Leu Ala lie Gly Cys 2340 2345 . 2350 Tyr Ser Gin Val Asn Pro He Thr Leu Thr Ala Ala Leu Phe Leu Leu 2355 2360 2365 Val Ala His Tyr Ala lie He Gly Pro Gly Leu Gin Ala Lys Ala Thr 2370 2375 2380 Arg Glu Ala Gin Lys Arg Ala Ala Ala Gly He Met Lys Asn Pro Thr 2385 2390 2395 2400 Val Asp Gly He Thr Val He Asp Leu Asp Pro He Pro Tyr Asp Pro 2405 2410 2415 Lys Phe Glu Lys Gin Leu Gly Gin Val Met Leu Leu Val Leu Cys Val 2420 2425 2430 Thr Gin Val Leu Met Met Arg Thr Thr Trp Ala Leu Cys Glu Ala Leu 2435 2440 2445 Thr Leu Ala Thr Gly Pro He Ser Thr Leu Trp Glu Gly Asn Pro Gly 2450 2455 2460 Arg Phe Trp Asn Thr Thr He Ala Val Ser Met Ala Asn lie Phe Arg 2465 2470 2475 2480 Gly Ser Tyr Leu Ala Gly Ala Gly Leu Leu Phe Ser He Met Lys Asn 2485 2490 2495 Thr Thr Asn Thr Arg Arg Gly Thr Gly Asn He Gly Glu Thr Leu Gly 2500 2505 2510 Glu Lys Trp Lys Ser Arg Leu Asn Ala Leu Gly Lys Ser Glu Phe Gin 2515 2520 2525 He Tyr Lys Lys Ser Gly He Gin Glu Val Asp Arg Thr Leu Ala Lys 2530 2535 2540 Glu Gly He Lys Arg Gly Glu Thr Asp His His Ala Val Ser Arg Gly 2545 2550 2555 2560 Ser Ala Lys Leu Arg Trp Phe Val Glu Arg Asn Met Val Thr Pro Glu 2565 2570 2575 Gly Lys Val Val Asp Leu Gly Cys Gly Arg Gly Gly Trp Ser Tyr Tyr 2580 2585 2590

    218

    2018200081 04 Jan 2018

    Cys Gly Gly Leu Lys Asn Val Arg Glu Val Lys Gly Leu Thr 2605 Lys Gly 2595 2600 Gly Pro Gly His .Glu Glu Pro He Pro Met Ser Thr Tyr Gly Trp Asn 2610 i 2615 2620 Leu Val Arg Leu Gin Ser Gly Val Asp Val Phe Phe He Pro Pro Glu 2625 2630 2635 2640 Lys Cys Asp Thr Leu Leu Cys Asp He Gly Glu Ser Ser Pro Asn Pro 2645 2650 2655 Thr Val Glu Ala Gly Arg Thr Leu Arg Val Leu Asn Leu Val Glu Asn 2660 2665 2670 Trp Leu Asn Asn Asn Thr Gin Phe Cys He Lys Val Leu Asn Pro Tyr 2675 2680 2685 Met Pro Ser Val He Glu Lys Met Glu Ala Leu Gin Arg Lys Tyr Gly 269C i 2695 2700 Gly Ala Leu Val Arg Asn Pro Leu Ser Arg Asn Ser Thr His Glu Met 2705 2710 2715 2720 Tyr Trp Val Ser Asn Ala Ser Gly Asn He Val Ser Ser Val Asn Met 2725 2730 2735 lie Ser Arg Met Leu He Asn Arg Phe Thr Met Arg Tyr Lys Lys Ala 2740 2745 2750 Thr Tyr Glu Pro Asp Val Asp Leu Gly Ser Gly Thr Arg Asn He Gly 2755 2760 2765 He Glu Ser Glu He Pro Asn Leu Asp He He Gly Lys Arg He Glu 277C I 2775 2780 Lys He Lys Gin Glu His Glu Thr Ser Trp His Tyr Asp Gin Asp His 2785 2790 2795 2800 Pro Tyr Lys Thr Trp Ala Tyr His Gly Ser Tyr Glu Thr Lys Gin Thr 2805 2810 2815 Gly Ser Ala Ser Ser Met Val Asn Gly Val Val Arg Leu Leu Thr Lys 2820 2825 2830 Pro Trp Asp Val Val Pro Met· Val Thr Gin Met Ala Met Thr Asp Thr 2835 2840 2845 Thr Pro Phe Gly Gin Gin Arg Val Phe Lys Glu Lys Val Asp Thr Arg 2850 2855 2860 Thr Gin Glu Pro Lys Glu Gly Thr Lys Lys Leu Met Lys He Thr Ala 2865 2870 2875 2880 Glu Trp Leu Trp Lys Glu Leu Gly Lys Lys Lys Thr Pro Arg Met Cys 2885 2890 2895 Thr Arg Glu Glu Phe Thr Arg Lys Val Arg Ser Asn Ala Ala Leu Gly 2900 2905 2910 Ala He Phe Thr Asp Glu Asn Lys Trp Lys Ser Ala Arg Glu Ala Val 2915 2920 2925 Glu Asp Ser Arg Phe Trp Glu Leu Val Asp Lys Glu Arg Asn Leu His 2930 2935 2940 Leu Glu Gly Lys Cys Glu Thr Cys Val Tyr Asn Met Met Gly Lys Arg 2945 2950 . 2955 2960 Glu Lys Lys Leu Gly Glu Phe Gly Lys Ala Lys Gly Ser Arg Ala He 2965 2970 2975 Trp Tyr Met Trp Leu Gly Ala Arg Phe Leu Glu Phe Glu Ala Leu Gly 2980 2985 2990 Phe Leu Asn Glu Asp His Trp Phe Ser Arg Glu Asn Ser Leu Ser Gly 2995 3000 3005 Val Glu Gly Glu Gly Leu His Lys Leu Gly Tyr He Leu Arg Asp Val 3010 3015 3020

    219

    2018200081 04 Jan 2018

    Ser Lys Lys Glu Gly Gly Ala Met Tyr Ala Asp Asp Thr Ala Gly Trp 3025 3030 3035 3040 Asp Thr Arg He Thr Leu Glu Asp Leu Lys Asn Glu Glu Met Val Thr 3045 ; 3050 3055 Asn His Met Glu Gly Glu His Lys Lys Leu Ala Glu Ala He Phe Lys 3060 3065 3070 Leu Thr Tyr Gin Asn Lys Val Val Arg Val Gin Arg Pro Thr Pro Arg 3075 3080 3085 Gly Thr Val Met Asp He He Ser Arg Arg Asp Gin Arg Gly Ser Gly 3090 3095 3100 Gin Val Gly Thr Tyr Gly Leu Asn Thr Phe Thr Asn Met Glu Ala Gin 3105 3110 3115 i 3120 Leu He Arg Gin Met Glu Gly Glu Gly Val Phe Lys Ser He Gin His 3125 1 3130 3135 Leu Thr He Thr Glu Glu He Ala Val Gin Asn Trp Leu Ala Arg Val 3140 3145 3150 Gly Arg Glu Arg Leu Ser Arg Met Ala lie Ser Gly Asp Asp Cys Val 3155 3160 3165 Val Lys Pro Leu Asp Asp Arg Phe Ala Ser Ala Leu Thr Ala Leu Asn 3170 3175 3180 Asp Met Gly Lys He Arg Lys Asp lie Gin Gin Trp Glu Pro Ser Arg 3185 3190 3195 1 3200 Gly Trp Asn Asp Trp Thr Gin Val Pro Phe Cys Ser His His Phe His 3205 1 3210 ' 3215 Glu Leu He Met Lys Asp Gly Arg Val Leu Val Val Pro Cys Arg Asn 3220 3225 3230 Gin Asp Glu Leu He Gly Arg Ala Arg He Ser Gin Gly Ala Gly Trp 3235 3240 3245 Ser Leu Arg Glu Thr Ala Cys Leu Gly Lys Ser Tyr Ala Gin Met Trp 3250 3255 3260 Ser Leu Met Tyr Phe His Arg Arg Asp Leu Arg Leu Ala Ala Asn Ala 3265 3270 3275 3280 lie Cys Ser Ala Val Pro Ser His Trp Val Pro Thr Ser Arg Thr Thr 3285 3290 3295 Trp Ser He His Ala Lys His Glu Trp Met Thr Thr Glu Asp Met Leu 3300 3305 3310 Thr Val Trp Asn Arg Val Trp He Gin Glu Asn Pro Trp Met Glu Asp 3315 3320 3325 Lys Thr Pro Val Glu Ser Trp Glu Glu He Pro Tyr Leu Gly Lys Arg 3330 3335 3340 Glu Asp Gin Trp Cys Gly Ser Leu He Gly Leu Thr Ser Arg Ala Thr 3345 3350 3355 3360 Trp Ala Lys Asn He Gin Ala Ala He Asn Gin Val Arg Ser Leu He 3365 3370 3375 Gly Asn Glu Glu Tyr Thr Asp Tyr Met Pro Ser Met Lys Arg Phe Arg 3380 3385 3390 Arg Glu Glu Glu Glu Ala Gly Val Leu Trp

    3395 3400 <210> 19 <211> 10699 <212> DNA <213> Artificial Sequence <220>

    2018200081 04 Jan 2018

    220 <223> Description of Artificial Sequence:/Note = synthetic construct <221> CDS <222> (95)...(10267) <400> 19 agttgttagt ctacgtggac cgacaagaac agtttcgact cggaagcttg cttaacgtag 60 tgctgacagt tttttattag agagcagatc tctg atg aac aac caa cgg aaa aag 115

    Met Asn Asn Gin Arg Lys Lys 1 5

    aeg gga. aaa ccg tct Ser ate He aat Asn atg Met 15 ctg Leu aaa Lys ege Arg gtg Val aga Arg 20 aac Asn cgt Arg gtg Val 163 Thr Gly Lys Pro 10 tea act gga tea cag ttg gcg aag aga ttc tea aga gga ttg ctg aac 211 Ser Thr Gly Ser Gin Leu Ala Lys Arg Phe Ser Arg Gly Leu Leu Asn 25 30 35 ggc caa gga cca atg aaa ttg gtt atg gca ttt ata get ttc etc aga 259 Gly Gin Gly Pro Met Lys Leu Val Met Ala Phe He Ala Phe Leu Arg 40 45 50 55 ttt eta gcc att cca ccg aca gca gga gtc ttg get aga tgg ggt acc 307 Phe Leu Ala He Pro Pro Thr Ala Gly Val Leu Ala Arg Trp Gly Thr 60 65 70 ttt aag aag teg ggg get att aag gtc tta aaa ggc ttc aag aag gag 355 Phe Lys Lys Ser Gly Ala He Lys Val Leu Lys Gly Phe Lys Lys Glu 75 80 85 ate tea aac atg ctg age att ate a'ac aaa cgg aaa aag aca teg etc 403 lie Ser Asn Met Leu Ser He He Asn Lys Arg Lys Lys Thr Ser Leu 90 95 100 tgt etc atg atg atg tta cca gca aca ett get ttc cac tta act tea 451 Cys Leu Met Met Met Leu Pro Ala Thr Leu Ala Phe His Leu Thr Ser 105 110 115 cga gat gga gag ccg ege atg att gtg ggg aag aat gaa aga gga aaa 499 Arg Asp Gly Glu Pro Arg Met He Val Gly Lys Asn Glu Arg Gly Lys 120 125 130 135 tcc eta ett ttc aag aca gcc tct gga ate aac atg tgc aca etc ata 547 Ser Leu Leu Phe Lys Thr Ala Ser Gly He Asn Met Cys Thr Leu He 140 145 150 gcc atg gat ctg gga gag atg tgt gat gac aeg gtc act tac aaa tgc 595 Ala Met Asp Leu Gly Glu Met Cys Asp Asp Thr Val Thr Tyr Lys Cys 155 160 165

    221

    2018200081 04 Jan 2018

    ccc Pro cac His att lie 170 acc gaa gtg gag cct gaa gac att He gac Asp tgc Cys 180 tgg Trp tgc Cys aac Asn 643 Thr Glu Val Glu Pro 175 Glu Asp ett aca teg aca tgg gtg act tat gga aca tgc aat caa get gga gag 691 Leu Thr Ser Thr Trp Val Thr Tyr Gly Thr Cys Asn Gin Ala Gly Glu 185 190 195 cat aga ege gat aag aga tea gtg gcg tta get ccc cat gtt ggc atg 739 His Arg Arg Asp Lys Arg Ser Val Ala Leu Ala Pro His Val Gly Met 200 205 210 215 gga ctg gac aca ege act caa acc tgg atg teg get gaa gga get tgg 787 Gly Leu Asp Thr Arg Thr Gin Thr Trp Met Ser Ala Glu Gly Ala Trp 220 225 230 aga caa gtc gag aag gta gag aca tgg gcc ett agg cac cca ggg ttt 835 Arg Gin Val Glu Lys Val Glu Thr Trp Ala Leu Arg His Pro Gly Phe 235 240 245 acc ata eta gcc eta ttt ett gee cat tac ata ggc act tcc ttg acc 883 Thr lie Leu Ala Leu Phe Leu Ala His Tyr He Gly Thr Ser Leu Thr 250 255 260 cag aaa gtg gtt att ttt ata eta tta atg ctg gtt acc cca tcc atg 931 Gin Lys Val Val He Phe He Leu Leu Met Leu Val Thr Pro Ser Met 265 270 275 aca atg aga tgt gta gga gta gga aac aga gat ttt gtg gaa ggc eta 979 Thr Met Arg Cys Val Gly Val Gly Asn Arg Asp Phe Val Glu Gly Leu 280 285 290 295 teg gga get aeg tgg gtt gac gtg gtg etc gag cac ggt ggg tgt gtg 1027 Ser Gly Ala Thr Trp Val Asp Val Val Leu Glu His Gly Gly Cys Val 300 305 310 act acc atg get aag aac aag ccc aeg ctg gac ata gag ett cag aag 1075 Thr Thr Met Ala Lys Asn Lys Pro Thr Leu Asp He Glu Leu Gin Lys 315 320 325 acc gag gcc acc caa ctg gcg acc eta agg aag eta tgc att gag gga 1123 Thr Glu Ala Thr Gin Leu Ala Thr Leu Arg Lys Leu Cys He Glu Gly 330 335 340 aaa att acc aac ata aca acc gac tea aga tgt ccc acc caa ggg gaa 1171 Lys He Thr Asn He Thr Thr Asp Ser Arg Cys Pro Thr Gin Gly Glu 345 350 355 gcg att tta cct gag gag cag gac cag aac tac gtg tgt aag cat aca 1219 Ala He Leu Pro Glu Glu Gin Asp Gin Asn Tyr Val Cys Lys His Thr 360 365 370 375 tac gtg gac aga ggc tgg gga aac ggt tgt ggt ttg ttt ggc aag gga 1267 Tyr Val Asp Arg Gly Trp Gly Asn Gly Cys Gly Leu Phe Gly Lys Gly 380 385 390

    222

    2018200081 04 Jan 2018

    age Ser ttg Leu gtg aca tgc Cys gcg Ala aaa Lys ttt Phe caa tgt tta gaa tea Ser ata He 405 gag Glu gga Gly 1315 Val Thr 395 Gin 400 Cys Leu Glu aaa gtg gtg caa cat gag aac etc aaa tac acc gtc ate ate aca gtg 1363 Lys Val Val 410 Gin His Glu Asn Leu 415 Lys Tyr Thr Val He 420 He Thr Val cac aca gga gac caa cac cag gtg gga aat gaa aeg cag gga gtc aeg 1411 His Thr 425 Gly Asp Gin His Gin 430 Val Gly Asn Glu Thr 435 Gin Gly Val Thr get gag ata aca ccc cag gca tea acc get gaa gcc att tta cct gaa 1459 Ala 440 Glu lie Thr Pro Gin 445 Ala Ser Thr Ala Glu 450 Ala He Leu Pro Glu 455 tat gga acc etc ggg eta gaa tgc tea cca egg aca ggt ttg gat ttc 1507 Tyr Gly Thr Leu Gly 460 Leu Glu Cys Ser Pro 465 Arg Thr Gly Leu Asp 470 Phe aat gaa atg ate .tea ttg aca atg aag aac aaa gca tgg atg gta cat 1555 Asn Glu Met He 475 Ser Leu Thr Met Lys 480 Asn Lys Ala Trp Met 485 Val His aga caa tgg ttc ttt gac tta ccc eta cca tgg aca tea gga get aca 1603 Arg Gin Trp 490 Phe Phe Asp Leu Pro 495 Leu Pro Trp Thr Ser 500 Gly Ala Thr gca gaa aca cca act tgg aac agg aaa gag ett ett gtg aca ttt aaa 1651 Ala Glu 505 Thr Pro Thr Trp Asn 510 Arg Lys Glu Leu Leu 515 Val Thr Phe Lys aat gca cat gca aaa aag caa gaa gta gtt gtt ett gga tea caa gag 1699 Asn 520 Ala His Ala Lys Lys 525 Gin Glu Val Val Val 530 Leu Gly Ser Gin Glu 535 gga gca atg cat aca gca ctg aca gga get aca gag ate caa acc tea 1747 Gly Ala Met His Thr 540 Ala Leu Thr Gly Ala 545 Thr Glu He Gin Thr 550 Ser gga ggc aca agt ate ttt gcg ggg cac tta aaa tgt aga etc aag atg 1795 Gly Gly Thr Ser 555 He Phe Ala Gly His 560 Leu Lys Cys Arg Leu 565 Lys Met gac aaa ttg gaa etc aag ggg atg age tat gca atg tgc ttg agt age 1843 Asp Lys Leu 570 Glu Leu Lys Gly Met 575 Ser Tyr Ala Met Cys 580 Leu Ser Ser ttt gtg ttg aag aaa gaa gtc tcc gaa aeg cag cat ggg aca ata etc 1891 Phe Val 585 Leu Lys Lys Glu Val 590 Ser Glu Thr Gin His 595 Gly Thr He Leu

    223

    2018200081 04 Jan 2018

    att lie 600 aag Lys gtt Val gag Glu tac Tyr aaa ggg gaa gat gca ccc Lys Gly Glu Asp Ala Pro tgc Cys aag Lys att He cct Pro ttc Phe 615 1939 605 610 tcc aeg gag gat gga caa gga aaa get cac aat ggc aga ctg ate aca 1987 Ser Thr Glu Asp Gly Gin Gly Lys Ala His Asn Gly Arg Leu He Thr 620 625 630 gcc aat cca gtg gtg acc aag aag gag gag cct gtc aac att gag get 2035 Ala Asn Pro Val Val Thr Lys Lys Glu Glu Pro Val Asn He Glu Ala 635 640 645 gaa cct cct ttt gga gaa agt aac ata gta att gga att gga gac aaa 2083 Glu Pro Pro Phe Gly Glu Ser Asn He Val He Gly lie Gly Asp Lys 650 655 660 gcc ctg aaa ate aac tgg tac aag aag gga agc teg att ggg aag atg 2131 Ala Leu Lys lie Asn Trp Tyr Lys Lys Gly Ser Ser He Gly Lys Met 665 670 675 ttc gag gcc act gcc aga ggt gca agg ege atg gcc ate ttg gga gac 2179 Phe Glu Ala Thr Ala Arg Gly Ala Arg Arg Met Ala He Leu Gly Asp 680 685 690 695 aca gcc tgg gac ttt gga tea gtg ggt ggt gtt ttg aat tea tta ggg 2227 Thr Ala Trp Asp Phe Gly Ser Val Gly Gly Val Leu Asn Ser Leu Gly 700 705 710 aaa atg gtc cac caa ata ttt ggg agt get tac aca gcc eta ttt ggt 2275 Lys Met Val His Gin He Phe Gly Ser Ala Tyr Thr Ala Leu Phe Gly 715 720 725 gga gtc tcc tgg atg atg aaa att gga ata ggt gtc etc tta acc tgg 2323 Gly Val Ser Trp Met Met Lys He Gly He Gly Val Leu Leu Thr Trp 730 735 740 ata ggg ttg aac tea aaa aat act tet atg tea ttt tea tgc ate geg 2371 He Gly Leu Asn Ser Lys Asn Thr Ser Met Ser Phe Ser Cys He Ala '745 750 755 ata gga ate att aca etc tat ctg gga gcc gtg gtg caa get gac atg 2419 He Gly He He Thr Leu Tyr Leu Gly Ala Val Val Gin Ala Asp Met 760 765 770 775 ggg tgt gtc ata aac tgg aaa ggc aaa gaa etc aaa tgt gga agt gga 2467 Gly Cys Val He Asn Trp Lys Gly Lys Glu Leu Lys Cys Gly Ser Gly 780 785 790 att ttc gtc act aat gag gtc cac acc tgg aca gag caa tac aaa ttt 2515 He Phe Val Thr Asn Glu Val His Thr Trp Thr Glu Gin Tyr Lys Phe 795 800 805 caa gca gac tcc ccc aag aga ctg gca aca gcc att gca ggc get tgg 2563 Gin Ala Asp Ser Pro Lys Arg Leu Ala Thr Ala He Ala Gly Ala Trp 810 815 820

    224

    2018200081 04 Jan 2018

    gaa aat Glu Asn 825 gga Gly gtg Val tgc Cys gga att agg Arg tea Ser aca Thr acc Thr aga Arg 835 atg Met gag Glu aac Asn etc Leu 2611 Gly He 830 ttg tgg aag caa ata gcc aat gaa ctg aat tac ata tta tgg gaa aac 2659 Leu Trp 840 Lys Gin He Ala 845 Asn Glu Leu Asn Tyr 850 He Leu Trp Glu Asn 855 aac att aaa tta aeg gta gtt gta ggc gac ata act ggg gtc tta gag 2707 Asn lie Lys Leu Thr 860 Val Val Val Gly Asp 865 He Thr Gly Val Leu 870 Glu caa ggg aaa aga aca eta aca cca caa ccc atg gag eta aaa tat tet 2755 Gin Gly Lys Arg 875 Thr Leu Thr Pro Gin 880 Pro Met Glu Leu Lys 885 Tyr Ser tgg aaa aca tgg gga aag gca aaa ata gtg aca get gaa aca caa aat 2803 Trp Lys Thr 890 Trp Gly Lys Ala Lys 895 He Val Thr Ala Glu 900 Thr Gin Asn tcc tet ttc ata ata gat ggg cca age aca ccg gag tgt cca agt gcc 2851 Ser Ser 905 Phe He He Asp Gly 910 Pro Ser Thr Pro Glu 915 Cys Pro Ser Ala tea aga gca tgg aat gtg tgg gag gtg gag gat tac ggg ttc gga gtt 2899 Ser Arg 920 Ala Trp Asn Val 925 Trp Glu Val Glu Asp 930 Tyr Gly Phe Gly Val 935 ttc aca acc aac ata tgg ctg aaa etc ega gag gtg tac acc caa eta 2947 Phe Thr Thr Asn He 940 Trp Leu Lys Leu Arg 945 Glu Val Tyr Thr Gin 950 Leu tgt gac cat agg eta atg teg gca gcc gtc aag gat gag agg get gta 2995 Cys Asp His Arg 955 Leu Met Ser Ala Ala 960 Val Lys Asp Glu Arg 965 Ala Val cat gcc gac atg ggc tat tgg ata gaa age caa aag aat ggg agt tgg 3043 His Ala Asp 970 Met Gly Tyr Trp He 975 Glu Ser Gin Lys Asn 980 Gly Ser Trp aag eta gaa aaa gca tcc ttc ata gag gtg aaa acc tgc aca tgg cca 3091 Lys Leu Glu 985 Lys Ala Ser Phe He 990 Glu Val Lys Thr Cys 995 Thr Trp Pro aaa tea cac act etc tgg age aat ggt gtg eta gag agt gac atg att 3139 Lys Ser 1000 His Thr Leu Trp Ser 1005 Asn Gly Val Leu Glu 1010 Ser Asp Met He 1015 ate cca aag agt eta get ggt ccc att teg caa cac aac cac agg ccc 3187 lie Pro Lys Ser Leu Ala Gly Pro He Ser Gin His Asn His Arg Pro

    1020 1025 1030

    2018200081 04 Jan 2018

    225 ggg tac cac acc caa aeg gca gga ccc tgg cac tta gga aaa ttg gag 3235

    Gly Tyr His Thr Gin Thr Ala Gly Pro Trp His Leu Gly Lys Leu Glu

    1035 1040 1045 ctg gac ttc aac tat tgt gaa gga aca aca gtt gtc ate tea gaa aac 3283

    Leu Asp Phe Asn Tyr Cys Glu Gly Thr Thr Val Val lie Ser Glu Asn

    1050 1055 1060

    tgt Cys ggg aca Gly Thr 1065 aga ggc cca Pro tea ttg aga Ser Leu Arg 1070 aca Thr aca Thr aeg gtg Thr Val 1075 tea Ser ggg Gly aag Lys 3331 Arg Gly ttg ata cac gaa tgg tgc tgc cgc teg tgc aca ett cct ccc eta ega 3379 Leu 108C He His 1 Glu Trp Cys 1085 Cys Arg Ser Cys Thr 109C Leu Pro 1 Pro Leu Arg 1095 tac atg gga gaa gac ggc tgc tgg tat ggc atg gaa ate aga ccc att 3427 Tyr Met Gly Glu Asp 110C Gly I Cys Trp Tyr Gly 1105 Met Glu He Arg Pro me He 1 aat gag aaa gaa gag aat atg gta aag tct eta gcc tea gca ggg agt 3475 Asn Glu Lys Glu Glu 1115 Asn Met Val Lys 112C Ser 1 Leu Ala Ser Ala 1125 Gly Ser gga aag gtg gac aac ttc aca atg ggt gtc ttg tgt ttg gca ate etc 3523 Gly Lys Val Asp 1130 Asn Phe Thr Met Gly 1135 Val Leu Cys Leu Ala 1140 He Leu ttt gaa gag 9tg atg aga gga aaa ttt ggg aaa aaa cac atg att gca 3571 Phe Glu Glu 1145 Val Met Arg Gly Lys Phe 1150 Gly Lys Lys His 1155 Met He Ala ggg gtt etc ttc aeg ttt gtg etc etc etc tea ggg caa ata aca tgg 3619 Gly Val Leu 1160 Phe Thr Phe Val Leu Leu 1165 Leu Ser Gly Gin 1170 He Thr Trp 1175 aga gac atg gcg cac aca etc ata atg att ggg tcc aac gcc tct gac 3667 Arg Asp Met Ala His Thr 1180 Leu He Met He Gly 1185 Ser Asn Ala Ser Asp 1190 aga atg ggg atg ggc gtc act tac eta get eta att gca aca ttt aaa 3715 Arg Met Gly Met Gly 1195 Val Thr Tyr Leu Ala 1200 Leu He Ala Thr Phe 1205 Lys att cag cca ttc ctg get ttg gga ttc ttc ctg agg aaa ctg aca tct 3763 He Gin Pro Phe 1210 Leu Ala Leu Gly Phe 1215 Phe Leu Arg Lys Leu 1220 Thr Ser aga gaa aat tta ttg ctg gga gtt ggg ttg gcc atg gca gca aeg tta 3811 Arg Glu Asn 1225 Leu Leu Leu Gly Val Gly 1230 Leu Ala Met Ala 1235 Ala Thr Leu ega ctg cca gag gac att gaa cag atg gcg aat gga att get ttg ggg 3859 Arg Leu Pro 1240 Glu Asp He Glu Gin Met 1245 Ala Asn Gly He 1250 Ala Leu Gly 1255

    226

    2018200081 04 Jan 2018

    etc Leu atg Met get Ala ett Leu aaa ctg Lys Leu 1260 ata He aca Thr caa Gin ttt gaa Phe Glu 1265 aca Thr tac Tyr caa Gin eta tgg Leu Trp 1270 3907 aeg gca tta gtt tcc eta aeg tgt tea aat aca att ttc aeg ttg act 3955 Thr Ala Leu Val 1275 Ser Leu Thr Cys Ser 128C Asn Thr He Phe Thr 1285 Leu Thr gtt gcc tgg aga aca gcc act ctg att tta gcc gga att teg ett ttg 4003 Val Ala Trp 129C Arg I Thr Ala Thr Leu 1295 He Leu Ala Gly lie 130C Ser I Leu Leu cca gtg tgc cag tet teg agc atg agg aaa aca gat tgg etc cca atg 4051 Pro Val Cys 1305 Gin Ser Ser Ser Met 1310 Arg Lys Thr Asp Trp 1315 Leu Pro Met act gtg gca get atg gga get caa ccc eta cca ett ttt att ttc agt 4099 Thr Val 1320 Ala Ala Met Gly Ala 1325 Gin Pro Leu Pro Leu 1330 Phe He Phe Ser 1335 ctg aaa gat aca etc aaa agg aga agc tgg cca ctg aat gag ggg gtg 4147 Leu Lys Asp Thr Leu Lys 1340 Arg Arg Ser Trp Pro 1345 Leu Asn Glu Gly Val 1350 atg gca gtt gga ett gtg agc att eta get agt tet etc ett agg aat 4195 Met Ala Val Gly 1355 Leu Val Ser He Leu Ala Ser 1360 Ser Leu Leu 1365 Arg Asn gat gtg cct atg get gga cca tta gtg get ggg ggc ttg ctg ata gcg 4243 Asp Val Pro Met 1370 Ala Gly Pro Leu Val 1375 Ala Gly Gly Leu Leu 1380 He Ala tgc tac gtc ata act ggc aeg tea gca gac etc act gta gaa aaa gca 4291 Cys Tyr Val 1385 He Thr Gly Thr Ser 1390 Ala Asp Leu Thr Val 1395 Glu Lys Ala gca gat gta aca tgg gag gaa gag gee gag caa aca gga gtg tcc cac 4339 Ala Asp 1400 Val Thr Trp Glu Glu 1405 Glu Ala Glu Gin Thr 1410 Gly Val Ser His 1415 aat tta atg gtc aca gtt gat gat gat gga aca atg aga ata aaa gat 4387 Asn Leu Met Val Thr Val 1420 Asp Asp Asp Gly Thr 1425 Met Arg He Lys Asp 1430 gac gag act gag aac ate tta aca gtg ett tta aaa aca gca eta eta 4435 Asp Glu Thr Glu Asn He 1435 Leu Thr Val Leu Leu 1440 Lys Thr Ala Leu Leu 1445 ata gta tea ggc ate ttt cca tac tcc ata ccc gca aca ctg ttg gtc 4483 lie Val Ser Gly 1450 lie Phe Pro Tyr Ser 1455 He Pro Ala Thr Leu 1460 Leu Val

    227

    2018200081 04 Jan 2018

    tgg cat act Thr tgg Trp caa aag Gin Lys caa acc Gin Thr 1470 caa Gin aga Arg tcc ggc gtc eta Leu tgg Trp gac Asp 4531 Trp His 1465 Ser Gly Val 1475 gta ccc age ccc cca gag aca cag aaa geg gaa ctg gaa gaa ggg gtc 4579 Val 148C Pro 1 Ser Pro Pro Glu 1485 Thr Gin Lys Ala Glu 149C Leu Glu 1 Glu Gly Val 1495 tat agg ate aaa cag caa gga att ttt ggg aaa acc caa gtg ggg gtt 4627 Tyr Arg lie Lys Gin Gin 1500 Gly He Phe Gly 1505 Lys Thr Gin Val Gly Val 1510 gga gta cag aaa gaa gga gtt ttc cac acc atg tgg cat gtc aca aga 4675 Gly Val Gin Lys 1515 Glu Gly Val Phe His Thr 1520 Met Trp His Val Thr 1525 Arg ggg gca gtg ttg aca cac aat ggg aaa aga ctg gaa cca aac tgg get 4723 Gly Ala Val Leu 1530 Thr His Asn Gly Lys 1535 Arg Leu Glu Pro Asn 1540 Trp Ala age gtg aaa aaa gat ctg att tea tac gga gga gga tgg aga ttg agt 4771 Ser Val 1545 Lys Lys Asp Leu He Ser 1550 •Tyr Gly Gly Gly Trp 1555 Arg Leu Ser gca caa tgg caa aag ggg gag gag gtg cag gtt att gcc gta gag cct 4819 Ala Gin 1560 Trp Gin Lys Gly 1565 Glu Glu Val Gin Val He Ala 1570 Val Glu Pro 1575 ggg aag aac cca aag aac ttt caa acc atg cca ggc att ttt cag aca 4867 Gly Lys Asn Pro Lys Asn 1580 Phe Gin Thr Met Pro 1585 Gly He Phe Gin Thr 1590 aca aca ggg gaa ata gga gca att gca ctg gat ttc aag cct gga act 4915 Thr Thr Gly Glu He Gly 1595 Ala He Ala Leu 1600 Asp Phe Lys Pro Gly 1605 Thr tea. gga tet ccc ate ata aac aga gag gga aag gta gtg gga ctg tat 4963 Ser Gly Ser Pro 1610 He He Asn Arg Glu 1615 Gly Lys Val Val Gly 1620 Leu Tyr ggc aat gga gtg gtt aca aag aat gga ggc tat gtc agt gga ata geg 5011 Gly Asn Gly 1625 Val Val Thr Lys Asn 1630 Gly Gly Tyr Val Ser 1635 Gly He Ala caa aca aat gca gaa cca gat gga ccg aca cca gag ttg gaa gaa gag 5059 Gin Thr 1640 Asn Ala Glu Pro Asp Gly 1645 Pro Thr Pro Glu Leu 1650 Glu Glu Glu 1655 atg ttc aaa aag ega aat eta acc ata atg gat etc cat cct ggg tea 5107 Met Phe Lys Lys Arg Asn 1660 Leu Thr He Met Asp 1665 Leu His Pro Gly Ser 1670 gga aag acg egg aaa tat ett cca get att gtt aga gag gca ate aag 5155 Gly Lys Thr Arg Lys Tyr Leu Pro Ala He Val Arg Glu Ala He Lys

    1675 1680 1685

    228

    2018200081 04 Jan 2018

    aga Arg cgc Arg tta agg Leu Arg 1690 act Thr eta Leu att He ttg gca Leu Ala 1695 cca Pro aca Thr agg Arg gta gtt Val Val 1700 gca Ala get Ala 5203 gag atg gaa gaa gca ttg aaa ggg etc cca ata agg tat caa aca act 5251 Glu Met 1705 Glu Glu Ala Leu Lys 171C Gly Leu 1 Pro He Arg Tyr Gin 1715 Thr Thr gca aca aaa tet gaa cac aca gga aga gag att gtt gat eta atg tgt 5299 Ala 172C Thr 1 Lys Ser Glu His 1725 Thr Gly Arg Glu He 173C Val I Asp Leu Met Cys 1735 cac gca aeg ttc aca atg cgc ttg ctg tea cca gtc agg gtt cca aac 5347 His Ala Thr Phe Thr 174C Met 1 Arg Leu Leu Ser 1745 Pro Val Arg Val Pro Asn 1750 tac aac ttg ata ata atg gat gag gcc cat ttc aca gac cca gcc agt 5395 Tyr Asn Leu He lie 1755 Met Asp Glu Ala • 176C His 1 Phe Thr Asp Pro Ala 1765 Ser ata gcg get aga ggg tac ata tea act cgt gta gga atg gga gag gca 5443 lie Ala Ala Arg 1770 Gly Tyr He Ser Thr 1775 Arg Val Gly Met Gly 1780 Glu Ala gcc gca att ttc atg aca gca aca ccc cct gga aca get gat gcc ttt 5491 Ala Ala He Phe 1785 Met Thr Ala Thr Pro 1790 Pro Gly Thr Ala Asp 1795 Ala Phe cct cag age aac get cca att caa gat gaa gag aga gac ata ccg gaa 5539 Pro Gin 1800 Ser Asn Ala Pro He 1805 Gin Asp Glu Glu Arg 1810 Asp He Pro Glu 1815 cgc tea tgg aat tea ggc aat gaa tgg att act gac ttt gtt ggg aag 5587 Arg Ser Trp Asn Ser Gly 1820 Asn Glu Trp He Thr 1825 Asp Phe Val Gly Lys 1830 aca gtg tgg ttt gtc cct age ate aaa gcc gga aat gac ata gca aac 5635 Thr Val Trp Phe Val 1835 Pro Ser He Lys Ala 1840 Gly Asn Asp He Ala 1845 Asn tgc ttg egg aaa aat gga aaa aag gtt att caa etc age agg aag acc 5683 Cys Leu Arg Lys 1850 Asn Gly Lys Lys Val 1855 He Gin Leu Ser Arg 1860 Lys Thr ttt gac aca gaa tat caa aag acc aaa ctg aat gat tgg gac ttt gtg 5731 Phe Asp Thr Glu 1865 Tyr Gin Lys Thr Lys 1870 Leu Asn Asp Trp Asp 1875 Phe Val gtg aca aca gac att tea gaa atg gga gcc aat ttc aaa gca gat aga 5779 Val Thr 1880 Thr Asp He Ser Glu 1885 Met Gly Ala Asn Phe 1890 Lys Ala Asp Arg 1895

    229

    2018200081 04 Jan 2018

    gtg Val ate lie gac Asp cca aga aga tgt Pro Arg Arg Cys 1900 etc Leu aag Lys ccg gtg Pro Val 1905 att He ttg Leu aca gat gga Thr Asp Gly 1910 5827 ccc gag egg gtg ate ctg get gga cca atg cca gtc acc gta gcg age 5875 Pro Glu Arg Val He Leu Ala 1915 Gly Pro 192C Met Pro 1 Val Thr Val Ala Ser 1925 get gcg caa agg aga ggg aga gtt ggc agg aac cca caa aaa gaa aat 5923 Ala Ala Gin Arg Arg Gly Arg 1930 Val 1935 Gly Arg Asn Pro Gin Lys Glu Asn 1940 gac cag tac ata ttc atg ggc cag cct etc aac aat gat gaa gac cat 5971 Asp Gin Tyr 1945 He Phe Met Gly Gin 1950 Pro Leu Asn Asn Asp 1955 Glu Asp His get cac tgg aca gaa gca aaa atg ctg ctg gac aac ate aac aca cca 6019 Ala His 1960 Trp Thr Glu Ala Lys 1965 Met Leu Leu Asp Asn 1970 He Asn Thr Pro 1975 gaa ggg att ata cca get etc ttt gaa cca gaa agg gag aag tea gcc 6067 Glu Gly He lie Pro Ala Leu 1980 Phe Glu Pro Glu 1985 Arg Glu Lys Ser Ala 1990 gcc ata gac ggc gaa tac ege ctg aag ggt gag tcc agg aag act ttc 6115 Ala He Asp Gly Glu Tyr Arg 1995 Leu Lys Gly Glu 2000 Ser Arg Lys Thr Phe 2005 gtg gaa etc atg agg agg ggt gac etc cca gtt tgg eta gcc cat aaa 6163 Val Glu Leu Met Arg Arg Gly 2010 Asp Leu 2015 Pro Val Trp Leu Ala His Lys 2020 gta gca tea gaa ggg ate aaa tat aca gat aga aaa tgg tgc ttt gat 6211 Val Ala Ser 2025 Glu Gly He Lys Tyr 2030 Thr Asp Arg Lys Trp 2035 Cys Phe Asp gga gaa cgt aat aat caa att tta gag gag aat atg gat gtg gaa ate 6259 Gly Glu 2040 Arg Asn Asn Gin He 2045 Leu Glu Glu Asn Met 2050 Asp Val Glu He 2055 tgg aca aag gaa gga gaa aag aaa aaa ctg aga cct agg tgg ett gat 6307 Trp Thr Lys Glu Gly Glu Lys 2060 Lys Lys Leu Arg 2065 Pro Arg Trp Leu Asp 2070 gcc ege act tat tea gat cct tta gca etc aaa gaa ttc aag gat ttt 6355 Ala Arg Thr Tyr Ser Asp Pro 2075 Leu Ala Leu Lys 2080 Glu Phe Lys Asp Phe 2085 gca get ggc aga aag tea ate gcc ett gat ett gtg aca gaa ata gga 6403 Ala Ala Gly Arg Lys Ser He 2090 Ala Leu 2095 Asp Leu Val Thr Glu He Gly 2100 aga gtg cct tea cac tta gcc cac aga acg aga aac gee ctg gat aat 6451 Arg Val Pro 2105 Ser His Leu Ala His 2110 Arg Thr Arg Asn Ala 2115 Leu Asp Asn

    230

    2018200081 04 Jan 2018

    ttg gtg Leu Val 2120 atg Met ctg Leu cac His aeg tea gaa Thr Ser Glu 2125 cat His ggc Gly ggt Gly 2130 agg gcc Arg Ala 1 tac Tyr agg Arg cat His 2135 6499 gca gtg gag gaa eta cca gaa aeg atg gaa aca etc tta etc ctg gga 6547 Ala Val Glu Glu Leu 214C Pro Glu Thr 1 Met Glu 2145 Thr Leu Leu Leu Leu 215C Gly 1 ctg atg ate ttg tta aca ggt gga gca atg c,tc ttc ttg ata tea ggt 6595 Leu Met He Leu 2155 Leu Thr Gly Gly Ala Met 2160 Leu Phe Leu lie Ser 2165 Gly aaa ggg att gga aag act tea ata gga etc att tgt gta att get tcc 6643 Lys Gly He Gly 2170 Lys Thr Ser He Gly 2175 Leu He Cys Val He 2180 Ala Ser agc ggc atg tta tgg atg get gat gtc cca etc caa tgg ate gca teg 6691 Ser Gly Met 2185 Leu Trp Met Ala Asp 2190 Val Pro Leu Gin Trp 2195 He Ala Ser get ata gtc ctg gag ttt ttt atg atg gtg ttg etc ata cca gaa cca 6739 Ala lie 2200 Val Leu Glu Phe Phe Met 2205 Met Val Leu Leu He 2210 Pro Glu Pro 2215 gaa aag cag aga act ccc caa gac aac caa etc gca tat gtc gtg ata 6787 Glu Lys Gin Arg Thr Pro Gin Asp 2220 Asn Gin Leu 2225 Ala Tyr Val Val He 2230 ggc ata ett aca ttg get gca ata gta geg gcc aat gaa atg gga ctg 6835 Gly He Leu Thr Leu 2235 Ala Ala He Val Ala 2240 Ala Asn Glu Met Gly 2245 Leu ttg gaa act aca aag aga gat tta gga atg tet aaa gaa cca ggt gtt 6883 Leu Glu Thr Thr 2250 Lys Arg Asp Leu Gly 2255 Met Ser Lys Glu Pro 2260 Gly Val gtt tet cca acc agc tat ttg gat gtg gac ttg cac cca gca tea gcc 6931 Val Ser Pro 2265 Thr Ser Tyr Leu Asp 2270 Val Asp Leu His Pro 2275 Ala Ser Ala tgg aca ttg tac gcc gtg gcc aca aca gta ata aca cca atg ttg aga 6979 Trp Thr 2280 Leu Tyr Ala Val Ala Thr 2285 Thr Val He Thr Pro 2290 Met Leu Arg 2295 cac acc ata gag aat tcc aca gca aat gtg tet ctg gca gcc ata get 7027 His Thr He Glu Asn Ser Thr Ala 2300 Asn Val Ser 2305 Leu Ala Ala He Ala 2310 aac cag gca gtg gtc ctg atg ggt tta gac aaa gga tgg ccg ata teg 7075 Asn Gin Ala Val Val Leu Met Gly Leu Asp Lys Gly Trp Pro He Ser

    2315 2320 2325

    231

    2018200081 04 Jan 2018

    aaa Lys atg Met gac ttg Asp Leu 2330 ggc Gly gta Val cca Pro eta ttg Leu Leu 2335 gca Ala ctg Leu ggt Gly tgc tat Cys Tyr 2340 tea Ser caa Gin 7123 gtg aac cca eta act ett gca gcg gca gta ett ttg eta gtc aca cat 7171 Val Asn 2345 Pro Leu Thr Leu Ala 235C Ala Ala 1 Val Leu Leu 2355 Leu Val Thr His tat gca att ata ggt cca gga ttg cag gca aaa gcc acc cgt gaa get 7219 Tyr 236C Ala 1 lie He Gly Pro 236E Gly Leu Gin Ala Lys Ala 2370 Thr Arg Glu Ala 2375 cag aaa agg aca get get gga ata atg aag aat cca aeg gtg gat gga 7267 Gin Lys Arg Thr Ala Ala 2380 Gly He Met Lys 238E Asn Pro Thr Val Asp Gly 2390 ata atg aca ata gac eta gat cct gta ata tat gat tea aaa ttt gaa 7315 lie Met Thr He Asp 2395 Leu Asp Pro Val He 2400 Tyr Asp Ser Lys 240E Phe Glu aag caa eta gga cag gtc atg etc ctg gtt ctg tgt gca gtc caa ett 7363 Lys Gin Leu Gly 2410 Gin Val Met Leu Leu 2415 Val Leu Cys Ala Val 2420 Gin Leu tta ttg atg aga aca tea tgg gcc ttg tgt gaa gtt eta acc eta gcc 7411 Leu Leu Met Arg 2425 Thr Ser Trp Ala Leu 2430 Cys Glu Val Leu Thr 2435 Leu Ala aca gga cca ata aca aca etc tgg gaa gga tea cct ggg aag ttc tgg 7459 Thr Gly 2440 Pro He Thr Thr Leu 2445 Trp Glu Gly Ser Pro 2450 Gly Lys Phe Trp 2455 aac acc aeg ata get gtt tcc atg gcg aac ate ttt aga ggg age tat 7507 Asn Thr Thr He Ala Val 2460 Ser Met Ala Asn He 2465 Phe Arg Gly Ser Tyr 2470 tta gca gga get ggg ett get ttt tet ate atg aaa tea gtt gga aca 7555 Leu Ala Gly Ala Gly 2475 Leu Ala Phe Ser He 2480 Met Lys Ser Val Gly 2485 Thr gga aag aga gga aca ggg tea caa ggt gaa acc tta gga gaa aag tgg 7603 Gly Lys Arg Gly 2490 Thr Gly Ser Gin Gly 2495 Glu Thr Leu Gly Glu 2500 Lys Trp aaa aag aaa tta aat cag tta tcc egg aaa gag ttt gac ett tac aag 7651 Lys Lys Lys Leu 2505 Asn Gin Leu Ser Arg 2510 Lys Glu Phe Asp Leu 2515 Tyr Lys aaa tcc gga ate acc gaa gtg gat aga aca gaa gcc aaa gaa ggg tta 7699 Lys Ser 2520 Gly lie Thr Glu Val 2525 Asp Arg Thr Glu Ala 2530 Lys Glu Gly Leu 2535 aaa aga gga gaa ata aca cac cat gcc gtg tcc aga ggc age gca aaa 7747 Lys Arg Gly Glu He Thr His His Ala Val Ser Arg Gly Ser Ala Lys

    2540 2545 2550

    232

    2018200081 04 Jan 2018

    ctt Leu caa Gin tgg ttc gtg Trp Phe Val 2555 gag aga aac Glu Arg Asn atg gtc Met Val 2560 att He cct Pro gaa Glu gga aga gtc Gly Arg Val 2565 7795 ata gac eta ggc tgt gga aga gga ggc tgg tea tat tac tgt gca gga 7843 lie Asp Leu Gly Cys 2570 Gly Arg Gly 2575 Gly Trp Ser Tyr Tyr 258C Cys Ala Gly 1 ctg aaa aaa gtt aca gaa gtg ega gga tac aca aaa ggc ggc cca gga 7891 Leu Lys 2585 Lys Val Thr Glu Val Arg 2590 Gly Tyr Thr Lys 2595 Gly Gly Pro Gly cac gaa gaa cca gta cct atg tet aca tac gga tgg aac ata gtc aag 7939 His Glu 2600 Glu Pro Val Pro Met Ser 2605 Thr Tyr Gly Trp 2610 Asn He Val Lys 2615 tta atg agt gga aag gat gtt ttt tat ctg cca cct gaa aag tgt gat 7987 Leu Met Ser Gly Lys Asp Val Phe 2620 Tyr Leu Pro 2625 Pro Glu Lys Cys Asp 2630 acc eta ttg tgt gac att gga gaa tet tea cca age cca aca gtg gaa 8035 Thr Leu Leu Cys Asp 2635 He Gly Glu Ser Ser 2640 Pro Ser Pro Thr Val Glu 2645 gaa age aga acc ata aga gtt ttg aag atg gtt gaa cca tgg eta aag 8083 Glu Ser Arg Thr He 2650 Arg Val Leu Lys Met 2655 Val Glu Pro Trp Leu Lys 2660 aac aac cag ttt tgc att aaa gta ttg aac cca tac atg cca act gtg 8131 Asn Asn Gin Phe Cys 2665 He Lys Val 2670 Leu Asn Pro Tyr Met 2675 Pro Thr Val att gag cac tta gaa aga eta caa agg aaa cat gga gga atg ctt gtg 8179 He Glu 2680 His Leu Glu Arg Leu Gin 2685 Arg Lys His Gly 2690 Gly Met Leu Val 2695 aga aat cca etc tea ega aac tcc acg cac gaa atg tat tgg ata tcc 8227 Arg Asn Pro Leu Ser Arg Asn Ser 2700 Thr His Glu 2705 Met Tyr Trp He Ser 2710 aat ggt aca ggc aat ate gtc tet tea gtc aac atg gta tcc aga ttg 8275 Asn Gly Thr Gly Asn 2715 He Val Ser Ser Val 2720 Asn Met Val Ser Arg Leu 2725 eta ctg aac aga ttc aca atg aca cac agg aga ccc acc ata gag aaa 8323 Leu Leu Asn Arg Phe 2730 Thr Met Thr His Arg 2735 Arg Pro Thr He Glu Lys 2740 gat gtg gat eta gga gca gga acc ega cat gtc aat gcg gaa cca gaa 8371 Asp Val Asp Leu Gly 2745 Ala Gly Thr 2750 Arg His Val Asn Ala 2755 Glu Pro Glu

    233

    2018200081 04 Jan 2018

    aca ccc Thr Pro 2760 aac Asn atg Met gat Asp gtc Val 2765 att ggg gaa aga Arg ata aaa agg He Lys Arg 2770 ate He aaa Lys gag Glu 2775 8419 He Gly Glu gag cat agt tea aca tgg cac tat gat gat gaa aat cct tac aaa aeg 8467 Glu His Ser Ser Thr 278C Trp 1 His Tyr Asp Asp 2785 Glu Asn Pro Tyr Lys 2790 Thr 1 tgg get tac cat gga tcc tat gaa gta aaa gcc aca ggc tea gcc tcc 8515 Trp Ala Tyr His Gly 2795 Ser Tyr Glu Val Lys 2800 Ala Thr Gly Ser Ala 2805 Ser tcc atg ata aat gga gtc gtg aaa etc etc aca aaa cca tgg gat gtg 8563 Ser Met lie Asn 2810 Gly Val Val Lys Leu 2815 Leu Thr Lys Pro Trp 2820 Asp Val gtg ccc atg gtg aca cag atg gca atg aca gat aca act cca ttc ggc 8611 Val Pro Met 2825 Val Thr Gin Met Ala 2830 Met Thr Asp Thr Thr 2835 Pro Phe Gly cag caa aga gtt ttt aaa gag aaa gtg gac acc agg aca cct agg ccc 8659 Gin Gin 2840 Arg Val Phe Lys 2845 Glu Lys Val Asp Thr Arg Thr 2850 Pro Arg Pro 2855 atg cca gga aca aga aag gtt atg gag ate aca geg gag tgg ctt tgg 8707 Met Pro Gly Thr Arg Lys 2860 Val Met Glu He Thr Ala Glu 2865 Trp Leu Trp 2870 agg acc ctg gga agg aac aaa aga ccc aga tta tgc aca agg gag gaa 8755 Arg Thr Leu Gly Arg 2875 Asn Lys Arg Pro Arg 2880 Leu Cys Thr Arg Glu 2885 Glu ttc aca aag aag gtc aga acc aac gca get atg ggc get gtc ttc aca 8803 Phe Thr Lys Lys 2890 Val Arg Thr Asn Ala 2895 Ala Met Gly Ala Val 2900 Phe Thr gaa gag aac caa tgg gac agt geg aga get get gtt gag gac gaa gaa 8851 Glu Glu Asn 2905 Gin Trp Asp Ser Ala 2910 Arg Ala Ala Val Glu 2915 Asp Glu Glu ttt tgg aaa ctt gtg gac aga gaa cgt gaa etc cac aaa ctg ggc aag 8899 Phe Trp 2920 Lys Leu Val ΑΞξ> Arg 2 925 Glu Arg Glu Leu His Lys 2930 Leu Gly Lys 2935 tgt gga age tgc gtt tac aac atg atg ggc aag aga gag aaa aaa ctt 8947 Cys Gly Ser Cys Val Tyr 2940 Asn Met Met Gly Lys Arg Glu 2945 Lys Lys Leu 2950 gga gag ttt ggt aaa gca aaa ggc agt agg get ata tgg tac atg tgg 8995 Gly Glu Phe Gly Lys 2955 Ala Lys Gly Ser Arg 2960 Ala He Trp Tyr Met 2965 Trp ttg gga gcc agg tac ctt gag ttc gag geg etc gga ttc etc aat gaa 9043 Leu Gly Ala Arg • 2970 Tyr Leu Glu Phe Glu 2975 Ala Leu Gly Phe Leu 2980 Asn Glu

    234

    2018200081 04 Jan 2018

    gac Asp cac tgg His Trp 2985 ttc Phe teg Ser cgt Arg gaa aac Glu Asn 2990 tet Ser tac Tyr agt Ser gga gta Gly Val 2995 gaa gga gaa Glu Gly Glu 9091 gga ctg cac aag ctg gga tac ate ttg aga gat att tcc aag ata ccc 9139 Gly 300C Leu His 1 Lys Leu Gly Tyr lie 3005 Leu Arg Asp 3010 He Ser Lys lie Pro 3015 gga gga gcc atg tat get gat gac aca gcc ggt tgg gac aca aga ata 9187 Gly Gly Ala Met Tyr 302C Ala I Asp Asp Thr Ala 302E Gly Trp Asp Thr Arg He 3030 aca gaa gat gac ctg cac aat gag gaa aaa ate aca cag cag atg gac 9235 Thr Glu Asp Asp 3035 Leu His Asn Glu Glu Lys 3040 He Thr Gin Gin Met Asp 3045 cct gaa cac agg cag eta gcg aac get ata ttc aag etc aca tac caa 9283 Pro Glu His Arg 3050 Gin Leu Ala Asn Ala 3055 He Phe Lys Leu Thr Tyr Gin 3060 aac aaa gtg gtc aaa gtc caa cga cca act cca aag ggc aeg gta atg 9331 Asn Lys Val 3065 Val Lys Val Gin Arg 3070 Pro Thr Pro Lys Gly 3075 Thr Val Met gac ate ata tet agg aaa gac caa aga ggc agt gga cag gtg gga act 9379 Asp lie He 3080 Ser Arg Lys Asp Gin 3085 Arg Gly Ser 309C Gly Gin I Val Gly Thr 3095 tat ggt ctg aac aca ttc acc aac atg gaa gcc cag eta ate aga caa 9427 Tyr Gly Leu Asn Thr Phe 3100 Thr Asn Met Glu Ala 3105 Gin Leu He Arg Gin 3110 atg gaa gga gaa ggc gtg ttg tea aag gca gac etc gag aac ccc cat 9475 Met Glu Gly Glu Gly 3115 Val Leu Ser Lys Ala 3120 Asp Leu Glu Asn Pro His 3125 ccg eta gag aag aaa att aca caa tgg ttg gaa act aaa gga gtg gaa 9523 Pro Leu Glu Lys 3130 Lys He Thr Gin Trp 3135 Leu Glu Thr Lys Gly Val Glu 3140 agg tta aaa aga atg gcc ate agc ggg gat gat tgc gtt gtg aaa cca 9571 Arg Leu Lys 3145 Arg Met Ala He Ser 3150 Gly Asp Asp Cys Val 3155 Val Lys Pro ate gac gac aga ttc gcc aat gcc ctg ctt gcc ctg aac gat atg gga 9619 He Asp Asp 3160 Arg Phe Ala Asn Ala 3165 Leu Leu Ala Leu Asn 3170 Asp Met Gly 3175 aag gtt aga aag gac ata cct caa tgg cag cca tea aag gga tgg cat 9667 Lys Val Arg Lys Asp He 3180 Pro Gin Trp Gin Pro 3185 Ser Lys Gly Trp His 3190

    235

    2018200081 04 Jan 2018

    gat Asp tgg Trp caa Gin cag gtc Gin Val 3195 ccc Pro ttc Phe tgc Cys tee cac Ser His 3200 cac His ttt Phe cat His gaa ttg ate 9715 Glu Leu 3205 He atg aaa gat gga aga aag ttg gta gtt ccc tgc aga ccc cag gac gaa 9763 Met Lys Asp Gly Arg Lys Leu Val Val Pro Cys Arg Pro Gin Asp Glu 3210 3215 3220 eta ata gga aga gcg aga ate tcc caa gga gca gga tgg age ett aga 9811 Leu lie Gly Arg Ala Arg He Ser Gin Gly Ala Gly Trp Ser Leu Arg 3225 3230 3235 gaa act gca tgt eta ggg aaa gcc tac get caa atg tgg get etc atg 9859 Glu Thr Ala Cys Leu Gly Lys Ala Tyr Ala Gin Met Trp Ala Leu Met 3240 3245 3250 3255 tat ttt cac aga aga gat ett aga eta gca tcc aac gcc ata tgt tea 9907 Tyr Phe His Arg Arg Asp Leu Arg Leu Ala Ser Asn Ala He Cys Ser 3260 3265 3270 gca gta cca gtc cac tgg gtc ccc aeg age aga aeg aca tgg tct att 9955 Ala Val Pro Val His Trp Val Pro Thr Ser Arg Thr Thr Trp Ser He 3275 3280 3285 cat get cac cat cag tgg atg act aca gaa gac atg ett act gtc tgg 10003 His Ala His His Gin Trp Met Thr Thr Glu Asp Met Leu Thr Val Trp 3290 3295 3300 aac agg gtg tgg ata gag gac aat cca tgg atg gaa gac aaa act cca 10051 Asn Arg Val Trp He Glu Asp Asn Pro Trp Met Glu Asp Lys Thr Pro 3305 3310 3315 gtc aca aeg tgg gaa gat gtt cca tat eta ggg aag aga gaa gac caa 10099 Val Thr Thr Trp Glu Asp Val Pro Tyr Leu Gly Lys Arg Glu Asp Gin 3320 3325 3330 3335 tgg tgc gga tea etc ata ggt etc act tcc aga gca acc tgg gcc cag 10147 Trp Cys Gly Ser Leu He Gly Leu Thr Ser Arg Ala Thr Trp Ala Gin 3340 3345 3350 aac ata etc aca gca ate caa cag gtg aga age etc ata ggc aat gaa 10195 Asn He Leu Thr Ala He Gin Gin Val Arg Ser Leu He Gly Asn Glu 3355 3360 3365 gag ttt ctg gac tac atg cct teg atg aag aga ttc agg aag gag gag 10243 Glu Phe Leu Asp Tyr Met Pro Ser Met Lys Arg Phe Arg Lys Glu Glu 3370 3375 3380 gag tea gag gga gcc att tgg taa aagcaggagg taaactgtca ggccacatta 10297 Glu Ser Glu Gly Ala He Trp * 3385 3390 agccacagta < eggaagaage tgtgcagcct gtgagccccg tccaaggacg ttaaaagaag 10357 aagteaggee < caaaagccac ggtttgagca aaccgtgctg cctgtagctc cgtcgtgggg 10417 aegtaaagee tgggaggctg caaaccgtgg aagctgtacg cacggtgtag cagactagtg 10477

    2018200081 04 Jan 2018

    236 gttagaggag acccctccca tgacacaacg cagcagcggg gcccgagcac tgagggaagc tgtacctcct tgcaaaggac tagaggttag aggagacccc ccgcaaacaa aaacagcata ttgacgctgg gagagaccag agatcctgct gtctcctcag catcattcca ggcacagaac gccagaaaat ggaatggtgc tgttgaatca acaggttcta gt <210> 20 <211> 3390 <212> PRT <213> Artificial Sequence

    10537

    10597

    10657

    10699 <220>

    <223> Description of Artificial Sequence:/Note =

    synthetic construct <400> 20 Met Asn Asn Gin Arg Lys Lys Thr Gly Lys Pro Ser He Asn Met Leu 1 5 10 15 Lys Arg Val Arg Asn Arg Val Ser Thr Gly Ser Gin Leu Ala Lys Arg 20 25 30 Phe Ser Arg Gly Leu Leu Asn Gly Gin Gly Pro Met Lys Leu Val Met 35 40 45 Ala Phe He Ala Phe Leu Arg Phe Leu Ala He Pro Pro Thr Ala Gly 50 55 60 Val Leu Ala Arg Trp Gly Thr Phe Lys Lys Ser Gly Ala lie Lys Val 65 70 75 80 Leu Lys Gly Phe Lys Lys Glu He Ser Asn Met • Leu Ser He He Asn 85 90 95 Lys Arg Lys Lys Thr Ser Leu Cys Leu Met Met Met Leu Pro Ala Thr 100 105 110 Leu Ala Phe His Leu Thr Ser Arg Asp Gly Glu Pro Arg Met He Val 115 120 125 Gly Lys Asn Glu Arg Gly Lys Ser Leu Leu Phe Lys Thr Ala Ser Gly 130 135 140 lie Asn Met Cys Thr Leu He Ala Met Asp Leu Gly Glu Met Cys Asp 145 150 155 160 Asp Thr Val Thr Tyr Lys Cys Pro His He Thr Glu Val Glu Pro Glu 165 170 175 Asp He Asp Cys Trp Cys Asn Leu Thr Ser Thr Trp Val Thr Tyr Gly 180 185 190 Thr Cys Asn Gin Ala Gly Glu His Arg Arg Asp Lys Arg Ser Val Ala 195 200 205 Leu Ala Pro His Val Gly Met Gly Leu Asp Thr Arg Thr Gin Thr Trp 210 215 220 Met Ser Ala Glu Gly Ala Trp Arg Gin Val Glu Lys Val Glu Thr Trp 225 230 235 240 Ala Leu Arg His Pro Gly Phe Thr He Leu Ala Leu Phe Leu Ala His 245 250 255 Tyr He Gly Thr Ser Leu Thr Gin Lys Val Val He Phe He Leu Leu 260 265 270 Met Leu Val Thr Pro Ser Met Thr Met Arg Cys Val Gly Val Gly Asn 275 280 285 Arg Asp Phe Val Glu Gly Leu Ser Gly Ala Thr Trp Val Asp Val Val 290 295 300

    237

    2018200081 04 Jan 2018

    Leu Glu His Gly Gly Cys Val Thr Thr Met Ala Lys Asn Lys Pro Thr 305 310 315 320 Leu Asp He Glu Leu Gin Lys Thr Glu Ala Thr Gin Leu Ala Thr Leu 325 330 335 Arg Lys Leu Cys He Glu Gly Lys He Thr Asn He Thr Thr Asp Ser 340 345 350 Arg Cys Pro Thr Gin Gly Glu Ala He Leu Pro Glu Glu Gin Asp Gin 355 360 365 Asn Tyr Val Cys Lys His Thr Tyr Val Asp Arg Gly Trp Gly Asn Gly 370 375 380 Cys Gly Leu Phe Gly Lys Gly Ser Leu Val Thr Cys Ala Lys Phe Gin 385 390 395 400 Cys Leu Glu Ser He Glu Gly Lys Val Val Gin His Glu Asn Leu Lys 405 410 415 Tyr Thr Val He He Thr Val His Thr Gly Asp Gin His Gin Val Gly 420 425 430 Asn Glu Thr Gin Gly Val Thr Ala Glu He Thr Pro Gin Ala Ser Thr 435 440 445 Ala Glu Ala He Leu Pro Glu Tyr Gly Thr Leu Gly Leu Glu Cys Ser 450 455 460 Pro Arg Thr Gly Leu Asp Phe Asn Glu Met He Ser Leu Thr Met Lys 465 470 475 480 Asn Lys Ala Trp Met Val His Arg Gin Trp Phe Phe Asp Leu Pro Leu 485 490 495 Pro Trp Thr Ser Gly Ala Thr Ala Glu Thr Pro Thr Trp Asn Arg Lys 500 505 510 Glu Leu Leu Val Thr Phe Lys Asn Ala His Ala Lys Lys Gin Glu Val 515 520 525 Val Val Leu Gly Ser Gin Glu Gly Ala Met His Thr Ala Leu Thr Gly 530 535 540 Ala Thr Glu He Gin Thr Ser Gly Gly Thr Ser He Phe Ala Gly His 545 550 555 560 Leu Lys Cys Arg Leu Lys Met Asp Lys Leu Glu Leu Lys Gly Met Ser 565 570 575 Tyr Ala Met Cys Leu Ser Ser Phe Val Leu Lys Lys Glu Val Ser Glu 580 585 590 Thr Gin His Gly Thr He Leu He Lys Val Glu Tyr Lys Gly Glu Asp 595 600 605 Ala Pro Cys Lys He Pro Phe Ser Thr Glu Asp Gly Gin Gly Lys Ala 610 615 620 His Asn Gly Arg Leu He Thr Ala Asn Pro Val Val Thr Lys Lys Glu 625 630 635 640 Glu Pro Val Asn He Glu Ala Glu Pro Pro Phe Gly Glu Ser Asn lie 645 650 655 Val lie Gly He Gly Asp Lys Ala Leu Lys He Asn Trp Tyr Lys Lys 660 665 670 Gly Ser Ser He Gly Lys Met Phe Glu Ala Thr Ala Arg Gly Ala Arg 675 680 685 Arg Met Ala He Leu Gly Asp Thr Ala Trp Asp Phe Gly Ser Val Gly 690 695 700 Gly Val Leu Asn Ser Leu Gly Lys Met Val His Gin He Phe Gly Ser 705 710 715 720 Ala Tyr Thr Ala Leu Phe Gly Gly Val Ser Trp Met Met Lys He Gly

    725 730 735

    238

    2018200081 04 Jan 2018

    lie Gly Val Leu 740 Leu Thr Trp He Gly Leu Asn Ser Lys Asn Thr Ser 745 750 Met Ser Phe 755 Ser Cys lie Ala He Gly 760 He He Thr Leu Tyr Leu Gly 765 Ala Val Val 770 Gin Ala Asp Met 775 Gly Cys Val He Asn Trp Lys Gly Lys 780 Glu 785 Leu Lys Cys Gly Ser Gly 790 He Phe Val Thr Asn Glu Val His Thr 795 800 Trp Thr Glu Gin Tyr 805 Lys Phe Gin Ala Asp Ser Pro Lys Arg Leu Ala 810 815 Thr Ala He Ala 820 Gly Ala Trp Glu Asn 825 Gly Val Cys Gly He Arg Ser 830 Thr Thr Arg 835 Met Glu Asn Leu Leu Trp 840 Lys Gin He Ala Asn Glu Leu 845 Asn Tyr lie 850 Leu Trp Glu Asn 855 Asn lie Lys Leu Thr Val Val Val Gly 860 Asp 865 He Thr Gly Val Leu Glu 870 Gin Gly Lys Arg Thr Leu Thr Pro Gin 875 880 Pro Met Glu Leu Lys 885 Tyr Ser Trp Lys Thr Trp Gly Lys Ala Lys He 890 895 Val Thr Ala Glu 900 Thr Gin Asn Ser Ser 905 Phe He He Asp Gly Pro Ser 910 Thr Pro Glu 915 Cys Pro Ser Ala Ser Arg 920 Ala Trp Asn Val Trp Glu Val 925 Glu Asp Tyr 930 Gly Phe Gly Val 935 Phe Thr Thr Asn He Trp Leu Lys Leu 940 Arg 945 Glu Val Tyr Thr Gin Leu 950 Cys Asp His Arg Leu Met Ser Ala Ala 955 960 Val Lys Asp Glu Arg 965 Ala Val His Ala Asp Met Gly Tyr Trp lie Glu 970 975 Ser Gin Lys Asn 980 Gly Ser Trp Lys Leu 985 Glu Lys Ala Ser Phe He Glu 990 Val Lys Thr 995 Cys Thr Trp Pro Lys Ser 1000 His Thr Leu Trp Ser Asn Gly 1005 Val Leu Glu 1010 Ser Asp Met He He Pro 1015 Lys Ser Leu Ala Gly Pro He 1020 Ser Gin His 1025 Asn His Arg Pro 1030 Gly Tyr His Thr Gin Thr Ala Gly Pro 1035 1040 Trp His Leu Gly Lys Leu Glu 1045 Leu Asp Phe Asn Tyr Cys Glu Gly Thr 1050 1055 Thr Val Val He Ser 1060 Glu Asn Cys Gly Thr Arg Gly Pro Ser Leu Arg 1065 1070 Thr Thr Thr Val 1075 Ser Gly Lys Leu He 1080 His Glu Trp Cys Cys Arg Ser 1085 Cys Thr Leu 1090 Pro Pro Leu Arg Tyr Met 1095 Gly Glu Asp Gly Cys Trp Tyr 1100 Gly Met Glu 1105 He Arg Pro He 1110 Asn Glu Lys Glu Glu Asn Met Val Lys 1115 1120 Ser Leu Ala Ser Ala Gly Ser 1125 Gly Lys Val Asp Asn Phe Thr Met Gly 1130 1135 Val Leu Cys Leu Ala 1140 lie Leu Phe Glu Glu Val Met Arg Gly Lys Phe 1145 1150 Gly Lys Lys His 1155 Met He Ala Gly Val 1160 Leu Phe Thr Phe Val Leu Leu 1165

    239

    2018200081 04 Jan 2018

    Leu Ser Gly 1170 Gin He Thr Trp Arg Asp Met Ala His Thr Leu He Met 1175 1180 lie Gly Ser Asn Ala Ser Asp Arg Met Gly Met Gly Val Thr Tyr Leu 1185 1190 1195 1200 Ala Leu lie Ala Thr Phe Lys He Gin Pro Phe Leu Ala Leu Gly Phe 1205 1210 1215 Phe Leu Arg Lys Leu Thr Ser Arg Glu Asn Leu Leu Leu Gly Val Gly 1220 122E i 1230 Leu Ala Met Ala Ala Thr Leu Arg Leu Pro Glu Asp He Glu Gin Met 1235 1240 1245 Ala Asn Gly He Ala Leu Gly Leu Met Ala Leu Lys Leu He Thr Gin 1250 1255 1260 Phe Glu Thr Tyr Gin Leu Trp Thr Ala Leu Val Ser Leu Thr Cys Ser 1265 1270 1275 1280 Asn Thr lie Phe Thr Leu Thr Val Ala Trp Arg Thr Ala Thr Leu He 1285 1290 1295 Leu Ala Gly He Ser Leu Leu Pro Val Cys Gin Ser Ser Ser Met Arg 1300 1305 1310 Lys Thr Asp Trp Leu Pro Met Thr Val Ala Ala Met Gly Ala Gin Pro 1315 1320 1325 Leu Pro Leu Phe He Phe Ser Leu Lys Asp Thr Leu Lys Arg Arg Ser 1330 1335 1340 Trp Pro Leu Asn Glu Gly Val Met Ala Val Gly Leu Val Ser He Leu 1345 1350 1355 1360 Ala Ser Ser Leu Leu Arg Asn Asp Val Pro Met Ala Gly Pro Leu Val 1365 1370 1375 Ala Gly Gly Leu Leu lie Ala'Cys Tyr Val He Thr Gly Thr Ser Ala 1380 1385 1390 Asp Leu Thr Val Glu Lys Ala Ala Asp Val Thr Trp Glu Glu Glu Ala 1395 1400 1405 Glu Gin Thr Gly Val Ser His Asn Leu Met Val Thr Val Asp Asp Asp 1410 1415 1420 Gly Thr Met Arg He Lys Asp Asp Glu Thr Glu Asn He Leu Thr Val 1425 1430 1435 1440 Leu Leu Lys Thr Ala Leu Leu He Val Ser Gly He Phe Pro Tyr Ser 1445 1450 1455 He Pro Ala Thr Leu Leu Val Trp His Thr Trp Gin Lys Gin Thr Gin 1460 1465 1470 Arg Ser Gly Val Leu Trp Asp Val Pro Ser Pro Pro Glu Thr Gin Lys 1475 1480 1485 Ala Glu Leu Glu Glu Gly Val Tyr Arg He Lys Gin Gin Gly He Phe 1490 1495 1500 Gly Lys Thr Gin Val Gly Val Gly Val Gin Lys Glu Gly Val Phe His 1505 1510 1515 1520 Thr Met Trp His Val Thr Arg Gly Ala Val Leu Thr His Asn Gly Lys 1525 1530 1535 Arg Leu Glu Pro Asn Trp Ala Ser Val Lys Lys Asp Leu He Ser Tyr 1540 1545 1550 Gly Gly Gly Trp Arg Leu Ser Ala Gin Trp Gin Lys Gly Glu Glu Val 1555 1560 1565 Gin Val lie Ala Val Glu Pro Gly Lys Asn Pro Lys Asn Phe Gin Thr 1570 1575 1580 Met Pro Gly He Phe Gin Thr Thr Thr Gly Glu He Gly Ala lie Ala 1585 1590 1595 1600

    240

    2018200081 04 Jan 2018

    Leu Asp Phe Lys Pro Gly Thr Ser Gly Ser Pro He He Asn Arg Glu 1615 1605 1610 Gly Lys Val Val Gly Leu Tyr Gly Asn Gly Val Val Thr Lys Asn Gly 1620 1625 1630 Gly Tyr Val Ser Gly He Ala Gin Thr Asn Ala Glu Pro Asp Gly Pro 1635 1640 1645 Thr Pro Glu Leu Glu Glu Glu Met Phe Lys Lys Arg Asn Leu Thr He 1650 1655 1660 Met Asp Leu His Pro Gly Ser Gly Lys Thr Arg Lys Tyr Leu Pro Ala 1665 1670 1675 1680 lie Val Arg Glu Ala He Lys Arg Arg Leu Arg Thr Leu He Leu Ala 1685 1690 1695 Pro Thr Arg Val Val Ala Ala Glu Met Glu Glu Ala Leu Lys Gly Leu 1700 1705 1710 Pro He Arg Tyr Gin Thr Thr Ala Thr Lys Ser Glu His Thr Gly Arg 1715 1720 1725 Glu He Val Asp Leu Met Cys His Ala Thr Phe Thr Met Arg Leu Leu 1730 1735 1740 Ser Pro Val Arg Val Pro Asn Tyr Asn Leu He He Met Asp Glu Ala 1745 1750 1755 1760 His Phe Thr Asp Pro Ala Ser He Ala Ala Arg Gly Tyr He Ser Thr 1765 1770 1775 Arg Val Gly Met Gly Glu Ala Ala Ala He Phe Met Thr Ala Thr Pro 1780 1785 1790 Pro Gly Thr Ala Asp Ala Phe Pro Gin Ser Asn Ala Pro He Gin Asp 1795 1800 1805 Glu Glu Arg Asp He Pro Glu Arg Ser Trp Asn Ser Gly Asn Glu Trp 1810 1815 1820 He Thr Asp Phe Val Gly Lys Thr Val Trp Phe Val Pro Ser He Lys 1825 1830 1835 1840 Ala Gly Asn Asp He Ala Asn Cys Leu Arg Lys Asn Gly Lys Lys Val 1845 1850 1855 lie Gin Leu Ser Arg Lys Thr Phe Asp Thr Glu Tyr Gin Lys Thr Lys 1860 1865 1870 Leu Asn Asp Trp Asp Phe Val Val Thr Thr Asp He Ser Glu Met Gly 1875 1880 1885 , Ala Asn Phe Lys Ala Asp Arg Val He Asp Pro Arg Arg Cys Leu Lys 1890 1895 1900 Pro Val He Leu Thr Asp Gly Pro Glu Arg Val He Leu Ala Gly Pro 1905 1910 1915 1920 Met Pro Val Thr Val Ala Ser Ala Ala Gin Arg Arg Gly Arg Val Gly 1925 1930 1935 Arg Asn Pro Gin Lys Glu Asn Asp Gin Tyr He Phe Met Gly Gin Pro 1940 1945 1950 Leu Asn Asn Asp Glu Asp His Ala His Trp Thr Glu Ala Lys Met Leu 1955 1960 1965 Leu Asp Asn He Asn Thr Pro Glu Gly He He Pro Ala Leu Phe Glu 1970 1975 1980 Pro Glu Arg Glu Lys Ser Ala Ala lie Asp Gly Glu Tyr Arg Leu Lys 1985 1990 1995 2000 Gly Glu Ser Arg Lys Thr Phe Val Glu Leu Met Arg Arg Gly Asp Leu 2005 2010 2015 Pro Val Trp Leu Ala His Lys Val Ala Ser Glu Gly He Lys Tyr Thr 2020 2025 2030

    241

    2018200081 04 Jan 2018

    Asp Arg Lys Trp Cys Phe Asp Gly Glu 2040 Arg Asn Asn Gin He 2045 Leu Glu 2035 Glu Asn Met Asp Val Glu He Trp Thr Lys Glu Gly Glu Lys Lys Lys 2050 2055 2060 Leu Arg Pro Arg Trp Leu Asp Ala Arg Thr Tyr Ser Asp Pro Leu Ala 2065 2070 2075 2080 Leu Lys Glu Phe Lys Asp Phe Ala Ala Gly Arg Lys Ser He Ala Leu 2085 2090 2095 Asp Leu Val Thr Glu He Gly Arg Val Pro Ser His Leu Ala His Arg 2100 2105 2110 Thr Arg Asn Ala Leu Asp Asn Leu Val Met Leu His Thr Ser Glu His 2115 2120 2125 Gly Gly Arg Ala Tyr Arg His Ala Val Glu Glu Leu Pro Glu Thr Met 2130 2135 2140 Glu Thr Leu Leu Leu Leu Gly Leu Met He Leu Leu Thr Gly Gly Ala 2145 2150 2155 2160 Met Leu Phe Leu He Ser Gly Lys Gly He Gly Lys Thr Ser He Gly 2165 2170 2175 Leu lie Cys Val He Ala Ser Ser Gly Met Leu Trp Met Ala Asp Val 2180 2185 2190 Pro Leu Gin Trp He Ala Ser Ala He Val Leu Glu Phe Phe Met Met 2195 2200 2205 Val Leu Leu He Pro Glu Pro Glu Lys Gin Arg Thr Pro Gin Asp Asn 2210 2215 2220 Gin Leu Ala Tyr Val Val lie Gly He Leu Thr Leu Ala Ala He Val 2225 2230 2235 2240 Ala Ala Asn Glu Met Gly Leu Leu Glu Thr Thr Lys Arg Asp Leu Gly 2245 2250 2255 Met Ser Lys Glu Pro Gly Val Val Ser Pro Thr Ser Tyr Leu Asp Val 2260 2265 2270 Asp Leu His Pro Ala Ser Ala Trp Thr Leu Tyr Ala Val Ala Thr Thr 2275 2280 2285 Val He Thr Pro Met Leu Arg His Thr He Glu Asn Ser Thr Ala Asn 2290 2295 2300 Val Ser Leu Ala Ala He Ala Asn Gin Ala Val Val Leu Met Gly Leu 2305 2310 2315 2320 Asp Lys Gly Trp Pro He Ser Lys Met Asp Leu Gly Val Pro Leu Leu 2325 2330 2335 Ala Leu Gly Cys Tyr Ser Gin Val Asn Pro Leu Thr Leu Ala Ala Ala 2340 2345 2350 Val Leu Leu Leu Val Thr His Tyr Ala He lie Gly Pro Gly Leu Gin 2355 2360 2365 Ala Lys Ala Thr Arg Glu Ala Gin Lys Arg Thr Ala Ala Gly He Met 2370 2375 2380 Lys Asn Pro Thr Val Asp Gly lie Met Thr He Asp Leu Asp Pro Val 2385 2390 2395 2400 He Tyr Asp Ser Lys Phe Glu Lys Gin Leu Gly Gin Val Met Leu Leu 2405 2410 2415 Val Leu Cys Ala Val Gin Leu Leu Leu Met Arg Thr Ser Trp Ala Leu 2420 2425 2430 Cys Glu Val Leu Thr Leu Ala Thr Gly Pro He Thr Thr Leu Trp Glu 2435 2440 2445 Gly Ser Pro Gly Lys Phe Trp Asn Thr Thr He Ala Val Ser Met Ala 2450 2455 2460

    242

    2018200081 04 Jan 2018

    Asn lie Phe Arg Gly Ser Tyr Leu Ala Gly Ala Gly Leu Ala Phe Ser 2465 2470 2475 2480 He Met Lys Ser Val Gly Thr Gly Lys Arg Gly Thr Gly Ser Gin Gly 2485 2490 2495 Glu Thr Leu Gly Glu Lys Trp Lys Lys Lys Leu Asn Gin Leu Ser Arg 250C I 2505 2510 Lys Glu Phe Asp Leu Tyr Lys Lys Ser Gly He Thr Glu Val Asp Arg 2515 2520 2525 Thr Glu Ala Lys Glu Gly Leu Lys Arg Gly Glu He Thr His His Ala 2530 2535 2540 Val Ser Arg Gly Ser Ala Lys Leu Gin Trp Phe Val Glu Arg Asn Met 2545 2550 2555 2560 Val He Pro Glu Gly Arg Val He Asp Leu Gly Cys Gly Arg Gly Gly 2565 2570 2575 Trp Ser Tyr Tyr Cys Ala Gly Leu Lys Lys Val Thr Glu Val Arg Gly 258C I 2585 2590 Tyr Thr Lys Gly Gly Pro Gly His Glu Glu Pro Val Pro Met Ser Thr 2595 2600 2605 Tyr Gly Trp Asn He Val Lys Leu Met Ser Gly Lys Asp Val Phe Tyr 2610 2615 2620 Leu Pro Pro Glu Lys Cys Asp Thr Leu Leu Cys Asp He Gly Glu Ser 2625 2630 2635 2640 Ser Pro Ser Pro Thr Val Glu Glu Ser Arg Thr He Arg Val Leu Lys 2645 2650 2655 Met Val Glu Pro Trp Leu Lys Asn Asn Gin Phe Cys He Lys Val Leu 2660 2665 2670 Asn Pro Tyr Met Pro Thr Val lie Glu His Leu Glu Arg Leu Gin Arg 2675 2680 2685 Lys His Gly Gly Met Leu Val Arg Asn Pro Leu Ser Arg Asn Ser Thr 2690 2695 2700 His Glu Met Tyr Trp He Ser Asn Gly Thr Gly Asn He Val Ser Ser 2705 2710 2715 2720 Val Asn Met Val Ser Arg Leu Leu Leu Asn Arg Phe Thr Met Thr His 2725 2730 2735 Arg Arg Pro Thr He Glu Lys Asp Val Asp Leu Gly Ala Gly Thr Arg 2740. 2745 2750 His Val Asn Ala Glu Pro Glu Thr Pro Asn Met Asp Val He Gly Glu 2755 2760 2765 Arg He Lys Arg He Lys Glu Glu His Ser Ser Thr Trp His Tyr Asp 2770 2775 2780 Asp Glu Asn Pro Tyr Lys Thr Trp Ala Tyr His Gly Ser Tyr Glu Val 2785 2790 2795 2800 Lys Ala Thr Gly Ser Ala Ser Ser Met He Asn Gly Val Val Lys Leu 2805 2810 2815 Leu Thr Lys Pro Trp Asp Val Val Pro Met Val Thr Gin Met Ala Met 2820 2825 2830 Thr Asp Thr Thr Pro Phe Gly Gin Gin Arg Val Phe Lys Glu Lys Val 2835 2840 2845 Asp Thr Arg Thr Pro Arg Pro Met Pro Gly Thr Arg Lys Val Met Glu 2850 2855 2860 He Thr Ala Glu Trp Leu Trp Arg Thr Leu Gly Arg Asn Lys Arg Pro 2865 2870 2875 2880 Arg Leu Cys Thr Arg Glu Glu Phe Thr Lys Lys Val Arg Thr Asn Ala 2885 2890 2895

    243

    2018200081 04 Jan 2018

    Ala Met Gly Ala Val Phe Thr Glu Glu Asn Gin Trp 2905 Asp Ser Ala 2910 Arg 2900 Ala Ala Val Glu Asp Glu Glu Phe Trp Lys Leu Val Asp Arg Glu Arg 2915 2920 2925 Glu Leu His Lys Leu Gly Lys Cys Gly Ser Cys Val Tyr Asn Met Met 2930 2935 2940 Gly Lys Arg Glu Lys Lys Leu Gly Glu Phe Gly Lys Ala Lys Gly Ser 2945 2950 2955 2960 Arg Ala He Trp Tyr Met Trp Leu Gly Ala Arg Tyr Leu Glu Phe Glu 2965 i 2970 2975 Ala Leu Gly Phe Leu Asn Glu Asp His Trp Phe Ser Arg Glu Asn Ser 2980 2985 2990 Tyr Ser Gly Val Glu Gly Glu Gly Leu His Lys Leu Gly Tyr He Leu 2995 3000 3005 Arg Asp He Ser Lys He Pro Gly Gly Ala Met Tyr Ala Asp Asp Thr 3010 3015 3020 Ala Gly Trp Asp Thr Arg He Thr Glu Asp Asp Leu His Asn Glu Glu 3025 3030 3035 3040 Lys lie Thr Gin Gin Met Asp Pro Glu His Arg Gin Leu Ala Asn Ala 3045 3050 3055 He Phe Lys Leu Thr Tyr Gin Asn Lys Val Val Lys Val Gin Arg Pro 3060 3065 3070 Thr Pro Lys Gly Thr Val Met Asp He He Ser Arg Lys Asp Gin Arg 3075 3080 3085 Gly Ser Gly Gin Val Gly Thr Tyr Gly Leu Asn Thr Phe Thr Asn Met 3090 3095 3100 Glu Ala Gin Leu He Arg Gin Met Glu Gly Glu Gly Val Leu Ser Lys 3105 3110 3115 3120 Ala Asp Leu Glu Asn Pro His Pro Leu Glu Lys Lys He Thr Gin Trp 3125 3130 3135 Leu Glu Thr Lys Gly Val Glu Arg Leu Lys Arg Met Ala He Ser Gly 3140 3145 3150 Asp Asp Cys Val Val Lys Pro lie Asp Asp Arg Phe Ala Asn Ala Leu 3155 3160 3165 Leu Ala Leu Asn Asp Met Gly Lys Val Arg Lys Asp He Pro Gin Trp 3170 3175 3180 Gin Pro Ser Lys Gly Trp His Asp Trp Gin Gin Val Pro Phe Cys Ser 3185 3190 3195 3200 His His Phe His Glu Leu lie Met Lys Asp Gly Arg Lys Leu Val Val 3205 3210 3215 Pro Cys Arg Pro Gin Asp Glu Leu He Gly Arg Ala Arg He Ser Gin 3220 3225 3230 Gly Ala Gly Trp Ser Leu Arg Glu Thr Ala Cys Leu Gly Lys Ala Tyr 3235 3240 3245 Ala Gin Met Trp Ala Leu Met Tyr Phe His Arg Arg Asp Leu Arg Leu 3250 3255 3260 Ala Ser Asn Ala He Cys Ser Ala Val Pro Val His Trp Val Pro Thr 3265 3270 3275 3280 Ser Arg Thr Thr Trp Ser He His Ala His His Gin Trp Met Thr Thr 3285 3290 3295 Glu Asp Met Leu Thr Val Trp Asn Arg Val Trp He Glu Asp Asn Pro 3300 3305 3310 Trp Met Glu Asp Lys Thr Pro Val Thr Thr Trp Glu Asp Val Pro Tyr 3315 3320 3325

    244

    2018200081 04 Jan 2018

    Leu Gly Lys 3330 Arg Glu Asp Gin Trp 3335 Cys Gly Ser Leu He Gly 3340 Leu Thr Ser Arg Ala Thr Trp Ala Gin Asn He Leu Thr Ala He Gin Gin Val 3345 3350 3355 3360 Arg Ser Leu lie Gly Asn Glu Glu Phe Leu Asp Tyr Met Pro Ser Met 3365 3370 3375 Lys Arg Phe Arg Lys Glu Glu Glu Ser Glu Gly Ala He Trp 3380 3385 i 3390

    <210> 21 <211> 10699 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <221> CDS ' <222> (95)...(10267) <400> 21 agttgttagt ctacgtggac cgacaagaac agtttcgact cggaagcttg cttaacgtag 60 tgctgacagt tttttattag agagcagatc tctg atg aac aac caa egg aaa aag 115

    Met Asn Asn Gin Arg Lys Lys 1 5

    aeg gga Thr Gly aaa Lys 10 ccg Pro tet Ser ate lie aat Asn atg ctg aaa ege gtg Val aga Arg 20 aac Asn cgt Arg gtg Val 163 Met 15 Leu Lys Arg tea act gga. tea cag ttg geg aag aga ttc tea aga gga ttg ctg aac 211 Ser Thr Gly Ser Gin Leu Ala Lys Arg Phe Ser Arg Gly Leu Leu Asn 25 30 35 ggc caa gga cca atg aaa ttg gtt atg gca ttt ata get ttc etc aga 259 Gly Gin Gly Pro Met Lys Leu Val Met Ala Phe He Ala Phe Leu Arg 40 45 50 55 ttt eta gcc' att cca ccg aca gca gga gtc ttg get aga tgg ggt acc 307 Phe Leu Ala He Pro Pro Thr Ala Gly Val Leu Ala Arg Trp Gly Thr 60 65 70 ttt aag aag teg ggg get att aag gtc tta aaa ggc ttc aag aag gag 355. Phe Lys Lys Ser Gly Ala He Lys Val Leu Lys Gly Phe Lys Lys Glu 75 80 85 ate tea aac atg ctg agc att ate aac aaa egg aaa aag aca teg etc 403 lie Ser Asn Met Leu Ser He He Asn Lys Arg Lys Lys Thr Ser Leu 90 95 100 tgt etc atg atg atg tta cca gca aca ett get ttc cac tta act tea 451 Cys Leu Met Met Met Leu Pro Ala Thr Leu Ala Phe His Leu Thr Ser 105 110 115

    245

    2018200081 04 Jan 2018

    ega gat Arg Asp 120 gga gag ccg Gly Glu Pro cgc Arg 125 atg att gtg ggg aag aat gaa aga gga aaa 499 Met He Val Gly Lys 130 Asn Glu Arg Gly Lys 135 tcc eta ett ttc aag aca gcc tet gga ate aac atg tgc aca etc ata 547 Ser Leu Leu Phe Lys Thr Ala Ser Gly He Asn Met Cys Thr Leu He 140 145 150 get atg gat ctg gga gag atg tgt gat gac aeg gtc act tac aaa tgc 595 Ala Met Asp Leu Gly Glu Met Cys Asp Asp Thr Val Thr Tyr Lys Cys 155 160 165 ccc cac att acc gaa gtg gag cct gaa gac att gac tgc tgg tgc aac 643 Pro His He Thr Glu Val Glu Pro Glu Asp He Asp Cys Trp Cys Asn 170 175 180 ett aca teg aca tgg gtg act tat gga aca tgc aat caa get gga gag 691 Leu Thr Ser Thr Trp Val Thr Tyr Gly Thr Cys Asn Gin Ala Gly Glu 185 190 195 cat aga cgc gat aag aga tea gtg gcg tta get ccc cat gtt ggc atg 739 His Arg Arg Asp Lys Arg Ser Val Ala Leu Ala Pro His Val Gly Met 200 205 210 215 gga ctg gac aca cgc act caa acc tgg atg teg get gaa gga get tgg 787 Gly Leu Asp Thr Arg Thr Gin Thr Trp Met Ser Ala Glu Gly Ala Trp 220 225 230 aga caa gtc gag aag gta gag aca tgg gee ett agg cac cca ggg ttt 835 Arg Gin Val Glu Lys Val Glu Thr Trp Ala Leu Arg His Pro Gly Phe 235 240 245 acc ata eta gee eta ttt ett gcc cat tac ata ggc act tee ttg acc 883 Thr lie Leu Ala Leu Phe Leu Ala His Tyr He Gly Thr Ser Leu Thr 250 255 260 cag aaa gtg gtt att ttt ata eta tta atg ctg gtt acc cca tcc atg 931 Gin Lys Val Val He Phe He Leu Leu Met Leu Val Thr Pro Ser Met 265 270 275 aca atg aga tgt gta gga gta gga aac aga gat ttt gtg gaa ggc eta 979 Thr Met Arg Cys Val Gly Val Gly Asn Arg Asp Phe Val Glu Gly Leu 280 285 290 295 teg gga get aeg tgg gtt gac gtg gtg etc gag cac ggt ggg tgt gtg 1027 Ser Gly Ala Thr Trp Val Asp Val Val Leu Glu His Gly Gly Cys Val 300 305 310 act acc atg get aag aac aag ccc aeg ctg gac ata gag ett cag aag 1075 Thr Thr Met Ala Lys Asn Lys Pro Thr Leu Asp He Glu Leu Gin Lys 315 320 325

    246

    2018200081 04 Jan 2018

    acc Thr gag gcc Glu Ala 330 acc Thr caa ctg Gin Leu geg acc eta agg aag eta tgc Cys 340 att He gag gga 1123 Ala Thr 335 Leu Arg Lys Leu Glu Gly aaa att acc aac ata aca acc gac tea aga tgt ccc acc caa ggg gaa 1171 Lys lie Thr Asn He Thr Thr Asp Ser Arg Cys Pro Thr Gin Gly Glu 345 350 355 geg att tta cct gag gag cag gac cag aac tac gtg tgt aag cat aca 1219 Ala He Leu Pro Glu Glu Gin Asp Gin Asn Tyr Val Cys Lys His Thr 360 365 370 375 tac gtg gac aga ggc tgg gga aac ggt tgt ggt ttg ttt ggc aag gga 1267 Tyr Val Asp Arg Gly Trp Gly Asn Gly Cys Gly Leu Phe Gly Lys Gly 380 385 390 age ttg gtg aca tgc geg aaa ttt caa tgt tta gaa tea ata gag gga 1315 Ser Leu Val Thr Cys Ala Lys Phe Gin Cys Leu Glu Ser He Glu Gly 395 400 405 aaa gtg gtg caa cat gag aac etc aaa tac acc gtc ate ate aca gtg 1363 Lys Val Val Gin His Glu Asn Leu Lys Tyr Thr Val He He Thr Val 410 415 420 cac aca gga gac caa cac cag gtg gga aat gaa acg cag gga gtc acg 1411 His Thr Gly Asp Gin His Gin Val Gly Asn Glu Thr Gin Gly Val Thr 425 430 435 get gag ata aca ccc cag gca tea acc get gaa gee att tta cct gaa 1459 Ala Glu He Thr Pro Gin Ala Ser Thr Ala Glu Ala He Leu Pro Glu 440 445 450 455 tat gga acc etc ggg eta gaa tgc tea cca egg aca ggt ttg gat ttc 1507 Tyr Gly Thr Leu Gly Leu Glu Cys Ser Pro Arg Thr Gly Leu Asp Phe 460 465 470 aat gaa atg ate tta ttg aca atg aag aac aaa gca tgg atg gta cat 1555 Asn Glu Met lie Leu Leu Thr Met Lys Asn Lys Ala Trp Met Val His 475 480 485 aga caa tgg ttc ttt gac tta ccc eta cca tgg aca tea gga get aca 1603 Arg Gin Trp Phe Phe Asp Leu Pro Leu Pro Trp Thr Ser Gly Ala Thr 490 495 500 gca gaa aca cca act tgg aac agg aaa gag ett ett gtg aca ttt aaa 1651 Ala Glu Thr Pro Thr Trp Asn Arg Lys Glu Leu Leu Val Thr Phe Lys 505 510 515 aat gca cat gca aaa aag caa gaa gta gtt gtt ett gga tea caa gag 1699 Asn Ala His Ala Lys Lys Gin Glu Val Val Val Leu Gly Ser Gin Glu 520 525 530 535 gga gca atg cat aca gca ctg aca gga get aca gag ate caa acc tea 1747 Gly Ala Met His Thr Ala Leu Thr Gly Ala Thr Glu He Gin Thr Ser 540 545 550

    247

    2018200081 04 Jan 2018

    gga ggc Gly Gly aca agt Thr Ser 555 ate lie ttt Phe gcg ggg cac His 560 tta aaa tgt Cys aga Arg etc Leu 565 aag Lys atg Met 1795 Ala Gly Leu Lys gac aaa ttg gaa etc aaa ggg atg age tat gca atg tgc ttg ggt age 1843 Asp Lys Leu Glu Leu Lys Gly Met Ser Tyr Ala Met Cys Leu Gly Ser 570 575 580 ttt gtg ttg aag aaa gaa gtc tcc gaa acg cag cat ggg aca ata etc 1891 Phe Val Leu Lys Lys Glu Val Ser Glu Thr Gin His Gly Thr He Leu 585 590 595 att aag gtt gag tac aaa ggg aaa gat gca ccc tgc aag att cct ttc 1939 lie Lys Val Glu Tyr Lys Gly Lys Asp Ala Pro Cys Lys He Pro Phe 600 605 610 615 tcc acg gag gat gga caa gga aaa get cac aat ggc aga ctg ate aca 1987 Ser Thr Glu Asp Gly Gin Gly Lys Ala His Asn Gly Arg Leu He Thr 620 625 630 gcc aat cca gtg gtg acc aag aag gag gag cct gtc aac att gag get 2035 Ala Asn Pro Val Val Thr Lys Lys Glu Glu Pro Val Asn He Glu Ala 635 640 645 gaa cct cct ttt gga gaa agt aac ata gta att gga att gga gac aaa 2083 Glu Pro Pro Phe Gly Glu Ser Asn He Val He Gly He Gly Asp Lys 650 655 660 gcc ctg aaa ate aac tgg tac aag aag gga age teg att ggg aag atg 2131 Ala Leu Lys He Asn Trp Tyr Lys Lys Gly Ser Ser He Gly Lys Met 665 670 675 ttc gag get act gcc aga ggt gca agg ege atg gcc ate ttg gga gac 2179 Phe Glu Ala Thr Ala Arg Gly Ala Arg Arg Met Ala He Leu Gly Asp 680 685 690 695 aca gcc tgg gac ttt gga tea gtg ggt ggt gtt ttg aat tea tta ggg 2227 Thr Ala Trp Asp Phe Gly Ser Val Gly Gly Val Leu Asn Ser Leu Gly 700 705 710 aaa atg gtc cac caa ata ttt ggg agt get tac aca gcc eta ttt ggt 2275 Lys Met Val His Gin He Phe Gly Ser Ala Tyr Thr Ala Leu Phe Gly 715 720 725 gga gtc tcc tgg atg atg aaa att gga ata ggt gtc etc tta acc tgg 2323 Gly Val Ser Trp Met Met Lys He Gly He Gly Val Leu Leu Thr Trp 730 735 740 ata ggg ttg aac tea aaa aat act tet atg tea ttt tea tgc ate gcg 2371 He Gly Leu Asn Ser Lys Asn Thr Ser Met Ser Phe Ser Cys He Ala

    745 750 755

    248

    2018200081 04 Jan 2018

    ata lie 760 gga Gly ate He att He aca Thr etc Leu 765 tat Tyr ctg gga gcc gtg Val 770 gtg Val caa get gac Asp atg Met 775 2419 Leu Gly Ala Gin Ala ggg tgt gtc ata aac tgg aaa ggc aaa gaa etc aaa tgt gga agt gga 2467 Gly Cys Val lie Asn 780 Trp Lys Gly Lys Glu 785 Leu Lys Cys Gly Ser 790 Gly att ttc gtc act aat gag gtc cac acc tgg aca gag caa tac aaa ttt 2515 He Phe Val Thr 795 Asn Glu Val His Thr 800 Trp Thr Glu Gin Tyr 805 Lys Phe caa gca gac tcc ccc aag aga ctg gca aca gcc att gca ggc get tgg 2563 Gin Ala Asp 810 Ser Pro Lys Arg Leu 815 Ala Thr Ala He Ala 820 Gly Ala Trp gaa aat gga gtg tgc gga att agg tea aca acc aga atg gag aac etc 2611 Glu Asn 825 Gly Val Cys Gly He 830 Arg Ser Thr Thr Arg 835 Met Glu Asn Leu ttg tgg aag caa ata gcc aat gaa ctg aat tac ata tta tgg gaa aac 2659 Leu 840 Trp Lys Gin He Ala 845 Asn Glu Leu Asn Tyr 850 He Leu Trp Glu Asn 855 aac att aaa tta aeg gta gtt gta ggc gap ata act ggg gtc tta gag 2707 Asn He Lys Leu Thr 860 Val Val Val Gly Asp 865 He Thr Gly Val Leu 870 Glu caa ggg aaa aga aca eta aca cca caa ccc atg gag eta aaa tat tet 2755 Gin Gly Lys Arg 875 Thr Leu Thr Pro Gin 880 Pro Met Glu Leu Lys 885 Tyr Ser tgg aaa aca tgg gga aag gca aaa ata gtg aca get gaa aca caa aat 2803 Trp Lys Thr 890 Trp Gly Lys Ala Lys 895 He Val Thr Ala Glu 900 Thr Gin Asn tcc tet ttc ata ata gat ggg cca age aca ccg gag tgt cca agt gcc 2851 Ser Ser 905 Phe He He Asp Gly 910 Pro Ser Thr Pro Glu 915 Cys Pro Ser Ala tea aga gca tgg aat gtg tgg gag gtg gag gat tac ggg ttc gga gtt 2899 Ser 920 Arg Ala Trp Asn Val 925 Trp Glu Val Glu Asp 930 Tyr Gly Phe Gly Val 935 ttc aca acc aac ata tgg ctg aaa etc ega gag gtg tac acc caa eta 2947 Phe Thr Thr Asn He 940 Trp Leu Lys Leu Arg 945 Glu Val Tyr Thr Gin 950 Leu tgt gac cat agg eta atg teg gca gcc gtc aag gat gag agg get gta 2995 Cys Asp His Arg 955 Leu Met Ser Ala Ala 960 Val Lys Asp Glu Arg 965 Ala Val cat gcc gac atg ggc tat tgg ata gaa age caa aag aat ggg agt tgg 3043 His Ala Asp 970 Met Gly Tyr Trp He 975 Glu Ser Gin Lys Asn 980 Gly Ser Trp

    249

    2018200081 04 Jan 2018

    aag Lys eta gaa Leu Glu 985 aaa Lys gca Ala tcc Ser ttc ata gag Phe He Glu 990 gtg aaa acc tgc aca Thr tgg Trp cca Pro 3091 Val Lys Thr Cys 995 aaa tea cac act etc tgg agc aat ggt gtg eta gag agt gac atg att 3139 Lys 100C Ser His 1 Thr Leu Trp 1005 Ser Asn Gly Val Leu Glu Ser 1010 Asp Met He 1015 ate cca aag agt eta get ggt ccc att teg caa cac aac cac agg ccc 3187 lie Pro Lys Ser Leu 102C Ala 1 Gly Pro He Ser 1025 Gin His Asn His Arg 103C Pro 1 ggg tac cac acc caa aeg gca gga ccc tgg cac tta gga aaa ttg gag 3235 Gly Tyr His Thr Gin 1035 Thr Ala Gly Pro Trp 1040 His Leu Gly Lys 1045 Leu Glu ctg gac ttc aac tat tgt gaa gga aca aca gtt gtc ate tea gaa aac 3283 Leu Asp Phe Asn 1050 Tyr Cys Glu Gly Thr 1055 Thr Val Val He Ser 1060 Glu Asn tgt ggg aca aga ggc cca tea ttg aga aca aca aeg gtg tea ggg aag 3331 Cys Gly Thr 1065 Arg Gly Pro Ser Leu Arg 1070 Thr Thr Thr Val 1075 Ser Gly Lys ttg ata cac gaa tgg tgc tgc cgc teg tgc aca ett cct ccc eta ega 3379 Leu He His 1080 Glu Trp Cys Cys Arg Ser 1085 Cys Thr Leu Pro 1090 Pro Leu Arg 1095 tac atg gga gaa gac ggc tgc tgg tat ggc atg gaa ate aga ccc att 3427 Tyr Met Gly Glu Asp Gly 1100 Cys Trp Tyr Gly Met 1105 Glu lie Arg Pro He 1110 aat gag aaa gaa gag aat atg gta aag tet eta gcc tea gca ggg agt 3475 Asn Glu Lys Glu Glu 1115 Asn Met Val Lys Ser 1120 Leu Ala Ser Ala Gly 1125 Ser gga aag gtg gac aac ttc aca atg ggt gtc ttg tgt ttg gca ate etc 3523 Gly Lys Val Asp 1130 Asn Phe Thr Met Gly 1135 Val Leu Cys Leu Ala 1140 He Leu ttt gaa gag gtg atg aga gga aaa ttt ggg aaa aaa cac atg att gca 3571 Phe Glu Glu 1145 Val Met Arg Gly Lys Phe 1150 Gly Lys Lys His 1155 Met He Ala ggg gtt etc ttc aeg ttt gtg etc etc etc tea ggg caa ata aca tgg 3619 Gly Val Leu 1160 Phe Thr Phe Val Leu Leu 1165 Leu Ser Gly Gin 1170 He Thr Trp 1175 aga gac atg geg cac aca etc ata atg att ggg tcc aac gcc tet gac 3667 Arg Asp Met Ala His Thr 1180 Leu He Met He Gly 1185 Ser Asn Ala Ser Asp 1190

    250

    2018200081 04 Jan 2018

    aga Arg atg Met ggg atg ggc Gly Met Gly 1195 gtc Val act Thr tac Tyr eta get Leu Ala 1200 eta Leu att gca aca ttt aaa Lys 3715 He Ala Thr Phe 1205 att cag cca etc ctg get ttg gga ttc ttc ctg agg aaa ctg aca tet 3763 lie Gin Pro Leu Leu 1210 Ala Leu Gly 1215 Phe Phe Leu Arg Lys Leu Thr 1220 Ser aga gaa aat tta ttg ctg gga gtt ggg ttg gcc atg gca gca acg tta 3811 Arg Glu Asn Leu Leu 1225 Leu Gly Val 1230 Gly Leu Ala Met Ala 1235 Ala Thr Leu ega ctg cca gag gac att gaa cag atg gcg aat gga att get ttg ggg 3859 Arg Leu 1240 Pro Glu Asp He Glu 1245 Gin Met Ala Asn Gly 1250 He Ala Leu Gly 1255 etc atg get ctt aaa ctg ata aca caa ttt gaa aca tac caa eta tgg 3907 Leu Met Ala Leu Lys Leu 1260 He Thr Gin Phe 1265 Glu Thr Tyr Gin Leu 127C Trp 1 acg gca tta gtt tcc eta acg tgt tea aat aca att ttc acg ttg act 3955 Thr Ala Leu Val Ser 1275 Leu Thr Cys Ser Asn 1280 Thr He Phe Thr Leu 1285 Thr gtt gcc tgg aga aca gcc act ctg att tta gcc gga att teg ctt ttg 4003 Val Ala Trp Arg Thr 1290 Ala Thr Leu He Leu 1295 Ala Gly He Ser Leu 1300 Leu cca gtg tgc cag tet teg age atg agg aaa aca gat tgg etc cca atg 4051 Pro Val Cys Gin Ser 1305 Ser Ser Met 1310 Arg Lys Thr Asp Trp 1315 Leu Pro Met act gtg gca get atg gga get caa ccc eta cca ctt ttt att ttc agt 4099 Thr Val 1320 Ala Ala Met Gly Ala 1325 Gin Pro Leu Pro Leu 1330 Phe He Phe Ser 1335 ctg aaa gat aca etc aaa agg aga age tgg cca ctg aat gag ggg gtg 4147 Leu Lys Asp Thr Leu Lys 1340 Arg Arg Ser Trp Pro 1345 Leu Asn Glu Gly Val 1350 atg gca gtt gga ctt gtg age att eta get agt tet etc ctt agg aat 4195 Met Ala Val Gly Leu 1355 Val Ser He Leu Ala 1360 Ser Ser Leu Leu Arg 1365 Asn gat gtg cct atg get gga cca tta gtg get ggg ggc ttg ctg ata gcg 4243 Asp Val Pro Met Ala 1370 Gly Pro Leu Val Ala 1375. Gly Gly Leu Leu He 1380 Ala tgc tac gtc ata act ggc acg tea gca gac etc act gta gaa aaa gca 4291 Cys Tyr Val lie Thr 1385 Gly Thr Ser 1390 Ala Asp Leu Thr Val 1395 Glu Lys Ala gca gat gta aca tgg gag gaa 9ag gcc gag caa aca gga gtg tcc cac 4339 Ala Asp Val Thr Trp Glu Glu Glu Ala Glu Gin Thr Gly Val Ser His

    1400 1405 1410 1415

    251

    2018200081 04 Jan 2018

    aat Asn tta Leu atg gtc Met Val aca gtt gat Thr Val Asp 1420 gat Asp gat Asp gga aca atg aga ata He aaa Lys 143C gat Asp 1 4387 Gly Thr Met 1425 Arg gac gag act gag aac ate tta aca gtg ett tta aaa aca gca eta eta 4435 Asp Glu Thr Glu 1435 Asn He Leu Thr Val 144C Leu Leu Lys 1 Thr Ala 1445 Leu Leu ata gta tea ggc ate ttt cca tac tcc ata ccc gca aca ctg ttg gtc 4483 lie Val Ser Gly 1450 He Phe Pro Tyr Ser 1455 He Pro Ala Thr Leu 1460 Leu Val tgg cat act tgg caa aag caa acc caa aga tcc ggc gtc eta tgg gac 4531 Trp His Thr Trp 1465 Gin Lys Gin Thr 1470 Gin Arg Ser Gly Val 1475 Leu Trp Asp gta ccc age ccc cca gag aca cag aaa gcg gaa ctg gaa gaa ggg gtc 4579 Val Pro 1480 Ser Pro Pro Glu Thr 1485 Gin Lys Ala Glu Leu 1490 Glu Glu Gly Val 1495 tat agg ate aaa cag caa gga att ttt ggg aaa acc caa gtg ggg gtt 4627 Tyr Arg He Lys Gin Gin Gly 1500 He Phe Gly Lys Thr 1505 Gin Val Gly Val 1510 gga gta cag aaa gaa gga gtt ttc cac acc atg tgg· cat gtc aca aga 4675 Gly Val Gin Lys 1515 Glu Gly Val Phe His 152C Thr Met Trp 1 His Val 1525 Thr Arg ggg gca gtg ttg aca cac aat ggg aaa aga ctg gaa cca aac tgg get 4723 Gly Ala Val Leu 1530 Thr His Asn Gly Lys 1535 Arg Leu Glu Pro Asn 1540 Trp Ala age gtg aaa aaa gat ctg att tea tac gga gga gga tgg aga ttg agt 4771 Ser Val Lys Lys 1545 Asp Leu He Ser 1550 Tyr Gly Gly Gly Trp 1555 Arg Leu Ser gca caa tgg aaa aag ggg gag gag gtg cag gtt att gcc gta gag cct 4819 Ala Gin 1560 Trp Lys Lys Gly Glu 1565 Glu Val Gin Val He 1570 Ala Val Glu Pro 1575 ggg aag aac cca aag aac ttt caa acc atg cca ggc att ttt cag aca 4867 Gly Lys Asn Pro Lys Asn Phe 1580 Gin Thr Met Pro Gly 1585 He Phe Gin Thr 1590 aca aca ggg gaa ata gga gca att gca ctg gat ttc aag cct gga act 4915 Thr Thr Gly Glu He Gly Ala 1595 He Ala Leu Asp Phe 1600 Lys Pro Gly 1605 Thr tea gga tet ccc ate ata aac aga gag gga aag gta gtg gga ctg tat 4963 Ser Gly Ser Pro He He Asn Arg Glu Gly Lys Val Val Gly Leu Tyr

    1610 1615 1620

    252

    2018200081 04 Jan 2018

    ggc Gly aat gga Asn Gly 1625 gtg Val gtt Val aca Thr aag aat Lys Asn 1630 gga Gly ggc Gly tat Tyr gtc agt Val Ser 1635 gga Gly ata He gcg Ala 5011 caa aca aat gca gaa cca gat gga ccg aca cca gag ttg gaa gaa gag 5059 Gin 164C Thr Asn 1 Ala Glu Pro 1645 Asp Gly Pro Thr Pro Glu Leu 1650 Glu Glu Glu 1655 atg ttc aaa aag cga aat eta acc· ata atg gat etc cat cct ggg tea 5107 Met Phe Lys Lys Arg 166C Asn 1 Leu Thr lie Met 1665 Asp Leu His Pro Gly 167C Ser 1 gga aag aeg egg aaa tat ctt cca get att gtt aga gag gca ate aag 5155 Gly Lys Thr Arg Lys 1675 Tyr Leu Pro Ala 168C He 1 Val Arg Glu Ala He 1685 Lys aga ege tta agg act eta att ttg gca cca aca agg gta gtt gca get 5203 Arg Arg Leu Arg 1690 Thr Leu He Leu Ala 1695 Pro Thr Arg Val Val 1700 Ala Ala gag atg gaa gaa gca ttg aaa ggg etc cca ata agg tat caa aca act 5251 Glu Met Glu 1705 Glu Ala Leu Lys Gly 1710 Leu Pro He Arg Tyr 1715 Gin Thr Thr gca aca aaa tet gaa cac aca gga aga gag att gtt gat eta atg tgt 5299 Ala Thr Lys 1720 Ser Glu His Thr Gly 1725 Arg Glu He Val Asp 1730 Leu Met Cys 1735 cac gca aeg ttc aca atg ege ttg ctg tea cca gtc agg gtt cca aac 5347 His Ala Thr Phe Thr 174C Met 1 Arg Leu Leu Ser Pro 1745 Val Arg Val Pro Asn 1750 tac aac ttg ata ata atg gat gag gcc cat ttc aca gac cca gcc agt 5395 Tyr Asn Leu He He 1755 Met Asp Glu Ala His 1760 Phe Thr Asp Pro Ala 1765 Ser ata gcg get aga ggg tac ata tea act cgt gta gga atg gga gag gca 5443 lie Ala Ala Arg 1770 ' Gly Tyr He Ser Thr 1775 Arg Val Gly Met Gly 1780 Glu Ala gcc gca att ttc atg aca gca aca ccc cct gga aca get gat gcc ttt 5491 Ala Ala He 1785 Phe Met Thr Ala Thr 1790 Pro Pro Gly Thr Ala 1795 Asp Ala Phe cct cag agc aac get cca att caa gat gaa gag aga gac ata ccg gaa 5539 Pro Gin Ser 1800 Asn Ala Pro He Gin 1805 Asp Glu Glu Arg Asp 1810 He Pro Glu 1815 ego tea tgg aat tea ggc aat gaa tgg att act gac ttt gtt ggg aag 5587 Arg Ser Trp Asn Ser Gly 1820 Asn Glu Trp He Thr 1825 Asp Phe Val Gly Lys 1830 aca gtg tgg ttt gtc cct agc ate aaa gee gga aat gac ata gca aac 5635 Thr Val Trp Phe Val 1835 Pro Ser He Lys Ala 1840 Gly Asn Asp He Ala 1845 Asn

    253

    2018200081 04 Jan 2018

    tgc Cys ttg Leu egg aaa Arg Lys 1850 aat Asn gga Gly aaa Lys aag gtt Lys Val 1855 att He caa Gin etc Leu age agg Ser Arg 1860 aag Lys acc Thr 5683 ttt gac aca gaa tat caa aag acc aaa ctg aat gat tgg gac ttt gtg 5731 Phe Asp 1865 Thr Glu Tyr Gin Lys 187C Thr Lys 1 Leu Asn Asp 1875 Trp Asp Phe Val gtg aca aca gac att tea gaa atg gga gcc aat ttc aaa gca gat aga 5779 Val 188C Thr 1 Thr Asp He Ser Glu 1885 Met Gly Ala Asn Phe 1890 Lys Ala Asp Arg 1895 gtg ate gac cca aga aga tgt etc aag ccg gtg att ttg aca gat gga 5827 Val lie Asp Pro Arg Arg 1900 Cys Leu Lys Pro Val 1905 lie Leu Thr Asp 191C Gly 1 ccc gag egg gtg ate ctg get gga cca atg cca gtc acc gta gcg agc 5875 Pro Glu Arg Val He 1915 Leu Ala Gly Pro Met 1920 Pro Val Thr Val Ala 1925 Ser get gcg caa agg aga ggg aga gtt ggc agg aac cca caa aaa gaa aat 5923 Ala Ala Gin Arg 1930 Arg Gly Arg Val Gly 1935 Arg Asn Pro Gin Lys 1940 Glu Asn gac cag tac ata ttc atg ggc cag cct etc aac aat gat gaa gac cat 5971 Asp Gin Tyr He 1945 Phe Met Gly Gin Pro 1950 Leu Asn Asn Asp Glu 1955 Asp His get cac tgg aca gaa gca aaa atg ctg ctg gac aac ate aac aca cca 6019 Ala His 1960 Trp Thr Glu Ala Lys 1965 Met Leu Leu Asp Asn 1970 He Asn Thr Pro 1975 gaa ggg att ata cca get etc ttt gaa cca gaa agg gag aag tea gcc 6067 Glu Gly He He Pro Ala 1980 Leu Phe Glu Pro Glu 1985 Arg Glu Lys Ser Ala 1990 gcc ata gac ggc gaa tac cgc ctg aag ggt gag tcc agg aag act ttc 6115 Ala He Asp Gly Glu 1995 Tyr Arg Leu Lys Gly 2000 Glu Ser Arg Lys Thr 2005 Phe gtg gaa etc atg agg agg ggt gac etc cca gtt tgg eta gcc cat aaa 6163 Val Glu Leu Met 2010 Arg Arg Gly Asp Leu 2015 Pro Val Trp Leu Ala 2020 His Lys gta gca tea gaa ggg ate aaa tat aca gat aga aaa tgg tgc ttt gat 6211 Val Ala Ser Glu 2025 Gly He Lys Tyr Thr 2030 Asp Arg Lys Trp Cys 2035 Phe Asp gga gaa cgt aat aat caa att tta gag gag aat atg gat gtg gaa ate 6259 Gly Glu Arg Asn Asn Gin He Leu Glu Glu Asn Met Asp Val Glu He

    2040 2045 2050 . 2055

    254

    2018200081 04 Jan 2018

    tgg Trp aca Thr aag Lys gaa Glu gga gaa Gly Glu 2060 aag Lys aaa Lys aaa Lys ctg aga Leu Arg 2065 cct Pro agg Arg tgg Trp ett gat ' Leu Asp 2070 6307 gcc ege act tat tea gat cct tta gca etc aaa gaa ttc aag gat ttt 6355 Ala Arg Thr Tyr 2075 Ser Asp Pro Leu Ala 208C Leu Lys 1 Glu Phe Lys Asp Phe 2085 gca get ggc aga aag tea ate gcc ett gat ett gtg aca gaa ata gga 6403 Ala Ala Gly Arg 2090 Lys Ser He Ala Leu 2095 Asp Leu Val Thr Glu 2100 He Gly aga gtg cct tea cac tta gcc cac aga aeg aga aac gee ctg gat aat 6451 Arg Val Pro 2105 Ser His Leu Ala His 2110 Arg Thr Arg Asn Ala 2115 Leu Asp Asn ttg gtg atg ctg cac aeg tea gaa cat ggc ggt agg gee tac agg cat 6499 Leu Val 2120 Met Leu His Thr Ser 2125 Glu His Gly Gly Arg 2130 Ala Tyr Arg His 2135 gca gtg gag gaa eta cca gaa aeg atg gaa aca etc tta etc ctg gga 6547 Ala Val Glu Glu Leu Pro 2140 Glu Thr Met Glu Thr 2145 Leu Leu Leu Leu Gly 2150 ctg atg ate ttg tta aca ggt gga gca atg etc ttc ttg ata tea ggt 6595 Leu Met He Leu Leu Thr 2155 Gly Gly Ala Met Leu 2160 Phe Leu lie Ser Gly 2165 aaa ggg att gga aag act tea ata gga etc att tgt gta att get tcc 6643 Lys Gly He Gly 2170 Lys Thr Ser He Gly 2175 Leu He Cys Val He 2180 Ala Ser age ggc atg tta tgg atg get gat gtc cca etc caa tgg ate gca teg 6691 Ser Gly Met 2185 Leu Trp Met Ala Asp 2190 Val Pro Leu Gin Trp 2195 He Ala Ser get ata gtc ctg gag ttt ttt atg atg gtg ttg etc ata cca gaa cca 6739 Ala lie 2200 Val Leu Glu Phe Phe 2205 Met Met Val Leu Leu 2210 He Pro Glu Pro 2215 gaa aag cag aga act ccc caa gac aac caa etc gca tat gtc gtg ata 6787 Glu Lys Gin Arg Thr Pro 2220 Gin Asp Asn Gin Leu 2225 Ala Tyr Val Val He · 2230 ggc ata ett aca ttg get gca ata gta geg gcc aat gaa atg gga ctg 6835 Gly He Leu Thr Leu Ala 2235 Ala He Val Ala Ala 2240 Asn Glu Met Gly Leu 2245 ttg gaa act aca aag aga gat tta gga atg tet aaa gaa cca ggt gtt 6883 Leu Glu Thr Thr 2250 Lys Arg Asp Leu Gly 2255 Met Ser Lys Glu Pro 2260 Gly Val gtt tet cca acc age tat ttg gat gtg gac ttg cac cca gca tea gcc 6931 Val Ser Pro 2265 Thr Ser Tyr Leu Asp 2270 Val Asp Leu His Pro 2275 Ala Ser Ala

    255

    2018200081 04 Jan 2018

    tgg aca Trp Thr 2280 ttg Leu tac Tyr gcc Ala gtg gcc Val Ala 2285 aca Thr aca Thr gta ata aca cca atg ttg aga Arg 2295 6979 Val He Thr 2290 Pro Met Leu cac acc ata gag aat tcc aca gca aat gtg tet ctg gca gcc ata get 7027 His Thr He Glu Asn 230C Ser Thr 1 Ala Asn Val 2305 Ser Leu Ala Ala He 231C Ala 1 aac cag gca gtg gtc ctg atg ggt tta gac aaa gga tgg ccg ata teg 7075 Asn Gin Ala Val Val 2315 Leu Met Gly Leu Asp 2320 Lys Gly Trp Pro 2325 He Ser aaa atg gac ttg ggc gta cca eta ttg gca ctg ggt tgc tat tea caa 7123 Lys Met Asp Leu 2330 Gly Val Pro Leu Leu 2335 Ala Leu Gly Cys Tyr 2340 Ser Gin gtg aac cca eta act ctt gca geg gca gta ctt ttg eta gtc aca cat 7171 Val Asn Pro 2345 Leu Thr Leu Ala Ala 2350 Ala Val Leu Leu Leu 2355 Val Thr His tat gca att ata ggt cca gga ttg cag gca aaa gcc acc cgt gaa get 7219 Tyr Ala 2360 lie lie Gly Pro Gly 2365 Leu Gin Ala Lys Ala 2370 Thr Arg Glu Ala 2375 cag aaa agg aca get get gga ata atg aag aat cca aeg gtg gat gga 7267 Gin Lys Arg Thr Ala Ala Gly 2380 He Met Lys Asn Pro 2385 Thr Val Asp Gly 2390 ata atg aca ata gac eta gat cct gta ata tat gat tea aaa ttt gaa 7315 lie Met Thr He Asp 2395 Leu Asp Pro Val He 2400 Tyr Asp Ser Lys 2405 Phe Glu aag caa eta gga cag gtc atg etc ctg gtt ctg tgt gca gtc caa ctt 7363 Lys Gin Leu Gly 2410 Gin Val Met Leu Leu 2415 Val Leu Cys Ala Val 2420 Gin Leu tta ttg atg aga aca tea tgg gcc ttg tgt gaa gtt eta acc eta gcc 7411 Leu Leu Met 2425 Arg Thr Ser Trp Ala 2430 Leu Cys Glu Val Leu 2435 Thr Leu Ala aca gga cca ata aca aca etc tgg gaa gga tea cct ggg aag ttc tgg 7459 Thr Gly 2440 Pro He Thr Thr Leu 2445 Trp Glu Gly Ser Pro 2450 Gly Lys Phe Trp 2455 aac acc aeg ata get gtt tcc atg geg aac ate ttt aga ggg age tat 7507 Asn Thr Thr He Ala Val Ser 2460 Met Ala Asn He Phe 2465 Arg Gly Ser Tyr 2470 tta gca gga get ggg ctt get ttt tet ate atg aaa tea gtt gga aca 7555 Leu Ala Gly Ala Gly Leu Ala 2475 Phe Ser He 2480 Met Lys Ser Val Gly 2485 Thr

    256

    2018200081 04 Jan 2018

    gga aag Gly Lys aga gga Arg Gly 2490 aca ggg tea caa ggt gaa Ser Gin Gly Glu 2495 acc Thr tta gga gaa Leu Gly Glu 2500 aag Lys tgg Trp 7603 Thr Gly aaa aag aaa tta aat cag tta tcc egg aaa gag ttt gac ett tac aag 7651 Lys Lys 2505 Lys Leu Asn Gin Leu Ser Arg Lys 2510 Glu Phe Asp Leu 2515 Tyr Lys aaa tcc gga ate acc gaa gtg gat aga aca gaa gcc aaa gaa ggg tta 7699 Lys Ser 2520 Gly He Thr Glu Val Asp Arg Thr 2525 Glu 253C Ala Lys Glu 1 Gly Leu 2535 aaa aga gga gaa ata aca cac cat gcc gtg tcc aga ggc age gca aaa 7747 Lys Arg Gly Glu He Thr 2540 His His Ala Val 2545 Ser Arg Gly Ser Ala 255C Lys 1 ett caa tgg ttc gtg gag aga aac atg gtc att cct gaa gga aga gtc 7795 Leu Gin Trp Phe Val 2555 Glu Arg Asn Met Val 2560 He Pro Glu Gly Arg 2565 Val ata gac eta ggc tgt gga aga gga ggc tgg tea tat tac tgt gca gga 7843 lie Asp Leu Gly 2570 Cys Gly Arg Gly Gly Trp 2575 Ser Tyr Tyr Cys 2580 Ala Gly ctg aaa aaa gtt aca gaa gtg ega gga tac aca aaa ggc ggc cca gga 7891 Leu Lys Lys Val 2585 Thr Glu Val Arg Gly Tyr 2590 Thr Lys Gly Gly 2595 Pro Gly cac gaa gaa cca gta cct atg tet aca tac gga tgg aac ata gtc aag 7939 His Glu 2600 Glu Pro Val Pro Met Ser Thr Tyr 2605 Gly Trp Asn He 2610 Val Lys 2615 tta atg agt gga aag gat gtt ttt tat ctg cca cct gaa aag tgt gat 7987 Leu Met Ser Gly Lys Asp 2620 Val Phe Tyr Leu Pro 2625 Pro Glu Lys Cys Asp 2630 acc eta ttg tgt gac att gga gaa tet tea cca age cca aca gtg gaa 8035 Thr Leu Leu Cys Asp 2635 He Gly Glu Ser Ser 2640 Pro Ser Pro Thr Val 2645 Glu gaa age aga acc ata aga gtt ttg aag atg gtt gaa cca tgg eta aag 8083 Glu Ser Arg Thr 2650 He Arg Val Leu Lys Met 2655 Val Glu Pro Trp 2660 Leu Lys aac aac cag ttt tgc att aaa gta ttg aac cca tac atg cca act gtg 8131 Asn Asn Gin Phe 2665 Cys He Lys Val Leu Asn 2670 Pro Tyr Met Pro 2675 Thr Val att gag cac tta gaa aga eta caa agg aaa cat gga gga atg ett gtg 8179 He Glu 2680 His Leu Glu Arg Leu Gin Arg Lys 2685 His Gly Gly Met 2690 Leu Val 2695 aga aat cca etc tea ega aac tcc aeg cac gaa atg tat tgg ata tcc 8227 Arg Asn Pro Leu Ser Arg Asn Ser Thr His Glu 2700 2705 Met Tyr Trp He Ser 2710

    257

    2018200081 04 Jan 2018

    aat Asn ggt Gly aca Thr ggc aat Gly Asn 2715 ate He gtc Val tct Ser tea gtc Ser Val 2720 aac Asn atg Met gta Val tcc aga Ser Arg 2725 ttg Leu 8275 eta ctg aac aga ttc aca atg aca cac agg aga ccc acc ata gag aaa 8323 Leu Leu Asn Arg Phe 2730 Thr Met Thr His Arg 2735 Arg Pro Thr 274C He Glu 1 Lys gat gtg gat eta gga gca gga acc ega cat gtc aat gcg gaa cca gaa 8371 Asp Val 2745 Asp Leu Gly Ala Gly 275C Thr 1 Arg His Val Asn 2755 Ala Glu Pro Glu aca ccc aac atg gat gtc att ggg gaa aga ata aaa agg ate aaa gag 8419 Thr 276C Pro 1 Asn Met Asp Val He 2765 Gly Glu Arg He Lys 2770 Arg He Lys Glu 2775 gag cat agt tea aca tgg cac tat gat gat gaa aat cct tac aaa aeg 8467 Glu His Ser Ser Thr Trp 2780 His Tyr Asp Asp Glu 2785 Asn Pro Tyr Lys Thr 2790 tgg get tac cat gga tcc tat gaa gta aaa gcc aca ggc tea gcc tcc 8515 Trp Ala Tyr His Gly 2795 Ser Tyr Glu Val Lys 2800 Ala Thr Gly Ser Ala 2805 Ser tcc atg ata aat gga gtc gtg aaa etc etc aca aaa cca tgg gat gtg 8563 Ser Met lie Asn Gly 2810 Val Val Lys Leu Leu 2815 Thr Lys Pro Trp Asp 2820 Val gtg ccc atg gtg aca cag atg gca atg aca gat aca act cca ttc ggc 8611 Val Pro Met 2825 Val Thr Gin Met Ala 2830 Met Thr Asp Thr Thr 2835 Pro Phe Gly cag caa aga gtt ttt aaa gag aaa gtg gac acc agg aca cct agg ccc 8659 Gin 284C Gin I Arg Val Phe Lys Glu 2845 Lys Val Asp Thr Arg 2850 Thr Pro Arg Pro 2855 atg cca gga aca aga aag gtt atg gag ate aca gcg gag tgg ett tgg 8707 Met Pro Gly Thr Arg Lys 2860 Val Met Glu He Thr 2865 Ala Glu Trp Leu Trp 2870 agg acc ctg gga agg aac aaa aga ccc aga tta tgc aca agg gag gaa 8755 Arg Thr Leu Gly Arg 2875 Asn Lys Arg Pro Arg 2880 Leu Cys Thr Arg Glu 2885 Glu ttc aca aag aag gtc aga acc aac gca get atg ggc get gtc ttc aca 8803 Phe Thr Lys Lys Val 2890 Arg Thr Asn Ala Ala 2895 Met Gly Ala Val Phe 2900 . Thr gaa gag aac caa tgg gac agt gcg aga get get gtt gag gac gaa gaa 8851 Glu Glu Asn 2905 Gin Trp Asp Ser Ala Arg Ala 2910 Ala Val Glu 2915 Asp Glu Glu

    258

    2018200081 04 Jan 2018

    ttt tgg aaa ett Leu gtg gac aga gaa Val Asp Arg Glu 2925 cgt Arg gaa Glu etc cac Leu His 2930 aaa Lys ctg Leu ggc Gly aag Lys 2935 8899 Phe Trp 2920 Lys tgt gga age tgc gtt tac aac atg atg ggc aag aga gag aaa aaa ett 8947 Cys Gly Ser Cys Val Tyr Asn Met 2940 Met Gly 2945 Lys Arg Glu Lys Lys 295C Leu 1 gga gag ttt ggt aaa gca aaa ggc agt agg get ata tgg tac atg tgg 8995 Gly Glu Phe Gly 2955 Lys Ala Lys Gly Ser Arg 2960 Ala lie Trp Tyr 2965 Met Trp ttg gga gcc agg tac ett gag ttc gag gcg etc gga ttc etc aat gaa 9043 Leu Gly Ala Arg 2970 Tyr Leu Glu Phe Glu 2975 Ala Leu Gly Phe Leu 2980 Asn Glu gac cac tgg ttc teg cgt gaa aac tct tac agt gga gta gaa gga gaa 9091 Asp His 298E Trp Phe Ser Arg Glu Asn 2990 Ser Tyr Ser Gly Val 2995 Glu Gly Glu gga ctg cac aag ctg gga tac ate ttg aga gat att tcc aag ata ccc 9139 Gly Leu 3000 His Lys Leu Gly Tyr He 3005 Leu Arg Asp He 3010 Ser Lys He Pro 3015 gga gga gcc atg tat get gat gac aca gcc ggt tgg gac aca aga ata 9187 Gly Gly Ala Met Tyr Ala Asp Asp 3020 Thr Ala Gly Trp 3025 Asp Thr Arg 303C He 1 aca gaa gat gac ctg cac aat gag gaa aaa ate aca cag cag atg gac 9235 Thr Glu Asp Asp Leu His Asn Glu 3035 Glu Lys 3040 He Thr Gin Gin Met 3045 Asp cct gaa cac agg cag eta gcg aac get ata ttc aag etc aca tac caa 9283 Pro Glu His Arg 3050 Gin Leu Ala Asn Ala 3055 He Phe Lys Leu Thr 3060 Tyr Gin aac aaa gtg gtc aaa gtc caa cga cca act cca aag ggc aeg gta atg · 9331 Asn Lys Val 3065 Val Lys Val Gin Arg 3070 Pro Thr Pro Lys Gly 3075 Thr Val Met gac ate ata tct agg aaa gac caa aga ggc agt gga cag gtg gga act 9379 Asp lie 3080 He Ser Arg Lys Asp Gin 3085 Arg Gly Ser Gly 3090 Gin Val Gly Thr 3095 tat ggt ctg aac aca ttc acc aac atg gaa gcc cag eta ate aga caa 9427 Tyr Gly Leu Asn Thr Phe Thr Asn 3100 Met Glu Ala Gin 3105 Leu He Arg Gin 3110 atg gaa gga gaa ggc gtg ttg tea aag gca gac etc gag aac CCC cat 9475 Met Glu Gly Glu Gly Val Leu Ser 3115 Lys Ala 3120 Asp Leu Glu Asn Pro 3125 His ccg eta gag aag aaa att aca caa tgg ttg gaa act aaa gga gtg gaa 9523 Pro Leu Glu Lys Lys He Thr Gin Trp Leu Glu Thr Lys Gly Val Glu

    3130 3135 3140

    259

    2018200081 04 Jan 2018

    agg tta aaa Arg Leu Lys aga atg gcc Arg Met Ala ate agc lie Ser 3150 ggg Gly gat Asp gat Asp tgc gtt Cys Val 3155 gtg Val aaa Lys cca Pro 9571 3145 ate gac gac aga ttc gcc aat gcc ctg ett gcc ctg aac gat atg gga 9619 lie 316C Asp Asp 1 Arg Phe Ala 3165 Asn Ala Leu Leu Ala 317C Leu Asn 1 Asp Met Gly 3175 aag gtt aga aag gac ata cct caa tgg cag cca tea aag gga tgg cat 9667 Lys Val Arg Lys Asp He 3180 ProGin Trp Gin Pro 3185 Ser Lys Gly Trp 319C His 1 gat tgg caa cag gtc ccc ttc tgc tcc cac cac ttt cat gaa ttg ate 9715 Asp Trp Gin Gin Val Pro 3195 Phe Cys Ser His 3200 His Phe His Glu Leu 3205 He atg aaa gat gga aga aag ttg gta gtt ccc tgc aga ccc cag gac gaa 9763 Met Lys Asp Gly Arg Lys 3210 Leu Val Val 3215 Pro Cys Arg Pro Gin 3220 Asp Glu eta ata gga aga geg aga ate tcc caa gga gca gga tgg age ett aga 9811 Leu He Gly 3225 Arg Ala Arg He Ser 3230 Gin Gly Ala Gly Trp 3235 Ser Leu Arg gaa act gca tgt eta ggg aaa gcc tac get caa atg tgg get etc atg 9859 Glu Thr Ala 3240 Cys Leu Gly 3245 Lys Ala Tyr Ala Gin 325C Met Trp 1 Ala Leu Met 3255 tat ttt cac aga aga gat ett aga eta gca tcc aac gcc ata tgt tea 9907 Tyr Phe His Arg Arg Asp 3260 Leu Arg Leu Ala Ser 3265 Asn Ala He Cys Ser 3270 gca gta cca gtc cac tgg gtc ccc aeg agc aga aeg aca tgg tet att 9955 Ala Val Pro Val His Trp 3275 Val Pro Thr Ser 3280 Arg Thr Thr Trp Ser 3285 He cat get cac cat cag tgg atg act aca gaa gac atg ett act gtc tgg 10003 His Ala His His Gin Trp 3290 Met Thr Thr 3295 Glu Asp Met Leu Thr 3300 Val Trp aac agg gtg tgg ata gag gac aat cca tgg atg gaa gac aaa act cca 10051 Asn Arg Val 3305 Trp He Glu Asp Asn 3310 Pro Trp Met Glu Asp 3315 Lys Thr Pro gtc aca aeg tgg gaa gat gtt cca tat eta ggg aag aga gaa gac caa 10099 Val Thr Thr 3320 Trp Glu Asp Val Pro 3325 Tyr Leu Gly Lys Arg 3330 Glu Asp Gin 3335 tgg tgc gga tea etc ata ggt etc act tcc aga gca acc tgg gcc cag 10147 Trp Cys Gly Ser Leu He 3340 Gly Leu Thr Ser Arg 3345 Ala Thr Trp Ala Gin 3350

    260

    2018200081 04 Jan 2018

    aac Asn ata etc aca gca ate caa Gin cag gtg aga age Gin Val Arg Ser 3360 etc ata ggc aat Asn gaa Glu 10195 lie Leu Thr Ala 3355 He Leu He Gly 3365 gag ttt ctg gac tac atg cct teg atg aag aga ttc agg aag gag gag 10243 Glu Phe Leu Asp Tyr Met Pro Ser Met Lys Arg Phe Arg Lys Glu Glu 3370 3375 3380 gag tea gag gga gcc att tgg taa aagcaggagg taaactgtca ggccacatta 10297 Glu Ser Glu Gly Ala He Trp *

    3385 3390 agccacagta cggaagaagc tgtgcagcct gtgagccccg tccaaggacg ttaaaagaag 10357 aagtcaggcc caaaagccac ggtttgagca aaccgtgctg cctgtagctc cgtcgtgggg 10417 acgtaaagcc tgggaggctg caaaccgtgg aagctgtacg cacggtgtag cagactagtg 10477 gttagaggag acccctccca tgacacaacg cagcagcggg gcccgagcac tgagggaagc 10537 tgtacctcct tgcaaaggac tagaggttag aggagacccc ccgcaaacaa aaacagcata 10597 ttgacgctgg gagagaccag agatcctgct gtctcctcag catcattcca ggcacagaac 10657 gccagaaaat ggaatggtgc tgttgaatca acaggttcta gt 10699 <210> 22 <211> 3390 <212> PRT <213> Artificial Sequence <22 0 >

    <223> Description of Artificial Sequence :/Note = synthetic construct

    <400> 22 Met Asn Asn Gin Arg Lys Lys Thr Gly Lys Pro Ser He Asn Met Leu 1 5 10 15 Lys Arg Val Arg Asn Arg Val Ser Thr Gly Ser Gin Leu Ala Lys Arg 20 25 30 Phe Ser Arg Gly Leu Leu Asn Gly Gin Gly Pro Met Lys Leu Val Met 35 40 45 Ala Phe He Ala Phe Leu Arg Phe Leu Ala He Pro Pro Thr Ala Gly 50 55 60 Val Leu Ala Arg Trp Gly Thr Phe Lys Lys Ser Gly Ala He Lys Val 65 70 75 80 Leu Lys Gly Phe Lys Lys Glu He Ser Asn Met Leu Ser He He Asn 85 90 95 Lys Arg Lys Lys Thr Ser Leu Cys Leu Met Met Met Leu Pro Ala Thr 100 105 110 Leu Ala Phe His Leu Thr Ser Arg Asp Gly Glu Pro Arg Met He Val 115 120 125 Gly Lys Asn Glu Arg Gly Lys Ser Leu Leu Phe Lys Thr Ala Ser Gly 13 0 135 140 He Asn Met Cys Thr Leu He Ala Met Asp Leu Gly Glu Met Cys Asp 145 150 155 160 Asp Thr Val Thr Tyr Lys Cys Pro His lie Thr Glu Val Glu Pro Glu 165 170 175 Asp He Asp Cys Trp Cys Asn Leu Thr Ser Thr Trp Val Thr Tyr Gly 180 185 190

    2018200081 04 Jan 2018

    Thr Cys Leu Ala 210 Met 225 Ser Ala Leu Tyr He Met Leu Arg Asp 290 Leu 305 Glu Leu Asp Arg Lys Arg Cys Asn Tyr 370 Cys 385 Gly Cys Leu Tyr Thr Asn Glu Ala Glu 450 Pro 465 Arg Asn Lys Pro Trp Glu Leu Val Val 530 Ala 545 Thr Leu Lys Tyr Ala Thr Gin Ala Pro 610

    Asn Gin 195 Pro His Ala Glu Arg His Gly Thr Val 260 Thr 275 Phe Val His Gly He Glu Leu Cys Pro 340 Thr 355 Val Cys Leu Phe Glu Ser Val lie Thr 420 Gin 435 Ala lie Thr Gly Ala Trp Thr Ser Leu 500 Val 515 Leu Gly Glu lie Cys Arg Met Cys His 580 Gly 595 Cys Lys

    Ala

    Val

    Gly

    Pro

    245

    Ser

    Pro

    Glu

    Gly

    Leu

    325

    He

    Gin

    Lys

    Gly

    He

    405

    He

    Gly

    Leu

    Leu

    Met

    485

    Gly

    Thr

    Ser

    Gin

    Leu

    565

    Leu

    Thr

    He

    Gly Glu Gly Met 215 Ala 230 Trp Gly Phe Leu Thr Ser Met Gly Leu 295 Cys 310 Val Gin Lys Glu Gly Gly Glu His Thr 375 Lys 390 Gly Glu Gly Thr Val Val Thr Pro Glu 455 Asp 470 Phe Val His Ala Thr Phe Lys Gin Glu 535 Thr 550 Ser Lys Met Gly Ser He Leu Pro Phe 615

    His Arg 200

    Gly Leu

    Arg Gin

    Thr lie

    Gin Lys 265

    Thr Met 280

    Ser Gly

    Thr Thr

    Thr Glu

    Lys He 345

    Ala He 360

    Tyr Val

    Ser Leu

    Lys Val

    His Thr 425

    Ala Glu 440

    Tyr Gly

    Asn Glu

    Arg Gin

    Ala Glu 505

    Asn Ala 520

    Gly Ala

    Gly Gly

    Asp Lys

    Phe Val 585

    He Lys 600

    Ser Thr

    261

    Arg Asp

    Asp Thr

    Val Glu 235

    Leu Ala 250

    Val Val

    Arg Cys

    Ala Thr

    Met Ala 315

    Ala Thr 330

    Thr Asn

    Leu Pro

    Asp Arg

    Val Thr 395

    Val Gin 410

    Gly Asp

    He Thr

    Thr Leu

    Met He 475

    Trp Phe 490

    Thr Pro

    His Ala

    Met His

    Thr Ser 555

    Leu Glu 570

    Leu Lys

    Val Glu

    Glu Asp

    Lys Arg 205 Arg 220 Thr Lys Val Leu Phe He Phe Val Gly 285 Trp 300 Val Lys Asn Gin Leu He Thr Glu Glu 365 Gly 380 Trp Cys Ala His Glu Gin His Pro Gin 445 Gly 460 Leu Leu Leu Phe Asp Thr Trp Lys Lys 525 Thr 540 Ala He Phe Leu Lys Lys Glu Tyr Lys 605 Gly 620 Gin

    Ser

    Gin

    Glu

    Leu

    He

    270

    Val

    Asp

    Lys

    Ala

    Thr

    350

    Gin

    Gly

    Lys

    Asn

    Gin

    430

    Ala

    Glu

    Thr

    Leu

    Asn

    510

    Gin

    Leu

    Ala

    Gly

    Val

    590

    Gly

    Gly

    Val Ala Thr Trp Thr Trp Ala 240 His 255 Leu Leu Gly Asn Val Val Pro Thr Thr 320 Leu 335 Asp Ser Asp Gin Asn Gly Phe Gin Leu 400 Lys 415 Val Gly Ser Thr Cys Ser Met Lys Pro 480 Leu 495 Arg Lys Glu Val Thr Gly Gly His Met 560 Ser 575 Ser Glu Lys Asp Lys Ala

    262

    2018200081 04 Jan 2018

    His Asn Gly Arg Leu He Thr Ala Asn Pro Val Val Thr Lys Lys Glu 625 630 635 640 Glu Pro Val Asn He Glu Ala Glu Pro Pro Phe Gly Glu Ser Asn He 645 650 655 Val lie Gly lie Gly Asp Lys Ala Leu Lys He Asn Trp Tyr Lys Lys 660 665 670 Gly Ser Ser He Gly Lys Met Phe Glu Ala Thr Ala Arg Gly Ala Arg 675 680 685 Arg Met Ala He Leu Gly Asp Thr Ala Trp Asp Phe Gly Ser Val Gly 690 695 700 Gly Val Leu Asn Ser Leu Gly Lys Met Val His Gin He Phe Gly Ser 705 710 715 720 Ala Tyr Thr Ala Leu Phe Gly Gly Val Ser Trp Met Met Lys He Gly 725 730 735 He Gly Val Leu Leu Thr Trp He Gly Leu Asn Ser Lys Asn Thr Ser 740 745 750 Met Ser Phe Ser Cys He Ala He Gly He He Thr Leu Tyr Leu Gly 755 760 765 Ala Val Val Gin Ala Asp Met Gly Cys Val He Asn Trp Lys Gly Lys 770 775 780 Glu Leu Lys Cys Gly Ser Gly He Phe Val Thr Asn Glu Val His Thr 785 790 795 800 Trp Thr Glu Gin Tyr Lys Phe Gin Ala Asp Ser Pro Lys Arg Leu Ala 805 810 815 Thr Ala Tie Ala Gly Ala Trp Glu Asn Gly Val Cys Gly He Arg Ser 820 825 830 Thr Thr Arg Met Glu Asn Leu Leu Trp Lys Gin He Ala Asn Glu Leu 835 840 845 Asn Tyr He Leu Trp Glu Asn Asn He Lys Leu Thr Val Val Val Gly 850 855 860 Asp He Thr Gly Val Leu Glu Gin Gly Lys Arg Thr Leu Thr Pro Gin 865 870 875 880 Pro Met Glu Leu Lys Tyr Ser Trp Lys Thr Trp Gly Lys Ala Lys He 885 890 895 Val Thr Ala Glu Thr Gin Asn Ser Ser Phe He He Asp Gly Pro Ser 900 905 910 Thr Pro Glu Cys Pro Ser Ala Ser Arg Ala Trp Asn Val Trp Glu Val 915 920 925 Glu Asp Tyr Gly Phe Gly Val Phe Thr Thr Asn He Trp Leu Lys Leu 930 935 940 Arg Glu Val Tyr Thr Gin Leu Cys Asp His Arg Leu Met Ser Ala Ala 945 950 955 960 Val Lys Asp Glu Arg Ala Val His Ala Asp Met Gly Tyr Trp He Glu 965 970 975 Ser Gin Lys Asn Gly Ser Trp Lys Leu Glu Lys Ala Ser Phe lie Glu 980 985 990 Val Lys Thr Cys Thr Trp Pro Lys Ser His Thr Leu Trp Ser Asn Gly 995 1000 1005 Val Leu Glu Ser Asp Met He He Pro Lys Ser Leu Ala Gly Pro He 1010 1015 1020 Ser Gin His Asn His Arg Pro Gly Tyr His Thr Gin Thr Ala Gly Pro 1025 1030 1035 1040 Trp His Leu Gly Lys Leu Glu Leu Asp Phe Asn Tyr Cys Glu Gly Thr 1045 1050 1055

    263

    2018200081 04 Jan 2018

    Thr Val Val He Ser 1060 Glu Asn Cys Gly Thr Arg Gly Pro 1065 Ser Leu Arg 1070 Thr Thr Thr Val Ser Gly Lys Leu He His Glu Trp Cys Cys Arg Ser 1075 108C 1 1085 Cys Thr Leu Pro Pro Leu Arg Tyr Met Gly Glu Asp Gly Cys Trp Tyr 1090 1095 1100 Gly Met Glu He Arg Pro He Asn Glu Lys Glu Glu Asn Met Val Lys 1105 1110 1115 1120 Ser Leu Ala Ser Ala Gly Ser Gly Lys Val Asp Asn Phe Thr Met Gly 1125 1130 1135 Val Leu Cys Leu Ala He Leu Phe Glu Glu Val Met Arg Gly Lys Phe 1140 1145 1150 Gly Lys Lys His Met He Ala Gly Val Leu Phe Thr Phe Val Leu Leu 1155 116C I 1165 Leu Ser Gly Gin He Thr Trp Arg Asp Met Ala His Thr Leu He Met 1170 1175 1180 He Gly Ser Asn Ala Ser Asp Arg Met Gly Met Gly Val Thr Tyr Leu 1185 1190 1195 1200 Ala Leu He Ala Thr Phe Lys He Gin Pro Leu Leu Ala Leu Gly Phe 1205 1210 1215 Phe Leu Arg Lys Leu Thr Ser Arg Glu Asn Leu Leu Leu Gly Val Gly 1220 1225 1230 Leu Ala Met Ala Ala Thr Leu Arg Leu Pro Glu Asp He Glu Gin Met 1235 1240 1245 Ala Asn Gly He Ala Leu Gly Leu Met Ala Leu Lys Leu He Thr Gin 1250 1255 1260 Phe Glu Thr Tyr Gin Leu Trp Thr Ala Leu Val Ser Leu Thr Cys Ser 1265 1270 1275 1280 Asn Thr He Phe Thr Leu Thr Val Ala Trp Arg Thr Ala Thr Leu He 1285 1290 1295 Leu Ala Gly He Ser Leu Leu Pro Val Cys Gin Ser Ser Ser Met Arg 1300 1305 1310 Lys Thr Asp Trp' Leu Pro Met Thr Val Ala Ala Met Gly Ala Gin Pro 1315 1320 1325 Leu Pro Leu Phe He Phe Ser Leu Lys Asp Thr Leu Lys Arg Arg Ser 1330 1335 1340 Trp Pro Leu Asn Glu Gly Val Met Ala Val Gly Leu Val Ser He Leu 1345 1350 1355 1360 Ala Ser Ser Leu Leu Arg Asn Asp Val Pro Met Ala Gly Pro Leu Val 1365 1370 1375 Ala Gly Gly Leu Leu He Ala Cys Tyr Val He Thr Gly Thr Ser Ala 1380 1385 1390 Asp Leu Thr Val Glu Lys Ala Ala Asp Val Thr Trp Glu Glu Glu Ala 1395 1400 1405 Glu Gin Thr Gly Val Ser His Asn Leu Met Val Thr Val Asp Asp Asp 1410 1415 1420 Gly Thr Met Arg He Lys Asp Asp Glu Thr Glu Asn He Leu Thr Val 1425 1430 1435 1440 Leu Leu Lys Thr Ala Leu Leu He Val Ser Gly He Phe Pro Tyr Ser 1445 1450 1455 He Pro Ala Thr Leu Leu Val Trp His Thr Trp Gin Lys Gin Thr Gin 1460 1465 1470 Arg Ser Gly Val Leu Trp Asp Val Pro Ser Pro Pro Glu Thr Gin Lys 1475 1480 1485

    264

    2018200081 04 Jan 2018

    Ala Glu Leu Glu Glu Gly Val Tyr Arg 1495 He Lys Gin Gin Gly 1500 He Phe 1490 Gly Lys Thr Gin Val Gly Val Gly Val Gin Lys Glu Gly Val Phe His 1505 1510 1515 1520 Thr Met Trp His Val Thr Arg Gly Ala Val Leu Thr His Asn Gly Lys 1525 1530 1535 Arg Leu Glu Pro Asn Trp Ala Ser Val Lys Lys Asp Leu He Ser Tyr 154C i 1545 • 1550 Gly Gly Gly Trp Arg Leu Ser Ala Gin Trp Lys Lys Gly Glu Glu Val 1555 1560 1565 Gin Val He Ala Val Glu Pro Gly Lys Asn Pro Lys Asn Phe Gin Thr 1570 1575 1580 Met Pro Gly He Phe Gin Thr Thr Thr Gly Glu He Gly Ala He Ala 1585 1590 1595 1600 Leu Asp Phe Lys Pro Gly Thr Ser Gly Ser Pro He He Asn Arg Glu 1605 1610 1615 Gly Lys Val Val Gly Leu Tyr Gly Asn Gly Val Val Thr Lys Asn Gly 162C 1 1625 i 1630 Gly Tyr Val Ser Gly He Ala Gin Thr Asn Ala Glu Pro Asp Gly Pro 1635 1640 1645 Thr Pro Glu Leu Glu Glu Glu Met Phe Lys Lys Arg Asn Leu Thr He 1650 1655 1660 Met Asp Leu His Pro Gly Ser Gly Lys Thr Arg Lys Tyr Leu Pro Ala 1665 1670 1675 1680 lie Val Arg Glu Ala He Lys Arg Arg Leu Arg Thr Leu He Leu Ala 1685 1690 1695 Pro Thr Arg Val Val Ala Ala Glu Met Glu Glu Ala Leu Lys Gly Leu 1700 1705 1710 Pro He Arg Tyr Gin Thr Thr Ala Thr Lys Ser Glu His Thr Gly Arg 1715 1720 1725 Glu He Val Asp Leu Met Cys His Ala Thr Phe Thr Met Arg Leu Leu 1730 1735 1740 Ser Pro Val Arg Val Pro Asn Tyr Asn Leu lie He Met Asp Glu Ala 1745 1750 1755 1760 His Phe Thr Asp Pro Ala Ser He Ala Ala Arg Gly Tyr He Ser Thr 1765 1770 1775 Arg Val Gly Met Gly Glu Ala Ala Ala He Phe Met Thr Ala Thr Pro 1780 1785 1790 Pro Gly Thr Ala Asp Ala Phe Pro Gin Ser Asn Ala Pro He Gin Asp 1795 1800 1805 Glu Glu Arg Asp lie Pro Glu Arg Ser Trp Asn Ser Gly Asn Glu Trp 1810 1815 1820 He Thr Asp Phe Val Gly Lys Thr Val Trp Phe Val Pro Ser He Lys 1825 1830 1835 1840 Ala Gly Asn Asp He Ala Asn Cys Leu Arg Lys Asn Gly Lys Lys Val 1845 1850 1855 He Gin Leu Ser Arg Lys Thr Phe Asp Thr Glu Tyr Gin Lys Thr Lys 1860 1865 1870 Leu Asn Asp Trp Asp Phe Val Val Thr Thr Asp He Ser Glu Met Gly 1875 1880 1885 Ala Asn Phe Lys Ala Asp Arg Val He Asp Pro Arg Arg Cys Leu Lys 1890 1895 1900 Pro Val lie Leu Thr Asp Gly Pro Glu Arg Val He Leu Ala Gly Pro 1905 1910 1915 1920

    265

    2018200081 04 Jan 2018

    Met Pro Val Thr Val Ala Ser Ala Ala Gin Arg Arg Gly Arg Val Gly 1925 1930 1935 Arg Asn Pro Gin Lys Glu Asn Asp Gin Tyr He Phe Met Gly Gin Pro 1940 1945 1950 Leu Asn Asn Asp Glu Asp His Ala His Trp Thr Glu Ala Lys Met Leu 1955 1960 1965 Leu Asp Asn He Asn Thr Pro Glu Gly lie He Pro Ala Leu Phe Glu 1970 1975 1980 Pro Glu Arg Glu Lys Ser Ala Ala He Asp Gly Glu Tyr Arg Leu Lys 1985 1990 1995 2000 Gly Glu Ser Arg Lys Thr Phe Val Glu Leu Met Arg Arg Gly Asp Leu 2005 2010 2015 Pro Val Trp Leu Ala His Lys Val Ala Ser Glu Gly He Lys Tyr Thr 2020 2025 2030 Asp Arg Lys Trp Cys Phe Asp Gly Glu Arg Asn Asn Gin lie Leu Glu 2035 2040 2045 Glu Asn Met Asp Val Glu He Trp Thr Lys Glu Gly Glu Lys Lys Lys 2050 2055 2060 Leu Arg Pro Arg Trp Leu Asp Ala Arg Thr Tyr Ser Asp Pro Leu Ala 2065 2070 2075 2080 Leu Lys Glu Phe Lys Asp Phe Ala Ala Gly Arg Lys Ser He Ala Leu 2085 2090 2095 Asp Leu Val Thr Glu He Gly Arg Val Pro Ser His Leu Ala His Arg 2100 2105 2110 Thr Arg Asn Ala Leu Asp Asn Leu Val Met Leu His Thr Ser Glu His 2115 2120 2125 Gly Gly Arg Ala Tyr Arg His Ala Val Glu Glu Leu Pro Glu Thr Met 2130 2135 2140 Glu Thr Leu Leu Leu Leu Gly Leu Met He Leu Leu Thr Gly Gly Ala 2145 2150 2155 2160 Met Leu Phe Leu He Ser Gly Lys Gly He Gly Lys Thr Ser He Gly 2165 2170 2175 Leu lie Cys Val lie Ala Ser Ser Gly Met Leu Trp Met Ala Asp Val 2180 2185 2190 Pro Leu Gin Trp He Ala Ser Ala He Val Leu Glu Phe Phe Met Met 2195 2200 2205 Val Leu Leu He Pro Glu Pro Glu Lys Gin Arg Thr Pro Gin Asp Asn 2210 2215 2220 Gin Leu Ala Tyr Val Val He Gly He Leu Thr Leu Ala Ala He Val 2225 2230 2235 2240 Ala Ala Asn Glu Met Gly Leu Leu Glu Thr Thr Lys Arg Asp Leu Gly 2245 2250 2255 Met Ser Lys Glu Pro Gly Val Val Ser Pro Thr Ser Tyr Leu Asp Val 2260 2265 2270 Asp Leu His Pro Ala Ser Ala Trp Thr Leu Tyr Ala Val Ala Thr Thr 2275 2280 2285 Val He Thr Pro Met Leu Arg His Thr He Glu Asn Ser Thr Ala Asn 2290 2295 2300 Val Ser Leu Ala Ala lie Ala Asn Gin Ala Val Val Leu Met Gly Leu 2305 2310 2315 2320 Asp Lys Gly Trp Pro lie Ser Lys Met Asp Leu Gly Val Pro Leu Leu 2325 2330 2335 Ala Leu Gly Cys Tyr Ser Gin Val Asn Pro Leu Thr Leu Ala Ala Ala 2340 2345 2350

    266

    2018200081 04 Jan 2018

    Val Leu Leu Leu Val Thr His Tyr Ala 2360 He He Gly Pro Gly 2365 Leu Gin 2355 Ala Lys Ala Thr Arg Glu Ala Gin Lys Arg Thr Ala Ala Gly He Met 2370 2375 2380 Lys Asn Pro Thr Val Asp Gly He Met Thr lie Asp Leu Asp Pro Val 2385 2390 2395 2400 lie Tyr Asp Ser Lys Phe Glu Lys Gin Leu Gly Gin Val Met Leu Leu 2405 2410 2415 Val Leu Cys Ala Val Gin Leu Leu Leu Met Arg Thr Ser Trp Ala Leu 2420 2425 2430 Cys Glu Val Leu Thr Leu Ala Thr Gly Pro He Thr Thr Leu Trp Glu 2435 2440 2445 Gly Ser Pro Gly Lys Phe Trp Asn Thr Thr He Ala Val Ser Met Ala 2450 2455 2460 Asn He Phe Arg Gly Ser Tyr Leu Ala Gly Ala Gly Leu Ala Phe Ser 2465 2470 2475 2480 He Met Lys Ser Val Gly Thr Gly Lys Arg Gly Thr Gly Ser Gin Gly 2485 2490 2495 Glu Thr Leu Gly Glu Lys Trp Lys Lys Lys Leu Asn Gin Leu Ser Arg 2500 2505 2510 Lys Glu Phe Asp Leu Tyr Lys Lys Ser Gly He Thr Glu Val Asp Arg 2515 2520 2525 Thr Glu Ala Lys Glu Gly Leu Lys Arg Gly Glu He Thr His His Ala 2530 2535 2540 Val Ser Arg Gly Ser Ala Lys Leu Gin Trp Phe Val Glu Arg Asn Met 2545 2550 2555 2560 Val He Pro Glu Gly Arg Val lie Asp Leu Gly Cys Gly Arg Gly Gly 2565 2570 2575 Trp Ser Tyr Tyr Cys Ala Gly Leu Lys Lys Val Thr Glu Val Arg Gly 2580 2585 2590 Tyr Thr Lys Gly Gly Pro Gly His Glu Glu Pro Val Pro Met Ser Thr 2595 2600 2605 Tyr Gly Trp Asn He Val Lys Leu Met Ser Gly Lys Asp Val Phe Tyr 2610 2615 2620 Leu Pro Pro Glu Lys Cys Asp. Thr Leu Leu Cys Asp He Gly Glu Ser 2625 2630 ) 2635 2640 Ser Pro Ser Pro Thr Val Glu Glu Ser Arg Thr He Arg Val Leu Lys 2645 2650 2655 Met Val Glu Pro Trp Leu Lys Asn Asn Gin Phe Cys He Lys Val Leu 2660 2665 2670 Asn Pro Tyr Met Pro Thr Val He Glu His Leu Glu Arg Leu Gin Arg 2675 2680 2685 Lys His Gly Gly Met Leu Val Arg Asn Pro Leu Ser Arg Asn Ser Thr 2690 2695 2700 His Glu Met Tyr Trp He Ser Asn Gly Thr Gly Asn He Val Ser Ser 2705 2710 2715 2720 Val Asn Met Val Ser Arg Leu Leu Leu Asn Arg Phe Thr Met Thr His 2725 2730 2735 Arg Arg Pro Thr He Glu Lys Asp Val Asp Leu Gly Ala Gly Thr Arg 2740 2745 2750 His Val Asn Ala Glu Pro Glu Thr Pro Asn Met Asp Val He Gly Glu 2755 2760 2765 Arg He Lys Arg He Lys Glu Glu His Ser Ser Thr Trp His Tyr Asp 2770 2775 2780

    267

    2018200081 04 Jan 2018

    Asp Glu Asn Pro Tyr Lys Thr Trp Ala Tyr His Gly Ser Tyr Glu Val 2785 i 2790 2795 2800 Lys Ala Thr Gly Ser Ala Ser Ser Met He Asn Gly Val Val Lys Leu 2805 2810 2815 Leu Thr Lys Pro Trp Asp Val Val Pro Met Val Thr Gin Met Ala Met 2820 2825 2830 Thr Asp Thr Thr Pro Phe Gly Gin Gin Arg Val Phe Lys Glu Lys Val 2835 2840 2845 Asp Thr Arg Thr Pro Arg Pro Met Pro Gly Thr Arg Lys Val Met Glu 2850 2855 2860 lie Thr Ala Glu Trp Leu Trp Arg Thr Leu Gly Arg Asn Lys Arg Pro 2865 ί 2870 2875 2880 Arg Leu Cys Thr Arg Glu Glu Phe Thr Lys Lys Val Arg Thr Asn Ala 2885 2890 2895 Ala Met Gly Ala Val Phe Thr Glu Glu Asn Gin Trp Asp Ser Ala Arg 2900 2905 2910 Ala Ala Val Glu Asp Glu Glu Phe Trp Lys Leu Val Asp Arg Glu Arg 2915 2920 2925 Glu Leu His Lys Leu Gly Lys Cys Gly Ser Cys Val Tyr Asn Met Met 2930 2935 2940 Gly Lys Arg Glu Lys Lys Leu Gly Glu Phe Gly Lys Ala Lys Gly Ser 2945 i 2950 2955 2960 Arg Ala He Trp Tyr Met Trp Leu Gly Ala Arg Tyr Leu Glu Phe Glu 2965 2970 2975 Ala Leu Gly Phe Leu Asn Glu Asp His Trp Phe Ser Arg Glu Asn Ser 2980 2985 2990 Tyr Ser Gly Val Glu Gly Glu Gly Leu His Lys Leu Gly Tyr He Leu 2995 3000 3005 Arg Asp He Ser Lys He Pro Gly Gly Ala Met Tyr Ala Asp Asp Thr 3010 3015 3020 Ala Gly Trp Asp Thr Arg lie Thr Glu Asp Asp Leu His Asn Glu Glu 3025 i 3030 3035 3040 Lys He Thr Gin Gin Met Asp Pro Glu His Arg Gin Leu Ala Asn Ala 3045 3050 3055 He Phe Lys Leu Thr Tyr Gin Asn Lys Val Val Lys Val Gin Arg Pro 3060 3065 3070 Thr Pro Lys Gly Thr Val Met Asp He He Ser Arg Lys Asp Gin Arg 3075 3080 3085 Gly Ser Gly Gin Val Gly Thr Tyr Gly Leu Asn Thr Phe Thr Asn Met 3090 3095 3100 Glu Ala Gin Leu He Arg Gin Met Glu Gly Glu Gly Val Leu Ser Lys 3105 ί 3110 3115 3120 Ala Asp Leu Glu Asn Pro His Pro Leu Glu Lys Lys lie Thr Gin Trp 3125 3130 3135 Leu Glu Thr Lys Gly Val Glu Arg Leu Lys Arg Met Ala He Ser Gly 3140 3145 3150 Asp Asp Cys Val Val Lys Pro He Asp Asp Arg Phe Ala Asn Ala Leu 3155 3160 3165 Leu Ala Leu Asn Asp Met Gly Lys Val Arg Lys Asp lie Pro Gin Trp 3170 3175 3180 Gin Pro Ser Lys Gly Trp His Asp Trp Gin Gin Val Pro Phe Cys Ser 3185 i 3190 3195 3200 His His Phe His Glu Leu He Met Lys Asp Gly Arg Lys Leu Val Val 3205 3210 3215

    268

    2018200081 04 Jan 2018

    Pro Cys Arg Pro Gin Asp Glu Leu He Gly Arg Ala Arg He Ser Gin Gly Ala Gly 322C Trp 1 Ser Leu Arg Glu 3225 Thr Ala Cys Leu 323C Gly Lys 1 Ala Tyr Ala Gin 3235 Met Trp Ala Leu Met 324C Tyr 1 Phe His Arg Arg 3245 Asp Leu Arg Leu Ala 3250 Ser Asn Ala He Cys 3255 Ser Ala Val Pro Val 3260 His Trp Val Pro Thr 3265 Ser Arg Thr Thr Trp 3270 Ser 1 He His Ala His 3275 His Gin Trp Met Thr 3280 Thr Glu Asp Met Leu 3285 Thr Val Trp Asn Arg 3290 Val Trp He Glu Asp 3295 Asn Pro Trp Met Glu 330C Asp 1 Lys Thr Pro Val 3305 Thr Thr Trp Glu Asp 331C Val 1 Pro Tyr Leu Gly 3315 Lys Arg Glu Asp Gin 332C Trp 1 Cys Gly Ser Leu 3325 He Gly Leu Thr Ser 3330 Arg Ala Thr Trp Ala 3335 Gin Asn He Leu Thr 3340 Ala He Gin Gin Val 3345 Arg Ser Leu lie Gly 335C Asn 1 ' Glu Glu Phe Leu 3355 Asp Tyr Met Pro Ser 3360 Met Lys Arg Phe Arg 3365 Lys Glu Glu Glu Ser 3370 Glu Gly Ala lie Trp 3375

    3380 3385 3390 <210> 23 <211> 10648 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <221> CDS <222> (102)...(10265) <400> 23 agttgttagt ctgtgtggac cgacaaggac agttccaaat cggaagcttg cttaacacag ttctaacagt ttgtttgaat agagagcaga tctctggaaa a atg aac caa ega aaa

    Met Asn Gin Arg Lys 1 5

    116

    aag Lys gtg gtt aga Arg cca Pro 10 cct Pro ttc Phe aat Asn atg Met ctg Leu 15 aaa Lys ege Arg gag Glu aga Arg aac Asn 20 ege Arg Val Val gta tea acc cct caa ggg ttg gtg aag aga ttc tea acc gga ett ttt Val Ser Thr Pro Gin Gly Leu Val Lys Arg Phe Ser Thr Gly Leu Phe 25 30 35 tet ggg aaa gga ccc tta egg atg gtg eta gca ttc ate aeg ttt ttg Ser Gly Lys Gly Pro Leu Arg Met Val Leu Ala Phe He Thr Phe Leu 40 45 50

    164

    212

    260

    269

    2018200081 04 Jan 2018

    ega Arg gtc Val 55 ett Leu tcc Ser ate He cca Pro cca aca gca ggg att He ctg Leu 65 aaa Lys aga Arg tgg Trp gga Gly 308 Pro 60 Thr Ala Gly cag ttg aag aaa aat aag gcc ate agg ata ctg att gga ttc agg aag 356 Gin Leu Lys Lys Asn Lys Ala lie Arg He Leu He Gly Phe Arg Lys 70 75 80 85 gag ata ggc ege atg ctg aac ate ttg aac ggg aga aaa agg tea acg 404 Glu lie Gly Arg Met Leu Asn He Leu Asn Gly Arg Lys Arg Ser Thr 90 95 100 ata aca ttg ctg tgc ttg att ccc acc gta atg gcg ttt cac ttg tea 452 lie Thr Leu Leu Cys Leu He Pro Thr Val Met Ala Phe His Leu Ser 105 110 115 aca aga gat ggc gaa ccc etc atg ata gtg gca aaa cat gaa agg ggg 500 Thr Arg Asp Gly Glu Pro Leu Met He Val Ala Lys His Glu. Arg Gly 120 125 130 aga cct etc ttg ttt aag aca aca gag ggg ate aac aaa tgc act etc 548 Arg Pro Leu Leu Phe Lys Thr Thr Glu Gly He Asn Lys Cys Thr Leu 135 140 145 att gcc atg gac ttg ggt gaa atg tgt gag gac act gtc acg tat aaa 596 He Ala Met Asp Leu Gly Glu Met Cys Glu Asp Thr Val Thr Tyr Lys 150 155 160 165 tgc ccc tta ctg gtc aat acc gaa cct gaa gac att gat tgc tgg tgc 644 Cys Pro Leu Leu Val Asn Thr Glu Pro Glu Asp He Asp Cys Trp Cys 170 175 180 aat etc acg tet acc tgg gtc atg tat ggg aca tgc acc cag age gga 692 Asn Leu Thr Ser Thr Trp Val Met Tyr Gly Thr Cys Thr Gin Ser Gly 185 190 195 gaa egg aga ega gag aag ege tea gta get tta aca cca cat tea gga 740 Glu Arg Arg Arg Glu Lys Arg Ser Val Ala Leu Thr Pro His Ser Gly 200 205 210 atg gga ttg gaa aca aga get gag aca tgg atg tea teg gaa ggg get 788 Met Gly Leu Glu Thr Arg Ala Glu Thr Trp Met Ser Ser Glu Gly Ala 215 220 225 tgg aag cat get cag aga gta gag age tgg ata etc aga aac cca gga 836 Trp Lys His Ala Gin Arg Val Glu Ser Trp He Leu Arg Asn Pro Gly 230 235 240 245 ttc gcg etc ttg gca gga ttt atg get tat atg att ggg caa aca gga 884 Phe Ala Leu Leu Ala Gly Phe Met Ala Tyr Met He Gly Gin Thr Gly 250 255 260 ate cag ega act gtc ttc ttt gtc eta atg atg ctg gtc gcc cca tcc 932 He Gin Arg Thr Val Phe Phe Val Leu Met Met Leu Val Ala Pro Ser

    265 270 275

    2018200081 04 Jan 2018

    270

    tac gga Tyr Gly atg Met 280 ega tgc gta Val gga gta gga aac aga gac ttt Phe 290 gtg gaa gga 980 Arg Cys Gly Val 285 Gly Asn Arg Asp Val Glu Gly gtc tea ggt gga gca tgg gtc gat ctg gtg eta gaa cat gga gga tgc 1028 Val Ser Gly Gly Ala Trp Val Asp Leu Val Leu Glu His Gly Gly Cys 295 300 305 gtc aca acc atg gcc cag gga aaa cca acc ttg gat ttt gaa ctg act 1076 Val Thr Thr Met Ala Gin Gly Lys Pro Thr Leu Asp Phe Glu Leu Thr 310 315 320 325 aag aca aca gcc aag gaa gtg get ctg tta aga acc tat tgc att gaa 1124 Lys Thr Thr Ala Lys Glu Val Ala Leu Leu Arg Thr Tyr Cys He Glu 330 335 340 gcc tea ata tea aac ata acc acg gca aca aga tgt cca acg caa gga 1172 Ala Ser He Ser Asn He Thr Thr Ala Thr Arg Cys Pro Thr Gin Gly 345 350 355 gag cct tat eta aaa gag gaa caa gac caa cag tac att tgc cgg aga 1220 Glu Pro Tyr Leu Lys Glu Glu Gin Asp Gin Gin Tyr He Cys Arg Arg 360 365 370 gat gtg gta gac aga ggg tgg ggc aat ggc tgt ggc ttg ttt gga aaa 1268 Asp Val Val Asp Arg Gly Trp Gly Asn Gly Cys Gly Leu Phe Gly Lys 375 380 385 gga gga gtt gtg aca tgt geg aag ttt tea tgt teg ggg aag ata aca 1316 Gly Gly Val Val Thr Cys Ala Lys Phe Ser Cys Ser Gly Lys He Thr 390 395 400 405 ggc aat ttg gtc caa att gag aac ett gaa tac aca gtg gtt gta aca 1364 Gly Asn Leu Val Gin He Glu Asn Leu Glu Tyr Thr Val Val Val Thr 410 415 420 gtc cac aat gga gac acc cat gca gta gga aat gac aca tcc aat cat 1412 Val His Asn Gly Asp Thr His Ala Val Gly Asn Asp Thr Ser Asn His 425 430 435 gga gtt aca gcc acg ata act ccc agg tea cca teg gtg gaa gtc aaa 1460 Gly Val Thr Ala Thr He Thr Pro Arg Ser Pro Ser Val Glu Val Lys 440 445 450 ttg ccg gac tat gga gaa eta aca etc gat tgt gaa ccc agg tet gga 1508 Leu Pro Asp Tyr Gly Glu Leu Thr Leu Asp Cys Glu Pro Arg Ser Gly 455 460 465 att gac ttt aat gag atg att ctg atg aaa atg aaa aag aaa aca tgg 1556 lie Asp Phe Asn Glu Met He Leu Met Lys Met Lys Lys Lys Thr Trp 470 475 480 485

    271

    2018200081 04 Jan 2018

    ett Leu gtg Val cat His aag Lys caa Gin 490 tgg Trp ttt Phe ttg Leu gat Asp eta Leu 495 cct Pro eta Leu cca Pro tgg Trp aca Thr 500 gca Ala 1604 gga gca gac aca tea gag gtt cac tgg aat tac aaa gag aga atg gtg 1652 Gly Ala Asp Thr 505 Ser Glu Val His Trp 510 Asn Tyr Lys Glu Arg 515 Met Val aca ttt aag gtt cct cat gcc aag aga cag gat gtg aca gtg ctg gga 1700 Thr Phe Lys 520 Val Pro His Ala Lys 525 Arg Gin Asp Val Thr 530 Val Leu Gly tet cag gaa gga gcc atg cat tet gcc etc get gga gcc aca gaa gtg 1748 Ser Gin 535 Glu Gly Ala Met His 540 Ser Ala Leu Ala Gly 545 Ala Thr Glu Val gac tcc ggt gat gga aat cac atg ttt gca gga cat etc aag tgc aaa 1796 Asp 550 Ser Gly Asp Gly Asn 555 His Met Phe Ala Gly 560 His Leu Lys Cys Lys 565 gtc cgt atg gag aaa ttg aga ate aag gga atg tea tac aeg atg tgt 1844 Val Arg Met Glu Lys 570 Leu Arg He Lys Gly 575 Met Ser Tyr Thr Met 580 Cys tea gga aag ttc tea att gac aaa gag atg gca gaa aca cag cat ggg 1892 Ser Gly Lys Phe 585 Ser He Asp Lys Glu 590 Met Ala Glu Thr Gin 595 His Gly aca aca gtg gtg aaa gtc aag tat gaa ggt get gga get ccg tgt aaa 1940 Thr Thr Val 600 Val Lys Val Lys Tyr 605 Glu Gly Ala Gly Ala 610 Pro Cys Lys gtc ccc ata gag ata aga gat gtg aac aag gaa aaa gtg gtt ggg cgt 1988 Val Pro 615 He Glu He Arg Asp 620 Val Asn Lys Glu Lys 625 Val Val Gly Arg ate ate tea tcc acc cct ttg get gag aat acc aac agt gca acc aac 2036 lie 630 He Ser Ser Thr Pro 635 Leu Ala Glu Asn Thr 640 Asn Ser Ala Thr Asn 645 ata gag tta gaa ccc ccc ttt ggg gac age tac ata gtg ata ggt gtt 2084 He Glu Leu Glu Pro 650 Pro Phe Gly Asp Ser 655 Tyr He Val He Gly 660 Val gga aac agt gca tta aca etc cat tgg ttc agg aaa ggg agt tcc att 2132 Gly Asn Ser Ala 665 Leu Thr Leu His Trp 670 Phe Arg Lys Gly Ser 675 Ser He ggc aag atg ttt gag tcc aca tac aga ggt gca aaa ega atg gcc att 2180 Gly Lys Met 680 Phe Glu Ser Thr Tyr 685 Arg Gly Ala Lys Arg 690 Met Ala He eta ggt gaa aca get tgg gat ttt ggt tcc gtt ggt gga ctg ttc aca 2228 Leu Gly 695 Glu Thr Ala Trp Asp 700 Phe Gly Ser Val Gly 705 Gly Leu Phe Thr

    272

    2018200081 04 Jan 2018

    tea Ser 710 ttg gga Leu Gly aag Lys get Ala gtg cac cag Gin gtt Val ttt Phe gga Gly 720 agt Ser gtg Val tat Tyr aca Thr acc Thr 725 2276 Val 715 His atg ttt gga gga gtc tea tgg atg att aga ate eta att ggg ttc eta 2324 Met Phe Gly Gly Val Ser Trp Met lie Arg lie Leu He Gly Phe Leu 730 735 740 gtg ttg tgg att ggc aeg aac tea agg aac act tea atg get atg aeg 2372 Val Leu Trp He Gly Thr Asn Ser Arg Asn Thr Ser Met Ala Met Thr 745 750 755 tgc ata get gtt gga gga ate act ctg ttt ctg ggc ttc aca gtt caa 2420 Cys lie Ala Val Gly Gly He Thr Leu Phe Led Gly Phe Thr Val Gin 760 765 770 gca gac atg ggt tgt gtg gtg tea tgg agt ggg aaa gaa ttg aag tgt 2468 Ala Asp Met Gly Cys Val Val Ser Trp Ser Gly Lys Glu Leu Lys Cys 775 780 785 gga agc gga att ttt gtg gtt gac aac gtg cac act tgg aca gaa cag 2516 Gly Ser Gly He Phe Val Val Asp Asn Val His Thr Trp Thr Glu Gin 790 795 800 805 tac aaa ttt caa ccg gag tcc cca gcg aga eta gcg tet gca ata ttg 2564 Tyr Lys Phe Gin Pro Glu Ser Pro Ala Arg Leu Ala Ser Ala He Leu 810 815 820 aat gcc cac aaa gat ggg gtc tgt gga att aga tea acc aeg agg ctg 2612 Asn Ala His Lys Asp Gly Val Cys Gly He Arg Ser Thr Thr Arg Leu 825 830 835 gaa aat gtc atg tgg aag caa ata acc aac gag eta aat tat gtt etc 2660 Glu Asn Val Met Trp Lys Gin He Thr Asn Glu Leu Asn Tyr Val Leu 840 845 850 tgg gaa gga gga cat gac etc act gta gtg get ggg gat gtg aag ggg 2708 Trp Glu Gly Gly His Asp Leu Thr Val Val Ala Gly Asp Val Lys Gly 855 860 865 gtg ttg acc aaa ggc aag aga gca etc aca ccc cca gtg aat gat ctg 2756 Val Leu Thr Lys Gly Lys Arg Ala Leu Thr Pro Pro Val Asn Asp Leu 870 875 880 885 aaa tat tea tgg aag aca tgg gga aaa gca aaa ate ttc acc cca gaa 2804 Lys Tyr Ser Trp Lys Thr Trp Gly Lys Ala Lys He Phe Thr Pro Glu 890 895 900 gca aga aat agc aca ttt tta ata gac gga cca gac acc tcc gaa tgc 2852 Ala Arg Asn Ser Thr Phe Leu He Asp Gly Pro Asp Thr Ser Glu Cys

    905 910 915

    2018200081 04 Jan 2018

    273 ccc aat gaa ega aga gca tgg aac ttt ctt gag gtg gaa gac tat gga 2900

    Pro Asn. Glu Arg Arg Ala Trp Asn Phe Leu Glu Val Glu Asp Tyr Gly

    920 925 930 ttt ggc atg ttc aeg acc aac ata tgg atg aaa ttc ega gaa gga agt 2948

    Phe Gly Met Phe Thr Thr Asn lie Trp Met Lys Phe Arg Glu Gly Ser

    935 940 945 tea gaa gtg tgt gac cac agg tta atg tea geg gca att aaa gat cag 2996

    Ser Glu Val Cys Asp His Arg Leu Met Ser Ala Ala He Lys Asp Gin

    950 955 960 965 aaa get gtg cat get gac atg ggt tat tgg ata gag age tea aaa aac 3044

    Lys Ala Val His Ala Asp Met Gly Tyr Trp He Glu Ser Ser Lys Asn

    970 975 980 cag acc tgg cag ata gag aaa gca tet ctt att gaa gtg aaa aca tgt 3092

    Gin Thr Trp Gin He Glu Lys Ala Ser Leu He Glu Val Lys Thr Cys

    985 990 995 ctg tgg ccc aag acc cac aca ttg tgg age aat gga gtg ctg gaa age 3140

    Leu Trp Pro Lys Thr His Thr Leu Trp Ser Asn Gly Val Leu Glu Ser

    1000 1005 1010 cag atg etc att cca aaa tea tat geg ggc cct ttt tea cag cac aat 3188

    Gin Met Leu He Pro Lys Ser Tyr Ala Gly Pro Phe Ser Gin His Asn

    1015 . 1020 1025 tac ege cag ggc tat gcc aeg caa acc gtg ggc cca tgg cac tta ggc 3236

    Tyr Arg Gin Gly Tyr Ala Thr Gin Thr Val Gly Pro Trp His Leu Gly

    1030 1035 1040 1045 aaa tta gag ata gac ttt gga gaa tgc ccc gga aca aca gtc gca att 3284

    Lys Leu Glu He Asp Phe Gly Glu Cys Pro Gly Thr Thr Val Ala He

    1050 1055 1060 cag gag gat tgt gac cat aga ggc cca tet ttg agg acc acc act gca 3332

    Gin Glu Asp Cys Asp His Arg Gly Pro Ser Leu Arg Thr Thr Thr Ala

    1065 1070 1075 tet gga aaa eta gtc aeg caa tgg tgc tgc ege tcc tgc aeg atg cct 3380

    Ser Gly Lys Leu Val Thr Gin Trp Cys Cys Arg Ser Cys Thr Met Pro

    1080 1085 1090 ccc tta agg ttc ttg gga gaa gat ggg tgc tgg tat ggg atg gag att 3428

    Pro Leu Arg Phe Leu Gly Glu Asp Gly Cys Trp Tyr Gly Met Glu He

    1095 1100 1105 agg ccc ttg agt gaa aaa gaa gag aac atg gtc aaa tea cag gta aeg 3476

    Arg Pro Leu Ser Glu Lys Glu Glu Asn Met Val Lys Ser.Gin Val Thr

    1110 1115 1120 1125 gcc gga cag ggc aca tea gaa act ttt tet atg ggt ctg ttg tgc ctg 3524

    Ala Gly Gin Gly Thr Ser Glu Thr Phe Ser Met Gly Leu Leu Cys Leu

    1130 113.5 1140

    274

    2018200081 04 Jan 2018

    acc Thr ttg Leu ttt Phe gtg gaa Val Glu 1145 gaa Glu tgc Cys ttg Leu agg aga Arg Arg 1150 aga Arg gtc Val act Thr agg aaa Arg Lys 1155 cac His 3572 atg ata ttg gtt gtg gtg ate act ett tgt gcc ate ate eta gga ggc 3620 Met lie Leu 116C Val Val 1 Val He Thr 1165 Leu Cys Ala He He Leu Gly 1170 Gly etc aca tgg atg gac tta eta ega gcc etc ate atg ttg ggg gac act 3 668 Leu Thr 1175 Trp Met Asp Leu Leu Arg 1180 Ala Leu He Met 1185 Leu Gly Asp Thr atg tct ggt aga ata gga gga cag ate cac eta gcc ate atg gca gtg 3716 Met 119C Ser 1 Gly Arg He Gly 1195 Gly Gin He His Leu Ala 1200 He Met Ala Val 1205 ttc aag atg tea cca gga tac gtg ctg ggt gtg ttt tta agg aaa etc 3764 Phe Lys Met Ser Pro Gly 1210 Tyr Val Leu Gly Val 1215 Phe Leu Arg Lys Leu 1220 act tea aga gag aca gca eta atg gta ata gga atg gcc atg aca aeg 3812 Thr Ser Arg Glu Thr 1225 Ala Leu Met Val He 1230 Gly Met Ala Met Thr 1235 Thr gtg ett tea att cca cat gac ett atg gaa etc att gat gga ata tea 3860 Val Leu Ser He Pro 1240 His Asp Leu Met Glu 1245 Leu He Asp Gly He 1250 Ser ctg ggg eta att ttg eta aaa ata gtg aca cat ttt gac aac acc caa 3908 Leu Gly Leu 1255 He Leu Leu Lys He 1260 Val Thr His Phe Asp 1265 Asn Thr Gin gtg gga acc tta gcc ett tcc ttg acc ttc ata aga tea aca atg cca 3956 Val Gly 1270 Thr Leu Ala Leu Ser 1275 Leu Thr Phe He Arg 1280 Ser Thr Met Pro 1285 ttg gtc atg get tgg agg acc att atg get gtg ttg ttt gtg gtc aca 4004 Leu Val Met Ala Trp Arg 1290 Thr He Met Ala Val 1295 Leu Phe Val Val Thr 1300 etc att cct ttg tgc agg aca agc tgt ett caa aaa cag tct cat tgg 4052 Leu He Pro Leu Cys 1305 Arg Thr Ser Cys Leu 1310 Gin Lys Gin Ser His 1315 Trp gta gaa ata aca gca etc ate eta gga gcc caa get ctg cca gtg tac 4100 Val Glu He Thr Ala 1320 Leu He Leu Gly Ala 1325 Gin Ala Leu Pro Val 1330 Tyr eta atg act ett atg aaa gga gcc tea aga aga tct tgg cct ett aac 4148 Leu Met Thr Leu Met Lys Gly Ala Ser Arg Arg Ser Trp Pro Leu Asn

    1335 1340 1345

    275

    2018200081 04 Jan 2018

    gag ggc Glu Gly 1350 ata atg get gtg ggt Val Gly 1355 ttg gtt agt Ser etc tta gga age get ett Leu 1365 4196 He Met Ala Leu Val Leu Leu 1360 Gly Ser Ala tta aag aat gat gtc cct tta get ggc cca atg gtg gca gga ggc tta 4244 Leu Lys Asn Asp Val 137C Pro Leu 1 Ala Gly Pro 1375 Met Val Ala Gly Gly 1380 Leu 1 ett ctg geg get tac gtg atg agt ggt age tea gca gat ctg tea eta 4292 Leu Leu Ala Ala 1385 Tyr Val Met Ser Gly 139C Ser 1 Ser Ala Asp Leu 1395 Ser Leu gag aag gcc gee aat gtg cag tgg gat gaa atg gca gac ata aca ggc 4340 Glu Lys Ala Ala 1400 Asn Val Gin Trp Asp 1405 Glu Met Ala Asp He 1410 Thr Gly tea age cca ate ata gaa gtg aag cag gat gaa gat ggc tet ttc tcc 4388 Ser Ser Pro . 1415 He He Glu Val Lys 1420 Gin Asp Glu Asp Gly 1425 Ser Phe Ser ata egg gac gtc gag gaa acc aat atg ata acc ett ttg gtg aaa ctg 4436 lie Arg 1430 Asp Val Glu Glu Thr 1435 Asn Met He Thr Leu 1440 Leu Val Lys Leu 1445 gca ctg ata aca gtg tea ggt etc tac ccc ttg gca att cca gtc aca 4484 Ala Leu He Thr Val Ser Gly 1450 Leu Tyr Pro 1455 Leu Ala He Pro Val 146C Thr 1 atg acc tta tgg tac atg tgg caa gtg aaa aca caa aga tea gga gcc 4532 Met Thr Leu Trp 1465 Tyr Met Trp Gin Val 147C Lys I Thr Gin Arg Ser Gly 1475 Ala ctg tgg gac gtc ccc tea ccc get gcc act caa aaa gee gca ctg tet 4580 Leu Trp Asp Val 1480 Pro Ser Pro Ala Ala 1485 Thr Gin Lys Ala Ala 1490 Leu Ser gaa gga gtg tac agg ate atg caa aga ggg tta ttt ggg aaa act cag 4628 Glu Gly Val 1495 Tyr Arg He Met Gin 1500 Arg Gly Leu Phe Gly 1505 Lys Thr Gin gtt gga gta ggg ata cac atg gaa ggt gta ttt cac aca atg tgg cat 4676 Val Gly 1510 Val Gly He His Met 1515 Glu Gly Val Phe His 1520 Thr Met Trp His 1525 gta aca aga gga tea gtg ate tgc cat gag act ggg aga ttg gag cca 4724 Val Thr Arg Gly Ser Val lie 1530 Cys His Glu Thr Gly 1535 Arg Leu Glu 154C Pro ) tet tgg get gac gtc agg aat gac atg ata tea tac ggt ggg gga tgg 4772 Ser Trp Ala Asp Val 1545 Arg Asn Asp Met He 1550 Ser Tyr Gly Gly Gly 1555 Trp aga ett gga gac aaa tgg gac aaa gaa gaa gat gtt cag gtc etc gee 4820 Arg Leu Gly Asp Lys Trp Asp Lys Glu Glu Asp Val Gin Val Leu Ala

    1560 1565 1570

    276

    2018200081 04 Jan 2018

    ata lie gaa cca gga Glu Pro Gly 1575 aaa Lys aat Asn cct aaa Pro Lys 1580 cat His gtc Val caa Gin aeg aaa Thr Lys 1585 ccc Pro ggc Gly ett Leu 4868 ttc aag acc eta act gga gaa att gga gca gta aca tta gat ttc aaa 4916 Phe 159C Lys Thr Leu 1 Thr Gly 1595 Glu He Gly Ala Val 160C Thr Leu 1 Asp Phe Lys 1605 ccc gga aeg tct ggt tct ccc ate ate aac agg aaa gga aaa gtc ate 4964 Pro Gly Thr Ser Gly 161C Ser 1 Pro He He Asn 1615 Arg Lys Gly Lys Val 1620 He 1 gga etc tat gga aat gga gta gtt acc aaa tea ggt gat tac gtc agt 5012 Gly Leu Tyr Gly Asn 1625 Gly Val Val Thr Lys 1630 Ser Gly Asp Tyr Val 1635 Ser gcc ata aeg caa gcc gaa aga att gga gag cca gat tat gaa gtg gat 5060 Ala He Thr Gin 1640 Ala Glu Arg He Gly 1645 Glu Pro Asp Tyr Glu 1650 Val Asp gag gac att ttt ega aag aaa aga tta act ata atg gac tta cac ccc 5108 Glu Asp He Phe 1655 Arg Lys Lys Arg 1660 Leu Thr He Met Asp 1665 Leu His Pro gga get gga aag aca aaa aga att ett cca tea ata gtg aga gaa gee 5156 Gly Ala Gly Lys 1670 Thr Lys Arg He 1675 Leu Pro Ser He Val 1680 Arg Glu Ala 1685 tta aaa agg agg ctg ega acc ttg att ttg get ccc aeg aga gtg gtg 5204 Leu Lys Arg Arg Leu Arg 1690 Thr Leu He Leu Ala 1695 Pro Thr Arg Val 170C Val 1 gcg gcc gag atg gaa gag gcc eta cgt gga ctg cca ate cgt tat cag 5252 Ala Ala Glu Met Glu 1705 Glu Ala Leu Arg Gly 1710 Leu Pro He Arg Tyr 1715 Gin acc cca get gtg aaa tea gaa cac aca gga aga gag att gta gac etc 5300 Thr Pro Ala Val 1720 Lys Ser Glu His Thr 1725 Gly Arg Glu He Val 1730 Asp Leu atg tgt cat gca acc ttc aca aca aga ett ttg tea tea acc aga gtt 5348 Met Cys His Ala 1735 Thr Phe Thr Thr 1740 Arg Leu Leu Ser Ser 1745 Thr Arg Val cca aat tac aac etc ata gtg atg gat gaa gca cat ttc acc gat cct 5396 Pro Asn Tyr Asn 1750 Leu He Val Met 1755 Asp Glu Ala His Phe 1760 Thr Asp Pro 1765 tct agt gtc gcg get aga gga tac ate teg acc agg gtg gaa atg gga 5444 Ser Ser Val Ala Ala Arg Gly Tyr 1770 He Ser Thr 1775 Arg Val Glu Met Gly 1780

    277

    2018200081 04 Jan 2018

    gag Glu gca Ala gca gcc ate Ala Ala He 1785 ttc Phe atg Met acc gca acc Thr Ala Thr 1790 cct Pro ccc Pro gga Gly gcg aca gat 5492 Ala Thr 1795 Asp ccc ttt ccc cag age aac age cca ata gaa gac ate gag agg gaa att 5540 Pro Phe Pro Gin Ser 1800 Asn Ser Pro He Glu 1805 Asp lie Glu Arg Glu 1810 He ccg gaa agg tea tgg aac aca ggg ttc gac tgg ata aca gac tac caa 5588 Pro Glu 1815 Arg Ser Trp Asn Thr 182C Gly Phe Asp 1 Trp He 1825 Thr Asp Tyr Gin ggg aaa act gtg tgg ttt gtt ccc age ata aaa get gga aat gac att 5636 Gly Lys 1830 Thr Val Trp Phe Val 1835 Pro Ser lie Lys Ala 1840 Gly Asn Asp He 1845 gca aat tgt ttg aga aag teg gga aag aaa gtt ate cag ttg agt agg 5684 Ala Asn Cys Leu Arg Lys 1850 Ser Gly Lys Lys Val 1855 He Gin Leu Ser Arg 1860 aaa acc ttt gat aca gag tat cca aaa aeg aaa etc aeg gac tgg gat 5732 Lys Thr Phe Asp Thr 1865 Glu Tyr Pro Lys Thr 1870 Lys Leu Thr Asp Trp 1875 Asp ttt gtg gtc act aca gac ata tct gaa atg ggg gcc aat ttt aga get 5780 Phe Val Val Thr Thr 1880 Asp He Ser Glu Met 1885 Gly Ala Asn Phe Arg 1890 Ala ggg aga gtg ata gac cct agg aga tgc etc aag cca gtt ate eta aca 5828 Gly Arg Val lie Asp 1895 Pro Arg Arg Cys Leu 1900 Lys Pro Val 1905 He Leu Thr gat ggg cca gag aga gtc att tta gca ggt cct att cca gtg act cca 5876 Asp Gly 1910 Pro Glu Arg Val He 1915 Leu Ala Gly Pro He 1920 Pro Val Thr Pro 1925 gca age get get cag aga aga ggg cga ata gga agg aac cca gca caa 5924 Ala Ser Ala Ala Gin Arg 1930 Arg Gly Arg He Gly 1935 Arg Asn Pro Ala Gin 1940 gaa gac gac caa tac gtt ttc tcc gga gac cca eta aaa aat gat gaa 5972 Glu Asp Asp Gin Tyr 1945 Val Phe Ser Gly Asp 1950 Pro Leu Lys Asn Asp 1955 Glu gat cat gcc cac tgg aca gaa gca aag atg ctg ett gac aat ate tac 6020 Asp His Ala His Trp 1960 Thr Glu Ala Lys Met 1965 Leu Leu Asp Asn He 1970 Tyr acc cca gaa ggg ate att cca aca ttg ttt ggt ccg gaa agg gaa aaa 6068 Thr Pro Glu Gly lie 1975 lie Pro Thr Leu Phe 1980 Gly Pro Glu 1985 Arg Glu Lys acc caa gcc att gat gga gag ttt cgc etc aga ggg gaa caa agg aag 6116 Thr Gin Ala He Asp Gly Glu Phe Arg Leu Arg Gly Glu Gin Arg Lys

    1990 1995 2000 2005

    278

    2018200081 04 Jan 2018

    act Thr ttt Phe gtg Val gaa Glu tta atg Leu Met 2010 agg Arg aga Arg gga Gly gac ett Asp Leu 2015 ccg Pro gtg Val tgg Trp ctg agc Leu Ser 2020 6164 tat aag gta get tet get ggc att tet tac aaa gat cgg gaa tgg tgc 6212 Tyr Lys Val Ala 2025 Ser Ala Gly He Ser 203C Tyr Lys 1 Asp Arg Glu 2035 Trp Cys ttc aca ggg gaa agg aat aac caa att tta gaa gaa aac atg gag gtt 6260 Phe Thr Gly Glu 2040 Arg Asn Asn Gin 2045 He Leu Glu Glu Asn Met 2050 Glu Val gaa att tgg act aga gag gga gaa aag aaa aag eta agg cca aga tgg 6308 Glu He Trp 2055 Thr Arg Glu Gly Glu 2060 Lys Lys Lys Leu Arg 2065 Pro Arg Trp tta gat gca cgt gta tac get gac ccc atg get ttg aag gat ttt aag 6356 Leu Asp 2070 Ala Arg Val Tyr Ala 2075 Asp Pro Met Ala Leu 2080 Lys Asp Phe Lys 2085 gag ttt get agt gga agg aag agc ata act etc gac ate eta aca gag 6404 Glu Phe Ala Ser Gly Arg 2090 Lys Ser He Thr Leu 2095 Asp He Leu Thr Glu 2100 att gcc agt ttg cca act tac ett tcc tet agg gcc aag etc gcc ett 6452 lie Ala Ser Leu Pro Thr 2105 Tyr Leu Ser 211C Ser Arg I Ala Lys Leu 2115 Ala Leu gat aac ata gtc atg etc cac aca aca gaa aga gga ggg agg gcc tac 6500 Asp Asn He Val 2120 Met Leu His Thr Thr 2125 Glu Arg Gly Gly Arg 2130 Ala Tyr caa cac gcc ctg aac gaa etc ccg gag tea ctg gaa aca ett atg ett 6548 Gin His Ala 2135 Leu Asn Glu Leu Pro 214 0 Glu Ser Leu Glu Thr 2145 Leu Met Leu gta get tta eta ggt get atg aca gca ggt ate ttc ctg ttt ttc atg 6596 Val Ala 2150 Leu Leu Gly Ala Met 2155 Thr Ala Gly He Phe 2160 Leu Phe Phe Met 2165 caa ggg aaa gga ata ggg aaa ttg tea atg ggt ttg ata acc att geg 6644 Gin Gly Lys Gly He Gly 2170 Lys Leu Ser Met Gly 2175 Leu He Thr He Ala 2180 gtg get agt ggc ttg etc tgg gta gca gaa att caa ccc cag tgg ata 6692 Val Ala Ser Gly Leu Leu 2185 Trp Val Ala Glu He 2190 Gin Pro Gin Trp He 2195 geg gcc tea ate ata eta gag ttt ttt etc atg gta ctg ttg ata ccg 6740 Ala Ala Ser He He Leu Glu Phe Phe Leu Met Val Leu Leu He Pro

    2200 2205 2210

    279

    2018200081 04 Jan 2018

    gaa cca gaa Glu Pro Glu 2215 aaa Lys caa Gin agg Arg acc cca Thr Pro 2220 caa Gin gac Asp aat Asn caa ttg Gin Leu 2225 ate He tac Tyr gtc Val 6788 ata ttg acc att etc acc att att ggt etc ata gca gcc aac gag atg 6836 lie Leu Thr 2230 He Leu Thr He He 2235 Gly Leu He 224C Ala Ala 1 Asn Glu Met 2245 ggg ctg att gaa aaa aca aaa aeg gat ttt ggg ttt tac cag gta aaa 6884 Gly Leu lie Glu Lys 2250 Thr 1 Lys Thr Asp Phe 2255 Gly Phe Tyr Gin Val 2260 Lys 1 aca gaa acc acc ate etc gat gtg gac ttg aga cca get tea gca tgg 6932 Thr Glu Thr Thr 2265 He Leu Asp Val Asp 227C Leu 1 Arg Pro Ala Ser Ala 2275 Trp aeg etc tat gca gta gcc acc aca att ctg act ccc atg ctg aga cac 6980 Thr Leu Tyr Ala 2280 Val Ala Thr Thr He 2285 Leu Thr Pro Met Leu 2290 Arg His acc ata gaa aac aeg teg gcc aac eta tct eta gca gcc att gcc aac 7028 Thr lie Glu 2295 Asn Thr Ser Ala Asn 2300 Leu Ser Leu Ala Ala 2305 He Ala Asn cag gcg gcc gtc eta atg ggg ett gga aaa gga tgg ccg etc cac aga 7076 Gin Ala Ala 2310 Val Leu Met Gly Leu 2315 Gly Lys Gly Trp Pro 2320 Leu His Arg 2325 atg gac etc ggt gtg ccg ctg tta gca atg gga tgc tat tct caa gtg 7124 Met Asp Leu Gly Val Pro 2330 Leu Leu Ala Met Gly 2335 Cys Tyr Ser Gin Val 2340 aac cca aca act ttg aca gca tcc tta gtc atg ett tta gtc cat tat 7172 Asn Pro Thr Thr Leu 2345 Thr Ala Ser Leu Val 2350 Met Leu Leu Val His 2355 Tyr gca ata ata ggt cca gga ttg cag gca aaa gcc aca aga gag gcc cag 7220 Ala He He Gly 2360 Pro Gly Leu Gin Ala 2365 Lys Ala Thr Arg Glu 2370 Ala Gin aaa agg aca get get ggg ate atg aaa aac ccc aeg gtg gac ggg ata 7268 Lys Arg Thr 2375 Ala Ala Gly He Met 2380 Lys Asn Pro Thr Val 2385 Asp Gly He aca gta ata gat eta gaa cca ata tcc tat gac cca aaa ttt gaa aag 7316 Thr Val lie 2390 Asp Leu Glu Pro He 2395 Ser Tyr Asp Pro Lys 2400 Phe Glu Lys 2405 caa tta ggg cag gtc atg eta etc gtc ttg tgt get gga caa eta etc 7364 Gin Leu Gly Gin Val Met 2410 Leu Leu Val Leu Cys 2415 Ala Gly Gin Leu Leu 2420 ttg atg aga aca aca tgg get ttc tgt gaa gtc ttg act ttg gcc aca 7412 Leu Met Arg Thr Thr Trp Ala Phe Cys Glu Val Leu Thr Leu Ala Thr

    2425 2430 2435

    280

    2018200081 04 Jan 2018

    gga Gly cca Pro ate ttg lie Leu 2440 acc Thr ttg tgg gag ggc aac Asn ccg Pro gga agg ttt Gly Arg Phe 2450 tgg Trp aac Asn 7460 Leu Trp Glu Gly 2445 aeg acc ata gcc gta tcc acc gcc aac att ttc agg gga agt tac ctg 7508 Thr Thr 2455 He Ala Val Ser Thr Ala Asn 2460 He Phe Arg Gly Ser 2465 Tyr Leu gcg gga get gga ctg get ttt tea etc ata aag aat gca caa acc cct 7556 Ala Gly 2470 Ala Gly Leu Ala 2475 Phe Ser Leu He Lys Asn Ala Gin 2480 Thr Pro 2485 agg agg gga act ggg acc aca gga gag aca ctg gga gag aag tgg aag 7604 Arg Arg Gly Thr Gly 249C Thr I Thr Gly Glu Thr Leu 2495 Gly Glu Lys Trp 250C Lys I aga cag eta aac tea tta gac aga aaa gag ttt gaa gag tat aaa aga 7652 Arg Gin Leu Asn Ser 2505 Leu Asp Arg Lys Glu 2510 Phe Glu Glu Tyr Lys 2515 Arg agt gga ata eta gaa gtg gac agg act gaa gcc aag tet gcc ctg aaa 7700 Ser Gly He Leu 2520 Glu Val Asp Arg Thr 2525 Glu Ala Lys Ser Ala 2530 Leu Lys gat ggg tet aaa ate aag cat gca gta tet aga ggg tcc agt aag att 7748 Asp Gly Ser Lys 2535 He Lys His Ala Val 2540 Ser Arg Gly Ser Ser 2545 Lys He aga tgg att gtt gag aga ggg atg gta aag cca aaa ggg aaa gtt gta 7796 Arg Trp 2550 He Val Glu Arg Gly 2555 Met Val Lys Pro Lys Gly Lys 2560 Val Val 2565 gat ett ggc tgt ggg aga gga gga tgg tet tat tac atg gcg aeg etc 7844 Asp Leu Gly Cys Gly Arg 2570 Gly Gly Trp Ser Tyr 2575 Tyr Met Ala Thr Leu 2580 aag aac gtg act gaa gtg aaa ggg tat aca aaa gga ggt cca gga cat 7892 Lys Asn Val Thr Glu 2585 Val Lys Gly Tyr Thr 2590 Lys Gly Gly Pro Gly 2595 His gaa gaa ccg att ccc atg get act tat ggc tgg aat ttg gtc aaa etc 7940 Glu Glu Pro He 2600 Pro Met Ala Thr Tyr 2605 Gly Trp Asn Leu Val 2610 Lys Leu cat tea ggg gtt gac gtg ttc tac aaa ccc aca gag caa gtg gac acc 7988 Hl 3 Ser Gly Val 2615 Asp Val Phe Tyr Lys 2620 Pro Thr Glu Gin Val 2625 Asp Thr ctg etc tgt gat att ggg gag tea tet tet aat cca aca ata gag gaa 8036 Leu Leu Cys Asp He Gly Glu Ser Ser Ser Asn Pro Thr He Glu Glu

    2630 2635 2640 2645

    281

    2018200081 04 Jan 2018

    gga Gly aga Arg aca Thr tta Leu aga gtt Arg Val 2650 ttg Leu aag Lys atg Met gtg gag Val Glu 2655 cca Pro tgg Trp etc Leu tct tea Ser Ser 2660 8084 aaa cct gaa ttc tgc ate aaa gtc ett aac ccc tac atg cca aca gtc 8132 Lys Pro Glu Phe 2665 Cys He Lys Val Leu Asn Pro 2670 Tyr Met Pro Thr Val 2675 ata gaa gag ctg gag aaa ctg cag aga aaa cat ggt ggg aac ett gtc 8180 lie Glu Glu Leu 2680 Glu Lys Leu Gin Arg 2685 Lys His Gly Gly 269C Asn 1 Leu Val aga tgc ccg ctg tcc agg aac tcc acc cat gag atg tat tgg gtg tea 8228 Arg Cys Pro 2695 Leu Ser Arg Asn Ser 2700 Thr His Glu Met Tyr 2705 Trp Val Ser gga gcg teg gga aac att gtg age tct gtg aac aca aca tea aag atg 8276 Gly Ala 2710 Ser Gly Asn He Val 2715 Ser Ser Val Asn 272C Thr ) Thr Ser Lys Met 2725 ttg ttg aac agg ttc aca aca agg cat agg aaa ccc act tat gag aag 8324 Leu Leu Asn Arg Phe Thr 2730 Thr Arg His Arg Lys 2735 Pro Thr Tyr Glu Lys 2740 gac gta gat ett ggg gca gga aeg aga agt gtc tcc act gaa aca gaa 8372 Asp Val Asp Leu 2745 Gly Ala Gly Thr Arg Ser Val 2750 Ser Thr Glu 2755 Thr Glu aaa cca gac atg aca att att ggg aga agg ett cag cga ttg caa gag 8420 Lys Pro Asp Met 2760 Thr He He Gly Arg 2765 Arg Leu Gin Arg 277C Leu 1 Gin Glu gag cac aaa gaa acc tgg cat tat gat cag gaa aac cca tac aga acc 8468 Glu His Lys 2775 Glu Thr Trp His Tyr 2780 Asp Gin Glu Asn Pro 2785 Tyr Arg Thr tgg gcg tat cat gga age tat gaa get cct teg aca ggc tct gca tcc 8516 Trp Ala 2790 Tyr His Gly Ser Tyr 2795 Glu Ala Pro Ser Thr 2800 Gly Ser Ala Ser 2805 tcc atg gtg aac ggg gta gta aaa ctg eta aca aaa cct tgg gat gtg 8564 Ser Met Val Asn Gly Val 2810 Val Lys Leu Leu Thr 2815 Lys Pro Trp Asp Val 2820 gtt cca atg gtg acc cag tta gcc atg aca gac aca acc cct ttt ggg 8612 Val Pro Met Val 2825 Thr Gin Leu Ala Met Thr Asp 2830 Thr Thr Pro Phe Gly 2835 caa caa aga gtg ttc aaa gag aag gtg gat acc aga aca cca caa cca 8660 Gin Gin Arg Val 2840 Phe Lys Glu Lys Val 2845 Asp Thr Arg Thr Pro 2850 Gin Pro aaa ccc ggt aca cga atg gtt atg acc aeg aca gcc aat tgg ctg tgg 8708 Lys Pro Gly 2855 Thr Arg Met Val Met 2860 Thr Thr Thr Ala Asn 2865 Trp Leu Trp

    282

    2018200081 04 Jan 2018

    gcc etc Ala Leu 2870 ett Leu ggg aag Gly Lys aag aaa aat Lys Lys Asn 2875 ccc Pro aga Arg etg tgc Leu Cys 2880 aca agg gaa Thr Arg Glu gag Glu 2885 8756 ttc ate tea aaa gtt aga tea aac gca gee ata ggc gca gtc ttt cag 8804 Phe lie Ser Lys Val 289C Arg Ser Asn 1 Ala Ala 2895 He Gly Ala Val Phe 2900 Gin 1 gaa gaa cag gga tgg aca tea gcc agt gaa get gtg aat gac agc egg 8852 Glu Glu Gin Gly Trp 2905 Thr Ser Ala Ser Glu 2910 Ala Val Asn Asp Ser 2915 Arg ttt tgg gaa ctg gtt gac aaa gaa agg gcc eta cac cag gaa ggg aaa 8900 Phe Trp Glu Leu Val 2920 Asp Lys Glu Arg 2925 Ala Leu His Gin Glu Gly 2930 Lys tgt gaa teg tgt gtc tac aac atg atg gga aaa cgt gag aaa aag tta 8948 Cys Glu Ser 2935 Cys Val Tyr Asn Met 2940 Met Gly Lys Arg Glu Lys Lys 2945 Leu gga gag ttt ggc aga gcc aag gga agc ega gca ate tgg tac atg tgg 8996 Gly Glu 2950 Phe Gly Arg Ala Lys Gly 2955 Ser Arg Ala He 2960 Trp Tyr Met Trp 2965 ctg gga gcg egg ttt ctg gaa ttt gaa gee ctg ggt ttt ttg aat gaa 9044 Leu Gly Ala Arg Phe Leu Glu Phe 2970 Glu Ala Leu Gly 2975 Phe Leu Asn Glu 2980 gat cac tgg ttt ggc aga gaa aat tea tgg agt gga gtg gaa ggg gaa 9092 Asp His Trp Phe Gly 2985 Arg Glu Asn Ser Trp 2990 Ser Gly Val Glu Gly 2995 Glu ggt ctg cac aga ttg gga tat ate ctg gag gag ata gac aag aag gat 9140 Gly Leu His Arg Leu 3000 Gly Tyr He Leu 3005 Glu Glu He Asp Lys Lys 3010 Asp gga gac eta atg tat get gat gac aca gca ggc tgg gac aca aga ate 9188 Gly Asp Leu 3015 Met Tyr Ala Asp Asp 3020 Thr Ala Gly Trp Asp Thr Arg 3025 He act gag gat gac ett caa aat gaa gaa ctg ate aeg gaa cag atg gcc 9236 Thr Glu 3030 Asp Asp Leu Gin Asn Glu 3035 Glu Leu He Thr 3040 Glu Gin Met Ala 3045 ccc cac cac aag ate eta gcc aaa gcc att ttc aaa eta acc tat caa 9284 Pro His His Lys He Leu Ala Lys 3050 Ala He Phe Lys 3055 Leu Thr Tyr Gin 3060 aac aaa gtg gtg aaa gtc etc aga ccc aca ccg aga gga gcg gtg atg 9332 Asn Lys Val Val Lys 3065 Val Leu Arg Pro Thr 3070 Pro Arg Gly Ala Val 3075 Met

    283

    2018200081 04 Jan 2018

    gat Asp ate lie ata tcc agg He Ser Arg 3080 aaa Lys gac Asp caa aga ggt Gin Arg Gly 3085 agt gga caa gtt gga aca Thr 9380 Ser Gly Gin Val 3090 Gly tat ggt ttg aac aca ttc acc aac atg gaa gtt caa etc ate ege caa 9428 Tyr Gly 3095 Leu Asn Thr Phe Thr 310C Asn Met Glu 1 Val Gin 3105 Leu He Arg Gin atg gaa get gaa gga gtc ate aca caa gat gac atg cag aac cca aaa 9476 Met 311C Glu 1 Ala Glu Gly Val 3115 He Thr Gin Asp Asp 312C Met 1 Gin Asn Pro Lys 3125 ggg ttg aaa gaa aga gtt gag aaa tgg ctg aaa gag tgt ggt gtc gac 9524 Gly Leu Lys Glu Arg 313C Val 1 Glu Lys Trp Leu 3135 Lys Glu Cys Gly Val 314C Asp 1 agg tta aag agg atg gca ate agt gga gac gat tgc gtg gtg aag ccc 9572 Arg Leu Lys Arg Met 3145 Ala He Ser Gly Asp 3150 Asp Cys Val Val Lys 3155 Pro ctg gat gag agg ttt ggc act tcc etc etc ttc ttg aac gac atg gga 9620 Leu Asp Glu Arg Phe 3160 Gly Thr Ser Leu Leu 3165 Phe Leu Asn Asp 3170 Met Gly aag gtg agg aaa gac att ccg cag tgg gaa cca tet aag gga tgg aaa 9668 Lys Val Arg Lys Asp 3175 He Pro Gin Trp Glu 3180 Pro Ser Lys Gly 3185 Trp Lys aac tgg caa gag gtt cct ttt tgc tcc cac cac ttt cac aag ate ttc 9716 Asn Trp 3190 Gin Glu Val Pro Phe 3195 Cys Ser His His Phe 3200 His Lys He Phe 3205 atg aag gat ggc ege tea eta gtt gtt cca tgt aga aac cag gat gaa 9764 Met Lys Asp Gly Arg Ser 3210 Leu Val Val Pro Cys 3215 Arg Asn Gin Asp Glu 3220 ctg ata ggg aga gcc aga ate teg cag ggg get gga tgg agc tta aga 9812 Leu lie Gly Arg Ala 3225 Arg He Ser Gin Gly 3230 Ala Gly Trp Ser Leu 3235 Arg gaa aca gcc tgc ctg ggc aaa get tac gcc cag atg tgg teg etc atg 9860 Glu Thr Ala Cys Leu 3240 Gly Lys Ala Tyr Ala 3245 Gin Met Trp Ser 3250 Leu Met tac ttc cac aga agg gat ctg cgt tta gcc tcc atg gcc ata tgc tea 9908 Tyr Phe His Arg Arg 3255 Asp Leu Arg Leu Ala 3260 Ser Met Ala He 3265 Cys Ser gca gtt cca aeg gaa tgg ttt cca aca agc aga aca aca tgg tea ate 9956 Ala Val 3270 Pro Thr Glu Trp Phe 3275 Pro Thr Ser Arg Thr 3280 Thr Trp Ser He 3285 cac get cat cat cag tgg atg acc act gaa gat atg etc aaa gtg tgg 10004 His Ala His His Gin Trp 3290 Met Thr Thr Glu Asp 3295 Met Leu Lys Val Trp 3300

    284

    2018200081 04 Jan 2018

    aac Asn aga Arg gtg Val tgg ata Trp lie 3305 gaa Glu gac Asp aac Asn cct aat Pro Asn 3310 atg Met act Thr gac Asp aag act Lys Thr 3315 cca Pro 10052 gtc cat teg tgg gaa gat ata cct tac eta ggg aaa aga gag gat ttg 10100 Val His Ser Trp Glu Asp He Pro Tyr Leu Gly Lys Arg Glu Asp Leu 3320 3325 3330 tgg tgt gga tcc ctg att gga ctt tet tcc aga gcc acc tgg geg aag 10148 Trp Cys Gly Ser Leu lie Gly Leu Ser Ser Arg Ala Thr Trp Ala Lys 3335 3340 3345 aac att cac aeg gcc ata acc cag gtc aga aac ctg ate gga aaa gag 10196 Asn He His Thr Ala He Thr Gin Val Arg Asn Leu He Gly Lys Glu 3350 3355 3360 3365 gaa tac gtg gat tac atg cca gta atg aaa aga tac age get cct tea 10244 Glu Tyr Val Asp Tyr Met Pro Val Met Lys Arg Tyr Ser Ala Pro Ser 3370 3375 3380 gag agt gaa gga gtt ctg taa ttaccaacaa caaacaccaa aggetattga 10295 Glu Ser Glu Gly Val Leu * 3385

    agtcaggcca cttgtgccac ggcttgagca aaccgtgctg cctgtagctc cgccaataat 10355 gggaggcgtg aaatccctag ggaggccatg cgccacggaa gctgtacgcg tggcatattg 10415 gactagcggt tagaggagac ccctcccatc actgacaaaa cgcagcaaaa gggggcccga 10475 agccaggagg aagctgtact cctggtggaa ggactagagg ttagaggaga cccccccaac 10535 acaaaaacag catattgacg ctgggaaaga ccagagatcc tgctgtctct gcaacatcaa 10595 tccaggcaca gagcgaagca agatggattg gtgttgttga tccaacaggt tet 10648 <210> 24 <211> 3387 <212> PRT <213> Artificial Sequence <220> ' <223> Description of Artificial Sequence :/Note = synthetic construct <400> 24

    Met Asn Gin Arg Lys Lys Val Val Arg Pro Pro Phe Asn Met Leu Lys 1 5 10 15 Arg Glu Arg Asn Arg Val Ser Thr Pro Gin Gly Leu Val Lys Arg Phe 20 25 30 Ser Thr Gly Leu Phe Ser Gly Lys Gly Pro Leu Arg Met Val Leu Ala 35 40 45 Phe He Thr Phe Leu Arg Val Leu Ser He Pro Pro Thr Ala Gly He 50 55 60 Leu Lys Arg Trp Gly Gin Leu Lys Lys Asn Lys Ala He Arg He Leu 65 70 75 80 He Gly Phe Arg Lys Glu He Gly Arg Met Leu Asn He Leu Asn Gly 85 90 95

    285

    2018200081 04 Jan 2018

    Arg Lys Arg Ser 100 Thr He Thr Leu Leu Cys 105 Leu He Pro Thr 110 Val Met Ala Phe His Leu Ser Thr Arg Asp Gly Glu Pro Leu Met He Val Ala 115 120 125 Lys His Glu Arg Gly Arg Pro Leu Leu Phe Lys Thr Thr Glu Gly lie 130 135 140 Asn Lys Cys Thr Leu He Ala Met Asp Leu Gly Glu Met Cys Glu Asp 145 150 155 160 Thr Val Thr Tyr Lys Cys Pro Leu Leu Val Asn Thr Glu Pro Glu Asp 165 170 175 lie Asp Cys Trp Cys Asn Leu Thr Ser Thr Trp Val Met Tyr Gly Thr 180 185 190 Cys Thr Gin Ser Gly Glu Arg Arg Arg Glu Lys Arg Ser Val Ala Leu 195 200 205 Thr Pro His Ser Gly Met Gly Leu Glu Thr Arg Ala Glu Thr Trp Met 210 215 220 Ser Ser Glu Gly Ala Trp Lys His Ala Gin Arg Val Glu Ser Trp He 225 230 235 240 Leu Arg Asn Pro Gly Phe Ala Leu Leu Ala Gly Phe Met Ala Tyr Met 245 250 255 He Gly Gin Thr Gly He Gin Arg Thr Val Phe Phe Val Leu Met Met 260 265 270 Leu Val Ala Pro Ser Tyr Gly Met Arg Cys Val Gly Val Gly Asn Arg 275 280 285 Asp Phe Val Glu Gly Val Ser Gly Gly Ala Trp Val Asp Leu Val Leu 290 295 300 Glu His Gly Gly Cys Val Thr Thr Met Ala Gin Gly Lys Pro Thr Leu 305 310 315 320 Asp Phe Glu Leu Thr Lys Thr Thr Ala Lys Glu Val Ala Leu Leu Arg 325 330 335 Thr Tyr Cys lie Glu Ala Ser He Ser Asn He Thr Thr Ala Thr Arg 340 345 350 Cys Pro Thr Gin Gly Glu Pro Tyr Leu Lys Glu Glu Gin Asp Gin Gin 355 360 365 Tyr He Cys Arg Arg Asp Val Val Asp Arg Gly Trp Gly Asn Gly Cys 370 375 380 Gly Leu Phe Gly Lys Gly Gly Val Val Thr Cys Ala Lys Phe Ser Cys 385 390 395 400 Ser Gly Lys He Thr Gly Asn Leu Val Gin He Glu Asn Leu Glu Tyr 405 410 415 Thr Val Val Val Thr Val His Asn Gly Asp Thr His Ala Val Gly Asn 420 425 430 Asp Thr Ser Asn His Gly Val Thr Ala Thr He Thr Pro Arg Ser Pro 435 440 445 Ser Val Glu Val Lys Leu Pro Asp Tyr Gly Glu Leu Thr Leu Asp Cys 450 455 460 Glu Pro Arg Ser Gly He Asp Phe Asn Glu Met He Leu Met Lys Met 465 470 475 480 Lys Lys Lys Thr Trp Leu Val His Lys Gin Trp Phe Leu Asp Leu Pro 485 490 495 Leu Pro Trp Thr Ala Gly Ala Asp Thr Ser Glu Val His Trp Asn Tyr 500 505 510 Lys Glu Arg Met Val Thr Phe Lys Val Pro His Ala Lys Arg Gin Asp 515 520 525

    286

    2018200081 04 Jan 2018

    Val Thr Val Leu Gly Ser Gin Glu Gly Ala Met His Ser Ala Leu Ala 530 535 540 Gly Ala Thr Glu Val Asp Ser Gly Asp Gly Asn His Met Phe Ala Gly 545 550 555 560 His Leu Lys Cys Lys Val Arg Met Glu Lys Leu Arg He Lys Gly Met 565 570 575 Ser Tyr Thr Met Cys Ser Gly Lys Phe Ser He Asp Lys Glu Met Ala 580 585 590 Glu Thr Gin His Gly Thr Thr Val Val Lys Val Lys Tyr Glu Gly Ala 595 600 605 Gly Ala Pro Cys Lys Val Pro He Glu He Arg Asp Val Asn Lys Glu 610 615 620 Lys Val Val Gly Arg He He Ser Ser Thr Pro Leu Ala Glu Asn Thr 625 630 635 640 Asn Ser Ala Thr Asn He Glu Leu Glu Pro Pro Phe Gly Asp Ser Tyr 645 650 655 lie Val lie Gly Val Gly Asn Ser Ala Leu Thr Leu His Trp Phe Arg 660 665 670 Lys Gly Ser Ser lie Gly Lys Met Phe Glu Ser Thr Tyr Arg Gly Ala 675 680 685 Lys Arg Met Ala He Leu Gly Glu Thr Ala Trp Asp Phe Gly Ser Val 690 695 700 Gly Gly Leu Phe Thr Ser Leu Gly Lys Ala Val His Gin Val Phe Gly 705 710 715 720 Ser Val Tyr Thr Thr Met Phe Gly Gly Val Ser Trp Met He Arg He 725 730 735 Leu He Gly Phe Leu Val Leu Trp He Gly Thr Asn Ser Arg Asn Thr 740 745 750 Ser Met Ala Met Thr Cys He Ala Val Gly Gly He Thr Leu Phe Leu 755 760 765 Gly Phe Thr Val Gin Ala Asp Met Gly Cys Val Val Ser Trp Ser Gly 770 775 780 Lys Glu Leu Lys Cys Gly Ser Gly He Phe Val Val Asp Asn Val His 785 790 795 800 Thr Trp Thr Glu Gin Tyr Lys Phe Gin Pro Glu Ser Pro Ala Arg Leu 805 810 815 Ala Ser Ala He Leu Asn Ala His Lys Asp Gly Val Cys Gly He Arg 820 825 830 Ser Thr Thr Arg Leu Glu Asn Val Met Trp Lys Gin He Thr Asn Glu 835 840 845 Leu Asn Tyr Val Leu Trp Glu Gly Gly His Asp Leu Thr Val Val Ala 850 855 860 Gly Asp Val Lys Gly Val Leu Thr Lys Gly Lys Arg Ala Leu Thr Pro 865 870 875 880 Pro Val Asn Asp Leu Lys Tyr Ser Trp Lys Thr Trp Gly Lys Ala Lys 885 890 895 He Phe Thr Pro Glu Ala Arg Asn Ser Thr Phe Leu He Asp Gly Pro 900 905 910 Asp Thr Ser Glu Cys Pro Asn Glu Arg Arg Ala Trp Asn Phe Leu Glu 915 920 925 Val Glu Asp Tyr Gly Phe Gly Met Phe Thr Thr Asn He Trp Met Lys 930 935 940 Phe Arg Glu Gly Ser Ser Glu Val Cys Asp His Arg Leu Met Ser Ala 945 950 955 960

    287

    2018200081 04 Jan 2018

    Ala He Lys Asp Gin Lys Ala Val His Ala Asp Met Gly Tyr Trp He 965 970 975 Glu Ser Ser Lys Asn Gin Thr Trp Gin He Glu Lys Ala Ser Leu He 980 985 990 Glu Val Lys Thr Cys Leu Trp Pro Lys Thr His Thr Leu Trp Ser Asn 995 1000 1005 Gly Val Leu Glu Ser Gin Met Leu He Pro Lys Ser Tyr Ala Gly Pro 1010 1015 1020 Phe Ser Gin His Asn Tyr Arg Gin Gly Tyr Ala Thr Gin Thr Val Gly 1025 1030 1035 1040 Pro Trp His Leu Gly Lys Leu Glu He Asp Phe Gly Glu Cys Pro Gly 1045 105C i 1055 Thr Thr Val Ala He Gin Glu Asp Cys Asp His Arg Gly Pro Ser Leu 1060 1065 1070 Arg Thr Thr Thr Ala Ser Gly Lys Leu Val Thr Gin Trp Cys Cys Arg 1075 1080 1085 Ser Cys Thr Met Pro Pro Leu Arg Phe Leu Gly Glu Asp Gly Cys Trp 1090 1095 1100 Tyr Gly Met Glu He Arg Pro Leu Ser Glu Lys Glu Glu Asn Met Val 1105 1110 1115 1120 Lys Ser Gin Val Thr Ala Gly Gin Gly Thr Ser Glu Thr Phe Ser Met 1125 113C 1 1135 Gly Leu Leu Cys Leu Thr Leu Phe Val Glu Glu Cys Leu Arg Arg Arg 1140 1145 1150 Val Thr Arg Lys His Met He Leu Val Val Val He Thr Leu Cys Ala 1155 1160 1165 lie He Leu Gly Gly Leu Thr Trp Met Asp Leu Leu Arg Ala Leu He 1170 1175 1180 Met Leu Gly Asp Thr Met Ser Gly Arg He Gly Gly Gin He His Leu 1185 1190 1195 1200 Ala He Met Ala Val Phe Lys Met Ser Pro Gly Tyr Val Leu Gly Val 1205 1210 1215 Phe Leu Arg Lys Leu Thr Ser Arg Glu Thr Ala Leu Met Val He Gly 1220 1225 1230 Met Ala Met Thr Thr Val Leu Ser He Pro His Asp Leu Met Glu Leu 1235 1240 1245 He Asp Gly He Ser Leu Gly Leu He Leu Leu Lys He Val Thr His 1250 1255 1260 Phe Asp Asn Thr Gin Val Gly Thr Leu Ala Leu Ser Leu Thr Phe He 1265 1270 1275 1280 Arg Ser Thr Met Pro Leu Val Met Ala Trp Arg Thr He Met Ala Val 1285 1290 1295 Leu Phe Val Val Thr Leu He Pro Leu Cys Arg Thr Ser Cys Leu Gin 1300 1305 1310 Lys Gin Ser His Trp Val Glu He Thr Ala Leu lie Leu Gly Ala Gin 1315 1320 1325 Ala Leu Pro Val Tyr Leu Met Thr Leu Met Lys Gly Ala Ser Arg Arg 1330 1335 1340 Ser Trp Pro Leu Asn Glu Gly He Met Ala Val Gly Leu Val Ser Leu 1345 1350 1355 1360 Leu Gly Ser Ala Leu Leu Lys Asn Asp Val Pro Leu Ala Gly Pro Met 1365 1370 1375 Val Ala Gly Gly Leu Leu Leu Ala Ala Tyr Val Met Ser Gly Ser Ser 1380 1385 1390

    288

    2018200081 04 Jan 2018

    Ala Asp Leu Ser Leu Glu Lys 1395 Ala Ala Asn Val Gin Trp Asp Glu Met 1400 1405 Ala Asp He Thr Gly Ser Ser Pro He He Glu Val Lys Gin Asp Glu 1410 1415 1420 · Asp Gly Ser Phe Ser He Arg Asp Val Glu Glu Thr Asn Met He Thr 1425 I 1430 1435 1440 Leu Leu Val Lys Leu Ala Leu He Thr Val Ser Gly Leu Tyr Pro Leu 1445 1450 1455 Ala He Pro Val Thr Met Thr Leu Trp Tyr Met Trp Gin Val Lys Thr 1460 1465 1 1470 Gin Arg Ser Gly Ala Leu Trp Asp Val Pro Ser Pro Ala Ala Thr Gin 1475 1480 1485 Lys Ala Ala Leu Ser Glu Gly Val Tyr Arg He Met Gin Arg Gly Leu 1490 1495 1500 Phe Gly Lys Thr Gin Val Gly Val Gly He His Met Glu Gly Val Phe 1505 1 1510 1515 1520 His Thr Met Trp His Val Thr Arg Gly Ser Val He Cys His Glu Thr 1525 1530 1535 Gly Arg Leu Glu Pro Ser Trp Ala Asp Val Arg Asn Asp Met He Ser 1540 1545 1550 Tyr Gly Gly Gly Trp Arg Leu Gly Asp Lys Trp Asp Lys Glu Glu Asp 1555 1560 1565 Val Gin Val Leu Ala He Glu Pro Gly Lys Asn Pro Lys His Val Gin 1570 1575 1580 Thr Lys Pro Gly Leu Phe Lys Thr Leu Thr Gly Glu He Gly Ala Val 1585 i 1590 1595 1600 Thr Leu Asp Phe Lys Pro Gly Thr Ser Gly Ser Pro He He Asn Arg 1605 1610 1615 Lys Gly Lys Val He Gly Leu Tyr Gly Asn Gly Val Val Thr Lys Ser 1620 1625 1630 Gly Asp Tyr Val Ser Ala He Thr Gin Ala Glu Arg lie Gly Glu Pro 1635 1640 1645 Asp Tyr Glu Val Asp Glu Asp He Phe Arg Lys Lys Arg Leu Thr He 1650 1655 1660 Met Asp Leu His Pro Gly Ala Gly Lys Thr Lys Arg He Leu Pro Ser 1665 1670 1675 1680 lie Val Arg Glu Ala Leu Lys Arg Arg Leu Arg Thr Leu He Leu Ala 1685 1690 1695 Pro Thr Arg Val Val Ala Ala Glu Met Glu Glu Ala Leu Arg Gly Leu 1700 1705 1710 Pro He Arg Tyr Gin Thr Pro Ala Val Lys Ser Glu His Thr Gly Arg 1715 1720 1725 Glu He Val Asp Leu Met Cys His Ala Thr Phe Thr Thr Arg Leu Leu 1730 1735 1740 Ser Ser Thr Arg Val Pro Asn Tyr Asn Leu He Val Met Asp Glu Ala 1745 i 1750 1755 1760 His Phe Thr Asp Pro Ser Ser Val Ala Ala Arg Gly Tyr He Ser Thr 1765 1770 1775 Arg Val Glu Met Gly Glu Ala Ala Ala He Phe Met Thr Ala Thr Pro 1780 1785 1790 Pro Gly Ala Thr Asp Pro Phe Pro Gin Ser Asn Ser Pro He Glu Asp 1795 1800 1805 He Glii Arg Glu lie Pro Glu Arg Ser Trp Asn Thr Gly Phe Asp Trp 1810 1815 1820

    289

    2018200081 04 Jan 2018

    lie Thr Asp Tyr Gin Gly Lys Thr Val Trp Phe Val Pro Ser He Lys 1825 1830 1835 1840 Ala Gly Asn Asp He Ala Asn Cys Leu Arg Lys Ser Gly Lys Lys Val 1845 1850 1855 He Gin Leu Ser Arg Lys Thr Phe Asp Thr Glu Tyr Pro Lys Thr Lys 1860 1865 1870 Leu Thr Asp Trp Asp Phe Val Val Thr Thr Asp He Ser Glu Met Gly 1875 1880 1885 Ala Asn Phe Arg Ala Gly Arg Val He Asp Pro Arg Arg Cys Leu Lys 189C 1 1895 1900 Pro Val He Leu Thr Asp Gly Pro Glu Arg Val He Leu Ala Gly Pro 1905 1910 1915 1920 He Pro Val Thr Pro Ala Ser Ala Ala Gin Arg Arg Gly Arg He Gly 1925 1930 1935 Arg Asn Pro Ala Gin Glu Asp Asp Gin Tyr Val Phe Ser Gly Asp Pro 1940 1945 1950 Leu Lys Asn Asp Glu Asp His Ala His Trp Thr Glu Ala Lys Met Leu 1955 1960 1965 Leu Asp Asn He Tyr Thr Pro Glu Gly He He Pro Thr Leu Phe Gly 1970 1975 1980 Pro Glu Arg Glu Lys Thr Gin Ala He Asp Gly Glu Phe Arg Leu Arg 1985 1990 1995 2000 Gly Glu Gin Arg Lys Thr Phe Val Glu Leu Met Arg Arg Gly Asp Leu 2005 2010 2015 Pro Val Trp Leu Ser Tyr Lys Val Ala Ser Ala Gly He Ser Tyr Lys 2020 2025 2030 Asp Arg Glu Trp Cys Phe Thr Gly Glu Arg Asn Asn Gin lie Leu Glu 2035 2040 2045 Glu Asn Met Glu Val Glu He Trp Thr Arg Glu Gly Glu Lys Lys Lys 2050 2055 2060 Leu Arg Pro Arg Trp Leu Asp Ala Arg Val Tyr Ala Asp Pro Met Ala 2065 2070 2075 2080 Leu Lys Asp Phe Lys Glu Phe Ala Ser Gly Arg Lys Ser He Thr Leu 2085 2090 2095 Asp He Leu Thr Glu He Ala Ser Leu Pro Thr Tyr Leu Ser Ser Arg 2100 2105 2110 Ala Lys Leu Ala Leu Asp Asn He Val Met Leu His Thr Thr Glu Arg 2115 2120 2125 Gly Gly Arg Ala Tyr Gin His Ala Leu Asn Glu Leu Pro Glu Ser Leu 2130 2135 2140 GlU Thr Leu Met Leu Val Ala Leu Leu Gly Ala Met Thr Ala Gly He 2145 2150 2155 2160 Phe Leu Phe Phe Met Gin Gly Lys Gly He Gly Lys Leu Ser Met Gly 2165 2170 2175 Leu He Thr He Ala Val Ala Ser Gly Leu Leu Trp Val Ala Glu He 2180 2185 2190 Gin Pro Gin Trp He Ala Ala Ser lie He Leu Glu Phe Phe Leu Met 2195 2200 2205 Val Leu Leu He Pro Glu Pro Glu Lys Gin Arg Thr Pro Gin Asp Asn 2210 2215 2220 Gin Leu He Tyr Val He Leu Thr He Leu Thr He He Gly Leu He 2225 2230 2235 2240 Ala Ala Asn Glu Met Gly Leu He Glu Lys Thr Lys Thr Asp Phe Gly 2245 2250 2255

    290

    2018200081 04 Jan 2018

    Phe Tyr Gin Val Lys Thr Glu Thr Thr He Leu Asp Val Asp Leu Arg 2260 2265 2270 Pro Ala Ser Ala Trp Thr Leu Tyr Ala Val Ala Thr Thr lie Leu Thr 2275 2280 2285 Pro Met Leu Arg His Thr He Glu Asn Thr Ser Ala Asn Leu Ser Leu 2290 2295 2300 Ala Ala lie Ala Asn Gin Ala Ala Val Leu Met Gly Leu Gly Lys Gly 2305 2310 2315 2320 Trp Pro Leu His Arg Met Asp Leu Gly Val Pro Leu Leu Ala Met Gly 2325 i 233C 1 2335 Cys Tyr Ser Gin Val Asn Pro Thr Thr Leu Thr Ala Ser Leu Val Met 2340 2345 2350 Leu Leu Val His Tyr Ala He lie Gly Pro Gly Leu Gin Ala Lys Ala 2355 2360 2365 Thr Arg Glu Ala Gin Lys Arg Thr Ala Ala Gly He Met Lys Asn Pro 2370 2375 2380 Thr Val Asp Gly He Thr Val He Asp Leu Glu Pro He Ser Tyr Asp 2385 2390 2395 2400 Pro Lys Phe Glu Lys Gin Leu Gly Gin Val Met Leu Leu Val Leu Cys 2405 1 2410 2415 Ala Gly Gin Leu Leu Leu Met Arg Thr Thr Trp Ala Phe Cys Glu Val 2420 2425 2430 Leu Thr Leu Ala Thr Gly Pro He Leu Thr Leu Trp Glu Gly Asn Pro 2435 2440 2445 Gly Arg Phe Trp Asn Thr Thr He Ala Val Ser Thr Ala Asn He Phe 2450 2455 2460 Arg Gly Ser Tyr Leu Ala Gly Ala Gly Leu Ala Phe Ser Leu He Lys 2465 2470 2475 2480 Asn Ala Gin Thr Pro Arg Arg Gly Thr Gly Thr Thr Gly Glu Thr Leu 2485 2490 2495 Gly Glu Lys Trp Lys Arg Gin Leu Asn Ser Leu Asp Arg Lys Glu Phe 2500 2505 2510 Glu Glu Tyr Lys Arg Ser Gly He Leu Glu Val Asp Arg Thr Glu Ala 2515 2520 2525 Lys Ser Ala Leu Lys Asp Gly Ser Lys He Lys His Ala Val Ser Arg 2530 2535 2540 Gly Ser Ser Lys He Arg Trp He Val Glu Arg Gly Met Val Lys Pro 2545 2550 2555 2560 Lys Gly Lys Val Val Asp Leu Gly Cys Gly Arg Gly Gly Trp Ser Tyr 2565 2570 2575 Tyr Met Ala Thr Leu Lys Asn Val Thr Glu Val Lys Gly Tyr Thr Lys 2580 2585 2590 Gly Gly Pro Gly His Glu Glu Pro He Pro Met Ala Thr Tyr Gly Trp 2595 2600 2605 Asn Leu Val Lys Leu His Ser Gly Val Asp Val Phe Tyr Lys Pro Thr 2610 2615 2620 Glu Gin Val Asp Thr Leu Leu Cys Asp He Gly Glu Ser Ser Ser Asn 2625 2630 2635 2640 Pro Thr He Glu Glu Gly Arg Thr Leu Arg Val Leu Lys Met Val Glu 2645 2650 2655 Pro Trp Leu Ser Ser Lys Pro Glu Phe Cys He Lys Val Leu Asn Pro 2660 2665 2670 Tyr Met Pro Thr Val He Glu Glu Leu Glu Lys Leu Gin Arg Lys His 2675 2680 2685

    291

    2018200081 04 Jan 2018

    Gly Gly Asn Leu Val Arg Cys Pro Leu Ser Arg Asn Ser Thr His Glu 2690 2695 2700 Met Tyr Trp Val Ser Gly Ala Ser Gly Asn lie Val Ser Ser Val Asn 2705 2710 2715 2720 Thr Thr Ser Lys Met Leu Leu Asn Arg Phe Thr Thr Arg His Arg Lys 2725 2730 2735 Pro Thr Tyr Glu Lys Asp Val Asp Leu Gly Ala Gly Thr Arg Ser Val 2740 2745 2750 Ser Thr Glu Thr Glu Lys Pro Asp Met Thr He He Gly Arg Arg Leu 275E i 276C I 2765 Gin Arg Leu Gin Glu Glu His Lys Glu Thr Trp His Tyr Asp Gin Glu 2770 2775 2780 Asn Pro Tyr Arg Thr Trp Ala Tyr His Gly Ser Tyr Glu Ala Pro Ser 2785 2790 2795 2800 Thr Gly Ser Ala Ser Ser Met Val Asn Gly Val Val Lys Leu Leu Thr 2805 2810 2815 Lys Pro Trp Asp Val Val Pro Met Val Thr Gin Leu Ala Met Thr Asp 2820 2825 2830 Thr Thr Pro Phe Gly Gin Gin Arg Val Phe Lys Glu Lys Val Asp Thr 2835 2840 2845 Arg Thr Pro Gin Pro Lys Pro Gly Thr Arg Met Val Met Thr Thr Thr 2850 2855 2860 Ala Asn Trp Leu Trp Ala Leu Leu Gly Lys Lys Lys Asn Pro Arg Leu 2865 2870 2875 2880 Cys Thr Arg Glu Glu Phe lie Ser Lys Val Arg Ser Asn Ala Ala lie 2885 2890 2895 Gly Ala Val Phe Gin Glu Glu Gin Gly Trp Thr Ser Ala Ser Glu Ala 2900 2905 2910 Val Asn Asp Ser Arg Phe Trp Glu Leu Val Asp Lys Glu Arg Ala Leu 2915 2920 2925 His Gin Glu Gly Lys Cys Glu Ser Cys Val Tyr Asn Met Met Gly Lys 2930 2935 2940 Arg Glu Lys Lys Leu Gly Glu Phe Gly Arg Ala Lys Gly Ser Arg Ala 2945 2950 2955 2960 lie Trp Tyr Met Trp Leu Gly Ala Arg Phe Leu Glu Phe Glu Ala Leu 2965 2970 2975 Gly Phe Leu Asn Glu Asp His Trp Phe Gly Arg Glu Asn Ser Trp Ser 2980 2985 2990 Gly Val Glu Gly Glu Gly Leu His Arg Leu Gly Tyr He Leu Glu Glu 2995 3000 3005 He Asp Lys Lys Asp Gly Asp Leu Met Tyr Ala Asp Asp Thr Ala Gly 3010 3015 3020 Trp Asp Thr Arg He Thr Glu Asp Asp Leu Gin Asn Glu Glu Leu He 3025 3030 3035 3040 Thr Glu Gin Met Ala Pro His His Lys He Leu Ala Lys Ala He Phe 3045 3050 3055 Lys Leu Thr Tyr Gin Asn Lys Val Val Lys Val Leu Arg Pro Thr Pro 3060 3065 3070 Arg Gly Ala Val Met Asp He He Ser Arg Lys Asp Gin Arg Gly Ser 3075 3080 3085 Gly Gin Val Gly Thr Tyr Gly Leu Asn Thr Phe Thr Asn Met Glu Val 3090 3095 3100 Gin Leu lie Arg Gin Met Glu Ala Glu Gly Val He Thr Gin Asp Asp 3105 3110 3115 3120

    292

    2018200081 04 Jan 2018

    Met Gin Asn Pro Lys Gly Leu Lys Glu Arg Val 3130 Glu Lys Trp Leu Lys 3135 3125 Glu Cys Gly Val Asp Arg Leu Lys Arg Met Ala He Ser Gly Asp Asp 3140 3145 3150 Cys Val Val Lys Pro Leu Asp Glu Arg Phe Gly Thr Ser Leu Leu Phe 3155 3160 3165 Leu Asn Asp Met Gly Lys Val Arg Lys Asp He Pro Gin Trp Glu Pro 3170 3175 3180 Ser Lys Gly Trp Lys Asn Trp Gin Glu Val Pro Phe Cys Ser His His 3185 3190 3195 3200 Phe His Lys lie Phe Met Lys Asp Gly Arg Ser Leu Val Val Pro Cys 3205 3210 3215 Arg Asn Gin Asp Glu Leu He Gly Arg Ala Arg He Ser Gin Gly Ala 3220 3225 3230 Gly Trp Ser Leu Arg Glu Thr Ala Cys Leu Gly Lys Ala Tyr Ala Gin 3235 3240 3245 Met Trp Ser Leu Met Tyr Phe His Arg Arg Asp Leu Arg Leu Ala Ser 3250 3255 3260 Met Ala He Cys Ser Ala Val Pro Thr Glu Trp Phe Pro Thr Ser Arg 3265 3270 3275 3280 Thr Thr Trp Ser He His Ala His His Gin Trp Met Thr Thr Glu Asp 3285 3290 3295 Met Leu Lys Val Trp Asn Arg Val Trp He Glu Asp Asn Pro Asn Met 3300 3305 3310 Thr Asp Lys Thr Pro Val His Ser Trp Glu Asp He Pro Tyr Leu Gly 3315 3320 3325 Lys Arg Glu Asp Leu Trp Cys Gly Ser Leu He Gly Leu Ser Ser Arg 3330 3335 3340 Ala Thr Trp Ala Lys Asn lie His Thr Ala He Thr Gin Val Arg Asn 3345 3350 3355 3360 Leu He Gly Lys Glu Glu Tyr Val Asp Tyr Met Pro Val Met Lys Arg 3365 3370 3375 Tyr Ser Ala Pro Ser Glu Ser Glu Gly Val Leu 3380 3385

    <210> 25 <211> 10648 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <221> CDS <222> (102)...(10265) <400> 25 agttgttagt ctgtgtggac cgacaaggac agttccaaat cggaagcttg cttaacacag ttctaacagt ttgtttgaat agagagcaga tctctggaaa a atg aac caa ega aaa

    Met Asn Gin Arg Lys 1 5

    116

    293

    2018200081 04 Jan 2018

    aag gtg gtt aga Arg cca Pro 10 cct Pro ttc Phe aat Asn atg Met ctg Leu 15 aaa ege gag Glu aga Arg aac Asn 20 ege Arg 164 Lys Val Val Lys Arg gta tea acc cct caa ggg ttg gtg aag aga ttc tea acc gga ctt ttt 212 Val Ser Thr Pro 25 Gin Gly Leu Val Lys 30 Arg Phe Ser Thr Gly 35 Leu Phe tet ggg aaa gga ccc tta egg atg gtg eta gca ttc ate aeg ttt ttg 260 Ser Gly Lys 40 Gly Pro Leu Arg Met 45 Val Leu Ala Phe lie 50 Thr Phe Leu cga gtc ctt tcc ate cca cca aca gca ggg att ctg aaa aga tgg gga 308 Arg Val 55 Leu Ser He Pro Pro 60 Thr Ala Gly He Leu 65 Lys Arg Trp Gly cag ttg aag aaa aat aag gcc ate agg ata ctg att gga ttc agg aag 356 Gin 70 Leu Lys Lys Asn Lys 75 Ala He Arg He Leu 80 He Gly Phe Arg Lys 85 gag ata ggc ege atg ctg aac ate ttg aac ggg aga aaa agg tea aeg 404 Glu He Gly Arg Met 90 Leu Asn He Leu Asn 95' Gly Arg Lys Arg Ser 100 Thr ata aca ttg ctg tgc ttg att ccc acc gta atg gcg ttt cac ttg tea 452 lie Thr Leu Leu 105 Cys Leu He Pro Thr 110 Val Met Ala Phe His 115 Leu Ser aca aga gat ggc gaa ccc etc atg ata gtg gca aaa cat gaa agg ggg 500 Thr Arg Asp 120 Gly Glu Pro Leu Met 125 He Val Ala Lys His 130 Glu Arg Gly aga cct etc ttg ttt aag aca aca gag ggg ate aac aaa tgc act etc 548 Arg Pro 135 Leu Leu Phe Lys Thr 140 Thr Glu Gly He Asn 145 Lys Cys Thr Leu att gcc atg gac ttg ggt gaa atg tgt gag gac act gtc aeg tat aaa 596 He 150 Ala Met Asp Leu Gly 155 Glu Met Cys Glu Asp 160 Thr Val Thr Tyr Lys 165 tgc ccc tta ctg gtc aat acc gaa cct gaa gac att gat tgc tgg tgc 644 Cys Pro Leu Leu Val 170 Asn Thr Glu Pro Glu 175 Asp He Asp Cys Trp 180 Cys aat etc aeg tet acc tgg gtc atg tat ggg aca tgc acc cag agc gga '692 Asn Leu Thr Ser 185 Thr Trp Val Met Tyr 190 Gly Thr Cys Thr Gin 195 Ser Gly gaa egg aga cga gag aag ege tea gta get tta aca cca cat tea gga 740 Glu Arg Arg 200 Arg Glu Lys Arg Ser 205 Val Ala Leu Thr Pro. 210 His Ser Gly atg gga ttg gaa aca aga get gag aca tgg atg tea teg gaa ggg get 788 Met Gly 215 Leu Glu Thr Arg Ala 220 Glu Thr Trp Met Ser 225 Ser Glu Gly Ala

    294

    2018200081 04 Jan 2018

    tgg aag cat get Ala cag aga Gin Arg 235 gta gag age Val Glu Ser tgg Trp ata etc aga aac cca Pro gga Gly 245 836 Trp 230 Lys His He 240 Leu Arg Asn ttc geg etc ttg gca gga ttt atg get tat atg att ggg caa aca gga 884 Phe Ala Leu Leu Ala Gly Phe Met Ala Tyr Met He Gly Gin Thr Gly 250 255 260 ate cag ega act gtc ttc ttt gtc eta atg atg ctg gtc gee cca tcc 932 lie Gin Arg Thr Val Phe Phe Val Leu Met Met Leu Val Ala Pro Ser 265 270 275 tac gga atg ega tgc gta gga gta gga aac aga gac ttt gtg gaa gga 980 Tyr Gly Met Arg Cys Val Gly Val Gly Asn Arg Asp Phe Val Glu Gly 280 285 290 gtc tea ggt gga gca tgg gtc gat ctg gtg eta gaa cat gga gga tgc 1028 Val Ser Gly Gly Ala Trp Val Asp Leu Val Leu Glu His Gly Gly Cys 295 300 305 gtc aca acc atg gcc cag gga aaa cca acc ttg gat ttt gaa ctg act 1076 Val Thr Thr Met Ala Gin Gly Lys Pro Thr Leu Asp Phe Glu Leu Thr 310 315 320 325 aag aca aca gee aag gaa gtg get ctg tta aga acc tat tgc att gaa 1124 Lys Thr Thr Ala Lys Glu Val Ala Leu Leu Arg Thr Tyr Cys He Glu 330 335 340 gcc tea ata tea aac ata acc aeg gca aca aga tgt cca aeg caa gga 1172 Ala Ser He Ser Asn He Thr Thr Ala Thr Arg Cys Pro Thr Gin Gly 345 350 355 gag cct tat eta aaa gag gaa caa gac caa cag tac ate tgc egg aga 1220 Glu Pro Tyr Leu Lys Glu Glu Gin Asp Gin Gin Tyr lie Cys Arg Arg 360 365 370 gat gtg gta gac aga ggg tgg ggc aat ggc tgt ggc ttg ttt gga aaa 1268 Asp Val Val Asp Arg Gly Trp Gly Asn Gly Cys Gly Leu Phe Gly Lys 375 380 385 gga gga gtt gtg aca tgt geg aag ttt tea tgt teg ggg aag ata aca 1316 Gly Gly Val Val Thr Cys Ala Lys Phe Ser Cys Ser Gly Lys He Thr 390 395 400 405 ggc aat ttg gtc caa att gag aac ett gaa tac aca gtg gtt gta aca 1364 Gly Asn Leu Val Gin He Glu Asn Leu Glu Tyr Thr Val Val Val Thr 410 415 420 gtc cac aat gga gac acc cat gca gta gga aat gac aca tcc aat cat 1412 Val His Asn Gly Asp Thr His Ala Val Gly Asn Asp Thr Ser Asn His 425 430 435

    295

    2018200081 04 Jan 2018

    gga gtt aca gcc aeg ata act ccc agg tea cca teg gtg gaa gtc Val aaa Lys 1460 Gly Val Thr Ala 440 Thr lie Thr Pro 445 Arg Ser Pro Ser Val 450 Glu ttg ccg gac tat gga gaa eta aca etc gat tgt gaa ccc agg tct gga 1508 Leu Pro Asp Tyr Gly Glu Leu Thr Leu Asp Cys Glu Pro Arg Ser Gly 455 460 465 att gac ttt aat gag atg att ctg atg aaa atg aaa aag aaa aca tgg 1556 lie Asp Phe Asn Glu Met He Leu Met Lys Met Lys Lys Lys Thr Trp 470 475 480 485 ett gtg cat aag caa tgg ttt ttg gat eta cct eta cca tgg aca gca 1604 Leu Val His Lys Gin Trp Phe Leu Asp Leu Pro Leu Pro Trp Thr Ala 490 495 500 gga gca gac aca tea gag gtt cac tgg aat tac aaa gag aga atg gtg 1652 Gly Ala Asp Thr Ser Glu Val His Trp Asn Tyr Lys Glu Arg Met Val 505 510 515 aca ttt aag gtt cct cat gcc aag aga cag gat gtg aca gtg ctg gga 1700 Thr Phe Lys Val Pro His Ala Lys Arg Gin Asp Val Thr Val Leu Gly 520 525 530 tct cag gaa gga gcc atg cat tct gcc etc get gga gcc aca gaa gtg 1748 Ser Gin Glu Gly Ala Met His Ser Ala Leu Ala Gly Ala Thr Glu Val 535 540 545 gac tcc ggt gat gga aat cac atg ttt gca gga cat etc aag tgc aaa 1796 Asp Ser Gly Asp Gly Asn His Met Phe Ala Gly His Leu Lys Cys Lys 550 555 560 565 gtc cgt atg gag aaa ttg aga ate aag gga atg tea tac aeg atg tgt 1844 Val Arg Met Glu Lys Leu Arg He Lys Gly Met Ser Tyr Thr Met Cys 570 575 580 tea gga aag ttc tea att gac aaa gag atg gca gaa aca cag cat ggg 1892 Ser Gly Lys Phe Ser He Asp Lys Glu Met Ala Glu Thr Gin His Gly 585 590 595 aca aca gtg gtg aaa gtc aag tat gaa ggt get gga get ccg tgt aaa 1940 Thr Thr Val Val Lys Val Lys Tyr Glu Gly Ala Gly Ala Pro Cys Lys 600 605 610 gtc ccc ata gag ata aga gat gtg aac aag aaa aaa gtg gtt ggg cgt 1988 Val Pro He Glu lie Arg Asp Val Asn Lys Lys Lys Val Val Gly Arg 615 620 625 ate ate tea tcc acc cct ttg get gag aat acc aac agt gca acc aac 2036 He He Ser Ser Thr Pro Leu Ala Glu Asn Thr Asn Ser Ala Thr Asn 630 635 640 645 ata gag tta gaa ccc ccc ttt ggg gac age tac ata gtg ata ggt gtt 2084 He Glu Leu Glu Pro Pro Phe Gly Asp Ser Tyr He Val He Gly Val 650 655 660

    296

    2018200081 04 Jan 2018

    gga aac Gly Asn agt Ser gca tta Ala Leu 665 aca Thr etc Leu cat His tgg ttc agg aaa ggg agt tcc Ser att lie 2132 Trp 670 Phe Arg Lys Gly Ser 675 ggc aag atg ttt gag tcc aca tac aga ggt gca aaa cga atg gcc att 2180 Gly Lys Met Phe Glu Ser Thr Tyr Arg Gly Ala Lys Arg Met Ala He 680 685 690 eta ggt gaa aca get tgg gat ttt ggt tcc gtt ggt gga ctg ttc aca 2228 Leu Gly Glu Thr Ala Trp Asp Phe Gly Ser Val Gly Gly Leu Phe Thr 695 700 705 tea ttg gga aag get gtg cac cag gtt ttt gga agt gtg tat aca acc 2276 Ser Leu Gly Lys Ala Val His Gin Val Phe Gly Ser Val Tyr Thr Thr 710 715 720 725 atg ttt gga gga gtc tea tgg atg att aga ate eta att ggg ttc eta 2324 Met Phe Gly Gly Val Ser Trp Met He Arg He Leu He. Gly Phe Leu 730 735 740 gtg ttg tgg att ggc aeg aac tea agg aac act tea atg get atg aeg 2372 Val Leu Trp He Gly Thr Asn Ser Arg Asn Thr Ser Met Ala Met Thr 745 750 755 tgc ata get gtt gga gga ate act ctg ttt ctg ggc ttc aca gtt caa 2420 Cys lie Ala Val Gly Gly He Thr Leu Phe Leu Gly Phe Thr Val Gin 760 765 770 gca gac atg ggt tgt gtg gtg tea tgg agt ggg aaa gaa ttg aag tgt 2468 Ala Asp Met Gly Cys Val Val Ser Trp Ser Gly Lys Glu Leu Lys Cys 775 780 785 gga age gga att ttt gtg gtt gac aac gtg cac act tgg aca gaa cag 2516 Gly Ser Gly He Phe Val Val Asp Asn Val His Thr Trp Thr Glu Gin 790 795 800 805 tac aaa ttt caa ccg gag tcc cca gcg aga eta gcg tct gca ata ttg 2564 Tyr Lys Phe Gin Pro Glu Ser Pro Ala Arg Leu Ala Ser Ala He Leu 810 815 820 aat gcc cac aaa gat ggg gtc tgt gga att aga tea acc aeg agg ctg 2612 Asn Ala His Lys Asp Gly Val Cys Gly He Arg Ser Thr Thr Arg Leu 825 830 835 gaa aat gtc atg tgg aag caa ata acc aac gag eta aat tat gtt etc 2660 Glu Asn Val Met Trp Lys Gin He Thr Asn Glu Leu Asn Tyr Val Leu 840 845 850 tgg gaa gga gga cat gac etc act gta gtg get ggg gat gtg aag ggg 2708 Trp Glu Gly Gly His Asp Leu Thr Val Val Ala Gly Asp Val Lys Gly 855 860 865

    297

    2018200081 04 Jan 2018

    gtg Val 870 ttg Leu acc Thr aaa Lys ggc Gly aag Lys 875 aga Arg gca Ala etc Leu aca ccc cca gtg aat Pro Val Asn gat Asp ctg Leu 885 2756 Thr Pro 880 aaa tat tea tgg aag aca tgg gga aaa gca aaa ate ttc acc cca gaa 2804 Lys Tyr Ser Trp Lys 890 Thr Trp Gly Lys Ala 895 Lys He Phe Thr Pro 900 Glu gca aga aat agc aca ttt tta ata gac gga cca gac acc tcc gaa tgc 2852 Ala Arg Asn Ser 905 Thr Phe Leu He Asp 910 Gly Pro Asp Thr Ser 915 Glu Cys ccc aat gaa ega aga gca tgg aac ttt ett gag gtg gaa gac tat gga 2900 Pro Asn Glu 920 Arg Arg Ala Trp Asn 925 Phe Leu Glu Val Glu Asp 930 Tyr Gly ttt ggc atg ttc aeg acc aac ata tgg atg aaa ttc ega gaa gga agt 2948 Phe Gly 935 Met Phe Thr Thr Asn 940 He Trp Met Lys Phe Arg Glu 945 Gly Ser tea gaa gtg tgt gac cac agg tta atg tea geg gca att aaa gat cag 2996 Ser 950 Glu Val Cys Asp His 955 Arg Leu Met Ser Ala 960 Ala He Lys Asp Gin 965 aaa get gtg cat get gac atg ggt tat tgg ata gag agc tea aaa aac 3044 Lys Ala Val His Ala 970 Asp Met Gly Tyr Trp 975 He Glu Ser Ser Lys 980 Asn cag acc tgg cag ata gag aaa gca tet ett att gaa gtg aaa aca tgt 3092 Gin Thr Trp Gin lie 985 Glu Lys Ala Ser Leu 990 He Glu Val Lys Thr 995 Cys ctg tgg CCC aag acc cac aca ttg tgg agc aat gga gtg ctg gaa age 3140 Leu Trp Pro Lys 1000 Thr His Thr Leu Trp 1005 Ser Asn Gly Val Leu 1010 Glu Ser cag atg etc att cca aaa tea tat geg ggc cct ttt tea cac cac aat 3188 Gin Met Leu 1015 He Pro Lys Ser Tyr 1020 Ala Gly Pro Phe Ser His 1025 His Asn tac ege cag ggc tat gee aeg caa acc gtg ggc cca tgg cac tta ggc 3236 Tyr Arg 1030 Gin Gly Tyr Ala Thr 1035 Gin Thr Val Gly Pro Trp His 1040 Leu Gly 1045 aaa tta gag ata gac ttt gga gaa tgc ccc gga aca aca gtc gca att 3284 Lys Leu Glu He Asp Phe 1050 Gly Glu Cys Pro Gly 1055 Thr Thr Val Ala He 1060 cag gag gat tgt gac cat aga ggc cca tet ttg agg acc acc act gca 3332 Gin Glu Asp Cys Asp 1065 His Arg Gly Pro Ser 1070 Leu Arg Thr Thr Thr 1075 Ala tet gga aaa eta gtc aeg caa tgg tgc tgc ege tcc tgc aeg atg cct 3380 Ser Gly Lys Leu 1080 Val Thr Gin Trp Cys 1085 Cys Arg Ser Cys Thr 1090 Met Pro

    298

    2018200081 04 Jan 2018

    ccc Pro tta agg Leu Arg 1095 ttc Phe ttg gga gaa gat ggg Gly tgc Cys tgg Trp tat ggg atg Tyr Gly Met 1105 gag Glu att lie 3428 Leu Gly Glu Asp 1100 agg ccc ttg agt gaa aaa gaa gag aac atg gtc aaa tea cag gta aeg 3476 Arg 1110 Pro Leu 1 Ser Glu Lys 1115 Glu Glu Asn Met Val 1120 Lys Ser Gin 1 Val Thr 1125 gcc gga cag ggc aca tea gaa act ttt tet atg ggt ctg ttg tgc ctg 3524 Ala Gly Gin Gly Thr 1130 Ser 1 Glu Thr Phe Ser Met 1135 Gly Leu Leu Cys 1140 Leu 1 acc ttg ttt gtg gaa gaa tgc ttg agg aga aga gtc act agg aaa cac 3572 Thr Leu Phe Val Glu 1145 Glu Cys Leu Arg 115C Arg 1 Arg Val Thr Arg Lys 1155 His atg ata ttg gtt gtg gtg ate act ett tgt gcc ate ate eta gga ggc 3620 Met lie Leu Val 1160 Val Val He Thr Leu 1165 Cys Ala He He Leu 1170 Gly Gly etc aca tgg atg gac tta eta ega gcc etc ate atg ttg ggg gac act 3668 Leu Thr Trp 1175 Met Asp Leu Leu Arg 1180 Ala Leu He Met Leu Gly 1185 Asp Thr atg tet ggt aga ata gga gga cag ate cac eta gcc ate atg gca gtg . 3716 Met 119C Ser Gly 1 Arg He Gly 1195 Gly Gin He His Leu 1200 Ala He Met 1 Ala Val 1205 ttc aag atg tea cca gga tac gtg ctg ggt gtg ttt tta agg aaa etc 3764 Phe Lys Met Ser Pro 121C Gly 1 Tyr Val Leu Gly Val 1215 Phe Leu Arg Lys 1220 Leu 1 act tea aga gag aca gca eta atg gta ata gga atg gcc atg aca aeg 3812 Thr Ser Arg Glu Thr 1225 Ala Leu Met Val He 1230 Gly Met Ala Met Thr 1235 Thr gtg ett tea att cca cat gac ett atg gaa etc att gat gga ata tea 3860 Val Leu Ser He 1240 Pro His Asp Leu Met 1245 Glu Leu He Asp Gly 1250 He Ser ctg ggg eta att ttg eta aaa ata gtg aca cat ttt gac aac acc caa 3908 Leu Gly Leu 1255 He Leu Leu Lys He 1260 Val Thr His Phe Asp Asn 1265 Thr Gin gtg gga acc tta gcc ett tcc ttg acc ttc ata aga tea aca atg cca 3956 Val Gly Thr 1270 Leu Ala Leu Ser Leu 1275 Thr Phe lie Arg Ser Thr 1280 Met Pro 12 85 ttg gtc atg get tgg agg acc att atg get gtg ttg ttt gtg gtc aca 4004 Leu Val Met Ala Trp Arg 1290 Thr He Met Ala Val 1295 Leu Phe Val Val 130C Thr I

    299

    2018200081 04 Jan 2018

    etc Leu att He cct Pro ttg tgc Leu Cys 1305 agg Arg aca Thr age Ser tgt ett Cys Leu 1310 caa Gin aaa Lys cag tct cat Gin Ser His • 1315 tgg Trp 4052 gta gaa ata aca gca etc ate eta gga gcc caa get ctg cca gtg tac 4100 Val Glu He 132C Thr Ala 1 Leu He Leu 1325 Gly Ala Gin Ala Leu Pro Val 1330 Tyr eta atg act ett atg aaa gga gcc tea aga aga tct tgg cct ett aac 4148 Leu Met 1335 Thr Leu Met Lys Gly Ala 1340 Ser Arg Arg Ser Trp Pro Leu 1345 Asn gag ggc ata atg get gtg ggt ttg gtt agt etc tta gga age get ett 4196 Glu 135C Gly I He Met Ala Val Gly 1355 Leu Val Ser Leu Leu 1360 Gly Ser Ala Leu 1365 tta aag aat gat gtc cct tta get ggc cca atg gtg gca gga ggc tta 4244 Leu Lys Asn Asp Val Pro 1370 Leu Ala Gly Pro Met 1375 Val Ala Gly Gly Leu 1380 ett ctg gcg get tac gtg atg agt ggt age tea gca gat ctg tea eta 4292 Leu Leu Ala Ala Tyr 1385 Val Met Ser Gly Ser 1390 Ser Ala Asp Leu Ser 1395 Leu gag aag gcc gcc aat gtg cag tgg gat gaa atg gca gac ata aca ggc 4340 Glu Lys Ala Ala Asn 1400 Val Gin Trp Asp Glu 1405 Met Ala Asp He Thr 1410 Gly tea age cca ate ata gaa gtg aag cag gat gaa gat ggc tct ttc tcc 4388 Ser Ser Pro 1415 lie He Glu Val Lys 1420 Gin Asp Glu Asp Gly Ser Phe 1425 Ser ata egg gac gtc gag gaa acc aat atg ata acc ett ttg gtg aaa ctg 4436 lie Arg 1430 Asp Val Glu Glu Thr 1435 Asn Met He Thr Leu 1440 Leu Val Lys Leu 1445 gca ctg ata aca gtg tea ggt etc tac ccc ttg gca att cca gtc aca 4484 Ala Leu He Thr Val Ser 1450 Gly Leu Tyr Pro Leu 1455 Ala He Pro Val Thr 1460 atg acc tta tgg tac atg tgg caa gtg aaa aca caa aga tea gga gcc 4532 Met Thr Leu Trp Tyr 1465 Met Trp Gin Val Lys 1470 Thr Gin Arg Ser Gly 1475 Ala ctg tgg gac gtc ccc tea ccc get gcc act caa aaa gcc gca ctg tct 4580 Leu Trp Asp Val Pro 1480 Ser Pro Ala Ala Thr 1485 Gin Lys Ala Ala Leu 1490 Ser gaa gga gtg tac agg ate atg caa aga ggg tta ttt ggg aaa act cag 4628 Glu Gly Val 1495 Tyr Arg He Met Gin 1500 Arg Gly Leu Phe Gly Lys Thr 1505 Gin gtt gga gta ggg ata cac atg gaa ggt gta ttt cac aca atg tgg cat 4676 Val Gly Val 1510 Gly lie His Met 1515 Glu Gly Val Phe His 1520 Thr Met Trp His 1525

    300

    2018200081 04 Jan 2018

    gta Val aca Thr aga gga Arg Gly tea gtg ate tgc Cys cat His gag act Glu Thr 1535 ggg Gly aga Arg ttg gag cca Leu Glu Pro 1540 4724 Ser Val 1530 lie tet tgg get gac gtc agg aat gac atg ata tea tac ggt ggg gga tgg 4772 Ser Trp Ala Asp 1545 Val Arg Asn Asp Met 1550 He Ser 1 Tyr Gly Gly Gly Trp 1555 aga ett gga gac aaa tgg gac aaa gaa gaa gat gtt cag gtc etc gcc 4820 Arg Leu Gly Asp 1560 Lys Trp Asp Lys Glu 1565 Glu Asp Val Gin Val Leu Ala 1570 ata gaa cca gga aaa aat cct aaa cat gtc caa aeg aaa ccc ggc ett 4868 lie Glu Pro Gly 1575 Lys Asn Pro Lys 1580 His Val Gin Thr Lys 1585 Pro Gly Leu ttc aag acc eta act gga gaa att gga gca gta aca tta gat ttc aaa 4916 Phe Lys 1590 Thr Leu Thr Gly Glu 1595 He Gly Ala Val Thr 1600 Leu Asp Phe Lys 1605 ccc gga aeg tet ggt tet ccc ate ate aac agg aaa gga aaa gtc ate 4964 Pro Gly Thr Ser Gly Ser 1610 Pro He He Asn Arg 1615 Lys Gly Lys Val He 1620 gga etc tat gga aat gga gta gtt acc aaa tea ggt gat tac gtc agt 5012 Gly Leu Tyr Gly Asn Gly 1625 Val Val Thr Lys Ser 1630 Gly Asp Tyr Val Ser 1635 gcc ata aeg caa gcc gaa aga att gga gag cca gat tat gaa gtg gat 5060 Ala He Thr Gin 1640 Ala Glu Arg He Gly 1645 Glu Pro Asp Tyr Glu Val Asp 1650 gag gac att ttt ega aag aaa aga tta act ata atg gac tta cac ccc 5108 Glu Asp He Phe 1655 Arg Lys Lys Arg 1660 Leu Thr He Met Asp 1665 Leu His Pro gga get gga aag aca aaa aga att ett cca tea ata gtg aga gaa gcc 5156 Gly Ala 1670 Gly Lys Thr Lys Arg 1675 He Leu Pro Ser He 1680 Val Arg Glu Ala 1685 tta aaa agg agg ctg ega acc ttg att ttg get ccc aeg aga gtg gtg 5204 Leu Lys Arg Arg Leu Arg 1690 Thr Leu He Leu Ala 1695 Pro Thr Arg Val Val 1700 gcg gcc gag atg gaa gag gcc eta cgt gga ctg cca ate cgt tat cag 5252 Ala Ala Glu Met Glu Glu 1705 Ala Leu Arg Gly Leu 1710 Pro He Arg Tyr Gin 1715 acc cca get gtg aaa tea gaa cac aca gga aga gag att gta gac etc 5300 Thr Pro Ala Val Lys Ser Glu His Thr Gly Arg Glu He Val Asp Leu

    1720 1725 1730

    301

    2018200081 04 Jan 2018

    atg Met tgt cat Cys His 1735 gca Ala acc Thr ttc Phe aca aca aga ett ttg Leu tea tea Ser Ser 1745 acc Thr aga Arg gtt Val 5348 Thr Thr 1740 Arg Leu cca aat tac aac etc ata gtg atg gat gaa gca cat ttc acc gat cct 5396 Pro Asn Tyr 1750 Asn Leu He 1755 Val Met Asp Glu Ala 176C His Phe 1 Thr Asp Pro 1765 tct agt gtc gcg get aga gga tac ate teg acc agg gtg gaa atg gga 5444 Ser Ser Val Ala Ala Arg 1770 Gly Tyr He Ser 1775 Thr Arg Val Glu Met 178C Gly 1 gag gca gca gcc ate ttc atg acc gca acc cct ccc gga gcg aca gat 5492 Glu Ala Ala Ala lie 1785 Phe Met Thr Ala Thr 1790 Pro Pro Gly Ala Thr 1795 Asp ccc ttt ccc cag age aac age cca ata gaa gac ate gag agg gaa att 5540 Pro Phe Pro Gin 1800 Ser Asn Ser Pro He 1805 Glu Asp He Glu Arg 1810 Glu He ccg gaa agg tea tgg aac aca ggg ttc gac tgg ata aca gac tac caa 5588 Pro Glu Arg 1815 Ser Trp Asn Thr Gly 1820 Phe Asp Trp He Thr 1825 Asp Tyr Gin ggg aaa act gtg tgg ttt gtt ccc age ata aaa get gga aat gac att 5636 Gly Lys Thr 1830 Val Trp Phe Val Pro 1835 Ser lie Lys Ala Gly 1840 Asn Asp He 1845 gca aat tgt ttg aga aag teg gga aag aaa gtt ate cag ttg agt agg 5684 Ala Asn Cys Leu Arg Lys 1850 Ser Gly Lys Lys 1855 Val He Gin Leu Ser I860 Arg 1 aaa acc ttt gat aca gag tat cca aaa aeg aaa etc aeg gac tgg gat 5732 Lys Thr Phe Asp Thr 1865 Glu Tyr Pro Lys Thr 1870 Lys Leu Thr Asp Trp 1875 Asp ttt gtg gtc act aca gac ata tct gaa atg ggg gcc aat ttt aga get 5780 Phe Val Val'Thr 1880 Thr Asp He Ser Glu 1885 Met Gly Ala Asn Phe 1890 Arg Ala ggg aga gtg ata gac cct agg aga tgc etc aag cca gtt ate eta aca 5828 Gly Arg Val 1895 He Asp Pro Arg Arg 1900 Cys Leu Lys Pro Val 1905 He Leu Thr gat ggg cca gag aga gtc att tta gca ggt cct att cca gtg act cca 5876 Asp Gly Pro 1910 Glu Arg Val He Leu 1915 Ala Gly Pro He Pro 1920 Val Thr Pro 1925 gca age get get cag aga aga ggg cga ata gga agg aac cca gca caa 5924 Ala Ser Ala Ala Gin Arg 1930 Arg Gly Arg He Gly 1935 Arg Asn Pro Ala Gin 1940 gaa gac gac caa tac gtt ttc tcc gga gac cca eta aaa aat gat gaa 5972 Glu Asp Asp Gin Tyr 1945 Val Phe Ser Gly Asp 1950 Pro Leu Lys Asn Asp 1955 Glu

    302

    2018200081 04 Jan 2018

    gat Asp cat His gcc cac Ala His 1960 tgg Trp aca Thr gaa Glu gca aag Ala Lys 1965 atg Met ctg Leu ett Leu gac aat Asp Asn 1970 ate lie tac Tyr 6020 acc cca gaa ggg ate att cca aca ttg ttt ggt ccg gaa agg gaa aaa 6068 Thr Pro 1975 Glu Gly lie He Pro 198C Thr Leu 1 Phe Gly Pro Glu Arg 1985 Glu Lys acc caa gcc att gat gga gag ttt ege etc aga ggg gaa caa agg aag 6116 Thr Gin 1990 Ala He Asp Gly Glu 1995 Phe Arg Leu Arg Gly 2000 Glu Gin Arg Lys 2005 act ttt gtg gaa tta atg agg aga gga gac ett ccg gtg tgg ctg agc 6164 Thr Phe Val Glu Leu Met 2010 Arg Arg Gly Asp Leu 2015 Pro Val Trp Leu 202C Ser 1 tat aag gta get tet get ggc att tet tac aaa gat egg gaa tgg tgc 6212 Tyr Lys Val Ala Ser 2025 Ala Gly He Ser Tyr 2030 Lys Asp Arg Glu Trp 2035 Cys ttc aca ggg gaa agg aat aac caa att tta gaa gaa aac atg gag gtt 6260 Phe Thr Gly Glu 2040 Arg Asn Asn Gin lie 2045 Leu Glu Glu Asn Met 2050 Glu Val gaa att tgg act aga gag gga gaa aag aaa aag eta agg cca aga tgg 6308 Glu He 2055 Trp Thr Arg Glu Gly 206C Glu Lys 1 Lys Lys Leu Arg Pro 2065 Arg Trp tta gat gca cgt gta tac get gac ccc atg get ttg aag gat ttt aag 6356 Leu Asp 2070 Ala Arg Val Tyr Ala 2075 Asp Pro Met Ala Leu 2080 Lys Asp Phe Lys 2085 gag ttt get agt gga agg aag agc ata act etc gac ate eta aca gag 6404 Glu Phe Ala Ser Gly Arg 2090 Lys Ser lie Thr Leu 2095 Asp lie Leu Thr Glu 2100 att gcc agt ttg cca act tac ett tcc tet agg gcc aag etc gcc ett 6452 lie Ala Ser Leu Pro 2105 Thr Tyr Leu Ser Ser 2110 Arg Ala Lys Leu 2115 Ala Leu gat aac ata gtc atg etc cac aca aca gaa aga gga ggg agg gcc tac 6500 Asp Asn He Val 2120 Met Leu His Thr Thr 2125 Glu Arg Gly Gly Arg 2130 Ala Tyr caa cac gcc ctg aac gaa etc ccg gag tea ctg gaa aca ett atg ett 6548 Gin His Ala Leu 2135 Asn Glu Leu Pro Glu 2140 Ser Leu Glu Thr Leu 2145 Met Leu gta get tta eta ggt get atg aca gca ggt ate ttc ctg ttt ttc atg 6596 Val Ala Leu Leu Gly Ala Met Thr Ala Gly He Phe Leu Phe Phe Met

    2150 2155 2160 2165

    303

    2018200081 04 Jan 2018

    caa Gin ggg Gly aaa Lys gga Gly ata ggg He Gly 2170 aaa Lys ttg Leu tea Ser atg ggt Met Gly 2175 ttg Leu ata He acc Thr att geg He Ala 2180 6644 gtg get agt ggc ttg ttc tgg gta gca gaa att caa ccc cag tgg ata 6692 Val Ala Ser Gly Leu Phe 2185 Trp Val Ala 219C Glu He 1 Gin Pro Gin Trp He 2195 geg gcc tea ate ata eta gag ttt ttt etc atg gta ctg ttg ata ccg 6740 Ala Ala Ser He 2200 He Leu Glu Phe Phe 2205 Leu Met Val Leu 221C Leu 1 He Pro gaa cca gaa aaa caa agg acc cca caa gac aat caa ttg ate tac gtc 6788 Glu Pro 2215 Glu Lys Gin Arg Thr Pro 2220 Gin Asp Asn Gin Leu 2225 He Tyr Val ata ttg acc att etc acc att att ggt etc ata gca gcc aac gag atg 6836 lie Leu 2230 Thr He Leu Thr 2235 He He Gly Leu He 224C Ala 1 Ala Asn Glu Met 2245 ggg ctg att gaa aaa aca aaa aeg gat ttt ggg ttt tac cag gta aaa 6884 Gly Leu He Glu Lys Thr 2250 Lys Thr Asp Phe Gly 2255 Phe Tyr Gin Val Lys 2260 aca gaa acc acc ate etc gat gtg gac ttg aga cca get tea gca tgg 6932 Thr Glu Thr Thr He Leu 2265 Asp Val Asp Leu Arg 2270 Pro Ala Ser Ala Trp 2275 aeg etc tat gca gta gcc acc aca ttt ctg act ccc atg ctg aga cac 6980 Thr Leu Tyr Ala 2280 Val Ala Thr Thr Phe 2285 Leu Thr Pro Met 229C Leu 1 Arg His acc ata gaa aac aeg teg gcc aac eta tet eta gca gcc att gcc aac 7028 Thr He Glu 2295 Asn Thr Ser Ala Asn 2300 Leu Ser Leu Ala Ala 2305 He Ala Asn cag geg gee gtc eta atg ggg ctt gga aaa gga tgg ccg etc cac aga 7076 Gin Ala 2310 Ala Val Leu Met Gly 2315 Leu Gly Lys Gly 232C Trp 1 Pro Leu His Arg 2325 atg gac etc ggt gtg ccg ctg tta gca atg gga tgc tat tet caa gtg 7124 Met Asp Leu Gly Val Pro 2330 Leu Leu Ala Met Gly 2335 Cys Tyr Ser Gin Val 2340 aac cca aca act ttg aca gca tcc tta gtc atg ctt tea gtc cat tat 7172 Asn Pro Thr Thr Leu Thr 2345 Ala Ser Leu Val Met 2350 Leu Ser Val His Tyr 2355 gca ata ata ggt cca gga ttg cag gca aaa gcc aca aga gag gcc cag 7220 Ala He lie Gly 2360 Pro Gly Leu Gin Ala 2365 Lys Ala Thr Arg Glu 2370 Ala Gin aaa agg aca get get ggg ate atg aaa aac ccc aeg gtg gac ggg ata 7268 Lys Arg Thr 2375 Ala Ala Gly He Met 2380 Lys Asn Pro Thr Val 2385 Asp Gly He

    304

    2018200081 04 Jan 2018

    aca gta Thr Val 2390 ata lie gat Asp eta gaa cca Leu Glu Pro 2395 ata He tcc Ser tat Tyr gac cca Asp Pro 2400 aaa Lys ttt Phe gaa Glu aag Lys 2405 7316 caa tta ggg cag gtc atg eta etc gtc ttg tgt get gga caa eta etc 7364 Gin Leu Gly Gin Val Met Leu Leu Val Leu Cys Ala Gly Gin Leu Leu 2410 2415 2420 ttg atg aga aca aca tgg get ttc tgt gaa gtc ttg act ttg gcc aca 7412 Leu Met Arg Thr Thr Trp Ala Phe Cys Glu Val Leu Thr Leu Ala Thr 2425 2430 2435 gga cca ate ttg acc ttg tgg gag ggc aac ccg gga agg ttt tgg aac 7460 Gly Pro He Leu Thr Leu Trp Glu Gly Asn Pro Gly Arg Phe Trp Asn 2440 2445 2450 acg acc ata gcc gta tcc acc gcc aac att ttc agg gga agt tac ctg 7508 Thr Thr He Ala Val Ser Thr Ala Asn He Phe Arg Gly Ser Tyr Leu 2455 2460 •fc. 2465

    geg gga get Ala Gly Ala 2470 gga ctg get ttt Ala Phe 2475 tea etc ata aag aat gta caa acc cct Pro 2485 7556 Gly Leu Ser Leu He Lys Asn 2480 Val Gin Thr agg agg gga act ggg acc aca gga gag aca ctg gga gag aag tgg aag 7604 Arg Arg Gly Thr Gly Thr Thr Gly Glu Thr Leu Gly Glu Lys Trp Lys 2490 2495 2500 aga cag eta aac tea tta tac aga aaa gag ttt gaa gag tat aaa aga 7652 Arg Gin Leu Asn Ser Leu Tyr Arg Lys Glu Phe Glu Glu Tyr Lys Arg 2505 2510 2515 agt gga ata eta gaa gtg gac agg act gaa gcc aag tet gcc ctg aaa 7700 Ser Gly He Leu Glu Val Asp Arg Thr Glu Ala Lys Ser Ala Leu Lys 2520 2525 2530 gat ggg tet aaa ate aag cat gca gta tet aga ggg tcc agt aag att 7748 Asp Gly Ser Lys He Lys His Ala Val Ser Arg Gly Ser Ser Lys He 2535 2540 2545 aga tgg att gtt gag aga ggg atg gta aag cca aaa ggg aaa gtt gta 7796 Arg Trp He Val Glu Arg Gly Met Val Lys Pro Lys Gly Lys Val Val 2550 2555 2560 2565 gat ett ggc tgt ggg aga gga gga tgg tet tat tac atg geg acg etc 7844 Asp Leu Gly Cys Gly Arg Gly Gly Trp Ser Tyr Tyr Met Ala Thr Leu 2570 2575 2580 aag aac gtg act gaa gtg aaa ggg tat aca aaa gga ggt cca gga cat 7892 Lys Asn Val Thr Glu Val Lys Gly Tyr Thr Lys Gly Gly Pro Gly His 2585 2590 2595

    305

    2018200081 04 Jan 2018

    gaa Glu gaa Glu ccg att Pro He 2600 ccc Pro atg get Met Ala act tat Thr Tyr 2605 ggc Gly tgg Trp aat Asn ttg gtc Leu Val 2610 aaa Lys etc Leu 7940 cat tea ggg gtt gac gtg ttc tac aaa ccc aca gag caa gtg gac acc 7988 His Ser 2615 Gly Val I Asp Val Phe 262C Tyr Lys 1 Pro Thr Glu 2625 Gin Val Asp Thr ctg etc I tgt gat att ggg gag tea tet tet aat cca aca ata gag gaa 8036 Leu 263C Leu 1 Cys Asp He Gly Glu 2635 Ser Ser Ser Asn 264C Pro 1 Thr He Glu Glu 2645 gga aga aca tta aga gtt ttg aag atg gtg gag cca tgg etc tet tea 8084 Gly Arg Thr Leu Arg Val Leu 2650 Lys Met Val Glu 2655 Pro Trp Leu Ser Ser 2660 aaa cct gaa ttc tgc ate aaa gtc ett aac ccc tac atg cca aca gtc 8132 Lys Pro Glu Phe Cys 2665 He Lys Val Leu Asn 2670 Pro Tyr Met Pro Thr 2675 Val ata gaa gag ctg gag aaa ctg cag aga aaa cat ggt ggg aac ett gtc 8180 lie Glu Glu Leu 2680 Glu Lys Leu Gin Arg 2685 Lys His Gly Gly Asn 2690 Leu Val aga tgc ccg ctg tcc agg aac tcc acc cat gag atg tat tgg gtg tea 8228 Arg Cys 2695 Pro Leu Ser Arg Asn Ser Thr 2700 His Glu Met Tyr Trp 2705 Val Ser gga gcg teg gga aac att gtg age tet gtg aac aca aca tea aag atg 8276 Gly Ala 2710 Ser Gly Asn He Val 2715 Ser Ser Val Asn Thr 2720 Thr Ser Lys Met 2725 ttg ttg aac agg ttc aca aca agg cat agg aaa ccc act tat gag aag 8324 Leu Leu Asn Arg Phe Thr Thr 2730 Arg His Arg Lys 2735 Pro Thr Tyr Glu 274C Lys ) gac gta gat ett ggg gca gga aeg aga agt gtc tcc act gaa aca gaa 8372 Asp Val Asp Leu Gly 2745 Ala Gly Thr Arg Ser 2750 Val Ser Thr Glu Thr 2755 Glu aaa cca gac atg aca att att ggg aga agg ett cag ega ttg caa gag 8420 Lys Pro Asp Met 2760 Thr He He Gly Arg 2765 Arg Leu Gin Arg Leu 2770 Gin Glu gag cac aaa gaa acc tgg cat tat gat cag gaa aac cca tac aga acc 8468 Glu His Lys Glu 2775 Thr Trp His Tyr Asp 2780 Gin Glu Asn Pro Tyr 2785 Arg Thr tgg gcg tat cat gga age tat gaa get cct teg aca ggc tet gca tcc 8516 Trp Ala 2790 Tyr His Gly Ser Tyr 2795 Glu Ala Pro Ser Thr 2800 Gly Ser Ala Ser 2805 tcc atg gtg aac ggg gta gta aaa ctg eta aca aaa cct tgg gat gtg 8564 Ser Met Val Asn Gly Val Val 2810 Lys Leu Leu Thr 2815 Lys Pro Trp Asp Val 2820

    306

    2018200081 04 Jan 2018

    gtt Val cca Pro atg Met gtg acc Val Thr 2825 cag Gin tta Leu gcc Ala atg aca Met Thr 2830 gac Asp aca Thr acc Thr cct ttt Pro Phe 2835 ggg Gly 8612 caa caa aga gtg ttc aaa gag aag gtg gat acc aga aca cca caa cca 8660 Gin. Gin Arg 284C Val Phe 1 Lys Glu Lys 2845 Val Asp Thr Arg Thr 285C Pro Gin 1 Pro aaa ccc ggt aca ega atg gtt atg acc acg aca gcc aat tgg ctg tgg 8708 Lys Pro 2855 Gly Thr Arg Met Val Met 2860 Thr Thr Thr Ala 2865 Asn Trp Leu Trp gcc etc ett ggg aag aag aaa aat ccc aga ctg tgc aca agg gaa gag 8756 Ala Leu 2870 Leu Gly Lys Lys Lys 2875 Asn Pro Arg Leu Cys 2880 Thr Arg Glu Glu 2885 ttc ate tea aaa gtt aga tea aac gca gcc ata ggc gca gtc ttt cag 8804 Phe lie Ser Lys Val Arg 2890 Ser Asn Ala Ala He 2895 Gly Ala Val Phe Gin 2900 gaa gaa cag gga tgg aca tea gcc agt gaa get gtg aat gac age egg 8852 Glu Glu Gin Gly Trp 2905 Thr Ser Ala Ser Glu 2910 Ala Val Asn Asp Ser 2915 Arg ttt tgg gaa ctg gtt gac aaa gaa agg gcc eta cac cag gaa ggg aaa 8900 Phe Trp Glu 292C Leu Val 1 Asp Lys Glu 2925 Arg Ala Leu His Gin Glu Gly 2930 Lys tgt gaa teg tgt gtc tac aac atg atg gga aaa cgt gag aaa aag tta 8948 Cys Glu 2935 Ser Cys Val Tyr Asn Met 2940 Met Gly Lys Arg Glu 2945 Lys Lys Leu gga gag ttt ggc aga gcc aag gga age ega gca ate tgg tac atg tgg 8996 Gly Glu 2950 Phe Gly Arg Ala Lys 2955 Gly Ser Arg Ala He 2960 Trp Tyr Met Trp 2965 ctg gga gcg egg ttt ctg gaa ttt gaa gcc ctg ggt ttt ttg aat gaa 9044 Leu Gly Ala Arg Phe Leu 2970 Glu Phe Glu Ala Leu 2975 Gly Phe Leu Asn Glu 2980 gat cac tgg ttt ggc aga gaa aat tea tgg agt gga gtg gaa ggg gaa 9092 Asp His Trp Phe Gly 2985 Arg Glu Asn Ser Trp 2990 Ser Gly Val Glu Gly 2995 Glu ggt ctg cac aga ttg gga tat ate ctg gag gag ata gac aag aag gat 9140 Gly Leu His Arg Leu 3000 Gly Tyr lie 3005 Leu Glu Glu He Asp Lys Lys 3010 Asp gga gac eta atg tat get gat gac aca gca ggc tgg gac aca aga ate 9188 Gly Asp Leu 3015 Met Tyr Ala Asp Asp 3020 Thr Ala Gly Trp Asp 3025 Thr Arg He

    307

    2018200081 04 Jan 2018

    act gag gat gac Thr Glu Asp Asp 3030 ett Leu caa aat Gin Asn 3035 gaa gaa ctg Leu ate aeg gaa He Thr Glu 3040 cag Gin atg Met gcc Ala 3045 9236 Glu Glu ccc cac cac aag ate eta gcc aaa gcc att ttc aaa eta acc tat caa 9284 Pro His His Lys He Leu Ala 3050 Lys Ala He 3055 Phe Lys Leu Thr Tyr 306C Gin 1 aac aaa gtg gtg aaa gtc etc aga ccc aca ccg aga gga gcg gtg atg 9332 Asn Lys Val Val Lys 3065 Val Leu Arg Pro 307C Thr 1 Pro Arg Gly Ala 3075 Val Met gat ate ata tcc agg aaa gac caa aga ggt agt gga caa gtt gga aca 9380 Asp lie He Ser 3080 Arg Lys Asp Gin 3085 Arg Gly Ser Gly Gin Val 3090 Gly Thr tat ggt ttg aac aca ttc acc aac atg gaa gtt caa etc ate ege caa 9428 Tyr Gly Leu Asn 3095 Thr Phe Thr Asn 3100 Met Glu Val Gin Leu 3105 He Arg Gin atg gaa get gaa gga gtc ate aca caa gat gac atg cag aac cca aaa 9476 Met Glu Ala Glu 3110 Gly Val He 3115 Thr Gin Asp Asp Met Gin 3120 Asn Pro Lys 3125 ggg ttg aaa gaa aga gtt gag aaa tgg ctg aaa gag tgt ggt gtc gac 9524 Gly Leu Lys Glu Arg Val Glu 3130 Lys Trp Leu Lys Glu Cys 3135 Gly Val Asp 3140 agg tta aag agg atg gca ate agt gga gac gat tgc gtg gtg aag ccc 9572 Arg Leu Lys Arg Met 3145 Ala He Ser Gly Asp 3150 Asp Cys Val Val Lys 3155 Pro ctg gat gag agg ttt ggc act tcc etc etc ttc ttg aac gac atg gga 9620 Leu Asp Glu Arg 3160 Phe Gly Thr Ser Leu 3165 Leu Phe Leu Asn Asp 3170 Met Gly aag gtg agg aaa gac att ccg cag tgg gaa cca tet aag gga tgg cl cl 3. 9668 Lys Val Arg Lys 3175 Asp He Pro Gin 3180 Trp Glu Pro Ser Lys 3185 Gly Trp Lys aac tgg caa gag gtt cct ttt tgc tcc cac cac ttt cac aag ate ttc 9716 Asn Trp Gin Glu 3190 Val Pro Phe 3195 Cys Ser His His Phe His 3200 Lys He Phe 3205 atg aag gat ggc ege tea eta gtt gtt cca tgt aga aac cag gat gaa 9764 Met Lys Asp Gly Arg Ser Leu 3210 Val Val Pro Cys Arg Asn 3215 Gin Asp Glu 3220 ctg ata ggg aga gcc aga ate teg cag 999 get gga tgg agc tta aga 9812 Leu He Gly Arg Ala 3225 Arg He Ser Gin Gly 3230 Ala Gly Trp Ser Leu 3235 Arg gaa aca gcc tgc ctg ggc aaa get tac gcc cag atg tgg teg etc atg 9860 Glu Thr Ala Cys Leu Gly Lys Ala Tyr Ala Gin Met Trp Ser Leu Met

    3240 3245 3250

    308

    2018200081 04 Jan 2018

    tac Tyr ttc Phe 3255 cac His aga Arg agg Arg gat Asp ctg cgt Leu Arg 3260 tta Leu gcc Ala tcc Ser atg gcc Met Ala 3265 ata He tgc Cys tea Ser 9908 gca gtt cca aeg gaa tgg ttt cca aca agc aga aca aca tgg tea ate 9956 Ala Val Pro Thr Glu Trp Phe Pro Thr Ser Arg Thr Thr Trp Ser He 3270 3275 3280 3285 cac get cat cat cag tgg atg acc act gaa gat atg etc aaa gtg tgg 10004 His Ala His His Gin Trp Met Thr Thr Glu Asp Met Leu Lys Val Trp 3290 3295 3300 aac aga gtg tgg ata gaa gac aac cct aat atg act gac aag act cca 10052 Asn Arg Val Trp He Glu Asp Asn Pro Asn Met Thr Asp Lys Thr Pro 3305 3310 3315 gtc cat teg tgg gaa gat ata cct tac eta ggg aaa aga gag gat ttg 10100 Val His Ser Trp Glu Asp He Pro Tyr Leu Gly Lys Arg Glu Asp Leu 3320 3325 3330 tgg tgt gga tcc ctg att gga ett tet tcc aga gcc acc tgg geg aag 10148 Trp Cys Gly Ser Leu He Gly Leu Ser Ser Arg Ala Thr Trp Ala Lys 3335 3340 3345 aac att cac aeg gcc ata acc cag gtc aga aac ctg ate gga aaa gag 10196 Asn lie His Thr Ala He Thr Gin Val Arg Asn Leu He Gly Lys Glu 3350 3355 3360 3365 gaa tac gtg gat tac atg cca gta atg aaa aga tac agc get cct tea 10244 Glu Tyr Val Asp Tyr Met Pro Val Met Lys Arg Tyr Ser Ala Pro Ser 3370 3375 3380 gag agt gaa gga gtt ctg taa ttaccaacaa caaacaccaa aggetattga 10295 Glu Ser Glu Gly Val Leu * 3385

    agtcaggcca cttgtgccac ggcttgagca aaccgtgctg cctgtagctc cgccaataat 10355 gggaggcgtg aaatccctag ggaggccatg cgccacggaa gctgtacgcg tggcatattg 10415 gactagcggt tagaggagac ccctcccatc actgacaaaa cgcagcaaaa gggggcccga 10475 agccaggagg aagctgtact cctggtggaa ggactagagg ttagaggaga cccccccaac 10535 acaaaaacag catafctgacg ctgggaaaga ccagagatcc tgctgtctct gcaacatcaa 10595 tccaggcaca gagcgaagca agatggattg gtgttgttga tccaacaggt tet 10648 <210> 26 <211> 3387 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 26

    309

    2018200081 04 Jan 2018

    Met Asn Gin Arg Lys Lys Val Val Arg Pro Pro Phe Asn Met Leu Lys 1 5 10 15 Arg Glu Arg Asn Arg Val Ser Thr Pro Gin Gly Leu Val Lys Arg Phe 20 25 30 Ser Thr Gly Leu Phe Ser Gly Lys Gly Pro Leu Arg Met Val Leu Ala 35 40 45 Phe He Thr Phe Leu Arg Val Leu Ser lie Pro Pro Thr Ala Gly He 50 55 60 Leu Lys Arg Trp Gly Gin Leu Lys Lys Asn Lys Ala He Arg He Leu 65 70 75 80 lie Gly Phe Arg Lys Glu He Gly Arg Met Leu Asn He Leu Asn Gly 85 90 95 Arg Lys Arg Ser Thr He Thr Leu Leu Cys Leu He Pro Thr Val Met 100 105 110 Ala Phe His Leu Ser Thr Arg Asp Gly Glu Pro Leu Met lie Val Ala 115 120 125 Lys His Glu Arg Gly Arg Pro Leu Leu Phe Lys Thr Thr Glu Gly He 130 135 140 Asn Lys Cys Thr Leu He Ala Met Asp Leu Gly Glu Met Cys Glu Asp 145 150 155 160 Thr Val Thr Tyr Lys Cys Pro Leu Leu Val Asn Thr Glu Pro Glu Asp 165 170 175 He Asp Cys Trp Cys Asn Leu Thr Ser Thr Trp Val Met Tyr Gly Thr 180 185 190 Cys Thr Gin Ser Gly Glu Arg Arg Arg Glu Lys Arg Ser Val Ala Leu 195 200 205 Thr Pro His Ser Gly Met Gly Leu Glu Thr Arg Ala Glu Thr Trp Met 210 215 220 Ser Ser Glu Gly Ala Trp Lys His Ala Gin Arg Val Glu Ser Trp lie 225 230 235 240 Leu Arg Asn Pro Gly Phe Ala Leu Leu Ala Gly Phe Met Ala Tyr Met 245 250 255 He Gly Gin Thr Gly He Gin Arg Thr Val Phe Phe Val Leu Met Met 260 265 270 Leu Val Ala Pro Ser Tyr Gly Met Arg Cys Val Gly Val Gly Asn Arg 275 280 285 Asp Phe Val Glu Gly Val Ser Gly Gly Ala Trp Val Asp Leu Val Leu 290 295 300 Glu His Gly Gly Cys Val Thr Thr Met Ala Gin Gly Lys Pro Thr Leu 305 310 315 320 Asp Phe Glu Leu Thr Lys Thr Thr Ala Lys Glu Val Ala Leu Leu Arg 325 330 335 Thr Tyr Cys He Glu Ala Ser He Ser Asn lie Thr Thr Ala Thr Arg 340 345 350 Cys Pro Thr Gin Gly Glu Pro Tyr Leu Lys Glu Glu Gin Asp Gin Gin 355 360 365 Tyr He Cys Arg Arg Asp Val Val Asp Arg Gly Trp Gly Asn Gly Cys 370 375 380 Gly Leu Phe Gly Lys Gly Gly Val Val Thr Cys Ala Lys Phe Ser Cys 385 390 395 400 Ser Gly Lys He Thr Gly Asn Leu Val Gin He Glu Asn Leu Glu Tyr 405 410 415 Thr Val Val Val Thr Val His Asn Gly Asp Thr His Ala Val Gly Asn 420 425 430

    310

    2018200081 04 Jan 2018

    Asp Thr Ser Asn His Gly Val 435 Thr 440 Ala Thr He Thr Pro Arg Ser Pro 445 Ser Val Glu Val Lys Leu Pro Asp Tyr Gly Glu Leu Thr Leu Asp Cys .450 455 460 Glu Pro Arg Ser Gly He Asp Phe Asn Glu Met He Leu Met Lys Met 465 470 475 480 Lys Lys Lys Thr Trp Leu Val His Lys Gin Trp Phe Leu Asp Leu Pro 485 490 495 Leu Pro Trp Thr Ala Gly Ala Asp Thr Ser Glu Val His Trp Asn Tyr 500 505 510 Lys Glu Arg Met Val Thr Phe Lys Val Pro His Ala Lys Arg Gin Asp 515 520 525 Val Thr Val Leu Gly Ser Gin Glu Gly Ala Met His Ser Ala Leu Ala 530 535 540 Gly Ala Thr Glu Val Asp Ser Gly Asp Gly Asn His Met Phe Ala Gly 545 550 555 560 His Leu Lys Cys Lys Val Arg Met Glu Lys Leu Arg He Lys Gly Met 565 570 575 Ser Tyr Thr Met Cys Ser Gly Lys Phe Ser He Asp Lys Glu Met Ala 580 585 590 Glu Thr Gin His Gly Thr Thr Val Val Lys Val Lys Tyr Glu Gly Ala 595 600 605 Gly Ala Pro Cys Lys Val Pro He Glu He Arg Asp Val Asn Lys Lys 610 615 620 Lys Val Val Gly Arg He He Ser Ser Thr Pro Leu Ala Glu Asn Thr 625 630 635 640 Asn Ser Ala Thr Asn He Glu Leu Glu Pro Pro Phe Gly Asp Ser Tyr 645 650 655 lie Val He Gly Val Gly Asn Ser Ala Leu Thr Leu His Trp Phe Arg 660 665 670 Lys Gly Ser Ser He Gly Lys Met Phe Glu Ser Thr Tyr Arg Gly Ala 675 680 685 Lys Arg Met Ala He Leu Gly Glu Thr Ala Trp Asp Phe Gly Ser Val 690 695 700 Gly Gly Leu Phe Thr Ser Leu Gly Lys Ala Val His Gin Val Phe Gly 705 710 715 720 Ser Val Tyr Thr Thr Met Phe Gly Gly Val Ser Trp Met He Arg He 725 730 735 Leu He Gly Phe Leu Val Leu Trp He Gly Thr Asn Ser Arg Asn Thr 740 745 750 Ser Met Ala Met Thr Cys He Ala Val Gly Gly He Thr Leu Phe Leu 755 760 765 Gly Phe Thr Val Gin Ala Asp Met Gly Cys Val Val Ser Trp Ser Gly 770 775 780 Lys Glu Leu Lys Cys Gly Ser Gly He Phe Val Val Asp Asn Val His 785 790 795 800 Thr Trp Thr Glu Gin Tyr Lys Phe Gin Pro Glu Ser Pro Ala Arg Leu 805 810 815 Ala Ser Ala He Leu Asn Ala His Lys Asp Gly Val Cys Gly He Arg 820 825 830 Ser Thr Thr Arg Leu Glu Asn Val Met Trp Lys Gin lie Thr Asn Glu 835 840 845 Leu Asn Tyr Val Leu Trp Glu Gly Gly His Asp Leu Thr Val Val Ala 850 855 860

    311

    2018200081 04 Jan 2018

    Gly Asp Val Lys Gly Val Leu Thr Lys Gly Lys Arg Ala Leu Thr Pro 865 870 875 880 Pro Val Asn Asp Leu Lys Tyr Ser Trp Lys Thr Trp Gly Lys Ala Lys 885 890 895 lie Phe Thr Pro Glu Ala Arg Asn Ser Thr Phe Leu He Asp Gly Pro 900 905 910 Asp Thr Ser Glu Cys Pro Asn Glu Arg Arg Ala Trp Asn Phe Leu Glu 915 920 925 Val Glu Asp Tyr Gly Phe Gly Met Phe Thr Thr Asn He Trp Met Lys 930 935 940 Phe Arg Glu Gly Ser Ser Glu Val Cys Asp His Arg Leu Met Ser Ala 945 950 955 960 Ala He Lys Asp Gin Lys Ala Val His Ala Asp Met Gly Tyr Trp He 965 970 975 Glu Ser Ser Lys Asn Gin Thr Trp Gin He Glu Lys Ala Ser Leu He 980 985 990 Glu Val Lys Thr Cys Leu Trp Pro Lys Thr His Thr Leu Trp Ser Asn 995- 1000 1005 Gly Val Leu Glu Ser Gin Met Leu He Pro Lys Ser Tyr Ala Gly Pro 1010 1015 1020 Phe Ser His His Asn Tyr Arg Gin Gly Tyr Ala Thr Gin Thr Val Gly 1025 1030 1035 1040 Pro Trp His Leu Gly Lys Leu Glu He Asp Phe Gly Glu Cys Pro Gly 1045 1050 1055 Thr Thr Val Ala lie Gin Glu Asp Cys Asp His Arg Gly Pro Ser Leu 1060 1065 1070 Arg Thr Thr Thr Ala Ser Gly Lys Leu Val Thr Gin Trp Cys Cys Arg ' 1075 1080 1085 Ser Cys Thr Met Pro Pro Leu Arg Phe Leu Gly Glu Asp Gly Cys Trp 1090 1095 1100 Tyr Gly Met Glu He Arg Pro Leu Ser Glu Lys Glu Glu Asn Met Val 1105 1110 1115 1120 Lys Ser Gin Val Thr Ala Gly Gin Gly Thr Ser Glu Thr Phe Ser Met 1125 1130 1135 Gly Leu Leu Cys Leu Thr Leu Phe Val Glu Glu Cys Leu Arg Arg Arg 1140 1145 1150 Val Thr Arg Lys His Met He Leu Val Val Val He Thr Leu Cys Ala 1155 1160 1165 lie He Leu Gly Gly Leu Thr Trp Met Asp Leu Leu Arg Ala Leu He 1170 1175 1180 Met Leu Gly Asp Thr Met Ser Gly Arg He Gly Gly Gin He His Leu 1185 1190 1195 1200 Ala He Met Ala Val Phe Lys Met Ser Pro Gly Tyr Val Leu Gly Val 1205 1210 1215 Phe Leu Arg Lys Leu Thr Ser Arg Glu Thr Ala Leu Met Val He Gly 1220 1225 1230 Met Ala Met Thr Thr Val Leu Ser He Pro His Asp Leu Met Glu Leu 1235 1240 1245 lie Asp Gly He Ser Leu Gly Leu He Leu Leu Lys He Val Thr His 1250 1255 1260 Phe Asp Asn Thr Gin Val Gly Thr Leu Ala Leu Ser Leu Thr Phe He 1265 1270 1275 1280 Arg Ser Thr Met Pro Leu Val Met Ala Trp Arg Thr lie Met Ala Val 1285 1290 1295

    312

    2018200081 04 Jan 2018

    Leu Phe Val Val Thr Leu He Pro Leu Cys Arg Thr Ser Cys Leu Gin 1300 1305 1310 Lys Gin Ser His Trp Val Glu He Thr Ala Leu He Leu Gly Ala Gin 1315 1320 1325 Ala Leu Pro Val Tyr Leu Met Thr Leu Met Lys Gly Ala Ser Arg Arg 1330 1335 1340 Ser Trp Pro Leu Asn Glu Gly He Met Ala Val Gly Leu Val Ser Leu 1345 1350 1355 1360 Leu Gly Ser Ala Leu Leu Lys Asn Asp Val Pro Leu Ala Gly Pro Met 1365 1370 1375 Val Ala Gly Gly Leu Leu Leu Ala Ala Tyr Val Met Ser Gly Ser Ser 1380 1385 1390 Ala Asp Leu Ser Leu Glu Lys Ala Ala Asn Val Gin Trp Asp Glu Met 1395 1400 1405 Ala Asp He Thr Gly Ser Ser Pro He He Glu Val Lys Gin Asp Glu 1410 1415 1420 Asp Gly Ser Phe Ser He Arg Asp Val Glu Glu Thr Asn Met He Thr 1425 1430 1435 1440 Leu Leu Val Lys Leu Ala Leu He Thr Val Ser Gly Leu Tyr Pro Leu 1445 1450 1455 Ala He Pro Val Thr Met Thr Leu Trp Tyr Met Trp Gin Val Lys Thr 1460 1465 1470 Gin Arg Ser Gly Ala Leu Trp Asp Val Pro Ser Pro Ala Ala Thr Gin 1475 1480 1485 Lys Ala Ala Leu Ser Glu Gly Val Tyr Arg He Met Gin Arg Gly Leu 1490 1495 1500 Phe Gly Lys Thr Gin Val Gly Val Gly He His Met Glu Gly Val Phe 1505 1510 1515 1520 His Thr Met · Trp His Val Thr Arg Gly Ser Val He Cys His Glu Thr 1525 1530 1535 Gly Arg Leu Glu Pro Ser Trp Ala Asp Val Arg Asn Asp Met He Ser 1540 1545 1550 Tyr Gly Gly Gly Trp Arg Leu Gly Asp Lys Trp Asp Lys Glu Glu Asp 1555 1560 1565 Val Gin Val Leu Ala He Glu Pro Gly Lys Asn Pro Lys His Val Gin 1570 1575 1580 Thr Lys Pro Gly Leu Phe Lys Thr Leu Thr Gly Glu He Gly Ala Val 1585 1590 1595 1600 Thr Leu Asp Phe Lys Pro Gly Thr Ser Gly Ser Pro He He Asn Arg 1605 1610 1615 Lys Gly Lys Val He Gly Leu Tyr Gly Asn Gly Val Val Thr Lys Ser 1620 1625 1630 Gly Asp Tyr Val Ser Ala He Thr Gin Ala Glu Arg He Gly Glu Pro 1635 1640 1645 Asp Tyr Glu Val Asp Glu Asp He Phe Arg Lys Lys Arg Leu Thr He 1650 1655 1660 Met Asp Leu His Pro Gly Ala Gly Lys Thr Lys Arg lie Leu Pro Ser 1665 1670 1675 1680 lie Val Arg Glu Ala Leu Lys Arg Arg Leu Arg Thr Leu He Leu Ala 1685 1690 1695 Pro Thr Arg Val Val Ala Ala Glu Met Glu Glu Ala Leu Arg Gly Leu 1700 1705 1710 Pro He Arg Tyr Gin Thr Pro Ala Val Lys Ser Glu His Thr Gly Arg

    1715 1720 1725

    313

    2018200081 04 Jan 2018

    Glu lie Val Asp Leu Met Cys His Ala Thr Phe Thr Thr Arg Leu Leu 1730 1735 1740 Ser Ser Thr Arg Val Pro Asn Tyr Asn Leu He Val Met Asp Glu Ala 1745 1750 1755 1760 His Phe Thr Asp Pro Ser Ser Val Ala Ala Arg Gly Tyr He Ser Thr 1765 177C I 1775 Arg Val Glu Met Gly Glu Ala Ala Ala He Phe Met Thr Ala Thr Pro 1780 1785 ' 1790 Pro Gly Ala Thr Asp Pro Phe Pro Gin Ser Asn Ser Pro He Glu Asp 1795 1800 1805 lie Glu Arg Glu He Pro Glu Arg Ser Trp Asn Thr Gly Phe Asp Trp 1810 1815 1820 He Thr Asp Tyr Gin Gly Lys Thr Val Trp Phe Val Pro Ser He Lys 1825 1830 1835 1840 Ala Gly Asn Asp He Ala Asn Cys Leu Arg Lys Ser Gly Lys Lys Val 1845 185C I 1855 He Gin Leu Ser Arg Lys Thr Phe Asp Thr Glu Tyr Pro Lys Thr Lys 1860 1865 1870 Leu Thr Asp Trp Asp Phe Val Val Thr Thr Asp He Ser Glu Met Gly 1875 1880 1885 Ala Asn Phe Arg Ala Gly Arg Val He Asp Pro Arg Arg Cys Leu Lys 1890 1895 1900 Pro Val lie Leu Thr Asp Gly Pro Glu Arg Val He Leu Ala Gly Pro 1905 1910 1915 1920 He Pro Val Thr Pro Ala Ser Ala Ala Gin Arg Arg Gly Arg He Gly 1925 . 1930 -1935 Arg Asn Pro Ala Gin Glu Asp Asp Gin Tyr Val Phe Ser Gly Asp Pro 1940 1945 1950 Leu Lys Asn Asp Glu Asp His Ala His Trp Thr Glu Ala Lys Met Leu 1955 1960 1965 Leu Asp Asn lie Tyr Thr Pro Glu Gly lie He Pro Thr Leu Phe Gly 1970 1975 1980 Pro Glu Arg Glu Lys Thr Gin Ala He Asp Gly Glu Phe Arg Leu Arg 1985 1990 1995 2000 Gly Glu Gin Arg Lys Thr Phe Val Glu Leu Met Arg Arg Gly Asp Leu 2005 2010 2015 Pro Val Trp Leu Ser Tyr Lys Val Ala Ser Ala Gly He Ser Tyr Lys 2020 2025 2030 Asp Arg Glu Trp Cys Phe Thr Gly Glu Arg Asn Asn Gin He Leu Glu 2035 2040 2045 Glu Asn Met Glu Val Glu He Trp Thr Arg Glu Gly Glu Lys Lys Lys 2050 2055 2060 Leu Arg Pro Arg Trp Leu Asp Ala Arg Val Tyr Ala Asp Pro Met Ala 2065 2070 2075 . 2080 Leu Lys Asp Phe Lys Glu Phe Ala Ser Gly Arg Lys Ser lie Thr Leu 2085 2090 2095 Asp He Leu Thr Glu He Ala Ser Leu Pro Thr Tyr Leu Ser Ser Arg 2100 2105 2110 Ala Lys Leu Ala Leu Asp Asn He Val Met Leu His Thr Thr Glu Arg 2115 2120 2125 Gly Gly Arg Ala Tyr Gin His Ala Leu Asn Glu Leu Pro Glu Ser Leu 2130 2135 2140 Glu Thr Leu Met Leu Val Ala Leu Leu Gly Ala Met Thr Ala Gly He 2145 2150 2155 2160

    314

    2018200081 04 Jan 2018

    Phe Leu Phe Phe Met Gin Gly Lys Gly lie Gly Lys Leu Ser Met Gly 2165 2170 2175 Leu lie Thr He Ala Val Ala Ser Gly Leu Phe Trp Val Ala Glu He 2180 2185 2190 Gin Pro Gin Trp He Ala Ala Ser lie He Leu Glu Phe Phe Leu Met 2195 2200 2205 Val Leu Leu lie Pro Glu Pro Glu Lys Gin Arg Thr Pro Gin Asp Asn 2210 2215 2220 Gin Leu He Tyr Val He Leu Thr He Leu Thr He He Gly Leu He 2225 2230 2235 2240 Ala Ala Asn Glu Met Gly Leu He Glu Lys Thr Lys Thr Asp Phe Gly 2245 2250 2255 Phe Tyr Gin Val Lys Thr Glu Thr Thr lie Leu Asp Val Asp Leu Arg 2260 2265 2270 Pro Ala Ser Ala Trp Thr Leu Tyr Ala Val Ala Thr Thr Phe Leu Thr 2275 2280 2285 Pro Met Leu Arg His Thr He Glu Asn Thr Ser Ala Asn Leu Ser Leu 2290 2295 2300 Ala Ala He Ala Asn Gin Ala Ala Val Leu Met Gly Leu Gly Lys Gly 2305 2310 2315 2320 Trp Pro Leu His Arg Met Asp Leu Gly Val Pro Leu Leu Ala Met Gly 2325 2330 2335 Cys Tyr Ser Gin Val Asn Pro Thr Thr Leu Thr Ala Ser Leu Val Met 2340 2345 2350 Leu Ser Val His Tyr Ala lie He Gly Pro Gly Leu Gin Ala Lys Ala 2355 2360 2365 Thr Arg Glu Ala Gin Lys Arg Thr Ala Ala Gly He Met Lys Asn Pro 2370 2375 2380 Thr Val Asp Gly He Thr Val He Asp Leu Glu Pro He Ser Tyr Asp 2385 2390 2395 2400 Pro Lys Phe Glu Lys Gin Leu Gly Gin Val Met Leu Leu Val Leu Cys 2405 2410 2415 Ala Gly Gin Leu Leu Leu Met Arg Thr Thr Trp Ala Phe Cys Glu Val 2420 2425 2430 Leu Thr Leu Ala Thr Gly Pro He Leu Thr Leu Trp Glu Gly Asn Pro 2435 2440 2445 Gly Arg Phe Trp Asn Thr Thr He Ala Val Ser Thr Ala Asn He Phe 2450 2455 2460 Arg Gly Ser Tyr Leu Ala Gly Ala Gly Leu Ala Phe Ser Leu lie Lys 2465 2470 2475 2480 Asn Val Gin Thr Pro Arg Arg Gly Thr Gly Thr Thr Gly Glu Thr Leu 2485 2490 2495 Gly Glu Lys Trp Lys Arg Gin Leu Asn Ser Leu Tyr Arg Lys Glu Phe 2500 2505 2510 Glu Glu Tyr Lys Arg Ser Gly He Leu Glu Val Asp Arg Thr Glu Ala 2515 2520 2525 Lys Ser Ala Leu Lys Asp Gly Ser Lys lie Lys His Ala Val Ser Arg 2530 2535 2540 Gly Ser Ser Lys He Arg Trp He Val Glu Arg Gly Met Val Lys Pro 2545 2550 2555 2560 Lys Gly Lys Val Val Asp Leu Gly Cys Gly Arg Gly Gly Trp Ser Tyr 2565 2570 2575 Tyr Met Ala Thr Leu Lys Asn Val Thr Glu Val Lys Gly Tyr Thr Lys 2580 2585 2590

    315

    2018200081 04 Jan 2018

    Gly Gly Pro Gly His Glu Glu Pro He Pro Met Ala Thr Tyr Gly Trp 2595 2600 2605 Asn Leu Val Lys Leu His Ser Gly Val Asp Val Phe Tyr Lys Pro Thr 2610 2615 2620 Glu Gin Val Asp Thr Leu Leu Cys Asp He Gly Glu Ser Ser Ser Asn 2625 2630 2635 2640 Pro Thr He Glu Glu Gly Arg Thr Leu Arg Val Leu Lys Met Val Glu 2645 i 2650 2655 Pro Trp Leu Ser Ser Lys Pro Glu Phe Cys lie Lys Val Leu Asn Pro 2660 2665 2670 Tyr Met Pro Thr Val He Glu Glu Leu Glu Lys Leu Gin Arg Lys His 2675 2680 2685 Gly Gly Asn Leu Val Arg Cys Pro Leu Ser Arg Asn Ser Thr His Glu 2690 2695 2700 Met Tyr Trp Val Ser Gly Ala Ser Gly Asn He Val Ser Ser Val Asn 2705 2710 2715 2720 Thr Thr Ser Lys Met Leu Leu Asn Arg Phe Thr Thr Arg His Arg Lys 2725 1 273C 1 2735 Pro Thr Tyr Glu Lys Asp Val Asp Leu Gly Ala Gly Thr Arg Ser Val 2740 2745 2750 Ser Thr Glu Thr Glu Lys Pro Asp Met Thr He He Gly Arg Arg Leu 2755 2760 2765 Gin Arg Leu Gin Glu Glu His Lys Glu Thr Trp His Tyr Asp Gin Glu 2770 2775 2780 Asn Pro Tyr Arg Thr Trp Ala Tyr His Gly Ser Tyr Glu Ala Pro Ser 2785 2790 2795 2800 Thr Gly Ser Ala Ser Ser Met Val Asn Gly Val Val Lys Leu Leu Thr 2805 1 2810 2815 Lys Pro Trp Asp Val Val Pro Met Val Thr Gin Leu Ala Met Thr Asp 2820 2825 2830 Thr Thr Pro Phe Gly Gin Gin Arg Val Phe Lys Glu Lys Val Asp Thr 2835 2840 2845 Arg Thr Pro Gin Pro Lys Pro Gly Thr Arg Met Val Met Thr Thr Thr 2850 2855 2860 Ala Asn Trp Leu Trp Ala Leu Leu Gly Lys Lys Lys Asn Pro Arg Leu 2865 2870 2875 2880 Cys Thr Arg Glu Glu Phe He Ser Lys Val Arg Ser Asn Ala Ala He 2885 i 2890 · 2895 Gly Ala Val Phe Gin Glu Glu Gin Gly Trp Thr Ser Ala Ser Glu Ala 2900 2905 2910 Val Asn Asp Ser Arg Phe Trp Glu Leu Val Asp Lys Glu Arg Ala Leu 2915 2920 2925 His Gin Glu Gly Lys Cys Glu Ser Cys Val Tyr Asn Met Met Gly Lys 2930 2935 2940 Arg Glu Lys Lys Leu Gly Glu Phe Gly Arg Ala Lys Gly Ser Arg Ala 2945 2950. 2955 2960 lie Trp Tyr Met Trp Leu Gly Ala Arg Phe Leu Glu Phe Glu Ala Leu 2965 2970 2975 Gly Phe Leu Asn Glu Asp His Trp Phe Gly Arg Glu Asn Ser Trp Ser 2980 2985 2990 Gly Val Glu Gly Glu Gly Leu His Arg Leu Gly Tyr He Leu Glu Glu 2995 3000 3005 He Asp Lys Lys Asp Gly Asp Leu Met Tyr Ala Asp Asp Thr Ala Gly 3010 3015 3020

    316

    2018200081 04 Jan 2018

    Trp Asp Thr Arg He Thr Glu Asp Asp Leu Gin Asn Glu Glu Leu lie 3025 3030 3035 3040 Thr Glu Gin Met Ala Pro His His Lys He Leu Ala Lys Ala He Phe 3045 3050 3055 Lys Leu Thr Tyr Gin Asn Lys Val Val Lys Val Leu Arg Pro Thr Pro 30S0 3065 3070 Arg Gly Ala Val Met Asp He He Ser Arg Lys Asp Gin Arg Gly Ser 3075 3080 3085 Gly Gin Val Gly Thr Tyr Gly Leu Asn Thr Phe Thr Asn Met Glu Val 3090 3095 3100 Gin Leu lie Arg Gin Met Glu Ala Glu Gly Val lie Thr Gin Asp Asp 3105 3110 3115 3120 Met Gin Asn Pro Lys Gly Leu Lys Glu Arg Val Glu Lys Trp Leu Lys 3125 3130 3135 Glu Cys Gly Val Asp Arg Leu Lys Arg Met Ala He Ser Gly Asp Asp 3140 3145 3150 Cys Val Val Lys Pro Leu Asp Glu Arg Phe Gly Thr Ser Leu Leu Phe 3155 3160 3165 Leu Asn Asp Met Gly Lys Val Arg Lys Asp He Pro Gin Trp Glu Pro 3170 3175 3180 Ser Lys Gly Trp Lys Asn Trp Gin Glu Val Pro Phe Cys Ser His His 3185 3190 3195 3200 Phe His Lys He Phe Met Lys Asp Gly Arg Ser Leu Val Val Pro Cys 3205 3210 3215 Arg Asn Gin Asp Glu Leu He Gly Arg Ala Arg He Ser Gin Gly Ala 3220 3225 3230 Gly Trp Ser Leu Arg Glu Thr Ala Cys Leu Gly Lys Ala Tyr Ala Gin 3235 3240 3245 Met Trp Ser Leu Met Tyr Phe His Arg Arg Asp Leu Arg Leu Ala Ser 3250 3255 3260 Met Ala He Cys Ser Ala Val Pro Thr Glu Trp Phe Pro Thr Ser Arg 3265 3270 3275 3280 Thr Thr Trp Ser He His Ala His His Gin Trp Met Thr Thr Glu Asp 3285 3290 3295 Met Leu Lys Val Trp Asn Arg Val Trp He Glu Asp Asn Pro Asn Met 3300 3305 3310 Thr Asp Lys Thr Pro Val His Ser Trp Glu Asp He Pro Tyr Leu Gly 3315 3320 3325 Lys Arg Glu Asp Leu Trp Cys Gly Ser Leu He Gly Leu Ser Ser Arg 3330 3335 3340 Ala Thr Trp Ala Lys Asn He His Thr Ala He Thr Gin Val Arg Asn 3345 3350 3355 3360 Leu He Gly Lys Glu Glu Tyr Val Asp Tyr Met Pro Val Met Lys Arg 3365 · 3370 3375 Tyr Ser Ala Pro Ser Glu Ser Glu Gly Val Leu 3380 3385

    <210> 27 <211> 10723 <212> DNA <213> Artificial Sequence · <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct

    317

    2018200081 04 Jan 2018 <221> CDS <222> (97)...(10272) <400> 27 agttgttagt ctacgtggac cgacaaagac agattctttg agggagctaa gctcaatgta 60 gttctaacag ttttttaatt agagagcaga tctctg atg aat aac caa cgg aaa 114

    Met Asn Asn Gin Arg Lys 1 5

    aag Lys gcg aaa aac Asn 10 aeg cct ttc Phe aat Asn atg Met 15 ctg aaa cgc Arg gag Glu aga Arg 20 aac Asn cgc Arg 162 Ala Lys Thr Pro Leu Lys gtg teg act gtg caa cag ctg aca aag aga ttc tea ett gga atg ctg 210 Val Ser Thr 25 Val Gin Gin Leu Thr 30 Lys Arg Phe Ser Leu 35 Gly Met Leu cag gga ega gga cca tta aaa ctg ttc atg gcc ctg gtg gcg ttc ett 258 Gin Gly 40 Arg Gly Pro Leu Lys 45 Leu Phe Met Ala Leu 50 Val Ala Phe Leu cgt ttc eta aca ate cca cca aca gca ggg ata ttg aag aga tgg gga 306 Arg 55 Phe Leu Thr He Pro 60 Pro Thr Ala Gly lie 65 Leu Lys Arg Trp Gly 70 aca att aaa aaa tea aaa get att aat gtt ttg aga ggg ttc agg aaa 354 Thr He Lys Lys Ser 75 Lys Ala He Asn Val 80 Leu Arg Gly Phe Arg 85 Lys gag att gga agg atg ctg aac ate ttg aat agg aga cgc aga tct gca 402 Glu He Gly Arg 90 Met Leu Asn He Leu 95 Asn Arg Arg Arg Arg 100 Ser Ala ggc atg ate att atg ctg att cca aca gtg atg gcg ttc cat tta acc 450 Gly Met He 105 He Met Leu He Pro 110 Thr Val Met Ala Phe 115 His Leu Thr aeg cgt ggg gga gag ccg cat atg ata gtt age aag cag gaa aga gga 498 Thr Arg 120 Gly Gly Glu Pro His 125 Met He Val Ser Lys 130 Gin Glu Arg Gly aag tea ett ttg ttc aag acc tct gca ggt gtc aac atg tgc acc etc 546 Lys 135 Ser Leu Leu Phe Lys 140 Thr Ser Ala Gly Val 145 Asn Met Cys Thr Leu 150 att gcg atg gat ttg gga gag ttg tgt gag gac aeg atg acc tac aaa 594 lie Ala Met Asp Leu 155 Gly Glu Leu Cys Glu 160 Asp Thr Met Thr Tyr 165 Lys tgc ccc egg ate act gag gcg gaa cca gat gac gtt gac tgt tgg tgc 642 Cys Pro Arg He 170 Thr Glu Ala Glu Pro 175 Asp Asp Val Asp Cys 180 Trp Cys

    318

    2018200081 04 Jan 2018

    aat Asn gee Ala aeg Thr 185 gac Asp aca tgg gtg acc tat Tyr gga Gly aeg Thr tgc Cys tct Ser 195 caa Gin act Thr ggc Gly 690 Thr Trp Val Thr 190 gaa cac ega ega gac aaa cgt tcc gtc gca ttg gcc cca cac gtg ggg 738 Glu His Arg Arg Asp Lys Arg Ser Val Ala Leu Ala Pro His Val Gly 200 205 210 ett ggc eta gaa aca aga gee gaa aeg tgg atg tcc tct gaa ggt get 786 Leu Gly Leu Glu Thr Arg Ala Glu Thr Trp Met Ser Ser Glu Gly Ala 215 220 225 230 tgg aaa cag ata caa aaa gta gag act tgg get ctg aga cat cca gga 834 Trp Lys Gin He Gin Lys Val Glu Thr Trp Ala Leu Arg His Pro Gly 235 240 245 ttc aeg gtg ata gcc ett ttt eta gca cat gcc ata gga aca tcc ate 882 Phe Thr Val He Ala Leu Phe Leu Ala His Ala He Gly Thr Ser He 250 255 260 acc cag aaa ggg ate att ttc att ttg ctg atg ctg gta aca cca tct 930 Thr Gin Lys Gly He He Phe He Leu Leu Met Leu Val Thr Pro Ser 265 270 275 atg gcc atg ega tgc gtg gga ata ggc aac aga gac ttc gtg gaa gga 978 Met Ala Met Arg Cys Val Gly He Gly Asn Arg Asp Phe Val Glu Gly 280 285 290 ctg tea gga gca aca tgg gtg gat gtg gta ctg gag cat gga agt tgc 1026 Leu Ser Gly Ala Thr Trp Val Asp Val Val Leu Glu His Gly Ser Cys 295 300 305 310 gtc acc acc atg gca aaa aac aaa cca aca ctg gac att gaa etc ttg 1074 Val Thr Thr Met Ala Lys Asn Lys Pro Thr Leu Asp He Glu Leu Leu 315 320 325 aag aeg gag gtc aca aac cct gca gtt ctg cgt aaa ttg tgc att gaa 1122 Lys Thr Glu Val Thr Asn Pro Ala Val Leu Arg Lys Leu Cys He Glu 330 335 340 get aaa ata tea aac acc acc acc gat teg aga tgt cca aca caa gga 1170 Ala Lys lie Ser Asn Thr Thr Thr Asp Ser Arg Cys Pro Thr Gin Gly 345 350 355 gaa gcc aca ctg gtg gaa gaa caa gac gcg aac ttt gtg tgc ega ega 1218 Glu Ala Thr Leu Val Glu Glu Gin Asp Ala Asn Phe Val Cys Arg Arg 360 365 370 aeg ttc gtg gac aga ggc tgg ggc aat ggc tgt ggg eta ttc gga aaa 1266 Thr Phe Val Asp Arg Gly Trp Gly Asn Gly Cys Gly Leu Phe Gly Lys 375 380 385 390 ggt agt eta ata aeg tgt gcc aag ttt aag tgt gtg aca aaa eta gaa 1314 Gly Ser Leu He Thr Cys Ala Lys Phe Lys Cys Val Thr Lys Leu Glu 395 400 405

    319

    2018200081 04 Jan 2018

    gga Gly aag ata gtt Val 410 caa Gin tat Tyr gaa aac eta Leu 415 aaa Lys tat Tyr tea gtg ata gtc Val acc Thr 1362 Lys lie Glu Asn Ser Val He 420 gtc cac act gga gat cag cac cag gtg gga aat gag act aca gaa cat 1410 Val His Thr 425 Gly Asp Gin His Gin 430 Val Gly Asn Glu Thr 435 Thr Glu His gga aca act gca acc ata aca cct caa get cct aeg teg gaa ata cag 1458 Gly Thr 440 Thr Ala Thr He Thr 445 Pro Gin Ala Pro Thr 450 Ser Glu He Gin ctg acc gac tac gga acc ett aca tta gat tgt tea cct agg aca ggg 1506 Leu 455 Thr Asp Tyr Gly Thr 460 Leu Thr Leu Asp Cys 465 Ser Pro Arg Thr Gly 470 eta gat ttt aac gag atg gtg ttg ctg aca atg aaa gaa aga tea tgg 1554 Leu Asp Phe Asn Glu 475 Met Val Leu Leu Thr 480 Met Lys Glu Arg Ser 485 Trp ett gtc cac aaa caa tgg ttc eta gac tta cca ctg cct tgg acc tet 1602 Leu Val His Lys 490 Gin Trp Phe Leu Asp 495 Leu Pro Leu Pro Trp 500 Thr Ser ggg get tea aca tcc caa gag act tgg aac aga caa gat tta ctg gtc 1650 Gly Ala Ser 505 Thr Ser Gin Glu Thr 510 Trp Asn Arg Gin Asp 515 Leu Leu Val aca ttt aag aca get cat gca aag aag cag gaa gta gtc gta eta gga 1698 Thr Phe 520 Lys Thr Ala His Ala 525 Lys Lys Gin Glu Val 530 Val Val Leu Gly tea caa gaa gga gca atg cac act gcg ctg act gga gcg aca gaa ate 1746 Ser 535 Gin Glu Gly Ala Met 540 His Thr Ala Leu Thr 545 Gly Ala Thr Glu He 550 caa aeg tea gga aeg aca aca att ttc gca gga cac eta aaa tgc aga 1794 Gin Thr Ser Gly Thr 555 Thr Thr He Phe Ala 560 Gly His Leu Lys Cys 565 Arg eta aaa atg gac aaa eta act tta aaa ggg atg tea tat gtg atg tgc 1842 Leu Lys Met Asp 570 Lys Leu Thr Leu Lys 575 Gly Met Ser Tyr Val 580 Met Cys aca ggc tea ttc aag tta gag aaa gaa gtg get gag acc cag cat gga 1890 Thr Gly Ser 585 Phe Lys Leu Glu Lys 590 Glu Val Ala Glu Thr 595 Gin His Gly act gtt ctg gtg cag gtt aaa tat gaa gga aca gac gca cca tgc aag 1938 Thr Val 600 Leu Val Gin Val Lys 605 Tyr Glu Gly Thr Asp 610 Ala Pro Cys Lys

    320

    2018200081 04 Jan 2018

    att lie 615 ccc ttt teg acc caa gat gag aaa gga gca acc cag aat ggg aga Gin Asn Gly Arg 630 1986 Pro Phe Ser Thr Gin 620 Asp Glu Lys Gly Ala 625 Thr tta ata aca gcc aac ccc ata gtc act gac aaa gaa aaa cca gtc aat 2034 Leu He Thr Ala Asn Pro He Val Thr Asp Lys Glu Lys Pro Val Asn 635 640 645 att gag gca gaa cca ccc ttt ggt 3ag agc tac ate gtg gta gga gca 2082 He Glu Ala Glu Pro Pro Phe Gly Glu Ser Tyr He Val Val Gly Ala 650 655 660 ggt gaa aaa get ttg aaa eta agc tgg ttc aag aaa gga agc age ata 2130 Gly Glu Lys Ala Leu Lys Leu Ser Trp Phe Lys Lys Gly Ser Ser He 665 670 675 ggg aaa atg ttt gaa gca act gcc ega gga gca ega agg atg gcc att 2178 Gly Lys Met Phe Glu Ala Thr Ala Arg Gly Ala Arg Arg Met Ala He 680 685 690 ctg gga gac acc gca tgg gac ttc ggt tet ata gga gga gtg ttc aeg 2226 Leu Gly Asp Thr Ala Trp Asp Phe Gly Ser He Gly Gly Val Phe Thr 695 700 705 710 tet atg gga aaa ctg gta cac cag gtt ttt gga act gca tat gga gtt 2274 Ser Met Gly Lys Leu Val His Gin Val Phe Gly Thr Ala Tyr Gly Val 715 720 725 ttg ttt agc gga gtt tet tgg acc atg aaa ata gga ata ggg att ctg 2322 Leu Phe Ser Gly Val Ser Trp Thr Met Lys He Gly He Gly He Leu 730 735 740 ctg aca tgg eta gga tta aat tea agg aac aeg tcc ett teg atg atg 2370 Leu Thr Trp Leu Gly Leu Asn Ser Arg Asn Thr Ser Leu Ser Met Met 745 750 755 tgc ate gca gcc ggc att gtg aca ctg tat ttg gga gtc atg gtg cag 2418 Cys He Ala Ala Gly He Val Thr Leu Tyr Leu Gly Val Met Val Gin 760 765 770 gcc gat agt ggt tgc gtt gtg agc tgg aaa aac aaa gaa ctg aaa tgt 2466 Ala Asp Ser Gly Cys Val Val Ser Trp Lys Asn Lys Glu Leu Lys Cys 775 780 785 790 ggc agt ggg att ttc ate aca gac aac gtg cac aca tgg aca gaa caa 2514 Gly Ser Gly lie Phe He Thr Asp Asn Val His Thr Trp Thr Glu Gin 795 800 805 tac aag ttc caa cca gaa tcc cct tea aaa eta get tea get ate cag 2562 Tyr Lys Phe Gin Pro Glu Ser Pro Ser Lys Leu Ala Ser Ala He Gin 810 815 820 aaa gcc cat gaa gag gac att tgt gga ate ege tea gta aca aga ctg 2610 Lys Ala His Glu Glu Asp He Cys Gly He Arg Ser Val Thr Arg Leu 825 830 835

    321

    2018200081 04 Jan 2018

    gag aat Glu Asn ctg atg Leu Met tgg Trp aaa Lys caa ata aca Thr cca Pro gaa Glu ttg Leu 850 aat Asn cac His att He eta Leu 2658 Gin 845 He 840 tea gaa aat gag gtg aag tta act att atg aca gga gac ate aaa gga 2706 Ser Glu Asn Glu Val Lys Leu Thr He Met Thr Gly Asp He Lys Gly 855 860 865 870 ate atg cag gca gga aaa cga tct ctg cgg cct cag ccc act gag ctg 2754 lie Met Gin Ala Gly Lys Arg Ser Leu Arg Pro Gin Pro Thr Glu Leu 875 880 885 aag tat tea tgg aaa aca tgg ggc aaa gca aaa atg etc tct aca gag 2802 Lys Tyr Ser Trp Lys Thr Trp Gly Lys Ala Lys Met Leu Ser Thr Glu 890 895 900 tct cat aac cag acc ttt etc att gat ggc ccc gaa aca gca gaa tgc 2850 Ser His Asn Gin Thr Phe Leu lie Asp Gly Pro Glu Thr Ala Glu Cys 905 910 915 ccc aac aca aat aga get tgg aat teg ttg gaa gtt gaa gac tat ggc 2898 Pro Asn Thr Asn Arg Ala Trp Asn Ser Leu Glu Val Glu Asp Tyr Gly 920 925 930 ttt gga gta ttc acc acc aat ata tgg eta aaa ttg aaa gaa aaa cag 2946 Phe Gly Val Phe Thr Thr Asn He Trp Leu Lys Leu Lys Glu Lys Gin 935 940 945 950 gat gta ttc tgc gac tea aaa etc atg tea gcg gcc ata aaa gac aac 2994 Asp Val Phe Cys Asp Ser Lys Leu Met Ser Ala Ala He Lys Asp Asn 955 960 965 aga gcc gtc cat gcc gat atg ggt tat tgg ata gaa agt gca etc aat 3042 Arg Ala Val His Ala Asp Met Gly Tyr Trp He Glu Ser Ala Leu Asn 970 975 980 gac aca tgg aag ata gag aaa gcc tct ttc att gaa gtt aaa aac tgc 3090 Asp Thr Trp Lys He Glu Lys Ala Ser Phe He Glu Val Lys Asn Cys

    985 990 995

    cac His tgg Trp 1000 cca aaa tea cac His acc etc Thr Leu 1005 tgg age aat gga gtg Asn Gly Val 1010 eta Leu gaa Glu agt Ser 3138 Pro Lys Ser Trp Ser gag atg ata att cca aag aat etc get gga cca gtg tct caa cac aac 3186 Glu Met He He Pro Lys Asn Leu Ala Gly Pro Val Ser Gin His Asn 1015 1020 1025 1030 tat aga cca ggc tac cat aca caa ata aca gga cca tgg cat eta ggt 3234 Tyr Arg Pro Gly Tyr His Thr Gin He Thr Gly Pro Trp His Leu Gly 1035 1040 1045

    322

    2018200081 04 Jan 2018

    aag ett gag atg gac Lys Leu Glu Met Asp 1050 ttt gat Phe Asp ttc tgt gat gga aca aca gtg gta gtg 3282 Phe Cys Asp Gly Thr Thr Val Val Val 1055 1060 act gag gac tgc gga aat aga gga ccc tet ttg aga aca acc act gcc 3330 Thr Glu Asp Cys Gly Asn Arg Gly Pro Ser Leu Arg Thr Thr Thr Ala 1065 1070 1075 tet gga aaa etc ata aca gaa tgg tgc tgc ega tet tgc aca tta cca 3378 Ser Gly Lys Leu lie Thr Glu Trp Cys Cys Arg Ser Cys Thr Leu Pro 1080 1085 1090 ccg eta aga tac aga ggt gag gat ggg tgc tgg tac ggg atg gaa ate 3426 Pro Leu Arg Tyr Arg Gly Glu Asp Gly Cys Trp Tyr Gly Met Glu lie 1095 ' 1100 1105 1110 aga cca ttg aag gag aaa gaa gag aat ttg gtc aac tcc ttg gtc aca 3474 Arg Pro Leu Lys Glu Lys Glu Glu Asn Leu Val Asn Ser Leu Val Thr 1115 1120 1125 get gga cat ggg cag gtc gac aac ttt tea eta gga gtc ttg gga atg 3522 Ala Gly His Gly Gin Val Asp Asn Phe Ser Leu Gly Val Leu Gly Met 1130 1135 1140 gca ttg ttc ctg gag gaa atg ett agg acc ega gta gga acg, aaa cat 3570 Ala Leu Phe Leu Glu Glu Met Leu Arg Thr Arg Val Gly Thr Lys His 1145 1150 1155 gca ata eta eta gtt gca gtt tet ttt gtg aca ttg ate aca ggg aac 3618 Ala He Leu Leu Val Ala Val Ser Phe Val Thr Leu He Thr Gly Asn 1160 1165 1170 atg tcc ttt aga gac ctg gga aga gtg atg gtt atg gta ggc gcc act 3666 Met Ser Phe Arg Asp Leu Gly Arg Val Met Val Met Val Gly Ala Thr 1175 1180 1185 1190 atg acg gat gac ata ggt atg ggc gtg act tat ett gcc eta eta gca 3714 Met Thr Asp Asp He Gly Met Gly Val Thr Tyr Leu Ala Leu Leu Ala 1195 1200 1205 gcc ttc aaa gtc aga cca act ttt gca get gga eta etc ttg aga aag 3762 Ala Phe Lys Val Arg Pro Thr Phe Ala Ala Gly Leu Leu Leu Arg Lys 1210 1215 1220 ctg acc tcc aag gaa ttg atg atg act act ata gga att gta etc etc 3810 Leu Thr Ser Lys Glu Leu Met Met Thr Thr He Gly lie Val Leu Leu 1225 1230 1235 tcc cag age acc ata cca gag acc att ett gag ttg act gat geg tta 3858 Ser Gin Ser Thr He Pro Glu Thr He Leu Glu Leu Thr Asp Ala Leu 1240 1245 1250 gcc tta ggc atg atg gtc etc aaa atg gtg aga aat atg gaa aag tat 3906 Ala Leu Gly Met Met Val Leu Lys Met Val Arg Asn Met Glu Lys Tyr 1255 1260 1265 1270

    323

    2018200081 04 Jan 2018

    caa Gin ttg Leu gca Ala gtg Val act ate Thr He 1275 atg get ate He ttg tgc Leu Cys 1280 gtc Val cca Pro aac Asn gca gtg Ala Val 1285 3954 Met Ala ata tta caa aac gca tgg aaa gtg agt tgc aca ata ttg gca gtg gtg 4002 lie Leu Gin Asn 129C Ala Trp 1 Lys Val Ser 1295 Cys Thr He Leu Ala 130C Val Val 1 tcc gtt tcc cca ctg ttc tta aca tcc tea cag caa aaa aca gat tgg 4050 Ser Val Ser Pro 1305 Leu Phe Leu Thr 131C Ser 1 Ser Gin Gin Lys Thr 1315 Asp Trp ata cca tta gca ttg aeg ate aaa ggt etc aat cca aca get att ttt 4098 He Pro Leu 1320 Ala Leu Thr lie Lys 1325 Gly Leu Asn Pro Thr 1330 Ala He Phe eta aca acc etc tea aga acc age aag aaa agg age tgg cca tta aat 4146 Leu Thr 1335 Thr Leu Ser Arg Thr 1340 Ser Lys Lys Arg Ser 1345 Trp Pro Leu Asn 1350 gag get ate atg gca gtc ggg atg gtg age att tta gcc agt tet etc 4194 Glu Ala He Met Ala Val 1355 Gly Met Val Ser He 1360 Leu Ala Ser Ser Leu 1365 eta aaa aat gat att ccc atg aca gga cca tta gtg get gga ggg etc 4242 Leu Lys Asn Asp He Pro 1370 Met Thr Gly Pro Leu 1375 Val Ala Gly Gly Leu 1380 etc act gtg tgc tac gtg etc act gga ega teg gcc gat ttg gaa ctg 4290 Leu Thr Val Cys 1385 Tyr Val Leu Thr Gly 1390 Arg Ser Ala Asp Leu 1395 Glu Leu gag aga gca gcc gat gtc aaa tgg gaa gac cag gca gag ata tea gga 4338 Glu Arg Ala 1400 Ala Asp Val Lys Trp 1405 Glu Asp Gin Ala Glu 1410 He Ser Gly age agt cca ate ctg tea ata aca ata tea gaa gat ggt age atg teg 4386 Ser Ser 1415 Pro He Leu Ser He 1420 Thr He Ser Glu Asp 1425 Gly Ser Met Ser 1430 ata aaa aat gaa gag gaa gaa caa aca ctg acc ata etc att aga aca 4434 He Lys Asn Glu Glu Glu 1435 Glu Gin Thr Leu Thr 1440 He Leu He Arg Thr 1445 gga ttg ctg gtg ate tea gga ctt ttt cct gta tea ata cca ate aeg 4482 Gly Leu Leu Val He Ser 1450 Gly Leu Phe Pro Val 1455 Ser He Pro He Thr 1460 gca gca gca tgg tac ctg tgg gaa gtg aag aaa caa egg gcc gga gta 4530 Ala Ala Ala Trp Tyr Leu Trp Glu Val Lys Lys Gin Arg Ala Gly Val

    1465 1470 1475

    324

    2018200081 04 Jan 2018

    ttg tgg gat gtt cct Pro tea Ser ccc cca ccc Pro Pro Pro 1485 atg gga aag get gaa Glu ctg Leu gaa Glu 4578 Leu Trp Asp Val 1480 Met Gly Lys Ala 1490 gat gga gcc tat aga att aag caa aaa ggg att ett gga tat tcc cag 4626 Asp 1495 Gly Ala Tyr Arg He 150C Lys Gin Lys 1 Gly He Leu Gly 1505 Tyr Ser Gin 1510 ate gga gcc gga gtt tac aaa gaa gga aca ttc cat aca atg tgg cat 4674 lie Gly Ala Gly Val 1515 Tyr Lys Glu Gly Thr 152C Phe His Thr 1 . Met Trp 1525 His gtc aca cgt ggc get gtt eta atg cat aaa gga aag agg att gaa cca 4722 Val Thr Arg Gly 153C Ala I Val Leu Met His Lys 1535 Gly Lys Arg He 154C Glu 1 Pro tea tgg gcg gac gtc aag aaa gac eta ata tea tat gga gga ggc tgg 4770 Ser Trp Ala Asp 1545 Val Lys Lys Asp Leu 1550 He Ser Tyr Gly Gly 1555 Gly Trp aag tta gaa gga gaa tgg aag gaa gga gaa gaa gtc cag gta ttg gca 4818 Lys Leu Glu Gly 1560 Glu Trp Lys Glu Gly 1565 Glu Glu Val Gin 1570 Val Leu Ala ctg gag cct gga aaa aat cca aga gcc gtc caa aeg aaa cct ggt ett 4866 Leu Glu Pro Gly 1575 Lys Asn 158C Pro Arg Ala 1 Val Gin Thr Lys 1585 Pro Gly Leu 1590 ttc aaa acc aac gee gga aca ata ggt get gta tet ctg gac ttt tet 4914 Phe Lys Thr Asn Ala Gly 1595 Thr He Gly Ala 160C Val Ser Leu 1 Asp Phe 1605 Ser cct gga aeg tea gga tet cca att ate gac aaa aaa gga •aaa gtt gtg 4962 Pro Gly Thr Ser Gly 1610 Ser Pro He He Asp 1615 Lys Lys Gly Lys 162C Val 1 Val ggt ett tat ggt aat ggt gtt gtt aca agg agt gga gca tat gtg agt 5010 Gly Leu Tyr Gly 1625 Asn Gly Val Val Thr 1630 Arg Ser Gly Ala Tyr 1635 val Ser get ata gcc cag act gaa aaa age att gaa gac aac cca gag ate gaa 5058 Ala He Ala Gin 1640 Thr Glu Lys Ser He 1645 Glu Asp Asn Pro 1650 Glu He Glu gat gac att ttc ega aag aga aga ctg acc ate atg gac etc cac cca 5106 Asp Asp He Phe 1655 Arg Lys Arg Arg Leu 1660 Thr He Met Asp 1665 Leu His Pro 1670 gga gcg gga aag aeg aag aga tac ett ccg gcc ata gtc aga gaa get 5154 Gly Ala Gly Lys Thr Lys 1675 Arg Tyr Leu Pro Ala He Val 1680 Arg Glu Ala 1685 ata aaa egg ggt ttg aga aca tta ate ttg gcc ccc act aga gtt gtg 5202 lie Lys Arg Gly Leu Arg Thr Leu He Leu Ala Pro Thr Arg Val Val

    1690 1695 1700

    325

    2018200081 04 Jan 2018

    gca Ala get Ala gaa atg Glu Met 1705 gag Glu gaa Glu gcc Ala ett aga Leu Arg- 1710 gga Gly ett Leu cca Pro ata aga He Arg 1715 tac Tyr cag Gin 5250 acc cca gcc ate aga get gtg cac acc ggg egg gag att gtg gac eta 5298 Thr Pro Ala lie 1720 Arg Ala Val His Thr 1725 · Gly Arg Glu 173C He Val 1 Asp Leu atg tgt cat gcc aca ttt acc atg agg ctg eta tea cca gtt aga gtg 5346 Met 1735 Cys His Ala Thr Phe Thr 1740 Met Arg Leu Leu Ser 1745 Pro Val Arg Val 1750 cca aac tac aac ctg att ate atg gac gaa gee cat ttc aca gac cca 5394 Pro Asn Tyr Asn Leu He 1755 He Met Asp Glu 176C Ala I His Phe Thr Asp 1765 Pro gca agt ata gca get aga gga tac ate tea act ega gtg gag atg ggt 5442 Ala Ser He Ala Ala 1770 Arg Gly Tyr He Ser 1775 Thr Arg Val Glu Met 1780 Gly gag gca get ggg att ttt atg aca gcc act ccc ccg gga age aga gac 5490 Glu Ala Ala Gly 1785 lie Phe Met Thr Ala 1790 Thr Pro Pro Gly Ser 1795 Arg Asp cca ttt cct cag age aat gca cca ate ata gat gaa gaa aga gaa ate 5538 Pro Phe Pro Gin 1800 Ser Asn Ala Pro lie 1805 He Asp Glu 181C Glu Arg 1 Glu He cct gaa ege teg tgg aat tcc gga cat gaa tgg gtc acg gat ttt aaa 5586 Pro Glu 1815 Arg Ser Trp Asn Ser 1820 Gly His Glu Trp Val 1825 Thr Asp Phe Lys 1830 ggg aag act gtt tgg ttc gtt cca agt ata aaa gca gga aat gat ata . 5634 Gly Lys Thr Val Trp Phe 1835 Val Pro Ser He Lys 1840 Ala Gly Asn Asp He 1845 gca get tgc ctg agg aaa aat gga aag aaa gtg ata caa etc agt agg 5682 Ala Ala Cys Leu Arg 1850 Lys Asn Gly Lys Lys 1855 Val He Gin Leu Ser 1860 Arg aag acc ttt gat tet gag tat gtc aag act aga acc aat gat tgg gac 5730 Lys Thr Phe Asp 1865 Ser Glu Tyr Val Lys 1870 Thr Arg Thr Asn Asp 1875 Trp Asp ttc gtg gtt aca act gac att tea gaa atg ggt gcc aat ttc aag get 5778 Phe Val Val Thr 1880 Thr Asp He Ser Glu 1885 Met Gly Ala Asn Phe 1890 Lys Ala gag agg gtt ata gac ccc aga ege tgc atg aaa cca gtc ata eta aca 5826 Glu Arg 1895 Val He Asp Pro Arg Arg Cys 1900 Met Lys Pro 1905 Val He Leu Thr 1910

    326

    2018200081 04 Jan 2018

    gat Asp ggt Gly gaa Glu gag Glu egg gtg Arg Val 1915 att He ctg Leu gca Ala gga cct Gly Pro 1920 atg Met cca Pro gtg Val acc cac Thr His 1925 5874 tet agt gca gca caa aga aga ggg aga ata gga aga aat cca aaa aat 5922 Ser Ser Ala Ala 1930 Gin Arg Arg Gly Arg 1935 He Gly Arg Asn Pro 194C Lys Asn 1 gag aat gac cag tac ata tac atg ggg gaa cct ctg gaa aat gat gaa 5970 Glu Asn Asp Gin 1945 Tyr lie Tyr Met Gly 1950 Glu Pro Leu Glu Asn 1955 Asp Glu gac tgt gca cac tgg aaa gaa get aaa atg etc eta gat aac ate aac 6018 Asp Cys Ala 1960 His Trp Lys Glu Ala 1965 Lys Met Leu Leu Asp 1970 Asn He Asn aeg cca gaa gga ate att cct agc atg ttc gaa cca gag cgt gaa aag 6066 Thr Pro 1975 Glu Gly He He 198C Pro 1 Ser Met Phe Glu Pro 1985 Glu Arg Glu Lys 1990 gtg gat gcc att gat ggc gaa tac ege ttg aga gga gaa gca agg aaa 6114 Val Asp Ala He Asp Gly 1995 Glu Tyr Arg Leu Arg 2000 Gly Glu Ala Arg Lys 2005 acc ttt gta gac tta atg aga aga gga gac eta cca gtc tgg ttg gcc 6162 Thr Phe Val Asp Leu Met 2010 Arg Arg Gly 2015 Asp Leu Pro Val Trp Leu Ala 2020 tac aga gtg gca get gaa ggc ate aac tac gca gac aga agg tgg tgt 6210 Tyr Arg Val Ala 2025 Ala Glu Gly He Asn 2030 Tyr Ala Asp Arg Arg 2035 Trp Cys ttt gat gga gtc aag aac aac caa ate eta gaa gaa aac gtg gaa gtt 6258 Phe Asp Gly 2040 Val Lys Asn Asn Gin 2045 He Leu Glu Glu Asn 2050 Val Glu Val gaa ate tgg aca aaa gaa ggg gaa agg aag aaa ttg aaa ccc aga tgg 6306 Glu lie 2055 Trp Thr Lys Glu Gly 2060 Glu Arg Lys Lys Leu 2065 Lys Pro Arg Trp 2070 ttg gat get agg ate tat tet gac cca ctg gcg eta aaa gaa ttt aag 6354 Leu Asp Ala Arg He Tyr 2075 Ser Asp Pro Leu Ala 2080 Leu Lys Glu Phe Lys 2085 · gaa ttt gca gcc gga aga aag tet ctg acc ctg aac eta ate aca gaa 6402 Glu Phe Ala Ala Gly Arg 2090 Lys Ser Leu Thr Leu 2095 Asn Leu lie Thr Glu 2100 atg ggt agg etc cca acc ttc atg act cag aag gca aga gac gca ctg 6450 Met Gly Arg Leu 2105 Pro Thr Phe Met Thr 2110 Gin Lys Ala Arg Asp 2115 Ala Leu gac aac tta gca gtg ctg cac aeg get gag gca ggt gga agg gcg tac 6498 Asp Asn Leu 2120 Ala Val Leu His Thr 2125 Ala Glu Ala Gly Gly Arg 2130 Ala Tyr

    327

    2018200081 04 Jan 2018

    aac cat Asn His 2135 get Ala etc Leu agt Ser gaa ctg Glu Leu 2140 ccg Pro gag Glu acc Thr ctg gag aca Leu Glu Thr 2145 ttg Leu ctt Leu tta Leu 2150 6546 ctg aca ctt ctg get aca gtc aeg gga ggg ate ttt tta ttc ttg atg 6594 Leu Thr Leu Leu Ala 2155 Thr Val Thr Gly Gly 216C lie Phe Leu 1 Phe Leu 2165 Met agc gca agg ggc ata ggg aag atg acc ctg gga atg tgc tgc ata ate 6642 Ser Ala Arg Gly 217C He 1 Gly Lys Met Thr Leu 2175 Gly Met Cys Cys 218C He 1 He aeg get agc ate etc eta tgg tac gca caa ata cag cca cac tgg ata 6690 Thr Ala Ser He 2185 Leu Leu Trp Tyr Ala 2190 Gin He Gin Pro His 2195 Trp He gca get tea ata ata ctg gag ttt ttt etc ata gtt ttg ctt att cca 6738 Ala Ala Ser 2200 He lie Leu Glu Phe 2205 Phe Leu He Val Leu 2210 Leu He Pro gaa cct gaa aaa cag aga aca CCC caa gac aac caa ctg acc tac gtt 6786 Glu Pro 2215 Glu Lys Gin Arg Thr 2220 Pro Gin Asp Asn Gin Leu 2225 Thr Tyr Val 2230 gtc ata gcc ate etc aca gtg gtg gcc gca acc atg gca aac gag atg 6834 Val lie Ala He Leu 2235 Thr Val Val Ala Ala 224C Thr Met Ala 1 Asn Glu 2245 Met ggt ttc eta gaa aaa aeg aag aaa gat etc gga ttg gga age att gca 6882 Gly Phe Leu Glu Lys 2250 Thr Lys Lys Asp Leu 2255 Gly Leu Gly Ser 226C He 1 Ala acc cag caa CCC gag agc aac ate ctg gac ata gat eta cgt cct gca 6930 Thr Gin Gin Pro 2265 Glu Ser Asn He Leu 2270 Asp He Asp Leu Arg 2275 Pro Ala tea gca tgg aeg ctg tat gcc gtg gcc aca aca ttt gtt aca cca atg 6978 Ser Ala Trp 2280 Thr Leu Tyr Ala Val 2285 Ala Thr Thr Phe Val 2290 Thr Pro Met ttg aga cat age att gaa aat tcc tea gtg aat gtg tcc eta aca get 7026 Leu Arg 2295 His Ser He Glu Asn 2300 Ser Ser Val Asn Val Ser 2305 Leu Thr Ala 2310 ata gcc aac caa gcc aca gtg tta atg ggt etc ggg aaa gga tgg cca 7074 He Ala Asn Gin Ala Thr Val 2315 Leu Met Gly Leu Gly Lys 2320 Gly Trp Pro 2325 ttg tea aag atg gac ate gga gtt ccc ctt etc gcc att gga tgc tac 7122 Leu Ser Lys Met Asp He Gly Val Pro Leu Leu Ala lie Gly Cys Tyr

    2330 2335 2340

    2018200081 04 Jan 2018

    328 tea caa gtc aac ccc ata act etc aca gca get ett ttc tta ttg gta 7170

    Ser Gin Val Asn Pro lie Thr Leu Thr Ala Ala Leu Phe Leu Leu Val

    2345 2350 2355

    gca Ala cat His 2360 tat Tyr 1 gcc Ala ate He ata He ggg cca Gly Pro 2365 gga Gly etc Leu caa gca aaa Gin Ala Lys 2370 gca Ala acc Thr aga Arg 7218 gaa get cag aaa aga gca geg geg ggc ate atg aaa aac cca act gtc 7266 Glu Ala 2375 Gin Lys Arg Ala 238C Ala Ala I Gly He Met Lys Asn 2385 Pro Thr Val 2390 gat gga ata aca gtg att gac eta gat cca ata cct tat gat cca aag 7314 Asp Gly He Thr Val lie 2395 Asp Leu Asp Pro 240C He Pro Tyr 1 Asp Pro Lys 2405 ttt gaa aag cag ttg gga caa gta atg etc eta gtc etc tgc gtg act 7362 Phe Glu Lys Gin Leu 2410 Gly Gin Val Met 241E Leu Leu Val Leu Cys Val 2420 Thr caa gta ttg atg atg agg act aca tgg get ctg tgt gag get tta acc 7410 Gin Val Leu Met 2425 Met Arg Thr Thr Trp 2430 Ala Leu Cys Glu Ala 2435 Leu Thr tta get acc ggg ccc ate tcc aca ttg tgg gaa gga aat cca ggg agg 7458 Leu Ala 244C Thr 1 Gly Pro He Ser Thr 2445 Leu Trp Glu Gly Asn 2450 Pro Gly Arg ttt tgg aac act acc att geg gtg tea atg get aac att ttt aga ggg 7506 Phe Trp 2455 Asn Thr Thr He Ala Val 2460 Ser Met Ala Asn He 2465 Phe Arg Gly 2470 agt tac ttg gcc gga get gga ett etc ttt tet att atg aag aac aca 7554 Ser Tyr Leu Ala Gly Ala 2475 Gly Leu Leu Phe Ser He Met 2480 Lys Asn Thr 2485 acc aac aca aga agg gga act ggc aac ata gga gag aeg ett gga gag 7602 Thr Asn Thr Arg Arg 2490 Gly Thr Gly Asn lie 2495 Gly Glu Thr Leu Gly 2500 Glu aaa tgg aaa agc ega ttg aac gca ttg gga aaa agt gaa ttc cag ate 7650 Lys Trp Lys Ser 2505 Arg Leu Asn Ala Leu 2510 Gly Lys Ser Glu Phe 2515 Gin He tac aag aaa agt gga ate cag gaa gtg gat aga acc tta gca aaa gaa 7698 Tyr Lys Lys 2520 Ser Gly He Gin Glu 2525 Val Asp Arg Thr Leu 2530 Ala Lys Glu ggc att aaa aga gga gaa aeg gac cat cac get gtg teg ega ggc tea 7746 Gly He 2535 Lys Arg Gly Glu Thr Asp 2540 His His Ala Val Ser 2545 Arg Gly Ser 2550 gca aaa ctg aga tgg ttc gtt gag aga aac atg gtc aca cca gaa ggg 7794 Ala Lys Leu Arg Trp Phe Val Glu Arg Asn Met Val Thr Pro Glu Gly

    2555 2560 2565

    329

    2018200081 04 Jan 2018

    aaa Lys gta Val gtg Val gac etc Asp Leu 2570 ggt Gly tgt Cys ggc Gly aga gga Arg Gly 2575 ggc Gly tgg Trp tea Ser tac tat Tyr Tyr 2580 tgt Cys 7842 gga gga eta aag aat gta aga gaa gtc aaa ggc eta aca aaa gga gga 7890 Gly Gly Leu Lys Asn 2585 Val Arg Glu 259C Val Lys 1 Gly Leu Thr 2595 Lys Gly Gly cca gga cac gaa gaa ccc ate ccc atg tea aca tat ggg tgg aat eta 7938 Pro Gly His 2600 Glu Glu Pro He Pro 2605 Met Ser Thr Tyr 261C Gly I Trp Asn Leu gtg cgt ctt caa agt gga gtt gac gtt ttc ttc ate ccg cca gaa aag 7986 Val Arg 2615 Leu Gin Ser Gly Val 2620 Asp Val Phe Phe He 2625 Pro Pro Glu Lys 2630 tgt gac aca tta ttg tgt gac ata ggg gag tea tea cca aat ccc aca 8034 Cys Asp Thr Leu Leu 2635 Cys Asp He Gly Glu Ser 2640 Ser Pro Asn Pro 2645 Thr gtg gaa gca gga ega aca etc aga gtc ctt aac tta gta gaa aat tgg 8082 Val Glu Ala Gly Arg 2650 Thr Leu Arg Val Leu 2655 Asn Leu Val Glu Asn 2660 Trp ttg aac aac aac act caa ttt tgc ata aag gtt etc aac cca tat atg 8130 Leu Asn Asn Asn Thr 2665 Gin Phe Cys 267C He Lys 1 Val Leu Asn 2675 Pro Tyr Met ccc tea gtc ata gaa aaa atg gaa gca eta caa agg aaa tat gga gga 8178 Pro Ser Val 2680 lie Glu Lys Met 2685 Glu Ala Leu Gin Arg 269C Lys 1 Tyr Gly Gly gcc tta gtg agg aat cca etc tea ega aac tcc aca cat gag atg tac 8226 Ala Leu 2695 Val Arg Asn Pro Leu 2700 Ser Arg Asn Ser Thr 2705 His Glu Met Tyr 2710 tgg gta tcc aat get tcc ggg aac ata gtg tea tea gtg aac atg att 8274 Trp Val Ser Asn Ala Ser 2715 Gly Asn He Val Ser 2720 Ser Val Asn Met He 2725 tea agg atg ttg ate aac aga ttt aca atg aga tac aag aaa gcc act 8322 Ser Arg Met Leu He 2730 Asn Arg Phe Thr Met 2735 Arg Tyr Lys Lys Ala 2740 Thr tac gag ccg gat gtt gac etc gga age gga acc cgt aac ate ggg att 8370 Tyr Glu Pro Asp Val 2745 Asp Leu Gly Ser Gly 2750 Thr Arg Asn He Gly 2755 lie gaa agt gag ata cca aac eta gat ata att ggg aaa aga ata gaa aaa 8418 Glu Ser Glu 2760 He Pro Asn Leu Asp 2765 He He Gly Lys Arg 2770 He Glu Lys

    330

    2018200081 04 Jan 2018

    ata aag caa gag cat gaa aca tea tgg cac taf gac Tyr Asp 2785 caa Gin gac Asp cac His cca Pro 2790 8466 lie Lys 2775 Gin Glu His Glu Thr 2780 Ser Trp His tac aaa aeg tgg gca tac cat ggt agc tat gaa aca aaa cag act gga 8514 Tyr Lys Thr Trp Ala Tyr His 2795 Gly Ser Tyr Glu Thr 2800 Lys Gin Thr 2805 Gly tea gca tea tcc atg gtc aac gga gtg gtc agg ctg ctg aca aaa cct 8562 Ser Ala Ser Ser 281C Met 1 Val Asn Gly Val 2815 Val Arg Leu Leu Thr Lys 2820 Pro tgg gac gtc gtc ccc atg gtg aca cag atg gca atg aca gac aeg act 8610 Trp Asp Val 2825 Val Pro Met Val Thr Gin 2830 Met Ala Met Thr Asp 2835 Thr Thr cca ttt gga caa cag ege gtt ttt aaa gag aaa gtg gac aeg aga acc 8658 Pro Phe Gly 2840 Gin Gin Arg Val Phe 2845 Lys Glu Lys Val Asp 2850 Thr Arg Thr caa gaa ccg aaa gaa ggc aeg aag aaa eta atg aaa ata aca gca gag 8706 Gin Glu 2855 Pro Lys Glu Gly Thr 2860 Lys Lys Leu Met Lys 2865 He Thr Ala Glu 2870 tgg ett tgg aaa gaa tta ggg aag aaa aag aca ccc agg atg tgc acc 8754 Trp Leu Trp Lys Glu Leu Gly 2875 Lys Lys Lys Thr Pro 2880 Arg Met Cys 2885 Thr aga gaa gaa ttc aca aga aag gtg aga agc aat gca gcc ttg ggg gcc 8802 Arg Glu Glu Phe 289C Thr 1 Arg Lys Val Arg 2895 Ser Asn Ala Ala Leu 290C Gly 1 Ala ata ttc act gat gag aac aag tgg aag teg gca cgt gag get gtt gaa 8850 He Phe Thr Asp 2905 Glu Asn Lys Trp Lys 2910 Ser Ala Arg Glu Ala 2915 Val Glu gat agt agg ttt tgg gag ctg gtt gac aag gaa agg aat etc cat ett 8898 Asp Ser Arg 2920 Phe Trp Glu Leu Val 2925 Asp Lys Glu Arg Asn 2930 Leu His Leu gaa gga aag tgt gaa aca tgt gtg tac aac atg atg gga aaa aga gag 8946 Glu Gly 2935 Lys Cys Glu Thr Cys 2940 Val Tyr Asn Met Met 2945 Gly Lys Arg Glu 2950 aag aag eta ggg gaa ttc ggc aag gca aaa ggc agc aga gcc ata tgg 8994 Lys Lys Leu Gly Glu Phe Gly 2955 Lys Ala Lys Gly Ser 2960 Arg Ala He Trp 2965 tac atg tgg ett gga gca ege ttc tta gag ttt gaa gcc eta gga ttc 9042 Tyr Met Trp Leu Gly 2970 Ala Arg Phe Leu Glu 2975 Phe Glu Ala Leu Gly 2980 Phe tta aat gaa gat cac tgg ttc tcc aga gag aac tcc ctg agt gga gtg 9090 Leu Asn Glu Asp His Trp Phe Ser Arg Glu Asn Ser Leu Ser Gly Val

    2985 2990 2995

    331

    2018200081 04 Jan 2018

    gaa gga gaa Glu Gly Glu ggg ctg cac aag eta ggt Lys Leu Gly 3005 tac Tyr att He eta aga gac gtg age 9138 Gly Leu His Leu Arg 3010 Asp Val Ser 3000 aag aaa gag gga gga gca atg tat gcc gat gac acc gca gga tgg gat 9186 Lys Lys Glu 3015 Gly Gly Ala Met Tyr Ala 3020 Asp Asp 3025 Thr Ala Gly Trp Asp 3030 aca aga ate aca eta gaa gac eta aaa aat gaa gaa atg gta aca aac 9234 Thr Arg He Thr Leu Glu 3035 Asp Leu Lys Asn Glu 3040 ' Glu Met Val Thr Asn 3045 cac atg gaa gga gaa cac aag aaa eta gcc gag gcc att ttc aaa eta 9282 His Met Glu Gly Glu His 3050 Lys Lys Leu Ala 3055 Glu Ala He Phe Lys 3060 Leu aeg tac caa aac aag gtg gtg cgt gtg caa aga cca aca cca aga ggc 9330 Thr Tyr Gin Asn 3065 Lys Val Val Arg Val 3070 Gin Arg Pro Thr Pro 3075 Arg Gly aca gta atg gac ate ata teg aga aga gac caa aga ggt agt gga caa 9378 Thr Val Met 3080 Asp He He Ser Arg Arg 3085 Asp Gin Arg Gly 3090 Ser Gly Gin gtt ggc acc tat gga etc aat act ttc acc aat atg gaa gcc caa eta 9426 Val Gly Thr 3095 Tyr Gly Leu Asn Thr Phe 3100 Thr Asn Met Glu 3105 Ala Gin Leu 3110 ate aga cag atg gag gga gaa gga gtc ttt aaa age att cag cac eta 9474 lie Arg Gin Met Glu Gly 3115 Glu Gly Val Phe Lys 3120 Ser He Gin His Leu 3125 aca ate aca gaa gaa ate get gtg caa aac tgg tta gca aga gtg ggg 9522 Thr He Thr Glu Glu He 3130 Ala Val Gin Asn 3135 Trp Leu Ala Arg Val 3140 Gly ege gaa agg tta tea aga atg gcc ate agt gga gat gat tgt gtt gtg 9570 Arg Glu Arg Leu 3145 Ser Arg Met Ala He 3150 Ser Gly Asp Asp Cys 3155 Val Val aaa cct tta gat gac agg ttc gca age get tta aca get eta aat gac 9618 Lys Pro Leu 3160 Asp Asp Arg Phe Ala Ser 3165 Ala Leu Thr Ala 3170 Leu Asn Asp atg gga aag att agg aaa gac ata caa caa tgg gaa cct tea aga gga 9666 Met Gly Lys 3175- He Arg Lys Asp He Gin 3180 Gin Trp Glu Pro 3185 Ser Arg Gly 3190 tgg aat gat tgg aca caa gtg ccc ttc tgt tea cac cat ttc cat gag 9714 Trp Asn Asp Trp Thr Gin 3195 Val Pro Phe Cys Ser 3200 His His Phe His Glu 3205

    332

    2018200081 04 Jan 2018

    tta Leu ate lie atg aaa gac ggt cgc gta etc gtt gtt cca tgt aga aac caa Pro Cys Arg Asn Gin 3220 9762 Met Lys Asp 3210 Gly Arg Val Leu Val Val 3215 gat gaa ctg att ggc aga gcc cga ate tcc caa gga gca ggg tgg tct 9810 Asp Glu Leu He Gly Arg Ala Arg He Ser Gin Gly Ala Gly Trp Ser 3225 3230 3235 ttg egg gag aeg gcc tgt ttg ggg aag tct tac gcc caa atg tgg age 9858 Leu Arg Glu Thr Ala Cys Leu Gly Lys Ser Tyr Ala Gin Met Trp Ser 3240 3245 3250 ttg atg tac ttc cac aga cgc gac etc agg ctg gcg gca aat get att 9906 Leu Met Tyr Phe His Arg Arg Asp Leu Arg Leu Ala Ala Asn Ala He 3255 3260 3265 3270 tgc teg gca gta cca tea cat tgg gtt cca aca agt cga aca acc tgg 9954 Cys Ser Ala Val Pro Ser His Trp Val Pro Thr Ser Arg Thr Thr Trp 3275 3280 3285 tcc ata cat get aaa cat gaa tgg atg aca aeg gaa gac atg ctg aca 10002 Ser He His Ala Lys His Glu Trp Met Thr Thr Glu Asp Met Leu Thr 3290 3295 3300 gtc, tgg aac agg gtg tgg att caa gaa aac cca tgg atg gaa gac aaa 10050 Val Trp Asn Arg Val Trp lie Gin Glu Asn Pro Trp Met Glu Asp Lys 3305 3310 3315 act cca gtg gaa tea tgg gag gaa ate cca tac ttg ggg aaa aga gaa 10098 Thr Pro Val Glu Ser Trp Glu Glu He Pro Tyr Leu Gly Lys Arg Glu 3320 3325 3330 gac caa tgg tgc ggc tea ttg att ggg tta aca age agg gcc acc tgg 10146 Asp Gin Trp Cys Gly Ser Leu He Gly Leu Thr Ser Arg Ala Thr Trp 3335 3340 3345 3350 gca aag aac ate caa gca gca ata aat caa gtt aga tcc ett ata ggc 10194 Ala Lys Asn He Gin Ala Ala He Asn Gin Val Arg Ser Leu He Gly 3355 3360 3365 aat gaa gaa tac aca gat tac atg cca tcc atg aaa aga ttc aga aga 10242 Asn Glu Glu Tyr Thr Asp Tyr Met Pro Ser Met Lys Arg Phe Arg Arg 3370 3375 3380 gaa gag gaa gaa gca gga gtt ctg tgg tag aaagcaaaac taacatgaaa 10292 Glu Glu Glu Glu Ala Gly Val Leu Trp * 3385 3390 caaggctaga agtcaggtcg gattaagcca tagtacggaa aaaactatgc tacctgtgag 10352 ccccgtccaa ggacgttaaa agaagtcagg ccatcataaa tgccatagct tgagtaaact 10412 atgcagcctg tagctccacc tgagaaggtg taaaaaatcc gggaggccac aaaccatgga 10472 agctgtacgc atggcgtagt ggactagcgg ttagaggaga cccctccctt acaaatcgca 10532 gcaacaatgg gggcccaagg cgagatgaag ctgtagtctc gctggaagga ctagaggtta 10592 gaggagaccc ccccgaaaca aaaaacagca tattgacgct gggaaagacc agagatcctg 10652 ctgtctcctc agcatcattc caggcacaga acgccagaaa atggaatggt gctgttgaat 10712

    2018200081 04 Jan 2018

    333 caacaggttc t <210> 28 <211> 3391 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct

    10723 <400> 28

    Met Asn Asn Gin Arg Lys Lys Ala Lys Asn Thr Pro Phe Asn Met Leu 1 5 10 15 Lys Arg Glu Arg Asn Arg Val Ser Thr Val Gin Gin Leu Thr Lys Arg 20 25 30 Phe Ser Leu Gly Met Leu Gin Gly Arg Gly Pro Leu Lys Leu Phe Met 35 40 45 Ala Leu Val Ala Phe Leu Arg Phe Leu Thr He Pro Pro Thr Ala Gly 50 55 60 lie Leu Lys Arg Trp Gly Thr He Lys Lys Ser Lys Ala He Asn Val 65 70 75 80 Leu Arg Gly Phe Arg Lys Glu He Gly Arg Met Leu Asn lie Leu Asn 85- 90 95 Arg Arg Arg Arg Ser Ala Gly Met He He Met Leu He Pro Thr Val 100 105 110 Met Ala Phe His Leu Thr Thr Arg Gly Gly Glu Pro His Met He Val 115 120 125 Ser Lys Gin Glu Arg Gly Lys Ser Leu Leu Phe Lys Thr Ser Ala Gly 130 135 140 Val Asn Met Cys Thr Leu He Ala Met Asp Leu Gly Glu Leu Cys Glu 145 150 155 160 Asp Thr Met Thr Tyr Lys Cys Pro Arg He Thr Glu Ala Glu Pro Asp 165 170 175 Asp Val Asp Cys Trp. Cys Asn Ala Thr Asp Thr Trp Val Thr Tyr Gly 180 185 190 Thr Cys Ser Gin Thr Gly Glu His Arg Arg Asp Lys Arg Ser Val Ala 195 200 205 Leu Ala Pro His Val Gly Leu Gly Leu Glu Thr Arg Ala Glu Thr Trp 210 215 220 Met Ser Ser Glu Gly Ala Trp Lys Gin He Gin Lys Val Glu Thr Trp 225 230 235 240 Ala Leu Arg His Pro Gly Phe Thr Val He Ala Leu Phe Leu Ala His 245 250 255 Ala He Gly Thr Ser He Thr Gin Lys Gly He He Phe He Leu Leu .260 265 270 Met Leu Val Thr Pro Ser Met Ala Met Arg Cys Val Gly He Gly Asn 275 280 285 Arg Asp Phe Val Glu Gly Leu Ser Gly Ala Thr Trp Val Asp Val Val 290 295 300 Leu Glu His Gly Ser Cys Val Thr Thr Met Ala Lys Asn Lys Pro Thr 305 310 315 320 Leu Asp He Glu Leu Leu Lys Thr Glu Val Thr Asn Pro Ala Val Leu 325 330 335

    334

    2018200081 04 Jan 2018

    Arg Lys Leu Cys He Glu Ala Lys He 345 Ser Asn Thr Thr Thr 350 Asp Ser 340 Arg Cys Pro Thr Gin Gly Glu Ala Thr Leu Val Glu Glu Gin Asp Ala 355 360 365 Asn Phe Val Cys Arg Arg Thr Phe Val Asp Arg Gly Trp Gly Asn Gly 370 375 380 Cys Gly Leu Phe Gly Lys Gly Ser Leu He Thr Cys Ala Lys Phe Lys 385 390 395 400 Cys Val Thr Lys Leu Glu Gly Lys He Val Gin Tyr Glu Asn Leu Lys 405 410 415 Tyr Ser Val He Val Thr Val His Thr Gly Asp Gin His Gin Val Gly 420 425 430 Asn Glu Thr Thr Glu His Gly Thr Thr Ala Thr He Thr Pro Gin Ala 435 440 445 Pro Thr Ser Glu He Gin Leu Thr Asp Tyr Gly Thr Leu Thr Leu Asp 450 455 460 Cys Ser Pro Arg Thr Gly Leu Asp Phe Asn Glu Met Val Leu Leu Thr 465 470 475 480 Met Lys Glu Arg Ser Trp Leu Val His Lys Gin Trp Phe Leu Asp Leu 485 490 495 Pro Leu Pro Trp Thr Ser Gly Ala Ser Thr Ser Gin Glu Thr Trp Asn 500 505 510 Arg Gin Asp Leu Leu Val Thr Phe Lys Thr Ala His Ala Lys Lys Gin 515 520 525 Glu Val Val Val Leu Gly Ser Gin Glu Gly Ala Met His Thr Ala Leu 530 535 540 Thr Gly Ala Thr Glu He Gin Thr Ser Gly Thr Thr Thr He Phe Ala 545 550 555 560 Gly His Leu Lys Cys Arg Leu Lys Met Asp Lys Leu Thr Leu Lys Gly 565 570 575 Met Ser Tyr Val Met Cys Thr Gly Ser Phe Lys Leu Glu Lys Glu Val 580 585 590 Ala Glu Thr Gin His Gly Thr Val Leu Val Gin Val Lys Tyr Glu Gly 595 600 605 Thr Asp Ala Pro Cys Lys He Pro Phe Ser Thr Gin Asp Glu Lys Gly 610 615 62 0 Ala Thr Gin Asn Gly Arg Leu He Thr Ala Asn Pro He Val Thr Asp 625 630 635 640 Lys Glu Lys Pro Val Asn He Glu Ala Glu Pro Pro Phe Gly Glu Ser 645 650 655 Tyr He Val Val Gly Ala Gly Glu Lys Ala Leu Lys Leu Ser Trp Phe 660 665 670 Lys Lys Gly Ser Ser He Gly Lys Met Phe Glu Ala Thr Ala Arg Gly 675 680 685 Ala Arg Arg Met Ala lie Leu Gly Asp Thr Ala Trp Asp Phe Gly Ser 690 695 700 lie Gly Gly Val Phe Thr Ser Met Gly Lys Leu Val His Gin Val Phe 705 710 715 720 Gly Thr Ala Tyr Gly Val Leu Phe Ser Gly Val Ser Trp Thr Met Lys 725 730 735 He Gly He Gly He Leu Leu Thr Trp Leu Gly Leu Asn Ser Arg Asn 740 745 750 Thr Ser Leu Ser Met Met Cys He Ala Ala Gly He Val Thr Leu Tyr 755 760 765

    335

    2018200081 04 Jan 2018

    Leu Gly Val Met Val 770 Gin Ala Asp Ser Gly Cys Val Val Ser Trp Lys 775 780 Asn 785 Lys Glu Leu Lys Cys Gly Ser Gly He 790 Phe He 795 Thr Asp Asn Val 800 His Thr Trp Thr Glu 805 Gin Tyr Lys Phe Gin 810 Pro Glu Ser Pro Ser 815 Lys Leu Ala Ser Ala He 820 Gin Lys Ala His Glu 825 Glu Asp He Cys 830 Gly lie Arg Ser Val Thr Arg 835 Leu Glu Asn Leu Met 840 Trp Lys Gin 845 He Thr Pro Glu Leu Asn His He 850 Leu Ser Glu Asn Glu 855 Val Lys 860 Leu Thr He Met Thr 865 Gly Asp He Lys Gly He Met Gin Ala 870 Gly Lys 875 Arg Ser Leu Arg 880 Pro Gin Pro Thr Glu 885 Leu Lys Tyr Ser Trp 890 Lys Thr Trp Gly Lys 895 Ala Lys Met Leu Ser Thr 900 Glu Ser His Asn Gin 905 Thr Phe Leu He 910 Asp Gly Pro Glu Thr Ala Glu 915 Cys Pro Asn Thr Asn 920 Arg Ala Trp 925 Asn Ser Leu Glu Val Glu Asp Tyr 930 Gly Phe Gly Val Phe 935 Thr Thr 940 Asn He Trp Leu Lys 945 Leu Lys Glu Lys Gin Asp Val Phe Cys 950 Asp Ser 955 Lys Leu Met Ser 960 Ala Ala He Lys Asp 965 Asn Arg Ala Val His 970 Ala Asp Met Gly Tyr 975 Trp lie Glu Ser Ala Leu 980 Asn Asp Thr Trp Lys 985 lie Glu Lys Ala 990 Ser Phe He Glu Val Lys Asn 995 Cys His Trp Pro Lys 1000 Ser His Thr Leu 1005 Trp Ser Asn Gly Val Leu Glu 1010 Ser Glu Met He lie 1015 Pro Lys Asn 1020 Leu Ala Gly Pro Val Ser Gin His 1025 Asn Tyr Arg Pro Gly 1030 Tyr His 1035 Thr Gin He Thr 1040 Gly Pro Trp His Leu Gly Lys Leu Glu Met Asp Phe 1045 1050 Asp Phe Cys Asp 1055 Gly Thr Thr Val Val 1060 Val Thr Glu Asp Cys 1065 Gly Asn Arg Gly Pro 1070 Ser Leu Arg Thr Thr Thr 1075 Ala Ser Gly Lys Leu 1080 He Thr Glu Trp 1085 Cys Cys Arg Ser Cys Thr Leu 1090 Pro Pro Leu Arg Tyr 1095 Arg Gly Glu 1100 Asp Gly Cys Trp Tyr Gly Met Glu 1105 He Arg Pro Leu Lys 1110 Glu Lys 1115 Glu Glu Asn Leu 1120 Val Asn Ser Leu Val Thr Ala Gly His Gly Gin Val 1125 1130 . Asp Asn Phe Ser 1135 Leu Gly Val Leu Gly 1140 Met Ala Leu Phe Leu 1145 Glu Glu Met Leu Arg 1150 Thr Arg Val Gly Thr Lys 1155 His Ala lie Leu Leu 1160 Val Ala Val, Ser 1165 Phe Val Thr Leu He Thr Gly 1170 Asn Met Ser Phe Arg 1175 Asp Leu Gly Arg 1180 Val Met Val Met Val Gly Ala Thr Met Thr Asp Asp He Gly Met Gly Val Thr

    1185 1190 1195 1200

    336

    2018200081 04 Jan 2018

    Tyr Leu Ala Leu Leu Ala 1205 Ala Phe Lys Val Arg Pro Thr Phe Ala Ala 1210 1215 Gly Leu Leu Leu Arg Lys Leu Thr Ser Lys Glu Leu Met Met Thr Thr 1220 1225 1230 lie Gly He Val Leu Leu Ser Gin Ser Thr He Pro Glu Thr He Leu 1235 1240 1245 Glu Leu Thr Asp Ala Leu Ala Leu Gly Met Met Val Leu Lys Met Val 1250 1255 1260 Arg Asn Met Glu Lys Tyr Gin Leu Ala Val Thr He Met Ala He Leu 1265 1270 1275 i 1280 Cys Val Pro Asn Ala Val He Leu Gin Asn Ala Trp Lys Val Ser Cys 1285 1290 1295 Thr He Leu Ala Val Val Ser Val Ser Pro Leu Phe Leu Thr Ser Ser 1300 1305 1310 Gin Gin Lys Thr Asp Trp lie Pro Leu Ala Leu Thr He Lys Gly Leu 1315 1320 1325 Asn Pro Thr Ala He Phe Leu Thr Thr Leu Ser Arg Thr Ser Lys Lys 1330 1335 1340 Arg Ser Trp Pro Leu Asn Glu Ala He Met Ala Val Gly Met Val Ser 1345 1350 1355 i 1360 lie Leu Ala Ser Ser Leu Leu Lys Asn Asp He Pro Met Thr Gly Pro 1365 1370 1375 Leu Val Ala Gly Gly Leu Leu Thr Val Cys Tyr Val Leu Thr Gly Arg 1380 1385 1390 Ser Ala Asp Leu Glu Leu Glu Arg Ala Ala Asp Val Lys Trp Glu Asp 1395 1400 1405 Gin Ala Glu He Ser Gly Ser Ser Pro He Leu Ser He Thr He Ser 1410 1415 1420 Glu Asp Gly Ser Met Ser He Lys Asn Glu Glu Glu Glu Gin Thr Leu 1425 1430 1435 i 1440 Thr He Leu He Arg Thr Gly Leu Leu Val lie Ser Gly Leu Phe Pro 1445 1450 1455 Val Ser He Pro He Thr Ala Ala Ala Trp Tyr Leu Trp Glu Val Lys 1460 1465 1470 Lys Gin Arg Ala Gly Val Leu Trp Asp Val Pro Ser Pro Pro Pro Met 1475 1480 1485 Gly Lys Ala Glu Leu Glu Asp Gly Ala Tyr Arg He Lys Gin Lys Gly 1490 1495 1500 lie Leu Gly Tyr Ser Gin lie Gly Ala Gly Val Tyr Lys Glu Gly Thr 1505 1510 1515 1520 Phe His Thr Met Trp His Val Thr Arg Gly Ala Val Leu Met His Lys 1525 1530 1535 Gly Lys Arg He Glu Pro Ser Trp Ala Asp Val Lys Lys Asp Leu He 1540 1545 1550 Ser Tyr Gly Gly Gly Trp Lys Leu Glu Gly Glu Trp Lys Glu Gly Glu 1555 1560 1565 Glu Val Gin Val Leu Ala Leu Glu Pro Gly Lys Asn Pro Arg Ala Val 1570 1575 1580 Gin Thr Lys Pro Gly Leu Phe Lys Thr Asn Ala Gly Thr He Gly Ala 1585 1590 1595 i 1600 Val Ser Leu Asp Phe Ser Pro Gly Thr Ser Gly Ser Pro He He Asp 1605 1610 1615 Lys Lys Gly Lys Val Val Gly Leu Tyr Gly Asn Gly Val Val Thr Arg 1620 1625 1630

    337

    2018200081 04 Jan 2018

    Ser Gly Ala Tyr Val Ser Ala He Ala Gin Thr Glu Lys Ser lie Glu 1635 1640 1645 Asp Asn Pro Glu He Glu Asp Asp He Phe Arg Lys Arg Arg Leu Thr 1650 1655 1660 lie Met Asp Leu His Pro Gly Ala Gly Lys Thr Lys Arg Tyr Leu Pro 1665 1670 1675 1680 Ala lie Val Arg Glu Ala He Lys Arg Gly Leu Arg Thr Leu lie Leu 1685 1690 1695 Ala Pro Thr Arg Val Val Ala Ala Glu Met Glu Glu Ala Leu Arg Gly 1700 1705 1710 Leu Pro He Arg Tyr Gin Thr Pro Ala He Arg Ala Val His Thr Gly 1715 1720 1725 Arg Glu lie Val Asp Leu Met Cys His Ala Thr Phe Thr Met Arg Leu 1730 1735 1740 Leu Ser Pro Val Arg Val Pro Asn Tyr Asn Leu He lie Met Asp Glu 1745 1750 1755 1760 Ala His Phe Thr Asp Pro Ala Ser He Ala Ala Arg Gly Tyr He Ser 1765 1770 1775 Thr Arg Val Glu Met Gly Glu Ala Ala Gly He Phe Met Thr Ala Thr 1780 1785 1790 Pro Pro Gly Ser Arg Asp Pro Phe Pro Gin Ser Asn Ala Pro He He 1795 1800 1805 Asp Glu Glu Arg Glu He Pro Glu Arg Ser Trp Asn Ser Gly His Glu 1810 1815 1820 Trp Val Thr Asp Phe Lys Gly Lys Thr Val Trp Phe Val Pro Ser He 1825 1830 1835 1840 Lys Ala Gly Asn Asp He Ala Ala Cys Leu Arg Lys Asn Gly Lys Lys 1845 1850 1855 Val He Gin Leu Ser Arg Lys Thr Phe Asp Ser Glu Tyr Val Lys Thr 1860 1865 1870 Arg Thr Asn Asp Trp Asp Phe Val Val Thr Thr Asp lie Ser Glu Met 1875 1880 1885 Gly Ala Asn Phe Lys Ala Glu Arg Val He Asp Pro Arg Arg Cys Met 1890 1895 1900 Lys Pro Val He Leu Thr Asp Gly Glu Glu Arg Val He Leu Ala Gly 1905 1910 1915 1920 Pro Met Pro Val Thr His Ser Ser Ala Ala Gin Arg Arg Gly Arg He 1925 1930 1935 Gly Arg Asn Pro Lys Asn Glu Asn Asp Gin Tyr He Tyr Met Gly Glu 1940 1945 1950 Pro Leu Glu Asn Asp Glu Asp Cys Ala His Trp Lys Glu Ala Lys Met 1955 1960 1965 Leu Leu Asp Asn He Asn Thr Pro Glu Gly lie He Pro Ser Met Phe 1970 1975 1980 Glu Pro Glu Arg Glu Lys Val Asp Ala He Asp Gly Glu Tyr Arg Leu 1985 1990 1995 2000 Arg Gly Glu Ala Arg Lys Thr Phe Val Asp Leu Met Arg Arg Gly Asp 2005 2010 2015 Leu Pro Val Trp Leu Ala Tyr Arg Val Ala Ala Glu Gly He Asn Tyr 2020 2025 2030 Ala Asp Arg Arg Trp Cys Phe Asp Gly Val Lys Asn Asn Gin lie Leu 2035 2040 2045 Glu Glu Asn Val Glu Val Glu He Trp Thr Lys Glu Gly Glu Arg Lys 2050 2055 2060

    338

    2018200081 04 Jan 2018

    Lys Leu Lys Pro Arg Trp Leu Asp Ala Arg He Tyr Ser Asp Pro Leu 2065 2070 2075 2080 Ala Leu Lys Glu Phe Lys Glu Phe Ala Ala Gly Arg Lys Ser Leu Thr 2085 i 2090 2095 Leu Asn Leu lie Thr Glu Met Gly Arg Leu Pro Thr Phe Met Thr Gin 2100 2105 2110 Lys Ala Arg Asp Ala Leu Asp Asn Leu Ala Val Leu His Thr Ala Glu 2115 2120 2125 Ala Gly Gly Arg Ala Tyr Asn His Ala Leu Ser Glu Leu Pro Glu Thr 2130 2135 2140 Leu Glu Thr Leu Leu Leu Leu Thr Leu Leu Ala Thr Val Thr Gly Gly 2145 2150 2155 2160 lie Phe Leu Phe Leu Met Ser Ala Arg Gly He Gly Lys Met Thr Leu 2165 i 2170 2175 Gly Met Cys Cys lie He Thr Ala Ser He Leu Leu Trp Tyr Ala Gin 2180 2185 2190 He Gin Pro His Trp He Ala Ala Ser He He Leu Glu Phe Phe Leu 2195 2200 2205 He Val Leu Leu He Pro Glu Pro Glu Lys Gin Arg Thr Pro Gin Asp 2210 2215 2220 Asn Gin Leu Thr Tyr Val Val He Ala He Leu Thr Val Val Ala Ala 2225 2230 2235 2240 Thr Met Ala Asn Glu Met Gly Phe Leu Glu Lys Thr Lys Lys Asp Leu 2245 i 2250 2255 Gly Leu Gly Ser He Ala Thr Gin Gin Pro Glu Ser Asn lie Leu Asp 2260 2265 2270 He Asp Leu Arg Pro Ala Ser Ala Trp Thr Leu Tyr Ala Val Ala Thr 2275 2280 2285 Thr Phe Val Thr Pro Met Leu Arg His Ser He Glu Asn Ser Ser Val 2290 2295 2300 Asn Val Ser Leu Thr Ala He Ala Asn Gin Ala Thr Val Leu Met Gly 2305 2310 2315 2320 Leu Gly Lys Gly Trp Pro Leu Ser Lys Met Asp lie Gly Val Pro Leu 2325 ; 2330 2335 Leu Ala He Gly Cys Tyr Ser Gin Val Asn Pro lie Thr Leu Thr Ala 2340 2345 2350 Ala Leu Phe Leu Leu Val Ala His Tyr Ala He lie Gly Pro Gly Leu 2355 2360 2365 Gin Ala Lys Ala Thr Arg Glu Ala Gin Lys Arg Ala Ala Ala Gly He 2370 2375 2380 Met Lys Asn Pro Thr Val Asp Gly He Thr Val He Asp Leu Asp Pro 2385 2390 2395 2400 lie Pro Tyr Asp Pro Lys Phe Glu Lys Gin Leu Gly Gin Val Met Leu 2405 2410 2415 Leu Val Leu Cys Val Thr Gin Val Leu Met Met Arg Thr Thr Trp Ala 2420 2425 2430 Leu Cys Glu Ala Leu Thr Leu Ala Thr Gly Pro He Ser Thr Leu Trp 2435 2440 2445 Glu Gly Asn Pro Gly Arg Phe Trp Asn Thr Thr lie Ala Val Ser Met 2450 2455 2460 Ala Asn He Phe Arg Gly Ser Tyr Leu Ala Gly Ala Gly Leu Leu Phe 2465 2470 2475 2480 Ser He Met Lys Asn Thr Thr Asn Thr Arg Arg Gly Thr Gly Asn He 2485 2490 2495

    339

    2018200081 04 Jan 2018

    Gly Glu Thr Leu Gly Glu Lys Trp Lys Ser Arg Leu Asn Ala Leu Gly 2500 2505 2510 Lys Ser Glu Phe Gin He Tyr Lys Lys Ser Gly He Gin Glu Val Asp 2515 2520 2525 Arg Thr Leu Ala Lys Glu Gly He Lys Arg Gly Glu Thr Asp His His 2530 2535 2540 Ala Val Ser Arg Gly Ser Ala Lys Leu Arg Trp Phe Val Glu Arg Asn 2545 2550 2555 2560 Met Val Thr Pro Glu Gly Lys Val Val Asp Leu Gly Cys Gly Arg Gly 2565 2570 2575 Gly Trp Ser Tyr Tyr Cys Gly Gly Leu Lys Asn Val Arg Glu Val Lys 2580 2585 2590 Gly Leu Thr Lys Gly Gly Pro Gly His Glu Glu Pro He Pro Met Ser 2595 2600 2605 Thr Tyr Gly Trp Asn Leu Val Arg Leu Gin Ser Gly Val Asp Val Phe 2610 2615 2620 Phe lie Pro Pro Glu Lys Cys Asp Thr Leu Leu Cys Asp He Gly Glu 2625 2630 2635 2640 Ser Ser Pro Asn Pro Thr Val Glu Ala Gly Arg Thr Leu Arg Val Leu 2645 2650 2655 Asn Leu Val Glu Asn Trp Leu Asn Asn Asn Thr Gin Phe Cys He Lys 2660 2665 2670 Val Leu Asn Pro Tyr Met Pro Ser Val He Glu Lys Met Glu Ala Leu 2675 2680 2685 Gin Arg Lys Tyr Gly Gly Ala Leu Val Arg Asn Pro Leu Ser Arg Asn 2690 2695 2700 Ser Thr His Glu Met Tyr Trp Val Ser Asn Ala Ser Gly Asn He Val 2705 2710 2715 2720 Ser Ser Val Asn Met He Ser Arg Met Leu He Asn Arg Phe Thr Met 2725 2730 2735 Arg Tyr Lys Lys Ala Thr Tyr Glu Pro Asp Val Asp Leu Gly Ser Gly 2740 2745 2750 Thr Arg Asn lie Gly lie Glu Ser Glu lie Pro Asn Leu Asp He He 2755 2760 2765 Gly Lys Arg He Glu Lys He Lys Gin Glu His Glu Thr Ser Trp His 2770 2775 2780 Tyr Asp Gin Asp His Pro Tyr Lys Thr Trp Ala Tyr His Gly Ser Tyr 2785 2790 2795 2800 Glu Thr Lys Gin Thr Gly Ser Ala Ser Ser Met Val Asn Gly Val Val 2805 2810 2815 Arg Leu Leu Thr Lys Pro Trp Asp Val Val Pro Met Val Thr Gin Met 2820 2825 2830 Ala Met Thr Asp Thr Thr Pro Phe Gly Gin Gin Arg Val Phe Lys Glu 2835 2840 2845 Lys Val Asp Thr Arg Thr Gin Glu Pro Lys Glu Gly Thr Lys Lys Leu 2850 2855 2860 Met Lys lie Thr Ala Glu Trp Leu Trp Lys Glu Leu Gly Lys Lys Lys 2865 2870 2875 2880 Thr Pro Arg Met Cys Thr Arg Glu Glu Phe Thr Arg Lys Val Arg Ser 2885 2890 2895 Asn Ala Ala Leu Gly Ala He Phe Thr Asp Glu Asn Lys Trp Lys Ser 2900 2905 2910 Ala Arg Glu Ala Val Glu Asp Ser Arg Phe Trp Glu Leu Val Asp Lys 2915 2920 2925

    340

    2018200081 04 Jan 2018

    Glu Arg Asn 2930 Leu His Leu Glu Gly 2935 Lys Cys Glu Thr Cys 2940 Val Tyr Asn Met Met Gly Lys Arg Glu Lys Lys Leu Gly Glu Phe Gly Lys Ala Lys 2945 2950 2955 2960 Gly Ser Arg Ala He Trp Tyr Met Trp Leu Gly Ala Arg Phe Leu Glu 2965 2970 2975 Phe Glu Ala Leu Gly Phe Leu Asn Glu Asp His Trp Phe Ser Arg Glu 2980 2985 2990 Asn Ser Leu Ser Gly Val Glu Gly Glu Gly Leu His Lys Leu Gly Tyr 2995 3000 3005 lie Leu Arg Asp Val Ser Lys Lys Glu Gly Gly Ala Met Tyr Ala Asp 3010 3015 3020 Asp Thr Ala Gly Trp Asp Thr Arg He Thr Leu Glu Asp Leu Lys Asn 3025 3030 3035 3040 Glu Glu Met Val Thr Asn His Met Glu Gly Glu His Lys Lys Leu Ala 3045 3050 3055 Glu Ala He Phe Lys Leu Thr Tyr Gin Asn Lys Val Val Arg Val Gin 3060 3065 3070 Arg Pro Thr Pro Arg Gly Thr Val Met Asp He He Ser Arg Arg Asp 3075 3080 3085 Gin Arg Gly Ser Gly Gin Val Gly Thr Tyr Gly Leu Asn Thr Phe Thr 3090 3095 3100 Asn Met Glu Ala Gin Leu lie Arg Gin Met Glu Gly Glu Gly Val Phe 3105 3110 3115 3120 Lys Ser He Gin His Leu Thr lie Thr Glu Glu He Ala Val Gin Asn 3125 3130 3135 Trp Leu Ala Arg Val Gly Arg Glu Arg Leu Ser Arg Met Ala He Ser 3140 3145 3150 Gly Asp Asp Cys Val Val Lys Pro Leu Asp Asp Arg Phe Ala Ser Ala 3155 3160 3165 Leu Thr Ala Leu Asn Asp Met Gly Lys He Arg Lys Asp He Gin Gin 3170 3175 3180 Trp Glu Pro Ser Arg Gly Trp Asn Asp Trp Thr Gin Val Pro Phe Cys 3185 3190 3195 3200 Ser His His Phe His Glu Leu lie Met Lys Asp Gly Arg Val Leu Val 3205 3210 3215 Val Pro Cys Arg Asn Gin Asp Glu Leu lie Gly Arg Ala Arg He Ser 3220 3225 3230 Gin Gly Ala Gly Trp Ser Leu Arg Glu Thr Ala Cys Leu Gly Lys Ser 3235 3240 3245 Tyr Ala Gin Met Trp Ser Leu Met Tyr Phe His Arg Arg Asp Leu Arg 3250 3255 3260 Leu Ala Ala Asn Ala He Cys Ser Ala Val Pro Ser His Trp Val Pro 3265 3270 3275 3280 Thr Ser Arg Thr Thr Trp Ser He His Ala Lys His Glu Trp Met Thr 3285 3290 3295 Thr Glu Asp Met Leu Thr Val Trp Asn Arg Val Trp He Gin Glu Asn 3300 3305 3310 Pro Trp Met Glu Asp Lys Thr Pro Val Glu Ser Trp Glu Glu lie Pro 3315 3320 3325 Tyr Leu Gly Lys Arg Glu Asp Gin Trp Cys Gly Ser Leu lie Gly Leu 3330 3335 3340 Thr Ser Arg Ala Thr Trp Ala Lys Asn lie Gin Ala Ala He Asn Gin 3345 3350 3355 3360

    341

    2018200081 04 Jan 2018

    Val Arg Ser Leu lie Gly Asn Glu Glu Tyr Thr Asp Tyr Met Pro Ser 3365 3370 3375

    Met Lys Arg Phe Arg Arg Glu Glu Glu Glu Ala Gly Val Leu Trp 3380 3385 3390 <210> 29 <211> 6 <212> RNA <213> Artificial Sequence <220> · <223> Description of Artificial Sequence:/Note = synthetic construct <400> 29 cuacgu <210> 30 <211> 6 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 30 acguag <210> 31 <211> 17 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 31 tagagagcag atctctg <210> 32 <211> 32 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 32 tgtgaccatg ccggctgcga tgcactcacc ga

    342

    2018200081 04 Jan 2018 <210> 33 <211> 38 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 33 tgctggccac ttaactacgc gtgatggaga gccgcgca 38 <210> 34 <211> 33 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 34 tgtaatgatg ccggccgcga tgcatgaaaa tga 33 <210> 35 <211> 38 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 35 ggcgtttcac ttgtcaacgc gtgatggcga acccctca 38 <210> 36 <211> 36 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 36 agtgattccg ccggcagcta tgcacgtcat agccat 36 <210> 37 <211> 39 <212> DNA <213> Artificial Sequence

    343

    2018200081 04 Jan 2018 <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 37 ggagcagtta ccctctctac gcgtcaaggg aaggtgatg 39 <210> 38 <211> 44 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 38 gaagagcaga actccgccgg ctgcgagaaa cgtgagagct atgg 44 <210> 39 <211> 28 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 39

    Ser Ala Gly Met lie He Met Leu He Pro Thr Val Met Ala Phe His 15 10 15

    Leu Thr Thr Arg Gin Gly Lys Val Met Met Thr Val 20 25 <210> 40 <211> 8 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 40

    Gin Gly Lys Val Met Met Thr Val 1 5 <210> 41 <211> 56 <212> DNA <213> Artificial Sequence

    344

    2018200081 04 Jan 2018 <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 41 aattcaacgc gtacatccgc gggcaccgga attgcagtca tgattggcct gatggc <210> 42 <211> 32 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 42

    Ser Ala Gly Thr Gly He Ala Val Met lie Gly Leu He Ala Ser Val 1 5 10 15 Gly Ala Val Thr Leu Ser Asn Phe Gin Gly Lys Val Met Met Thr Val 20 25 30

    <210> 43 <211> 29 <212> PRT <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence:/Note = synthetic construct <400> 43

    Thr Gly lie Ala Val Met He Gly Leu He Ala Ser Val Gly Ala Val 15 10 15

    Thr Leu Ser Asn Phe Gin Gly Lys Val Met Met Thr Val 20 25 <210> 44 <211> 26 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 44 ttcatattga gctatctttc cttcta <210> 45 <211> 20

    345

    2018200081 04 Jan 2018

    <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 45 gtgtgccaag tttaagtgtg 20

    <210> 46 <211> 19 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 46 tggacggtga ctatcactg 19

    <210> 47 <211> 26 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 47 aagccatgat ttctttttca ttgtca 26

    <210> 48 <211> 20 <212> DNA <213> Artificial Sequence .

    <220> <223> synthetic construct

    <400> 48 cagggctaga ttttaacgag 20

    <210> 49 <211> 21 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 49 agtggtaagt ctagaaacca c 21 <210> 50 <211> 24

    346

    2018200081 04 Jan 2018

    <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 50 tccacaaaca gtggtttcta gact 24

    <210> <211> 51 22 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 51 tgttgctgac aatgaaaaag aa 22

    <210> <211> 52 21 <212> <213> DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 52 tccaagtctc ttgggatgtt a 21

    <210> 53 <211> 23 ' <212> <213> DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 53 tgggatgtta aagccccaga ggt 23

    <210> 54 <211> <212> <213> 21 DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 54 tcatggcttg tccacaaaca g . 21 <210> 55 <211> 21

    347

    2018200081 04 Jan 2018

    <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 55 ccagtaaatc ttgtctgttc c 21

    <210> 56 <211> 23 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 56 cgtccctttc ggtgatgtgc ate 23

    <210> <211> 57 20 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 57 attctgctga catggctagg 20

    <210> 58 <211> 19 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 58 tcctaggtac agtgtgacc 19

    <210> <211> 59 23 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 59 agattccact aacgtctccc aeg 23 <210> 60 <211> 21

    348

    2018200081 04 Jan 2018 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 60 aattgaacca catcctactt g <210> 61 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 61 ttgtgttcca tgggttgtgg <210> 62 <211> 25 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 62 tatgatttta gcttttcccc agctt <210> 63 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 63 gccacaaccc atggaacac <210> 64 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 64 atgaaggtgg tgttctgtac <210> 65 <211> 24

    349

    2018200081 04 Jan 2018

    <212> <213> DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 65 tcctaaacac cttgtcctca atct 24

    <210> 66 <211> 20 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 66 gctaaggcat cacaagaagg 20

    <210> <211> <212> <213> 67 19 DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 67 cgatcctgga tgtaggtcc 19

    <210> 68 <211> <212> 21 DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 68 cagccctctt tgagccggag a 21

    <210> <211> 69 20 <212> <213> DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 69 aatataaaca caccagaagg 20 <210> 70 <211> 19

    350

    2018200081 04 Jan 2018 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 70 tccccgtcta tagctgcac <210> 71 <211> 25 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 71 tgtcaatatc acgaataaca gacct <210> 72 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 72 cacaggacaa ccagctagc <210> 73 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 73 aataatccca tctcattgg <210> 74 <211> 26 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 74 atttgaaaaa cagctaggcc aaataa <210> 75 <211> 20

    351

    2018200081 04 Jan 2018 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 75 cttagatccc gtggtttacg <210> 76 <211> 22 . , <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 76 aatctgtgat gtgcaaagta tc <210> 77 <211> 25 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 77 aaagattccc tcagactcca tttgt <210> 78 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 78 cactttcacc aacatggagg <210> 79 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 79 cgagaactct tccggctag <210> 80

    2018200081 04 Jan 2018

    352 <211> 24 <212> DNA <213> Artificial Sequence <2 2 0 >

    <223> synthetic construct <400> 80 agctaagctc aatgtagtct aaca 24

    <210> <211> 81 19 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 81 cgtggaccga caaagacag 19

    <210> 82 <211> 20 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 82 tcatcagaga tctgctctct 20

    <210> 83 <211> <212> <213> 24 · DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 83 atgttcacgc caacctctgt ttta 24

    <210> <211> <212> 84 _ 19 DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 84 gatcgtcagc agacaagag 19 <210> 85

    2018200081 04 Jan 2018

    353 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 85 caattcacca aggtccatgg 20

    <210> 86 <211> 23 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 86 aacctccatt tggagacagc tac 23

    <210> 87 <211> 22 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 87 aattgtgaca gaaaaagata gc 22

    <210> 88 <211> 19 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 88 tcagttgtcc cggctctac 19

    <210> <211> <212> <213> 89 24 DNA Artificial Sequence

    <220>

    <223> synthetic construct <400> 89 attccacaaa tgtcctcttc atgg 24 <210> 90

    354

    2018200081 04 Jan 2018

    <211> <212> <213> 21 DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 90 tacaagttcc aaccagaatc c 21

    <210> <211> <212> 91 20 DNA <213> Artificial Sequence

    <220> <223> synthetic construct .

    <400> 91 catcagattc tccagtcttg 20

    <210> <211> 92 24 <212> <213> DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 92 tttccccact gttcttaaca tcct 24

    <210> <211> 93 22 <212> <213> DNA ' Artificial Sequence

    <220> <223> synthetic construct

    <400> 93 gaaagtgagt tgcacaatat tg 22

    <210> 94 <211> <212> 21 ' DNA <213> Artificial Sequence

    <220> <223> synthetic construct .

    <400> 94 atgctaatgg tatccaatct g 21 <210> 95

    355

    2018200081 04 Jan 2018 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 95 catcagagct gagcacaccg g <210> 96 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 96 catcagagct gtgcacaccg g <210> 97 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 97 ccttagagga cttccaataa g <210> 98 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 98 aatgtggcat gacacattag g <210> 99 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 99 atccctgaac gctcgtggaa ttc <210> 100

    356

    2018200081 04 Jan 2018

    <211> 21 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 100 agagcaatgc accaatcata g 21

    <210> 101 <211> 20 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct <400> 101

    gaacgaacca aacagtcttc 20

    <210> <211> <212> <213> 102 22 DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 102 tatgcccctt gcgctcatca ag 22

    <210> 103 <211> 19 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 103 cacttctggc tacagtcac 19

    <210> <211> <212> <213> 104 20 DNA Artificial Sequence

    <220>

    <223> synthetic construct <400> 104 gtgattatgc agcacattcc 20 <210> 105

    357

    2018200081 04 Jan 2018

    <211> 22 <212> <213> DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 105 cttgggacgt tgtccccatg gt 22

    <210> 106 <211> 20 <212> <213> DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 106 cagcatcatc catggtcaac 20

    <210> <211> 107 19 <212> <213> DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 107 ggagtcgtgt ctgtcattg 19

    <210> <211> 108 23 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 108 cactcatagc tatggatctg gga 23

    <210> 109 <211> <212> 20 DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 109 cttttcaaga cagcctctgg . 20 <210> 110

    358

    2018200081 04 Jan 2018 <211> 20 <212> DNA <213> Artificial Sequence .<220>

    <223> synthetic construct <400> 110 catttgtaag tgaccgtgtc <210> 111 <211> 27 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 111 caatgaaatg atctcattga caatgaa <210> 112 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 112 aatgctcacc acggacagg <210> 113 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 113 ttgtctatgt accatccatg c <210> 114 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 114 catagctcat ccctttgagt tcc <210> 115

    2018200081 04 Jan 2018 • 359 <211> 19 .

    <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 115 gaggcacaag tatctttgc 19

    <210> 116 <211> 21 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 116 tttcttcaac acaaagctac c 21 <210> 117 <211> 24

    <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct .

    <400> 117 acacaaagct acccaagcac attg 24

    <210> <211> 118 22 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 118 gatggacaaa ttggaactca aa 22

    <210> <211> <212> <213> 119 . 20 DNA ' Artificial Sequence

    <220> <223> synthetic construct

    <400> 119 atcttgcagg gtgcatcttt 20 <210> 120

    360

    2018200081 04 Jan 2018

    <211> 23 <212> <213> DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 120 agggtgcatc tttccctttg tac 23

    <210> 121 <211> 19 <212> DNA ' <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 121 gcagcatggg acaatactc 19

    <210> 122 <211> <212> <213> 20 DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 122 gtgatcagtc tgccattgtg 20

    <210> 123 <211> 25 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 123 cctctggcag tagcctcgaa catct 25

    <210> <211> 124 20 <212> <213> DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 124 actggtacaa gaagggaagc 20 <210> 125

    361

    2018200081 04 Jan 2018

    <211> 19 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 125 acccactgat ccaaagtcc 19

    <210> 126 <211> 21 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 126 tcagccactc ctggctttgg g 21

    <210> 127 <211> 19 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 127 ggcgtcactt acctagctc 19

    <210> 128 <211> <212> <213> 20 DNA Artificial Sequence

    <220> <223> synthetic construct

    <400> 128 tagatgtcag tttcctcagg 20

    <210> 129 <211> 22 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 129 cctccccctt tttccattgt gc 22 <210> 130

    362

    2018200081 04 Jan 2018 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 130 tttcatacgg aggaggatgg <210> 131 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 131 aggctctacg gcaataacc <210> 132 <211> 23 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 132 caacagt.aca tctgccggag aga <210> 133 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 133 gagagcctta tctaaaagag g <210> 134 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 134 cttttccaaa caagccacag <210> 135

    2018200081 04 Jan 2018

    363 <211> 26 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 135 aaccactttt ttcttgttca catctc 26

    <210> 136 <211> 19 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 136 tggagctccg tgtaaagtc 19

    <210> 137 <211> 20 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 137 gcactgttgg tattctcagc 20

    <210> 138 <211> 24 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 138 ccctttttca caccacaatt accg 24

    <210> <211> <212> <213> 139 20 DNA Artificial Sequence

    <220>

    <223> synthetic construct <400> 139 gaaagccaga tgctcattcc 20 <210> 140

    2018200081 04 Jan 2018 . 364 ..

    <211> 22 <212> DNA .

    <213> Artificial Sequence <220>

    <223> synthetic construct <400> 140 tatctctaat ttgcctaagt gc 22

    <210> 141 <211> 22 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 141 ctacccagaa caagccacta gc 22

    <210> <211> 142 . 22 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 142 attgtcaatg ggtttgataa cc 22

    <210> 143 <211> 20 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 143 tatgattgag gccgctatcc 20

    <210> 144 <211> 25 <212> DNA <213> Artificial Sequence

    <220> <223> synthetic construct

    <400> 144 tagtcatgct ttcagtccat tatgc 25 <210> 145

    2018200081 04 Jan 2018 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 145 agtgaaccca acaactttga c <210> 146 <211> 19 <212> DNA <213> Artificial Sequence <220>

    <223> synthetic construct <400> 146 tggcttttgc ctgcaatcc <210> 147 <211> 5 <212> PRT <213> Artificial Sequence <220>

    <223> synthetic construct <400> 147

    Gly Ala Gly Lys Thr 1 5 <210> 148 <211> 5 <212> PRT <213> Artificial Sequence <220>

    <223> synthetic construct <400> 148

    Gly Arg lie Gly Arg 1 5