KR20190039930A - 변이체 아데노-연관 바이러스 및 사용 방법 - Google Patents
변이체 아데노-연관 바이러스 및 사용 방법 Download PDFInfo
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- KR20190039930A KR20190039930A KR1020197001327A KR20197001327A KR20190039930A KR 20190039930 A KR20190039930 A KR 20190039930A KR 1020197001327 A KR1020197001327 A KR 1020197001327A KR 20197001327 A KR20197001327 A KR 20197001327A KR 20190039930 A KR20190039930 A KR 20190039930A
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Abstract
본 개시내용은 뉴런에서 역행 이동에 대한 선호도를 나타내는 AAV 변이체 및 이러한 변이체를 사용하는 방법을 제공한다.
Description
연방 후원 연구 또는 개발
본 발명은 국립 보건원에 의해 수여된 EY022975 하의 정부 지원으로 수행되었다. 정부는 본 발명에서 특정 권리를 갖는다.
관련 출원에 대한 상호 참조
본 출원은 35 U.S.C. § 119(e) 하에 2016년 6월 15일에 출원된 미국 출원 번호 62/350,361 및 2016년 10월 5일에 출원된 미국 출원 번호 62/404,585에 대한 우선권의 이익을 청구한다.
기술 분야
본 개시내용은 일반적으로, 변이체 아데노-연관 바이러스 및 그의 제조 및 사용 방법에 관한 것이다.
뇌 기능, 예컨대 지각, 인지 및 이동의 제어는 대규모 뉴런 네트워크의 협응 작용에 좌우되며, 이는 특정 계산을 수행하는 국부 회로 모듈로 구성되고 이들 계산의 결과를 분산시키는 긴-범위의 연결에 의해 함께 연결된다. 이러한 긴 범위의 연결은 특수화된 투사 뉴런에 의해 형성되며, 이는 종종, 각각이 네트워크 내의 상이한 하류 표적으로 투사하는 여러 개의 뒤섞인 부류들을 포함한다. 투사 뉴런은 또한 여러 신경변성 질환을 공간적으로 국재화된 발병 부위로부터 확산시키는데 연루되어 왔다. 따라서, 트랜스진 전달을 위해 특정 부류의 투사 뉴런을 선택적으로 표적화하는 능력 (예를 들어 표적화된 유전자 녹-아웃 또는 병리학적 돌연변이의 복구를 위한 활동 모니터링/조작 또는 게놈 편집을 위함)은 대규모 네트워크가 뇌 기능에 어떻게 기여하는지에 대한 이해의 획득, 및 긴 안목으로, 신경변성 질환에의 치료적 개입 둘 다를 위해 중요할 것이다.
바이러스 벡터는 트랜스진을 특정 뉴런 집단으로 도입하는데 중요한 부류의 도구를 구성하고, 축삭 말단에서의 진입을 통해 투사 뉴런을 표적화하고 그의 페이로드를 세포 핵에 역행 수송하기 위한 유전자적 접근을 위한 훨등하게 뛰어난 옵션이다. 특히 광견병, 폴리오바이러스 및 단순 포진 바이러스 (HSV)를 포함한, 수많은 자연 진화 신경영양 바이러스는 그의 생활주기의 일부로서 역행 확산을 나타낸다. 이들 중에서, 광견병 바이러스는 특히 신경-침습성이고, 신경계를 통해 세포횡단 전달을 통해 신속하게 전파된다. 그러나, 생물학적 조사 및 유전자 요법 둘 다를 위한 그의 잠재력은, 그의 독성을 감소시키는 방향으로 진전이 이루어지고 있지만, 과도한 병독성에 의해 방해받는다. 자연 신경향성 계통에 더하여, 많은 다른 바이러스는 신경계에 직접 투여되었을 때 뉴런을 감염시킬 수 있고, "가성광견병" (SuHV1, 실제로 헤르페스바이러스), 아데노바이러스 및 렌티바이러스가 동물 연구에서 가장 통상적으로 사용된다. 개 아데노바이러스-2 (CAV-2)는 이러한 부류의 바이러스 중 최고의 감염성 및 역행 수송을 나타내고, 점차적으로 투사 뉴런에의 접근을 위해 선택되는 시약이 되었다. 그러나, CAV-2는 단지 보통 수준의 트랜스진 발현을 매개하고, 독성 잠재력을 나타내며, 현재 임상-등급 또는 심지어 대형 동물 연구를 위한 규모화가능하고 강건한 생산과 용이하게 호환가능하지 않다. 따라서, 상이한 트랜스진의 가요성 패키징을 제공하고, 강건하게 내재화되고, 축삭에 의해 역행 수송되고, 장기간 높은-수준의 페이로드 발현을 지지하는 비-독성의, 용이하게 제조되는 바이러스 벡터의 개발이 매우 필요하다.
센서 및 이펙터의 전달을 위한 투사 뉴런에의 효율적인 역행 접근은 회로 해부를 위한 중요하고 가능한 능력을 구성한다. 이러한 접근법은 또한 기능적으로 연결되고 고도로 분포된 네트워크를 통한 병리학적 확장을 특징으로 하는 신경변성 장애의 치료를 포함한 유전자 요법에 유용할 것이다. 바이러스 벡터는, 특히, 신경계에 대한 강력한 유전자 전달 비히클이지만, 모든 이용가능한 도구는 비효율적인 역행 수송 또는 제한된 임상 잠재력을 갖는다. 이러한 필요를 다루기 위해, 생체내 방향적 진화를 적용하여, 신경과학 연구 및 클리닉에서 유망성을 보여준 벡터인 아데노-연관 바이러스 (AAV)의 캡시드에 강력한 역행 기능성을 조작하였다. rAAV2-레트로로 지칭되는 본원에 기재된 변이체는 전형적 합성 역행 표지 시약과 대등한 효율로 투사 뉴런에 대한 강건한 역행 접근을 가능하게 하고, 표적화된 뉴런 집단에서 CRISPR/Cas9를 사용한 기능적 회로 조사 및 생체내 게놈 편집을 위해 충분히 높은 발현 수준을 발생시킬 수 있다.
한 측면에서, xxDxTKx (서열식별번호(SEQ ID NO): 1) 및 xDxTKxx (서열식별번호: 2)로 이루어진 군으로부터 선택된 서열을 포함하는 바이러스 캡시드 단백질이 제공된다. 한 실시양태에서, 바이러스 캡시드 단백질은 서열식별번호: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 또는 78에 대해 적어도 95% 서열 동일성을 갖는다. 한 실시양태에서, 바이러스 캡시드 단백질은 서열식별번호: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 또는 78에 제시된 서열을 갖는다. 한 실시양태에서, 바이러스 캡시드 단백질은 서열식별번호: 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 또는 77에 대해 적어도 95% 서열 동일성을 갖는 핵산에 의해 코딩된다. 한 실시양태에서, 바이러스 캡시드 단백질은 서열식별번호: 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 및 77에 제시된 서열을 갖는 핵산에 의해 코딩된다.
또 다른 측면에서, 본원에 기재된 바와 같은 바이러스 캡시드 단백질을 포함하는 바이러스 입자가 제공된다. 일부 실시양태에서, 바이러스 입자는 역행 이동에 대한 선호도를 나타낸다. 일부 실시양태에서, 바이러스 입자는 역행 수송 능력을 보유한다.
일부 실시양태에서, 본원에 기재된 바와 같은 바이러스 입자는 페이로드를 코딩하는 핵산을 추가로 포함한다. 일부 실시양태에서, 페이로드를 코딩하는 핵산은 페이로드를 코딩하는 코딩 서열에 작동가능하게 연결된 프로모터 서열을 포함한다. 대표적인 프로모터 서열은, 비제한적으로, 시냅신-1, CMV, GFAP, CAG, CaMKII, MBP, EF1알파, TRE 및 mDlx를 포함한다. 일부 실시양태에서, 페이로드를 코딩하는 코딩 서열은 단백질-코딩 유전자 및 억제 RNA 핵산으로 이루어진 군으로부터 선택된다. 일부 실시양태에서, 억제 RNA 핵산은 안티센스 올리고뉴클레오티드, siRNA 또는 RNAi이다.
일부 실시양태에서, 페이로드는 이펙터 단백질이다. 대표적인 이펙터 단백질, 비제한적으로, 레콤비나제 (예를 들어, Cre 또는 Flp), 유전자 편집 시스템 (예를 들어, CRISPR/Cas9, TALEN, 아연 핑거 뉴클레아제), 광유전학 시약 (활성화제 (예를 들어, 채널로돕신 또는 그의 변이체) 또는 억제제 (예를 들어, 할로로돕신 또는 Arch)), 화학유전학 시약 (예를 들어, DREADD 또는 PSAM/PSEM 시스템의 활성화제/억제제 버전), 세포계 경로의 활성화제 및/또는 억제제, 및 후성학의 제어를 위한 효소를 포함한다.
일부 실시양태에서, 페이로드는 광학 리포터 구축물이다. 대표적인 광학 리포터 구축물은, 비제한적으로, GCaMP6 (s, m 또는 f), 형광단 (예를 들어, 녹색 형광 단백질 (GFP), 증강 GFP (EGFP), 적색 형광 단백질 (RFP), 황색 형광 단백질 (YFP), tdTomato), 색-전환 구축물 (예를 들어, 하나의 세포 집단에서 하나의 리포터 및 또 다른 집단에서 상이한 리포터를 발현하는 페이로드), 글루코스 센서, jRCaMP, jRGECO, 및 CaMPARI, 전압 인디케이터, 2차 메신저, 수용체 신호기, 전사 리포터, 후성적 리포터 및 신경조정제 리포터를 포함한다.
일부 실시양태에서, 페이로드는 바이러스 단백질이다. 대표적인 바이러스 단백질은 광견병 G 단백질이다. 일부 실시양태에서, 바이러스 단백질은 AAV 외의 다른 바이러스의 기능을 보완하는 단백질 또는 세포 및 세포횡단 수송과 관련된 단백질이다.
일부 실시양태에서, 페이로드를 코딩하는 코딩 서열은 치료 유전자이다. 일부 실시양태에서, 치료 유전자는 신경변성 장애의 치료를 위한 것이다. 일부 실시양태에서, 치료 유전자는 알츠하이머병 또는 독성 단백질 응집체를 갖는 다른 질환을 치료하기 위한 HSP104이다. 일부 실시양태에서, 치료 유전자는 프리드라이히 운동실조의 치료를 위한 프라탁신이다. 일부 실시양태에서, 치료 유전자는 파킨슨병의 치료를 위한 리소솜 글루코세레브로시다제 (GBA)이다. 일부 실시양태에서, 치료 유전자는 헌팅턴병의 치료를 위한 폴리Q-결합 단백질이다. 일부 실시양태에서, 치료 유전자는 척수성 근육 위축, 근위축성 측삭 경화증 (ALS), 자폐증, 치매, 말초 신경병증, 정신분열증 또는 망막 변성의 치료를 위한 생존 운동 뉴런 1이다.
일부 실시양태에서, 페이로드는 치료 모이어티이다. 대표적인 치료 모이어티는 항체 또는 그의 단편이다. 대표적인 치료 모이어티는 면역조정 단백질이다. 대표적인 치료 모이어티는 RNA 간섭 분자이다.
일부 실시양태에서, 본원에 기재된 바이러스 입자는 개 아데노바이러스-2 (CAV-2)보다 피질-뇌교 투사 뉴런에 대해 최대 두 자릿수 더 큰 역행 접근을 나타낸다. 일부 실시양태에서, 피질-뇌교 투사 뉴런 또는 배내측 선조체 (DMS)에 대한 구심성 뉴런에 대한 역행 접근은 합성 추적자인 플루오로-골드 형광 비드와 대등하다.
또 다른 측면에서, 페이로드를 1개 이상의 뉴런에 전달하는 방법이 제공된다. 이러한 방법은 전형적으로 내부에 패키징된 페이로드를 포함하는 변이체 아데노-연관 바이러스 (AAV)와 1개 이상의 뉴런을 접촉시키는 단계를 포함하며, 여기서 변이체 AAV는 xxDxTKx (서열식별번호: 1) 및 xDxTKxx (서열식별번호: 2)로 이루어진 군으로부터 선택된 서열을 포함하는 캡시드 단백질을 포함한다. 일부 실시양태에서, 변이체 AAV는 뉴런에서 역행 이동을 나타낸다.
일부 실시양태에서, 뉴런은 투사 뉴런이다. 일부 실시양태에서, 뉴런은 대상체 내에 (예를 들어, 대상체의 중추 신경계 (CNS) 내에) 존재한다. 일부 실시양태에서, 대상체는 인간이다. 일부 실시양태에서, 대상체는 비-인간 (예를 들어, 영장류, 설치류, 파충류, 또는 조류)이다. 일부 실시양태에서, 접촉시키는 단계는 세포 배양물에서 이루어진다. 일부 실시양태에서, 접촉시키는 단계는 두개내, 척수내 또는 근육내 주사를 통해 생체내에서 이루어진다.
달리 정의되지 않는 한, 본원에 사용된 모든 기술 과학 용어는 방법 및 물질의 조성물이 속하는 기술분야의 통상의 기술자가 통상적으로 이해하는 것과 동일한 의미를 갖는다. 본원에 기재된 것과 유사하거나 등가의 방법 및 물질이 방법 및 물질의 조성물의 실시 또는 시험에 사용될 수 있지만, 적합한 방법 및 물질이 하기 기재된다. 또한, 물질, 방법 및 예는 단지 예시적이며, 제한하는 것으로 의도되지 않는다. 본원에 언급된 모든 간행물, 특허 출원, 특허, 및 다른 참고문헌은 그 전문이 참조로 포함된다.
도 1은 rAAV2-레트로의 방향적 진화를 보여준다. 도 1의 패널 a는 방향적 진화 절차의 개략도이다. 오류 유발 PCR, 펩티드 삽입, 루프 영역 무작위화, 및 DNA 셔플링에 의해 이전에 생산한 변이체 AAV 캡 유전자를 함유하는 플라스미드 라이브러리를 패키징하고, 흑색질 또는 심부 소뇌핵 내로 주사하였다. 3주 후, 선조체 또는 후뇌 조직을 각각 제거하고, 바이러스 게놈을 단리하고, 선택된 캡 유전자를 증폭시키고, 다음 선택 라운드를 위해 패키징하였다. 도 1의 패널 b는 상응하는 축삭 필드에서 상이한 형광 단백질을 운반하는 rAAV2-레트로를 주사함으로써 역행 표지된 선조체 (CP: 미상-피각), 시상 및 상구 (SC)로 투사하는 피질 뉴런의 뒤섞인 하위집단을 보여준다.
도 2는 역행 수송 효율을 정량화한 실험으로부터의 결과를 보여준다. 도 2의 패널 a는 rAAV2-레트로의 기저 뇌교 주사를 통해 표지된 피질-뇌교로를 보여준다 [패널 a의 상부 패널은 실험의 개략도를 보여주고; 표적화 및 주사 품질의 일관성을 AAV1-CAG-EGFP를 공동-주사함으로써 모니터링하였다. 패널 a의 하부 패널은 주사 3주 후의 발현 수준을 보여준다. 축척 막대: 1 mm]. 도 2의 패널 b는 정량화 검정 설계를 보여준다 [패널 b의 상부 패널은 실험의 개략도를 보여주고; 화살표는 피질-뇌교로의 피질 뉴런에서의 예상되는 핵 GFP 표지를 나타낸다. 패널 b의 중간 패널은 AAV2-주사된 뇌의 대표적 영상을 보여준다. 패널 b의 하부 패널은 rAAV2레트로-주사된 뇌의 대표적 영상을 보여준다. 축척 막대: 1 mm]. 도 2의 패널 c는 반-자동 정량화 절차의 개략도를 보여준다. 형광 핵 (녹색)이 자동 검출되었고, 피질층 V의 길이를 추적한 수동으로 그린 선을 따라 (흑색) 카운팅하였다. 도 2의 패널 d는 상이한 AAV 혈청형 및 개 아데노바이러스-2 (CAV-2)에 대한 역행 수송 효율을 보여준다. 오차 막대는 SEM을 나타낸다. 또한 도 8을 참조한다.
도 3은 rAAV2-레트로에 의해 제공된 역행 수송의 일반론을 입증하기 위한 실험으로부터의 결과를 보여준다. 도 3의 패널 a는 피질 (영상 #1), 편도체 (영상 #3), 및 시상 (영상 #4)을 포함한 배측 선조체로의 주요 입력 구조에서 광범위한 표지를 보여주는 대표적인 영상이다. 도 3의 패널 b는 역행 표지의 자동화된 전체-뇌 정량화의 개략도를 보여준다. rAAV2-레트로 hSyn1-Cre가 주사된 Rosa26-LSL-H2B-GFP의 뇌를 영상화하여 DAPI-염색된 핵, 및 H2B-GFP-발현 핵으로부터의 녹색 형광을 가시화하였다. 녹색 채널은 표지된 뉴런을 검출하는데 사용되고; 청색 채널은 알렌 뇌 연구소(Allen Brain Institute)의 표준 마우스 뇌로부터의 니슬 영상과 정렬된다. 정렬은 검출된 뉴런이 뇌 아틀라스에 의해 제공된 주석을 사용하여 상이한 영역으로 할당되게 한다. 축척 막대: 1.25 mm. 도 3의 패널 c는 배-내측 선조체의 작은 영역 중 역행 표지의 전체-뇌 정량화를 보여준다. 상이한 뇌 구역에 대한 약어는 알렌 뇌 아틀라스(Allen Brain Atlas)에 따라 주어진다. 화살표는 SNc를 강조한다. 오차 막대는 SEM을 나타낸다.
도 4는 rAAV2-레트로 시스템을 Cre 드라이버 라인과 조합한 실험으로부터의 데이터이다. 도 4의 패널 a는 실험의 개략도를 보여준다. Cre-의존성 색-전환 형광 리포터를 운반하는 rAAV2-레트로를 피질 층 V-특이적 Cre-라인의 선조체 내로 주사하였다. 도 4의 패널 b는 한 경로에서는 리포터의 Cre-의존성 반전을 통해 차등 표지된 2개의 피질-선조체 경로를 보여주지만, 다른 경로에서는 그렇지 않다.
도 5는 rAAV2-레트로가 기능적 회로 조사를 위한 충분한 트랜스진 발현을 지지한다는 것을 보여주는 실험으로부터의 데이터이다. 도 5의 패널 a는 실험의 개략도이다. rAAV2-레트로의 기저 뇌교 내로의 국재화된 주사를 사용하면 칼슘 인디케이터 GCaMP6f의 발현은 피질-뇌교 뉴런으로 제한된다. 도 5의 패널 b는 피질-뇌교로 도처의 GCaMP6f 발현을 보여주는 뇌의 단면도이다. 도 5의 패널 c는 층 V 추체로 세포체 및 정단 수상돌기를 보여주는 2-광자 칼슘 영상의 최대 투사를 보여준다. 도 5의 패널 d는 단일 손 뻗기 반복 동안의 89개 ROI의 활성을 보여준다 (파선은 톤 "진행" 신호를 나타냄). 도 5의 패널 e 및 패널 f는 40회 연속 시험 동안의 단일 피질-뇌교 뉴런의 2가지 예이다 (도 5의 패널 b 및 패널 d에서와 동일한 동물).
도 6은 rAAV2-레트로 시스템이 CRISPR/Cas9를 사용하여 생체내 게놈 편집을 할 수 있다는 것을 보여주는 데이터이다. 도 6의 패널 a는 실험의 개략도이다 [패널 a의 상부 패널은 스타필로코쿠스 아우레우스(Staphylococcus aureus) Cas9 (SaCas9) - tdTomato의 발현을 제거하도록 조작된 단일 가이드 RNA 조합물을 전달하는데 rAAV2-레트로 시스템이 사용되었음을 보여준다. 패널 a의 하부 패널은 SaCas9-항-tdTomato 페이로드를 운반하는 rAAV2-레트로가 층 V 뉴런 내 단일 게놈 유전자좌로부터 tdTomato를 발현하는 마우스의 기저 뇌교 내로 주사되었음을 보여준다]. 도 6의 패널 b는 tdTomato에 대해 표적화된 또는 비-표적화된 가이드를 운반하는 CRISPR/Cas9 시스템을 제공받은 동물의 뇌 절편으로부터의 대표적인 영상을 보여준다. SaCas9는 에피토프 태그부착되어, 역행 표지 뉴런 (녹색 채널)의 확인을 가능하게 하였다. 상향 화살표는 tdTomato의 성공적인 제거에 따라 예상되는 표지를 나타내고; 하향 화살표는 tdTomato 발현이 영향을 받지 않은 경우의 예상되는 표지를 나타낸다. 도 6의 패널 c는 제거 효율을 보여준다. 오차 막대는 SEM을 나타낸다.
도 7은 rAAV2-레트로가 래트에서 투사 뉴런에의 효율적 접근을 매개한다는 것을 보여주는 데이터이다 (도 7에 제시된 데이터는 도 1에 제시된 데이터와 관련됨). 도 7의 패널 a는 주사의 개략도이다. EGFP 또는 tdTomato를 발현하는 rAAV2-레트로의 개별 로트를 선조체 또는 상구에 각각 주사하였다. 도 7의 패널 b-e는 이들 국재화된 주사를 통해 접근된, 바이러스 전달 3주 후에 영상화된 다양한 뇌 영역 내의 투사 뉴런을 보여준다.
도 8은 어떠한 자연-발생 AAV 혈청형도 피질-뇌교 회로에서 rAAV2-레트로 성능과 매칭되지 않는다는 것을 보여주는, 기저 뇌교에 다양한 AAV 혈청형으로 주사된 동물로부터의 뇌의 대표적 영상이다 (도 8에 제시된 데이터는 도 2에 제시된 데이터와 관련됨).
도 9는 그의 모 혈청형 AAV2와 비교하여 rAAV2-레트로에 대해 감소된 헤파린 친화도를 보여주는 데이터이다 (도 9에 제시된 데이터는 도 1에 제시된 데이터와 관련됨). 도 9의 패널 a는 헤파린 결합 검정의 개략도이다. 도 9의 패널 b는 150 mM NaCl 중 로딩 후 증가하는 농도의 NaCl에 의해 용리된 바이러스의 분율을 보여준다. 로드 분율은 150 mM NaCl 중 샘플 로딩 후 칼럼 유동-분출에서 회수된 바이러스를 나타낸다. 오차 막대는 SD를 나타낸다.
도 2는 역행 수송 효율을 정량화한 실험으로부터의 결과를 보여준다. 도 2의 패널 a는 rAAV2-레트로의 기저 뇌교 주사를 통해 표지된 피질-뇌교로를 보여준다 [패널 a의 상부 패널은 실험의 개략도를 보여주고; 표적화 및 주사 품질의 일관성을 AAV1-CAG-EGFP를 공동-주사함으로써 모니터링하였다. 패널 a의 하부 패널은 주사 3주 후의 발현 수준을 보여준다. 축척 막대: 1 mm]. 도 2의 패널 b는 정량화 검정 설계를 보여준다 [패널 b의 상부 패널은 실험의 개략도를 보여주고; 화살표는 피질-뇌교로의 피질 뉴런에서의 예상되는 핵 GFP 표지를 나타낸다. 패널 b의 중간 패널은 AAV2-주사된 뇌의 대표적 영상을 보여준다. 패널 b의 하부 패널은 rAAV2레트로-주사된 뇌의 대표적 영상을 보여준다. 축척 막대: 1 mm]. 도 2의 패널 c는 반-자동 정량화 절차의 개략도를 보여준다. 형광 핵 (녹색)이 자동 검출되었고, 피질층 V의 길이를 추적한 수동으로 그린 선을 따라 (흑색) 카운팅하였다. 도 2의 패널 d는 상이한 AAV 혈청형 및 개 아데노바이러스-2 (CAV-2)에 대한 역행 수송 효율을 보여준다. 오차 막대는 SEM을 나타낸다. 또한 도 8을 참조한다.
도 3은 rAAV2-레트로에 의해 제공된 역행 수송의 일반론을 입증하기 위한 실험으로부터의 결과를 보여준다. 도 3의 패널 a는 피질 (영상 #1), 편도체 (영상 #3), 및 시상 (영상 #4)을 포함한 배측 선조체로의 주요 입력 구조에서 광범위한 표지를 보여주는 대표적인 영상이다. 도 3의 패널 b는 역행 표지의 자동화된 전체-뇌 정량화의 개략도를 보여준다. rAAV2-레트로 hSyn1-Cre가 주사된 Rosa26-LSL-H2B-GFP의 뇌를 영상화하여 DAPI-염색된 핵, 및 H2B-GFP-발현 핵으로부터의 녹색 형광을 가시화하였다. 녹색 채널은 표지된 뉴런을 검출하는데 사용되고; 청색 채널은 알렌 뇌 연구소(Allen Brain Institute)의 표준 마우스 뇌로부터의 니슬 영상과 정렬된다. 정렬은 검출된 뉴런이 뇌 아틀라스에 의해 제공된 주석을 사용하여 상이한 영역으로 할당되게 한다. 축척 막대: 1.25 mm. 도 3의 패널 c는 배-내측 선조체의 작은 영역 중 역행 표지의 전체-뇌 정량화를 보여준다. 상이한 뇌 구역에 대한 약어는 알렌 뇌 아틀라스(Allen Brain Atlas)에 따라 주어진다. 화살표는 SNc를 강조한다. 오차 막대는 SEM을 나타낸다.
도 4는 rAAV2-레트로 시스템을 Cre 드라이버 라인과 조합한 실험으로부터의 데이터이다. 도 4의 패널 a는 실험의 개략도를 보여준다. Cre-의존성 색-전환 형광 리포터를 운반하는 rAAV2-레트로를 피질 층 V-특이적 Cre-라인의 선조체 내로 주사하였다. 도 4의 패널 b는 한 경로에서는 리포터의 Cre-의존성 반전을 통해 차등 표지된 2개의 피질-선조체 경로를 보여주지만, 다른 경로에서는 그렇지 않다.
도 5는 rAAV2-레트로가 기능적 회로 조사를 위한 충분한 트랜스진 발현을 지지한다는 것을 보여주는 실험으로부터의 데이터이다. 도 5의 패널 a는 실험의 개략도이다. rAAV2-레트로의 기저 뇌교 내로의 국재화된 주사를 사용하면 칼슘 인디케이터 GCaMP6f의 발현은 피질-뇌교 뉴런으로 제한된다. 도 5의 패널 b는 피질-뇌교로 도처의 GCaMP6f 발현을 보여주는 뇌의 단면도이다. 도 5의 패널 c는 층 V 추체로 세포체 및 정단 수상돌기를 보여주는 2-광자 칼슘 영상의 최대 투사를 보여준다. 도 5의 패널 d는 단일 손 뻗기 반복 동안의 89개 ROI의 활성을 보여준다 (파선은 톤 "진행" 신호를 나타냄). 도 5의 패널 e 및 패널 f는 40회 연속 시험 동안의 단일 피질-뇌교 뉴런의 2가지 예이다 (도 5의 패널 b 및 패널 d에서와 동일한 동물).
도 6은 rAAV2-레트로 시스템이 CRISPR/Cas9를 사용하여 생체내 게놈 편집을 할 수 있다는 것을 보여주는 데이터이다. 도 6의 패널 a는 실험의 개략도이다 [패널 a의 상부 패널은 스타필로코쿠스 아우레우스(Staphylococcus aureus) Cas9 (SaCas9) - tdTomato의 발현을 제거하도록 조작된 단일 가이드 RNA 조합물을 전달하는데 rAAV2-레트로 시스템이 사용되었음을 보여준다. 패널 a의 하부 패널은 SaCas9-항-tdTomato 페이로드를 운반하는 rAAV2-레트로가 층 V 뉴런 내 단일 게놈 유전자좌로부터 tdTomato를 발현하는 마우스의 기저 뇌교 내로 주사되었음을 보여준다]. 도 6의 패널 b는 tdTomato에 대해 표적화된 또는 비-표적화된 가이드를 운반하는 CRISPR/Cas9 시스템을 제공받은 동물의 뇌 절편으로부터의 대표적인 영상을 보여준다. SaCas9는 에피토프 태그부착되어, 역행 표지 뉴런 (녹색 채널)의 확인을 가능하게 하였다. 상향 화살표는 tdTomato의 성공적인 제거에 따라 예상되는 표지를 나타내고; 하향 화살표는 tdTomato 발현이 영향을 받지 않은 경우의 예상되는 표지를 나타낸다. 도 6의 패널 c는 제거 효율을 보여준다. 오차 막대는 SEM을 나타낸다.
도 7은 rAAV2-레트로가 래트에서 투사 뉴런에의 효율적 접근을 매개한다는 것을 보여주는 데이터이다 (도 7에 제시된 데이터는 도 1에 제시된 데이터와 관련됨). 도 7의 패널 a는 주사의 개략도이다. EGFP 또는 tdTomato를 발현하는 rAAV2-레트로의 개별 로트를 선조체 또는 상구에 각각 주사하였다. 도 7의 패널 b-e는 이들 국재화된 주사를 통해 접근된, 바이러스 전달 3주 후에 영상화된 다양한 뇌 영역 내의 투사 뉴런을 보여준다.
도 8은 어떠한 자연-발생 AAV 혈청형도 피질-뇌교 회로에서 rAAV2-레트로 성능과 매칭되지 않는다는 것을 보여주는, 기저 뇌교에 다양한 AAV 혈청형으로 주사된 동물로부터의 뇌의 대표적 영상이다 (도 8에 제시된 데이터는 도 2에 제시된 데이터와 관련됨).
도 9는 그의 모 혈청형 AAV2와 비교하여 rAAV2-레트로에 대해 감소된 헤파린 친화도를 보여주는 데이터이다 (도 9에 제시된 데이터는 도 1에 제시된 데이터와 관련됨). 도 9의 패널 a는 헤파린 결합 검정의 개략도이다. 도 9의 패널 b는 150 mM NaCl 중 로딩 후 증가하는 농도의 NaCl에 의해 용리된 바이러스의 분율을 보여준다. 로드 분율은 150 mM NaCl 중 샘플 로딩 후 칼럼 유동-분출에서 회수된 바이러스를 나타낸다. 오차 막대는 SD를 나타낸다.
재조합 아데노-연관 바이러스 (rAAV)는 그것이 높은-수준의 트랜스진 발현을 매개하고, 비-독성이고, 최소 면역 반응을 유발하기 때문에 생체내 유전자 요법을 위한 효과적인 플랫폼으로서 부상하였다. 이들 특성은 지단백질 리파제 결핍의 rAAV-매개 회복에 대한 임의의 유전자 요법 치료의 최초의 전체 규제 승인을 허여한 결정의 중심에 있었다 (예를 들어, 문헌 [Gaudet et al., 2010, Atherosclerosis Supplem., 11:55-60] 참조). rAAV는 다양한 신경계 장애에 대한 임상 시험에서 큰 유망성을 보유하며, 그것은 신경과학 연구에서 가장 보편적인 벡터 중 일부를 구성한다. AAV가 역행 수송을 겪을 수 있다는 최초 발견 이후로 (Kaspar et al., 2002, Mol. Ther., 5:50-56), rAAV는 선택 회로에서 투사 뉴런에 대한 어느 정도의 역행 접근을 제공하였으나, 역행 수송에 대한 그의 본래 성향이 낮아 회로 계산 또는 질환 진행에서 투사 뉴런의 역할을 다루려는 노력을 방해하였다.
본 개시내용은, 노출 부위에서 뉴런 세포체를 감염시키는 그의 정규 능력에 더하여, 축삭에 의해 강건하게 내재화되고 전형적인 역행 표지 시약 예컨대 합성 염료와 대등한 효능을 갖는 투사 뉴런에 대한 역행 접근을 매개하는 새로운 rAAV 변이체 (rAAV2-레트로)를 기재한다. 본원에 기재된 rAAV2-레트로 유전자 전달 시스템은 그 자체로 또는 Cre 레콤비나제 드라이버 라인과 함께 사용되어, 신경 회로 기능의 효과적인 기능적 조사, 뿐만 아니라 표적화된 뉴런 집단에서의 게놈 편집을 위해 충분한 장기간, 높은-수준의 트랜스진 발현을 달성할 수 있다.
역행 수송은 축삭 말단으로부터 세포체 쪽으로 분자 및/또는 소기관을 셔틀링한다. 역행 축삭 수송은 세포질 디네인에 의해 매개되고, 예를 들어 엔도리소솜으로 향하는 화학적 메시지 및 세포내이입 산물을 축삭으로부터 세포로 돌려보내는데 사용된다. 대략 2 μm/초의 평균 속도로 생체내에서 작동하는 고속 역행 수송은 1일에 10-20 센티미터를 커버할 수 있다. 고속 역행 수송은 사용된 시냅스 소포 및 다른 물질을 신경세포체로 되돌리고, 신경세포체에 축삭 말단의 상태를 알려준다. 따라서, 본원에 사용된 "역행" 수송은 축삭에서의 그의 세포체로의 이동을 지칭한다.
아데노-연관 바이러스 (AAV) 핵산 및 폴리펩티드 서열
본원에 기재된 바와 같이, 컨센서스 서열이 AAV 캡시드 단백질 내에 존재하는 경우에, 역행 수송의 효능에서 상당한 증진을 발생시키는 것으로 확인되었다. 이들 컨센서스 서열은 xxDxTKx (서열식별번호: 1) 또는 xDxTKxx (서열식별번호: 2)이다. 역행 수송 능력을 부여하기 위한 본원에 기재된 컨센서스 서열의 유효성을 입증하기 위해, 각각 본원에 기재된 바와 같은 컨센서스 서열을 함유하는 17개의 상이한 캡시드 서열을 생성하였으며, 이는 뉴런에서의 역행 이동에 대해 선호도를 나타내는 것으로 밝혀졌다. 이들 40개의 캡시드 서열의 핵산 서열은 서열식별번호: 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 및 77에 제시되고, 각각 본원에 기재된 컨센서스 서열 중 1개를 함유하는 코딩된 캡시드 폴리펩티드는 각각 서열식별번호: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 및 78에 제시된다.
서열식별번호: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 및 78에 제시된 서열을 갖는 캡시드 폴리펩티드에 더하여, 서열식별번호: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 및 78에 제시된 서열을 갖는 캡시드 폴리펩티드에 대해 적어도 95% 서열 동일성 (예를 들어, 적어도 96%, 적어도 97%, 적어도 98%, 적어도 99% 또는 100% 서열 동일성)을 갖는 폴리펩티드가 제공된다. 유사하게, 서열식별번호: 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 및 77에 제시된 서열을 갖는 핵산 분자에 더하여, 서열식별번호: 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 및 77에 제시된 서열을 갖는 핵산 분자에 대해 적어도 95% 서열 동일성 (예를 들어, 적어도 96%, 적어도 97%, 적어도 98%, 적어도 99% 또는 100% 서열 동일성)을 갖는 핵산 분자가 제공된다.
퍼센트 서열 동일성을 계산하는 경우에, 2개의 서열을 정렬하고, 2개의 서열 사이의 뉴클레오티드 또는 아미노산 잔기의 동일한 매치의 수를 결정한다. 동일한 매치의 수를 정렬된 영역의 길이 (즉, 정렬된 뉴클레오티드 또는 아미노산 잔기의 수)로 나누고 100을 곱하여 퍼센트 서열 동일성 값에 도달한다. 정렬된 영역의 길이는 가장 짧은 서열의 전장 크기까지 하나 또는 둘 다의 서열의 부분일 수 있는 것으로 인지될 것이다. 또한, 단일 서열이 1개 초과의 다른 서열과 정렬될 수 있으며, 따라서 각각의 정렬된 영역에 걸쳐 상이한 퍼센트 서열 동일성 값을 가질 수 있는 것으로 인지될 것이다.
퍼센트 서열 동일성을 결정하기 위한 2개 이상의 서열의 정렬은 월드 와이드 웹 상 ncbi.nlm.nih.gov에서 이용가능한, BLAST (베이직 로컬 얼라인먼트 서치 툴) 프로그램 내에 혼입된 문헌 [Altschul et al. (1997, Nucleic Acids Res., 25:3389 3402)]에 의해 기재된 알고리즘을 사용하여 수행될 수 있다. BLAST 서치는 문헌 [Altschul et al.] 알고리즘을 사용하여 정렬된 서열 (핵산 또는 아미노산)과 임의의 다른 서열 또는 그의 부분 사이의 퍼센트 서열 동일성을 결정하기 위해 수행될 수 있다. BLASTN은 핵산 서열을 정렬하고 그 사이의 동일성을 비교하는데 사용되는 프로그램이고, BLASTP는 아미노산 서열을 정렬하고 그 사이의 동일성을 비교하는데 사용되는 프로그램이다. 서열과 또 다른 서열 사이의 퍼센트 동일성을 계산하는데 BLAST 프로그램을 이용하는 경우에, 각각의 프로그램의 디폴트 파라미터가 일반적으로 사용된다.
폴리펩티드를 코딩하는 핵산 분자를 함유하는 벡터가 또한 제공된다. 발현 벡터를 포함한 벡터는 상업적으로 입수가능하거나 또는 재조합 기술에 의해 생산될 수 있다. 핵산 분자를 함유하는 벡터는 이러한 핵산 분자에 작동가능하게 연결된 1종 이상의 발현 요소를 가질 수 있고, 추가로 서열 예컨대 선택 마커를 코딩하는 것들 (예를 들어, 항생제 내성 유전자), 및/또는 폴리펩티드의 정제에 사용될 수 있는 것들 (예를 들어, 6xHis 태그)을 포함할 수 있다. 발현 요소는 핵산 코딩 서열의 발현을 지시 및 조절하는 핵산 서열을 포함한다. 발현 요소의 한 예는 프로모터 서열이다. 발현 요소는 또한 인트론, 인핸서 서열, 반응 요소, 또는 핵산 분자의 발현을 조정하는 유도성 요소 중 1종 이상을 포함할 수 있다. 발현 요소는 박테리아, 효모, 곤충, 포유동물 또는 바이러스 기원의 것일 수 있고, 벡터는 상이한 기원으로부터의 발현 요소의 조합을 함유할 수 있다. 본원에 사용된 작동가능하게 연결된은 발현 요소가 코딩 서열의 발현을 지시 또는 조절하는 방식으로 코딩 서열과 관련하여 벡터 내에 위치하는 것을 의미한다.
핵산 분자, 예를 들어, 벡터 (예를 들어, 발현 벡터, 바이러스 벡터) 내의 핵산 분자는 숙주 세포 내로 도입될 수 있다. 용어 "숙주 세포"는 핵산 분자가 도입된 특정한 세포(들), 뿐만 아니라 이러한 세포의 자손 또는 잠재적 자손을 지칭한다. 많은 적합한 숙주 세포는 관련 기술분야의 통상의 기술자에게 공지되어 있으며; 숙주 세포는 원핵 세포 (예를 들어, 이. 콜라이(E. coli)) 또는 진핵 세포 (예를 들어, 효모 세포, 곤충 세포, 식물 세포, 포유동물 세포)일 수 있다. 대표적인 숙주 세포는, 비제한적으로 A549, WEHI, 3T3, 10T1/2, BHK, MDCK, COS 1, COS 7, BSC 1, BSC 40, BMT 10, VERO, WI38, HeLa, 293 세포, Saos, C2C12, L 세포, HT1080, HepG2, 및 인간, 원숭이, 마우스, 래트, 토끼 및 햄스터를 포함한 포유동물로부터 유래된 1차 섬유모세포, 간세포 및 근모세포를 포함한다. 핵산 분자를 숙주 세포 내로 도입하는 방법은 관련 기술분야에 널리 공지되어 있으며, 비제한적으로 인산칼슘 침전, 전기천공, 열 쇼크, 리포펙션, 미세주사, 및 바이러스-매개 핵산 전달 (예를 들어, 형질도입)을 포함한다.
폴리펩티드와 관련하여, "정제된"은 폴리펩티드 (즉, 펩티드 또는 폴리펩티드)가 그것과 자연적으로 동반되는 세포 성분으로부터 분리 또는 정제된 것을 지칭한다. 전형적으로, 폴리펩티드는 그것과 자연적으로 회합되는 폴리펩티드 및 자연 발생 분자가 건조 중량 기준 적어도 70% (예를 들어, 적어도 75%, 80%, 85%, 90%, 95%, 또는 99%) 없는 경우에 "정제된" 것으로 간주된다. 화학적으로 합성된 폴리펩티드는 그것과 자연적으로 동반되는 성분으로부터 본래 분리되므로 합성 폴리펩티드는 "정제된" 것으로 간주되지만, 폴리펩티드를 합성하는데 사용된 성분 (예를 들어, 아미노산 잔기)이 추가로 제거될 수 있다. 핵산 서열과 관련하여, "단리된"은 핵산 분자가 게놈 내에서 통상적으로 그것과 회합되는 다른 핵산 분자로부터 분리된 것을 지칭한다. 또한, 단리된 핵산 분자는 조작된 핵산 분자 예컨대 재조합 또는 합성 핵산 분자를 포함할 수 있다.
폴리펩티드는 공지된 방법 예컨대 DEAE 이온 교환, 겔 여과, 및/또는 히드록시아파타이트 크로마토그래피에 의해 천연 공급원 (예를 들어, 생물학적 샘플)으로부터 수득 (예를 들어, 정제)될 수 있다. 정제된 폴리펩티드는 또한, 예를 들어 발현 벡터에서 핵산 분자를 발현시킴으로써 또는 화학적 합성에 의해 수득될 수 있다. 폴리펩티드의 순도의 정도는 임의의 적절한 방법, 예를 들어, 칼럼 크로마토그래피, 폴리아크릴아미드 겔 전기영동, 또는 HPLC 분석을 사용하여 측정될 수 있다. 유사하게, 핵산 분자는 상용 방법 예컨대, 비제한적으로, 재조합 핵산 기술 (예를 들어, 제한 효소 소화 및 라이게이션) 또는 폴리머라제 연쇄 반응 (PCR; 예를 들어, 문헌 [PCR Primer: A Laboratory Manual, Dieffenbach & Dveksler, Eds., Cold Spring Harbor Laboratory Press, 1995] 참조)을 사용하여 수득 (예를 들어, 단리)될 수 있다. 또한, 단리된 핵산 분자는 화학적으로 합성될 수 있다.
뉴런에서의 역행 이동에 대해 선호도를 나타내는 바이러스 입자를 제조하는 방법
캡시드 폴리펩티드가 생산되면, 또는 캡시드 폴리펩티드를 생산하기 위해 핵산 분자가 생성되고 발현되면, 폴리펩티드는 예를 들어 패키징 숙주 세포를 사용하여 바이러스 입자 내로 어셈블리될 수 있다. 바이러스 입자의 성분 (예를 들어, rep 서열, 캡 서열, 역전된 말단 반복부 (ITR) 서열)은 1종 이상의 벡터를 사용하여 패키징 숙주 세포 내로 일시적으로 또는 안정적으로 도입될 수 있다. 바이러스 입자의 캡시드 폴리펩티드는 본원에 기재된 바와 같은 컨센서스 서열을 함유할 수 있고, 나머지 성분은 1종 이상의 공지된 AAV 혈청형 (예를 들어, AAV2, AAV8 등)으로부터의 것일 수 있다.
이러한 바이러스 입자는 상용 방법을 사용하여 정제될 수 있다. 본원에 사용된 "정제된" 바이러스 입자는 그것이 제조된 혼합물 중의 성분 예컨대, 비제한적으로, 바이러스 성분 (예를 들어, rep 서열, 캡 서열), 패키징 숙주 세포, 및 부분적- 또는 불완전-조립된 바이러스 입자로부터 분리된 바이러스 입자를 지칭한다.
조립되면, 바이러스 입자는 예를 들어 복제하는 능력; 유전자 전달 특성; 수용체 결합 능력; 및/또는 집단 (예를 들어, 인간 집단) 내 혈청학적 유병률에 대해 스크리닝될 수 있다. 바이러스 입자가 복제할 수 있는지 결정하는 것은 관련 기술분야에서 상용적이며, 전형적으로 소정량의 바이러스 입자로 숙주 세포를 감염시키는 것 및 바이러스 입자의 수가 시간 경과에 따라 증가하는지 결정하는 것을 포함한다. 바이러스 입자가 유전자 전달을 수행할 수 있는지 결정하는 것은 또한 관련 기술분야에서 상용적이며, 전형적으로 트랜스진 (예를 들어, 검출가능한 트랜스진 예컨대 리포터 유전자)을 함유하는 바이러스 입자로 숙주 세포를 감염시키는 것을 포함한다. 바이러스의 감염 및 클리어런스 후에, 숙주 세포는 트랜스진의 존재 또는 부재에 대해 평가될 수 있다. 바이러스 입자가 그의 수용체에 결합하는지 결정하는 것은 관련 기술분야에서 상용적이며, 이러한 방법은 시험관내 또는 생체내에서 수행될 수 있다.
바이러스 입자의 혈청학적 유병률을 결정하는 것은 관련 기술분야에서 상용적으로 수행되며, 전형적으로 면역검정을 사용하여 특정한 개체 집단으로부터의 샘플 (예를 들어, 혈액 샘플) 중 1종 이상의 항체의 출현율을 결정하는 것을 포함한다. 혈청학적 유병률은 관련 기술분야에서 집단 중 혈청반응양성인 (즉, 특정한 병원체 또는 면역원에 노출된 적 있는) 대상체의 비율을 지칭하는 것으로 이해되며, 이는 집단 중 특정한 병원체 또는 면역원에 대한 항체를 생산하는 대상체의 수를 검사받은 집단 중 총 개체수로 나눔으로써 계산된다. 면역검정은 관련 기술분야에 널리 공지되어 있으며, 비제한적으로 면역도트, 웨스턴 블롯, 효소 면역검정 (EIA), 효소-연결된 면역흡착 검정 (ELISA), 또는 방사선면역검정 (RIA)을 포함한다. 유사하게, 혈청 샘플 중 중화 항체의 정도를 결정하는 여러 방법이 이용가능하다. 예를 들어, 중화 항체 검정은 실험 샘플이 항체가 없는 대조군 샘플과 비교하여 감염을 50% 이상만큼 중화시키는 항체 농도를 함유하는 때의 역가를 측정한다. 또한, 문헌 [Fisher et al. (1997, Nature Med., 3:306-12); 및 Manning et al. (1998, Human Gene Ther., 9:477-85)]을 참조한다.
뉴런에서의 역행 이동에 대해 선호도를 나타내는 바이러스를 사용하는 방법
본원에 기재된 바와 같은 바이러스 또는 그의 부분은 다수의 연구 및/또는 치료 용도로 사용될 수 있다. 예를 들어, 본원에 기재된 바와 같은 바이러스 또는 그의 부분은 유전자 요법을 위한 (예를 들어, 유전자 전달을 위한 벡터 또는 벡터 시스템에서) 또는 백신접종을 위한 (예를 들어, 항원 제시를 위한) 인간 또는 동물 의약에 사용될 수 있다. 보다 구체적으로, 본원에 기재된 바와 같은 바이러스 또는 그의 부분은 유전자 부가, 유전자 증대, 폴리펩티드 치료제의 유전적 전달, 유전적 백신접종, 유전자 침묵, 게놈 편집, 유전자 요법, RNAi 전달, cDNA 전달, mRNA 전달, miRNA 전달, miRNA 스폰징, 유전적 면역화, 광유전학 유전자 요법, 유전자도입, DNA 백신접종, 또는 DNA 면역화에 사용될 수 있다.
숙주 세포는 바이러스 또는 그의 부분으로 시험관내에서 (예를 들어, 배양물 중에서 성장시키면서) 또는 생체내에서 (예를 들어, 대상체, 예를 들어, 인간 또는 비-인간 내에서) 형질도입되거나 감염될 수 있다. 바이러스 또는 그의 부분으로 시험관내에서 형질도입되거나 감염될 수 있는 숙주 세포가 본원에 기재되며; 바이러스 또는 그의 부분으로 생체내에서 형질도입되거나 감염될 수 있는 숙주 세포는 비제한적으로 투사 뉴런 (예를 들어, 피질-뇌교 투사 뉴런, 교감 투사 뉴런, 중추 신경계 투사 뉴런), 배내측 선조체 (DMS)에 대한 구심성 뉴런, 척수 피질/진균 뉴런, 전-소뇌 뉴런, 기저 신경절로의 입력 뉴런, 전-시상 뉴런, 운동 뉴런, 감각 뉴런, 또는 중추 신경계의 다른 뉴런 또는 세포를 포함한다.
본원에 기재된 바와 같은 바이러스 또는 그의 부분은 페이로드를 포함하도록 변형될 수 있다. 페이로드는 전형적으로 적어도 1종의 핵산 (예를 들어, 페이로드를 코딩하는 코딩 서열에 작동가능하게 연결된 프로모터 서열)을 포함한다. 특정 경우에, 페이로드는 억제 핵산일 수 있다. 억제 핵산은 관련 기술분야에 공지되어 있으며, 예를 들어 안티센스 올리고뉴클레오티드, 짧은 간섭 RNA (siRNA), 및 RNA 간섭 (RNAi) 분자를 포함한다. 특정 경우에, 페이로드는 1종 이상의 단백질-코딩 유전자일 수 있다. 비제한적으로, 단백질-코딩 유전자는 광학 리포터 구축물, 치료 유전자, 또는 이펙터 단백질을 포함한다.
많은 유형의 광학 리포터 구축물이 관련 기술분야에 공지되어 있으며, 하기 목록은 대표적인 것이고 총망라하는 것은 아닌 것으로 의도된다. 예를 들어, 광학 리포터 구축물은 비제한적으로 GCaMP6 (GCaMP6s, GCaMP6m, 또는 GCaMP6f; WO 2014/059154 참조), 형광단 (예를 들어, 녹색 형광 단백질 (GFP), 증강 GFP (EGFP), 적색 형광 단백질 (RFP), 황색 형광 단백질 (YFP), tdTomato), 색-전환 구축물 (예를 들어, 하나의 세포 집단에서의 하나의 리포터 및 또 다른 집단에서의 상이한 리포터를 발현하는 페이로드), 글루코스 센서 (예를 들어, US 2015/0111222), iRCaMP (미국 특허 번호 9,644,007), iRGECO (예를 들어, 미국 특허 번호 9,644,007), CaMPARI (예를 들어, 미국 특허 번호 9,518,996), 전압 인디케이터, 2차 메신저, 수용체 신호기, 전사 리포터, 후성적 리포터 및 신경조정제 리포터를 포함한다.
치료 유전자는 또한 관련 기술분야에 널리 공지되어 있으며, 치료될 특정한 질환 또는 장애에 따라 달라질 것이다. 예를 들어, 치료 유전자는 신경변성 장애의 치료를 위한 것일 수 있다. 대표적인 치료 유전자 (또는 코딩된 폴리펩티드) 및 그의 연관된 신경변성 장애는, 비제한적으로, 알츠하이머병의 치료를 위한 HSP104, 프리드라이히 운동실조의 치료를 위한 아탁시스(Ataxis) (예를 들어, 프라탁신), 파킨슨병의 치료를 위한 리소솜 글루코세레브로시다제 (GBA), 헌팅턴병의 치료를 위한 폴리Q-결합 단백질, 척수성 근육 위축, 및 근위축성 측삭 경화증 (ALS), 자폐증, 치매, 말초 신경병증, 정신분열증, 및 망막 변성의 치료를 위한 생존 운동 뉴런 1을 포함한다. 일부 경우에, 페이로드는 치료 모이어티일 수 있다 (유전자와 대조됨). 치료 모이어티는 예를 들어, 항체 또는 그의 단편, 면역조정 단백질, 또는 RNA 간섭 (RNAi) 분자를 포함한다.
본원에 사용된 "이펙터" 단백질은 세포 또는 그의 내용물 (예를 들어, 핵산, 단백질, 소기관 또는 상기 중 임의의 것을 수반하는 과정)에 대해 효과를 부여하는 임의의 유형의 단백질을 지칭한다. 예를 들어, 이펙터 단백질은 비제한적으로 레콤비나제 (예를 들어, Cre 또는 Flp), 유전자 편집 시스템 (예를 들어, CRISPR/Cas9, TALEN, 아연 핑거 뉴클레아제), 광유전학 시약 (활성화제 (예를 들어, 채널로돕신 또는 그의 변이체) 또는 억제제 (예를 들어, 할로로돕신 또는 Arch)), 화학유전학 시약 (예를 들어, DREADD 또는 PSAM/PSEM 시스템의 활성화제/억제제 버전), 세포계 경로의 활성화제 및/또는 억제제, 및 후성학의 제어를 위한 효소를 포함한다.
바이러스 (예를 들어, AAV 이외의 바이러스)의 기능을 보완하거나 억제하는 바이러스 단백질을 전달하는 것이 바람직할 수 있음이 인지될 것이다. 예를 들어, 진입 수용체인 바이러스 단백질 (예를 들어, 세포 및/또는 세포횡단 수송과 관련된 단백질인 광견병 G 단백질).
임의의 수의 프로모터가 페이로드를 코딩하는 서열을 구동하는데 사용될 수 있다. 구성적 프로모터가 관련 기술분야에 공지되어 있으며, 조직-특이적 프로모터 (예를 들어, 뉴런-특이적 프로모터)도 그러하다. 단순하게 예로서, 프로모터는 시냅신-1, CMV, GFAP, CAG, CaMKII, MBP, EF1알파, mDlx, 또는 TRE 프로모터일 수 있다.
통상적으로 생리학상 상용성인 담체 중에 현탁된 바이러스 또는 그의 부분은 대상체 (예를 들어, 인간 또는 비-인간 대상체 (예를 들어, 영장류, 설치류, 파충류 또는 조류))에게 투여될 수 있다. 적합한 담체는 다양한 완충 용액과 함께 제제화될 수 있는 염수 (예를 들어, 포스페이트 완충 염수), 락토스, 수크로스, 인산칼슘, 젤라틴, 덱스트란, 한천, 펙틴 및 물을 포함한다. 바이러스 또는 그의 부분은 세포를 형질도입하거나 감염시키기에, 및 과도한 유해 효과 없이 치료 이익을 제공하기 위한 유전자 전달 및 발현의 충분한 수준을 제공하기에 충분한 양으로 투여된다. 전형적인 및 제약상 허용되는 투여 경로는 두개내, 척수내 또는 근육내 주사를 포함하나 이에 제한되지는 않는다. 추가의 투여 경로는 예를 들어 경구, 비강내, 기관내, 흡입에 의한 것, 정맥내, 안구내, 피하, 피내, 경점막, 또는 다른 투여 경로에 의한 것을 포함한다. 투여 경로는 원하는 경우에 조합될 수 있다.
대상체에게 투여되는 바이러스 또는 그의 부분의 용량은 주로 인자 예컨대 치료될 상태, 및 대상체의 연령, 체중 및 건강에 따라 달라질 것이다. 예를 들어, 인간 대상체에게 투여될 바이러스 또는 그의 부분의 치료 유효 투여량은 일반적으로 바이러스의 약 1 x 101 내지 1 x 1012개의 게놈 카피 (GC) (예를 들어, 약 1 x 103 내지 1 x 109개의 GC)의 농도를 함유하는 용액의 약 0.1 ml 내지 약 10 ml 범위 내이다. 형질도입 및/또는 트랜스진의 발현은 DNA, RNA 또는 단백질 검정에 의해 투여 후 다양한 시점에서 모니터링될 수 있다. 일부 경우에, 트랜스진의 발현 수준은 투여 빈도 및/또는 투여량을 결정하기 위해 모니터링될 수 있다.
유의하게, 본원에 기재된 AAV-레트로 입자는, 예를 들어 개 아데노바이러스-2 (CAV-2)보다 피질-뇌교 투사 뉴런에 대해 최대 두 자릿수 더 큰 역행 접근을 나타내고, 특정 뉴런 (예를 들어, 피질-뇌교 투사 뉴런 또는 배내측 선조체 (DMS)에 대한 구심성 뉴런)에 대한 역행 접근은 합성 추적자 예컨대 플루오로-골드® 형광 비드에서 관찰된 것과 대등하다.
본 발명에 따르면, 관련 기술분야의 기술 내의 통상적인 분자 생물학, 미생물학, 생화학적, 및 재조합 DNA 기술이 사용될 수 있다. 이러한 기술은 문헌에 충분히 설명되어 있다. 본 발명은 하기 실시예에서 추가로 기재될 것이며, 이는 청구범위에 기재된 방법 및 물질의 조성물의 범주를 제한하지 않는다.
실시예
실시예 1-실험 절차
모든 절차는 자넬리아(Janelia) 연구 캠퍼스 및 캘리포니아 대학교 버클리 동물 실험 윤리 위원회에 의해 승인된 프로토콜에 따라 수행되었다.
실시예 2-라이브러리 생성 및 바이러스 생산
4개의 이전에 생성된 바이러스 라이브러리를 방향적 진화 절차의 시작 시에 사용하였다: 1) AAV2 캡 유전자 (바이러스 단백질 VP1-3 및 어셈블리-활성화 단백질 (AAP)을 코딩함)를 오류 유발 PCR에 적용시킴으로써 생성된 무작위 돌연변이유발 라이브러리 (Maheshri et al., 2006, Nat. Biotechnol., 24:198-204); 2) N587과 R588 사이에 7-량체 펩티드 삽입물을 함유하는 AAV2 캡 유전자 변이체의 라이브러리 (Mueller et al., 2003, Nat. Biotechnol., 21:1040-6); 3) 무작위화 루프 영역을 함유하는 AAV2 캡 유전자 변이체의 라이브러리 (Koerber et al., 2009, Mol. Ther., 17:2088-95); 및 4) 야생형 AAV1, AAV2, AAV4, AAV5, AAV6, AAV8 및 AAV9 캡 유전자 서열로부터 생성된 DNA 셔플링 라이브러리 (Koerber et al., 2008, Mol. Ther., 16:1703-9). 돌연변이체 DNA의 각각의 풀은 원래, AAV 비리온 내로 패키징될 때 임의의 새로운 특성 또는 기능을 위해 선택될 수 있는 바이러스 플라스미드 라이브러리를 생성하도록 복제-적격 AAV 패키징 플라스미드 내로 서브클로닝되었다. 복제-적격 AAV 시스템은 돌연변이체 캡 유전자를 바이러스 페이로드에 혼입시키고, 이에 따라 각 변이체의 유전자형은 그의 표현형에 연결된다. 그 후, 목적하는 특성의 캡시드 서열을 캡슐화된 AAV 게놈의 DNA 서열 분석에 의해 회수할 수 있다.
4개의 복제-적격 AAV 라이브러리를 HEK293-T 세포의 인산칼슘 일시적 형질감염에 이어서, 바이러스 수거, 아이오딕사놀 구배 원심분리, 및 아미콘(Amicon) 여과에 의해 패키징하였다 (Maheshri et al., 2006, Nat. Biotechnol., 24:198-204).
실시예 3-생체내 바이러스 또는 추적자 주사
국재화된 생체내 바이러스 전달을 위해, 마우스 또는 래트를 이소플루란 (O2 중 ~2 부피%; 서지벳(SurgiVet), 스미스 메디컬(Smiths Medical))에 의해 마취시키고, 필요한 주사 부위 (표 1 참조) 위의 두개골에 작은 구멍을 드릴링하였다. 일부 주사 부위에 대해서는, 상이한 깊이 (표 1 참조)에서 수회 주사하였다. 바이러스 주사를 위해, 바이러스-함유 용액 ~ 50-100 nl (마우스) 또는 250-500 nl (래트)를 조직 내로 각각의 깊이에서 천천히 주사하였다. 추적자 주사를 위해, 0.9% NaCl 중 5% 플루오로-골드 (플루오로크롬(Fluorochrome), 콜로라도주 덴버) 50 nl 또는 0.9% NaCl 중 1:1 희석된 레트로-비즈 (루마플루오르(LumaFluor), 노스캐롤라이나주 더햄) 100 nl를 각각의 주사 표적에 대해 동일 부위 세트에서 주사하였다. 주사는 미네랄 오일로 재충전된 풀링된 유리 피펫 (25-30 μm (외부 직경)로 경사지게 파단됨; 드루몬드 사이언티픽(Drummond Scientific), 와이어트롤(Wiretrol) II 모세관 마이크로디스펜서)을 사용하여 수행하였다. 맞는 플런저를 피펫 내로 삽입하고 유압 조작기 (나라시게(Narashige), MO-10)를 사용하여 전진시켜 내용물을 이동시켰다.
플런저의 당김을 사용하여 피펫에 바이러스를 로딩하였다. 주사 피펫을 수터(Sutter) MP-285 조작기와 함께 배치하였다.
표 1. 본 연구에 사용된 좌표
* 모든 A/P 좌표는 브레그마(Bregma)에 대하여 제시된다.
실시예 4-라이브러리 선택 및 진화
4개의 돌연변이체 바이러스 라이브러리를 풀링하고 성체 (6-8주령) 야생형 C57/Bl6J 마우스 (임의의 성별; 찰스 리버(Charles River))의 SNr 내로 또는 소뇌 내로 주사하였다. 주사 3주 후에, 선조체 또는 후뇌 조직을 그에 맞춰 분리하고, DNA를 추출하고, 원위 역행 표적 조직에 성공적으로 도달했었던 비리온을 PCR-증폭시키고 rcAAV 패키징 플라스미드 내로 재클로닝하여 다음 선택 라운드를 위한 새로운 복제 적격 AAV 라이브러리를 생성하였다. 3회의 선택 단계 후에, 구제한 캡 유전자를 각각 정방향 및 역방향 프라이머로서 5'-ACG CGG AAG CTT CGA TCA ACT ACG CAG-3' (서열식별번호: 79) 및 5'-AGA CCA AAG TTC AAC TGA AAC GAA TTA AAC GG-3' (서열식별번호: 80)를 사용하여 오류 유발 PCR에 의해 무작위로 돌연변이시켰다.
이어서, 2회의 추가의 생체내 선택 라운드를 수행하였다. 라운드 4 및 5 후에 개별 단리물을 서열분석하여 라이브러리 풍부화의 정도 (표 2)를 평가하였다.
표 2. 라운드 4 및 5에서 단리된 변이체에 대한 펩티드 삽입물 서열의 수렴
17개의 변이체를 라운드 5의 종료 시에 2차 스크리닝을 위해 선택하였고, 상응하는 캡 유전자 서열을 rAAV 헬퍼 플라스미드 내로 재클로닝하였다. 이어서, 모 야생형 AAV2의, 및 CMV-EGFP 페이로드를 운반하는 각각의 선택된 17개의 돌연변이체 변이체의 개별 고역가 프렙을 벡터 바이오랩스, 인크(Vector BioLabs, Inc) (펜실베니아주 필라델피아)에 의해 수행하였다. CMV 프로모터는 뉴런에서 전형적으로 약하고, 따라서 이러한 2차 스크린은 역행 수송의 효율에 대한 엄격한 시험을 제공하였다. 개별 AAV 변이체를 소뇌 내로 또는 담창구 내로 주사하였다. 3주 후에, 역행 수송이 효율적이었으면 표지될 것으로 예상되는 영역에서 내인성, 비증폭 EGFP 형광이 가시화되었다. 돌연변이체 5R-Hind6 (서열식별번호: 44를 코딩하는 서열식별번호: 43)이 양쪽 회로에서 가장 강한 역행 수송을 나타냈고, 따라서 이를 추가의 분석을 위해 선택하고 rAAV2-레트로로 명명하였다.
실시예 5-헤파린 결합 검정
AAV2-레트로 및 야생형 AAV2의 헤파린 친화도를 이전에 기재된 바와 같이 분석하였다 (Jang et al., 2011, Mol. Ther., 19:667-75). 간략하게, 대략 1011개의 정제된 게놈 입자를 사전에 150 mM NaCl 및 50 mM 트리스로 pH 7.5에서 평형화시킨 1 mL 하이트랩(HiTrap) 헤파린 칼럼 (지이 헬스케어 사이언시스(GE Healthcare Sciences), 뉴저지주 피스카타웨이) 상으로 로딩하였다. 이어서, NaCl의 농도를 950 mM의 최종 농도까지 50 mM의 단계로 증가시킨 다음 1M NaCl로 세척하여 용리를 수행하였다. 각 용리액의 작은 분획을 사용하여 HEK293T 세포를 감염시켰고, GFP 양성 세포의 백분율을 구아바 이지사이트(Guava EasyCyte) 6HT 유동 세포측정기 (이엠디/밀리포어(EMD/Millipore))를 사용하여 감염-48시간 후에 정량화하였다.
실시예 6-본 연구에 사용된 페이로드
모든 후속 실험에 대해, CMV 프로모터를 성체 뉴런에서 보다 강건한 것으로 알려져 있는 프로모터로 대체하였다. Cre 레콤비나제 및 GCaMP6f 칼슘 센서를 인간 시냅신-1 (hSyn1) 프로모터에 의해 구동시켰다. 모든 형광단을 CAG 프로모터에 의해 구동시켰고, 색-전환 구축물을 EF1-알파 프로모터에 의해 구동시켰다.
실시예 7-역행 효율의 정량화를 위한 바이러스 생산
hSyn-Cre 페이로드를 자넬리아 바이러스 공유 리소스(Janelia Viral Shared Resource)에서 AAV1, AAV2, AAV5, AAV8, AAV9, DJ 및 AAV2-레트로 캡시드를 사용하여 패키징하였다. 모든 7종의 바이러스 제제를 병행 프로세싱하였고, 생체내 주사 전에 역가 매칭하였다. 모든 로트를 가장 낮은 측정 역가 (1.3E12 GC/ml)로 희석하였고, 각각의 바이러스를 3마리의 성체 Rosa26Lox-STOP-LoxH2B-GFP 마우스 (He et al., 2012, Neuron, 73:35-48)의 우측 뇌교핵 내로 주사하였다.
실시예 8-조직학
동물을 바이러스 주사 3주 후에 희생시켰으며, 이 시점에 뇌를 수거하고 우반구를 50 μm의 두께로 시상 절단하였다. 절편을 DAPI (벡터 래보러토리즈(Vector Laboratories))를 함유하는 벡타쉴드(VECTASHIELD) 안티페이드(Antifade) 마운팅 배지에 마운팅하고, 20x 대물렌즈 및 FITC 및 DAPI 필터를 사용하는 P-E 판노라믹(Pannoramic) 슬라이드 스캐너 (3D 히스테크(3D Histech))를 사용하여 영상화하였다.
실시예 9-역행 수송 정량화
판노라믹 슬라이드 스캐너에 의해 수득된 영상을 스티칭한 다음, 매트랩(Matlab) (매스웍스(Mathworks))으로 작성된 맞춤 소프트웨어를 사용하여 분석하여 피질에 걸쳐 GFP 표지된 핵을 검출하였다. 자동화된 세포 카운팅을 위한 영상 내 지역을 분리하기 위해 피질 주위에 관심 영역 (ROI)을 수동으로 그렸다. 이어서, 핵의 검출을 증진시키기 위해, 영상을 2개의 가우시안 (26.00 μm 분산 및 3.25 μm 분산)의 차이를 포함하는 "멕시칸 햇" 커넬로 컨볼빙하였다. 영상 노이즈를 중앙값 필터를 사용하여 감소시켰고, 이어서 기초 피크 검출을 수행하였다.
실시예 10-역행 수송의 보편성 분석
Rosa26-LSL-H2B-GFP 마우스에게 rAAV2-레트로 hSyn1-Cre 25 nl를 배측 선조체에 주사하였다. 주사 3주 후에, 관상 절단된 뇌를 판노라믹 스캐너를 사용하여 영상화하여 DAPI 염색된 핵 및 H2B-GFP 발현 핵으로부터의 녹색 형광을 가시화하였다. 녹색 채널을 2개의 가우시안의 차이로 컨볼빙하였고, 이어서 피크를 매트랩으로 작성된 맞춤 기능을 사용하여 이들 임계값 영상의 국부 최대치로서 검출하였다. 각 절편의 청색 채널을 매트랩 영상 처리 툴박스의 도움으로 작성된 맞춤 분석 루틴을 사용하여 알렌 뇌 연구소의 표준화된 마우스 뇌 아틀라스로부터의 니슬(Nissl) 영상에 정렬하였다. 이어서, ABI의 마우스 뇌 아틀라스로부터의 주석달린 영역을 사용하여, 정렬된 절편에서 검출된 뉴런을 특정한 뇌 영역으로 할당하였다.
개별 뇌의 해부학적 가변성과 함께 참조 아틀라스의 한정된 정밀도가 이러한 반-자동화된 프로세스의 강건성을 현저한 구심성 입력 뉴런으로 제한한다는 것이 주목되었다.
실시예 11-GCaMP6f의 역행 전달 후 생체내 뉴런 집단 활성의 영상화
7마리의 성체 마우스를 이소플루란 (2%)으로 마취하고 37℃ 온열 패드 상에서 정위 프레임 (코프 인스트루먼츠(Kopf Instruments); 캘리포니아주 터헝가) 내에 위치시켰다. 두개골 위의 두피 및 골막을 제거하였고, UV-경화 옵티본드(OptiBond) 접착제 (커(Kerr); 캘리포니아주 오렌지)의 층을 적용하였으며, 맞춤 제작된 헤드포스트(headpost) (Osborne and Dudman, 2014, PLoS One, 9(2):e89007)를 구강용 시멘트로 고정하였다. hSynGCaMP6f 페이로드를 운반하는 AAV2-레트로를 나노리터(Nanoliter) 2010 주사기 (WPI)를 사용하여 BPN (브레그마에 대해 후방 3.9 mm 및 측방 0.4 mm, 깊이 5.8, 5.6 및 5.4 mm, 각 깊이에서 100 nl) 내로 주사하였다. 두개골 창 (레이저-커팅 유리의 하나의 170 μm-두께 판유리, 2 mm 직경)을 1차 운동 피질 위에 위치시켰다 (브레그마에 대해 전방 0.7 mm 및 측방 1.6 mm을 중심으로 함).
수술 후, 케토프로펜 (5 mg/kg) 및 부프레노르핀 (0.1 mg/kg; 헨리 샤인 애니멀 헬스(Henry Schein Animal Health); 뉴욕주 멜빌)의 주사를 피하로 투여하였다. 마우스를 수술 후 1주 동안 회복시키고, 이어서 2-광자 현미경 하에 간략하게 영상화하여 바이러스 발현을 평가하였다. 모든 동물은 주사 1주 후 M1의 층 V에서 GCaMP6f 발현 세포를 가시적으로 확인하였다. 이어서, 동물을 맞춤 제작 장치에서 머리 고정에 길들이고 이전에 기재된 바와 같이 음식물 펠릿을 찾아오도록 훈련시켰다 (Guo et al., 2014, Nat. Med., 20:130-8).
GCaMP6f를 Ti:사파이어 레이저 (카멜레온(Chameleon), 코히런트(Coherent))로 920nm (전형적으로 후방 개구에서 20-40mW)로 자극하고, 니콘 16x, 0.8-N.A. 대물렌즈를 통하여 영상화하였다. 방출광은 565 DCXR 이색성 필터 (크로마 테크놀로지(Chroma Technology)) 및 ET525/70m-2p 필터 (크로마 테크놀로지)를 통과했고, 이를 GaAsP 광전자증배관 (10770PB-40, 하마마츠(Hamamatsu))에 의해 검출하였다. 영상 (512x512 픽셀)은 스캔이미지(ScanImage) 소프트웨어를 사용하여 공명 스캐너로 ~30 Hz에서 획득하였다.
실시예 12-CRISPR/Cas9 게놈 편집
pAAV-CMV-SaCas9-empty의 CMV 프로모터 (Slaymaker et al., 2016, Science, 351:84-8)를 hSyn1로 대체하여 pAAV-hSyn1-SaCas9-empty를 생성하였다. sgRNA 프로토스페이서 서열을 코딩하는 올리고뉴클레오티드를 맞춤 주문하고, 인산화시키고, 혼성화시키고, pAAV-hSyn1-SaCas9-emtpy의 BsaI 제한 부위로 라이게이션하여 pAAV-hSyn1-SaCas9-tdTomato-1 내지 -10을 생성하였다. 사용된 올리고뉴클레오티드 서열은 다음과 같았다:
tdTomato sgRNA 1 Fwd: CAC CGC AAG GGC GAG GAG GTC ATC A (서열식별번호: 86)
tdTomato sgRNA 1 Rev: AAA CTG ATG ACC TCC TCG CCC TTG C (서열식별번호: 87)
tdTomato sgRNA 2 Fwd: CAC CGT GGA GGG CTC CAT GAA CGG CC (서열식별번호: 88)
tdTomato sgRNA 2 Rev: AAA CGG CCG TTC ATG GAG CCC TCC AC (서열식별번호: 89)
tdTomato sgRNA 3 Fwd: CAC CGA GGA CGG CGG CCA CTA CCT GG (서열식별번호: 90)
tdTomato sgRNA 3 Rev: AAA CCC AGG TAG TGG CCG CCG TCC TC (서열식별번호: 91)
tdTomato sgRNA 4 Fwd: CAC CGA CAA CAA CAT GGC CGT CAT CA (서열식별번호: 92)
tdTomato sgRNA 4 Rev: AAA CTG ATG ACG GCC ATG TTG TTG TC (서열식별번호: 93)
tdTomato sgRNA 5 Fwd: CAC CGA AGG ACG GCG GCC ACT ACC TGG (서열식별번호: 94)
tdTomato sgRNA 5 Rev: AAA CCC AGG TAG TGG CCG CCG TCC TTC (서열식별번호: 95)
tdTomato sgRNA 6 Fwd: CAC CGA CAA CAA CAT GGC CGT CAT CA (서열식별번호: 96)
tdTomato sgRNA 6 Rev: AAA CTG ATG ACG GCC ATG TTG TTG TC (서열식별번호: 97)
tdTomato sgRNA 7 Fwd: CAC CGG TCA CCT TCA GCT TGG CGG T (서열식별번호: 98)
tdTomato sgRNA 7 Rev: AAA CAC CGC CAA GCT GAA GGT GAC C (서열식별번호: 99)
tdTomato sgRNA 8 Fwd: CAC CGC CGT ACA TGA ACT GGG GGG A (서열식별번호: 100)
tdTomato sgRNA 8 Rev: AAA CTC CCC CCA GTT CAT GTA CGG (서열식별번호: 101)
tdTomato sgRNA 9 Fwd: CAC CGT CTT GTA ATC GGG GAT GTC GG (서열식별번호: 102)
tdTomato sgRNA 9 Rev: AAA CCC GAC ATC CCC GAT TAC AAG AC (서열식별번호: 103)
tdTomato sgRNA 10 Fwd: CAC CGC CGT CCT GCA GGG AGG AGT C (서열식별번호: 104)
tdTomato sgRNA 10 Rev: AAA CGA CTC CTC CCT GCA GGA CGG C (서열식별번호: 105)
각 올리고가 게놈 편집을 지시하는 능력을 시험관내에서 먼저 평가하였다. Neuro2A 세포를 폴리에틸렌이민을 사용하여 pAAV-hSyn1-SaCas9-tdTomato-1 내지 -10 800 ng, pAAV-FLEX-CAGtdTomato 100 ng, 및 pAAV-CAG-EGFP 100 ng으로 형질감염시켰다. 형질감염 72시간 후에, 세포를 수거하였고, ~70,000개의 EGFP 양성 Neuro2A 세포를 BD 인플럭스(BD Influx) 분류기 (비디 바이오사이언시스(BD Biosciences))를 사용하여 형광 활성화 세포 분류 (FACS)에 의해 단리하였다. 이어서, 게놈 DNA를 추출하였고, tdTomato 유전자 변형의 빈도를 이전에 기재된 바와 같이 (Cong et al., 2013, Science, 339:819-23) 서베이어(Surveyor) 뉴클레아제 검정 (인티그레이티드 DNA 테크놀로지스(Integrated DNA Technologies))에 의해 평가하였다. sgRNA 7 - tdTomato 서열 내에 2개의 절단 사건을 지시하는 것으로 나타난 둘 중 하나 - 을 retro-AAV2 내로 패키징하고 생체내 게놈 편집에 사용하였다.
이어서, AAV2-레트로-hSyn1-SaCas9-tdTomato 또는 AAV2retro-hSyn1-SaCas9-empty ~100 nl (5 x 1013 벡터 게놈 (vg)/ml)를 상기 기재된 바와 같이 Rbp4-Cre x tdTomato 마우스의 BPN 내로 주사하였다. 주사 6주 후에, 뇌를 수거하였고, 40 μm-두께 관상 절편을 절단하고 HA-태그부착된 Cas9 (셀 시그널링(Cell Signaling)으로부터의 항-HA 항체 C29F4, 1:1600으로 희석됨; 2차 항체: 당나귀 항-마우스 알렉사 플루오르(Alexa Fluor) 488 (1:250; 잭슨 이뮤노리서치(Jackson ImmunoResearch))에 대하여, 및 NeuN 뉴런 마커 (밀리포어로부터의 항-NeuN 항체 A60, 1:250으로 희석됨; 2차 항체: 당나귀 항-토끼 알렉사 플루오르 647 (1:500; 써모피셔(ThermoFisher), A-31573))에 대하여 염색하였다. 항체 염색 후, 절편을 DAPI (벡터 래보러토리즈) 함유 벡타쉴드 안티페이드 마운팅 배지와 슬라이드 상으로 마운팅하고, 자이스 악시오 옵저버 A1(Zeiss Axio Observer A1) 도립 현미경 (자이스(Zeiss))을 사용하여 가시화하였다. 면역염색의 정량화는 이미지J(ImageJ) 분석 소프트웨어 (NIH)를 사용하여 수행하였다.
실시예 13-rAAV2-레트로의 방향적 진화
증진된 역행 수송을 갖는 신규 rAAV를 조작하기 위해, 긴-범위의 투사를 마우스 뇌의 바이러스 주사 부위로 보내는 뉴런의 세포체로 효율적으로 수송된 rAAV 캡시드 변이체를 풍부화하는 생체내 방향적 진화 접근을 설계하였다 (도 1a). 목적하는 특성을 갖는 변이체를 회수할 가능성을 최대화하기 위해, 이전에 기재된 rAAV 캡 변이체 라이브러리의 다양한 혼합물 (Koerber et al., 2008, Mol. Ther., 16:1703-9; Koerber et al., 2009, Mol. Ther., 17:2088-95; Koerber et al., 2006, Nat. Protocols, 1:701-6; Mueller et al., 2003, Nat. Biotechnol., 21:1040-6)을 출발 물질로서 사용하였다. 각각의 변이체 캡시드를 상응하는 캡 유전자를 함유하는 AAV 게놈에 연결하는 방식으로 바이러스 입자를 패키징하였고, 영역 AAV2로의 무작위 7-량체 펩티드 삽입을 갖는 변이체인, 점 돌연변이체를 포함하는 캡시드 변이체의 최종 풀이, 그의 보조-수용체, 헤파란 술페이트, 및 7종의 모 혈청형으로부터의 캡시드 유전자 서열의 무작위 키메라에 결합시키기 위해 이용된다 (도 1a). 넓은 역행 향성을 갖는 변이체를 확인하기 위해, 투사 뉴런의 2개의 독립적 집단을 표적화하였다: 흑색질 레티쿨라타 (SNr)로 투사하는 선조체 GABA성 뉴런 및 소뇌 피질로 투사하는 글루타메이트성 후뇌 뉴런. rAAV 변이체의 전체 풀을 SNr 또는 소뇌 (동물당 1회 주사) 내로 주사하고 3주 후에, 선조체 또는 후뇌 조직을 각각 분리하였고, 캡 서열을 PCR에 의해 회수하였으며, 바이러스를 재패키징하였다 (도 1b). 추가의 2회의 선택 단계 후에, 추가로 라이브러리를 다양화하기 위해 오류-유발 PCR, 이어서 2회의 최종 생체내 선택 단계를 수행하였다.
4번째 진화 라운드 후에 30개의 캡 변이체를 서열분석하였고, 대부분 삽입 라이브러리로부터 유래하고 야생형 AAV2 VP1 캡시드 유전자의 N587과 R588 사이에 외인성 7-량체 펩티드를 함유하였다. 흥미롭게도, 모든 회수된 삽입물은 형태 LA xxDxTKx A (서열식별번호: 106) 또는 LA xDxTKxx A (서열식별번호: 107) (여기서 볼드체표시, 이탤릭체표시된 잔기가 삽입물로부터의 것임)였고; 서열에서 다른 돌연변이도 또한 풍부화되었다 (표 2). 5번째 진화 라운드 후에 추가의 22개의 클론을 서열분석하였고, 이러한 추가의 진화 라운드로 인해 모든 서열은 LA xxDxTKx A (서열식별번호: 106) / LA xDxTKxx A (서열식별번호: 107) 삽입을 갖는 AAV2 돌연변이체였으며 (표 2), 이는 현저한 정도의 추가적 수렴을 입증한다. 이러한 수렴은 헤파린-결합 루프로의 특정한 펩티드 삽입이 역행 기능성, 및 다른 부위로부터의 잠재적 2차 기여에 대해 주로 책임이 있었음을 시사하였다.
캡시드 서열에서 펩티드 삽입과 점 돌연변이의 상이한 조합을 소유하는 17개의 단리된 변이체에 대한 2차 스크린을 다음으로 검사하였다. 높은 수준의 엄격도를 적용하기 위해, 뉴런에서 전형적으로 약한 CMV 프로모터에 의해 구동되는 증진된 녹색 형광 단백질 (EGFP) 트랜스진으로 선택된 변이체를 패키징하였다. 각 캡시드 변이체에 대해, 주사 3주 후 비-항체-증폭된 EGFP 신호의 검출을 허용하는, 충분한 페이로드를 주요 구심성 영역에서 세포체로 전달하는 그의 능력을 평가하였다. 이러한 2차 스크린에서 2개의 독립적인 회로 (피질에서 담창구 및 하부 올리브/기저 뇌교핵에서 소뇌)에서 가장 강한 역행 수송을 나타낸 클론 (삽입물 LA DQDYTKT A (서열식별번호: 85) + V708I + N382D)을 추가의 분석을 위해 선택하고 rAAV2-레트로로 명명하였다. 설치류 생체내 연구에서 보다 통상적으로 사용되는 2종의 추가의 프로모터 (CAG - 도 1b, 또는 인간 시냅신-1, 데이터는 제시되지 않음)를 평가하였을 때, 주목할 만한 역행 표지 효율이 마우스 및 래트에서 다양한 상이한 회로에서의 이러한 rAAV 변이체로 관찰되었다 (도 1b 및 도 7). 7-량체 삽입을 다른 회수된 서열 중 하나로 교환하거나, 스크린에서 확인된 추가의 점 돌연변이를 추가하는 것은 역행 수송의 추가적 증가로 이어지지 않았다.
실시예 14-투사 뉴런에 대한 효율적인 역행 접근
하행 운동 경로 내에서, 피질-뇌교로는 현저하게 수렴적이고, 구심성 뉴런의 95% 초과가 기저 뇌교 핵 (BPN)에 기여하는 것으로 알려져 있다. 따라서 이 경로는 투사 뉴런의 축삭 말단에 의한 바이러스 흡수 및 역행 수송의 효율을 정량화하기 위한 특히 유리한 시스템을 나타낸다. 실제로, BPN 내로의 rAAV2-레트로의 주사는 층 V 뉴런의 고밀도 표지를 유발하였으며 (도 2a), 이는 지난 추적 연구와 일치한다 (Legg et al., 1989, J. Comp. Neurol., 286(4):427-41).
다음에, rAAV2-레트로 대 여러 통상적으로 사용된 AAV 혈청형에 대한 피질-뇌교 회로에서의 역행 수송의 효능을 동일한 감염 및 프로세싱 조건 하에서 비교하였다 (도 2b-d). 정량화 정확도를 보장하고, 트랜스진 발현 수준에서 세포-대-세포 가변성의 가능한 혼동을 제거하기 위해, AAV를 사용하여 Rosa26-Lox-STOP-Lox-H2B-GFP 트랜스제닉 마우스에 Cre 레콤비나제를 전달하였다 (He et al., 2012, Neuron, 73:35-48). 심지어 낮은 농도의 Cre 효소도 이러한 Cre-의존성 카세트의 발현을 켜기에 충분하고, 히스톤-융합된 리포터의 엄격한 핵 국재화는 신경망 신호를 혼동하지 않으면서 감염된 세포의 명백한 확인을 제공하는 것으로 나타났다.
반-자동화 분석 절차를 사용하여 BPN 내 국부 바이러스 주사 3주 후에 수거된 마우스 뇌로부터의 영상화된 시상면 절편에서 감염된 피질 투사 뉴런의 선형 밀도를 계산하였다 (도 2c). rAAV2로 감염된 동물에 대해, 최소 피질 GFP 발현이 관찰되었다 (선형 밀도 0.98 ± 0.20 뉴런/mm, 평균 ± sem, n=5; 도 2b, 중앙 패널). 대조적으로, 및 보다 초기의 관찰 (도 2a)과 일치하게, GFP-양성 층 V 투사 뉴런의 고밀도 층이 rAAV2-레트로-주사된 동물 내 피질의 전후방 축 전반에 걸쳐 관찰될 수 있었다 (선형 밀도 130.11±11.08 뉴런/mm, n=4; 도 2b, 하부 패널). 다른 통상적으로 사용된 AAV 혈청형도, 개 아데노바이러스-2도, 조작된 rAAV2-레트로 변이체의 역행 효율과 매칭되지 않았다 (선형 밀도 AAV1: 0.05 ± 0.04, AAV2: 0.98 ± 0.2, AAV5: 2.38 ± 1.24, AAV8: 1.43 ± 1.43, AAV9: 1.98 ± 0.86, DJ: 24.82 ± 14.32, CAV-2: 5.56 ± 4.13, 각각 n=3 내지 5; 도 2d, 도 8). 추가로, rAAV2-레트로에 의해 표지된 피질 투사 뉴런의 밀도는 강건한 합성 역행 추적자인 플루오로-골드 (Schmued and Fallon, 1986, Brain Res., 377:147-54)로 달성된 경우와 대등하였다 (선형 밀도 81.03 ± 11.08 뉴런/mm, n= 3). 따라서, rAAV2-레트로는 피질-뇌교 투사 뉴런에 대한 역행 접근에서 기존 혈청형에 비해 최대 두 자릿수의 증진을 나타내고, 합성 역행 추적자의 효능에 필적한다.
실시예 15-역행 기능성의 일반론
rAAV2-레트로의 역행 기능성이 다른 회로로 확장되었는지 여부는, 구체적으로 그것이 배내측 선조체 (DMS) - 다양한 피질 및 피질하 영역으로부터의 긴-범위의 입력을 받는 기저 신경절의 부분에 대한 다양한 구심성 뉴런을 표지한 정도를 특징화함으로써 다음에 검사하였다. DMS - 피질, 시상 및 편도체 - 내로의 가장 강한 구심성 입력 뉴런에 대한 rAAV2-레트로-매개된 역행 접근의 효능은 역행 추적에 전형적으로 사용된 형광 비드의 경우와 대등한 것으로 발견되었다 (도 3a). DMS로의 유의한 긴-범위의 입력을 제공하는 것으로 알려진 모든 뇌 영역에서의 역행으로 표지된 뉴런의 수에 대한 불편 추정치를 제공하기 위해, 마우스 뇌의 영상화된 절편 내 임의의 검출된 형광 표지를, 주석달린 알렌 뇌 아틀라스에 대해 상기 절편을 정렬함으로써 특정 뇌 영역에 할당하는 알고리즘을 개발하였다 (도 3b-c). 정량 분석 (도 3c)은 현저한 투사를 선조체에 보내는 것으로 이전에 보고된 대다수의 영역에서 강한 역행 표지가 발견되었다는 것을 밝혀냈다 (Pan et al., 2010, Front Neuroanat., 4:147). 하나의 주목할 만한 예외로, 흑색질 치밀부가 DMS로의 강한 도파민성 입력의 공급원임에도 불구하고 그 안에서 단지 보통의 표지만이 관찰되었다 (도 3c, SNc에 대한 세포 카운트에서 화살표). 투사 뉴런 부류의 소형 하위세트는 시험된 다른 회로의 일부에서 rAAV2-레트로에 의한 역행 접근에 대해 유사하게 불응성인 것으로 발견되었다 (표 3; 시험된 모든 다른 AAV 혈청형은 또한 이들 투사를 표지하는데 실패하였다는 것을 주목한다). 이들 예외에도 불구하고, rAAV2-레트로는 중추 신경계 내에서 광범위하게 적용가능하다.
표 3. 다양한 회로에서의 rAAV2-레트로 효율. 피질-시상 및 피질-구 투사에서의 역행 수송의 부재보다는 오히려 낮은 효율이 투사 뉴런 세포체로의 Cre-의존성 페이로드의 국부 전달 후 투사 뉴런의 효율적인 표지에 의해 시사된다
실시예 16-유전학적으로 정의된 뉴런 집단에 대한 역행 접근
rAAV2-레트로의 역행 기능성이 투사 뉴런의 특정 부류의 조사를 가능하게 하기 위해 Cre 트랜스제닉 세포주의 특이성과 조합될 수 있는지 여부가 또한 결정되었다. 구체적으로, rAAV2-레트로 및 Cre 트랜스제닉 세포주가 조합되어 2개의 뇌 영역 사이에서 병행 실행되는 2개의 기능적으로 구별되는 긴-범위의 연결을 분리할 수 있는지 여부를 결정하기 위해 실험을 수행하였다. 뇌 피질로부터 선조체로의 투사는 주로 층 V 내 뉴런으로부터 일어나지만 층 II 및 III 내 일부 뉴런도 또한 선조체 입력을 제공한다. 상이한 피질 층으로부터 선조체로의 입력은 개별 경로를 구성하며, 이때 층 V 내 뉴런은 선조체의 패치 구획으로 투사하고 층 II 및 III 내 뉴런은 매트릭스로 투사한다. 패치 및 매트릭스 마이크로-구획의 서로 맞물린 성질은 rAAV2-레트로 시스템 단독에 의한 기능적 조사를 위해 이들 경로를 선택적으로 표적화하는 것을 어렵게 만든다. 따라서 2개의 입력이 rAAV2-레트로를 층 II 및 III 내 뉴런을 제외한, 모든 층 V 뉴런에서 Cre 레콤비나제를 발현하는 트랜스제닉 세포주와 조합함으로써 분리될 수 있는지 여부를 탐구하였다 (Gerfen et al., 2013, Neuron, 80:1368-83) (도 4a).
동일한 실험에서 둘 다의 경로를 강조하기 위해, Cre의 부재 하에서 tdTomato를 발현하지만 Cre-양성 세포에서는 EGFP의 발현을 구동하도록 반전되는 Cre-의존성 색-전환 페이로드를 선택하였다 (Saunders et al., 2012, Front Neural Circuits, 6:47). 이러한 페이로드를 운반하는 rAAV2-레트로를 층 V-특이적 Cre 드라이버 라인, Rbp4_KL100 Cre의 배내측 선조체 내로 주사한 경우에 (Gerfen et al., 2013, Neuron, 80:1368-83), 오직 선조체로 투사하는 층 V 뉴런만이 EGFP를 발현하였다. 추가로, 층 II 및 III 피질선조체 경로는 tdTomato의 발현에 의해 명확히 구별가능하였다 (도 4b). 피질-선조체 투사의 지형학적 성질에 따라, 배내측 선조체 내로의 바이러스의 고도로 국재화된 주사는 상응하게 피질의 소형 절편의 표지로 이어졌다. 그러나, 층 V 및 층 II 및 III 피질-선조체 집단은 항상 공동-표지되었으며 (도 4b, 하부 패널), 이는 동일한 피질 영역으로부터의 2개의 경로가 선조체 내 이웃 매트릭스 및 패치 마이크로-구획을 통해 횡단한다는 것을 시사한다.
이 실험이 둘 다의 경로를 강조하였지만, "Cre-온" 또는 "Cre-오프" 페이로드를 선택하는 것은 다른 것을 배제하면서 하나에 대한 선택적 접근을 허용할 것이다. 본 실시예는, 따라서, 고도로 효율적인 역행 바이러스를 이용가능한 Cre (또는 Flp) 드라이버 라인과 조합함으로써 달성될 수 있는 회로 조사의 부가된 특이성을 강조한다.
실시예 17-회로 조사 및 유전자 조작을 위한 rAAV2-레트로의 사용
회로 조사를 위한 rAAV2-레트로의 유용성은 유전학적으로 코딩되는 지시자 및 이펙터의 발현의 높은 수준을 매개하는 그의 능력에 좌우될 것이다. 투사 뉴런의 정의된 부류에서의 신경 활성을 모니터링하는 능력을 먼저 GCaMP6f의 rAAV2-레트로-매개된 발현을 통해 평가하였다 (Chen et al., 2013, Nature, 499:295-300) (도 5a-c). 생체내 2-광자 Ca2 + 영상화를 사용하여, 수지상 및 체성 Ca2 + 과도현상을 이르게는 BPN으로의 바이러스 전달 7일 후에 주요 운동 피질에서 검출하였다 (도 5d). Ca2 + 신호의 일시적 프로파일은 신호를 받은 뻗기 과제의 구조를 반영하였으며, 이때 많은 피질-뇌교 뉴런에서의 신호는 "진행" 신호와 밀접하게 연결되어 있다 (도 5e-f) (Li et al., 2015, Nature, 519:51-6). 확인된 뉴런으로부터의 반복 기록은 발현 시간 과정 중 초기 세션 내 시험에 걸쳐 (도 5e, f), 및 감염후 2개월 초과 동안 많은 행동 세션에 걸쳐 둘 다에서 가능하였다. 따라서, rAAV2-레트로는 영상화에 충분한 수준으로 투사 뉴런에서 센서를 발현하는 능력을 부여하여, 회로 계산에 대한 특정 투사의 기여를 해독하기 위한 많은 새로운 기회를 창출한다.
최종적으로, rAAV2-레트로의 유용성을 이펙터, 예컨대 CRISPR/Cas9 유전자 편집 시스템의 투사 뉴런으로의 전달에 대해 평가하였다 (도 6). 구체적으로, 스타필로코쿠스 아우레우스 Cas9 (SaCas9 (Slaymaker et al., 2016, Science, 351:84-8)) 및 tdTomato의 발현을 제거하도록 설계된 단일 가이드 RNA를 rAAv2-레트로 내로 패키징하였다. 피질 층 V 흥분성 뉴런에서 tdTomato를 발현하는 동물의 BPN으로의 rAAV2-레트로-SaCas9-항tdTomato의 전달은 SaCas9-발현 층 V 뉴런의 88.6 ± 0.7%에서 tdTomato 발현의 억제를 유발하였다 (도 6b, 하부 패널 및 도 6c, n = 3). 대조적으로, 비-표적화된 SaCas9의 전달은 임의의 식별가능한 변화로 이어지지 않았으며, 이때 세포의 단지 4.4 ± 3.2%만이 tdTomato 발현의 잠재적 감소를 디스플레이하였다 (도 6b, 상부 패널 및 도 6c, n = 3). 추가로, tdTomato 발현은 뇌교 주사를 통해 접근불가능한 층 V 뉴런에서는 영향을 받지 않은 채로 남아있었다. 따라서 rAAV2-레트로 시스템은 특정 관심 영역으로 투사하는 뉴런에서 선택적으로 효율적인 유전자 변형을 허용한다.
종합적으로, 이들 관찰은 신경 회로의 기능적 조사를 위해, 및 결국에는, 가능한 치료제를 위해 투사 뉴런에 유전학적으로 접근하는 효과적인 시약으로서 rAAV2-레트로를 확립한다.
실시예 18-논의
재조합 아데노-연관 바이러스는 포유동물 신경 회로의 기능적 해부를 대단히 용이하게 할 수 있고, 신경계 장애에서의 치료적 개입에 대한 유망성을 보유할 수 있다. 방향적 진화를 사용하여 많은 회로에서 투사 뉴런에의 효율적인 역행 접근에 대한 추가의 능력을 AAV 캡시드에 부여하였다. 새롭게 조작된 rAAV2-레트로는 통상적으로 사용된 AAV 혈청형과 비교하여 최대 두 자릿수의 역행 수송의 증진을 제공하며, 이는 많은 회로에서 합성 역행 추적자의 효능과 매칭된다. 역행 접근을 통해 rAAV2-레트로에 의해 달성된 트랜스진 발현의 수준은 신경 회로 기능을 조사하기 위해 충분할 뿐만 아니라 뉴런 게놈의 표적화된 조작을 위해서도 충분하다. 따라서, 상이한 뇌 영역을 연결하는 투사 뉴런의 선택적 모니터링 및 조작을 가능하게 함으로써, rAAV2-레트로-기반 도구는 대규모 네트워크가 뇌를 기능하게 하는 방법에 대한 통찰력을 제공하고, 진행성 대규모 네트워크 기능장애를 특징으로 하는 질환에서의 치료적 개입에 대한 유망성을 보유하도록 준비된다.
모 혈청형 AAV2와 비교하여 rAAV2-레트로에 의해 제공된 역행 접근의 현저하게 증가된 효능은 헤파란 술페이트에 대한 천연 결합 부위의 삽입-매개된 파괴를 통해 및/또는 삽입된 펩티드를 포함하는 새로운 결합 표면의 생성을 통해 가능해졌을 수 있다. 이 변이체는, AAV1 및 AAV6에서 관찰된 바와 같이, 감소된 헤파린 친화도를 가져 (도 9), 시냅스 간극의 세포외 매트릭스에서 바이러스 격리를 감소시키고 국부 벡터 확산을 증진시킬 수 있었다. 그러나, 다른 삽입된 7-량체 서열이 헤파린 결합을 유사하게 파괴하지만 역행 수송에는 영향을 미치지 않음에 따라, 유발된 벡터 확산의 증가 단독으로는 역행 수송의 효능을 설명할 수 없다. 추가로, AAV5 및 AAV9는 헤파린에 결합하지 않지만, 그의 역행 수송 효율은 AAV2의 경우와 유사하다. 대안적 설명의 지지로, 원래 선택에서 선택된 펩티드 삽입물 (LAxxDxTKxA (서열식별번호: 106) / LAxDxTKxxA (서열식별번호: 107에서))은 동일한 전체 조성을 공유하며, 단순히 보존된 모티프의 레지스터만 상이하다. 조작된 펩티드 삽입물은 AAV 경로에서 기존 세포 보조-인자 (예를 들어, 최근에 확인된 통상적인 AAV 수용체)에 대한 증진된 결합을 지지할 수 있거나, 또는 세포 기구 - 세포-표면 수용체 및/또는 소포 트래픽킹 또는 핵 진입 경로의 성분과의 신규 상호작용을 생성할 수 있다.
rAAV2-레트로가 기존 혈청형에 비해 제공하는 역행 수송의 다수 자릿수 개선에도 불구하고, 투사 뉴런 부류의 소형 세트는 이러한 새롭게 진화된 rAAV 변이체에 의한 효율적인 역행 감염에 대해 불응성인 것처럼 보인다 (표 3). 그러나, 다른 AAV 혈청형도 또한 이들 투사를 표지하는데 실패한 것이 주목되어야 한다. 이들 뉴런에서 이러한 신규 AAV 변이체와 접속하는 중요한 세포 인자의 발현 수준이 단지 극도로 낮은지 여부 - 예를 들어, rAAV2-레트로가 여전히 충분한 Cre 레콤비나제를 세포체로 전달하여 국부로 전달된 Cre-의존성 페이로드에 대한 발현의 높은 수준을 지시할 수 있다는 관찰에 의해, 피질-시상 및 피질-구 투사에 대해 지지된 결론 (표 3, 강조된 엔트리) - 또는 인자가 전적으로 누락되어 있는지 여부는 각각의 경우에서 결정되도록 남아있다. 이러한 또는 다른 변이체에 대한 추가의 향후 캡시드 변형은 이들 뉴런 부류의 증진된 역행 전달을 가능하게 할 수 있다.
rAAV2-레트로 벡터 시스템은 신경 회로 기능을 해부하기 위한 유전적 툴키트에 중요한 부가를 제공하며, 투사 뉴런의 개별 부류에 대한 접근 획득이 국부 회로 역학 및 대규모 네트워크 기능이 조화되는 방법을 설명하는데 있어서 중요한 가능한 단계일 것이기 때문이다. 국부 회로 계산은 특정한 국부 회로 모듈 내 전체 뉴런 집단의 역학에 좌우되는 것으로 점점 생각된다. 이들 역학이 투사 뉴런의 상이한 부류 상에 맵핑되는 방법 - 및 따라서 무슨 정보가 상이한 하류 표적으로 전달되는지 -는 대부분의 회로에 대해 미해결인 채로 남아있다. rAAV2-레트로 기반 벡터는 단독으로 또는 특정 Cre 트랜스제닉 세포주와 조합되어, 투사 뉴런의 특정 집단에 대한 유전적 접근을 허용한다. 차례로, 광견병 G 당단백질을 운반하는 rAAV2-레트로는 투사 뉴런의 특정한 부류에 영향을 주는 시냅스전 마이크로-회로에 대한 접근을 위해 새롭게 개발된 비-독성 조건부 광견병 벡터를 트랜스-보완하는데 사용될 수 있다. 개별 투사 뉴런 부류 및 그의 국부 마이크로회로의 활성을 선택적으로 모니터링하고 조작하는 생성된 능력은 투사 뉴런이 그의 각각의 대규모 네트워크에 대한 국부 회로 역학을 해석하는 방법에 대한 통찰을 제공할 것이다.
rAAV2-레트로는 또한 여러 가능한 적용에서 치료적 개입에 대한 유망성을 보유한다. 예를 들어, 병리상태가 신경 조직의 거대 부피에 영향을 미치는 상황 - 예컨대 알츠하이머병 또는 리소솜 축적 질환 -에서 다수회 주사는 안전성 위험을 제기하고, 필요한 전달 수준을 달성하는데 불충분할 수 있다. 그러나, 전략적인 위치에서의 적은 횟수의 주사는 거대 부피 (예를 들어, BPN 내 수렴점으로부터의 피질-뇌교로) 또는 접근 곤란 조직 (예를 들어, 근육으로부터의 척수 운동 뉴런) 상에 벡터 분산을 가능하게 할 수 있다. 추가로, 대규모 기능적 네트워크는 그의 공간적으로 국재화된 발병으로부터 많은 신경변성 장애의 확산에 연루되었다. 저명한 신생 견해는, 취약한 뉴런 집단에서의 비정상적 단백질 어셈블리물의 침착이 대규모 기능적 네트워크 내의 이상 뉴런 활성의 병리학적 캐스케이드 및 상기 네트워크의 붕괴를 촉발하여, 궁극적으로 신경학적 기능의 실패로 이어진다는 것을 상정한다. 흥미롭게는, 많은 신경변성 질환을 갖는 환자가 종종 극적인 개선의 기간을 디스플레이함에 따라, 영향을 받은 신경 네트워크는 질환의 초기에 이상 역학을 일시적으로 극복할 수 있는 것으로 보인다. 따라서, 병리상태의 피질 기원으로부터 응집체의 확산을 저속화하는 것을 목표로 한 초기 개입은 인지 기능을 안정화시키거나 또는 심지어 회복시키기에 충분할 수 있다. 이러한 관점으로부터, 병리학적 단백질 응집체가 알츠하이머 및 파킨슨 장애 둘 다에서 처음 출현한 중피질 영역 내 피질하-투사 뉴런은 매력적인 개입 표적을 구성한다. 예를 들어 시스로 추가의 응집을 정지시킬 수 있는 돌연변이를 도입하거나 또는 응집체를 해체할 수 있는 샤페론을 전달하도록 설계된 rAAV2레트로-기반 도구를 사용하여 상기 투사 뉴런에 접근하는 것은 가장 쇠약한 인지 증상의 진행을 저속화시키는 잠재력을 갖는다. 비-인간 영장류에서 rAAV2-레트로 시약의 효율 및 장기 안전성을 평가하는 것은 이들 및 다른 유전자 요법 접근법에 대한 궁극적으로 고려해야 할 길을 열어줄 것이다.
방법 및 물질의 조성물이 다수의 상이한 측면과 함께 본원에 기재되었지만, 다양한 측면의 상기 기재는 예시를 위해 의도되고 방법 및 물질의 조성물의 범주의 제한을 위해 의도되는 것이 아님이 이해되어야 한다. 다른 측면, 이점 및 변형은 하기 청구범위의 범주 내에 있다.
개시된 방법 및 조성물에 사용될 수 있는, 그와 함께 사용될 수 있는, 그의 제조에 사용될 수 있는, 또는 그의 생성물인 방법 및 조성물이 개시된다. 이들 및 다른 물질이 본원에 개시되며, 이는 이들 방법 및 조성물의 조합, 하위세트, 상호작용, 군 등이 개시된 것으로 이해된다. 즉, 이들 조성물 및 방법의 각각의 다양한 개별적 및 집합적 조합 및 순열에 대한 구체적 언급이 명시적으로 개시되지 않을 수 있지만, 각각은 본원에서 구체적으로 고려되고 기재된다. 예를 들어, 물질의 특정한 조성물 또는 특정한 방법이 개시 및 논의되고 다수의 조성물 또는 방법이 논의된 경우에, 달리 구체적으로 나타내지 않는 한, 조성물 및 방법의 각각의 및 모든 조합 및 순열이 구체적으로 고려된다. 마찬가지로, 이들의 임의의 하위세트 또는 조합이 또한 구체적으로 고려되고 개시된다.
SEQUENCE LISTING
<110> Howard Hughes Medical Institute
<120> VARIANT ADENO-ASSOCIATED VIRUSES AND METHODS OF USING
<130> 30872-0013WO1
<140> PCT/US2017/037781
<141> 2017-06-15
<150> 62/404,585
<151> 2016-10-05
<150> 62/350,361
<151> 2016-06-15
<160> 108
<170> PatentIn version 3.5
<210> 1
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<220>
<221> misc_feature
<222> (1)..(2)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc_feature
<222> (4)..(4)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa can be any naturally occurring amino acid
<400> 1
Xaa Xaa Asp Xaa Thr Lys Xaa
1 5
<210> 2
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<220>
<221> misc_feature
<222> (1)..(1)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc_feature
<222> (3)..(3)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc_feature
<222> (6)..(7)
<223> Xaa can be any naturally occurring amino acid
<400> 2
Xaa Asp Xaa Thr Lys Xaa Xaa
1 5
<210> 3
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 3
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaatc tccgaccaga caaaacacgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 4
<211> 746
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 4
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Ile Ser Asp
580 585 590
Gln Thr Lys His Ala Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr
595 600 605
Gln Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu
610 615 620
Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His
625 630 635 640
Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln
645 650 655
Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe
660 665 670
Ser Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln
675 680 685
Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg
690 695 700
Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn
705 710 715 720
Val Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro
725 730 735
Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 5
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 5
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
aacgaagagg aaatcagggc aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaatc tccgaccaga caaaacacgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 6
<211> 746
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 6
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Pro Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asp
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Ala Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Ile Ser Asp
580 585 590
Gln Thr Lys His Ala Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr
595 600 605
Gln Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu
610 615 620
Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His
625 630 635 640
Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln
645 650 655
Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe
660 665 670
Ser Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln
675 680 685
Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg
690 695 700
Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn
705 710 715 720
Val Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro
725 730 735
Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 7
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 7
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaaag gatcagacaa aaagcaccgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 8
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 8
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Lys Asp Gln
580 585 590
Thr Lys Ser Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 9
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 9
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acacctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaaac caagactaca caaaaactgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tgttaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 10
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 10
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Pro Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Asn Gln Asp
580 585 590
Tyr Thr Lys Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Val Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 11
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 11
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatatgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaatc tccgaccaga caaaacacgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 12
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 12
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Tyr Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Ile Ser Asp
580 585 590
Gln Thr Lys His Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 13
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 13
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagggcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaaac caagactaca caaaaactgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 14
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 14
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Gly Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Asn Gln Asp
580 585 590
Tyr Thr Lys Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 15
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 15
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaatc tccgaccaga caaaacacgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 16
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 16
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Ile Ser Asp
580 585 590
Gln Thr Lys His Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 17
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 17
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcacac gacatcacca agaatattgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 18
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 18
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala His Asp Ile
580 585 590
Thr Lys Asn Ile Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 19
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 19
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcacac gacatcacca agaatattgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 20
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 20
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala His Asp Ile
580 585 590
Thr Lys Asn Ile Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 21
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 21
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga cgcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcgg tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcacac gacatcacca agaatattgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 22
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 22
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Asp Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Gly Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala His Asp Ile
580 585 590
Thr Lys Asn Ile Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 23
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 23
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcacac gacatcacca agaatattgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 24
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 24
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala His Asp Ile
580 585 590
Thr Lys Asn Ile Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 25
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 25
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggagct 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaatc tccgaccaga caaaacacgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 26
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 26
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Ala Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Ile Ser Asp
580 585 590
Gln Thr Lys His Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 27
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 27
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagggcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagaacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acacctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaaac caagactaca caaaaactgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 28
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 28
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Gly Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Glu Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Pro Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Asn Gln Asp
580 585 590
Tyr Thr Lys Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 29
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 29
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg accccaggcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacgacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaatc tccgaccaga caaaacacgc taggcaagca 1800
gctaccgcaa atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 30
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 30
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Arg Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Ile Ser Asp
580 585 590
Gln Thr Lys His Ala Arg Gln Ala Ala Thr Ala Asn Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 31
<211> 2188
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 31
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggctgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact acaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcagac caagactaca caaaaactgc taggcaagca 1800
ggacagagat gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca 1860
ttttcacccc tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct 1920
catcaagaac accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc 1980
ttccttcatc acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca 2040
gaaggaaaac agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc 2100
tattaatgtg gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg 2160
caccagatac ctgactcgta atctgtaa 2188
<210> 32
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 32
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Tyr Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Asp Gln Asp
580 585 590
Tyr Thr Lys Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 33
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 33
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagaggcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagaacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaatc tccgaccaga caaaacacgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 34
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 34
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Glu Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Glu Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Ile Ser Asp
580 585 590
Gln Thr Lys His Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 35
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 35
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagaacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataactacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaatc tccgaccaga caaaacacgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 36
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 36
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Glu Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Tyr
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Ile Ser Asp
580 585 590
Gln Thr Lys His Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 37
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 37
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacgc cgcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agccttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcaatacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcacag cctgacgcca caaaaaacgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 38
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 38
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Ala Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Ile Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Gln Pro Asp
580 585 590
Ala Thr Lys Asn Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 39
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 39
atggctgccg atggttatct tccagattgg ctcgtggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacgc cgcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttga gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcgg tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcacac gacatcacca agaatattgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 40
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 40
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Val Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Glu Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Gly Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala His Asp Ile
580 585 590
Thr Lys Asn Ile Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 41
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 41
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacgc cgcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agggaggcaa cctagcaaac caagactaca caaaaactgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttctgtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 42
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 42
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Gly Gly Asn Leu Ala Asn Gln Asp
580 585 590
Tyr Thr Lys Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Cys
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 43
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 43
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacgacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcagac caagactaca caaaaactgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 44
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 44
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Asp Gln Asp
580 585 590
Tyr Thr Lys Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 45
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 45
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacgc cgcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaaac caagactaca caaaaactgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 46
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 46
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Asn Gln Asp
580 585 590
Tyr Thr Lys Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 47
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 47
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagggcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcagac caagactaca caaaaactgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 48
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 48
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Gly Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Asp Gln Asp
580 585 590
Tyr Thr Lys Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 49
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 49
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagggcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataagcttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaaac caagactaca caaaaactgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 50
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 50
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Gly Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Lys Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Asn Gln Asp
580 585 590
Tyr Thr Lys Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 51
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 51
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcacac gacatcacca agaatattgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 52
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 52
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala His Asp Ile
580 585 590
Thr Lys Asn Ile Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 53
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 53
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcaact acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaatc tccgaccaga caaaacacgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 54
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 54
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Asn Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Ile Ser Asp
580 585 590
Gln Thr Lys His Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 55
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 55
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagacg ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaatc tccgaccaga caaaacacgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 56
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 56
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asp Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Ile Ser Asp
580 585 590
Gln Thr Lys His Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 57
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 57
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcacac gacatcacca agaatattgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 58
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 58
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala His Asp Ile
580 585 590
Thr Lys Asn Ile Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 59
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 59
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacgc cgcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcagac caagactaca caaaaactgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 60
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 60
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Asp Gln Asp
580 585 590
Tyr Thr Lys Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 61
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 61
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaatc tccgaccaga caaaacacgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 62
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 62
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Ile Ser Asp
580 585 590
Gln Thr Lys His Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 63
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 63
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcttaaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacgc cgcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtagc ccactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcgg tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcacac gacatcacca agaatattgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 64
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 64
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg Leu Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Ala His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Gly Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala His Asp Ile
580 585 590
Thr Lys Asn Ile Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 65
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 65
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagggcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaga ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acacctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcag cctagcaaac caagactaca caaaaactgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 66
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 66
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Gly Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asp Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Pro Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Ser Leu Ala Asn Gln Asp
580 585 590
Tyr Thr Lys Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 67
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 67
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagggcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacgc cgcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcacac gacatcacca agaatattgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 68
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 68
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Gly Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala His Asp Ile
580 585 590
Thr Lys Asn Ile Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 69
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 69
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
ggcagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacgc cgcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttgaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcggacc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acacctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaaac caagactaca caaaaactgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 70
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 70
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Gly Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Glu Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Asp Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Pro Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Asn Gln Asp
580 585 590
Tyr Thr Lys Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 71
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 71
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcagggc aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcagac caagactaca caaaaactgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 72
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 72
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Ala Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Asp Gln Asp
580 585 590
Tyr Thr Lys Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 73
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 73
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcgcacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacgc cgcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttgaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcgg tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcacag cctgacgcca caaaaaacgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 74
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 74
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Ala Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Glu Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Gly Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Gln Pro Asp
580 585 590
Ala Thr Lys Asn Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 75
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 75
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaaag gatcagacaa aaagcaccgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 76
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 76
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Lys Asp Gln
580 585 590
Thr Lys Ser Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 77
<211> 2238
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 77
atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60
cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120
gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180
aagggagagc cggtcaacgc cgcagacgcc gcggccctcg agcacgacaa agcctacgac 240
cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300
caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360
gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420
ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480
aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540
tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600
aatacgatgg ctacaggcgg tggcgcacca atggcagaca ataacgaggg cgccgacgga 660
gtgggtaatt cctcgggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780
tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840
tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900
aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960
aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020
caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080
tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140
aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200
cagatgctgc gtaccggaaa cagctttacc ttcagctaca cttttgagga cgttcctttc 1260
cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320
tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380
cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440
ccctgttacc gccagcagcg agtatcaaag acacctgcgg ataacaacaa cagtgaatac 1500
tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560
ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620
atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680
gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740
accaacctcc agagaggcaa cctagcaaac caagactaca caaaaactgc taggcaagca 1800
gctaccgcag atgtcaacac acaaggcgtt cttccaggca tggtctggca ggacagagat 1860
gtgtaccttc aggggcccat ctgggcaaag attccacaca cggacggaca ttttcacccc 1920
tctcccctca tgggtggatt cggacttaaa caccctcctc cccagattct catcaagaac 1980
accccggtac ctgcgaatcc ttcgaccacc ttcagtgcgg caaagtttgc ttccttcatc 2040
acacagtact ccacgggaca ggtcagcgtg gagatcgagt gggagctgca gaaggaaaac 2100
agcaaacgct ggaatcccga aattcagtac acttccaact acaacaagtc tattaatgtg 2160
gactttactg tggacactaa tggcgtgtat tcagagcctc gccccattgg caccagatac 2220
ctgactcgta atctgtaa 2238
<210> 78
<211> 745
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 78
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Gly Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Ser Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Pro Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Asn Gln Asp
580 585 590
Tyr Thr Lys Thr Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Ile Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 79
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 79
acgcggaagc ttcgatcaac tacgcag 27
<210> 80
<211> 32
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 80
agaccaaagt tcaactgaaa cgaattaaac gg 32
<210> 81
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 81
Leu Ala Ile Ser Asp Gln Thr Lys His Ala
1 5 10
<210> 82
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 82
Leu Ala Lys Asp Gln Thr Lys Ser Thr Ala
1 5 10
<210> 83
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 83
Leu Ala Asn Gln Asp Tyr Thr Lys Thr Ala
1 5 10
<210> 84
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 84
Leu Ala His Asp Ile Thr Lys Asn Ile Ala
1 5 10
<210> 85
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 85
Leu Ala Asp Gln Asp Tyr Thr Lys Thr Ala
1 5 10
<210> 86
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 86
Leu Ala Gln Pro Asp Ala Thr Lys Asn Ala
1 5 10
<210> 87
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 87
caccgcaagg gcgaggaggt catca 25
<210> 88
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 88
aaactgatga cctcctcgcc cttgc 25
<210> 89
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 89
caccgtggag ggctccatga acggcc 26
<210> 90
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 90
aaacggccgt tcatggagcc ctccac 26
<210> 91
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 91
caccgaggac ggcggccact acctgg 26
<210> 92
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 92
aaacccaggt agtggccgcc gtcctc 26
<210> 93
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 93
caccgacaac aacatggccg tcatca 26
<210> 94
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 94
aaactgatga cggccatgtt gttgtc 26
<210> 95
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 95
caccgaagga cggcggccac tacctgg 27
<210> 96
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 96
aaacccaggt agtggccgcc gtccttc 27
<210> 97
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 97
caccgacaac aacatggccg tcatca 26
<210> 98
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 98
aaactgatga cggccatgtt gttgtc 26
<210> 99
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 99
caccggtcac cttcagcttg gcggt 25
<210> 100
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 100
aaacaccgcc aagctgaagg tgacc 25
<210> 101
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 101
caccgccgta catgaactgg gggga 25
<210> 102
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 102
aaactccccc cagttcatgt acgg 24
<210> 103
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 103
caccgtcttg taatcgggga tgtcgg 26
<210> 104
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 104
aaacccgaca tccccgatta caagac 26
<210> 105
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 105
caccgccgtc ctgcagggag gagtc 25
<210> 106
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<400> 106
aaacgactcc tccctgcagg acggc 25
<210> 107
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<220>
<221> misc_feature
<222> (3)..(4)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc_feature
<222> (9)..(9)
<223> Xaa can be any naturally occurring amino acid
<400> 107
Leu Ala Xaa Xaa Asp Xaa Thr Lys Xaa Ala
1 5 10
<210> 108
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetically generated sequence
<220>
<221> misc_feature
<222> (3)..(3)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc_feature
<222> (5)..(5)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc_feature
<222> (8)..(9)
<223> Xaa can be any naturally occurring amino acid
<400> 108
Leu Ala Xaa Asp Xaa Thr Lys Xaa Xaa Ala
1 5 10
Claims (43)
- xxDxTKx (서열식별번호: 1) 및 xDxTKxx (서열식별번호: 2)로 이루어진 군으로부터 선택된 서열을 포함하는 바이러스 캡시드 단백질.
- 제1항에 있어서, 서열식별번호: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 및 78로 이루어진 군으로부터 선택된 아미노산 서열에 대해 적어도 95% 서열 동일성을 갖는 바이러스 캡시드 단백질.
- 제1항에 있어서, 서열식별번호: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 및 78로 이루어진 군으로부터 선택된 아미노산 서열을 갖는 바이러스 캡시드 단백질.
- 제1항에 있어서, 서열식별번호: 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 및 77로 이루어진 군으로부터 선택된 핵산 서열에 대해 적어도 95% 서열 동일성을 갖는 핵산에 의해 코딩된 바이러스 캡시드 단백질.
- 제1항에 있어서, 서열식별번호: 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 및 77로 이루어진 군으로부터 선택된 서열을 갖는 핵산에 의해 코딩된 바이러스 캡시드 단백질.
- 제1항 내지 제5항 중 어느 한 항의 바이러스 캡시드 단백질을 포함하는 바이러스 입자.
- 제6항에 있어서, 역행 이동에 대한 선호도를 나타내는 바이러스 입자.
- 제6항에 있어서, 역행 수송 능력을 보유한 바이러스 입자.
- 제6항 내지 제8항 중 어느 한 항에 있어서, 페이로드를 코딩하는 핵산을 추가로 포함하는 바이러스 입자.
- 제9항에 있어서, 페이로드를 코딩하는 핵산이 페이로드를 코딩하는 코딩 서열에 작동가능하게 연결된 프로모터 서열을 포함하는 것인 바이러스 입자.
- 제10항에 있어서, 프로모터가 시냅신-1, CMV, GFAP, CAG, CaMKII, MBP, EF1알파, TRE 및 mDlx로 이루어진 군으로부터 선택된 것인 바이러스 입자.
- 제10항 또는 제11항에 있어서, 페이로드를 코딩하는 코딩 서열이 단백질-코딩 유전자 및 억제 RNA 핵산으로 이루어진 군으로부터 선택된 것인 바이러스 입자.
- 제12항에 있어서, 억제 RNA 핵산이 안티센스 올리고뉴클레오티드, siRNA, 또는 RNAi인 바이러스 입자.
- 제9항에 있어서, 페이로드가 이펙터 단백질인 바이러스 입자.
- 제14항에 있어서, 이펙터 단백질이 레콤비나제 (예를 들어, Cre 또는 Flp), 유전자 편집 시스템 (예를 들어, CRISPR/Cas9, TALEN, 아연 핑거 뉴클레아제), 광유전학 시약 (활성화제 (예를 들어, 채널로돕신 또는 그의 변이체) 또는 억제제 (예를 들어, 할로로돕신 또는 Arch)), 화학유전학 시약 (예를 들어, DREADD 또는 PSAM/PSEM 시스템의 활성화제/억제제 버전), 세포계 경로의 활성화제 및/또는 억제제, 및 후성학의 제어를 위한 효소로 이루어진 군으로부터 선택된 것인 바이러스 입자.
- 제9항에 있어서, 페이로드가 광학 리포터 구축물인 바이러스 입자.
- 제16항에 있어서, 광학 리포터 구축물이 GCaMP6 (s, m 또는 f), 형광단 (예를 들어, 녹색 형광 단백질 (GFP), 증강 GFP (EGFP), 적색 형광 단백질 (RFP), 황색 형광 단백질 (YFP), tdTomato), 색-전환 구축물 (예를 들어, 하나의 세포 집단에서 하나의 리포터 및 또 다른 집단에서 상이한 리포터를 발현하는 페이로드), 글루코스 센서, jRCaMP, jRGECO, 및 CaMPARI, 전압 인디케이터, 2차 메신저, 수용체 신호기, 전사 리포터, 후성적 리포터 및 신경조정제 리포터로 이루어진 군으로부터 선택된 것인 바이러스 입자.
- 제9항에 있어서, 페이로드가 바이러스 단백질인 바이러스 입자.
- 제18항에 있어서, 바이러스 단백질이 광견병 G 단백질인 바이러스 입자.
- 제18항에 있어서, 바이러스 단백질이 AAV 외의 다른 바이러스의 기능을 보완하는 단백질 또는 세포 및 세포횡단 수송과 관련된 단백질인 바이러스 입자.
- 제9항에 있어서, 페이로드를 코딩하는 코딩 서열이 치료 유전자인 바이러스 입자.
- 제21항에 있어서, 치료 유전자가 신경변성 장애의 치료를 위한 것인 바이러스 입자.
- 제22항에 있어서, 치료 유전자가 알츠하이머병 또는 독성 단백질 응집체를 갖는 다른 질환의 치료를 위한 HSP104인 바이러스 입자.
- 제22항에 있어서, 치료 유전자가 프리드라이히 운동실조의 치료를 위한 프라탁신인 바이러스 입자.
- 제22항에 있어서, 치료 유전자가 파킨슨병의 치료를 위한 리소솜 글루코세레브로시다제 (GBA)인 바이러스 입자.
- 제22항에 있어서, 치료 유전자가 헌팅턴병의 치료를 위한 폴리Q-결합 단백질인 바이러스 입자.
- 제22항에 있어서, 치료 유전자가 척수성 근육 위축, 근위축성 측삭 경화증 (ALS), 자폐증, 치매, 말초 신경병증, 정신분열증 또는 망막 변성의 치료를 위한 생존 운동 뉴런 1인 바이러스 입자.
- 제9항에 있어서, 페이로드가 치료 모이어티인 바이러스 입자.
- 제28항에 있어서, 치료 모이어티가 항체 또는 그의 단편인 바이러스 입자.
- 제28항에 있어서, 치료 모이어티가 면역조정 단백질인 바이러스 입자.
- 제28항에 있어서, 치료 모이어티가 RNA 간섭 분자인 바이러스 입자.
- 제6항 내지 제28항 중 어느 한 항에 있어서, 바이러스 입자가 개 아데노바이러스-2 (CAV-2)보다 피질-뇌교 투사 뉴런에 대해 최대 두 자릿수 더 큰 역행 접근을 나타내는 것인 바이러스 입자.
- 제6항 내지 제28항 중 어느 한 항에 있어서, 피질-뇌교 투사 뉴런 또는 배내측 선조체 (DMS)에 대한 구심성 뉴런에 대한 역행 접근이 합성 추적자인 플루오로-골드 형광 비드와 대등한 것인 바이러스 입자.
- 내부에 패키징된 페이로드를 포함하는 변이체 아데노-연관 바이러스 (AAV)와 1개 이상의 뉴런을 접촉시키는 단계이며, 여기서 변이체 AAV는 xxDxTKx (서열식별번호: 1) 및 xDxTKxx (서열식별번호: 2)로 이루어진 군으로부터 선택된 서열을 포함하는 캡시드 단백질을 포함하는 것인 단계
를 포함하는, 페이로드를 1개 이상의 뉴런에 전달하는 방법. - 제34항에 있어서, 변이체 AAV가 뉴런에서 역행 이동을 나타내는 것인 방법.
- 제34항에 있어서, 뉴런이 투사 뉴런인 방법.
- 제34항 내지 제36항 중 어느 한 항에 있어서, 뉴런이 대상체 내에 존재하는 것인 방법.
- 제34항 내지 제37항 중 어느 한 항에 있어서, 뉴런이 대상체의 중추 신경계 (CNS) 내에 존재하는 것인 방법.
- 제34항 내지 제38항 중 어느 한 항에 있어서, 대상체가 인간인 방법.
- 제34항 내지 제38항 중 어느 한 항에 있어서, 대상체가 비-인간인 방법.
- 제40항에 있어서, 비-인간 대상체가 영장류, 설치류, 파충류, 및 조류인 방법.
- 제34항 내지 제36항 중 어느 한 항에 있어서, 접촉시키는 단계가 세포 배양물에서 이루어지는 것인 방법.
- 제34항 내지 제41항 중 어느 한 항에 있어서, 접촉시키는 단계가 두개내, 척수내 또는 근육내 주사를 통해 생체내에서 이루어지는 것인 방법.
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