KR20070110104A - 단백질 미스폴딩 및 응집 조절인자 및 그의 사용 방법 - Google Patents
단백질 미스폴딩 및 응집 조절인자 및 그의 사용 방법 Download PDFInfo
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- KR20070110104A KR20070110104A KR1020077021968A KR20077021968A KR20070110104A KR 20070110104 A KR20070110104 A KR 20070110104A KR 1020077021968 A KR1020077021968 A KR 1020077021968A KR 20077021968 A KR20077021968 A KR 20077021968A KR 20070110104 A KR20070110104 A KR 20070110104A
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Abstract
단백질 응집을 특징으로 하는 신경계 질환을 위한 폴리뉴클레오티드 분자, 상기 분자에 의해 코딩된 단백질, 진단 방법 및 치료 방법을 제공한다. 알파-시뉴클레인과 같은 응집되기 쉬운 단백질의 미스폴딩, 및 그 후의 응집에 영향을 주고, 파킨슨병과 같이 단백질 응집과 관련된 신경계 질병의 진단 및 치료와 관련성을 갖는 유전자를 본 원에 개시한다. RNAi를 사용한 본 원에 기술된 유전자 발현의 넉다운은 단백질 응집의 C. 엘레간스 모델에서 알파-시뉴클레인 단백질을 응집시킨다. 신경독인 6-OHDA에 노출시킨 후, 또는 알파-시뉴클레인이 과발현된 후, 상기 단백질의 과발현으로 도파민성 신경보호를 제공받을 수 있다. 단백질 미스폴딩 및 응집과 관련된 유전자에 대한 지식은 진단 선별 방법, 돌연변이 분석법을 개발하는데 효과적인 수단과, 파킨슨병과 같은 신경계 질병을 치료하기 위한 신규의 치료학적 및 신경보호성 화합물 개발을 위한 약물 디자인 정보를 제공한다.
Description
관련 출원에 대한 상호 참조
본 출원은 2005년 2월 25일 출원된 미국 가특허 출원 제60/656,334호, 2005년 11월 21일 출원된 미국 가특허 출원 제60/738,761호, 및 2005년 12월 12일 출원된 미국 가특허 출원 제60/749,910호(본 원에서 참조로 인용된다)의 잇점을 주장한다.
본 발명의 기술분야
본 발명은 단백질 응집을 조절하는 신경보호 단백질을 코딩하는 폴리뉴클레오티드 분자, 및 그것을 사용하는 방법에 관한 것이다. 더욱 특히, 본 발명은 단백질 미스폴딩(misfolding) 및 도파민성 신경변성을 예방하기 위해 폴리뉴클레오티드 분자 및 그에 의해 코딩된 신경보호 단백질을 사용하는 방법에 관한 것이다.
신경세포 기능장애 및 손상은 독성의 응집되기 쉬운 단백질에 의해 유발될 수 있고, 다수의 신경계 질환은 그러한 용태를 특징으로 한다. 이들은 근위축성 측삭 경화증, 알츠하이머병, 파킨슨병, 프리온 질병, 폴리글루타민 확장증, 척수소뇌성 실조증, 척수 및 연수 근육위축, 해면 뇌병증, 타우증(tauopathy), 헌팅톤병, 또는 근육긴장이상과 같은 질환을 포함한다. 상기 질환을 유발하는, 독성의 응집되기 쉬운 단백질을 코딩하는 단백질, 및 단백질을 코딩하는 유전자가 동정되었다. 정상적인 대사 효소는 합성 및 분해의 영구적인 순환을 형성하는 단백질을 재순환시킨다. 상기 유전자가 돌연변이화될 경우, 미스폴딩된 단백질은 비정상적으로 축적되고 분해된다. 이러한 미스폴딩된 단백질이 신경세포 손상의 지시일 수 있는 신경세포 봉입체 및 플라크를 유발하는 것으로 공지되어 있다. 따라서, 세포 기전을 이해하고, 상기 미스폴딩된 단백질을 감소시키고, 저해하고, 호전시키기 위해 필요한 분자 수단을 동정하는 것이 중요하다. 추가로, 단백질 미스폴딩 및 응집이 신경세포 생존에 미치는 효과를 이해함으로써 이들 질환에 대한 합리적이고 유효한 치료법을 개발할 수 있을 것이다.
파킨슨병은 사지 떨림, 느린 운동 또는 무운동, 사지 경직, 셔플링 보행, 및 웅크린 자세를 특징으로 하는 신경계 질환이다. 다른 증상으로는 우울증, 인격 변화, 수면 장애, 언어 장애, 또는 성적 장애를 포함할 수 있다. 이러한 용태는 점진적으로 중증화된다. 증상은 대뇌 기저핵, 특히, 솔기핵 ( raphe nuclei ) 및 청반( locus ceruleus )에서 2차 변성을 갖는 흑색질에서의 신경세포 변성의 결과이다. 이러한 신경세포 변성은 공통적으로 단백질 알파-시뉴클레인의 미스폴딩 및 그 후의 응집과 관련된다. 흑색질에서의 신경세포 변성은 신경전달물질인 도파민을 감소 시켜 중증의 운동 능력 장애를 유발하는 신경전달물질 결핍을 초래한다.
알파-시뉴클레인의 돌연변이체 형태는 미스폴딩 성향을 증가시킬 뿐만 아니라, 다른 단백질이 응집체내로 혼입되도록 유도한다고 여겨지고 있다. 단백질 분해 효소의 결핍 또한 단백질 축적, 응집의 원인이 될 수 있고, 세포 항상성을 변화시킬 수 있다. 이러한 응집체가 루이 소체로 공지되어 있고, 이는 주로 알파-시뉴클레인으로 구성되어 있다. 이는 파킨슨병, 루이 소체 치매 및 다른 신경변성 질병의 병적 특질을 구성한다. 루이 소체는 알츠하이머 환자에서 발견되는 베타-아밀로이드 플라크와 유사하다. 사실상, 알파-시뉴클레인은 또한 이들 알츠하이머-관련 플라크중 가장 큰 성분이다. 파킨슨 환자의 뇌에 루이 소체가 존재하는 것은 도파민성 신경세포의 손실 및 그 이후의 운동 조절 상실과 부합되는 것이다. 신경섬유농축제중 알파-시뉴클레인이 존재하는 것 또한 알츠하이머병, 피크병, 진행성 핵상마비, 및 피질 기저핵 변성과 관련성을 갖는다.
신경변성 질환을 둘러싼 주된 장애물은, 환자가 임상적 증상이 명백하게 나타나는 시점까지 신경세포 변성의 원인이 되는 신경세포 환경이 발전하고 있음을 인식하지 못한다는 점이다. 임상적 증상이 명백하게 나타날 때까지 신경세포는 이미 크게 손실된 상태이고, 신경세포 환경은 신경세포가 생존하기에는 불리한 심각한 상태이다. 단백질 응집 및 신경세포 손실을 초기에 검출할 수 있는, 신뢰성이 있는 방법이 부족하기 때문에 이러한 변성적 질병은 신경세포가 이미 손실되었기 때문에 치료법이 효과가 없거나 불필요한 시점까지 조정되지 않을 정도로(unmonitored) 발전할 수 있는 것이다. 추가로, 초기에 검출할 수 있는, 신뢰성 이 있는 방법이 이용가능하지만, 현 요법은 이러한 변성적 질병을 장기간 치료하는데는 효과가 없고, 신규한 약물 및 치료 방법이 필요하다.
심각하게 신경세포가 파괴되기 이전의 초기 단계에 상기 질환을 진단하고, 약물 디자인 및 개발을 위한 모델 시스템을 제공하기 위해 개선된 방법을 개발하기 위해서는 비정상적인 단백질 응집에 대한 분자 기전 및 단백질 조절인자를 이해하여야 한다. 단백질 응집과 관련된 특정 유전자 및 유전자 산물을 표적하는 화합물은 모델 시스템에 대해 선별되고, 모델 시스템를 사용하여 개발될 수 있다. 또한, 비정상적인 단백질 미스폴딩 및 응집의 근본적인 원인에 대한 보다 효과적인 치료법이 개발될 수 있을 때까지는 신경변성 기전을 이해하고, 신경세포 손실을 예방하거나 감쇠시킬 수 있는 신경보호 화합물을 개발하는 것이 필요하다.
발명의 요약
본 발명은 신경세포 기능장애, 신경변성 또는 단백질 미스폴딩 및 그 후의 응집을 특징으로 하는 신경계 질환을 진단 및 치료하는 방법에서 사용하기 위한, 폴리뉴클레오티드 분자 및 상기 분자에 의해 코딩된 단백질을 사용하는 신규한 방법에 관한 것이다. 특히, 응집되기 쉬운 단백질의 미스폴딩 및 그 후의 응집에 영향을 주고, 단백질 응집과 관련된 신경계 질병의 진단 및 치료와 관련성을 갖는 다수의 유전자가 본 원에 기술된다. 본 원에 기술된 유전자는 RNAi 선별에서 넉다운되었을 때, 특히, 알파-시뉴클레인의 단백질 미스폴딩 및 응집을 증가시킨다. 이러한 과정과 관련된 유전자에 대한 지식은 진단 선별 방법, 돌연변이 분석법을 개발하는데 효과적인 수단과, 파킨슨병과 같은 신경계 질병을 치료하기 위한 신규의 치료학적 및 신경보호성 화합물 개발을 위한 약물 디자인 정보를 제공한다. 이러한 방법은 단백질 미스폴딩을 감소시키거나 방지하거나, 신경보호를 제공하기 위해 다수의 단백질의 활성을 조절하는 것을 포함한다. 이는 유비퀴틴-프로테아좀 분해 시스템 단백질, 자가포식(autophagy) 단백질, 분자 샤페론, 전사 인자, 소낭 수송(trafficking) 단백질, Mn2 +/Fe2 + 수송체, HSPC117 단백질, 아세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질을 포함한다.
따라서, 본 발명의 목적은 단백질 미스폴딩 및 응집과 관련된 신경계 질환을 검출하고 치료하는 방법 및 그를 위한 조성물을 제공하는 것이다.
특히, 알파-시뉴클레인 미스폴딩 및 응집에 기인한 파킨슨병 또는 파킨슨 질환을 검출하고 치료하는 방법 및 그를 위한 조성물을 제공하는 것이 본 발명의 또다른 목적이다.
단백질 미스폴딩 및 응집과 관련된 유전자의 발현 수준에서의 변화, 또는 상기 유전자에서 하나 이상의 돌연변이를 특징으로 하는, 신경변성 질환이 인간에 존재하는지 여부를 검출하는 방법을 제공하는 것이 본 발명의 또다른 목적이다.
포유동물에서의 명백한 임상적 증상으로서 유전자의 신경해부학적 발현과 일치하는 증상을 일으키는 특정 표현형을 부여하는데 관여하는 다른 신경세포 유전자에서의 돌연변이 또는 다형성을 검출하는 방법을 제공하는 것이 본 발명의 또다른 목적이다.
인간에서 단백질 미스폴딩 및 응집과 관련된 신경계 질환을 진단하는 방법을 제공하는 것이 본 발명의 또다른 목적이다. 바람직하게, 인간에서의 상기 질환의 존재 또는 부재를 검출하는 방법; 상기 질환이 발생할 수 있는 가능성 또는 발생할 수 있는 소인을 예측하는 방법이 본 원에서 제공된다.
신경세포 질병에 대한 감수성을 증가시키는 단백질 응집과 관련된 신경세포 유전자에서의 돌연변이 또는 다형성을 동정하는 방법을 제공하는 것이 본 발명의 또다른 목적이다.
본 화합물의 존재하에서 단백질 미스폴딩 및 응집의 양과, 본 화합물의 부재하에서 단백질 미스폴딩 및 응집의 양을 비교함으로써 단백질 미스폴딩 및 응집을 감소, 저해, 호전 또는 예방하는 화합물을 선별하는 방법을 제공하는 것이 본 발명의 또다른 목적이다.
본 화합물의 존재하에서 신경변성의 양과, 본 화합물의 부재하에서 신경변성의 양을 비교함으로써 신경변성을 감소, 저해, 호전 또는 예방하는 화합물을 선별하는 방법을 제공하는 것이 본 발명의 또다른 목적이다.
단백질 응집을 촉진시키는 상태에 대하여 감수성인 신경세포에 신경보호를 제공하는 치료학적 화합물 또는 단백질 미스폴딩 및 응집을 방지하거나 감쇠시키는 화합물 또는 단백질 응집체를 가용화시키는 화합물을 디자인하고 개발하는 방법을 제공하는 것이 본 발명의 또다른 목적이다.
단백질 응집의 결과로서의 세포 기능이상을 감소, 정지, 완화, 호전 또는 예방하는 방법을 제공하는 것이 본 발명의 또다른 목적이다.
치료를 필요로 하는 동물에서 단백질 미스폴딩 및 응집을 감소시키거나 신경보호를 제공하는, 유효량의 조성물로 약제학적 제형을 제공하는 것이 본 발명의 또다른 목적이다.
본 발명은 또한 단백질 응집을 촉진시키는 상태에 대하여 감수성인 신경세포에 신경보호를 제공하기 위해 폴리뉴클레오티드 분자 및 그에 의해 코딩된 폴리펩티드를 사용하는 방법에 관한 것이다.
단백질 미스폴딩 및 응집과 관련된 신경계 질병을 치료하기 위한 의약을 제조하는 방법을 제공하는 것이 본 발명의 또다른 목적이다.
신경계 질환을 치료하는 신규한 요법을 선별하는데 사용하기 위한 트랜스제닉 동물을 제공하는 것이 본 발명의 또다른 목적이다.
인간으로부터 수득한 샘플중 유전자의 돌연변이를 검출하기 위한 하나 이상의 시약을 포함하는, 인간에서의 신경변성 질환의 존재 또는 부재를 진단하기 위한 키트를 제공하는 것이 본 발명의 또다른 목적이다.
개시한 실시태양 및 첨부되는 청구의 범위에 대한 하기의 상세한 설명을 리뷰한 후에 본 발명의 이러한 목적 및 다른 목적, 특성 및 잇점은 자명하게 될 것이다.
도 1a는 양성 후보에 대한 알파-시뉴클레인::GFP + TOR-2 트랜스제닉 선충류 의 선별 결과를 나타내는 다이어그램을 제공한다.
도 1b는 알파-시뉴클레인::GFP + TOR-2 트랜스제닉 선충류의 1차 선별로부터의 양성 후보의 분포를 나타내는 다이어그램을 제공한다.
도 2a는 DJ-1과 PINK1의 공-발현에 관한 마이크로어레이 실험으로부터 동정된 후보의 중복을 나타내는 다이어그램을 제공한다.
도 2b는, 선별로부터 이들 유전자들의 표 I의 작용상의 분포에 나열되어 있는 17개의 후보가 그들 분류에 있어 현저한 중복이 존재함을 입증한다는 것을 나타내는 다이어그램을 제공한다.
도 3a은 노화되는 만큼 시간이 경과함에 따라 6-OHDA 노출 후, 도파민성 신경세포에서 C. 엘레간스 M7.5 단백질 발현이 신경보호에 미치는 효과를 나타내는 그래프를 제공한다.
도 3b는 6-OHDA에 의해 유도된 도파민성 신경세포의 신경변성에 대한 TOR-2 와 자가포식 단백질 M7.5 사이의 신경보호 특질 비교를 나타내는 그래프를 제공한다.
도 4는 인간 알파-시뉴클레인의 과발현에 의해 유도된 도파민성 신경세포 변성에 대한 TOR-2 및 자가포식 단백질 M7.5의 신경보호 능력을 나타내는 그래프를 제공한다.
본 발명의 상세한 설명
본 발명은 본 원에 포함된 특정 실시태양에 대한 하기의 상세한 설명을 참고 로 하여 더욱 용이하게 이해될 수 있다. 본 발명이 그의 특정 실시태양의 구체적인 설명을 참고로 하여 설명되지만, 그러한 상세한 설명이 본 발명의 범주를 제한하는 것으로서 간주시키고자 하는 것은 아니다. 본 원에서 언급된 참고 문헌은 그 전체가 본 원에서 참고로 인용된다.
신경세포는 특히 돌연변이체 또는 미스폴딩된 단백질의 독성 효과에 영향을 받기 쉽다. 원치않고, 잠재적으로 유해성인 단백질을 처리하는 정상적인 세포 기전에 대한 이해에 기초하여, 본 발명은 미스폴딩되거나 응집된 단백질이 신경세포에 미친 영향을 제거하는 특유의 방법 및 조성물을 제공한다. 돌연변이체 또는 미스폴딩된 단백질은 신경세포를 손상, 변성 또는 사멸시킬 수 있지만, 신경세포는 생존해 있되, 세포 과정이 손상되어 신경계 질병의 임상적 증상이 개시되는 신경세포 기능장애도 유발할 수 있다.
본 명세서 및 첨부되는 청구의 범위에서, 단수 형태 "하나의(a)," "하나의(an)," 및 "그(the)"는 문맥에서 달리 분명하게 언급되지 않으면 복수 형태를 포함한다.
하기 논의는 특히 인간 환자에 대한 것이지만, 본 교시는 또한 표 I의 단백질을 발현시키는 임의의 동물에 적용될 수 있음을 이해하여야 한다. 본 원에서 정의되는 바, 용어 "포유동물"은 단공류, 및 유대동물을 비롯한 임의의 척추동물을 언급한다. 포유동물 종의 일례로 영장류(예로서, 인간, 원숭이, 침팬지, 비비), 설치류(예로서, 래트, 마우스, 기니아 피그, 햄스터) 및 반추동물(예로서, 소, 말)을 포함한다.
본 발명의 범주에서 "치료"는 제한하는 것은 아니지만, 파킨슨병을 비롯한 신경변성 질병과 같이, 이상과 관련된 증상 또는 분자 이벤트를 감소, 저해, 호전 또는 예방하는 것을 포함한다. 바람직하게, 단백질 응집, 단백질 미스폴딩 및 응집의 결과로서의 세포 기능이상 및 응집 및 단백질-응집-관련 질병도 치료될 수 있다.
"신경계 질환"은 신경세포의 변성 및/또는 손실을 특징으로 하는 임상적 용태를 포함한다. 근위축성 측삭 경화증, 알츠하이머병, 파킨슨병, 프리온 질병, 전측두엽 치매, 폴리글루타민 확장증, 척수소뇌성 실조증, 척수 & 연수 근육위축, 해면뇌병증, 타우증, 헌팅톤병, 근육긴장이상 등이 상기 질환에 포함된다.
본 원에서 사용되는 바, 용어 "충(worm)"은 모델 유기체가 선충동물문(Phylum Nematoda)으로부터의 것인, 본 발명의 단백질 응집을 연구하기 위하여 사용되는 모델 시스템을 언급한다. 특정 선충류인 꼬마선충(Caenorhabditis elegan) 또는 C. 엘레간스(C. elegans)가 본 의미에 포함된다.
바람직한 폴딩은 단백질이 가능은 하지만 바람직하지 못한 입체형태의 배열로부터 하나의 특정 구조를 취할 것을 요한다. 폴리펩티드가 그의 적합한 구조를 채용하지 못한 것이 세포 작용 및 생육성에 대한 주된 위협이 된다. 미스폴딩된 단백질은 그 자체로, 및 그 스스로 독성일 수 있고, 매우 중증이거나 심지어는 치명적인 결과를 초래할 수 있는 응집체를 형성할 수 있다. 결과적으로, 정교한 시스템은 미스폴딩된 단백질의 유해 효과로부터 세포를 보호하도록 진화하였다.
본 발명의 범주내에서 "단백질"은 전장(full-length) 단백질, 동족체, 당화 가 변화된 단백질, 단백질 단편, 스플라이스 변이체, 작용상 등가인 변이체, 돌연변이체 및 야생형 단백질과 실질적으로 동일한 작용을 유지하고 있는 그의 보존적 치환체를 포함한다.
본 발명의 범주내에서 "단백질 응집"은 폴리펩티드중 하나가 탈용매화 상태가 되도록 하는 방식으로 적어도 2개의 폴리펩티드가 서로 접촉하고 있는 현상을 포함한다. 이는 또한 폴리펩티드 본래의 작용 또는 활성의 손실도 포함할 수 있다.
본 발명의 범주내에서 "단백질-응집-관련 질병"은 임의의 질병, 질환, 및/또는 고통, 신경변성 질환을 비롯한 단백질-응집-관련 질병을 포함한다.
본 발명에 포함되는, 기본적인 기법을 수행하기 위한 수단 및 방법과 정의를 포함하는 분자 생물학 표준 참고서를 참조한다. 예로서, 문헌[Sambrook et al., Molecular Cloning: A Laboratory Manual, Third Edition, Cold Spring Harbor Laboratory Press, New York (2001), Current Protocols in Molecular Biology, Ausebel et al (eds.), John Wiley & Sons, New York (2001)] 및 그 내부에 인용된 각종 참조 문헌을 참조한다.
본 발명은 단백질 미스폴딩/응집 및 신경보호와 관련된 단백질을 코딩하는 다수의 폴리뉴클레오티드를 제공한다. 몇몇 후보 유전자는 현재까지 공지된 바 없는 작용 또는 활성을 갖는 가상 단백질을 코딩한다. 그러나, 본 발명은, 이들 단백질의 적어도 하나의 공통 작용 또는 활성이 단백질 미스폴딩 및 응집의 방지라는 것을 입증한다. RNAi를 사용하여 이들 단백질의 활성을 감소시키는 것이 C. 엘레간스 모델에서 단백질 미스폴딩 및 알파-시뉴클레인 응집체를 초래한다. 발현 및/또 는 활성을 감소시키는, 이들 단백질 및 상기를 코딩하는 폴리뉴클레오티드의 변화 또한 단백질 미스폴딩 및 응집을 초래할 것이다.
이들 단백질중 몇몇은 도파민-함유 신경세포과 같은 신경세포에 신경보호를 제공한다. 따라서, 본 발명은 도파민 함유 신경세포의 신경보호를 위해 본 원에 기술된 폴리뉴클레오티드를 사용하는 것을 포함하는, 신경변성 질병에서 치료학적 개입을 위한 신규한 접근법을 제공하고; 그 자체로서, 본 발명은 파킨슨병의 치료법을 개발하기 위한 또다른 방법을 제공한다. 도파민성 신경세포에서 신경보호 특질을 부여하는 단백질을 코딩하는 유전자는 유전자 및 단백질 요법, 항체 요법을 개발하기 위하여 사용될 수 있고, 도파민성 신경세포에 신경보호를 제공하기 위한 신규한 약물에 대한 디자인 및 선별에서 사용될 수 있다. 유사하게, 이들 분자의 변화로 신경세포는 불리한 조건하에서는 손상되고 사멸하기 쉽다. 이들 유전자에 의해 코딩되는 단백질은 UPS 성분, 자가포식 기관(machinery)의 성분, 분자 샤페론, 전사 인자, 소낭 수송 단백질, Mn2 +/Fe2 + 수송체, HSPC117 단백질, 아세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질을 포함한다. 이들 단백질 목록은 표 I에 제공한다.
표 I:
| C. 엘레간스 ORF -식별자 | 예측되는 작용 | 인간 동족체 | E-값 |
| Y37A1B.13 (tor-2) | AAA+ 수퍼패밀리의 ATPase, 루이 소체의 성분(샤페론) | 토신 A, 조기 발병 근육긴장이상의 원인이 됨 | 2.4e-63 |
| F57B10.5 | 막 수송 단백질의 Emp24/gp25L/p24 패밀리 (소낭 수송) | CGI-109 단백질 | 2.7e-58 |
| R05D11.6 | 전사 인자 | 가상 단백질 MGC 13017 | 9.1e-05 |
| F16A11.2 | 비특징화된 보존 단백질 (HSPC 117 단백질) | 가상 단백질 HSPC 117 | 2e-207 |
| F26E4.11 | E3 유비퀴틴 리가아제 (UPS 단백질) | 자가 운동 인자 수용체, 이소폼 2 | 1.9e-39 |
| B0432.2 (DJ-1) | 작용은 알려지지 않음 (DJ-1 단백질) | PD-관련 단백질, DJ-1 | 1.3e-45 |
| EEED8.9 (PINK-1) | BRPK/PTEN-유도성 단백질 키나제, PD-관련 단백질 (PINK-1 단백질) | 스플라이스 이소폼 1; 세린/트레오닌 키나제 PINK1, 미토콘드리아 전구체 | 2.1e-53 |
| C35D10.2 | RGS-GAIP 상호작용 단백질 GIPC(자가포식 단백질) | RGS-19 상호작용 단백질 1 | 1.1e-49 |
| F11H8.1 (rfl-1) | NEDD8-활성화 복합체, 촉매 성분 UBA3 (UPS 단백질) | 유비퀴틴-활성화 효소 E1C | 5.3e-117 |
| T13A10.2 | 예측되는 E3 유비퀴틴 리가아제 (UPS 단백질) | 세부분으로 된(tripartite) 모티프 단백질 2 | 0.00012 |
| M7.5 | 유비퀴틴 활성화 E1 효소-양 단백질(자가포식 단백질) | E1-양 단백질 | 7.4e-87 |
| T08D2.4 | RING 핑거 모티프를 갖는 가상 단백질(E3 리가아제) (UPS 단백질) | 세부분으로 된 모티프 단백질 32 | 2.1e-06 |
| C24G6.5 (dnj-6) | 분자 샤페론(DnaJ 수퍼패밀리) (샤페론) | DnaJ 동족체 서브패밀리 A 구성원 2 | 1.9e-77 |
| T07F12.4 | 세린/트레오닌-단백질 키나제 (자가포식 단백질) | ULK2 단백질 | 4.3e-29 |
| F32A6.3 | 공포 어셈블리/분류 단백질 VPS41 (자가포식 단백질) | 공포 어셈블리 단백질 VPS41 동족체의 스플라이스 이소폼 1 | 73-82 |
| K11G12.4 (smf-1) | NRAMP 패밀리의 Mn2 + 및 Fe2 + 수송체(Mn/Fe 수송체) | 2가 금속 수송체 | 3e-148 |
| F48E3.7 (acr-22) | 아세틸콜린 수용체 서브유니트 | 신경세포 아세틸콜린 수용체 단백질, 알파 9 쇄 전구체 | 8e-50 |
본 발명과 관련하여, "단리된" 또는 "정제된"은 자연 환경으로부터 분리된 것으로서, 세포 추출물에서 종종 발견되는 다른 오염 단백질, 폴리뉴클레오티드 및 /또는 다른 생물학적 물질을 실질적으로 포함하지 않는다는 의미이다.
본 발명과 관련하여, "폴리뉴클레오티드"는 일반적으로 폴리리보뉴클레오티드 및 폴리데옥시리보뉴클레오티드를 의미하며, 변형되지 않은 RNA 또는 DNA, 또는 변형된 RNA 또는 DNA일 수 있다. 폴리뉴클레오티드 분자는 단백질 또는 비코딩 RNA 또는 DNA를 코딩하는 유전자 및 RNA를 포함할 수 있다.
표 I에 제시한 분자는 C. 엘레간스 오픈 리딩 프레임(ORF: open reading frame) 식별자의 명칭으로 열거되어 있지만, 본 발명을 단지 C. 엘레간스 서열로만 제한하여서는 안된다. 표 I에 열거된 분자의 다른 종의 동족체, 특히 인간 동족체가 본 발명에서의 사용을 위해 주시되고 있다. C. 엘레간스의 서열 및 상응하는 인간 유전자 및 단백질을 본 원에서 제공한다. 상응하는, C. 엘레간스 뉴클레오티드 및 단백질 서열 뿐만 아니라, 인간 뉴클레오티드 및 단백질 서열을 표 II에 나타낸다.
표
II
:
| C. 엘레간스 ORF -식별자 | 명칭 | 서열번호 | 서열 공급원 & 타입 |
| Y37A1B.13 | tor-2 | 1 | C. 엘레간스 뉴클레오티드 |
| tor-2 | 2 | C. 엘레간스 단백질 | |
| 토신 A | 3 | 인간 뉴클레오티드 | |
| 토신 A | 4 | 인간 단백질 | |
| F57B10.5 | 5 | C. 엘레간스 뉴클레오티드 | |
| 6 | C. 엘레간스 단백질 | ||
| CGI-109 | 7 | 인간 뉴클레오티드 | |
| CGI-109 | 8 | 인간 단백질 | |
| R05D11.6 | 9 | C. 엘레간스 뉴클레오티드 | |
| 10 | C. 엘레간스 단백질 | ||
| MCG13017 | 11 | 인간 뉴클레오티드 | |
| MCG13017 | 12 | 인간 단백질 | |
| F16A11.2 | 13 | C. 엘레간스 뉴클레오티드 | |
| 14 | C. 엘레간스 단백질 | ||
| HSPC 117 | 15 | 인간 뉴클레오티드 | |
| HSPC 117 | 16 | 인간 단백질 |
| F26E4.11 | 17 | C. 엘레간스 뉴클레오티드 | |
| 18 | C. 엘레간스 단백질 | ||
| 19 | 인간 뉴클레오티드 | ||
| 20 | 인간 단백질 | ||
| B0432.2 | 21 | C. 엘레간스 뉴클레오티드 | |
| 22 | C. 엘레간스 단백질 | ||
| DJ-1 | 23 | 인간 뉴클레오티드 | |
| DJ-1 | 24 | 인간 단백질 | |
| EEED8.9 | PINK-1 | 25 | C. 엘레간스 뉴클레오티드 |
| PINK-1 | 26 | C. 엘레간스 단백질 | |
| PINK-1 | 27 | 인간 뉴클레오티드 | |
| PINK-1 | 28 | 인간 단백질 | |
| C35D10.2 | 29 | C. 엘레간스 뉴클레오티드 | |
| 30 | C. 엘레간스 단백질 | ||
| RGS-19 | 31 | 인간 뉴클레오티드 | |
| RGS-19 | 32 | 인간 단백질 | |
| F11H8.1 | rfl-1 | 33 | C. 엘레간스 뉴클레오티드 |
| rfl-1 | 34 | C. 엘레간스 단백질 | |
| E1C | 35 | 인간 뉴클레오티드 | |
| E1C | 36 | 인간 단백질 | |
| T13A10.2 | 37 | C. 엘레간스 뉴클레오티드 | |
| 38 | C. 엘레간스 단백질 | ||
| 39 | 인간 뉴클레오티드 | ||
| 40 | 인간 단백질 | ||
| M7.5 | 41 | C. 엘레간스 뉴클레오티드 | |
| 42 | C. 엘레간스 단백질 | ||
| E1-양 | 43 | 인간 뉴클레오티드 | |
| E1-양 | 44 | 인간 단백질 | |
| T08D2.4 | 45 | C. 엘레간스 뉴클레오티드 | |
| 46 | C. 엘레간스 단백질 | ||
| 47 | 인간 뉴클레오티드 | ||
| 48 | 인간 단백질 | ||
| C24G6.5 | dnj-6 | 49 | C. 엘레간스 뉴클레오티드 |
| dnj-6 | 50 | C. 엘레간스 단백질 | |
| DnaJ | 51 | 인간 뉴클레오티드 | |
| DnaJ | 52 | 인간 단백질 | |
| T07F12.4 | 53 | C. 엘레간스 뉴클레오티드 | |
| 54 | C. 엘레간스 단백질 | ||
| ULK2 | 55 | 인간 뉴클레오티드 | |
| ULK2 | 56 | 인간 단백질 | |
| F32A6.3 | 57 | C. 엘레간스 뉴클레오티드 | |
| 58 | C. 엘레간스 단백질 | ||
| VPS41 | 59 | 인간 뉴클레오티드 | |
| VPS41 | 60 | 인간 단백질 | |
| K11G12.4 | smf-1 | 61 | C. 엘레간스 뉴클레오티드 |
| smf-1 | 62 | C. 엘레간스 단백질 | |
| 63 | 인간 뉴클레오티드 | ||
| 64 | 인간 단백질 | ||
| F48E3.7 | acr-22 | 65 | C. 엘레간스 뉴클레오티드 |
| acr-22 | 66 | C. 엘레간스 단백질 | |
| 67 | 인간 뉴클레오티드 | ||
| 68 | 인간 단백질 |
당업계의 숙련자는 인간 이외의 다른 유기체(예를 들어, 진핵세포; 더욱 특히, 포유류(바람직하게는, 고릴라, 붉은털 원숭이 및 침팬지), 설치류, 충(바람직하게는, C. 엘레간스), 곤충(바람직하게는, D. 멜라노가스터(D. melanogaster)), 조류, 어류, 효모 및 식물)도 상기 유전자를 포함할 것이라는 것을 인지할 것이다. 본 발명은, 제한하는 것은 아니지만, 표 I에 열거되어 있는 단백질을 코딩하는, 전술한 유기체로부터 단리된 핵산 분자를 포함한다.
다수의 이들 유전자에 대하여는 주목할 만하게 진화적으로 보존되고 있고, 이는 종간의 단백질에 대한 고도의 상동성을 입증한다. 예를 들면, 인간 HSPC117은 C. 엘레간스 F16A11.2 및, 또한, 노랑초파리(Drosophila melanogaster)(서열번호: 69 및 70), 다니오 레리오(Danio rerio)(서열번호: 71 및 72), 소(서열번호: 73 및 74), 마우스(서열번호: 75 및 76), 및 래트(서열번호: 77 및 78)의 유전자/단백질과 상동성이다. 이들 서열 모두의 e-값(e-value)은 본질적으로 0이며, 이는 상기 유전자가 진화를 통해서도 고도로 보존된다는 것을 입증하는 것이다. 구조상의 고도한 상동성을 고려해 볼 때, 이들 서열은 적절한 수준으로 발현될 경우, 신경변성, 단백질 미스폴딩 및 응집을 감소시키기 위한 동일한 작용을 가져야 한다.
본 발명의 단리된 핵산 분자는 또한 화학적으로 합성된 핵산 분자를 포함한다. 예를 들면, 유전자의 발현 산물을 코딩하는 뉴클레오티드 서열을 갖는 핵산 분자를 디자인할 수 있으며, 필요할 경우, 적절히 더 작은 단편으로 분할할 수 있다. 이어서, 핵산 분자에 상응하거나, 분할된 단편 각각에 상응하는 올리고머를 합성할 수 있다. 그러한 합성 올리고뉴클레오티드는 합성하여 제조하거나[Matteucci et al., 1981, J Am . Chem. Soc. 103:3185-3191], 자동화된 DNA 합성기를 사용하여 제조할 수 있다. 올리고뉴클레오티드를 합성적으로, 또는 클로닝하여 유도할 수 있다. 필요할 경우, 올리고뉴클레오티드의 5' 말단은 T4 폴리뉴클레오티드 키나제를 사용하여 인산화시킬 수 있다. 올리고뉴클레오티드의 5' 말단의 키나제 처리는, 예를 들면, 5' 말단에 방사성동위원소(대체로 32P)를 결합시켜 특정 올리고뉴클레오티드를 표지하는 방법을 제공한다. 이후, 올리고뉴클레오티드를 어닐링시키고, T4 리가아제 등으로 결찰시킬 수 있다.
추가로, 표 II의 서열로부터 생성된, 프라이머를 사용하여 폴리머라제 연쇄 반응(PCR)에 의해 제조된 DNA 서열도 본 발명은 본 발명에 유용하다. 올리고뉴클레오티드는 전형적으로 길이가 적어도 15개인 뉴클레오티드이다.
상응하는 방식으로 표 I에 열거한 단백질로부터 생성된 아미노산 서열 및 그의 용도도 본 발명에서 주시되고 있다.
핵산 서열과 관련하여 "본질적으로 ∼로 구성된"은, 이하 명세서 및 청구의 범위 중에 제3 염기 축퇴성과 관련된 바와 같은 뉴클레오티드의 치환을 의미할 목적으로 사용된 용어이다. 당업계의 숙련자라면 알 수 있는 바와 같이, 제3 염기 축퇴성으로 인하여 거의 모든 아미노산은 코딩 뉴클레오티드 서열 중에 하나 이상의 트리플릿 코돈에 의해 제시될 수 있다. 추가로, 소수의 염기쌍 변화가 코딩된 아미노산 서열의 변이(보존적 치환)를 초래할 수 있지만, 유전자 산물의 생물학적 활성 을 실질적으로 변화시킨다고는 예측되지 않는다. 따라서, 본 명세서에 개시된 바와 같이 단백질 또는 펩티드를 코딩하는 핵산 서열은 그 서열이 약간 변형될 수 있으며(예로서, 트리플릿 코돈에서의 뉴클레오티드 치환), 여전히 동일한 아미노산 서열의 각 유전자 산물을 코딩한다.
본 원에서 사용되는 바, 폴리뉴클레오티드 서열상의 "변화(alteration)"는 유전자의 넉아웃 또는 넉다운에 의해 유발되는 서열 발현 수준 차이, 예로서, 증가 또는 감소를 언급한다. 야생형 단백질에 의해 제공받는 적합한 단백질 폴딩 및 신경보호에 영향을 미치는 서열 그 자체의 차이도 포함한다. 그러한 변화는 폴리뉴클레오티드 분자 또는 단백질의 발현, 돌연변이, 절단 및 결실상의 증가 또는 감소를 포함한다. 결과적으로, 유비퀴틴-프로테아좀 분해 시스템 단백질, 자가포식 단백질, 분자 샤페론, 전사 인자, 소낭 수송 단백질, Mn2 +/Fe2 + 수송체, HSPC117 단백질, 아세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질 또는 그의 단편을 코딩하는 폴리뉴클레오티드 분자와 혼성화하는 DNA 서열이 본 발명을 구성한다.
당업계의 숙련자는 혼성화로 DNA 서열을 동정하는 방법을, 특히 베링거 만하임 게엠베하(독일 만하임 소재, 1993)의 안내서 [The DIG System Users Guide for Filter Hybridization] 및 [International Journal of Systematic Bacteriology 41: 255-260 (1991)](Liebl et al.,)에서 찾을 수 있다. 혼성화는 엄격한 조건, 즉 프로브 및 표적 서열, 즉, 프로브로 처리된 폴리뉴클레오티드가 70% 이상 일치하는 하나의 혼성이 형성되는 조건하에 실시한다. 세척 단계를 비롯하여 혼성화의 엄격 도(stringency)는 완충액 조성, 온도 및 염 농도를 다양하게 하여 영향을 주거나 결정한다. 혼성화 반응은 세척 단계와 비교하여 비교적 낮은 엄격도 하에서 수행하는 것이 바람직하다[Hybaid Hybridisation Guide, Hybaid Limited, Teddington, UK, 1996].
예를 들면, 약 50℃-68℃의 온도에서 5 x SSC 완충액을 혼성화 반응에 사용할 수 있다. 프로브를, 프로브의 서열과의 일치성이 70% 미만인 폴리뉴클레오티드와 혼성화시킬 수 있다. 그러한 하이브리드는 안정성이 보다 작고, 엄격한 조건하에서 세척함으로써 제거된다. 예를 들면, 염 농도를 2 x SSC로 낮추고, 임의로 그 후 0.5 x SSC로 낮추어 실행될 수 있으며[The DIG System User's Guide for Filter Hybridisation, Boehringer Mannheim, Mannheim, Germany, 1995], 온도는 약 50℃-68℃로 정해진다. 임의로 염 농도를 0.1 x SSC로 낮출 수 있다. 예를 들면, 사용된 프로브의 서열과 적어도 70%, 또는 적어도 80%, 또는 적어도 90% 내지 95% 일치하는 폴리뉴클레오티드 단편은 대략 1℃-2℃씩 50℃에서 68℃로 단계적으로 혼성화 온도를 증가시켜 단리시킬 수 있다. 혼성화에 대한 추가의 설명은 소위 키트의 형태로 시장에서 입수할 수 있다(예로서, DIG Easy Hyb, 독일 만하임의 Roche Diagnostics GmbH, 카탈로그 번호 1603558).
"돌연변이"는 딸세포에게 전달되고, 가능하게는 그 후속 세대에게 전달되어 돌연변이체 세포 또는 돌연변이체 개체를 유발할 수 있는 유전 물질의 임의의 검출가능한 변화이다. 돌연변이는 화학적 또는 물리적 구성, 돌연변이능, 복제, 표현형 작용 또는 하나 이상의 데옥시리보뉴클레오티드의 재조합에 영향을 주는 임의의 검 출가능한, 비자연적인 변화(또는 이의 조합)일 수 있으며; 뉴클레오티드는 삽입, 결실, 치환, 역전, 또는 역전의 유무 하에 새로운 위치로 전좌될 수 있다. 본 명세서에서 사용된 용어 "돌연변이"는 또한 본 원에 기술된 단백질중 하나를 코딩하는 핵산 서열의 임의의 변형을 의미할 수 있다. 예를 들면, 돌연변이는 점 돌연변이 또는 하나 이상의 뉴클레오티드의 첨가, 결실, 삽입 및/또는 치환, 또는 그의 임의의 조합일 수 있다. 변형은 미스센스(missense) 또는 프레임쉬프트(frameshift) 돌연변이일 수 있다. 돌연변이는, 예를 들면, 보존되거나 비보존된 돌연변이, 천연 또는 비천연 돌연변이일 수 있다. 또한, 단백질의 N 및/또는 C 말단에 대한 변화는 그 기능을 실질적으로 손상시킬 수 없거나, 심지어 그 기능을 안정화시킬 수 있다고 공지되어 있다. 이러한 정황에 대한 정보는 전문가들이, 특히, ([Journal of Bacteriology 169:751-757 (1987)](Ben-Bassat et al.,), [Gene 77:237-251 (1989)](O'Regan et al.,), [Protein Sciences 3:240-247 (1994)](Sahin-Toth et al.,), [Bio/Technology 6:1321-1325 (1988)](Hochuli et al.,)) 및 공지된 유전학 및 분자 생물학의 교과서에서 동정할 수 있다. 표 II에 열거된 폴리뉴클레오티드 분자에 상응하는 폴리뉴클레오티드 분자 또는 그의 단편과의 혼성화에 의해 돌연변이는 단리될 수 있다.
본 발명은 또한 다수의 폴리펩티드 분자, 예로서, 단백질 미스폴딩 예방에 관한 단백질을 사용하는 방법, 및 그의 사용법에 주시하고 있다. 단백질은 표 I에 기재되어 있고, 아미노산 서열은 표 II에 열거되어 있다. 이들 단백질은 바람직하게 오염 단백질, 폴리뉴클레오티드 또는 다른 오염 화합물을 포함하지 않는, 실질 적으로 순수한 상태로 정제되거나 단리된다.
본 원에서 사용되는 바, 단백질상의 "변화"는 야생형 단백질에 의해 제공받는 바와 같이 적합한 단백질 폴딩에 도움을 주고 신경보호를 제공하는 단백질의 능력상의 변화를 언급한다. 예를 들면, 그러한 변화로는, 단백질의 활성을 변화시키는 다른 변화도 주시되고 있지만, 단백질 발현, 단백질 서열상의 돌연변이, 및 다르게는 스플라이싱된 형태를 포함할 수 있다.
또다른 실시태양에서, 폴리펩티드는 표 II에 기술한 아미노산 서열 또는 그의 돌연변이체 또는 종 변이체; 또는 적어도 70%의 일치성, 추가로 적어도 80%의 일치성, 또는/및 심지어 적어도 90%의 일치성(바람직하게, 적어도 90%, 95%, 96%, 97%, 98%, 또는 99%의 일치성 또는 적어도 95%, 96%, 97%, 98%, 또는 99%의 유사성), 또는 적어도 6개의 인접 아미노산(바람직하게는, 적어도 10, 15, 20, 25, 또는 50개의 인접 아미노산)을 갖는다.
본 발명의 단백질은 당화된 형태 및 비당화된 형태로 제공될 수 있다. 당화된 단백질 또는 그의 단편의 제조 방법은 당업계에 공지되어 있으며, 전형적으로는 진핵 세포중 펩티드를 코딩하는 재조합 DNA의 발현을 포함한다. 유사하게, 비당화된 펩티드를 수득하기 위해서 원핵(예, 박테리아) 세포내에 펩티드를 코딩하는 재조합 DNA를 발현시키는 방법이 당업계에 공지되어 있다. 당단백질 상의 당질 부분을 변화시키는 이러한 방법 및 다른 방법은 [Essentials of Glycobiology (1999), Edited By Ajit Varki, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.](그의 내용은 본 원에서 참고로 인용된다)에 개시되어 있다.
표 I에 열거된 단백질에 대한 폴리펩티드 서열을 본질적으로 구성하는 폴리펩티드 분자 또한 주시되고 있다.
본 발명의 단백질은 하나 이상의 보호된 아미노산 잔기를 포함할 수 있다. 보호된 아미노산은 공지된 방법에 의해 보호기 또는 보호기들로 보호된 작용기 또는 작용기들을 갖는 아미노산이며, 다양한 보호된 아미노산은 상업적으로 구입가능하다. 단백질 또는 그의 단편은 또한 하나 이상의 변형된 아미노산을 포함할 수 있다. 그러한 아미노산에 대한 목록은 미국 특허 공개번호 2003/0235823(그의 내용은 본 원에서 참고로 인용된다)에서 찾아볼 수 있다.
아미노산 서열 변이의 도입 부위는 미리 정해져 있지만, 돌연변이 그 자체를 미리 정할 필요는 없다. 예를 들면, 원하는 활성에 대해 특정 폴리펩티드의 성능을 최적화하기 위해서, 폴리펩티드의 표적 코돈 또는 영역에 무작위 돌연변이 유발을 수행할 수 있으며, 발현된 변이체를 원하는 최적 활성에 대해 선별할 수 있다. 공지된 서열을 갖는 DNA내의 소정 부위에서 치환 돌연변이를 형성시키는 방법, 예로서, 위치 특이적 돌연변이유발법이 공지되어 있다.
아미노산 서열 결실은 일반적으로 범위가 약 1 내지 30개의 잔기, 더욱 바람직하게는, 1 내지 10개의 잔기이다. 아미노산 서열 삽입은 하나의 또는 다수의 아미노산 잔기의 서열내 삽입 뿐만 아니라, 하나의 잔기 내지 실질적으로 비제한된 길이의 폴리펩티드의 아미노 및/또는 카르복실 말단 융합을 포함한다. 서열내 삽입(즉, 완전 단백질 서열내의 삽입)은 일반적으로 범위가 약 1 내지 10개의 잔기, 더욱 바람직하게는 1 내지 5개의 잔기일 수 있다.
제3 군의 변이체는 폴리펩티드 분자에서의 적어도 하나의 아미노산 잔기, 및 바람직하게는 오직 하나의 잔기가 제거되고, 그 위치에 상이한 잔기가 삽입된 것이다.
작용상 또는 면역학적 아이덴티티의 실질적인 변화는 덜 보존적인 치환을 선택하여, 즉 a) 치환 영역에서의 폴리펩티드 백본의 구조, 예로서, 병풍형 또는 나선형 입체형태, b) 표적 부위에서의 분자의 전하 또는 소수성, 또는 c) 측쇄의 벌크를 유지하는데 있어서의 영향이 유의적으로 상이한 잔기를 선택하여 만든다. 보존적 치환은 치환 아미노산(자연발생된 것 또는 변형된 것)이 구조적으로는 치환되는 아미노산과 관련성을 갖는, 즉, 치환되는 아미노산과 동일한 크기 및 전기적 성질이 거의 동일한 크기 및 성질을 갖는 치환이다. 따라서, 치환 아미노산은 원래의 아미노산과 동일하거나 유사한 작용기를 가질 것이다. 작용상 유사한 아미노산을 제공하는 보존적 치환표는 당업계에 잘 공지되어 있다. 하기 6개의 군은 각각 서로서로에 대하여 보조적 치환체인 아미노산을 포함한다:
1) 알라닌(A), 세린(S), 트레오닌(T);
2) 아스파르트산(D), 글루탐산(E);
3) 아스파라긴(N), 글루타민(Q);
4) 아르기닌(R), 리신(K);
5) 이소류신(I), 류신(L), 메티오닌(M), 발린(V); 및
6) 페닐알라닌(F), 티로신(Y), 트립토판(W).
추가의 치환으로는
a) 글리신 및/또는 프롤린이 또다른 아미노산으로 치환되거나, 결실 또는 삽입된 것;
b) 친수성 잔기, 예로서, 세릴 또는 트레오닐이 소수성 잔기, 예로서, 류실, 이소류실, 페닐알라닐, 발릴 또는 알라닐 대신에 치환된 것;
c) 시스테인 잔기가 임의의 다른 잔기 대신에 치환된 것;
d) 양전하 측쇄를 갖는 잔기, 예로서, 리실, 아르기닐, 또는 히스티딜이 음전하를 갖는 잔기, 예로서, 글루타밀 또는 아스파틸 대신에 치환된 것; 또는
e) 벌크가 큰 측쇄를 갖는 잔기, 즉 페닐알라닌이 측쇄를 갖지 않는 잔기, 예로서, 글리신 대신에 치환된 것을 포함할 수 있다.
일부 결실, 삽입 및 치환은 단백질의 특징적인 라디칼 변화를 생성할 것으로 예상되지 않는다. 당업계의 숙련자는, 치환의 효과가 본 원에 개시된 모델과 같은 동물 모델 뿐만 아니라, 생화학물질 및 생체내 선별 분석법을 사용함으로써 통상적으로 평가될 수 있다는 것을 이해할 것이다.
하나의 실시태양에서, 본 발명은 항체 반응을 유도하기 위하여 표 I에 기술된 단백질의 에피토프를 사용하는 방법에 관한 것이다. 항원성 에피토프 단편을 선택하는 방법은 당업계에 잘 공지되어 있다[Sutcliffe et al., 1983, Science. 219:660-666]. 본 발명의 항원성 에피토프-보유 펩티드 및 폴리펩티드는 폴리펩티드를 특이적으로 인식하는 면역 반응을 일으키는 데 유용하다. 본 발명의 항원성 에피토프-보유 펩티드 및 폴리펩티드는 단백질의 적어도 4개의 아미노산(바람직하게, 6, 7, 9, 10, 12, 15 또는 20개의 아미노산)을 포함한다. 표 I에 열거된 단백 질의 아미노산 서열 변이체는 DNA의 돌연변이로 제조할 수 있다. 그러한 변이체의 예로는 표 II에 제시된 아미노산 서열내의 잔기로부터의 결실, 또는 삽입 또는 그의 치환을 포함할 수 있다. 결실, 삽입 및 치환의 임의의 조합으로 최종 작제물을 얻을 수 있되, 단, 최종 작제물은 원하는 활성을 보유해야 한다. 하나의 실시태양에서, 본 단백질의 야생형 또는 변화된 형태에 상응하는 폴리펩티드 서열에 특이적인 항체를 제조하기 위하여 본 원에 기술된 단백질은 사용된다. 항체는 또한 프로브로서, 또는 예방요법 또는 치료요법을 위해 사용될 수 있다.
본 발명은 미스폴딩과 관련된 단백질 및 단백질 응집을 선별하는 방법을 제공한다. 예를 들면, 표 I에 열거된 서열은, 인간 알파-시뉴클레인::GFP 융합 단백질을 과발현시키는 트랜즈제닉 선충류 계를 사용한 RNAi 라이브러리의 선별로부터 유래되었다. 다른 리포토 분자, 예로서, GFP, RFP, BFP, YFP 및 루시퍼라아제가 또한 알파-시뉴클레인과 함께 융합 단백질로서 발현될 수 있다. 다른 신경계 질병에 대한 단백질 미스폴딩 및 응집을 연구하기 위하여 기타의 응집되기 쉬운 단백질이 상기 방식으로 과발현될 수 있고, 그러한 예로서, 제한하는 것은 아니지만, 알츠하이머병에서 타우(tau) 및 베타-아밀로이드 단백질, 헌팅톤병에서 돌연변이체-헌팅톤, 근위축성 측삭 경화증에서 SOD1 및 신경미세섬유, 및 척수 및 연수 근육위축에서 돌연변이체 안드로겐 수용체가 있다. 특별히 파킨슨병과 관련하여, 알파-시뉴클레인의 과발현으로, 선충류 C. 엘레간스에서 형광 현미경으로 검출가능한 가시적인 알파-시뉴클레인 응집체가 형성된다. unc-54 프로모터의 조절하에서 유전자 발현은 용이한 가시화를 위해 체벽에서 발현되도록 한다. TOR-2는 알파-시뉴클레인를 과발 현시키는 C. 엘레간스에서 단백질 응집을 감소시키는 것으로 나타난 단백질이다. 알파-시뉴클레인::GFP +TOR-2를 함유하는 트랜스제닉 충 계(worm line)는 미스폴딩 및 단백질 응집과 관련된 후보 유전자의 RNAi 선별을 위해 사용될 수 있다. TOR-2에 의한, 미스폴딩 및 단백질 응집의 유사한 억제는 폴리글루타민-의존 단백질 응집에 대하여 앞서 보고된 바 있다[Caldwell et al. Hum Mol Genet. 2003 Feb 1;12(3):307-19]. 이러한 트랜스제닉 유기체는 유전자 발현의 알파-시뉴클레인 응집 RNAi 넉다운에서 재발을 유발하는 유전자를 찾기 위해 알파-시뉴클레인::GFP + TOR-2를 함유하는 충의 체벽 근육에 공급함으로써 RNAi를 사용하는 신속한 선별 방법을 제공한다. C. 엘레간스 유전자 라이브러리는 재현가능한 결과로 알파-시뉴클레인의 응집에 유전자 넉다운이 미치는 효과를 측정하기 위해 RNAi를 사용하는 통상의 실험법을 사용하여 선별될 수 있다. 일반적으로, 단백질 응집과 관련된 것으로서 평가되는(score) 표적 유전자의 경우, 응집체 표현형은 분석되는 알파-시뉴클레인::GFP + TOR-2 유기체의 대략 80%에서 출현하게 된다. 상동성 서열은 NCBI BLAST 데이타베이스(NCBI, 메릴랜즈주 베데스다에 소재하는 National Library of Medicine, NIH)를 사용하여 결정될 수 있다.
또다른 실시태양에서, 본 발명의 유전자는 신경세포에 신경보호 특질을 부여하는 단백질을 코딩한다. 본 원의 교시에 따라, C. 엘레간스 유전자 라이브러리는후보 유전자가 신경세포를 보호하는지 여부를 측정하기 위하여 선별될 수 있다. 예를 들면, 신경독 6-OHDA로 처리로 인하여 C. 엘레간스 모델에서는 도파민성 신경세포가 손실된다. 선택 유전자의 과발현이 6-OHDA 처리로 인하여 유발된 도파민성 신 경세포 손실을 방지한다. 6-OHDA 처리는 활성 산소종을 형성함으로써 손상시키고 사멸시킨다. 그 자체로, 6-OHDA 처리는 활성 산소종 형성과 관련된 신경계 질병에 대한 신경보호를 분석하기 위하여 모델을 제공한다. 유사하게, 신경계 질병과 관련된, 응집되기 쉬운 단백질을 발현시키는 신경계 질병 모델이 생산될 수 있다. 예를 들면, C. 엘레간스는 그들이 노화되는 만큼 시간이 경과함에 따라 도파민성 신경세포의 손실을 나타내는 바, C. 엘레간스의 도파민성 신경세포에서 인간 알파-시뉴클레인의 과발현은 파킨슨병의 신경변성 측면을 반복한다[Cao et al, J Neurosci. 2005 Apr 13;25(15):3801-12]. 이와 관련하여, 트랜스제닉 충은 특정 화합물 및 유전자의 신경보호 작용을 동정시켜 주는 모델 시스템을 나타낸다.
표적 유전자를 과발현시키는 C. 엘레간스는 신경세포 특이 프로모터의 조절하에서 형광 단백질, 예로서, GFP, RFP, BFP, 루시퍼라아제 등을 발현시키는 트랜스제닉 충을 시작으로 제조된다. 신경세포 특이 프로모터는 당업계에서 통상 이용가능하며, 제한하는 것은 아니지만, 신경전달물질 합성 효소 및 신경전달물질 수송체의 발현을 조절하는 프로모터, 예로서, 티로신 수산화효소, 도파민 베타 수산화효소, 도파민 수송체, 세로토닌 수송체, 소낭 아세틸콜린 수송체 등을 포함한다.
또다른 실시태양에서, 본 발명은 엄격한 혼성화 및 세척 조건하에 핵산에 혼성화하는 전술된 핵산 분자 또는 적어도 그의 단편에 상응하는 DNA 또는 RNA 분자를 비롯한, 샘플중의 관련 핵산의 존재를 특이적으로 검출하기 위해 핵산 프로브를 사용하는 방법에 관한 것이다.
특정의 적용에 있어서, 본 원에 기술된 폴리뉴클레오티드 검출 방법은 신경 변성 질병과 관련된 단백질 미스폴딩 또는 응집의 존재 또는 그에 대한 성향을 지시하기 위하여 진단 분석법에 통합될 수 있다. 하나의 바람직한 실시태양에서, 본 발명은 RNA 또는 DNA 단편에 우선적으로 혼성화하는 10개 내지 1000개의 뉴클레오티드(바람직하게는, 10개 내지 500개, 10개 내지 100개, 10개 내지 50개, 10개 내지 35개, 20 내지 1000개, 20 내지 500개, 20 내지 100개, 20 내지 50개, 또는 20 내지 35개)로 구성된 단리된 핵산 프로브에 관한 것으로서, 상기 핵산 프로브는 표 II에 열거된 것으로부터의 폴리펩티드를 코딩하는 뉴클레오티드 서열; 상기 뉴클레오티드 서열중 임의의 것에 상보적인 뉴클레오티드 서열; 및 전술한 바와 같은 임의의 뉴클레오티드 서열중 하나 이상에 대해 적어도 90% 일치하는 폴리뉴클레오티드 서열을 포함하는 핵산 분자로부터의 적어도 10개의 연속 뉴클레오티드(바람직하게는, 15, 18, 20, 25 또는 30개)로 구성된 뉴클레오티드 서열이거나, 또는 이에 상보적이다.
본 발명의 혼성화 프로브는 검출하기 위해 방사성표지화, 형광 표지화, 바이오틴/아비딘 표지화, 화학발광 등과 같은 표준 표지화 방법에 의해 표지될 수 있다. 혼성화 후, 공지된 방법을 사용하여 프로브를 가시화할 수 있다.
또다른 실시태양에서, 본 발명은 혼성화가 일어나도록 하는 특정 혼성화 조건하에서 전술된 핵산 프로브와 샘플을 접촉시키고, 핵산 분자에 결합된 프로브의 존재를 검출함으로써 샘플내 핵산의 존재를 검출하는 방법에 관한 것이다. 당업계의 숙련자는 전술된 바와 같이 당업계에 공지된 방법에 따라 핵산 프로브를 선택할 수 있다. 시험하고자 하는 샘플은 제한하는 것은 아니지만, 인간 조직으로부터의 RNA 또는 DNA 샘플을 포함한다.
본 발명의 핵산 프로빙 방법에 적절한 시험 샘플은, 예로서, 세포 또는 세포의 핵산 추출물, 또는 생물학적 유체를 포함한다. 기술된 방법에 사용된 샘플은 분석 형식, 검출 방법과, 및 분석에 사용된 조직, 세포 또는 추출물의 특성에 따라 달라질 것이다. 세포의 핵산 추출물을 제조하는 방법은 당업계에 공지되어 있으며, 사용된 방법과 상용성인 샘플을 수득하기 위하여 용이하게 적합화될 수 있다.
미스폴딩/응집과 관련된 단백질 또는 신경보호를 제공하는 단백질상의 변화를 검출함으로써 신경계 질병을 진단하는 방법을 제공한다. 이러한 방법에서는 개체로부터의 조직 샘플을 유비퀴틴-프로테아좀 분해 시스템 단백질, 자가포식 단백질, 분자 샤페론, 전사 인자, 소낭 수송 단백질, Mn2 +/Fe2 + 수송체, HSPC117 단백질, 아세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질로부터 선택되는 단백질상의 변화에 대하여 분석하는데, 여기에서, 변화되었다는 것은 신경계 질병에 대한 소인, 또는 그의 존재를 지시하는 것이다. 본 원에서 사용되는 바, "조직"은 개체로부터의 생물학적 샘플을 언급한다. 그러한 샘플의 일례로, 제한하는 것은 아니지만, 세포 샘플, 개체 세포, 세포가 샘플내 존재하거나 존재하지 않을 수 있는, 혈액, 림프, 또는 타액과 같은 체액 샘플을 포함한다.
하나의 실시태양에서, 본 발명은 면역복합체를 형성하는 조건하에서 샘플을 전술된 항체(또는 단백질)와 접촉시키고; 폴리펩티드에 결합한 항체의 존재를 검출하는 단계를 포함하는, 샘플중 유비퀴틴-프로테아좀 분해 시스템 단백질, 자가포식 단백질, 분자 샤페론, 전사 인자, 소낭 수송 단백질, Mn2 +/Fe2 + 수송체, HSPC117 단백질, 아세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질로부터 선택되는 단백질을 검출하는 것을 포함한다. 특이적으로 결합하는 항체 또는 단백질은 검출가능한 표지에 접합화될 수 있다. 상세하게, 본 방법은 시험 샘플을 하나 이상의 본 발명의 항체와 함께 인큐베이션시키고, 항체가 시험 샘플과 결합하였는지를 여부를 분석하는 단계를 포함한다. 정상 수준과 비교하였을 때 샘플중 단백질의 수준 또는 활성 변화가 특정 질병을 지시할 수 있다.
추가의 실시태양에서, 본 발명은 면역복합체를 형성하는 조건하에서 샘플을 표 I로부터의 단백질과 접촉시키고, 항체 또는 단백질에 결합한 항체에 결합한 단백질의 존재를 검출하는 단계를 포함하는, 샘플중 표 I로부터의 단백질에 특이적인 항체를 검출하는 방법에 관한 것이다. 상세하게, 본 방법은 시험 샘플을 하나 이상의 본 발명의 단백질과 함께 인큐베이션시키고, 항체가 시험 샘플과 결합하였는지를 여부를 분석하는 단계를 포함한다.
항체와 시험 샘플을 인큐베이션하기 위한 조건은 다양하다. 인큐베이션 조건은 분석에 사용되는 포맷, 사용되는 검출 방법, 및 분석에 사용되는 항체의 유형 및 성질에 좌우된다. 당업계의 숙련자는 통상 이용가능한 면역학적 분석 포맷(예로서, 방사선 면역 분석법, 효소-결합 면역흡착 분석법, 확산 기초 오크터로니(Ouchterlony), 또는 로켓 면역 형광 분석법)중 임의의 하나가 본 발명의 항체를 사용하는데 용이하게 적합화될 수 있다는 것을 인식할 것이다([Chard, In: An Introduction to Radioimmunoassay and Related Techniques, Elsevier Science Publishers, Amsterdam, The Netherlands (1986)]; [Bullock, et al., In: Techniques in Immunocytochemistry, Academic Press, Orlando, Fla. Vol. 1(1982), Vol. 2(1983), Vol. 3(1985)]; [Tijssen, In: Practice and Theory of enzyme Immunoassays: Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers, Amsterdam, The Netherlands (1985)]).
본 발명의 면역학적 분석 시험 샘플은 세포, 단백질 또는 세포의 막 추출물, 또는 혈액, 혈청, 혈장, 또는 뇨와 같은 생체 유체를 포함한다. 전술한 방법에 사용되는 시험 샘플은 분석 포맷, 검출 방법의 성질 및 분석되는 샘플로서 사용되는 조직, 세포 또는 추출물에 따라 달라질 것이다. 세포의 단백질 추출물 또는 막 추출물을 제조하는 방법은 당업계에 잘 공지되어 있고, 사용되는 시스템과 더불어 가능한 샘플을 수득하기 위하여 용이하게 적합화될 수 있다.
청구된 발명은 응집하고 신경계 질병을 유발하는 단백질을 결정할 수 있는 수개의 적합한 분석법을 사용한다. 적합한 분석법은 면역학적 방법, 예로서, 방사선 면역 분석법, 효소-결합 면역흡수 분석법(ELISA: enzyme-linked immunosorbent assays), 및 화학발광 분석법 등을 포함한다.
수개의 바람직한 실시태양에서, 면역학적 기술은 단클론 및/또는 다클론 항체, 및 그들의 혼합물을 포함하는 항체 칵테일(즉, 하나 이상의 항체)을 수단으로 하여 표 I로부터의 단백질 수준을 검출한다. 예로서, 이러한 면역학적 기술은 다클론 및/또는 단클론 항체의 혼합물, 예로서, 뮤린의 단클론과 토끼의 다클론 칵테일 을 사용할 수 있다.
당업계의 숙련자는 적절한 면역원, 예로서, 단리된 단백질 및/또는 재조합 단백질 또는 그의 일부분 또는 단편(합성 펩티드와 같은 합성 분자 포함)에 대한 항체를 발생시킬 수 있다. 하나의 실시태양에서, 표 I의 목록으로부터의 단리된 단백질 및/또는 재조합 단백질 또는 일부분 또는 그의 단편(예로서, 펩티드)에 대한 항체 또는 이들 재조합 단백질을 발현시키는 숙주세포에 대한 항체가 발생한다. 게다가, 재조합 단백질을 발현시키는 세포, 예로서, 형질감염된 세포는, 면역원으로서 사용되거나, 단백질에 결합하는 항체의 선별에서 사용될 수 있다.
본 방법에 따라, 분석법은 생물학적 샘플중 단백질의 수준 또는 농도를 측정할 수 있다. 단백질의 양을 측정하는데 있어, 분석법은 항체와 단백질 사이에서 복합체가 형성되기 적합한 조건하에서 시험하고자 하는 샘플과, 단백질에 대한 특이성을 갖는 항체를 배합시키는 단계, 및 복합체의 형성을 (직접 또는 간접적으로) 검출하거나 측정하는 단계를 포함한다. 특정 샘플(예로서, 전혈, 조직 추출물, 혈청) 및 선택된 분석 포맷에 적합한 방법에 의해 샘플은 수득되고 제조될 수 있다. 예를 들면, 전혈 채혈에 적합한 방법은 정맥 천자이거나, 내재하는 정맥 라인으로부터 혈액을 얻는 것이다. 채혈용 용기는 CACD-A, 헤파린, 또는 EDTA와 같은 항-응고제를 함유할 수 있다. 샘플과 항체를 배합하는 방법, 및 복합체 형성을 검출하는 방법 또한 분석 포맷과 양립할 수 있는 것으로 선택된다. 적합한 표지는 방사선활성, 형광 또는 화학발광 표지와 같이 직접 검출될 수 있거나; 효소 표지, 및 바이오틴 및 콜로이드성 골드와 같이 다른 항원성 또는 특이적 결합 파트너와 같은 표 지를 사용하여 간접적으로 검출될 수 있다. 그러한 표지의 일례로 플루오레세인과 같은 형광 표지, 로다민, CY5, APC, 루시퍼라제와 같은 화학 발광 표지, 32P, 125I, 131I와 같은 방사성 동위원소 표지, 호오스 래디쉬 퍼옥시다제와 같은 효소 표지, 및 알칼리성 포스파타제, 베타-갈락토시다제, 바이오틴, 아비딘, 스핀 표지 등을 포함한다. 복합체중 항체의 검출은 또한 추후 검출되는 제2 항체를 사용하여 면역학적으로 수행될 수 있다. 종래의 방법 또는 다른 적합한 방법은 직접적으로 또는 간접적으로 항체를 표지한다.
또다른 실시태양에서, 표 I에 열거된 화합물은 인간에서 신경세포 질병을 유발하는 유전자 돌연변이의 존재, 또는 부재를 검출하는 것을 포함하는 진단 방법 및 선별 방법에 사용될 수 있다. 예를 들면, 본 발명의 진단 방법 및 선별 방법은, 가족력에 기초하여 표 I로부터의 단백질의 발현 수준의 변화과 관련된 질환의 발병의 위험이 있는 것으로 의심이 되는 인간 환자, 또는 이들 단백질과 관련된 질환을 진단하는 것이 바람직한 환자에 있어서 신경세포 유전자에서의 돌연변이 또는 다형성의 존재, 또는 부재를 진단하는데 특히 유용하다.
또다른 실시태양에서, 본 원에 기술된 폴리뉴클레오티드는 돌연변이체의 존재, 또는 야생형 서열, 또는 개체가 신경계 질환에 걸리기 쉽도록 하는 서열의 부재를 선별하기 위한 마이크로어레이로 개발될 수 있다. 마이크로어레이는 개체로부터의 조직 샘플중 유전자 발현에서의 변화를 검출하기 위하여 야생형 서열 또는 본 원에 기술된 변화된 서열을 포함할 수 있다. 본 어레이는 본 원에서 제공된 서열 모두, 또는 샘플중 상보적인 서열과 특이적으로 결합하는, 상기 서열의 단편 및 돌연변이체를 포함할 수 있다. 본 어레이는 또한 신경계 질환의 소인이 되는 야생형 유전자의 발현에서의 증가 또는 감소를 측정하거나, 신경계 질환의 존재를 지시하는데 사용될 수 있다. 어느 경우든 조직 샘플로부터 유래된 상보적인 서열이 검출될 수 있도록 하는 대표량으로 전체 서열을 어레이상에 제공한다. 어레이 또는 마이크로어레이의 폴리뉴클레오티드는 일반적으로 핵산, 예로서, DNA, RNA, PNA, 및 cDNA이지만, 단백질, 폴리펩티드, 올리고당, 세포, 조직, 및 표적 분자와 특이적으로 결합할 수 있는 상기의 임의의 치환체도 포함할 수 있다. 마이크로어레이상에서의 선별은 어레이상의 핵산 서열에 특이적인 검출가능한 표지를 사용하는 것을 포함한다. 예를 들면, 집적 마이크로어레이에 의해, 또는 아피메트릭스, 인코포레이티드(Affymetrix, Inc.)(캘리포니아주 산타 클라라에 소재)의 단편 DNA 마이크로어레이 기술을 사용하여, 제조사의 설명서(및 본질적으로는 ([Schena et al., Proc. Natl. Acad. Sci. USA 93:10614-10619, 1996] 및 [Heller et al., Proc. Natl. Acad. Sci. USA 94:2150-2155, 1997])에 기재된 것)에 따라 상기 선별을 실시할 수 있다. 유전자 발현 분석시 마이크로어레이의 용도는 일반적으로 ([Fritz et al Science 288:316, 2000; "Microarray Biochip Technology," L Shi, www.Gene-Chips.com]에서 리뷰된다. 마이크로어레이 분석법을 실시하기 위한 시스템 및 시약은 예로서, 캘리포니아주 산타 클라라에 소재하는 아피메트릭스, 인코포레이티드; 메릴랜드주 콜롬비아에 소재하는 진 로직, 인코포레이티드(Gene Logic Inc.); 캘리포니아주 서니밸리에 소재하는 하이세큐, 인코포레이티드(HySeq Inc.); 캘리포니아 주 서니밸리에 소재하는 몰레큘라 다이나믹스, 인코포레이티드(Molecular Dynamics Inc.); 캘리포니아주 샌디아고에 소재하는 나노겐(Nanogen); 및 캘리포니아주 프리몬트에 소재하는 신테니 인코포레이티드(Synteni Inc.)(캘리포니아주 팔로알토에 소재하는 Incyte Genomics에 의해 취득됨)와 같은 회사로부터 상업적으로 구입가능하다.
본 원에서 상호교환적으로 사용되는 바, "마이크로어레이" 및 "어레이"는 중앙집중화된 위치의 뉴클레오티드 서열 집합의 배열을 언급한다. 어레이는 표면, 예를 들면, 고체 기판, 예로서, 유리 슬라이드상에, 또는 반-고체 기판, 예로서, 니트로셀룰로오스 막상에 존재할 수 있다. 뉴클레오티드 서열은 DNA, RNA, 또는 임의의 그의 치환체일 수 있다. 당업계에 공지되어 있는 바, 마이크로어레이는 기판(표면)상의 규정된 위치에 고정되어 있는 상이한 폴리뉴클레오티드들 또는 올리고뉴클레오티드들의 어셈블리를 언급한다. 어레이는 종이, 유리, 플라스틱(예로서, 폴리프로필렌, 나일론), 폴리아크릴아미드, 니트로셀룰로오스, 실리콘, 광학 섬유, 폴리스티렌, 또는 임의의 다른 적합한 고체 또는 반-고체 지지체와 같은 물질로 제작된 기판상에 형성되고, 평면 형상(예로서, 유리 플레이트, 실리콘 칩) 또는 3차 구조(예로서, 핀, 섬유, 비드, 플라스틱, 마이크로티터 웰, 모세관)로 배열된다. 어레이를 형성하는 폴리뉴클레오티드들 또는 올리고뉴클레오티드는 (i) 포토리소그래피 기술을 사용한 계내 합성(예로서, 고밀도 올리고뉴클레오티드 어레이)([Fodor et al., Science (1991), 251:767-773]; [Pease et al., Proc. Natl. Acad. Sci. U.S.A. (1994), 91:5022-5026]; [Lockhart et al., Nature Biotechnology (1996), 14:1675]; 미국 특허번호 제 5,578,832호; 제5,556,752호; 및 제5,510,270호] 참조); (ii) 유리, 나일론 또는 니트로셀룰로오스상의 중밀도 내지 저밀도 (예로서, cDNA 프로브) 스폿팅/프린팅([Schena et al, Science (1995), 270:467-470, DeRisi et al, Nature Genetics (1996), 14:457-460]; [Shalon et al., Genome Res. (1996), 6:639-645]; 및 [Schena et al., Proc. Natl. Acad. Sci. U.S.A. (1995), 93:10539-11286] 참조); (iii) 차폐[Maskos and Southern, Nuc. Acids. Res. (1992), 20:1679-1684] 및 (iv) 나일론 또는 니트로셀룰로오스 혼성화 막상의 도트-블로팅(예로서, [Sambrook et al., Eds., 1989, Molecular Cloning: A Laboratory Manual, 2nd ed., Vol. 1-3, Cold Spring Harbor Laboratory (Cold Spring Harbor, N. Y.)] 참조)과 같은 임의의 다수의 방법에 의해 기판에 부착될 수 있다.
하나의 실시태양에서, 마이크로어레이는 신경계 질환을 진단하는 어레이의 제조에서 유비퀴틴-프로테아좀 분해 시스템 단백질, 자가포식 단백질, 분자 샤페론, 전사 인자, 소낭 수송 단백질, Mn/Fe 수송체, HSPC117 단백질, 아세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질로부터 선택되는 단백질과 관련된 서열을 포함한다.
또다른 실시태양에서, 본 발명은 표 I로부터의 단백질의 활성을 자극시키거나 감소시키는 화합물을 선별하는 방법에 관한 것이다. 이들 단백질은 또한 선별 분석법을 위해 시험관내에서 발현되고 정제될 수 있고, 단백질 미스폴딩/응집 및 신경독성에 대하여 동물 모델에서 발현될 수 있다. 무작위 선별의 경우, 펩티드, 당질, 약학적 시약 등과 같은 시약이 무작위로 선택되고, 단백질에 결합할 수 있거 나, 단백질의 활성을 자극/감소시킬 수 있는 그의 능력에 대하여 분석된다. 그러한 방법은 단백질을 발현시키는 세포를 시험하고자 하는 화합물과 함께 인큐베이션시키고; 화합물이 단백질의 ATP 결합에 미치는 효과를 측정함으로써 단백질의 활성에 대하여 세포를 분석하는 것을 포함한다. 임의의 세포가 단백질의 작용성 형태를 발현시키고, 단백질 활성이 측정될 수 있는 한, 임의의 세포가 상기 분석법에서 사용될 수 있다. 바람직한 발현 세포는 진핵 세포 또는 유기체이다. 그러한 세포는 당업계에 공지되어 있는 통상이 방법을 사용하여 단백질을 코딩하는 DNA 서열을 포함하도록 변형될 수 있다. 별법으로, 당업계의 숙련자는 단백질을 코딩하는 mRNA을 직접 세포내로 도입시킬 수 있다.
또다른 실시태양에서, 본 발명은 변화된 단백질의 발현 또는 비정상적인 활성을 중화시킬 수 있는 약제(예로서, 약물)에 대한 선별 방법에 관한 것이다. 바람직하게, 본 원에 기재된 벡터 기술을 사용하여 돌연변이체 형태의 단백질을 과발현시키기 위하여 신경세포 배양물이 사용된다. 신경세포 형태 및 단백질 분포상의 변화가 평가되고, 정량화 수단이 사용된다. 이어서, 이러한 바이오어레이가 표현형을 개선시킬 수 있는 약물에 대한 스크린으로써 사용된다. 표 I로부터의 단백질에 대한 리간드(전술한 바와 같은 길항제 및 효현제(agonist) 포함)를 사용하여, 본 발명은 추가로 세포에서 단백질을 활성을 조절하는 방법을 제공한다. 일반적으로, 단백질의 활성을 차단하거나 자극시키는 것으로 동정된 제제(길항제 및 효현제)는 제제화됨으로써, 상기 화합물은 생체내에서 단백질을 발현시키는 세포와 접촉하게 된다. 그러한 세포와 그러한 제제의 접촉을 통해 결과적으로는 단백질의 활성을 생체 내에서 조절할 수 있게 된다.
후보 화합물은 종래의 치료제 부류, 예로서, 소분자 화합물, 펩티드 화합물, 펩티드 모사체, 항체, 항체 단편, 항체 유도체, 뉴클레오티드 분자, 호르몬 등으로부터 선택될 수 있다.
하나의 실시태양에서, 후보 소분자 화합물은 토포아이소머라제 II 저해제, 세균성 칼슘 채널 차단제, 트랜스펩티다제 저해제, 사이클로옥시게나제 저해제, 엽산 합성 저해제 및 나트륨 채널 차단제를 포함할 수 있다. 이들 분자는 미국 가특허 출원 제60/738,761호 및 제60/749,910호(본 원에서 그의 전문이 참고로 인용된다)에 개시된 바와 같이 단백질 미스폴딩 및 응집을 방지하거나 신경보호를 제공한다.
하나의 실시태양에서, 토포아이소머라제 II 저해제는 제한하는 것은 아니지만, 로메플로사신, 시녹사신, 암사크린, 에토포시드, 테니포시드, 옥솔린산, 날리딕산, 수라민, 머바론, 제니스테인, 에피루비신 HCl, 엘립티신, 독소루비신, 또는 아우린트리카복실산(ATA: aurintricarboxylic acid)을 포함할 수 있다.
또다른 실시태양에서, 세균성 트랜스펩티다제 저해제는 제한하는 것은 아니지만, 암피실린, 클록사실린, 피페라실린, 아목시실린, 세파드록실, 디클로옥시아실린, 카르베니실린, 페니실린, 메탐피실린, 아목시실린 또는 세폭사틴을 포함할 수 있다.
또다른 실시태양에서, 칼슘 채널 차단제는, 제한하는 것은 아니지만, 니모디핀, 디프로테베린, 베라파밀, 니트렌디핀, 딜티아젬, 미오플라진, 로페라마이드, 플루나리진, 베프리딜, 리도플라진, CERM-196, R 58735, R-56865, 라놀라진, 니솔디핀, 니카르디핀, PN200-110, 펠로디핀, 암로디핀, R-(-)-202-791, 또는 R-(+) Bay K-8644를 포함할 수 있다.
또다른 실시태양에서, 사이클로옥시게나제 저해제는 제한하는 것은 아니지만, 나프록센, 플루페남산, 톨페남산, 펜부펜, 케토프로펜, 페나세틴, 다이피론, 플루르비프로펜, 메클로펜아미드, 피록시캠, 또는 인도메타신을 포함할 수 있다 .
또다른 실시태양에서, 엽산 합성 저해제는 제한하는 것은 아니지만, 설파메톡사졸, 설파다이아진, 설파독신, 답손, 트리메토프림, 디아베리딘, 피리메타민, 또는 메토트렉세이트를 포함할 수 있다.
또다른 실시태양에서, 나트륨 채널 차단제는 제한하는 것은 아니지만, 리도카인, 디클로닌 HCl, 멕실리틴, 페니토인, 케타민, 플레케나이드, 또는 아만타딘을 포함할 수 있다.
본 분석법으로 선별되는 다른 시약은 제한하는 것은 아니지만, 펩티드, 당질, 비타민 유도체, 또는 다른 약학적 제제일 수 있다. 이들 제재는 무작위로, 합리적인 선택에 의해 또는 예로서, 단백질 또는 리간드 모델링 기술(바람직하게는, 컴퓨터 모델링)을 사용하는 디자인에 의해 선택될 수 있으며 선별될 수 있다.
뉴클레오티드 서열 및 표 I에 기술된 단백질은 또한 내인성 분자에 대한 효현제, 길항제, 또는 결합 파트너로서 작용하는 신규의 화합물을 디자인하는데 사용될 수 있다. 본 원에 기술된 선별 방법에 의해 동정된 것으로서, 미스폴딩 및 단백질 응집에 영향을 미치는 활성 시험제는 유사 화합물 합성을 위한 선도 화합물로서 작용할 수 있다. 전형적으로, 유사 화합물은 선도 화합물의 것과 유사한 전자 배치 및 분자 입체형태를 갖도록 합성된다. 유사 화합물의 동정은 자체-일관성 장(SCF: self-consistent field) 분석법, 구성 상호작용(CI: configuration interaction) 분석법, 및 정상 양식 역학 분석법과 같은 기술을 사용하여 실시도리 수 있다. 이러한 기술을 실행시키는 컴퓨터 프로그램은 이용가능하다. 예로서, 문헌[Rein et al., (1989) Computer-Assisted Modeling of Receptor-Ligand Interactions (Alan Liss, New York)]을 참조한다.
일단 유사체가 제조되면, 이는 단백질 응집을 조절하는 능력이 증가된 유사체를 동정하기 위하여 본 원에 개시된 방법을 사용하여 선별될 수 있다. 이어서, 그러한 화합물은 약제로서 가장 큰 효능을 갖는 화합물을 동정하기 위하여 추가 분석될 수 있다. 별법으로, 선별 방법을 통해 활성을 갖는 것으로 나타난 유사체는, 본 원에 기술된 방법에 의해 선별될 수 있는 추가의 유사체 제조에서 선도 화합물로서 작용할 수 있다. 선별, 유사체 합성 및 재선별의 순환은 여러 차례에 걸쳐 반복될 수 있다.
별법으로, 제제는 합리적으로 선택될 수 있거나 디자인될 수 있다. 본 원에서 사용되는 바, 제제가 단백질의 구조에 근거하여 선택될 때, 그 제제는 "합리적으로 선택되거나 디자인된다"고 한다.
정량적 구조-활성 관계(QSAR: Quantitative Structure-Activity Relationship) 방법을 사용하여 화합물의 화학적 구조와 그의 생물학적 활성간의 관계를 정량화할 수 있다. 화합물 부류와 관련된 하나 이상의 구조와 관련성을 갖 는 하나 이상의 활성을 동정하는 구조-활성 관계(SAR: structure-activity relationship) 및/또는 정량적 구조-활성 관계(QSAR) 방법을 사용하여 광범위한 스펙트럼 효과에 대하여 각 화합물 부류를 정량화하거나 등급화할 수 있다. 이어서, 예로서, 합성가능성, 가요성, 특허성, 활성, 독성, 및/또는 대사와 같은 인자에 기초하여 이들 화합물 부류 각각을 우선 순위화할 수 있다. 이 경우, 각 특정 화합물 부류내의 모든 화합물 세트 또는 추가의 화합물 세트를 검정하고 분석할 수 있다. 몇몇 화합물 부류는 매우 클 수 있기 때문에, 상기 부류중의 상기 화합물의 서브세트가 검정되고 분석될 수 있고, 상기 부류가 계속적으로 소정 수준을 초과하여 효과를 입증할 경우에는 남은 구성원도 검정될 것이다. 이러한 접근법을 통해서는 또한 본 발명에서 사용하기 위한 화합물을 작용성의 유사체 및 화합물 부류를 동정하게 될 것이다. 이어서, 작용성의 유사체의 활성은 C. 엘레간스 모델을 사용하여 신경보호 및 단백질 미스폴딩 및 응집에 대한 작용에 대하여 선별함으로써 동정될 수 있다.
컴퓨터 모델링 기술을 통해 선택된 분자의 3차원 원자 구조를 가시화할 수 있고, 상기 분자와 상호작용할 수 있는 신규한 화합물을 합리적으로 디자인할 수 있다. 이러한 방법은 신경보호에 대한 작용 및 단백질 미스폴딩 및 응집에 대한 작용을 갖는 것으로 공지되어 있는 공지 소분자 화합물의 작용상의 유사체를 찾는 방법을 제공한다. 화합물이 표적 단백질에 결합하는 바, 화합물의 3차원 구조 분석은 상호작용 부위를 동정하게 될 것이며, 이어서, 상기 상호작용 부위는 유사하 결합 성질을 갖는 유사 화합물 및 작용상의 유사체를 동정하는데 사용된다. 3차원 구조 체는 전형적으로 선택된 분자의 x-선 결정학적 분석 또는 NMR 영상화로부터 얻은 데이타에 의존한다. 분자 역학은 역장 데이타를 필요로 한다. 컴퓨터 그래프 시스템은 신규한 화합물이 표적 분자에 연결되는 방법을 예측가능하게 하고, 화합물과 표적 분자가 완전한 결합 특이성을 갖도록 실험적으로 조작할 수 있게 한다. 분자 또는 화합물중 하나 또는 양자 모두에서 작은 변화가 존재할 때 분자-화합물간의 상호작용은 어떠한지를 예측하는 것은, 대체로 분자 디자인 프로그램과 사용자 간의 사용이 간편한 메뉴로 진행되는(menu-driven) 인터페이스로 연결된 분자 역학 소프트웨어 및 연산 집약적 컴퓨터를 필요로 한다.
분자 모델링 시스템의 일례는 매사추세츠주 월샘에 소재하는 폴리겐 코포레이션(Polygen Corporation)으로부터의 챰(CHARMm) 및 콴타(QUANTA) 프로그램이다. 챰은 에너지 최소화 및 분자 역학 작용을 수행한다. 콴타는 분자 구조의 구성, 그래픽 모델링 및 분석을 수행한다. 콴타는 상호작용 구성, 변경, 가시화, 및 분자간 서로의 행동 분석을 허용한다.
다수의 논문에 특이 단백질과 상호작용하는 약물의 컴퓨터 모델링에 대하여 리뷰되어 있다([Schneider and Fechner, Nat Rev Drug Discov. 2005 Aug;4(8):649-63]; [Guner, IDrugs. 2005 Jul;8(7):567-72]; 및 [Hanai, Curr Med Chem . 2005;12(5):501-25]). 화학물질을 선별하고 그래프로 도시하는 다른 컴퓨터 프로그램으로는 예로서, 캘리포니아주 패서디나에 소재하는 바이오디자인 인코포레이티드(BioDesign, Inc.), 및 온타리오주 케임브리지에 소재하는 하이퍼큐브 인코포레이티드(Hypercube, Inc.)로부터 이용가능하다. 주로 특정 단백질에 특이적인 약물 에 적용하기 위해 디자인되지만, 이는 일단 동정되면 DNA 또는 RNA의 영역에 특이적인 약물을 디자인하기 위하여 적합화될 수 있다. 결합을 변화시킬 수 있는 화합물의 디자인 및 생성과 관련하여 전술한 바 있지만, 저해제 또는 활성제인 화합물에 대하여 천연물 또는 합성 화학물질을 비롯한 공지 화합물, 및 단백질을 비롯한 생물학적으로 활성인 물질의 라이브러리를 선별할 수 있다. 이 접근법을 사용하여 동정된 화합물의 활성은 C. 엘레간스 모델을 사용하여 신경보호 및 단백질 미스폴딩 및 응집에 대한 작용에 대하여 선별함으로써 동정될 수 있다.
본 발명은 또한 예방적 및 치료적 적용을 위한 화합물의 선별에서 사용하기 위한 트랜스제닉 동물 모델을 제공한다. 본 발명의 트랜스제닉 동물은 비자연적인 수단(즉, 인간의 조작에 의해)에 의해, 동물에서 자연적으로 발생하지 않는 하나 이상의 유전자, 예로서, 외인성 유전자, 유전자적으로 조작된 내인성 유전자 등을 도입받은 동물이다. 비-자연적으로 도입되는 유전자, 트랜스진으로 알려진 것은 그 구조상 그리고/또는 트랜스진에 의해 수여된 염색체 좌위에서 동물에서 자연적으로 발견되지 않는 것으로서 그 동물과 동일하거나 상이한 종으로부터 유래할 수 있다.
트랜스진은 외인성 DNA 서열, 즉, 숙주 동물의 게놈에서 정상적으로 발견되지 않는 서열을 포함할 수 있다. 별법으로 또는 추가로, 트랜스진은, 그들이 유전자 발현의 생체내 정상 패턴을 바꾸기 위해, 또는 그 유전자에 의해 코딩되는 내인성 유전자의 생물학적 활성을 변경시키거나 제거하기 위하여 시험관내에서 재배열되었거나 돌연변이화되었다는 점에서 비정상적인 내인성 DNA 서열을 포함할 수 있다([Watson, J. D., et al., In: Recombinant DNA, 2d Ed., W. H. Freeman & Co., New York (1992), pg. 255-272]; [Gordon, J. W., 1989, Intl . Rev . Cytol. 115:171-229]; [Jaenisch, R., 1989, Science. 240:1468-1474]; [Rossant, J., 1990, Neuron. 2:323-334]). 이 모두 당업계의 통상의 숙련자에게 공지되어 있는 트랜스진은 전핵 주사, ES 세포 전달, 바이러스 통합 방법에 의해 트랜스진은 혼입될 수 있다.
본 발명에서 인간 이외의 동물은 트랜스진에 의한 중단 또는 내인성 유전자(들)의 변형을 갖는 임의의 동물(넉아웃 동물) 및/또는 그의 게놈내로 유비퀴틴- 프로테아좀 분해 시스템 단백질, 자가포식 단백질, 분자 샤페론, 전사 인자, 소낭 수송 단백질, Mn/Fe 수송체, HSPC117 단백질, 아세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질로부터 선택되는 단백질의 발현을 지시하는 하나 이상의 트랜스진이 도입된 것을 포함한다.
그러한 인간 이외의 동물은 설치류, 인간 이외의 영장류, 양, 재, 소, 양서류, 파충류 등과 같은 척추동물을 포함한다. 바람직한 인간 이외의 동물은 인간 이외의 동물중 포유동물 종으로부터 선택되며, 가장 바람직하게는, 래트와 마우스를 포함하는 설치류 과로부터 선택되며, 가장 바람직한 것은 마우스이다.
질병에 걸리기 쉽거나, 그 안에서 트랜스진이 질병을 유발하는, 생성된 트랜스제닉의 인간 이외의 동물은 그 질병을 유도하는 조성물을 동정하기 위해, 및 그 질병을 유도하는 것으로 공지되었거나, 그로 의심되는 조성물의 병적 효능을 평가하기 위해(미국 특허번호 제5,174,986호((Bems, A. J. M.)), 또는 그 질병을 치료하거나 그것의 증상을 호전시키는데 사용될 수 있는 조성물을 평가하기 위해 (WO 94/12627(Scott, et al.,)) 사용될 수 있다.
표적 유전자의 염색체는 통합되고, 이들 트랜스제닉 유기체에서 표적 단백질을 과발현시킨다.
하나의 실시태양에서, 본 발명은 결손 단백질 폴딩 기관 또는 응집되기 쉬운 단백질을 발현시킴으로써 단백질 미스폴딩 및 응집과 관련된 신경계 질병의 증상을 나타내는 트랜스제닉 동물을 제공한다. 다른 응집되기 쉬운 단백질, 예로서, 돌연변이체-헌팅톤, 베타-아밀로이드, 타우, 알파-시뉴클레인, 돌연변이체 안드로겐 수용체, 돌연변이체 SODI, 돌연변이체 아탁신 등이 다른 신경계 질병을 모델링하는데 사용될 수 있다. 일례로서, 하나의 실시태양에서는, 신경세포 특이 프로모터를 사용하여 알파-시뉴클레인 단백질을 신경세포에서 과발현시키는 트랜스제닉 유기체가 사용된다. 알파-시뉴클레인의 과발현으로 미스폴딩된 단백질 중간체, 단백질 응집 및 신경세포 변성이 생성된다. 표적 유전자 산물이 신경보호 특질을 부여하고 알파-시뉴클레인의 미스폴딩 및 응집의 독성 효과를 감소시키는지 여부를 측정하기 위하여, 이러한 트랜스제닉 계는 앞서 RNAi 선별로부터 동정된 표적 유전자를 과발현시키는 유기체와 이종 교배될 수 있다. 트랜스진이 유비퀴틴-프로테아좀 분해 시스템 단백질, 자가포식 단백질, 분자 샤페론, 전사 인자, 소낭 수송 단백질, Mn2 +/Fe2 + 수송체, HSPC117 단백질, 아세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질로부터 선택되는 유전자의 변화된 형태인 다른 모델을 사용할 수 있다. 변화는 발현의 증가 또는 감소, 또는 돌연변이화 또는 별법으로 신경계 질병의 증상을 초래하는 단백질의 스플라이싱된 형태를 포함할 수 있다.
신경보호를 분석하기 위한 모델에서, 도파민 함유 신경세포를 파괴하는 것으로 공지되어 있는 6-하이드록시도파민(6-OHDA: 6-hydroxydopamine)과 같은 신경독으로 트랜스제닉 유기체를 처리하였다. 다른 신경독 또한 본 선별 방법에 사용될 수 있고, 이는 당업계의 통상의 숙련자에게는 공지되어 있다. 독소에 노출시킨 후, 신경세포 형태를 형광 현미경을 사용하여 통상적으로 선별할 수 있다.
예를 들면, 본 선별 방법을 통해 도파민성 신경세포를 6-OHDA 상해로부터 보호할 수 있는 능력을 특징으로 하는 하나의 유전자 산물을 동정하였다. C. 엘레간스 유전자는 M7.5(서열번호:41)로 명명되고, 이는 인간 E1-양 유전자(서열번호:43)에 상응한다. e-값이 0인 인간, 충, 소, 래트, 및 마우스의 서열과는 상기 유전웸가 고도로 보존된다. 그 자체로서, 다른 종의 동족체는 신경보호를 제공하는 동일한 작용을 가져야 한다. 신경독 6-OHDA에 노출된 후, M7.5의 과발현은 도파민성 신경세포에 신경보호를 부여한다. 유사하게, 토신 단백질 또한 신경독 6-OHDA에 노출된 후 도파민성 신경세포에 신경보호를 부여한다[Cao et al, J Neurosci. 2005 Apr 13;25(15):3801-12). 트랜스제닉 충은 다른 유전자 또는 화합물의 신경보호 효과를 선별하기 위한 모델 시스템을 제공한다.
본 원에서 사용되는 바, 세포가 유전자 조작을 통해 정상적으로는 생산되지 않는 단백질을 생산하거나, 정상적으로는 낮은 수준으로 생산되는 단백질을 생산하도록 조작되었을 때, 세포는 "원하는 펩티드를 발현시키도록 변형되었다"는 것으로 언급된다. 당업계의 숙련자는 게놈, cDNA, 또는 합성 서열을 진핵 또는 원핵 세포 내로 도입시키고 발현시키기 위하여 방법을 용이하게 적합화시킬 수 있다.
핵산 분자, 예로서, DNA가 전사 및 해독 조절 정보를 포함하는 뉴클레오티드 서열을 포함하고, 상기 서열은 폴리펩티드를 코딩하는 뉴클레오티드 서열에 "작동가능하게 연결되어 있다"면, 핵산 분자, 예로서, DNA는 "발현시킬 수 있다"는 것으로 언급된다. 작동가능한 연결은, 조절 DNA 서열 및 발현되어야 하는 DNA 서열이 유전자 발현을 허용하는 방식으로 접속하고 있는 연결이다.
본 원에서 기술하는 핵산 분자 및 단백질은 신경계 질병을 치료하기 위한 치료학적 표적을 제공한다. 결핍 또는 결손 유전자에 의해 유발되는 신경계 질병은 유전자 또는 단백질의 작용을 회복시켜 줌으로써 치료될 수 있다. 그러한 회복은 유전자 요법을 사용하거나, 정상적인 유전자 또는 단백질의 작용을 회복시켜 주는 화합물을 투여함으로써 달성될 수 있다.
작용성 DNA는 결핍 또는 결손 유전자에 의해 유발되는 신경계 질병으로 고생하거나, 상기 질병에 걸리기 쉬운 환자를 치료하기 위한 충분한 양으로 한동안, 상기 유전자를 코딩하는 단백질의 발현을 허용하는 방식과 양으로 환자 세포에 제공될 수 있다. 세포로부터의 유전자 또는 단백질 소실이 필요한 인간 환자에 전달할 수 있도록 하는 다수의 벡터 시스템이 당업계에 공지되어 있다. 예를 들면, 레트로바이러스 시스템, 특히 변형된 레트로바이러스 시스템 및 특히 헤르페스 단순 바이러스 시스템이 사용될 수 있다([Breakefield, X. O., et al., 1991, New Biologist. 3:203-218]; [Huang, Q., et al., 1992, Experimental Neurology. 115:303-316]; WO93/03743; WO90/09441). 작용성 단백질을 코딩하는 DNA 서열의 전 달은 질환을 유발하는, 소실 또는 돌연변이화된 유전자를 효과적으로 대체하게 된다.
본 발명의 또다른 실시태양에서, 유전자는 세포중에 재조합 유전자로서 발현되며, 따라서, 그 세포들은 포유동물, 바람직하게는 유전자 요법을 필요로 하는 인간에게 이식될 수 있다. 유전자 요법을 개체에게 제공하기 위해, 유전자 전체 또는 일부를 코딩하는 유전자 서열이 벡터내로 삽입되고 숙주 세포 내로 도입된다. 또다른 실시태양에서, 결손 또는 기능장애 단백질의 발현은 RNAi의 사용으로 감소될 수 있다. 그러한 방법은 [Curr Drug Targets. 2005 Feb;6(1):21-9](Forte et al.)에서 리뷰된다.
유전자 요법에 적합할 수 있는 질병의 일례로, 제한하는 것은 아니지만, 신경변성 질병 또는 질환을 포함한다. 그러한 질환으로는 파킨슨병, 알츠하이머병, 프리온 질병, 폴리글루타민 질병, 타우증, 헌팅톤병, 근육긴장이상, 가족성 근위축성 측삭 경화증, 피크병, 진행성 핵상마비 및 피질 변성을 포함한다.
유전자 요법의 방법은 표 I로부터의 단백질의 코딩 서열을 환자에게 전달하기 위하여 사용될 수 있다([Chattedee and Wong, 1996, Curr Top . Microbiol . Immunol. 218:61-73]; [Zhang, 1996, J. Mol . Med . 74:191-204]; [Sclimidt-Wolf and Schmidt-Wolf, 1995, J. Hematotherapy. 4:551-561]; [Shaughnessy, et al., 1996, Seminars in Oncology. 23:159-171]; [Dunbar, 1996, Annu . Rev . Med. 47:11-20]).
유전자 요법에 사용될 수 있는 벡터의 일례는, 제한하는 것은 아니지만, 결 손 레트로바이러스, 아데노바이러스, 또는 다른 바이러스성 벡터를 포함한다[Mulligan, R. C., 1993, Science. 260:926-932]. 유전자를 운반하는 벡터가 세포 내로 도입될 수 있는 수단은, 미세주사법, 전기천공, 형질도입, 또는 DEAE-덱스트란을 사용하는 형질감염, 리포펙션, 인산 칼슘 또는 당업계의 숙련자에게 공지된 다른 방법을 포함한다[Sambrook, J., Fritsch, E. F., and Maniatis, T., 1989, In: Molecular Cloning. A Laboratory Manual., Cold Spring Harbor Laboratory Press, Cold Spring Harbor].
기술된 선별 방법을 사용하여 발견된 치료학적 화합물을 비롯한, 본 발명의 화합물은 신경계 질병을 치료하기 위하여 투여될 수 있다. 하나의 실시태양에서, 신경계 질병의 증상을 치료하거나, 감소시키거나, 근절시키기 위한 치료학적 유효량의 화합물을 포함하는 조성물을 투여한다. 당업계의 숙련자는 또한 임의의 특정 치료 프로토콜에 대하여 투여되는 양을 용이하게 결정할 수 있다는 것을 이해할 것이다. 투여량은 원치않는 교차-반응, 과민성 반응 등과 같은 부작용을 일으킬 만큼 크지 않다. 일반적으로, 투여량은, 환자의 연령, 증상, 성별 및 질병의 정도, 개개 의사에 의해 조정되는 반대 지시, 만약 있다면, 다른 변수에 따라 달라질 것이다. 면역 자극을 제공하기 위해 본 발명에서 사용되는 투여량은 약 0.1㎍ 내지 약 500㎍을 포함하며, 이는 0.5, 1.0, 1.5, 2.0, 5.0, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 및 450㎍을 포함하며, 그들 사이의 모든 범위 및 부분범위를 포함한다. 이와 같은 양은 단일 투여량으로서 투여될 수 있거나, 그 후의 증폭(booster) 투여를 포함하는 요법에 따라 투여될 수 있으며, 그로써 효과적으로 되고, 예로서, 본 발명의 조성물은 1회 또는 며칠, 수주, 수개월 및/또는 수년의 기간의 과정에 걸쳐 연속적으로 투여될 수 있다. 투여량은 약제학적으로 허용가능한 담체로 투여될 수 있다.
또한, 주사가능 제제와 같은 제형(액제, 현탁제, 에멀젼, 사용시 용해되는 고체 등), 정제, 캡슐제, 과립제, 분제, 액체, 리포좀 봉입체, 연고, 겔, 외용 분제, 스프레이, 흡인식 분제, 점안제, 안연고, 좌약, 페서리 등은 투여 방법에 따라 적절하게 사용될 수 있으며, 본 발명의 펩티드는 그에 맞게 제형화될 수 있다. 약학적 제제는 일반적으로 당업계에 공지되어 있으며, 예로서, [Chapter 25.2 of Comprehensive Medicinal Chemistry, Volume 5, Editor Hansch et al, Pergamon Press 1990]에 기재되어 있다.
표 I로부터의 단백질 또는 그의 리간드는 주사 또는 시간에 걸친 점진적인 관류에 의해 비경구적으로 투여될 수 있다. 정맥내로, 복강내로, 근육내로, 또는 피하로 투여될 수 있다. 화합물이 혈액뇌장벽을 가로지를 수 있게 하는 다른 방법은 화합물을 투여하는데 사용하기 위한 것으로 주시되고 있다.
비경구적 투여용 제제는 무균 또는 수성 또는 비-수성 액제, 현탁제, 및 에멀젼을 포함한다. 비수성 용매의 일례는 프로필렌 글리콜, 폴리에틸렌 글리콜, 올리브유와 같은 식물유, 에틸 올레이트와 같은 주사용 유기 에스테르이다. 수성 담체는, 염수 및 완충처리된 매질을 포함하는 물, 알콜성/수성 용액, 에멀젼 또는 현탁액을 포함한다. 비경구 비히클은 염화나트륨 용액, 링거 덱스트로스와 염화나트륨, 락테이트화된 링거, 또는 고정유를 포함한다. 정맥내 비히클은 유체 및 영양제 보충제, 전해질 보충제, 예로서, 링거 덱스트로스를 기초로 하는 것 등을 포함한다. 예로서, 항미생물제, 항산화제, 킬레이트화제, 불활성 기체 등과 같은 방부제 및 다른 첨가제 또한 존재할 수 있다[Remington's Pharmaceutical Science, 16th ed., Eds.: Osol, A., Ed., Mack, Easton Pa. (1980)].
또다른 실시태양에서, 본 발명은 단백질의 활성을 변화시키기에 충분한 양의 표 I로부터의 단백질 또는 그의 리간드, 및 약제학적으로 허용가능한 희석제, 담체, 또는 부형제를 포함하는 약학적 조성물에 관한 것이다. 적절한 농도 및 단위 제형 크기는 전술한 바와 같이 당업계의 숙련자에 의해 용이하게 결정될 수 있다([Remington's Pharmaceutical Sciences, 16th ed., Eds.: Osol, A., Ed., Mack, Easton Pa. (1980)]; WO 91/19008).
본 발명에서 사용될 수 있는 약제학적으로 허용가능한 담체는 제한하는 것은 아니지만, 의약 분야에서 통상 사용되는 부형제, 결합제, 활택제, 착색제, 붕해제, 완충제, 등장화제, 방부제, 마취제 등을 포함한다.
또다른 실시태양에서, 본 발명은 동물에서 단백질의 변화된 수준에 영향을 주기에 충분한 양으로 표 I로부터의 단백질 또는 상기 단백질의 리간드(길항제 및 효현제 포함)를 동물(바람직하게, 포유동물(더욱 바람직하게, 인간))에게 투여하는 방법에 관한 것이다. 투여된 단백질 또는 리간드는 특히 단백질-관련 작용에 영향을 줄 수 있다. 추가로, 표 I의 단백질은 뇌 조직에서 발현되기 때문에 단백질 또는 리간드를 투여하여 뇌에서의 단백질 수준 또는 작용을 변화시킬 수 있다. 본 방법으로 치료될 수 있는 신경계 질환은 단백질 응집 질환, 예로서, 알츠하이머병, 파킨슨병, 프리온 질병, 폴리글루타민 질병, 타우증, 헌팅톤병, 가족성 근위축성 측삭 경화증, 피크병, 진행성 핵상마비 및 피질 변성을 포함한다.
또다른 실시태양에서, 본 발명은 샘플중 표 I에 열거된 핵산 또는 단백질의 존재를 검출하기 위한 키트에 관한 것이다. 하나의 실시태양에서, 키트는 변화된 단백질을 검출하거나 신경계 질병에 대한 소인을 진단하거나 신경계 질병의 존재를 진단하기 위한 그의 사용에 대한 설명서 및 시약을 포함한다. 키트는 전술된 핵산 프로브가 내부에 배치되어 있는 적어도 하나의 용기를 포함할 수 있다. 바람직한 실시태양에서, 키트는 세척 시약 및/또는 혼성화된 핵산 프로브의 존재를 검출할 수 있는 시약을 포함하는 또다른 용기를 추가로 포함한다. 검출 시약의 일례로 제한하는 것은 아니지만, 방사성표지된 프로브, 효소 프로브(호스래디쉬 퍼옥시다제, 알칼리 포스파타제), 및 친화도 표지된 프로브(바이오틴, 아비딘 또는 스트렙타비딘)를 포함한다. 하나의 실시태양에서, 키트는 PCR, 혼성화 또는 서열-기반 분석법 또는 그의 임의의 조합, 예로서, 마이크로어레이를 수행하여 질환을 검출하기 위한 하나 이상의 시약을 포함한다.
상세히 설명하면, 구획화된 키트는 시약이 별도의 용기 내에 포함된 임의의 키트를 포함한다. 그러한 용기는 작은 유리 용기, 플라스틱 용기 또는 플라스틱 또는 종이로 된 스트립을 포함한다. 그러한 용기는, 샘플과 시약이 서로 오염되지 않고 각 용기의 용액 또는 시약을 하나의 구획으로부터 또다른 구획으로 정량적 방식으로 첨가할 수 있도록 하나의 구획으로부터 또다른 구획으로 시약을 효율적으로 전달할 수 있다. 그러한 용기는 테스트 샘플을 수용하는 용기, 분석에 사용되는 프 로브 또는 프라이머를 포함하는 용기, 세척 시약을 포함하는 용기(예, 인산염 완충 처리된 염수, 트리스 완충액 등) 및 혼성화된 프로브, 결합된 항체, 증폭된 산물 등을 검출하는 데 사용되는 시약을 포함하는 용기를 포함한다.
당업계의 숙련자는 본 발명에 개시된 핵산 프로브를 당업계에 공지되어 있는 확립된 키트 포맷중 하나에 쉽게 도입할 수 있음을 인지할 것이다.
본 발명의 또다른 실시태양에서, 표 I에 열거된 단백질의 존재 또는 부재; 표 I에 열거된 단백질의 존재 또는 부재에 기초하여 포유동물에서 질환이 발병될 수 있는 가능성을 검출하기 위한 키트가 제공된다. 본 특정 키트는 앞서 기술된 검출 방법을 수행하기 위해 필수적인 모든 시약을 포함한다.
예를 들면, 키트는 전술된 항체를 포함하는 제1 용기 수단, 및 항체의 결합 파트너 및 표지를 포함하는 접합체를 포함하는 제2 용기 수단을 포함할 수 있다.
키트는 또한 전술된 단백질을 포함하는 제1 용기 수단, 및 바람직하게 단백질의 결합 파트너 및 표지를 포함하는 접합체를 포함하는 제2 용기 수단도 포함할 수 있다. 더욱 특히, 진단 키트는 잠재적으로 감염된 동물 또는 인간 혈청내 항체를 검출하기 위한, 전술된 바와 같은 표 I에 열거된 단백질을 포함한다.
본 발명의 또다른 실시태양에서, 키트는 세척 시약 및/또는 혼성화된 핵산 프로브의 존재를 검출할 수 있는 시약중 하나 이상을 포함하는 하나 이상의 다른 용기를 포함한다. 검출 시약의 일례로 제한하는 것은 아니지만, 표지된 2차 항체를 포함하거나, 별법으로는, 1차 항체가 표지된 경우, 표지된 항체와 반응할 수 있는 발색단, 효소, 또는 항체 결합 시약을 포함한다. 구획화된 키트는 핵산 프로브 키 트에 대하여 전술된 것과 동일할 수 있다. 키트는 예를 들면, RIA 키트 또는 ELISA 키트일 수 있다.
당업계의 숙련자는 본 발명에 기술된 항체가 당업계에 공지된 확립된 키트 포맷중 하나의 내부로 용이하게 도입될 수 있다는 것을 용이하게 인지할 것이다.
본 발명은 구체적인 실시예를 통해 보다 상세하게 설명될 것이다. 하기 실시예는 설명하기 위한 목적으로 제공되는 것이며, 어느 방식으로든 본 발명을 제한하거나 규정짓고자 하는 것은 아니다.
실시예 1: RNAi를 사용한 파킨슨병에서의 단백질 응집을 조절하는 유전자 선별
알파-시뉴클레인::GFP를 과발현시키는 트랜스제닉 C. 엘레간스 계를 생산하고, 형광 현미경에 의해 검출가능한 알파-시뉴클레인의 가시적 응집체를 형성시켰다. 유전자 발현은 체벽으로의 발현을 지시하는 unc-54 프로모터의 조절하에 있다. 알파-시뉴클레인::GFP + TOR-2를 포함하는 또다른 트랜스제닉 충 계는 단백질 응집과 관련된 후보 유전자의 RNAi 선별을 위해 사용하였다. 알파-시뉴클레인::GFP + TOR-2 충에 TOR-2가 존재하기 때문에 체벽 근육 세포에서의 알파-시뉴클레인::GFP 융합 단백질의 응집은 저지되고, 이로써 형광은 확산된다. TOR-2에 의한, 미스폴딩 및 단백질 응집의 유사한 억제는 폴리글루타민-의존 단백질 응집에 대하여 앞서 보고된 바 있다[Caldwell et al. Hum Mol Genet. 2003 Feb 1;12(3):307-19]. 이러한 트랜스제닉 유기체는 알파-시뉴클레인::GFP + TOR-2를 함유하는 충의 체벽 근육에 공급함으로써 RNAi를 사용하는 신속한 선별 방법이 미스폴딩을 증가시키고, RNAi에 의해 제거되었을 때에는 알파-시뉴클레인 응집으로 복귀하는 유전자를 찾을 수 있도록 한다.
알파-시뉴클레인의 응집에 유전자 넉다운이 미치는 효과를 측정하기 위하여 RNAi를 사용하여 C. 엘레간스 유전자 라이브러리를 선별하였다. C. 엘레간스에서의 게놈-와이드(genome-wide) RNAi 선별에서 세균 공급에 사용하기 위하여 18,000개의 세균 균주의 RNAi 라이브러리를 구입하였다(캠브리지 소재의 Sanger Centre). 전체 C. 엘레간스 게놈의 광범위한 선별을 수행하기 보다는 ER-결합 분해(ERAD: ER-associated degradation), 유비퀴틴 프로테오좀 시스템(UPS: ubiquitin proteosome system), 자가포식, 파킨슨병 및 상호작용체(interactome)와 관련된 유전자의 합리적인 표적화와 마이크로어레이 공-발현 데이타를 통해 선별을 위해 단백질 응집에 영향을 주는 후보 분자를 동정하였다.
간략하게는, 앰피실린 및 테트라사이클린을 함유하는 LB 아가 플레이트상에서 표적 유전자 dsRNA를 발현시키는 새로운 E. 콜라이(E. coli)를 제조하고, 밤새도록 배양하였다. 다우어 알파-시뉴클레인::GFP 충의 새로운 배양물, 및 표적 유전자를 공-발현시키는, 3ml의 E. 콜라이 세균 배양물을 그 다음날 제조하였다. 실험 당일, 표적 유전자당 하나의 작은, 하나의 배지 플레이트를 IPTG로 코팅한 후, 각 물질로 코팅하는 사이사이의 시간동안 세균 배양물을 건조시켰다. 5마리의 L4 충을 대략 42시간동안 25℃에서 각각의 배지 플레이트상에 놓았다. 이어서, 원래의 성충 모두를 9시간동안 소량의 IPTG/세균 코팅된 플레이트로 전달한 후, 원래의 성충은 소각시켰다. 생성된 표현형을 발현시키기 위하여 36시간 이후에 자손을 분석하였다.
단백질 응집과의 관련성에 기초하여 741개 이상의 가능한 유전자 표적군을 선택하고, 초기 RNAi 선별에 사용하였다. 모든 양성 후보 유전자는 위양성을 제거하기 위하여 2차에 선별하였다. 1차 및 2차 선별 결과, 113개의 양성 유전자를 수득하였다. 알파-시뉴클레인::GFP + TOR-2 충을 사용한 이들 741개의 유전자의 1차 선별에서 응집체 존재에 대해 동정된 유전자의 분포는 도 1b에 나타내었다.
후보는 또한 선별 과정의 모든 단계에서 DJ-1 및 PINK1 간의 마이크로어레이 실험으로써 동정되었다. 공지된 파킨슨병 유전자 DJ-1 및 PINK1과 공-발현되는 89개의 후보 샘플을 선택하였다. 후보 분자의 중복 부분을 도 2a에 나타낸다. RNAi를 사용하여 2회에 걸쳐 선별한 후, 원래의 89개의 유전자 세트로부터 7개의 양성 후보가 알파-시뉴클레인 응집을 변화시켰고, DJ-1 및 PINK1과 공-발현되었다. 흥미롭게도, 7개중 2개의 양성 중복 유전자가 가상 단백질을 코딩하였다.
노화됨에 따라 더욱 강력한 효과를 나타내는 후보를 동정하기 위하여 발생 단계별로 동물에서 다수회에 걸쳐 RNAi 분석(유전자당 50마리의 충; 2회 반복; >80%로 응집이 증가된 충을 양성으로서 간주한다)을 수행하고, 2차의 보다 엄격한 선별을 수행함으로써 넉다운되었을 때 인간 알파-시뉴클레인의 미스폴딩을 재현가능하게 감소시키는, 표 I에 나열되어 있는 17개의 후보 유전자를 동정하게 되었다. 이들 유전자는 DJ-1, PINK1 및 토신 A의 C. 엘레간스 동족체; UPS 성분 4개(E1 리 가아제 1개, E3 리가아제 3개), 자가포식 기관의 성분 4개, 예상 샤페론 1개, 전사 인자 1개, 소낭 수송에 관여하는 유전자 산물 1개, 및 앞서 공지된 바 없는 작용을 갖는 가상 단백질 3개를 포함한다.
후보의 계통적 RNAi 넉다운에 이어 응집된 상태로 복귀한 것에 대하여 알파-시뉴클레인::GFP +TOR-2 충을 선별한 후 다양한 표현형을 얻었다. 이러한 표현형은 핵 주변의 응집체의 간헐적인 집락화를 포함하였다.
이러한 실험상의 발견을 통해 통상의 실험을 수행함으로써 알파-시뉴클레인 응집과 관련된 단백질을 선별하는, 신뢰할 수 있는 방법을 제공한다. 이러한 실험상의 결과를 통해 합리적인 약물 디자인을 위한 단백질 표적도 제공함과 동시에, 병적 표현형을 유발하는 그들내의 돌연변이를 연구하기 위한 표적 단백질의 아이덴티티를 제공한다.
실시예 2: 6-OHDA 노출 후, 후보 유전자 발현에 의한 도파민성 신경세포의 신경보호
C. 엘레간스는, 도파민 유사체로서 신경세포에서 활성 산소종을 형성하는 신경독인 6-하이드록시도파민(6-OHDA)으로 처리되었을 때 패턴이 용이하게 식별가능하게 변성되는, 정확하게 8개의 도파민성 신경세포를 갖는다. 도파민성 신경세포에서 인간 토신 A 또는 C. 엘레간스 TOR-2의 과발현은 알파-시뉴클레인이 과발현된 후, 또는 6-OHDA로 처리된 후, 신경세포 변성을 현저하게 억제시킬 수 있다(Cao et al, J Neurosci. 2005).
단백질 응집 선별로부터의 데이타를 사용하여 도파민성 신경보호에서 이들 유전자의 잠재적 활성에 대한 차후의 3차 선별에 대하여 우선 순위화하였다. 도파민성 신경세포에서 GFP를 발현시키는 트랜스제닉 충을 작제하고, 6-OHDA에 노출시킨 후 철저하게 분석하였다([Nass et al 2002]; [Cao et al 2005]). 노출 후 2시간, 전형적으로는 6시간내에 표현형에 있어 변화가 뚜렷이 나타났고, 대부분의 도파민성 신경세포는 완전히 변성되었다. 도파민성 신경세포에서 발현되었을 때 이들 후보 파킨슨병-관련 유전자중 임의의 것이 신경보호 활성을 나타내는지 여부를 측정하기 위하여 도파민 프로모터(dat -1)의 조절하에 RNAi 선별로부터 후보 단백질를 코딩하는 cDNA를 클로닝하였다. 후보중 야생형 cDNAs를 dat-1 프로모터 벡터내로 클로닝하고, 충에 주입하고, 6-OHDA에 노출시킨 후 신경세포 보호에 대하여 분석하였다. 이어서, 선택된 후보 유전자를 파킨슨병을 앓는 환자의 게놈 DNA 선별에 사용하였다.
추가로, 특히 신경보호의 입증을 위한 후보 PD 유전자를 선별하기 위하여 새로운 동종 동계의 선충류를 디자인하였다. 상기의 새로운 동종 동계의 선충류는 발생 및 노화되는 동안 생체내에서 신경변성을 평가하기 위하여 GFP와 함께 도파민성 신경세포에서 인간 알파-시뉴클레인을 과발현시키는, 염색체적으로 통합된 트랜스진을 함유하였다. 상기 계는 C. 엘레간스 발생중 4-일째의 성충기에서 대략 30-40%의 변성을 나타내었고, 이는 알파-시뉴클레인 소인이 도파민성 신경변성에 영향을 줄 수 있는 환경적 인자/유전적 인자의 연구를 위한 이상적인 도구를 나타낸다. 알파-시뉴클레인 계의 도파민성 신경세포에서 상응하는 cDNAs를 과발현시키는 동물을 교배시킨 후, 신경보호에 대한 증거를 찾음으로써 양성 RNAi 선별 후보의 계통적 평가를 실시하였다. 상기 계는 또한 알파-시뉴클레인 의존성 분해의 소분자 저해제에 대한 중효율(medium through-put) 선별에서도 사용될 수 있다.
재료 및 방법
C.
엘레간스
계 및 프로토콜
선충류는 표준 방법을 사용하여 유지시켰다[Brenner, 1974]. Pdat -1::GFP를 Pdat-1;M7.5[계 UA38 (baEx38)] 또는 Pdat -1::토신 A 및 Pdat -1::TOR-2과 함께 야생형 C. 엘레간스(N2 브리스톨 변종)내로 형질전환시켜 트랜스제닉 계를 생성하였다. α-시뉴클레인을 과발현시키는 계를 작제하기 위하여 Pdat -1::GFP 및 Pdat -1::α-시뉴클레인[계 UA18 (baEx18)]를 N2 충에 주입하였다. 각각의 플라스미드 작제물의 조합물에 대하여 안정적인 염색체외의 어레이를 발현시키는 다수의 충 계를 비교하고, 단, 6-OHDA 실험을 제외한 실험적 분석을 위해 3개의 대표적인 계를 사용하였고, 여기에서, 1개의 대표적인 트랜스제닉 계는 안정적인 모든 계에 대한 초기 실험 후의 반복되는 실험에서 사용하였다.
플라스미드
작제
및
돌연변이화
게이트웨이™ 기술(캘리포니아주 칼즈배드 소재의 Invitrogen)을 사용하여 플라스미드를 작제하였다. 특히, HindIII 및 KpnI를 사용하여 이중 분해함으로써 pPD30.38(Andrew Fire로부터 기증받음)로부터 unc-54 프로모터 영역을 제거하고, pRN200으로부터 증폭된 dat -1 프로모터 영역 단편으로 대체시켰다(Nass et al., 2002). 이어서, 생성된 신규의 벡터는 게이트웨이™ 기술을 사용하여 게이트웨이™ 지정 벡터, pDEST-DAT-1로 전환시켰다. 인간 α-시뉴클레인 cDNA 플라스미드는 필립 카일(Philipp Kahle)로부터 입수하였다. 게이트웨이™ 엔트리 벡터는 M7.5(서열번호: 41) α-시뉴클레인을 코딩하는 PCR 증폭된 cDNA 단편, GFP를 사용하여 BP와 pDONR201 또는 pDONR221을 반응시킴으로써 생성하였다. 이어서, 각 엔트리 벡터와 LR의 반응을 통해 모든 유전자를 pDEST-DAT-1 벡터내로 클로닝시켰다.
면역블롯팅을
위한 C.
엘레간스
추출물 제조
2개의 100mm NGM 플레이트상에서 거의 융합될 때까지 각 트랜스제닉 계를 배양한 후 추출물을 제조하였다. M9 완충액으로 세척하고, 5,000 x g에서 1분동안 1.5ml의 미세원심분리 튜브에서 원심분리하여 농축시킴으로써 충을 수거하였다. 충의 펠릿을 재현탁시키고, 5분동안 비등시켜 0.5ml의 충 용해 완충액(10OmM 트리스, pH 6.8, 2% SDS, 15% 글리세롤)에서 용해시켰다. 상기 용해물을 13,200 x g에서 10분동안 다시 원심부리한 후, 상등액을 수거하고, 14,000 x g에서 30분동안 센트리콘(Centricon) YM-10 칼럼(Millipore)을 사용하여 농축시켰다. 단백질 농축물은 바이신코닌산 단백질 분석법(미주리주 세인트루이스 소재의 Sigma)을 사용하여 측정하였다.
SDS
-
PAGE
및
웨스턴
블롯팅
달리 언급하지 않는 한, 앞서 기술된 바와 같이[Caldwell et al., 2003] SDS-PAGE 및 웨스턴 블롯팅을 실시하였다. TOR-2 검출을 위해, 래빗-항-TOR-2 1차 항체[Caldwell et al., 2003]의 1:800의 희석액 및 호오스 래디쉬 퍼옥시다제-접합 된 고트-항-래빗 IgG 2차 항체(뉴저지주 피츠카타웨이 소재의 Amersham-Pharmacia)의 1:10,000의 희석액를 사용하였다. 액틴 검출을 위해서는, 마우스-항-액틴 항체(ICN)의 1:8000의 희석액 및 호오스 래디쉬 퍼옥시다제-접합된 고트-항-래빗 IgG 2차 항체(Amersham-Pharmacia)의 1:10,000의 희석액를 사용하였다. GFP 검출을 위해서는, 140㎍의 전체 단백질을 로딩하고, 래빗-항-GFP 1차 항체(캘리포니아주 팔로알토 소재의 Clontech)의 1:1000의 희석액 및 호오스 래디쉬 퍼옥시다제-접합된 고트-항-래빗 IgG 2차 항체(Amersham-Pharmacia)의 1:10,000의 희석액를 사용하였다.
6-
OHDA
노출 및 신경세포 변성의 정량적 분석
배(embryos)를 분리시키기 위하여 2% 차아염소산나트륨, 0.5M NaOH로 수태한 성충을 처리함으로써 연령-동기(synchronized)의 충을 수득하였다[Lewis and Fleming, 1995]. 상기 배를 30분동안 25℃에서 배양시켰다. L3-기의 유충을 매 10분마다 완만히 교반시키면서 1OmM(또는 5OmM) 6-OHDA 및 2mM(또는 1OmM) 아스코르브산과 함께 1시간동안 인큐베이션시켰다[Nass et al., 2002]. 이어서, 상기 충을 세척하고, 세균(OP50)이 시딩되어 있는 NGM 플레이트상에 스프레드시키고, 6-OHDA 노출 후 2 내지 72시간의 범위의 시점에서 평가하였다.
6-OHDA 처리후 즉시, 통합되지 않은 트랜스진을 함유하는 충을 형광 해부 현미경하에 GFP 존재에 기초하여 선택하고, OP50이 시딩되어 있는 새로운 NGM 플레이트로 전달하였다. 각 시점에 30-40마리의 충을 2% 아가로스 패드에 적용시키고, 3mM 레바미솔을 사용하여 고정시켰다. 엔도우 GFP HYQ(Endow GFP HYQ) 필터 큐 브(Chroma)가 장착된 니콘 이클립스 E800(Nikon Eclipse E800) 표면 형광 현미경하에서 충을 관찰하였다. 용이한 분석을 위해 충의 머리내에 존재하는 오직 4개의 CEP 도파민성 신경세포만을 평가하였다. CEP 신경세포 4개 모두가 존재하고, 그들의 신경세포 과정이 손상되지 않았을 때(intact) 충을 "야생형"으로서 평가하고; 4개의 신경세포 가지돌기 또는 세포체중 적어도 하나가 "가지돌기 수포화(dendrite blebbing)," "세포체 구형화," 또는 "세포체 손실"과 같은 결손이 있는 경우, 충은 "가지돌기 수포화," "세포체 구형화," 또는 "세포체 손실"을 갖는 것으로 평가된다. 본 실험은 3회에 걸쳐 반복하였다. 메타모프 소프트웨어(MetaMorph Software)(Universal Imaging)로 작동하는 쿨 스탭 HQ CCD(Cool Snap HQ CCD) 카메라(Photometries)를 사용하여 영상을 포착하였다.
알파-
시뉴클레인
또는
CAT
-2-유도성 신경변성 분석
7일된 α-시뉴클레인 및 CAT-2 트랜스제닉 계의 동물을 수득하기 위하여 녹색 형광을 갖는 비통합 L1 및 L2 충을 선택하고, 4일간(부화후 대략 7일)의 성충기동안 배양하였다. 각 선택된 단계에서의 30-40마리의 충을 각각의 비통합 계에 대하여 분석하고, 각 조합의 트랜스진에 대하여 안정적인 적어도 3개의 계의 평균을 기록하였다. 가지돌기의 형태와는 상관없이 4개의 CEP 세포체 모두가 보존되었을 때 충을 야생형으로 평가하였다.
결과
트랜스제닉 C. 엘레간스내에서 신경보호 분석법으로 평가하기 위하여 후보로부터의 야생형 cDNAs를 도파민 발현 벡터내로 클로닝하였다. 이러한 선별 접근법은 자가포식-관련 유전자 산물이 RNAi로 넉다운되었을 때 알파-시뉴클레인 미스폴딩을 증가시켰을 뿐만 아니라, 토신 A 동족체, TOR-2 양자 모두는 특히 C. 엘레간스 도파민성 신경세포에서 과발현되었을 때, 6-OHDA 노출로부터 놀랄만한 신경보호를 나타내었다는 증거를 통해 확인되었다. DA 신경세포에서의 야생형 토신(Pdat -1::토신 A 및 Pdat -1::TOR-2)의 과발현은 대조군 충과 비교하였을 때, 적어도 72시간동안의 1OmM 농도의 6-OHDA에 대한 DA 신경세포의 내성을 현저하게 증가시켰다. 상기 선별 방법을 통해 도파민성 신경세포를 6-OHDA 상해로부터 보호할 수 있는 능력을 특징으로 하는 하나의 유전자 산물을 확인하였다. C. 엘레간스 유전자는 M7.5(서열번호:41)로 명명되고, 이는 인간 E1-양 유전자(서열번호:43)에 상응한다. 이 유전자는 유비퀴틴 활성화 E1 효소-양 단백질 계열의 구성원이고 자가포식에 작용한다. M7.5 cDNA는 GFP-표지된 도파민성 신경세포에서 과발현되었고, 6-OHDA에 노출시킨 후, 신경보호에 대하여 분석하였다. 3개의 독립적으로 M7.5 발현 트랜스제닉 계를 수득하였다. 이들 3개 모두는 6-OHDA-유도된 산화적 스트레스로부터 도파민성 신경세포를 현저하게 보호하는 것으로 나타났다. DA 신경세포에서 신경보호에 대하여 상기 단백질이 미치는 작용은 도 3에 나타내었다. 추가의 연구를 통해 발생 초기에 응집체를 나타낸 다른 후보와 노후됨에 따라 응집체만을 갖는 다른 후보를 구별할 것이다.
실시예 3: 인간에서 단백질 변화를 검출하고, 파킨슨병에 대한 소인을 진단 하거나 신경계 질병의 존재를 진단하기 위해 마이크로어레이를 사용하는 방법
파킨슨병
마이크로어레이
제작
아피메트릭스, 인코포레이티드에 의해 사용되는 집적 마이크로어레이 또는 고밀도, 올리고뉴클레오티드-기반 플랫폼과 같은 상업적으로 구입가능한 마이크로어레이 기술을 사용하여 파킨슨병 마이크로어레이를 제작하였다. 적당한 갯수 내지 다수의 유전자 및/또는 전사체를 분석, 즉, 발현(또는 반응) 프로파일에 대하여 선택하였다. 본 발명의 방법에서 모니터할 수 있는 핵산 서열은 제한하는 것은 아니지만, 국립 생명공학 정보 센터(National Center for Biotechnology Information)(월드 와이드 웹 ncbi.nlm.nih.gov)와 함께 GenBank.RTM. 데이터베이스에 열거된 것, 및 기타 공개된 데이터베이스 또는 상업적으로 구입가능한 데이터베이스(예를 들면, NCBI EST 서열 데이터베이스, EMBL 뉴클레오디트 서열 데이터베이스; 인사이츠(Incyte's) (캘리포니아주 팔로알토 소재) LifeSeq.TM. 데이터베이스, 및 셀레라스(Celera's)(메릴랜드주 로크빌 소재) "디스커버리 시스템(Discovery System)".TM. 데이터베이스)에 의해 제공받은 서열을 포함한다. 본 마이크로어레이는 또한 표 I로부터의 단백질의 인간 동족체를 코딩하는 서열에 상응하는 전사체를 포함한다. 본 어레이는 샘플중 유전자/전사체에 상응하는 전장 서열, 또는 유전자/전사체의 검출을 허용할 수 있는 충분한 특이성을 제공하는 전장 서열의 단편 또는 단편들을 포함할 수 있다. 서열번호: 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 또는 67에 상응하는 전사체 또는 단편 및 그의 조합물과 상기 서열의 돌연변이체 형태 및 스플라이스 변이체가 마이크로어레이 상에 포함된다. 파킨슨병과 관련되는 기타 공지 유전자를 포함하는 어레이상에 다른 서열도 포함된다. 산화적 스트레스 및 단백질 기능이상과 관련된 유전자 서열 또한, 그들의 과정이 파킨슨병에서 중요한 역할을 하는 것으로 공지되어 있기 때문에 마이크로어레이상에 포함된다[Miller et al., Neuroscientist. 2005 Dec;11(6):539-49]. SNPs와 같이 파킨슨병과 관련된 다른 유전자 또한 어레이상에 포함될 수 있다[Maraganore et al., Am J Hum Genet. 2005 Nov;77(5):685-93]. 본 어레이는 또한 양성 대조군 및 음성 대조군을 포함한다.
파킨슨병
마이크로어레이의
용도
마이크로어레이 프로브를 제작하기 위한 표준 방법을 사용하여 예로서, 생검과 같은 개체로부터의 조직 샘플을 개체로부터 수거하고, 샘플을 표지된 폴리뉴클레오티드 프로브로 전환시키고, 어레이에 혼성화시키고, 비결합 프로브는 세척하여 제거하였다. 이어서, 종래의 어레이 스캐너를 사용하여 어레이를 스캐닝함으로써 표지를 검출하고, 환자의 샘플중에서 야생형 또는 돌연변이체 형태의 유전자의 존재 또는 부재(정성적 변화) 뿐만 아니라, 발현 수준상의 변화(정량적 변화)를 측정하였다. 표준의 상업적으로 구입가능한 데이타 조사 소프트웨어를 사용하여 유전적 프로파일을 분석하고 클러스터링하였다.
마이크로어레이를 사용하여 얻은 결과는 약물유전학(predictive medicine) 및 예측 의약의 적용에 유용하다. 환자 여러명의 유전자 프로파일을 질병의 증상의 정도, 발병 및 중증도와 서로 관련시켜 파킨슨병 프로파일의 데이터베이스를 컴파일링시켰다. 환자의 프로파일을 현 치료 방법, 예로서, L-DOPA 요법에 대한 환자의 반응과도 서로 관련시켰다. 신규한 치료법에 대한 최적의 유전자 프로파일을 결정하기 위하여 초기 임상 실험시에 신규한 치료학적 화합물의 효능 또한 환자의 프로파일과 서로 관련시켰다.
SEQUENCE LISTING
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290 295 300
aca ttt ttc ccc aaa gag gag aga gtt ttc tca gat aaa ggc tgc aaa 960
Thr Phe Phe Pro Lys Glu Glu Arg Val Phe Ser Asp Lys Gly Cys Lys
305 310 315 320
acg gtg ttc acc aag tta gat tat tac tac gat gat tga 999
Thr Val Phe Thr Lys Leu Asp Tyr Tyr Tyr Asp Asp
325 330
<210> 4
<211> 332
<212> PRT
<213> Homo sapiens
<400> 4
Met Lys Leu Gly Arg Ala Val Leu Gly Leu Leu Leu Leu Ala Pro Ser
1 5 10 15
Val Val Gln Ala Val Glu Pro Ile Ser Leu Gly Leu Ala Leu Ala Gly
20 25 30
Val Leu Thr Gly Tyr Ile Tyr Pro Arg Leu Tyr Cys Leu Phe Ala Glu
35 40 45
Cys Cys Gly Gln Lys Arg Ser Leu Ser Arg Glu Ala Leu Gln Lys Asp
50 55 60
Leu Asp Asp Asn Leu Phe Gly Gln His Leu Ala Lys Lys Ile Ile Leu
65 70 75 80
Asn Ala Val Phe Gly Phe Ile Asn Asn Pro Lys Pro Lys Lys Pro Leu
85 90 95
Thr Leu Ser Leu His Gly Trp Thr Gly Thr Gly Lys Asn Phe Val Ser
100 105 110
Lys Ile Ile Ala Glu Asn Ile Tyr Glu Gly Gly Leu Asn Ser Asp Tyr
115 120 125
Val His Leu Phe Val Ala Thr Leu His Phe Pro His Ala Ser Asn Ile
130 135 140
Thr Leu Tyr Lys Asp Gln Leu Gln Leu Trp Ile Arg Gly Asn Val Ser
145 150 155 160
Ala Cys Ala Arg Ser Ile Phe Ile Phe Asp Glu Met Asp Lys Met His
165 170 175
Ala Gly Leu Ile Asp Ala Ile Lys Pro Phe Leu Asp Tyr Tyr Asp Leu
180 185 190
Val Asp Gly Val Ser Tyr Gln Lys Ala Met Phe Ile Phe Leu Ser Asn
195 200 205
Ala Gly Ala Glu Arg Ile Thr Asp Val Ala Leu Asp Phe Trp Arg Ser
210 215 220
Gly Lys Gln Arg Glu Asp Ile Lys Leu Lys Asp Ile Glu His Ala Leu
225 230 235 240
Ser Val Ser Val Phe Asn Asn Lys Asn Ser Gly Phe Trp His Ser Ser
245 250 255
Leu Ile Asp Arg Asn Leu Ile Asp Tyr Phe Val Pro Phe Leu Pro Leu
260 265 270
Glu Tyr Lys His Leu Lys Met Cys Ile Arg Val Glu Met Gln Ser Arg
275 280 285
Gly Tyr Glu Ile Asp Glu Asp Ile Val Ser Arg Val Ala Glu Glu Met
290 295 300
Thr Phe Phe Pro Lys Glu Glu Arg Val Phe Ser Asp Lys Gly Cys Lys
305 310 315 320
Thr Val Phe Thr Lys Leu Asp Tyr Tyr Tyr Asp Asp
325 330
<210> 5
<211> 612
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(612)
<400> 5
atg ctc aaa ttt gtc ata gtt tca tca att ctt gtg gcc cta ggt ctg 48
Met Leu Lys Phe Val Ile Val Ser Ser Ile Leu Val Ala Leu Gly Leu
1 5 10 15
tca atc gaa ttg aca ttc gaa ctt cca gac aac gca aat cag tgt ttt 96
Ser Ile Glu Leu Thr Phe Glu Leu Pro Asp Asn Ala Asn Gln Cys Phe
20 25 30
tat gaa gat ctg aaa aag gat gtt gac aca gtg ttt gaa ttc caa gtt 144
Tyr Glu Asp Leu Lys Lys Asp Val Asp Thr Val Phe Glu Phe Gln Val
35 40 45
gtt act gga ggc cat tat gac gta gac ttg atc att gag gat cca aat 192
Val Thr Gly Gly His Tyr Asp Val Asp Leu Ile Ile Glu Asp Pro Asn
50 55 60
gga aaa gtt ttg tat aaa gat act aaa aag cag tac gac agt atc aac 240
Gly Lys Val Leu Tyr Lys Asp Thr Lys Lys Gln Tyr Asp Ser Ile Asn
65 70 75 80
ttc aag gcc gaa gtt gaa gga aca tac aaa gca tgc ttt tca aat gaa 288
Phe Lys Ala Glu Val Glu Gly Thr Tyr Lys Ala Cys Phe Ser Asn Glu
85 90 95
ttc tcc aca ttc tct cat aaa atc gtt tac atg gat tgg caa ttc ggt 336
Phe Ser Thr Phe Ser His Lys Ile Val Tyr Met Asp Trp Gln Phe Gly
100 105 110
gat caa aat gct ctt cat gct gcc gtt act caa gga gct cat gca atg 384
Asp Gln Asn Ala Leu His Ala Ala Val Thr Gln Gly Ala His Ala Met
115 120 125
act caa tta gaa aat tat gca gtc gct att gga gat aaa ttg aga aca 432
Thr Gln Leu Glu Asn Tyr Ala Val Ala Ile Gly Asp Lys Leu Arg Thr
130 135 140
att gat gac tat caa act cat cat cgt ctc cgt gaa gca act ggt cgc 480
Ile Asp Asp Tyr Gln Thr His His Arg Leu Arg Glu Ala Thr Gly Arg
145 150 155 160
aaa cgt gca gaa gaa ctc aac gag cgc gtg atg atc tgg tcc ctt ggt 528
Lys Arg Ala Glu Glu Leu Asn Glu Arg Val Met Ile Trp Ser Leu Gly
165 170 175
caa tct gcc gtc gta gta ttc att gga att ggc caa gtt ttc ctg ctc 576
Gln Ser Ala Val Val Val Phe Ile Gly Ile Gly Gln Val Phe Leu Leu
180 185 190
aaa tca ttt ttc aat gat aaa aga act cgt tat taa 612
Lys Ser Phe Phe Asn Asp Lys Arg Thr Arg Tyr
195 200
<210> 6
<211> 203
<212> PRT
<213> Caenorhabditis elegans
<400> 6
Met Leu Lys Phe Val Ile Val Ser Ser Ile Leu Val Ala Leu Gly Leu
1 5 10 15
Ser Ile Glu Leu Thr Phe Glu Leu Pro Asp Asn Ala Asn Gln Cys Phe
20 25 30
Tyr Glu Asp Leu Lys Lys Asp Val Asp Thr Val Phe Glu Phe Gln Val
35 40 45
Val Thr Gly Gly His Tyr Asp Val Asp Leu Ile Ile Glu Asp Pro Asn
50 55 60
Gly Lys Val Leu Tyr Lys Asp Thr Lys Lys Gln Tyr Asp Ser Ile Asn
65 70 75 80
Phe Lys Ala Glu Val Glu Gly Thr Tyr Lys Ala Cys Phe Ser Asn Glu
85 90 95
Phe Ser Thr Phe Ser His Lys Ile Val Tyr Met Asp Trp Gln Phe Gly
100 105 110
Asp Gln Asn Ala Leu His Ala Ala Val Thr Gln Gly Ala His Ala Met
115 120 125
Thr Gln Leu Glu Asn Tyr Ala Val Ala Ile Gly Asp Lys Leu Arg Thr
130 135 140
Ile Asp Asp Tyr Gln Thr His His Arg Leu Arg Glu Ala Thr Gly Arg
145 150 155 160
Lys Arg Ala Glu Glu Leu Asn Glu Arg Val Met Ile Trp Ser Leu Gly
165 170 175
Gln Ser Ala Val Val Val Phe Ile Gly Ile Gly Gln Val Phe Leu Leu
180 185 190
Lys Ser Phe Phe Asn Asp Lys Arg Thr Arg Tyr
195 200
<210> 7
<211> 675
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(675)
<400> 7
atg ccg cgg ccg ggg tcc gcg cag cgc tgg gcg gcc gtc gcg ggc cgt 48
Met Pro Arg Pro Gly Ser Ala Gln Arg Trp Ala Ala Val Ala Gly Arg
1 5 10 15
tgg ggg tgc agg ctg ctc gca ctg ctg cta ctg gtg cct gga ccc ggc 96
Trp Gly Cys Arg Leu Leu Ala Leu Leu Leu Leu Val Pro Gly Pro Gly
20 25 30
ggc gcc tct gag atc acc ttc gag ctt cct gac aac gcc aag cag tgc 144
Gly Ala Ser Glu Ile Thr Phe Glu Leu Pro Asp Asn Ala Lys Gln Cys
35 40 45
ttc tac gag gac atc gct cag ggc acc aag tgc acc ctg gag ttc cag 192
Phe Tyr Glu Asp Ile Ala Gln Gly Thr Lys Cys Thr Leu Glu Phe Gln
50 55 60
gtg att act ggt ggt cac tat gat gta gat tgt cga tta gaa gat cct 240
Val Ile Thr Gly Gly His Tyr Asp Val Asp Cys Arg Leu Glu Asp Pro
65 70 75 80
gat ggt aaa gtg tta tac aaa gag atg aag aaa cag tat gat agt ttt 288
Asp Gly Lys Val Leu Tyr Lys Glu Met Lys Lys Gln Tyr Asp Ser Phe
85 90 95
acc ttc aca gcc tcc aaa aat ggg aca tac aaa ttt tgc ttc agc aat 336
Thr Phe Thr Ala Ser Lys Asn Gly Thr Tyr Lys Phe Cys Phe Ser Asn
100 105 110
gaa ttt tct act ttc aca cat aaa act gta tat ttt gat ttt caa gtt 384
Glu Phe Ser Thr Phe Thr His Lys Thr Val Tyr Phe Asp Phe Gln Val
115 120 125
gga gaa gac cca cct ttg ttt cct agt gag aac cga gtc agt gct ctt 432
Gly Glu Asp Pro Pro Leu Phe Pro Ser Glu Asn Arg Val Ser Ala Leu
130 135 140
acc cag atg gaa tct gcc tgt gtt tca att cac gaa gct ctg aag tct 480
Thr Gln Met Glu Ser Ala Cys Val Ser Ile His Glu Ala Leu Lys Ser
145 150 155 160
gtc atc gat tat cag act cat ttc cgt tta aga gaa gct caa ggc cga 528
Val Ile Asp Tyr Gln Thr His Phe Arg Leu Arg Glu Ala Gln Gly Arg
165 170 175
agc cga gca gag gat cta aat aca aga gtg gcc tat tgg tca gta gga 576
Ser Arg Ala Glu Asp Leu Asn Thr Arg Val Ala Tyr Trp Ser Val Gly
180 185 190
gaa gcc ctc att ctt ctg gtg gtt agc ata ggg cag gta ttt ctt ttg 624
Glu Ala Leu Ile Leu Leu Val Val Ser Ile Gly Gln Val Phe Leu Leu
195 200 205
aaa agc ttt ttc tca gat aaa aga acc acc aca act cgt gtt gga tca 672
Lys Ser Phe Phe Ser Asp Lys Arg Thr Thr Thr Thr Arg Val Gly Ser
210 215 220
taa 675
<210> 8
<211> 224
<212> PRT
<213> Homo sapiens
<400> 8
Met Pro Arg Pro Gly Ser Ala Gln Arg Trp Ala Ala Val Ala Gly Arg
1 5 10 15
Trp Gly Cys Arg Leu Leu Ala Leu Leu Leu Leu Val Pro Gly Pro Gly
20 25 30
Gly Ala Ser Glu Ile Thr Phe Glu Leu Pro Asp Asn Ala Lys Gln Cys
35 40 45
Phe Tyr Glu Asp Ile Ala Gln Gly Thr Lys Cys Thr Leu Glu Phe Gln
50 55 60
Val Ile Thr Gly Gly His Tyr Asp Val Asp Cys Arg Leu Glu Asp Pro
65 70 75 80
Asp Gly Lys Val Leu Tyr Lys Glu Met Lys Lys Gln Tyr Asp Ser Phe
85 90 95
Thr Phe Thr Ala Ser Lys Asn Gly Thr Tyr Lys Phe Cys Phe Ser Asn
100 105 110
Glu Phe Ser Thr Phe Thr His Lys Thr Val Tyr Phe Asp Phe Gln Val
115 120 125
Gly Glu Asp Pro Pro Leu Phe Pro Ser Glu Asn Arg Val Ser Ala Leu
130 135 140
Thr Gln Met Glu Ser Ala Cys Val Ser Ile His Glu Ala Leu Lys Ser
145 150 155 160
Val Ile Asp Tyr Gln Thr His Phe Arg Leu Arg Glu Ala Gln Gly Arg
165 170 175
Ser Arg Ala Glu Asp Leu Asn Thr Arg Val Ala Tyr Trp Ser Val Gly
180 185 190
Glu Ala Leu Ile Leu Leu Val Val Ser Ile Gly Gln Val Phe Leu Leu
195 200 205
Lys Ser Phe Phe Ser Asp Lys Arg Thr Thr Thr Thr Arg Val Gly Ser
210 215 220
<210> 9
<211> 1008
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(1008)
<400> 9
atg ggg aag tta gaa gac gtg gaa gct gaa aag aaa tta tgg gag agc 48
Met Gly Lys Leu Glu Asp Val Glu Ala Glu Lys Lys Leu Trp Glu Ser
1 5 10 15
gac gat gcg tgg gag ctc cga aaa gca ttc atg ctg gca cat tat gat 96
Asp Asp Ala Trp Glu Leu Arg Lys Ala Phe Met Leu Ala His Tyr Asp
20 25 30
gac tat ccg aaa atc caa ctt caa tgc ctc tca caa tta ttc att aat 144
Asp Tyr Pro Lys Ile Gln Leu Gln Cys Leu Ser Gln Leu Phe Ile Asn
35 40 45
gta aca ctt ctc gga tgt gaa tat tct cag act tta atg caa aag att 192
Val Thr Leu Leu Gly Cys Glu Tyr Ser Gln Thr Leu Met Gln Lys Ile
50 55 60
cga aca atg ggt gct gga att gct gct aac aaa gat cgt aca aaa act 240
Arg Thr Met Gly Ala Gly Ile Ala Ala Asn Lys Asp Arg Thr Lys Thr
65 70 75 80
gga agt tac gtg aag gca tct gca gcg aaa aag cga caa gca gtg aag 288
Gly Ser Tyr Val Lys Ala Ser Ala Ala Lys Lys Arg Gln Ala Val Lys
85 90 95
aca tca gat tta gaa gga gct tct gat gag tct aaa aaa gta aaa atg 336
Thr Ser Asp Leu Glu Gly Ala Ser Asp Glu Ser Lys Lys Val Lys Met
100 105 110
gaa aag tct cca tcg cca gta gct cgt gaa tct ttt gat gaa cgt ctt 384
Glu Lys Ser Pro Ser Pro Val Ala Arg Glu Ser Phe Asp Glu Arg Leu
115 120 125
gga aaa ctc aag gca tct ctt gca atg aca cct cac cat cta acg ggc 432
Gly Lys Leu Lys Ala Ser Leu Ala Met Thr Pro His His Leu Thr Gly
130 135 140
gaa caa atg atg aaa act gcc acg aat agt tgt ctc atg aag tgg cac 480
Glu Gln Met Met Lys Thr Ala Thr Asn Ser Cys Leu Met Lys Trp His
145 150 155 160
gtg aac aag att aac cag aaa att gaa ata act atc gat cga tat gtg 528
Val Asn Lys Ile Asn Gln Lys Ile Glu Ile Thr Ile Asp Arg Tyr Val
165 170 175
gcc ttc aga cat aca ttc tcc caa tac tgt gtt gat cca agg gat tgt 576
Ala Phe Arg His Thr Phe Ser Gln Tyr Cys Val Asp Pro Arg Asp Cys
180 185 190
gca atc aat act cta att gaa agc att ctt tcg tgt gac gcc gct gtt 624
Ala Ile Asn Thr Leu Ile Glu Ser Ile Leu Ser Cys Asp Ala Ala Val
195 200 205
cac gaa gaa agc tac gaa att aga ttt gat gga gtt ccg gtg gac gag 672
His Glu Glu Ser Tyr Glu Ile Arg Phe Asp Gly Val Pro Val Asp Glu
210 215 220
tgt tac gct aaa tca gtc acc aga aga ctt gca aaa att aaa tca gca 720
Cys Tyr Ala Lys Ser Val Thr Arg Arg Leu Ala Lys Ile Lys Ser Ala
225 230 235 240
gtt tct aat ggt gca cat aca gtt aaa ggt ctt aca aca tat ttg gat 768
Val Ser Asn Gly Ala His Thr Val Lys Gly Leu Thr Thr Tyr Leu Asp
245 250 255
gca gtt aac atg tca atg att caa aat act caa aaa ttg gaa gga tgg 816
Ala Val Asn Met Ser Met Ile Gln Asn Thr Gln Lys Leu Glu Gly Trp
260 265 270
tct caa caa ctt gat ctc gtc act gcc gat ctt ctt cta tct tct cgt 864
Ser Gln Gln Leu Asp Leu Val Thr Ala Asp Leu Leu Leu Ser Ser Arg
275 280 285
gtt tta tcc agc act gaa tgc act aaa cca gcg atg gca acg atc gcg 912
Val Leu Ser Ser Thr Glu Cys Thr Lys Pro Ala Met Ala Thr Ile Ala
290 295 300
aat caa atg agc gaa gac gtg tgt caa ctg att ctc aac gat aaa atc 960
Asn Gln Met Ser Glu Asp Val Cys Gln Leu Ile Leu Asn Asp Lys Ile
305 310 315 320
aac gtc att aac tct atg aaa tct cac agc tct ctt gca ttc caa taa 1008
Asn Val Ile Asn Ser Met Lys Ser His Ser Ser Leu Ala Phe Gln
325 330 335
<210> 10
<211> 335
<212> PRT
<213> Caenorhabditis elegans
<400> 10
Met Gly Lys Leu Glu Asp Val Glu Ala Glu Lys Lys Leu Trp Glu Ser
1 5 10 15
Asp Asp Ala Trp Glu Leu Arg Lys Ala Phe Met Leu Ala His Tyr Asp
20 25 30
Asp Tyr Pro Lys Ile Gln Leu Gln Cys Leu Ser Gln Leu Phe Ile Asn
35 40 45
Val Thr Leu Leu Gly Cys Glu Tyr Ser Gln Thr Leu Met Gln Lys Ile
50 55 60
Arg Thr Met Gly Ala Gly Ile Ala Ala Asn Lys Asp Arg Thr Lys Thr
65 70 75 80
Gly Ser Tyr Val Lys Ala Ser Ala Ala Lys Lys Arg Gln Ala Val Lys
85 90 95
Thr Ser Asp Leu Glu Gly Ala Ser Asp Glu Ser Lys Lys Val Lys Met
100 105 110
Glu Lys Ser Pro Ser Pro Val Ala Arg Glu Ser Phe Asp Glu Arg Leu
115 120 125
Gly Lys Leu Lys Ala Ser Leu Ala Met Thr Pro His His Leu Thr Gly
130 135 140
Glu Gln Met Met Lys Thr Ala Thr Asn Ser Cys Leu Met Lys Trp His
145 150 155 160
Val Asn Lys Ile Asn Gln Lys Ile Glu Ile Thr Ile Asp Arg Tyr Val
165 170 175
Ala Phe Arg His Thr Phe Ser Gln Tyr Cys Val Asp Pro Arg Asp Cys
180 185 190
Ala Ile Asn Thr Leu Ile Glu Ser Ile Leu Ser Cys Asp Ala Ala Val
195 200 205
His Glu Glu Ser Tyr Glu Ile Arg Phe Asp Gly Val Pro Val Asp Glu
210 215 220
Cys Tyr Ala Lys Ser Val Thr Arg Arg Leu Ala Lys Ile Lys Ser Ala
225 230 235 240
Val Ser Asn Gly Ala His Thr Val Lys Gly Leu Thr Thr Tyr Leu Asp
245 250 255
Ala Val Asn Met Ser Met Ile Gln Asn Thr Gln Lys Leu Glu Gly Trp
260 265 270
Ser Gln Gln Leu Asp Leu Val Thr Ala Asp Leu Leu Leu Ser Ser Arg
275 280 285
Val Leu Ser Ser Thr Glu Cys Thr Lys Pro Ala Met Ala Thr Ile Ala
290 295 300
Asn Gln Met Ser Glu Asp Val Cys Gln Leu Ile Leu Asn Asp Lys Ile
305 310 315 320
Asn Val Ile Asn Ser Met Lys Ser His Ser Ser Leu Ala Phe Gln
325 330 335
<210> 11
<211> 351
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(351)
<400> 11
atg gtc ggt ggc gag gcg gct gcc gca gtg gag gag ctg gtt tcg ggg 48
Met Val Gly Gly Glu Ala Ala Ala Ala Val Glu Glu Leu Val Ser Gly
1 5 10 15
gtg cgg cag gcg gcc gac ttc gcg gag cag ttc cgc tcc tac tca gag 96
Val Arg Gln Ala Ala Asp Phe Ala Glu Gln Phe Arg Ser Tyr Ser Glu
20 25 30
agc gag aag caa tgg aag gcc cgc atg gaa ttc atc ctg cgc cac ctg 144
Ser Glu Lys Gln Trp Lys Ala Arg Met Glu Phe Ile Leu Arg His Leu
35 40 45
ccc gac tac cgc gac ccg ccc gac ggc agt ggc cgc ctg gac cag ctg 192
Pro Asp Tyr Arg Asp Pro Pro Asp Gly Ser Gly Arg Leu Asp Gln Leu
50 55 60
ctc tcc ctc tcc atg gtc tgg gcc aac cat ctc ttc cta ggc tgc agt 240
Leu Ser Leu Ser Met Val Trp Ala Asn His Leu Phe Leu Gly Cys Ser
65 70 75 80
tac aat aaa gac ctt tta gac aag gtg atg gaa atg gcc gat ggg att 288
Tyr Asn Lys Asp Leu Leu Asp Lys Val Met Glu Met Ala Asp Gly Ile
85 90 95
gaa gtg gaa gac ctg cca caa ttt act acc aga agt gaa tta atg aaa 336
Glu Val Glu Asp Leu Pro Gln Phe Thr Thr Arg Ser Glu Leu Met Lys
100 105 110
aag cat caa agc taa 351
Lys His Gln Ser
115
<210> 12
<211> 116
<212> PRT
<213> Homo sapiens
<400> 12
Met Val Gly Gly Glu Ala Ala Ala Ala Val Glu Glu Leu Val Ser Gly
1 5 10 15
Val Arg Gln Ala Ala Asp Phe Ala Glu Gln Phe Arg Ser Tyr Ser Glu
20 25 30
Ser Glu Lys Gln Trp Lys Ala Arg Met Glu Phe Ile Leu Arg His Leu
35 40 45
Pro Asp Tyr Arg Asp Pro Pro Asp Gly Ser Gly Arg Leu Asp Gln Leu
50 55 60
Leu Ser Leu Ser Met Val Trp Ala Asn His Leu Phe Leu Gly Cys Ser
65 70 75 80
Tyr Asn Lys Asp Leu Leu Asp Lys Val Met Glu Met Ala Asp Gly Ile
85 90 95
Glu Val Glu Asp Leu Pro Gln Phe Thr Thr Arg Ser Glu Leu Met Lys
100 105 110
Lys His Gln Ser
115
<210> 13
<211> 1518
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(1518)
<400> 13
atg cct cgc aca ttt gaa gaa gaa tgt gat ttt atc gat cgc ttg aca 48
Met Pro Arg Thr Phe Glu Glu Glu Cys Asp Phe Ile Asp Arg Leu Thr
1 5 10 15
gac aca aag ttt cga att aag aaa ggt ttt gtg ccg aat atg aat gtg 96
Asp Thr Lys Phe Arg Ile Lys Lys Gly Phe Val Pro Asn Met Asn Val
20 25 30
gag gga cga ttt tat gtg aat aat agt ctc gaa caa tta atg ttt gac 144
Glu Gly Arg Phe Tyr Val Asn Asn Ser Leu Glu Gln Leu Met Phe Asp
35 40 45
gag tta aag ttc tca tgt gat gga caa gga atc ggt gga ttt ttg cca 192
Glu Leu Lys Phe Ser Cys Asp Gly Gln Gly Ile Gly Gly Phe Leu Pro
50 55 60
gcg gtc aga caa att gcc aac gtg gca tcc cta cca gga att gtt gga 240
Ala Val Arg Gln Ile Ala Asn Val Ala Ser Leu Pro Gly Ile Val Gly
65 70 75 80
cat tcg att ggt ctt cca gat att cac tct ggt tat ggt ttt tcc att 288
His Ser Ile Gly Leu Pro Asp Ile His Ser Gly Tyr Gly Phe Ser Ile
85 90 95
gga aac atc gct gcg ttc gac gtt gga aat cca gaa tct gta atc tca 336
Gly Asn Ile Ala Ala Phe Asp Val Gly Asn Pro Glu Ser Val Ile Ser
100 105 110
ccc gga ggc gtc ggt ttt gat atc aac tgt gga gta cga tta ctt cga 384
Pro Gly Gly Val Gly Phe Asp Ile Asn Cys Gly Val Arg Leu Leu Arg
115 120 125
acg aat ctt ttt gaa gaa aat gta aag cca tta aaa gaa caa cta aca 432
Thr Asn Leu Phe Glu Glu Asn Val Lys Pro Leu Lys Glu Gln Leu Thr
130 135 140
caa tca ctt ttt gat cat att cca gtt gga gtt ggt tca cgt ggt gca 480
Gln Ser Leu Phe Asp His Ile Pro Val Gly Val Gly Ser Arg Gly Ala
145 150 155 160
att cca atg ctt gca tca gat ctt gtt gaa tgt tta gaa atg gga atg 528
Ile Pro Met Leu Ala Ser Asp Leu Val Glu Cys Leu Glu Met Gly Met
165 170 175
gat tgg aca tta cgt gaa ggt tat tca tgg gca gaa gat aaa gaa cat 576
Asp Trp Thr Leu Arg Glu Gly Tyr Ser Trp Ala Glu Asp Lys Glu His
180 185 190
tgt gaa gaa tat gga cga atg tta caa gca gat gca tcg aaa gtt tca 624
Cys Glu Glu Tyr Gly Arg Met Leu Gln Ala Asp Ala Ser Lys Val Ser
195 200 205
ttg aga gct aaa aaa cgt gga ctt cca caa ttg gga act ctt gga gca 672
Leu Arg Ala Lys Lys Arg Gly Leu Pro Gln Leu Gly Thr Leu Gly Ala
210 215 220
gga aat cat tac gca gaa gtt caa gtt gtc gat gag att tat gat aaa 720
Gly Asn His Tyr Ala Glu Val Gln Val Val Asp Glu Ile Tyr Asp Lys
225 230 235 240
cat gct gca agt aca atg gga att gat gaa gaa ggg caa gtt gtt gta 768
His Ala Ala Ser Thr Met Gly Ile Asp Glu Glu Gly Gln Val Val Val
245 250 255
atg ctt cat tgt gga agt cga gga ctt gga cat caa gtt gca act gac 816
Met Leu His Cys Gly Ser Arg Gly Leu Gly His Gln Val Ala Thr Asp
260 265 270
tca tta gtt gaa atg gaa aaa gca atg gct aga gat gga att gtt gta 864
Ser Leu Val Glu Met Glu Lys Ala Met Ala Arg Asp Gly Ile Val Val
275 280 285
aat gat aag cag ctt gcg tgt gca aga att aat tcg gtt gaa ggc aaa 912
Asn Asp Lys Gln Leu Ala Cys Ala Arg Ile Asn Ser Val Glu Gly Lys
290 295 300
aac tac ttt tcc gga atg gcg gct gct gca aac ttc gcc tgg gtt aac 960
Asn Tyr Phe Ser Gly Met Ala Ala Ala Ala Asn Phe Ala Trp Val Asn
305 310 315 320
aga tcg tgt atc aca ttc tgt gtt cgt aat gca ttc caa aag aca ttt 1008
Arg Ser Cys Ile Thr Phe Cys Val Arg Asn Ala Phe Gln Lys Thr Phe
325 330 335
gga atg tca gca gat gat atg gat atg caa gta atc tat gac gtg tca 1056
Gly Met Ser Ala Asp Asp Met Asp Met Gln Val Ile Tyr Asp Val Ser
340 345 350
cat aat gta gca aaa atg gaa gag cat atg gtt gat ggt aga cca cgt 1104
His Asn Val Ala Lys Met Glu Glu His Met Val Asp Gly Arg Pro Arg
355 360 365
cag ctg tgt gtt cat cga aaa gga gct aca cgc gct ttt ccg gct cat 1152
Gln Leu Cys Val His Arg Lys Gly Ala Thr Arg Ala Phe Pro Ala His
370 375 380
cat cca tta ata cca gtt gat tat cag tta att gga caa cct gta cta 1200
His Pro Leu Ile Pro Val Asp Tyr Gln Leu Ile Gly Gln Pro Val Leu
385 390 395 400
att ggt gga agt atg gga act tgt agt tat gtt cta aca gga act gaa 1248
Ile Gly Gly Ser Met Gly Thr Cys Ser Tyr Val Leu Thr Gly Thr Glu
405 410 415
caa gga tta gtg gaa act ttt gga aca aca tgt cat gga gct gga cga 1296
Gln Gly Leu Val Glu Thr Phe Gly Thr Thr Cys His Gly Ala Gly Arg
420 425 430
gca ctt tca cgt gcc aaa tca cgc cga act atc act tgg gat tcg gta 1344
Ala Leu Ser Arg Ala Lys Ser Arg Arg Thr Ile Thr Trp Asp Ser Val
435 440 445
att gat gat ttg aaa aag aag gag atc tca att cgc att gca tcg cct 1392
Ile Asp Asp Leu Lys Lys Lys Glu Ile Ser Ile Arg Ile Ala Ser Pro
450 455 460
aaa ttg att atg gaa gaa gca ccc gaa tcg tat aag aat gtg acg gac 1440
Lys Leu Ile Met Glu Glu Ala Pro Glu Ser Tyr Lys Asn Val Thr Asp
465 470 475 480
gtt gta gac acg tgt gat gca gct ggc atc agt aaa aag gcg gtc aaa 1488
Val Val Asp Thr Cys Asp Ala Ala Gly Ile Ser Lys Lys Ala Val Lys
485 490 495
ctg aga cca att gcg gtc atc aag gga taa 1518
Leu Arg Pro Ile Ala Val Ile Lys Gly
500 505
<210> 14
<211> 505
<212> PRT
<213> Caenorhabditis elegans
<400> 14
Met Pro Arg Thr Phe Glu Glu Glu Cys Asp Phe Ile Asp Arg Leu Thr
1 5 10 15
Asp Thr Lys Phe Arg Ile Lys Lys Gly Phe Val Pro Asn Met Asn Val
20 25 30
Glu Gly Arg Phe Tyr Val Asn Asn Ser Leu Glu Gln Leu Met Phe Asp
35 40 45
Glu Leu Lys Phe Ser Cys Asp Gly Gln Gly Ile Gly Gly Phe Leu Pro
50 55 60
Ala Val Arg Gln Ile Ala Asn Val Ala Ser Leu Pro Gly Ile Val Gly
65 70 75 80
His Ser Ile Gly Leu Pro Asp Ile His Ser Gly Tyr Gly Phe Ser Ile
85 90 95
Gly Asn Ile Ala Ala Phe Asp Val Gly Asn Pro Glu Ser Val Ile Ser
100 105 110
Pro Gly Gly Val Gly Phe Asp Ile Asn Cys Gly Val Arg Leu Leu Arg
115 120 125
Thr Asn Leu Phe Glu Glu Asn Val Lys Pro Leu Lys Glu Gln Leu Thr
130 135 140
Gln Ser Leu Phe Asp His Ile Pro Val Gly Val Gly Ser Arg Gly Ala
145 150 155 160
Ile Pro Met Leu Ala Ser Asp Leu Val Glu Cys Leu Glu Met Gly Met
165 170 175
Asp Trp Thr Leu Arg Glu Gly Tyr Ser Trp Ala Glu Asp Lys Glu His
180 185 190
Cys Glu Glu Tyr Gly Arg Met Leu Gln Ala Asp Ala Ser Lys Val Ser
195 200 205
Leu Arg Ala Lys Lys Arg Gly Leu Pro Gln Leu Gly Thr Leu Gly Ala
210 215 220
Gly Asn His Tyr Ala Glu Val Gln Val Val Asp Glu Ile Tyr Asp Lys
225 230 235 240
His Ala Ala Ser Thr Met Gly Ile Asp Glu Glu Gly Gln Val Val Val
245 250 255
Met Leu His Cys Gly Ser Arg Gly Leu Gly His Gln Val Ala Thr Asp
260 265 270
Ser Leu Val Glu Met Glu Lys Ala Met Ala Arg Asp Gly Ile Val Val
275 280 285
Asn Asp Lys Gln Leu Ala Cys Ala Arg Ile Asn Ser Val Glu Gly Lys
290 295 300
Asn Tyr Phe Ser Gly Met Ala Ala Ala Ala Asn Phe Ala Trp Val Asn
305 310 315 320
Arg Ser Cys Ile Thr Phe Cys Val Arg Asn Ala Phe Gln Lys Thr Phe
325 330 335
Gly Met Ser Ala Asp Asp Met Asp Met Gln Val Ile Tyr Asp Val Ser
340 345 350
His Asn Val Ala Lys Met Glu Glu His Met Val Asp Gly Arg Pro Arg
355 360 365
Gln Leu Cys Val His Arg Lys Gly Ala Thr Arg Ala Phe Pro Ala His
370 375 380
His Pro Leu Ile Pro Val Asp Tyr Gln Leu Ile Gly Gln Pro Val Leu
385 390 395 400
Ile Gly Gly Ser Met Gly Thr Cys Ser Tyr Val Leu Thr Gly Thr Glu
405 410 415
Gln Gly Leu Val Glu Thr Phe Gly Thr Thr Cys His Gly Ala Gly Arg
420 425 430
Ala Leu Ser Arg Ala Lys Ser Arg Arg Thr Ile Thr Trp Asp Ser Val
435 440 445
Ile Asp Asp Leu Lys Lys Lys Glu Ile Ser Ile Arg Ile Ala Ser Pro
450 455 460
Lys Leu Ile Met Glu Glu Ala Pro Glu Ser Tyr Lys Asn Val Thr Asp
465 470 475 480
Val Val Asp Thr Cys Asp Ala Ala Gly Ile Ser Lys Lys Ala Val Lys
485 490 495
Leu Arg Pro Ile Ala Val Ile Lys Gly
500 505
<210> 15
<211> 1518
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(1518)
<400> 15
atg agt cgc agc tat aat gat gag ctg cag ttc ttg gag aag atc aat 48
Met Ser Arg Ser Tyr Asn Asp Glu Leu Gln Phe Leu Glu Lys Ile Asn
1 5 10 15
aaa aac tgc tgg agg atc aag aag ggc ttc gtg ccc aac atg cag gtt 96
Lys Asn Cys Trp Arg Ile Lys Lys Gly Phe Val Pro Asn Met Gln Val
20 25 30
gaa ggt gtt ttc tat gtg aat gat gct ctg gag aaa ttg atg ttt gag 144
Glu Gly Val Phe Tyr Val Asn Asp Ala Leu Glu Lys Leu Met Phe Glu
35 40 45
gaa tta agg aat gcc tgt cga ggt ggt ggt gtt ggt ggc ttc ctg cca 192
Glu Leu Arg Asn Ala Cys Arg Gly Gly Gly Val Gly Gly Phe Leu Pro
50 55 60
gcc atg aaa cag att ggc aat gtg gca gcc ctg cct gga att gtt cat 240
Ala Met Lys Gln Ile Gly Asn Val Ala Ala Leu Pro Gly Ile Val His
65 70 75 80
cga tct att ggg ctt cct gat gtc cat tca gga tat ggg ttt gct att 288
Arg Ser Ile Gly Leu Pro Asp Val His Ser Gly Tyr Gly Phe Ala Ile
85 90 95
ggg aac atg gca gcc ttt gat atg aat gac cct gaa gca gta gta tcc 336
Gly Asn Met Ala Ala Phe Asp Met Asn Asp Pro Glu Ala Val Val Ser
100 105 110
cca ggt ggt gtc ggg ttt gac atc aac tgt ggt gtc cgc ttg cta aga 384
Pro Gly Gly Val Gly Phe Asp Ile Asn Cys Gly Val Arg Leu Leu Arg
115 120 125
acc aat tta gat gaa agt gat gtc cag cct gtg aag gag caa ctt gcc 432
Thr Asn Leu Asp Glu Ser Asp Val Gln Pro Val Lys Glu Gln Leu Ala
130 135 140
caa gct atg ttt gac cac att cct gtt ggg gtg ggg tca aaa ggt gtc 480
Gln Ala Met Phe Asp His Ile Pro Val Gly Val Gly Ser Lys Gly Val
145 150 155 160
atc cca atg aat gcc aaa gac ttg gag gag gcc ttg gag atg ggg gtg 528
Ile Pro Met Asn Ala Lys Asp Leu Glu Glu Ala Leu Glu Met Gly Val
165 170 175
gac tgg tcc tta aga gaa ggg tat gcc tgg gct gaa gac aag gag cac 576
Asp Trp Ser Leu Arg Glu Gly Tyr Ala Trp Ala Glu Asp Lys Glu His
180 185 190
tgc gag gag tac gga agg atg ctg cag gct gac ccc aat aaa gtt tct 624
Cys Glu Glu Tyr Gly Arg Met Leu Gln Ala Asp Pro Asn Lys Val Ser
195 200 205
gca agg gcg aag aaa aga ggc ctt cct cag ttg ggg acc ctg gga gca 672
Ala Arg Ala Lys Lys Arg Gly Leu Pro Gln Leu Gly Thr Leu Gly Ala
210 215 220
ggc aac cat tat gca gaa atc cag gtt gtg gat gag att ttc aat gag 720
Gly Asn His Tyr Ala Glu Ile Gln Val Val Asp Glu Ile Phe Asn Glu
225 230 235 240
tat gct gct aaa aaa atg ggc atc gac cat aag gga cag gtg tgt gtg 768
Tyr Ala Ala Lys Lys Met Gly Ile Asp His Lys Gly Gln Val Cys Val
245 250 255
atg atc cac agt gga agc aga ggc ttg ggc cac caa gta gcc aca gat 816
Met Ile His Ser Gly Ser Arg Gly Leu Gly His Gln Val Ala Thr Asp
260 265 270
gcg ctg gta gct atg gag aag gcc atg aag aga gac aag att ata gtc 864
Ala Leu Val Ala Met Glu Lys Ala Met Lys Arg Asp Lys Ile Ile Val
275 280 285
aat gat cgg cag ttg gct tgt gct cga atc gct tcc cca gag ggt caa 912
Asn Asp Arg Gln Leu Ala Cys Ala Arg Ile Ala Ser Pro Glu Gly Gln
290 295 300
gac tat ctg aag gga atg gca gct gct ggg aac tat gcc tgg gtc aac 960
Asp Tyr Leu Lys Gly Met Ala Ala Ala Gly Asn Tyr Ala Trp Val Asn
305 310 315 320
cgc tct tcc atg acc ttc tta acc cgt cag gct ttc gcc aag gtc ttc 1008
Arg Ser Ser Met Thr Phe Leu Thr Arg Gln Ala Phe Ala Lys Val Phe
325 330 335
aac aca acc cct gat gac ttg gac cta cat gtg att tat gat gtt tct 1056
Asn Thr Thr Pro Asp Asp Leu Asp Leu His Val Ile Tyr Asp Val Ser
340 345 350
cac aac att gcc aaa gtg gag cag cat gtg gtg gac gga aag gaa cgg 1104
His Asn Ile Ala Lys Val Glu Gln His Val Val Asp Gly Lys Glu Arg
355 360 365
aca ctg tta gta cac agg aag gga tcc acc cgc gct ttc cct cct cac 1152
Thr Leu Leu Val His Arg Lys Gly Ser Thr Arg Ala Phe Pro Pro His
370 375 380
cat ccc ctc att gct gtt gat tac caa ctc act gga cag cca gtg ctc 1200
His Pro Leu Ile Ala Val Asp Tyr Gln Leu Thr Gly Gln Pro Val Leu
385 390 395 400
att ggt ggc acc atg gga acc tgt agt tat gtt ctt act ggc act gaa 1248
Ile Gly Gly Thr Met Gly Thr Cys Ser Tyr Val Leu Thr Gly Thr Glu
405 410 415
cag ggc atg act gag acc ttt gga aca acc tgt cat gga gcg ggc cgt 1296
Gln Gly Met Thr Glu Thr Phe Gly Thr Thr Cys His Gly Ala Gly Arg
420 425 430
gca ttg tcc cga gca aaa tct cga cgt aat tta gat ttc cag gat gtc 1344
Ala Leu Ser Arg Ala Lys Ser Arg Arg Asn Leu Asp Phe Gln Asp Val
435 440 445
tta gac aaa ttg gca gat atg gga att gcg atc cgt gtt gcc tca ccc 1392
Leu Asp Lys Leu Ala Asp Met Gly Ile Ala Ile Arg Val Ala Ser Pro
450 455 460
aaa ctg gtt atg gaa gag gct cct gag tcc tat aag aat gtg aca gat 1440
Lys Leu Val Met Glu Glu Ala Pro Glu Ser Tyr Lys Asn Val Thr Asp
465 470 475 480
gtg gta aat acc tgc cat gat gct gga atc agc aag aaa gcc att aaa 1488
Val Val Asn Thr Cys His Asp Ala Gly Ile Ser Lys Lys Ala Ile Lys
485 490 495
ctg aga cca att gct gtg atc aaa gga tag 1518
Leu Arg Pro Ile Ala Val Ile Lys Gly
500 505
<210> 16
<211> 505
<212> PRT
<213> Homo sapiens
<400> 16
Met Ser Arg Ser Tyr Asn Asp Glu Leu Gln Phe Leu Glu Lys Ile Asn
1 5 10 15
Lys Asn Cys Trp Arg Ile Lys Lys Gly Phe Val Pro Asn Met Gln Val
20 25 30
Glu Gly Val Phe Tyr Val Asn Asp Ala Leu Glu Lys Leu Met Phe Glu
35 40 45
Glu Leu Arg Asn Ala Cys Arg Gly Gly Gly Val Gly Gly Phe Leu Pro
50 55 60
Ala Met Lys Gln Ile Gly Asn Val Ala Ala Leu Pro Gly Ile Val His
65 70 75 80
Arg Ser Ile Gly Leu Pro Asp Val His Ser Gly Tyr Gly Phe Ala Ile
85 90 95
Gly Asn Met Ala Ala Phe Asp Met Asn Asp Pro Glu Ala Val Val Ser
100 105 110
Pro Gly Gly Val Gly Phe Asp Ile Asn Cys Gly Val Arg Leu Leu Arg
115 120 125
Thr Asn Leu Asp Glu Ser Asp Val Gln Pro Val Lys Glu Gln Leu Ala
130 135 140
Gln Ala Met Phe Asp His Ile Pro Val Gly Val Gly Ser Lys Gly Val
145 150 155 160
Ile Pro Met Asn Ala Lys Asp Leu Glu Glu Ala Leu Glu Met Gly Val
165 170 175
Asp Trp Ser Leu Arg Glu Gly Tyr Ala Trp Ala Glu Asp Lys Glu His
180 185 190
Cys Glu Glu Tyr Gly Arg Met Leu Gln Ala Asp Pro Asn Lys Val Ser
195 200 205
Ala Arg Ala Lys Lys Arg Gly Leu Pro Gln Leu Gly Thr Leu Gly Ala
210 215 220
Gly Asn His Tyr Ala Glu Ile Gln Val Val Asp Glu Ile Phe Asn Glu
225 230 235 240
Tyr Ala Ala Lys Lys Met Gly Ile Asp His Lys Gly Gln Val Cys Val
245 250 255
Met Ile His Ser Gly Ser Arg Gly Leu Gly His Gln Val Ala Thr Asp
260 265 270
Ala Leu Val Ala Met Glu Lys Ala Met Lys Arg Asp Lys Ile Ile Val
275 280 285
Asn Asp Arg Gln Leu Ala Cys Ala Arg Ile Ala Ser Pro Glu Gly Gln
290 295 300
Asp Tyr Leu Lys Gly Met Ala Ala Ala Gly Asn Tyr Ala Trp Val Asn
305 310 315 320
Arg Ser Ser Met Thr Phe Leu Thr Arg Gln Ala Phe Ala Lys Val Phe
325 330 335
Asn Thr Thr Pro Asp Asp Leu Asp Leu His Val Ile Tyr Asp Val Ser
340 345 350
His Asn Ile Ala Lys Val Glu Gln His Val Val Asp Gly Lys Glu Arg
355 360 365
Thr Leu Leu Val His Arg Lys Gly Ser Thr Arg Ala Phe Pro Pro His
370 375 380
His Pro Leu Ile Ala Val Asp Tyr Gln Leu Thr Gly Gln Pro Val Leu
385 390 395 400
Ile Gly Gly Thr Met Gly Thr Cys Ser Tyr Val Leu Thr Gly Thr Glu
405 410 415
Gln Gly Met Thr Glu Thr Phe Gly Thr Thr Cys His Gly Ala Gly Arg
420 425 430
Ala Leu Ser Arg Ala Lys Ser Arg Arg Asn Leu Asp Phe Gln Asp Val
435 440 445
Leu Asp Lys Leu Ala Asp Met Gly Ile Ala Ile Arg Val Ala Ser Pro
450 455 460
Lys Leu Val Met Glu Glu Ala Pro Glu Ser Tyr Lys Asn Val Thr Asp
465 470 475 480
Val Val Asn Thr Cys His Asp Ala Gly Ile Ser Lys Lys Ala Ile Lys
485 490 495
Leu Arg Pro Ile Ala Val Ile Lys Gly
500 505
<210> 17
<211> 1695
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(1695)
<400> 17
atg ggg gtt gtc aat cta cta tcc cga tca tca ttt cca tct gtc gac 48
Met Gly Val Val Asn Leu Leu Ser Arg Ser Ser Phe Pro Ser Val Asp
1 5 10 15
tca tat ctg gca ttg tca gtt ctt gtt gca att gtt gct tct gtc act 96
Ser Tyr Leu Ala Leu Ser Val Leu Val Ala Ile Val Ala Ser Val Thr
20 25 30
gta ttt aca aca ttt cgc tca caa ccc gag cta cag aag ctt atc gaa 144
Val Phe Thr Thr Phe Arg Ser Gln Pro Glu Leu Gln Lys Leu Ile Glu
35 40 45
gaa gaa ctt cgg aat aat aca cga ctg tca tca gca tat ggt ttg aat 192
Glu Glu Leu Arg Asn Asn Thr Arg Leu Ser Ser Ala Tyr Gly Leu Asn
50 55 60
att gaa gca ttg tcc ggg cac aca ttc ttt caa att gct cat tac att 240
Ile Glu Ala Leu Ser Gly His Thr Phe Phe Gln Ile Ala His Tyr Ile
65 70 75 80
tta tct gat aca acg cta atc tgg gtt gct ata aac tcg tat ttt gcc 288
Leu Ser Asp Thr Thr Leu Ile Trp Val Ala Ile Asn Ser Tyr Phe Ala
85 90 95
ata cta gca gtt tgt acg aga cta ata atc aaa tta aca ttc aaa gag 336
Ile Leu Ala Val Cys Thr Arg Leu Ile Ile Lys Leu Thr Phe Lys Glu
100 105 110
ctc gcc cga cag gag gaa aat gtg gcc cgt caa gct ttc ttc tgt tat 384
Leu Ala Arg Gln Glu Glu Asn Val Ala Arg Gln Ala Phe Phe Cys Tyr
115 120 125
gtc ctg tta aca atc gtc tac tta tca gtt gtg atc gga ccg caa aag 432
Val Leu Leu Thr Ile Val Tyr Leu Ser Val Val Ile Gly Pro Gln Lys
130 135 140
ggg cat cgt gta atg cca tgg atg atc tgg ggt ggt att tgt gct ttc 480
Gly His Arg Val Met Pro Trp Met Ile Trp Gly Gly Ile Cys Ala Phe
145 150 155 160
tta tcc cat ttg cag ttt atc aca tgt cag agg ctc aag cat atc tct 528
Leu Ser His Leu Gln Phe Ile Thr Cys Gln Arg Leu Lys His Ile Ser
165 170 175
cca tcc tgt gat cgt gga agt cag aag att tca ttc ctc tcg ttg ttc 576
Pro Ser Cys Asp Arg Gly Ser Gln Lys Ile Ser Phe Leu Ser Leu Phe
180 185 190
ctc ttc ttc gtt tcg att gcc atg acg ttc ttg att tct cga ttc caa 624
Leu Phe Phe Val Ser Ile Ala Met Thr Phe Leu Ile Ser Arg Phe Gln
195 200 205
cat cac tta aca tgg caa cct gct gta ctt tta tat ttt gat tgc ctt 672
His His Leu Thr Trp Gln Pro Ala Val Leu Leu Tyr Phe Asp Cys Leu
210 215 220
ctc gca gta ttc cgt tcc act tac att ctg ttc cga tgc att tct tca 720
Leu Ala Val Phe Arg Ser Thr Tyr Ile Leu Phe Arg Cys Ile Ser Ser
225 230 235 240
tct cgt gta ttc tcc ttc aat cct gac tct gtt cgt cat ttc aac tat 768
Ser Arg Val Phe Ser Phe Asn Pro Asp Ser Val Arg His Phe Asn Tyr
245 250 255
tgg ctc gag ctt atc acc aac ttt gtc tgc gaa ctc att caa atg ctc 816
Trp Leu Glu Leu Ile Thr Asn Phe Val Cys Glu Leu Ile Gln Met Leu
260 265 270
agt ttt gct caa ctt ttg gca ttc tca cct gga ctt aat ctc aca agc 864
Ser Phe Ala Gln Leu Leu Ala Phe Ser Pro Gly Leu Asn Leu Thr Ser
275 280 285
atc ttc ttc ttg tat cac atg aag ctt acc tac aac tgc atg act gaa 912
Ile Phe Phe Leu Tyr His Met Lys Leu Thr Tyr Asn Cys Met Thr Glu
290 295 300
caa tta agt cgt cat cgt aat cat aag aag atc ttc gaa cac att gag 960
Gln Leu Ser Arg His Arg Asn His Lys Lys Ile Phe Glu His Ile Glu
305 310 315 320
aga tca tat cca agt gtt aaa tgt gct aat ggt gat gat cgt tgc gtt 1008
Arg Ser Tyr Pro Ser Val Lys Cys Ala Asn Gly Asp Asp Arg Cys Val
325 330 335
gtt tgc tgg gaa ttg ctc gga aca tct cga aga ctt cca tgc tct cat 1056
Val Cys Trp Glu Leu Leu Gly Thr Ser Arg Arg Leu Pro Cys Ser His
340 345 350
caa ttc cat gat tgg tgt ctc atg tgg tgg ctt gct cag gat tct tca 1104
Gln Phe His Asp Trp Cys Leu Met Trp Trp Leu Ala Gln Asp Ser Ser
355 360 365
tgt cca acg tgt cgt tgt act att cca tct cca caa gat caa atc aga 1152
Cys Pro Thr Cys Arg Cys Thr Ile Pro Ser Pro Gln Asp Gln Ile Arg
370 375 380
caa cca cca gag gtt gga aat agt aca aga tta cgt ttc aat ggt gga 1200
Gln Pro Pro Glu Val Gly Asn Ser Thr Arg Leu Arg Phe Asn Gly Gly
385 390 395 400
tca ttt gga ttc gtt cat ttc cca gca ttc act ctt gaa gta gct gct 1248
Ser Phe Gly Phe Val His Phe Pro Ala Phe Thr Leu Glu Val Ala Ala
405 410 415
aac ttc ggg cct ttc ttt ggt cga gca gcc gaa cca aca gaa gag caa 1296
Asn Phe Gly Pro Phe Phe Gly Arg Ala Ala Glu Pro Thr Glu Glu Gln
420 425 430
ttg caa aca atg ctc gag caa gtc agg gag atg ttc ccg cag atg tct 1344
Leu Gln Thr Met Leu Glu Gln Val Arg Glu Met Phe Pro Gln Met Ser
435 440 445
gtt gat ata ata atg acg gat cta cga caa tcg gga tcc gct cag tct 1392
Val Asp Ile Ile Met Thr Asp Leu Arg Gln Ser Gly Ser Ala Gln Ser
450 455 460
aca atc gaa aat att cta gaa gga agg ata gga atg aat gca tca ttt 1440
Thr Ile Glu Asn Ile Leu Glu Gly Arg Ile Gly Met Asn Ala Ser Phe
465 470 475 480
atg ccc ggt ggg gtt ttg gat gat gaa ctc tca gat gag agt gaa aac 1488
Met Pro Gly Gly Val Leu Asp Asp Glu Leu Ser Asp Glu Ser Glu Asn
485 490 495
gaa ata gaa tat gaa gag ccc gcc gaa ata gtc caa gaa cca gat aat 1536
Glu Ile Glu Tyr Glu Glu Pro Ala Glu Ile Val Gln Glu Pro Asp Asn
500 505 510
ggc cgt caa aga acg tgg aca aaa ttg agt tct tca tca gga gat gaa 1584
Gly Arg Gln Arg Thr Trp Thr Lys Leu Ser Ser Ser Ser Gly Asp Glu
515 520 525
gat cta tca tac tat gaa atc cag cga gcc aaa atg atc gaa act tac 1632
Asp Leu Ser Tyr Tyr Glu Ile Gln Arg Ala Lys Met Ile Glu Thr Tyr
530 535 540
cga cgg aaa tat ctg gag tct gat aaa gct gcc gat cta cga gca atg 1680
Arg Arg Lys Tyr Leu Glu Ser Asp Lys Ala Ala Asp Leu Arg Ala Met
545 550 555 560
gga atc acc gaa taa 1695
Gly Ile Thr Glu
<210> 18
<211> 564
<212> PRT
<213> Caenorhabditis elegans
<400> 18
Met Gly Val Val Asn Leu Leu Ser Arg Ser Ser Phe Pro Ser Val Asp
1 5 10 15
Ser Tyr Leu Ala Leu Ser Val Leu Val Ala Ile Val Ala Ser Val Thr
20 25 30
Val Phe Thr Thr Phe Arg Ser Gln Pro Glu Leu Gln Lys Leu Ile Glu
35 40 45
Glu Glu Leu Arg Asn Asn Thr Arg Leu Ser Ser Ala Tyr Gly Leu Asn
50 55 60
Ile Glu Ala Leu Ser Gly His Thr Phe Phe Gln Ile Ala His Tyr Ile
65 70 75 80
Leu Ser Asp Thr Thr Leu Ile Trp Val Ala Ile Asn Ser Tyr Phe Ala
85 90 95
Ile Leu Ala Val Cys Thr Arg Leu Ile Ile Lys Leu Thr Phe Lys Glu
100 105 110
Leu Ala Arg Gln Glu Glu Asn Val Ala Arg Gln Ala Phe Phe Cys Tyr
115 120 125
Val Leu Leu Thr Ile Val Tyr Leu Ser Val Val Ile Gly Pro Gln Lys
130 135 140
Gly His Arg Val Met Pro Trp Met Ile Trp Gly Gly Ile Cys Ala Phe
145 150 155 160
Leu Ser His Leu Gln Phe Ile Thr Cys Gln Arg Leu Lys His Ile Ser
165 170 175
Pro Ser Cys Asp Arg Gly Ser Gln Lys Ile Ser Phe Leu Ser Leu Phe
180 185 190
Leu Phe Phe Val Ser Ile Ala Met Thr Phe Leu Ile Ser Arg Phe Gln
195 200 205
His His Leu Thr Trp Gln Pro Ala Val Leu Leu Tyr Phe Asp Cys Leu
210 215 220
Leu Ala Val Phe Arg Ser Thr Tyr Ile Leu Phe Arg Cys Ile Ser Ser
225 230 235 240
Ser Arg Val Phe Ser Phe Asn Pro Asp Ser Val Arg His Phe Asn Tyr
245 250 255
Trp Leu Glu Leu Ile Thr Asn Phe Val Cys Glu Leu Ile Gln Met Leu
260 265 270
Ser Phe Ala Gln Leu Leu Ala Phe Ser Pro Gly Leu Asn Leu Thr Ser
275 280 285
Ile Phe Phe Leu Tyr His Met Lys Leu Thr Tyr Asn Cys Met Thr Glu
290 295 300
Gln Leu Ser Arg His Arg Asn His Lys Lys Ile Phe Glu His Ile Glu
305 310 315 320
Arg Ser Tyr Pro Ser Val Lys Cys Ala Asn Gly Asp Asp Arg Cys Val
325 330 335
Val Cys Trp Glu Leu Leu Gly Thr Ser Arg Arg Leu Pro Cys Ser His
340 345 350
Gln Phe His Asp Trp Cys Leu Met Trp Trp Leu Ala Gln Asp Ser Ser
355 360 365
Cys Pro Thr Cys Arg Cys Thr Ile Pro Ser Pro Gln Asp Gln Ile Arg
370 375 380
Gln Pro Pro Glu Val Gly Asn Ser Thr Arg Leu Arg Phe Asn Gly Gly
385 390 395 400
Ser Phe Gly Phe Val His Phe Pro Ala Phe Thr Leu Glu Val Ala Ala
405 410 415
Asn Phe Gly Pro Phe Phe Gly Arg Ala Ala Glu Pro Thr Glu Glu Gln
420 425 430
Leu Gln Thr Met Leu Glu Gln Val Arg Glu Met Phe Pro Gln Met Ser
435 440 445
Val Asp Ile Ile Met Thr Asp Leu Arg Gln Ser Gly Ser Ala Gln Ser
450 455 460
Thr Ile Glu Asn Ile Leu Glu Gly Arg Ile Gly Met Asn Ala Ser Phe
465 470 475 480
Met Pro Gly Gly Val Leu Asp Asp Glu Leu Ser Asp Glu Ser Glu Asn
485 490 495
Glu Ile Glu Tyr Glu Glu Pro Ala Glu Ile Val Gln Glu Pro Asp Asn
500 505 510
Gly Arg Gln Arg Thr Trp Thr Lys Leu Ser Ser Ser Ser Gly Asp Glu
515 520 525
Asp Leu Ser Tyr Tyr Glu Ile Gln Arg Ala Lys Met Ile Glu Thr Tyr
530 535 540
Arg Arg Lys Tyr Leu Glu Ser Asp Lys Ala Ala Asp Leu Arg Ala Met
545 550 555 560
Gly Ile Thr Glu
<210> 19
<211> 1932
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(1932)
<400> 19
atg ccg ctg ctc ttc ctc gag cgc ttc ccc tgg ccc agc ctc cgc acc 48
Met Pro Leu Leu Phe Leu Glu Arg Phe Pro Trp Pro Ser Leu Arg Thr
1 5 10 15
tac acg ggc ctc agc ggc ctg gcc ctg ctg ggc acc atc atc agc gcc 96
Tyr Thr Gly Leu Ser Gly Leu Ala Leu Leu Gly Thr Ile Ile Ser Ala
20 25 30
tac cgc gcg ctc agc cag ccc gag gcc ggc ccc ggc gag ccg gac cag 144
Tyr Arg Ala Leu Ser Gln Pro Glu Ala Gly Pro Gly Glu Pro Asp Gln
35 40 45
cta acg gcc tcg ctg cag cct gag ccg ccg gcg ccc gcc cgg ccg agc 192
Leu Thr Ala Ser Leu Gln Pro Glu Pro Pro Ala Pro Ala Arg Pro Ser
50 55 60
gcc ggg gga ccc cgg gcc cgc gat gtg gcc cag tac ctg ctc tca gac 240
Ala Gly Gly Pro Arg Ala Arg Asp Val Ala Gln Tyr Leu Leu Ser Asp
65 70 75 80
agc ctc ttc gtg tgg gtt cta gta aat acc gct tgc tgt gtt ttg atg 288
Ser Leu Phe Val Trp Val Leu Val Asn Thr Ala Cys Cys Val Leu Met
85 90 95
ttg gtg gct aag ctc atc cag tgt att gtg ttt ggc cct ctt cga gtg 336
Leu Val Ala Lys Leu Ile Gln Cys Ile Val Phe Gly Pro Leu Arg Val
100 105 110
agt gag aga cag cat ctc aaa gac aaa ttt tgg aat ttt att ttc tac 384
Ser Glu Arg Gln His Leu Lys Asp Lys Phe Trp Asn Phe Ile Phe Tyr
115 120 125
aag ttc att ttc atc ttt ggt gtg ctg aat gtc cag aca gtg gaa gag 432
Lys Phe Ile Phe Ile Phe Gly Val Leu Asn Val Gln Thr Val Glu Glu
130 135 140
gtg gtc atg tgg tgc ctc tgg ttt gcc gga ctt gtc ttt ctg cac ctg 480
Val Val Met Trp Cys Leu Trp Phe Ala Gly Leu Val Phe Leu His Leu
145 150 155 160
atg gtt cag ctc tgc aag gat cga ttt gaa tat ctt tcc ttc tcg ccc 528
Met Val Gln Leu Cys Lys Asp Arg Phe Glu Tyr Leu Ser Phe Ser Pro
165 170 175
acc acg ccg atg agc agc cac ggt cga gtc ctg tcc ctg ttg gtt gcc 576
Thr Thr Pro Met Ser Ser His Gly Arg Val Leu Ser Leu Leu Val Ala
180 185 190
atg ctg ctt tcc tgc tgt gga ctg gcg gcc gtc tgc tcc atc acc ggc 624
Met Leu Leu Ser Cys Cys Gly Leu Ala Ala Val Cys Ser Ile Thr Gly
195 200 205
tac acc cac gga atg cac acc ttg gct ttc atg gct gca gag tct ctt 672
Tyr Thr His Gly Met His Thr Leu Ala Phe Met Ala Ala Glu Ser Leu
210 215 220
ctt gtg aca gtg agg act gct cat gtg att tta cga tac gta att cac 720
Leu Val Thr Val Arg Thr Ala His Val Ile Leu Arg Tyr Val Ile His
225 230 235 240
ctc tgg gac ctc aac cac gaa ggg acg tgg gaa gga aag ggg acg tat 768
Leu Trp Asp Leu Asn His Glu Gly Thr Trp Glu Gly Lys Gly Thr Tyr
245 250 255
gtc tat tac aca gac ttt gtc atg gag ctc act ctc ctg tcc ctg gac 816
Val Tyr Tyr Thr Asp Phe Val Met Glu Leu Thr Leu Leu Ser Leu Asp
260 265 270
ctc atg cac cat att cac atg ttg tta ttt ggc aac atc tgg tta tcc 864
Leu Met His His Ile His Met Leu Leu Phe Gly Asn Ile Trp Leu Ser
275 280 285
atg gcc agc ctg gtc atc ttt atg cag ctg cgt tac ctg ttt cat gag 912
Met Ala Ser Leu Val Ile Phe Met Gln Leu Arg Tyr Leu Phe His Glu
290 295 300
gtg caa cgt cga att cgt cgg cac aag aac tat cta cgt gtg gtt gga 960
Val Gln Arg Arg Ile Arg Arg His Lys Asn Tyr Leu Arg Val Val Gly
305 310 315 320
aac atg gag gcc agg ttt gca gtt gca act cca gag gag ctg gct gtc 1008
Asn Met Glu Ala Arg Phe Ala Val Ala Thr Pro Glu Glu Leu Ala Val
325 330 335
aac aat gac gac tgt gcc atc tgt tgg gac tcc atg cag gct gcg cgg 1056
Asn Asn Asp Asp Cys Ala Ile Cys Trp Asp Ser Met Gln Ala Ala Arg
340 345 350
aaa ctg ccc tgt gga cat ctt ttc cac aac tcc tgt ctt cgt tcc tgg 1104
Lys Leu Pro Cys Gly His Leu Phe His Asn Ser Cys Leu Arg Ser Trp
355 360 365
cta gaa caa gac acc tcc tgt cca aca tgc aga atg tct ctt aat att 1152
Leu Glu Gln Asp Thr Ser Cys Pro Thr Cys Arg Met Ser Leu Asn Ile
370 375 380
gcc gac aat aat cgt gtc agg gaa gaa cat caa gga gag aac ttg gat 1200
Ala Asp Asn Asn Arg Val Arg Glu Glu His Gln Gly Glu Asn Leu Asp
385 390 395 400
gag aat ttg gtt cct gta gca gca gcc gaa ggg aga cct cgc tta aac 1248
Glu Asn Leu Val Pro Val Ala Ala Ala Glu Gly Arg Pro Arg Leu Asn
405 410 415
caa cac aat cac ttc ttc cat ttc gat ggg tct cgg att gcg agc tgg 1296
Gln His Asn His Phe Phe His Phe Asp Gly Ser Arg Ile Ala Ser Trp
420 425 430
ctg ccg agt ttt tcg gtt gaa gtg atg cac acc acc aac att ctt ggc 1344
Leu Pro Ser Phe Ser Val Glu Val Met His Thr Thr Asn Ile Leu Gly
435 440 445
att acg cag gcc agc aac tcc cag ctc aat gca atg gct cat cag att 1392
Ile Thr Gln Ala Ser Asn Ser Gln Leu Asn Ala Met Ala His Gln Ile
450 455 460
caa gag atg ttt ccc cag gtt cca tac cat ctg gta ctg cag gac ctc 1440
Gln Glu Met Phe Pro Gln Val Pro Tyr His Leu Val Leu Gln Asp Leu
465 470 475 480
cag ctg aca cgc tca gtt gaa ata aca aca gac aat att tta gaa gga 1488
Gln Leu Thr Arg Ser Val Glu Ile Thr Thr Asp Asn Ile Leu Glu Gly
485 490 495
cgg att caa gta cct ttt cct aca cag cgg tca gat agc atc aga cct 1536
Arg Ile Gln Val Pro Phe Pro Thr Gln Arg Ser Asp Ser Ile Arg Pro
500 505 510
gca ttg aac agt cct gtg gaa agg cca agc agt gac cag gaa gag gga 1584
Ala Leu Asn Ser Pro Val Glu Arg Pro Ser Ser Asp Gln Glu Glu Gly
515 520 525
gaa act tct gct cag acc gag cgt gtg cca ctg gac ctc agt cct cgc 1632
Glu Thr Ser Ala Gln Thr Glu Arg Val Pro Leu Asp Leu Ser Pro Arg
530 535 540
ctg gag gag acg ctg gac ttc ggc gag gtg gaa gtg gag ccc agt gag 1680
Leu Glu Glu Thr Leu Asp Phe Gly Glu Val Glu Val Glu Pro Ser Glu
545 550 555 560
gtg gaa gac ttc gag gct cgt ggg agc cgc ttc tcc aag tct gct gat 1728
Val Glu Asp Phe Glu Ala Arg Gly Ser Arg Phe Ser Lys Ser Ala Asp
565 570 575
gag aga cag cgc atg ctg gtg cag cgt aag gac gaa ctc ctc cag caa 1776
Glu Arg Gln Arg Met Leu Val Gln Arg Lys Asp Glu Leu Leu Gln Gln
580 585 590
gct cgc aaa cgt ttc ttg aac aaa agt tct gaa gat gat gcg gcc tca 1824
Ala Arg Lys Arg Phe Leu Asn Lys Ser Ser Glu Asp Asp Ala Ala Ser
595 600 605
gag agc ttc ctc ccc tcg gaa ggt gcg tcc tct gac ccc gtg acc ctg 1872
Glu Ser Phe Leu Pro Ser Glu Gly Ala Ser Ser Asp Pro Val Thr Leu
610 615 620
cgt cga agg atg ctg gct gcc gcc gcg gaa cgg agg ctt cag aag cag 1920
Arg Arg Arg Met Leu Ala Ala Ala Ala Glu Arg Arg Leu Gln Lys Gln
625 630 635 640
cag acc tcc tag 1932
Gln Thr Ser
<210> 20
<211> 643
<212> PRT
<213> Homo sapiens
<400> 20
Met Pro Leu Leu Phe Leu Glu Arg Phe Pro Trp Pro Ser Leu Arg Thr
1 5 10 15
Tyr Thr Gly Leu Ser Gly Leu Ala Leu Leu Gly Thr Ile Ile Ser Ala
20 25 30
Tyr Arg Ala Leu Ser Gln Pro Glu Ala Gly Pro Gly Glu Pro Asp Gln
35 40 45
Leu Thr Ala Ser Leu Gln Pro Glu Pro Pro Ala Pro Ala Arg Pro Ser
50 55 60
Ala Gly Gly Pro Arg Ala Arg Asp Val Ala Gln Tyr Leu Leu Ser Asp
65 70 75 80
Ser Leu Phe Val Trp Val Leu Val Asn Thr Ala Cys Cys Val Leu Met
85 90 95
Leu Val Ala Lys Leu Ile Gln Cys Ile Val Phe Gly Pro Leu Arg Val
100 105 110
Ser Glu Arg Gln His Leu Lys Asp Lys Phe Trp Asn Phe Ile Phe Tyr
115 120 125
Lys Phe Ile Phe Ile Phe Gly Val Leu Asn Val Gln Thr Val Glu Glu
130 135 140
Val Val Met Trp Cys Leu Trp Phe Ala Gly Leu Val Phe Leu His Leu
145 150 155 160
Met Val Gln Leu Cys Lys Asp Arg Phe Glu Tyr Leu Ser Phe Ser Pro
165 170 175
Thr Thr Pro Met Ser Ser His Gly Arg Val Leu Ser Leu Leu Val Ala
180 185 190
Met Leu Leu Ser Cys Cys Gly Leu Ala Ala Val Cys Ser Ile Thr Gly
195 200 205
Tyr Thr His Gly Met His Thr Leu Ala Phe Met Ala Ala Glu Ser Leu
210 215 220
Leu Val Thr Val Arg Thr Ala His Val Ile Leu Arg Tyr Val Ile His
225 230 235 240
Leu Trp Asp Leu Asn His Glu Gly Thr Trp Glu Gly Lys Gly Thr Tyr
245 250 255
Val Tyr Tyr Thr Asp Phe Val Met Glu Leu Thr Leu Leu Ser Leu Asp
260 265 270
Leu Met His His Ile His Met Leu Leu Phe Gly Asn Ile Trp Leu Ser
275 280 285
Met Ala Ser Leu Val Ile Phe Met Gln Leu Arg Tyr Leu Phe His Glu
290 295 300
Val Gln Arg Arg Ile Arg Arg His Lys Asn Tyr Leu Arg Val Val Gly
305 310 315 320
Asn Met Glu Ala Arg Phe Ala Val Ala Thr Pro Glu Glu Leu Ala Val
325 330 335
Asn Asn Asp Asp Cys Ala Ile Cys Trp Asp Ser Met Gln Ala Ala Arg
340 345 350
Lys Leu Pro Cys Gly His Leu Phe His Asn Ser Cys Leu Arg Ser Trp
355 360 365
Leu Glu Gln Asp Thr Ser Cys Pro Thr Cys Arg Met Ser Leu Asn Ile
370 375 380
Ala Asp Asn Asn Arg Val Arg Glu Glu His Gln Gly Glu Asn Leu Asp
385 390 395 400
Glu Asn Leu Val Pro Val Ala Ala Ala Glu Gly Arg Pro Arg Leu Asn
405 410 415
Gln His Asn His Phe Phe His Phe Asp Gly Ser Arg Ile Ala Ser Trp
420 425 430
Leu Pro Ser Phe Ser Val Glu Val Met His Thr Thr Asn Ile Leu Gly
435 440 445
Ile Thr Gln Ala Ser Asn Ser Gln Leu Asn Ala Met Ala His Gln Ile
450 455 460
Gln Glu Met Phe Pro Gln Val Pro Tyr His Leu Val Leu Gln Asp Leu
465 470 475 480
Gln Leu Thr Arg Ser Val Glu Ile Thr Thr Asp Asn Ile Leu Glu Gly
485 490 495
Arg Ile Gln Val Pro Phe Pro Thr Gln Arg Ser Asp Ser Ile Arg Pro
500 505 510
Ala Leu Asn Ser Pro Val Glu Arg Pro Ser Ser Asp Gln Glu Glu Gly
515 520 525
Glu Thr Ser Ala Gln Thr Glu Arg Val Pro Leu Asp Leu Ser Pro Arg
530 535 540
Leu Glu Glu Thr Leu Asp Phe Gly Glu Val Glu Val Glu Pro Ser Glu
545 550 555 560
Val Glu Asp Phe Glu Ala Arg Gly Ser Arg Phe Ser Lys Ser Ala Asp
565 570 575
Glu Arg Gln Arg Met Leu Val Gln Arg Lys Asp Glu Leu Leu Gln Gln
580 585 590
Ala Arg Lys Arg Phe Leu Asn Lys Ser Ser Glu Asp Asp Ala Ala Ser
595 600 605
Glu Ser Phe Leu Pro Ser Glu Gly Ala Ser Ser Asp Pro Val Thr Leu
610 615 620
Arg Arg Arg Met Leu Ala Ala Ala Ala Glu Arg Arg Leu Gln Lys Gln
625 630 635 640
Gln Thr Ser
<210> 21
<211> 564
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(564)
<400> 21
atg gct caa aaa tcg gct tta atc ata ttg gcg gcc gaa gga gct gag 48
Met Ala Gln Lys Ser Ala Leu Ile Ile Leu Ala Ala Glu Gly Ala Glu
1 5 10 15
gaa atg gag gtc att atc act gga gat gta ctt gct cgt ggt gaa att 96
Glu Met Glu Val Ile Ile Thr Gly Asp Val Leu Ala Arg Gly Glu Ile
20 25 30
cgt gtg gtt tat gcc gga tta gat gga gcc gaa ccg gta aaa tgt gct 144
Arg Val Val Tyr Ala Gly Leu Asp Gly Ala Glu Pro Val Lys Cys Ala
35 40 45
cgc gga gcc cac atc gtg cca gac gtc aaa ctc gaa gac gtg gaa acc 192
Arg Gly Ala His Ile Val Pro Asp Val Lys Leu Glu Asp Val Glu Thr
50 55 60
gaa aaa ttc gat att gtg att ctt cca ggc ggc caa ccg ggc agc aac 240
Glu Lys Phe Asp Ile Val Ile Leu Pro Gly Gly Gln Pro Gly Ser Asn
65 70 75 80
acg ttg gct gaa agc cta ctt gtc cgc gat gtt ctc aag agc caa gta 288
Thr Leu Ala Glu Ser Leu Leu Val Arg Asp Val Leu Lys Ser Gln Val
85 90 95
gag tct ggt ggg ctg att gga gca att tgt gca gct cca att gca ctc 336
Glu Ser Gly Gly Leu Ile Gly Ala Ile Cys Ala Ala Pro Ile Ala Leu
100 105 110
ttg agc cat gga gtc aag gca gaa ctt gtg aca agt cat cca agt gtt 384
Leu Ser His Gly Val Lys Ala Glu Leu Val Thr Ser His Pro Ser Val
115 120 125
aag gag aaa ctc gag aaa gga ggc tac aag tac tcg gag gat cgt gtt 432
Lys Glu Lys Leu Glu Lys Gly Gly Tyr Lys Tyr Ser Glu Asp Arg Val
130 135 140
gtt gtc agt ggc aaa atc atc acc tct cgt gga ccc gga act gcc ttc 480
Val Val Ser Gly Lys Ile Ile Thr Ser Arg Gly Pro Gly Thr Ala Phe
145 150 155 160
gaa ttt gcg ctg aaa att gtg gag ctg ctt gag gga aag gac aag gcc 528
Glu Phe Ala Leu Lys Ile Val Glu Leu Leu Glu Gly Lys Asp Lys Ala
165 170 175
acc agc ctt att gct ccg atg ctc ctg aag ctc taa 564
Thr Ser Leu Ile Ala Pro Met Leu Leu Lys Leu
180 185
<210> 22
<211> 187
<212> PRT
<213> Caenorhabditis elegans
<400> 22
Met Ala Gln Lys Ser Ala Leu Ile Ile Leu Ala Ala Glu Gly Ala Glu
1 5 10 15
Glu Met Glu Val Ile Ile Thr Gly Asp Val Leu Ala Arg Gly Glu Ile
20 25 30
Arg Val Val Tyr Ala Gly Leu Asp Gly Ala Glu Pro Val Lys Cys Ala
35 40 45
Arg Gly Ala His Ile Val Pro Asp Val Lys Leu Glu Asp Val Glu Thr
50 55 60
Glu Lys Phe Asp Ile Val Ile Leu Pro Gly Gly Gln Pro Gly Ser Asn
65 70 75 80
Thr Leu Ala Glu Ser Leu Leu Val Arg Asp Val Leu Lys Ser Gln Val
85 90 95
Glu Ser Gly Gly Leu Ile Gly Ala Ile Cys Ala Ala Pro Ile Ala Leu
100 105 110
Leu Ser His Gly Val Lys Ala Glu Leu Val Thr Ser His Pro Ser Val
115 120 125
Lys Glu Lys Leu Glu Lys Gly Gly Tyr Lys Tyr Ser Glu Asp Arg Val
130 135 140
Val Val Ser Gly Lys Ile Ile Thr Ser Arg Gly Pro Gly Thr Ala Phe
145 150 155 160
Glu Phe Ala Leu Lys Ile Val Glu Leu Leu Glu Gly Lys Asp Lys Ala
165 170 175
Thr Ser Leu Ile Ala Pro Met Leu Leu Lys Leu
180 185
<210> 23
<211> 570
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(570)
<400> 23
atg gct tcc aaa aga gct ctg gtc atc ctg gct aaa gga gca gag gaa 48
Met Ala Ser Lys Arg Ala Leu Val Ile Leu Ala Lys Gly Ala Glu Glu
1 5 10 15
atg gag acg gtc atc cct gta gat gtc atg agg cga gct ggg att aag 96
Met Glu Thr Val Ile Pro Val Asp Val Met Arg Arg Ala Gly Ile Lys
20 25 30
gtc acc gtt gca ggc ctg gct gga aaa gac cca gta cag tgt agc cgt 144
Val Thr Val Ala Gly Leu Ala Gly Lys Asp Pro Val Gln Cys Ser Arg
35 40 45
gat gtg gtc att tgt cct gat gcc agc ctt gaa gat gca aaa aaa gag 192
Asp Val Val Ile Cys Pro Asp Ala Ser Leu Glu Asp Ala Lys Lys Glu
50 55 60
gga cca tat gat gtg gtg gtt cta cca gga ggt aat ctg ggc gca cag 240
Gly Pro Tyr Asp Val Val Val Leu Pro Gly Gly Asn Leu Gly Ala Gln
65 70 75 80
aat tta tct gag tct gct gct gtg aag gag ata ctg aag gag cag gaa 288
Asn Leu Ser Glu Ser Ala Ala Val Lys Glu Ile Leu Lys Glu Gln Glu
85 90 95
aac cgg aag ggc ctg ata gcc gcc atc tgt gca ggt cct act gct ctg 336
Asn Arg Lys Gly Leu Ile Ala Ala Ile Cys Ala Gly Pro Thr Ala Leu
100 105 110
ttg gct cat gaa ata ggt ttt gga agt aaa gtt aca aca cac cct ctt 384
Leu Ala His Glu Ile Gly Phe Gly Ser Lys Val Thr Thr His Pro Leu
115 120 125
gct aaa gac aaa atg atg aat gga ggt cat tac acc tac tct gag aat 432
Ala Lys Asp Lys Met Met Asn Gly Gly His Tyr Thr Tyr Ser Glu Asn
130 135 140
cgt gtg gaa aaa gac ggc ctg att ctt aca agc cgg ggg cct ggg acc 480
Arg Val Glu Lys Asp Gly Leu Ile Leu Thr Ser Arg Gly Pro Gly Thr
145 150 155 160
agc ttc gag ttt gcg ctt gca att gtt gaa gcc ctg aat ggc aag gag 528
Ser Phe Glu Phe Ala Leu Ala Ile Val Glu Ala Leu Asn Gly Lys Glu
165 170 175
gtg gcg gct caa gtg aag gct cca ctt gtt ctt aaa gac tag 570
Val Ala Ala Gln Val Lys Ala Pro Leu Val Leu Lys Asp
180 185
<210> 24
<211> 189
<212> PRT
<213> Homo sapiens
<400> 24
Met Ala Ser Lys Arg Ala Leu Val Ile Leu Ala Lys Gly Ala Glu Glu
1 5 10 15
Met Glu Thr Val Ile Pro Val Asp Val Met Arg Arg Ala Gly Ile Lys
20 25 30
Val Thr Val Ala Gly Leu Ala Gly Lys Asp Pro Val Gln Cys Ser Arg
35 40 45
Asp Val Val Ile Cys Pro Asp Ala Ser Leu Glu Asp Ala Lys Lys Glu
50 55 60
Gly Pro Tyr Asp Val Val Val Leu Pro Gly Gly Asn Leu Gly Ala Gln
65 70 75 80
Asn Leu Ser Glu Ser Ala Ala Val Lys Glu Ile Leu Lys Glu Gln Glu
85 90 95
Asn Arg Lys Gly Leu Ile Ala Ala Ile Cys Ala Gly Pro Thr Ala Leu
100 105 110
Leu Ala His Glu Ile Gly Phe Gly Ser Lys Val Thr Thr His Pro Leu
115 120 125
Ala Lys Asp Lys Met Met Asn Gly Gly His Tyr Thr Tyr Ser Glu Asn
130 135 140
Arg Val Glu Lys Asp Gly Leu Ile Leu Thr Ser Arg Gly Pro Gly Thr
145 150 155 160
Ser Phe Glu Phe Ala Leu Ala Ile Val Glu Ala Leu Asn Gly Lys Glu
165 170 175
Val Ala Ala Gln Val Lys Ala Pro Leu Val Leu Lys Asp
180 185
<210> 25
<211> 1926
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(1926)
<400> 25
atg tct atg aaa cga ttc gga aaa gca gca tat cga atc gca aat gag 48
Met Ser Met Lys Arg Phe Gly Lys Ala Ala Tyr Arg Ile Ala Asn Glu
1 5 10 15
tta gtt gca aaa ggt gga cga cta cca att ttc caa cgc ttc ctg ccg 96
Leu Val Ala Lys Gly Gly Arg Leu Pro Ile Phe Gln Arg Phe Leu Pro
20 25 30
aga ata ttt ccc gcc act tat aat tta gga gtt cat gtc gta ctc aaa 144
Arg Ile Phe Pro Ala Thr Tyr Asn Leu Gly Val His Val Val Leu Lys
35 40 45
aag gct cca ttt cca cga caa aat gct cta cga att gct cgc ctt gta 192
Lys Ala Pro Phe Pro Arg Gln Asn Ala Leu Arg Ile Ala Arg Leu Val
50 55 60
act cgc cac ggt cga gtt ttc cgg cca ttt tcc tca gta ata atc gaa 240
Thr Arg His Gly Arg Val Phe Arg Pro Phe Ser Ser Val Ile Ile Glu
65 70 75 80
aga cat cga ttt caa aat caa aat gat tgg cgt cga aag ttt caa ccg 288
Arg His Arg Phe Gln Asn Gln Asn Asp Trp Arg Arg Lys Phe Gln Pro
85 90 95
att cgt aaa gaa ttg cca aga aat gtg gat tta gtc gaa cga atc agg 336
Ile Arg Lys Glu Leu Pro Arg Asn Val Asp Leu Val Glu Arg Ile Arg
100 105 110
cag ata ttt ggc aat tct cta cga tac aat gag gat ttg aaa agc act 384
Gln Ile Phe Gly Asn Ser Leu Arg Tyr Asn Glu Asp Leu Lys Ser Thr
115 120 125
gaa tgg ccg aat aga att gat tct tat gag ttt ggg gaa ttt ctc ggt 432
Glu Trp Pro Asn Arg Ile Asp Ser Tyr Glu Phe Gly Glu Phe Leu Gly
130 135 140
caa gga tgc aat gca gca gtt tac tct gcg aga tta gcc aat tct gat 480
Gln Gly Cys Asn Ala Ala Val Tyr Ser Ala Arg Leu Ala Asn Ser Asp
145 150 155 160
gca gaa tcc tca ggg aat act cac tat ggt gca ggg ttt aat gaa gtc 528
Ala Glu Ser Ser Gly Asn Thr His Tyr Gly Ala Gly Phe Asn Glu Val
165 170 175
aca aat ata ctt gca gaa att ccg cca gtt agc aaa gtt gca caa aag 576
Thr Asn Ile Leu Ala Glu Ile Pro Pro Val Ser Lys Val Ala Gln Lys
180 185 190
aaa ttc ccg ttg gca atc aaa tta atg ttt aat ttt gaa cat gat cgc 624
Lys Phe Pro Leu Ala Ile Lys Leu Met Phe Asn Phe Glu His Asp Arg
195 200 205
gat gga gat gct cat ctc ttg aaa tca atg gga aat gaa ttg gct cca 672
Asp Gly Asp Ala His Leu Leu Lys Ser Met Gly Asn Glu Leu Ala Pro
210 215 220
tat ccg aat gct gca aag ttg ctc aat gga caa atg gga aca ttt aga 720
Tyr Pro Asn Ala Ala Lys Leu Leu Asn Gly Gln Met Gly Thr Phe Arg
225 230 235 240
cct ctt cca gca aaa cat cca aat gtt gtt cga att cag aca gct ttt 768
Pro Leu Pro Ala Lys His Pro Asn Val Val Arg Ile Gln Thr Ala Phe
245 250 255
att gat tcg tta aaa gtt ttg cca gat gcg att gaa cga tat cca gat 816
Ile Asp Ser Leu Lys Val Leu Pro Asp Ala Ile Glu Arg Tyr Pro Asp
260 265 270
gcc ctt cac act gca cgt tgg tat gag tca att gcc tcc gaa ccg aaa 864
Ala Leu His Thr Ala Arg Trp Tyr Glu Ser Ile Ala Ser Glu Pro Lys
275 280 285
aca atg tac gta gta atg aga cga tac cga caa aca ctt cat gaa tat 912
Thr Met Tyr Val Val Met Arg Arg Tyr Arg Gln Thr Leu His Glu Tyr
290 295 300
gta tgg act cgt cat cga aat tat tgg aca gga cga gtg ata att gct 960
Val Trp Thr Arg His Arg Asn Tyr Trp Thr Gly Arg Val Ile Ile Ala
305 310 315 320
caa cta tta gaa gca tgt aca tat ctt cat aag cat aaa gtt gct cag 1008
Gln Leu Leu Glu Ala Cys Thr Tyr Leu His Lys His Lys Val Ala Gln
325 330 335
cga gac atg aaa agt gat aat att ctt ctg gaa tat gat ttt gac gac 1056
Arg Asp Met Lys Ser Asp Asn Ile Leu Leu Glu Tyr Asp Phe Asp Asp
340 345 350
gag att ccc caa tta gtt gtc gcc gat ttt gga tgt gca ctt gca tgt 1104
Glu Ile Pro Gln Leu Val Val Ala Asp Phe Gly Cys Ala Leu Ala Cys
355 360 365
gac aat tgg caa gta gac tat gaa tca gat gaa gtt agt ctt gga gga 1152
Asp Asn Trp Gln Val Asp Tyr Glu Ser Asp Glu Val Ser Leu Gly Gly
370 375 380
aat gcc aag aca aaa gca cca gaa att gcg acg gct gtt cct gga aag 1200
Asn Ala Lys Thr Lys Ala Pro Glu Ile Ala Thr Ala Val Pro Gly Lys
385 390 395 400
aat gta aaa gta aac ttc gaa atg gca gat aca tgg gca gct gga ggc 1248
Asn Val Lys Val Asn Phe Glu Met Ala Asp Thr Trp Ala Ala Gly Gly
405 410 415
ctt tct tat gaa gtt cta aca cga tca aat cca ttc tac aaa ctt ctt 1296
Leu Ser Tyr Glu Val Leu Thr Arg Ser Asn Pro Phe Tyr Lys Leu Leu
420 425 430
gat act gca aca tac cag gaa tca gaa cta cca gca ctc cca tct cgt 1344
Asp Thr Ala Thr Tyr Gln Glu Ser Glu Leu Pro Ala Leu Pro Ser Arg
435 440 445
gtc aat ttt gtg gca cga gat gtc att ttt gac cta ctc aag cga gat 1392
Val Asn Phe Val Ala Arg Asp Val Ile Phe Asp Leu Leu Lys Arg Asp
450 455 460
cct aat gaa aga gtc aag ccg aat att gct gca aat gcg ttg aat ttg 1440
Pro Asn Glu Arg Val Lys Pro Asn Ile Ala Ala Asn Ala Leu Asn Leu
465 470 475 480
tca ttg ttc aga atg gga gaa gat gtg aag cag atg atg gaa aaa tgt 1488
Ser Leu Phe Arg Met Gly Glu Asp Val Lys Gln Met Met Glu Lys Cys
485 490 495
gga ata tct caa atg act act cta ttg gct gga agt tct aaa gtt ttg 1536
Gly Ile Ser Gln Met Thr Thr Leu Leu Ala Gly Ser Ser Lys Val Leu
500 505 510
agt caa aaa atc aat agt cgt ctg gac aaa gtg atg aat ctg att act 1584
Ser Gln Lys Ile Asn Ser Arg Leu Asp Lys Val Met Asn Leu Ile Thr
515 520 525
gct gaa act atc atg gcc aac cta gct cca cat ttg att agt cga gca 1632
Ala Glu Thr Ile Met Ala Asn Leu Ala Pro His Leu Ile Ser Arg Ala
530 535 540
gaa cga caa ctt cga gca aca ttt ctt tca aga atg aat cga gaa gat 1680
Glu Arg Gln Leu Arg Ala Thr Phe Leu Ser Arg Met Asn Arg Glu Asp
545 550 555 560
att tgg aga agt ctt caa tat ttc ttc cca gct ggt gtt caa ctt gac 1728
Ile Trp Arg Ser Leu Gln Tyr Phe Phe Pro Ala Gly Val Gln Leu Asp
565 570 575
aca cct gcc aca tca tca gac tgt ttg gag act att tcc agt ttg atg 1776
Thr Pro Ala Thr Ser Ser Asp Cys Leu Glu Thr Ile Ser Ser Leu Met
580 585 590
tcg agt ttt tca aat gat tca gaa aat tac gag aag caa cag aaa ccg 1824
Ser Ser Phe Ser Asn Asp Ser Glu Asn Tyr Glu Lys Gln Gln Lys Pro
595 600 605
gct aaa aat gga tac aac aat gtt cca ctt ctt ctc aga aat gtt atc 1872
Ala Lys Asn Gly Tyr Asn Asn Val Pro Leu Leu Leu Arg Asn Val Ile
610 615 620
cgt aca gat gcg gat gga atc aat gga att gta cat aga gtt cga tct 1920
Arg Thr Asp Ala Asp Gly Ile Asn Gly Ile Val His Arg Val Arg Ser
625 630 635 640
aaa tag 1926
Lys
<210> 26
<211> 641
<212> PRT
<213> Caenorhabditis elegans
<400> 26
Met Ser Met Lys Arg Phe Gly Lys Ala Ala Tyr Arg Ile Ala Asn Glu
1 5 10 15
Leu Val Ala Lys Gly Gly Arg Leu Pro Ile Phe Gln Arg Phe Leu Pro
20 25 30
Arg Ile Phe Pro Ala Thr Tyr Asn Leu Gly Val His Val Val Leu Lys
35 40 45
Lys Ala Pro Phe Pro Arg Gln Asn Ala Leu Arg Ile Ala Arg Leu Val
50 55 60
Thr Arg His Gly Arg Val Phe Arg Pro Phe Ser Ser Val Ile Ile Glu
65 70 75 80
Arg His Arg Phe Gln Asn Gln Asn Asp Trp Arg Arg Lys Phe Gln Pro
85 90 95
Ile Arg Lys Glu Leu Pro Arg Asn Val Asp Leu Val Glu Arg Ile Arg
100 105 110
Gln Ile Phe Gly Asn Ser Leu Arg Tyr Asn Glu Asp Leu Lys Ser Thr
115 120 125
Glu Trp Pro Asn Arg Ile Asp Ser Tyr Glu Phe Gly Glu Phe Leu Gly
130 135 140
Gln Gly Cys Asn Ala Ala Val Tyr Ser Ala Arg Leu Ala Asn Ser Asp
145 150 155 160
Ala Glu Ser Ser Gly Asn Thr His Tyr Gly Ala Gly Phe Asn Glu Val
165 170 175
Thr Asn Ile Leu Ala Glu Ile Pro Pro Val Ser Lys Val Ala Gln Lys
180 185 190
Lys Phe Pro Leu Ala Ile Lys Leu Met Phe Asn Phe Glu His Asp Arg
195 200 205
Asp Gly Asp Ala His Leu Leu Lys Ser Met Gly Asn Glu Leu Ala Pro
210 215 220
Tyr Pro Asn Ala Ala Lys Leu Leu Asn Gly Gln Met Gly Thr Phe Arg
225 230 235 240
Pro Leu Pro Ala Lys His Pro Asn Val Val Arg Ile Gln Thr Ala Phe
245 250 255
Ile Asp Ser Leu Lys Val Leu Pro Asp Ala Ile Glu Arg Tyr Pro Asp
260 265 270
Ala Leu His Thr Ala Arg Trp Tyr Glu Ser Ile Ala Ser Glu Pro Lys
275 280 285
Thr Met Tyr Val Val Met Arg Arg Tyr Arg Gln Thr Leu His Glu Tyr
290 295 300
Val Trp Thr Arg His Arg Asn Tyr Trp Thr Gly Arg Val Ile Ile Ala
305 310 315 320
Gln Leu Leu Glu Ala Cys Thr Tyr Leu His Lys His Lys Val Ala Gln
325 330 335
Arg Asp Met Lys Ser Asp Asn Ile Leu Leu Glu Tyr Asp Phe Asp Asp
340 345 350
Glu Ile Pro Gln Leu Val Val Ala Asp Phe Gly Cys Ala Leu Ala Cys
355 360 365
Asp Asn Trp Gln Val Asp Tyr Glu Ser Asp Glu Val Ser Leu Gly Gly
370 375 380
Asn Ala Lys Thr Lys Ala Pro Glu Ile Ala Thr Ala Val Pro Gly Lys
385 390 395 400
Asn Val Lys Val Asn Phe Glu Met Ala Asp Thr Trp Ala Ala Gly Gly
405 410 415
Leu Ser Tyr Glu Val Leu Thr Arg Ser Asn Pro Phe Tyr Lys Leu Leu
420 425 430
Asp Thr Ala Thr Tyr Gln Glu Ser Glu Leu Pro Ala Leu Pro Ser Arg
435 440 445
Val Asn Phe Val Ala Arg Asp Val Ile Phe Asp Leu Leu Lys Arg Asp
450 455 460
Pro Asn Glu Arg Val Lys Pro Asn Ile Ala Ala Asn Ala Leu Asn Leu
465 470 475 480
Ser Leu Phe Arg Met Gly Glu Asp Val Lys Gln Met Met Glu Lys Cys
485 490 495
Gly Ile Ser Gln Met Thr Thr Leu Leu Ala Gly Ser Ser Lys Val Leu
500 505 510
Ser Gln Lys Ile Asn Ser Arg Leu Asp Lys Val Met Asn Leu Ile Thr
515 520 525
Ala Glu Thr Ile Met Ala Asn Leu Ala Pro His Leu Ile Ser Arg Ala
530 535 540
Glu Arg Gln Leu Arg Ala Thr Phe Leu Ser Arg Met Asn Arg Glu Asp
545 550 555 560
Ile Trp Arg Ser Leu Gln Tyr Phe Phe Pro Ala Gly Val Gln Leu Asp
565 570 575
Thr Pro Ala Thr Ser Ser Asp Cys Leu Glu Thr Ile Ser Ser Leu Met
580 585 590
Ser Ser Phe Ser Asn Asp Ser Glu Asn Tyr Glu Lys Gln Gln Lys Pro
595 600 605
Ala Lys Asn Gly Tyr Asn Asn Val Pro Leu Leu Leu Arg Asn Val Ile
610 615 620
Arg Thr Asp Ala Asp Gly Ile Asn Gly Ile Val His Arg Val Arg Ser
625 630 635 640
Lys
<210> 27
<211> 1746
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(1746)
<400> 27
atg gcg gtg cga cag gcg ctg ggc cgc ggc ctg cag ctg ggt cga gcg 48
Met Ala Val Arg Gln Ala Leu Gly Arg Gly Leu Gln Leu Gly Arg Ala
1 5 10 15
ctg ctg ctg cgc ttc acg ggc aag ccc ggc cgg gcc tac ggc ttg ggg 96
Leu Leu Leu Arg Phe Thr Gly Lys Pro Gly Arg Ala Tyr Gly Leu Gly
20 25 30
cgg ccg ggc ccg gcg gcg ggc tgt gtc cgc ggg gag cgt cca ggc tgg 144
Arg Pro Gly Pro Ala Ala Gly Cys Val Arg Gly Glu Arg Pro Gly Trp
35 40 45
gcc gca gga ccg ggc gcg gag cct cgc agg gtc ggg ctc ggg ctc cct 192
Ala Ala Gly Pro Gly Ala Glu Pro Arg Arg Val Gly Leu Gly Leu Pro
50 55 60
aac cgt ctc cgc ttc ttc cgc cag tcg gtg gcc ggg ctg gcg gcg cgg 240
Asn Arg Leu Arg Phe Phe Arg Gln Ser Val Ala Gly Leu Ala Ala Arg
65 70 75 80
ttg cag cgg cag ttc gtg gtg cgg gcc tgg ggc tgc gcg ggc cct tgc 288
Leu Gln Arg Gln Phe Val Val Arg Ala Trp Gly Cys Ala Gly Pro Cys
85 90 95
ggc cgg gca gtc ttt ctg gcc ttc ggg cta ggg ctg ggc ctc atc gag 336
Gly Arg Ala Val Phe Leu Ala Phe Gly Leu Gly Leu Gly Leu Ile Glu
100 105 110
gaa aaa cag gcg gag agc cgg cgg gcg gtc tcg gcc tgt cag gag atc 384
Glu Lys Gln Ala Glu Ser Arg Arg Ala Val Ser Ala Cys Gln Glu Ile
115 120 125
cag gca att ttt acc cag aaa agc aag ccg ggg cct gac ccg ttg gac 432
Gln Ala Ile Phe Thr Gln Lys Ser Lys Pro Gly Pro Asp Pro Leu Asp
130 135 140
acg aga cgc ttg cag ggc ttt cgg ctg gag gag tat ctg ata ggg cag 480
Thr Arg Arg Leu Gln Gly Phe Arg Leu Glu Glu Tyr Leu Ile Gly Gln
145 150 155 160
tcc att ggt aag ggc tgc agt gct gct gtg tat gaa gcc acc atg cct 528
Ser Ile Gly Lys Gly Cys Ser Ala Ala Val Tyr Glu Ala Thr Met Pro
165 170 175
aca ttg ccc cag aac ctg gag gtg aca aag agc acc ggg ttg ctt cca 576
Thr Leu Pro Gln Asn Leu Glu Val Thr Lys Ser Thr Gly Leu Leu Pro
180 185 190
ggg aga ggc cca ggt acc agt gca cca gga gaa ggg cag gag cga gct 624
Gly Arg Gly Pro Gly Thr Ser Ala Pro Gly Glu Gly Gln Glu Arg Ala
195 200 205
ccg ggg gcc cct gcc ttc ccc ttg gcc atc aag atg atg tgg aac atc 672
Pro Gly Ala Pro Ala Phe Pro Leu Ala Ile Lys Met Met Trp Asn Ile
210 215 220
tcg gca ggt tcc tcc agc gaa gcc atc ttg aac aca atg agc cag gag 720
Ser Ala Gly Ser Ser Ser Glu Ala Ile Leu Asn Thr Met Ser Gln Glu
225 230 235 240
ctg gtc cca gcg agc cga gtg gcc ttg gct ggg gag tat gga gca gtc 768
Leu Val Pro Ala Ser Arg Val Ala Leu Ala Gly Glu Tyr Gly Ala Val
245 250 255
act tac aga aaa tcc aag aga ggt ccc aag caa cta gcc cct cac ccc 816
Thr Tyr Arg Lys Ser Lys Arg Gly Pro Lys Gln Leu Ala Pro His Pro
260 265 270
aac atc atc cgg gtt ctc cgc gcc ttc acc tct tcc gtg ccg ctg ctg 864
Asn Ile Ile Arg Val Leu Arg Ala Phe Thr Ser Ser Val Pro Leu Leu
275 280 285
cca ggg gcc ctg gtc gac tac cct gat gtg ctg ccc tca cgc ctc cac 912
Pro Gly Ala Leu Val Asp Tyr Pro Asp Val Leu Pro Ser Arg Leu His
290 295 300
cct gaa ggc ctg ggc cat ggc cgg acg ctg ttc ctc gtt atg aag aac 960
Pro Glu Gly Leu Gly His Gly Arg Thr Leu Phe Leu Val Met Lys Asn
305 310 315 320
tat ccc tgt acc ctg cgc cag tac ctt tgt gtg aac aca ccc agc ccc 1008
Tyr Pro Cys Thr Leu Arg Gln Tyr Leu Cys Val Asn Thr Pro Ser Pro
325 330 335
cgc ctc gcc gcc atg atg ctg ctg cag ctg ctg gaa ggc gtg gac cat 1056
Arg Leu Ala Ala Met Met Leu Leu Gln Leu Leu Glu Gly Val Asp His
340 345 350
ctg gtt caa cag ggc atc gcg cac aga gac ctg aaa tcc gac aac atc 1104
Leu Val Gln Gln Gly Ile Ala His Arg Asp Leu Lys Ser Asp Asn Ile
355 360 365
ctt gtg gag ctg gac cca gac ggc tgc ccc tgg ctg gtg atc gca gat 1152
Leu Val Glu Leu Asp Pro Asp Gly Cys Pro Trp Leu Val Ile Ala Asp
370 375 380
ttt ggc tgc tgc ctg gct gat gag agc atc ggc ctg cag ttg ccc ttc 1200
Phe Gly Cys Cys Leu Ala Asp Glu Ser Ile Gly Leu Gln Leu Pro Phe
385 390 395 400
agc agc tgg tac gtg gat cgg ggc gga aac ggc tgt ctg atg gcc cca 1248
Ser Ser Trp Tyr Val Asp Arg Gly Gly Asn Gly Cys Leu Met Ala Pro
405 410 415
gag gtg tcc acg gcc cgt cct ggc ccc agg gca gtg att gac tac agc 1296
Glu Val Ser Thr Ala Arg Pro Gly Pro Arg Ala Val Ile Asp Tyr Ser
420 425 430
aag gct gat gcc tgg gca gtg gga gcc atc gcc tat gaa atc ttc ggg 1344
Lys Ala Asp Ala Trp Ala Val Gly Ala Ile Ala Tyr Glu Ile Phe Gly
435 440 445
ctt gtc aat ccc ttc tac ggc cag ggc aag gcc cac ctt gaa agc cgc 1392
Leu Val Asn Pro Phe Tyr Gly Gln Gly Lys Ala His Leu Glu Ser Arg
450 455 460
agc tac caa gag gct cag cta cct gca ctg ccc gag tca gtg cct cca 1440
Ser Tyr Gln Glu Ala Gln Leu Pro Ala Leu Pro Glu Ser Val Pro Pro
465 470 475 480
gac gtg aga cag ttg gtg agg gca ctg ctc cag cga gag gcc agc aag 1488
Asp Val Arg Gln Leu Val Arg Ala Leu Leu Gln Arg Glu Ala Ser Lys
485 490 495
aga cca tct gcc cga gta gcc gca aat gtg ctt cat cta agc ctc tgg 1536
Arg Pro Ser Ala Arg Val Ala Ala Asn Val Leu His Leu Ser Leu Trp
500 505 510
ggt gaa cat att cta gcc ctg aag aat ctg aag tta gac aag atg gtt 1584
Gly Glu His Ile Leu Ala Leu Lys Asn Leu Lys Leu Asp Lys Met Val
515 520 525
ggc tgg ctc ctc caa caa tcg gcc gcc act ttg ttg gcc aac agg ctc 1632
Gly Trp Leu Leu Gln Gln Ser Ala Ala Thr Leu Leu Ala Asn Arg Leu
530 535 540
aca gag aag tgt tgt gtg gaa aca aaa atg aag atg ctc ttt ctg gct 1680
Thr Glu Lys Cys Cys Val Glu Thr Lys Met Lys Met Leu Phe Leu Ala
545 550 555 560
aac ctg gag tgt gaa acg ctc tgc cag gca gcc ctc ctc ctc tgc tca 1728
Asn Leu Glu Cys Glu Thr Leu Cys Gln Ala Ala Leu Leu Leu Cys Ser
565 570 575
tgg agg gca gcc ctg tga 1746
Trp Arg Ala Ala Leu
580
<210> 28
<211> 581
<212> PRT
<213> Homo sapiens
<400> 28
Met Ala Val Arg Gln Ala Leu Gly Arg Gly Leu Gln Leu Gly Arg Ala
1 5 10 15
Leu Leu Leu Arg Phe Thr Gly Lys Pro Gly Arg Ala Tyr Gly Leu Gly
20 25 30
Arg Pro Gly Pro Ala Ala Gly Cys Val Arg Gly Glu Arg Pro Gly Trp
35 40 45
Ala Ala Gly Pro Gly Ala Glu Pro Arg Arg Val Gly Leu Gly Leu Pro
50 55 60
Asn Arg Leu Arg Phe Phe Arg Gln Ser Val Ala Gly Leu Ala Ala Arg
65 70 75 80
Leu Gln Arg Gln Phe Val Val Arg Ala Trp Gly Cys Ala Gly Pro Cys
85 90 95
Gly Arg Ala Val Phe Leu Ala Phe Gly Leu Gly Leu Gly Leu Ile Glu
100 105 110
Glu Lys Gln Ala Glu Ser Arg Arg Ala Val Ser Ala Cys Gln Glu Ile
115 120 125
Gln Ala Ile Phe Thr Gln Lys Ser Lys Pro Gly Pro Asp Pro Leu Asp
130 135 140
Thr Arg Arg Leu Gln Gly Phe Arg Leu Glu Glu Tyr Leu Ile Gly Gln
145 150 155 160
Ser Ile Gly Lys Gly Cys Ser Ala Ala Val Tyr Glu Ala Thr Met Pro
165 170 175
Thr Leu Pro Gln Asn Leu Glu Val Thr Lys Ser Thr Gly Leu Leu Pro
180 185 190
Gly Arg Gly Pro Gly Thr Ser Ala Pro Gly Glu Gly Gln Glu Arg Ala
195 200 205
Pro Gly Ala Pro Ala Phe Pro Leu Ala Ile Lys Met Met Trp Asn Ile
210 215 220
Ser Ala Gly Ser Ser Ser Glu Ala Ile Leu Asn Thr Met Ser Gln Glu
225 230 235 240
Leu Val Pro Ala Ser Arg Val Ala Leu Ala Gly Glu Tyr Gly Ala Val
245 250 255
Thr Tyr Arg Lys Ser Lys Arg Gly Pro Lys Gln Leu Ala Pro His Pro
260 265 270
Asn Ile Ile Arg Val Leu Arg Ala Phe Thr Ser Ser Val Pro Leu Leu
275 280 285
Pro Gly Ala Leu Val Asp Tyr Pro Asp Val Leu Pro Ser Arg Leu His
290 295 300
Pro Glu Gly Leu Gly His Gly Arg Thr Leu Phe Leu Val Met Lys Asn
305 310 315 320
Tyr Pro Cys Thr Leu Arg Gln Tyr Leu Cys Val Asn Thr Pro Ser Pro
325 330 335
Arg Leu Ala Ala Met Met Leu Leu Gln Leu Leu Glu Gly Val Asp His
340 345 350
Leu Val Gln Gln Gly Ile Ala His Arg Asp Leu Lys Ser Asp Asn Ile
355 360 365
Leu Val Glu Leu Asp Pro Asp Gly Cys Pro Trp Leu Val Ile Ala Asp
370 375 380
Phe Gly Cys Cys Leu Ala Asp Glu Ser Ile Gly Leu Gln Leu Pro Phe
385 390 395 400
Ser Ser Trp Tyr Val Asp Arg Gly Gly Asn Gly Cys Leu Met Ala Pro
405 410 415
Glu Val Ser Thr Ala Arg Pro Gly Pro Arg Ala Val Ile Asp Tyr Ser
420 425 430
Lys Ala Asp Ala Trp Ala Val Gly Ala Ile Ala Tyr Glu Ile Phe Gly
435 440 445
Leu Val Asn Pro Phe Tyr Gly Gln Gly Lys Ala His Leu Glu Ser Arg
450 455 460
Ser Tyr Gln Glu Ala Gln Leu Pro Ala Leu Pro Glu Ser Val Pro Pro
465 470 475 480
Asp Val Arg Gln Leu Val Arg Ala Leu Leu Gln Arg Glu Ala Ser Lys
485 490 495
Arg Pro Ser Ala Arg Val Ala Ala Asn Val Leu His Leu Ser Leu Trp
500 505 510
Gly Glu His Ile Leu Ala Leu Lys Asn Leu Lys Leu Asp Lys Met Val
515 520 525
Gly Trp Leu Leu Gln Gln Ser Ala Ala Thr Leu Leu Ala Asn Arg Leu
530 535 540
Thr Glu Lys Cys Cys Val Glu Thr Lys Met Lys Met Leu Phe Leu Ala
545 550 555 560
Asn Leu Glu Cys Glu Thr Leu Cys Gln Ala Ala Leu Leu Leu Cys Ser
565 570 575
Trp Arg Ala Ala Leu
580
<210> 29
<211> 1074
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(1074)
<400> 29
atg caa gga caa gga tca cca ttc tgc cgt tct aga acc cgc tcg aga 48
Met Gln Gly Gln Gly Ser Pro Phe Cys Arg Ser Arg Thr Arg Ser Arg
1 5 10 15
tct cgt gga gct ttc aat cgt agc tcc aac cac ggt tca gtg ctt cca 96
Ser Arg Gly Ala Phe Asn Arg Ser Ser Asn His Gly Ser Val Leu Pro
20 25 30
att cag cct gcc gta ttg gat tca att gcc gag gaa tca tcg tct act 144
Ile Gln Pro Ala Val Leu Asp Ser Ile Ala Glu Glu Ser Ser Ser Thr
35 40 45
atc atg aca gta gtc aat cct ttg atg gtg gca gca aga cag ctc aaa 192
Ile Met Thr Val Val Asn Pro Leu Met Val Ala Ala Arg Gln Leu Lys
50 55 60
ttt gct tgc cag atg gct cat gga agt cca gtt gga atc atc gac aaa 240
Phe Ala Cys Gln Met Ala His Gly Ser Pro Val Gly Ile Ile Asp Lys
65 70 75 80
tgg aac aat atg gag gaa ttg tat caa tca att gcc gat tgc ttt aca 288
Trp Asn Asn Met Glu Glu Leu Tyr Gln Ser Ile Ala Asp Cys Phe Thr
85 90 95
att tca aaa gat gat atc att ttc ctg aca gtc aat gat ttt aag cca 336
Ile Ser Lys Asp Asp Ile Ile Phe Leu Thr Val Asn Asp Phe Lys Pro
100 105 110
gac atg aag aac atg ttc act gga aca ctg aac ttc aag gat atg ctc 384
Asp Met Lys Asn Met Phe Thr Gly Thr Leu Asn Phe Lys Asp Met Leu
115 120 125
ttc gcc cac att cgc gga caa gca acc gag ctc cga gtc gtc aaa gat 432
Phe Ala His Ile Arg Gly Gln Ala Thr Glu Leu Arg Val Val Lys Asp
130 135 140
gct aaa aac ttt gga gtg aca atc acg gac aac gga ctc ggg aat gca 480
Ala Lys Asn Phe Gly Val Thr Ile Thr Asp Asn Gly Leu Gly Asn Ala
145 150 155 160
ttt atc aag gtc ata agc cca gat tcg gtg ttt gat cgt atg cgt cca 528
Phe Ile Lys Val Ile Ser Pro Asp Ser Val Phe Asp Arg Met Arg Pro
165 170 175
gcc act caa gtt ggt caa ctc att gag gcg gtc aat gga gaa tgt gtg 576
Ala Thr Gln Val Gly Gln Leu Ile Glu Ala Val Asn Gly Glu Cys Val
180 185 190
ctc ggg aaa agg cat tac caa gtt gcc cga att ttg aaa aat gtt cgt 624
Leu Gly Lys Arg His Tyr Gln Val Ala Arg Ile Leu Lys Asn Val Arg
195 200 205
cgc ggc gag gaa tgc gtg gtt cga ttg att gct cca aag act gct gat 672
Arg Gly Glu Glu Cys Val Val Arg Leu Ile Ala Pro Lys Thr Ala Asp
210 215 220
cca gga acc atg aag acg act gga aaa act ggc gga ggt ctg gca aaa 720
Pro Gly Thr Met Lys Thr Thr Gly Lys Thr Gly Gly Gly Leu Ala Lys
225 230 235 240
gga acc att cgt ttc aaa tcg gaa ggc gga ttt gct gtt gag gat gtt 768
Gly Thr Ile Arg Phe Lys Ser Glu Gly Gly Phe Ala Val Glu Asp Val
245 250 255
caa gat cag atg atc caa gct gag atg tgc gga aag ctc aat gag ata 816
Gln Asp Gln Met Ile Gln Ala Glu Met Cys Gly Lys Leu Asn Glu Ile
260 265 270
ttc gac caa tac ttg gga gtt caa gat gat cag ctg gcc atg aga atc 864
Phe Asp Gln Tyr Leu Gly Val Gln Asp Asp Gln Leu Ala Met Arg Ile
275 280 285
tgg gaa act gct tca aac tgc gag acg ctt ttg caa ctc agt gaa gcc 912
Trp Glu Thr Ala Ser Asn Cys Glu Thr Leu Leu Gln Leu Ser Glu Ala
290 295 300
atc aaa gag tcg gag ctc tca atg ttc gat ttc ccg gat gga atg gtt 960
Ile Lys Glu Ser Glu Leu Ser Met Phe Asp Phe Pro Asp Gly Met Val
305 310 315 320
ttc gat atg tgg gga atc atc ggt gat ttg aag cgg gag caa cgt gag 1008
Phe Asp Met Trp Gly Ile Ile Gly Asp Leu Lys Arg Glu Gln Arg Glu
325 330 335
aag aag cca tcc cca gtc atg aag aat gcg att tca aga cca tcg gct 1056
Lys Lys Pro Ser Pro Val Met Lys Asn Ala Ile Ser Arg Pro Ser Ala
340 345 350
atg aaa ctc ttt gag taa 1074
Met Lys Leu Phe Glu
355
<210> 30
<211> 357
<212> PRT
<213> Caenorhabditis elegans
<400> 30
Met Gln Gly Gln Gly Ser Pro Phe Cys Arg Ser Arg Thr Arg Ser Arg
1 5 10 15
Ser Arg Gly Ala Phe Asn Arg Ser Ser Asn His Gly Ser Val Leu Pro
20 25 30
Ile Gln Pro Ala Val Leu Asp Ser Ile Ala Glu Glu Ser Ser Ser Thr
35 40 45
Ile Met Thr Val Val Asn Pro Leu Met Val Ala Ala Arg Gln Leu Lys
50 55 60
Phe Ala Cys Gln Met Ala His Gly Ser Pro Val Gly Ile Ile Asp Lys
65 70 75 80
Trp Asn Asn Met Glu Glu Leu Tyr Gln Ser Ile Ala Asp Cys Phe Thr
85 90 95
Ile Ser Lys Asp Asp Ile Ile Phe Leu Thr Val Asn Asp Phe Lys Pro
100 105 110
Asp Met Lys Asn Met Phe Thr Gly Thr Leu Asn Phe Lys Asp Met Leu
115 120 125
Phe Ala His Ile Arg Gly Gln Ala Thr Glu Leu Arg Val Val Lys Asp
130 135 140
Ala Lys Asn Phe Gly Val Thr Ile Thr Asp Asn Gly Leu Gly Asn Ala
145 150 155 160
Phe Ile Lys Val Ile Ser Pro Asp Ser Val Phe Asp Arg Met Arg Pro
165 170 175
Ala Thr Gln Val Gly Gln Leu Ile Glu Ala Val Asn Gly Glu Cys Val
180 185 190
Leu Gly Lys Arg His Tyr Gln Val Ala Arg Ile Leu Lys Asn Val Arg
195 200 205
Arg Gly Glu Glu Cys Val Val Arg Leu Ile Ala Pro Lys Thr Ala Asp
210 215 220
Pro Gly Thr Met Lys Thr Thr Gly Lys Thr Gly Gly Gly Leu Ala Lys
225 230 235 240
Gly Thr Ile Arg Phe Lys Ser Glu Gly Gly Phe Ala Val Glu Asp Val
245 250 255
Gln Asp Gln Met Ile Gln Ala Glu Met Cys Gly Lys Leu Asn Glu Ile
260 265 270
Phe Asp Gln Tyr Leu Gly Val Gln Asp Asp Gln Leu Ala Met Arg Ile
275 280 285
Trp Glu Thr Ala Ser Asn Cys Glu Thr Leu Leu Gln Leu Ser Glu Ala
290 295 300
Ile Lys Glu Ser Glu Leu Ser Met Phe Asp Phe Pro Asp Gly Met Val
305 310 315 320
Phe Asp Met Trp Gly Ile Ile Gly Asp Leu Lys Arg Glu Gln Arg Glu
325 330 335
Lys Lys Pro Ser Pro Val Met Lys Asn Ala Ile Ser Arg Pro Ser Ala
340 345 350
Met Lys Leu Phe Glu
355
<210> 31
<211> 1002
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(1002)
<400> 31
atg ccg ctg gga ctg ggg cgg cgg aaa aag gcg ccc cct cta gtg gaa 48
Met Pro Leu Gly Leu Gly Arg Arg Lys Lys Ala Pro Pro Leu Val Glu
1 5 10 15
aat gag gag gct gag cca ggc cgt gga ggg ctg ggc gtg ggg gag cca 96
Asn Glu Glu Ala Glu Pro Gly Arg Gly Gly Leu Gly Val Gly Glu Pro
20 25 30
ggg cct ctg ggc gga ggt ggg tcg ggg ggc ccc caa atg ggc ttg ccc 144
Gly Pro Leu Gly Gly Gly Gly Ser Gly Gly Pro Gln Met Gly Leu Pro
35 40 45
ccc cct ccc cca gcc ctg cgg ccc cgc ctc gtg ttc cac acc cag ctg 192
Pro Pro Pro Pro Ala Leu Arg Pro Arg Leu Val Phe His Thr Gln Leu
50 55 60
gcc cat ggc agt ccc act ggc cgc atc gag ggc ttc acc aac gtc aag 240
Ala His Gly Ser Pro Thr Gly Arg Ile Glu Gly Phe Thr Asn Val Lys
65 70 75 80
gag ctg tat ggc aag atc gcc gag gcc ttc cgc ctg cca act gcc gag 288
Glu Leu Tyr Gly Lys Ile Ala Glu Ala Phe Arg Leu Pro Thr Ala Glu
85 90 95
gtg atg ttc tgc acc ctg aac acc cac aaa gtg gac atg gac aag ctc 336
Val Met Phe Cys Thr Leu Asn Thr His Lys Val Asp Met Asp Lys Leu
100 105 110
ctg ggg ggc cag atc ggg ctg gag gac ttc atc ttc gcc cac gtg aag 384
Leu Gly Gly Gln Ile Gly Leu Glu Asp Phe Ile Phe Ala His Val Lys
115 120 125
ggg cag cgc aag gag gtg gag gtg ttc aag tcg gag gat gca ctc ggg 432
Gly Gln Arg Lys Glu Val Glu Val Phe Lys Ser Glu Asp Ala Leu Gly
130 135 140
ctc acc atc acg gac aac ggg gct ggc tac gcc ttc atc aag cgc atc 480
Leu Thr Ile Thr Asp Asn Gly Ala Gly Tyr Ala Phe Ile Lys Arg Ile
145 150 155 160
aag gag ggc agc gtg atc gac cac atc cac ctc atc agc gtg ggc gac 528
Lys Glu Gly Ser Val Ile Asp His Ile His Leu Ile Ser Val Gly Asp
165 170 175
atg atc gag gcc att aac ggg cag agc ctg ctg ggc tgc cgg cac tac 576
Met Ile Glu Ala Ile Asn Gly Gln Ser Leu Leu Gly Cys Arg His Tyr
180 185 190
gag gtg gcc cgg ctg ctc aag gag ctg ccc cga ggc cgt acc ttc acg 624
Glu Val Ala Arg Leu Leu Lys Glu Leu Pro Arg Gly Arg Thr Phe Thr
195 200 205
ctg aag ctc acg gag cct cgc aag gcc ttc gac atg atc agc cag cgt 672
Leu Lys Leu Thr Glu Pro Arg Lys Ala Phe Asp Met Ile Ser Gln Arg
210 215 220
tca gcg ggt ggc cgc cct ggc tct ggc cca caa ctg ggc act ggc cga 720
Ser Ala Gly Gly Arg Pro Gly Ser Gly Pro Gln Leu Gly Thr Gly Arg
225 230 235 240
ggg acc ctg cgg ctc cga tcc cgg ggc ccc gcc acg gtg gag gat ctg 768
Gly Thr Leu Arg Leu Arg Ser Arg Gly Pro Ala Thr Val Glu Asp Leu
245 250 255
ccc tct gcc ttt gaa gag aag gcc att gag aag gtg gat gac ctg ctg 816
Pro Ser Ala Phe Glu Glu Lys Ala Ile Glu Lys Val Asp Asp Leu Leu
260 265 270
gag agt tac atg ggt atc agg gac acg gag ctg gcg gcc acc atg gtg 864
Glu Ser Tyr Met Gly Ile Arg Asp Thr Glu Leu Ala Ala Thr Met Val
275 280 285
gag ctg gga aag gac aaa agg aac ccg gat gag ctg gcc gag gcc ctg 912
Glu Leu Gly Lys Asp Lys Arg Asn Pro Asp Glu Leu Ala Glu Ala Leu
290 295 300
gac gaa cgg ctg ggt gac ttt gcc ttc cct gac gag ttc gtc ttt gac 960
Asp Glu Arg Leu Gly Asp Phe Ala Phe Pro Asp Glu Phe Val Phe Asp
305 310 315 320
gtc tgg ggc gcc att ggg gac gcc aag gtc ggc cgc tac tag 1002
Val Trp Gly Ala Ile Gly Asp Ala Lys Val Gly Arg Tyr
325 330
<210> 32
<211> 333
<212> PRT
<213> Homo sapiens
<400> 32
Met Pro Leu Gly Leu Gly Arg Arg Lys Lys Ala Pro Pro Leu Val Glu
1 5 10 15
Asn Glu Glu Ala Glu Pro Gly Arg Gly Gly Leu Gly Val Gly Glu Pro
20 25 30
Gly Pro Leu Gly Gly Gly Gly Ser Gly Gly Pro Gln Met Gly Leu Pro
35 40 45
Pro Pro Pro Pro Ala Leu Arg Pro Arg Leu Val Phe His Thr Gln Leu
50 55 60
Ala His Gly Ser Pro Thr Gly Arg Ile Glu Gly Phe Thr Asn Val Lys
65 70 75 80
Glu Leu Tyr Gly Lys Ile Ala Glu Ala Phe Arg Leu Pro Thr Ala Glu
85 90 95
Val Met Phe Cys Thr Leu Asn Thr His Lys Val Asp Met Asp Lys Leu
100 105 110
Leu Gly Gly Gln Ile Gly Leu Glu Asp Phe Ile Phe Ala His Val Lys
115 120 125
Gly Gln Arg Lys Glu Val Glu Val Phe Lys Ser Glu Asp Ala Leu Gly
130 135 140
Leu Thr Ile Thr Asp Asn Gly Ala Gly Tyr Ala Phe Ile Lys Arg Ile
145 150 155 160
Lys Glu Gly Ser Val Ile Asp His Ile His Leu Ile Ser Val Gly Asp
165 170 175
Met Ile Glu Ala Ile Asn Gly Gln Ser Leu Leu Gly Cys Arg His Tyr
180 185 190
Glu Val Ala Arg Leu Leu Lys Glu Leu Pro Arg Gly Arg Thr Phe Thr
195 200 205
Leu Lys Leu Thr Glu Pro Arg Lys Ala Phe Asp Met Ile Ser Gln Arg
210 215 220
Ser Ala Gly Gly Arg Pro Gly Ser Gly Pro Gln Leu Gly Thr Gly Arg
225 230 235 240
Gly Thr Leu Arg Leu Arg Ser Arg Gly Pro Ala Thr Val Glu Asp Leu
245 250 255
Pro Ser Ala Phe Glu Glu Lys Ala Ile Glu Lys Val Asp Asp Leu Leu
260 265 270
Glu Ser Tyr Met Gly Ile Arg Asp Thr Glu Leu Ala Ala Thr Met Val
275 280 285
Glu Leu Gly Lys Asp Lys Arg Asn Pro Asp Glu Leu Ala Glu Ala Leu
290 295 300
Asp Glu Arg Leu Gly Asp Phe Ala Phe Pro Asp Glu Phe Val Phe Asp
305 310 315 320
Val Trp Gly Ala Ile Gly Asp Ala Lys Val Gly Arg Tyr
325 330
<210> 33
<211> 1293
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(1293)
<400> 33
atg gtc agc gtg gat cca ttg gca acg gag cgt tgg agg agc atc aga 48
Met Val Ser Val Asp Pro Leu Ala Thr Glu Arg Trp Arg Ser Ile Arg
1 5 10 15
aga tta aca gat cgc gac tct gca tat aaa gtt cca tgg ttt gtt ccc 96
Arg Leu Thr Asp Arg Asp Ser Ala Tyr Lys Val Pro Trp Phe Val Pro
20 25 30
gga ccg gaa aac ttt gaa gca ctg caa aac acg aag att ctt gtt att 144
Gly Pro Glu Asn Phe Glu Ala Leu Gln Asn Thr Lys Ile Leu Val Ile
35 40 45
ggt gct ggt gga ttg ggt tgt gag ttg tta aag aac ttg gct ttg agc 192
Gly Ala Gly Gly Leu Gly Cys Glu Leu Leu Lys Asn Leu Ala Leu Ser
50 55 60
gga ttc cga aca att gaa gtt atc gat atg gac aca att gat gta tca 240
Gly Phe Arg Thr Ile Glu Val Ile Asp Met Asp Thr Ile Asp Val Ser
65 70 75 80
aac cta aat cgt caa ttc tta ttt agg gaa tct gac gtt gga aaa tca 288
Asn Leu Asn Arg Gln Phe Leu Phe Arg Glu Ser Asp Val Gly Lys Ser
85 90 95
aaa gct gag gta gct gct gct ttc gtt caa caa aga gtt gtt gga tgt 336
Lys Ala Glu Val Ala Ala Ala Phe Val Gln Gln Arg Val Val Gly Cys
100 105 110
cag gtg act gcg cac aac tgt aga att gaa gac aag ggt caa gaa ttt 384
Gln Val Thr Ala His Asn Cys Arg Ile Glu Asp Lys Gly Gln Glu Phe
115 120 125
tat cga aaa ttc tct ata att atc tgt gga ctt gat tcg att cca gcc 432
Tyr Arg Lys Phe Ser Ile Ile Ile Cys Gly Leu Asp Ser Ile Pro Ala
130 135 140
aga aga tgg atc aac gga atg ctg tgt gat ttg gtt ttg gaa atg gcc 480
Arg Arg Trp Ile Asn Gly Met Leu Cys Asp Leu Val Leu Glu Met Ala
145 150 155 160
gac gga aaa cct gat gag aac aca att att cca atg att gac gga gga 528
Asp Gly Lys Pro Asp Glu Asn Thr Ile Ile Pro Met Ile Asp Gly Gly
165 170 175
act gaa gga ttt aaa gga aat gct cgt gtc ata tat ccg aaa ttc aca 576
Thr Glu Gly Phe Lys Gly Asn Ala Arg Val Ile Tyr Pro Lys Phe Thr
180 185 190
gcc tgt att gat tgt act ctt gat ctt tat cca cct caa gtc aat ttt 624
Ala Cys Ile Asp Cys Thr Leu Asp Leu Tyr Pro Pro Gln Val Asn Phe
195 200 205
cca ttg tgc aca att gct cac act cct cga ctt cca gaa cat tgt att 672
Pro Leu Cys Thr Ile Ala His Thr Pro Arg Leu Pro Glu His Cys Ile
210 215 220
gaa tac att aaa gta gtt gtt tgg cca gag gaa aaa cca ttt gaa ggt 720
Glu Tyr Ile Lys Val Val Val Trp Pro Glu Glu Lys Pro Phe Glu Gly
225 230 235 240
gtt tct ctt gac gct gac gat ccg atc cac gtt gaa tgg gtt ctc gaa 768
Val Ser Leu Asp Ala Asp Asp Pro Ile His Val Glu Trp Val Leu Glu
245 250 255
aga gca agt ctt cgt gca gaa aaa tac aat att cga ggt gtg gat cgt 816
Arg Ala Ser Leu Arg Ala Glu Lys Tyr Asn Ile Arg Gly Val Asp Arg
260 265 270
cgt ttg aca tct gga gtt cta aaa aga att att ccg gct gtt gca tca 864
Arg Leu Thr Ser Gly Val Leu Lys Arg Ile Ile Pro Ala Val Ala Ser
275 280 285
aca aat gca gtt atc gct gca tca tgt gcc cta gaa gct ctg aaa ttg 912
Thr Asn Ala Val Ile Ala Ala Ser Cys Ala Leu Glu Ala Leu Lys Leu
290 295 300
gcc aca aac att gcc aaa cca atc gat aat tat ctt aat ttc act caa 960
Ala Thr Asn Ile Ala Lys Pro Ile Asp Asn Tyr Leu Asn Phe Thr Gln
305 310 315 320
att cac gga gca tat acc agt gtt gtt tca atg atg aaa gat gac aat 1008
Ile His Gly Ala Tyr Thr Ser Val Val Ser Met Met Lys Asp Asp Asn
325 330 335
tgt ctc act tgt agt ggt ggg cgt ctt cca ttc gaa gtt tca cca tct 1056
Cys Leu Thr Cys Ser Gly Gly Arg Leu Pro Phe Glu Val Ser Pro Ser
340 345 350
tca act ctt gaa tcg ctt atc atc aga ctc tcg gag cgt ttc cat ctc 1104
Ser Thr Leu Glu Ser Leu Ile Ile Arg Leu Ser Glu Arg Phe His Leu
355 360 365
aaa cat ccg aca cta gcg acc tca act cga aaa ctt tac tgt att agc 1152
Lys His Pro Thr Leu Ala Thr Ser Thr Arg Lys Leu Tyr Cys Ile Ser
370 375 380
agt ttc atg cca caa ttt gaa caa gaa agc aaa gaa aat ctg cat act 1200
Ser Phe Met Pro Gln Phe Glu Gln Glu Ser Lys Glu Asn Leu His Thr
385 390 395 400
tcg atg aaa gat ctt gtt agc gat ggc gaa gaa ata ctg gta tcc gac 1248
Ser Met Lys Asp Leu Val Ser Asp Gly Glu Glu Ile Leu Val Ser Asp
405 410 415
gaa gca ttg tct cgt gca ctt aca cta cga att cag ctc atc taa 1293
Glu Ala Leu Ser Arg Ala Leu Thr Leu Arg Ile Gln Leu Ile
420 425 430
<210> 34
<211> 430
<212> PRT
<213> Caenorhabditis elegans
<400> 34
Met Val Ser Val Asp Pro Leu Ala Thr Glu Arg Trp Arg Ser Ile Arg
1 5 10 15
Arg Leu Thr Asp Arg Asp Ser Ala Tyr Lys Val Pro Trp Phe Val Pro
20 25 30
Gly Pro Glu Asn Phe Glu Ala Leu Gln Asn Thr Lys Ile Leu Val Ile
35 40 45
Gly Ala Gly Gly Leu Gly Cys Glu Leu Leu Lys Asn Leu Ala Leu Ser
50 55 60
Gly Phe Arg Thr Ile Glu Val Ile Asp Met Asp Thr Ile Asp Val Ser
65 70 75 80
Asn Leu Asn Arg Gln Phe Leu Phe Arg Glu Ser Asp Val Gly Lys Ser
85 90 95
Lys Ala Glu Val Ala Ala Ala Phe Val Gln Gln Arg Val Val Gly Cys
100 105 110
Gln Val Thr Ala His Asn Cys Arg Ile Glu Asp Lys Gly Gln Glu Phe
115 120 125
Tyr Arg Lys Phe Ser Ile Ile Ile Cys Gly Leu Asp Ser Ile Pro Ala
130 135 140
Arg Arg Trp Ile Asn Gly Met Leu Cys Asp Leu Val Leu Glu Met Ala
145 150 155 160
Asp Gly Lys Pro Asp Glu Asn Thr Ile Ile Pro Met Ile Asp Gly Gly
165 170 175
Thr Glu Gly Phe Lys Gly Asn Ala Arg Val Ile Tyr Pro Lys Phe Thr
180 185 190
Ala Cys Ile Asp Cys Thr Leu Asp Leu Tyr Pro Pro Gln Val Asn Phe
195 200 205
Pro Leu Cys Thr Ile Ala His Thr Pro Arg Leu Pro Glu His Cys Ile
210 215 220
Glu Tyr Ile Lys Val Val Val Trp Pro Glu Glu Lys Pro Phe Glu Gly
225 230 235 240
Val Ser Leu Asp Ala Asp Asp Pro Ile His Val Glu Trp Val Leu Glu
245 250 255
Arg Ala Ser Leu Arg Ala Glu Lys Tyr Asn Ile Arg Gly Val Asp Arg
260 265 270
Arg Leu Thr Ser Gly Val Leu Lys Arg Ile Ile Pro Ala Val Ala Ser
275 280 285
Thr Asn Ala Val Ile Ala Ala Ser Cys Ala Leu Glu Ala Leu Lys Leu
290 295 300
Ala Thr Asn Ile Ala Lys Pro Ile Asp Asn Tyr Leu Asn Phe Thr Gln
305 310 315 320
Ile His Gly Ala Tyr Thr Ser Val Val Ser Met Met Lys Asp Asp Asn
325 330 335
Cys Leu Thr Cys Ser Gly Gly Arg Leu Pro Phe Glu Val Ser Pro Ser
340 345 350
Ser Thr Leu Glu Ser Leu Ile Ile Arg Leu Ser Glu Arg Phe His Leu
355 360 365
Lys His Pro Thr Leu Ala Thr Ser Thr Arg Lys Leu Tyr Cys Ile Ser
370 375 380
Ser Phe Met Pro Gln Phe Glu Gln Glu Ser Lys Glu Asn Leu His Thr
385 390 395 400
Ser Met Lys Asp Leu Val Ser Asp Gly Glu Glu Ile Leu Val Ser Asp
405 410 415
Glu Ala Leu Ser Arg Ala Leu Thr Leu Arg Ile Gln Leu Ile
420 425 430
<210> 35
<211> 1392
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(1392)
<400> 35
atg gcg gat ggc gag gag ccg gag aag aaa aga agg aga ata gag gag 48
Met Ala Asp Gly Glu Glu Pro Glu Lys Lys Arg Arg Arg Ile Glu Glu
1 5 10 15
ctg ctg gct gag aaa atg gct gtt gat ggt ggg tgt ggg gac act gga 96
Leu Leu Ala Glu Lys Met Ala Val Asp Gly Gly Cys Gly Asp Thr Gly
20 25 30
gac tgg gaa ggt cgc tgg aac cat gta aag aag ttc ctc gag cga tct 144
Asp Trp Glu Gly Arg Trp Asn His Val Lys Lys Phe Leu Glu Arg Ser
35 40 45
gga ccc ttc aca cac cct gat ttc gaa ccg agc act gaa tct ctc cag 192
Gly Pro Phe Thr His Pro Asp Phe Glu Pro Ser Thr Glu Ser Leu Gln
50 55 60
ttc ttg tta gat aca tgt aaa gtt cta gtc att gga gct ggc ggc tta 240
Phe Leu Leu Asp Thr Cys Lys Val Leu Val Ile Gly Ala Gly Gly Leu
65 70 75 80
gga tgt gag ctc ctg aaa aat ctg gcc ttg tct ggt ttt aga cag att 288
Gly Cys Glu Leu Leu Lys Asn Leu Ala Leu Ser Gly Phe Arg Gln Ile
85 90 95
cat gtt ata gat atg gac act ata gat gtt tcc aat cta aat agg cag 336
His Val Ile Asp Met Asp Thr Ile Asp Val Ser Asn Leu Asn Arg Gln
100 105 110
ttt tta ttt agg cct aaa gat att gga aga cct aag gct gaa gtt gct 384
Phe Leu Phe Arg Pro Lys Asp Ile Gly Arg Pro Lys Ala Glu Val Ala
115 120 125
gca gaa ttt cta aat gac aga gtt cct aat tgc aat gta gtt cca cat 432
Ala Glu Phe Leu Asn Asp Arg Val Pro Asn Cys Asn Val Val Pro His
130 135 140
ttc aac aag att caa gat ttt aac gac act ttc tat cga caa ttt cat 480
Phe Asn Lys Ile Gln Asp Phe Asn Asp Thr Phe Tyr Arg Gln Phe His
145 150 155 160
att att gta tgt gga ctg gac tct atc atc gcc aga aga tgg ata aat 528
Ile Ile Val Cys Gly Leu Asp Ser Ile Ile Ala Arg Arg Trp Ile Asn
165 170 175
ggc atg ctg ata tct ctt cta aat tat gaa gat ggt gtc tta gat cca 576
Gly Met Leu Ile Ser Leu Leu Asn Tyr Glu Asp Gly Val Leu Asp Pro
180 185 190
agc tcc att gtc cct ttg ata gat ggg ggg aca gaa ggt ttt aaa gga 624
Ser Ser Ile Val Pro Leu Ile Asp Gly Gly Thr Glu Gly Phe Lys Gly
195 200 205
aat gcc cgg gtg att ctg cct gga atg act gct tgt atc gaa tgc acg 672
Asn Ala Arg Val Ile Leu Pro Gly Met Thr Ala Cys Ile Glu Cys Thr
210 215 220
ctg gaa ctt tat cca cca cag gtt aat ttt ccc atg tgc acc att gca 720
Leu Glu Leu Tyr Pro Pro Gln Val Asn Phe Pro Met Cys Thr Ile Ala
225 230 235 240
tct atg ccc agg cta cca gaa cac tgt att gag tat gta agg atg ttg 768
Ser Met Pro Arg Leu Pro Glu His Cys Ile Glu Tyr Val Arg Met Leu
245 250 255
cag tgg cct aag gag cag cct ttt gga gaa ggg gtt cca tta gat gga 816
Gln Trp Pro Lys Glu Gln Pro Phe Gly Glu Gly Val Pro Leu Asp Gly
260 265 270
gat gat cct gaa cat ata caa tgg att ttc caa aaa tcc cta gag aga 864
Asp Asp Pro Glu His Ile Gln Trp Ile Phe Gln Lys Ser Leu Glu Arg
275 280 285
gca tca caa tat aat att agg ggt gtt acg tat agg ctc act caa ggg 912
Ala Ser Gln Tyr Asn Ile Arg Gly Val Thr Tyr Arg Leu Thr Gln Gly
290 295 300
gta gta aaa aga atc att cct gca gta gct tcc aca aat gca gtc att 960
Val Val Lys Arg Ile Ile Pro Ala Val Ala Ser Thr Asn Ala Val Ile
305 310 315 320
gca gct gtg tgt gcc act gag gtt ttt aaa ata gcc aca agt gca tac 1008
Ala Ala Val Cys Ala Thr Glu Val Phe Lys Ile Ala Thr Ser Ala Tyr
325 330 335
att ccc ttg aat aat tac ttg gtg ttt aat gat gta gat ggg ctg tat 1056
Ile Pro Leu Asn Asn Tyr Leu Val Phe Asn Asp Val Asp Gly Leu Tyr
340 345 350
aca tac aca ttt gaa gca gaa aga aag gaa aac tgc cca gct tgt agc 1104
Thr Tyr Thr Phe Glu Ala Glu Arg Lys Glu Asn Cys Pro Ala Cys Ser
355 360 365
cag ctt cct caa aat att cag ttt tct cca tca gct aaa cta cag gag 1152
Gln Leu Pro Gln Asn Ile Gln Phe Ser Pro Ser Ala Lys Leu Gln Glu
370 375 380
gtt ttg gat tat cta acc aat agt gct tct ctg caa atg aaa tct cca 1200
Val Leu Asp Tyr Leu Thr Asn Ser Ala Ser Leu Gln Met Lys Ser Pro
385 390 395 400
gcc atc aca gcc acc cta gag gga aaa aat aga aca ctt tac tta cag 1248
Ala Ile Thr Ala Thr Leu Glu Gly Lys Asn Arg Thr Leu Tyr Leu Gln
405 410 415
tcg gta acc tct att gaa gaa cga aca agg cca aat ctc tcc aaa aca 1296
Ser Val Thr Ser Ile Glu Glu Arg Thr Arg Pro Asn Leu Ser Lys Thr
420 425 430
ttg aaa gaa ttg ggg ctt gtt gat gga caa gaa ctg gcg gtt gct gat 1344
Leu Lys Glu Leu Gly Leu Val Asp Gly Gln Glu Leu Ala Val Ala Asp
435 440 445
gtc acc acc cca cag act gta cta ttc aaa ctt cat ttt act tct taa 1392
Val Thr Thr Pro Gln Thr Val Leu Phe Lys Leu His Phe Thr Ser
450 455 460
<210> 36
<211> 463
<212> PRT
<213> Homo sapiens
<400> 36
Met Ala Asp Gly Glu Glu Pro Glu Lys Lys Arg Arg Arg Ile Glu Glu
1 5 10 15
Leu Leu Ala Glu Lys Met Ala Val Asp Gly Gly Cys Gly Asp Thr Gly
20 25 30
Asp Trp Glu Gly Arg Trp Asn His Val Lys Lys Phe Leu Glu Arg Ser
35 40 45
Gly Pro Phe Thr His Pro Asp Phe Glu Pro Ser Thr Glu Ser Leu Gln
50 55 60
Phe Leu Leu Asp Thr Cys Lys Val Leu Val Ile Gly Ala Gly Gly Leu
65 70 75 80
Gly Cys Glu Leu Leu Lys Asn Leu Ala Leu Ser Gly Phe Arg Gln Ile
85 90 95
His Val Ile Asp Met Asp Thr Ile Asp Val Ser Asn Leu Asn Arg Gln
100 105 110
Phe Leu Phe Arg Pro Lys Asp Ile Gly Arg Pro Lys Ala Glu Val Ala
115 120 125
Ala Glu Phe Leu Asn Asp Arg Val Pro Asn Cys Asn Val Val Pro His
130 135 140
Phe Asn Lys Ile Gln Asp Phe Asn Asp Thr Phe Tyr Arg Gln Phe His
145 150 155 160
Ile Ile Val Cys Gly Leu Asp Ser Ile Ile Ala Arg Arg Trp Ile Asn
165 170 175
Gly Met Leu Ile Ser Leu Leu Asn Tyr Glu Asp Gly Val Leu Asp Pro
180 185 190
Ser Ser Ile Val Pro Leu Ile Asp Gly Gly Thr Glu Gly Phe Lys Gly
195 200 205
Asn Ala Arg Val Ile Leu Pro Gly Met Thr Ala Cys Ile Glu Cys Thr
210 215 220
Leu Glu Leu Tyr Pro Pro Gln Val Asn Phe Pro Met Cys Thr Ile Ala
225 230 235 240
Ser Met Pro Arg Leu Pro Glu His Cys Ile Glu Tyr Val Arg Met Leu
245 250 255
Gln Trp Pro Lys Glu Gln Pro Phe Gly Glu Gly Val Pro Leu Asp Gly
260 265 270
Asp Asp Pro Glu His Ile Gln Trp Ile Phe Gln Lys Ser Leu Glu Arg
275 280 285
Ala Ser Gln Tyr Asn Ile Arg Gly Val Thr Tyr Arg Leu Thr Gln Gly
290 295 300
Val Val Lys Arg Ile Ile Pro Ala Val Ala Ser Thr Asn Ala Val Ile
305 310 315 320
Ala Ala Val Cys Ala Thr Glu Val Phe Lys Ile Ala Thr Ser Ala Tyr
325 330 335
Ile Pro Leu Asn Asn Tyr Leu Val Phe Asn Asp Val Asp Gly Leu Tyr
340 345 350
Thr Tyr Thr Phe Glu Ala Glu Arg Lys Glu Asn Cys Pro Ala Cys Ser
355 360 365
Gln Leu Pro Gln Asn Ile Gln Phe Ser Pro Ser Ala Lys Leu Gln Glu
370 375 380
Val Leu Asp Tyr Leu Thr Asn Ser Ala Ser Leu Gln Met Lys Ser Pro
385 390 395 400
Ala Ile Thr Ala Thr Leu Glu Gly Lys Asn Arg Thr Leu Tyr Leu Gln
405 410 415
Ser Val Thr Ser Ile Glu Glu Arg Thr Arg Pro Asn Leu Ser Lys Thr
420 425 430
Leu Lys Glu Leu Gly Leu Val Asp Gly Gln Glu Leu Ala Val Ala Asp
435 440 445
Val Thr Thr Pro Gln Thr Val Leu Phe Lys Leu His Phe Thr Ser
450 455 460
<210> 37
<211> 486
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(486)
<400> 37
atg ggt gat gac gac cgt tgc aag acg gga att ctt atc cgg tgt ctt 48
Met Gly Asp Asp Asp Arg Cys Lys Thr Gly Ile Leu Ile Arg Cys Leu
1 5 10 15
ggc gat ctt caa gaa atg gag gac ggc tac ctt cgc aaa atg gaa gtc 96
Gly Asp Leu Gln Glu Met Glu Asp Gly Tyr Leu Arg Lys Met Glu Val
20 25 30
atg gag aaa gaa cag gtg gct gcc gaa aaa cga ctt gtt gaa tgc agg 144
Met Glu Lys Glu Gln Val Ala Ala Glu Lys Arg Leu Val Glu Cys Arg
35 40 45
gaa gac gtt gca aag tta cgg gca gaa aac gca cag ttg gcg acc gat 192
Glu Asp Val Ala Lys Leu Arg Ala Glu Asn Ala Gln Leu Ala Thr Asp
50 55 60
atc gac aat ctc aag act gca acc gaa aac acc gga cgc ctc aat gca 240
Ile Asp Asn Leu Lys Thr Ala Thr Glu Asn Thr Gly Arg Leu Asn Ala
65 70 75 80
gaa att gcc cag tta cga acg gaa ctg tcc gcc gtg ccc cgc cct tgt 288
Glu Ile Ala Gln Leu Arg Thr Glu Leu Ser Ala Val Pro Arg Pro Cys
85 90 95
tgc gcg gtt tgt cac gat tca tac gcc tcc cgc ggt cca aaa aaa ccc 336
Cys Ala Val Cys His Asp Ser Tyr Ala Ser Arg Gly Pro Lys Lys Pro
100 105 110
aag gtt tgt tcc tgt ctg cac act tat tgt ggc gcg tgc att agg gaa 384
Lys Val Cys Ser Cys Leu His Thr Tyr Cys Gly Ala Cys Ile Arg Glu
115 120 125
att tcg agc cgc cac aat ggt gaa atg aaa tgc ccc gaa tgc gtt gcg 432
Ile Ser Ser Arg His Asn Gly Glu Met Lys Cys Pro Glu Cys Val Ala
130 135 140
gac gtc cgc ata ctg gga aca aac ttt ggg ata aca aat gcg ttt cgg 480
Asp Val Arg Ile Leu Gly Thr Asn Phe Gly Ile Thr Asn Ala Phe Arg
145 150 155 160
tca tga 486
Ser
<210> 38
<211> 161
<212> PRT
<213> Caenorhabditis elegans
<400> 38
Met Gly Asp Asp Asp Arg Cys Lys Thr Gly Ile Leu Ile Arg Cys Leu
1 5 10 15
Gly Asp Leu Gln Glu Met Glu Asp Gly Tyr Leu Arg Lys Met Glu Val
20 25 30
Met Glu Lys Glu Gln Val Ala Ala Glu Lys Arg Leu Val Glu Cys Arg
35 40 45
Glu Asp Val Ala Lys Leu Arg Ala Glu Asn Ala Gln Leu Ala Thr Asp
50 55 60
Ile Asp Asn Leu Lys Thr Ala Thr Glu Asn Thr Gly Arg Leu Asn Ala
65 70 75 80
Glu Ile Ala Gln Leu Arg Thr Glu Leu Ser Ala Val Pro Arg Pro Cys
85 90 95
Cys Ala Val Cys His Asp Ser Tyr Ala Ser Arg Gly Pro Lys Lys Pro
100 105 110
Lys Val Cys Ser Cys Leu His Thr Tyr Cys Gly Ala Cys Ile Arg Glu
115 120 125
Ile Ser Ser Arg His Asn Gly Glu Met Lys Cys Pro Glu Cys Val Ala
130 135 140
Asp Val Arg Ile Leu Gly Thr Asn Phe Gly Ile Thr Asn Ala Phe Arg
145 150 155 160
Ser
<210> 39
<211> 2235
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(2235)
<400> 39
atg gcc agt gaa ggc acc aac atc cca agt cct gtg gtg cgc cag att 48
Met Ala Ser Glu Gly Thr Asn Ile Pro Ser Pro Val Val Arg Gln Ile
1 5 10 15
gac aag cag ttt ctg att tgc agt ata tgc ctg gaa cgg tac aag aat 96
Asp Lys Gln Phe Leu Ile Cys Ser Ile Cys Leu Glu Arg Tyr Lys Asn
20 25 30
ccc aag gtt ctc ccc tgt ctg cac act ttc tgc gag agg tgc ctg cag 144
Pro Lys Val Leu Pro Cys Leu His Thr Phe Cys Glu Arg Cys Leu Gln
35 40 45
aac tac att cct gcc cac agt tta acc ctc tcc tgc cca gtg tgc cgc 192
Asn Tyr Ile Pro Ala His Ser Leu Thr Leu Ser Cys Pro Val Cys Arg
50 55 60
cag acc tcc atc ctg ccc gag aaa ggg gtg gcc gcg ctc cag aac aat 240
Gln Thr Ser Ile Leu Pro Glu Lys Gly Val Ala Ala Leu Gln Asn Asn
65 70 75 80
ttc ttc atc aca aac ctg atg gac gtg ctg cag cga act cca ggc agc 288
Phe Phe Ile Thr Asn Leu Met Asp Val Leu Gln Arg Thr Pro Gly Ser
85 90 95
aac gct gag gag tct tcc atc ctg gag aca gtc act gct gtg gct gcg 336
Asn Ala Glu Glu Ser Ser Ile Leu Glu Thr Val Thr Ala Val Ala Ala
100 105 110
gga aag cct ctc tct tgc cca aac cac gat ggg aat gtg atg gaa ttt 384
Gly Lys Pro Leu Ser Cys Pro Asn His Asp Gly Asn Val Met Glu Phe
115 120 125
tac tgc cag tcc tgt gag act gcc atg tgt cgg gag tgc acg gag ggg 432
Tyr Cys Gln Ser Cys Glu Thr Ala Met Cys Arg Glu Cys Thr Glu Gly
130 135 140
gag cac gca gag cac ccc aca gtt cca ctc aag gat gtg gtg gaa cag 480
Glu His Ala Glu His Pro Thr Val Pro Leu Lys Asp Val Val Glu Gln
145 150 155 160
cac aag gcc tcg ctc cag gtc cag ctg gat gct gtc aac aaa agg ctc 528
His Lys Ala Ser Leu Gln Val Gln Leu Asp Ala Val Asn Lys Arg Leu
165 170 175
cca gaa ata gat tct gct ctt cag ttc atc tct gaa atc att cat cag 576
Pro Glu Ile Asp Ser Ala Leu Gln Phe Ile Ser Glu Ile Ile His Gln
180 185 190
tta acc aac caa aag gcc agc atc gtg gat gac att cat tcc acc ttt 624
Leu Thr Asn Gln Lys Ala Ser Ile Val Asp Asp Ile His Ser Thr Phe
195 200 205
gat gag ctc cag aag act tta aat gtg cgc aag agt gtg ctg ctt atg 672
Asp Glu Leu Gln Lys Thr Leu Asn Val Arg Lys Ser Val Leu Leu Met
210 215 220
gaa ttg gag gtc aac tat ggc ctc aaa cac aaa gtc ctc cag tcg cag 720
Glu Leu Glu Val Asn Tyr Gly Leu Lys His Lys Val Leu Gln Ser Gln
225 230 235 240
ctg gat act ctg ctc cag ggg cag gag agc att aag agc tgc agc aac 768
Leu Asp Thr Leu Leu Gln Gly Gln Glu Ser Ile Lys Ser Cys Ser Asn
245 250 255
ttc aca gcg cag gcc ctc aac cat ggc acg gag acc gag gtc cta ctg 816
Phe Thr Ala Gln Ala Leu Asn His Gly Thr Glu Thr Glu Val Leu Leu
260 265 270
gtg aag aag cag atg agc gag aag ctg aac gag ctg gcc gac cag gac 864
Val Lys Lys Gln Met Ser Glu Lys Leu Asn Glu Leu Ala Asp Gln Asp
275 280 285
ttc ccc ttg cac ccg cgg gag aac gac cag ctg gat ttc atc gtg gaa 912
Phe Pro Leu His Pro Arg Glu Asn Asp Gln Leu Asp Phe Ile Val Glu
290 295 300
acc gag ggg ctg aag aag tcc atc cac aac ctc ggg acg atc tta acc 960
Thr Glu Gly Leu Lys Lys Ser Ile His Asn Leu Gly Thr Ile Leu Thr
305 310 315 320
acc aac gcc gtt gcc tca gag aca gtg gcc acg ggc gag ggg ctg cgg 1008
Thr Asn Ala Val Ala Ser Glu Thr Val Ala Thr Gly Glu Gly Leu Arg
325 330 335
cag acc atc atc ggg cag ccc atg tcc gtc acc atc acc acc aag gac 1056
Gln Thr Ile Ile Gly Gln Pro Met Ser Val Thr Ile Thr Thr Lys Asp
340 345 350
aaa gac ggt gag ctg tgc aaa acc ggc aac gcc tac ctc acc gcc gaa 1104
Lys Asp Gly Glu Leu Cys Lys Thr Gly Asn Ala Tyr Leu Thr Ala Glu
355 360 365
ctg agc acc ccc gac ggg agc gtg gca gac ggg gag atc ctg gac aac 1152
Leu Ser Thr Pro Asp Gly Ser Val Ala Asp Gly Glu Ile Leu Asp Asn
370 375 380
aag aac ggc acc tat gag ttt ttg tac act gtc cag aag gaa ggg gac 1200
Lys Asn Gly Thr Tyr Glu Phe Leu Tyr Thr Val Gln Lys Glu Gly Asp
385 390 395 400
ttt acc ctg tct ctg aga ctc tat gac cag cac atc cga ggc agc ccg 1248
Phe Thr Leu Ser Leu Arg Leu Tyr Asp Gln His Ile Arg Gly Ser Pro
405 410 415
ttt aag ctg aaa gtg atc cga tcc gct gat gtg tct ccc acc aca gaa 1296
Phe Lys Leu Lys Val Ile Arg Ser Ala Asp Val Ser Pro Thr Thr Glu
420 425 430
ggc gtg aag agg cgc gtt aag tcc ccg ggg agc ggc cac gtc aag cag 1344
Gly Val Lys Arg Arg Val Lys Ser Pro Gly Ser Gly His Val Lys Gln
435 440 445
aaa gct gtg aaa aga ccc gca agc atg tac agc act gga aaa cga aaa 1392
Lys Ala Val Lys Arg Pro Ala Ser Met Tyr Ser Thr Gly Lys Arg Lys
450 455 460
gag aat ccc atc gaa gac gat ttg atc ttt cga gtg ggt acc aaa gga 1440
Glu Asn Pro Ile Glu Asp Asp Leu Ile Phe Arg Val Gly Thr Lys Gly
465 470 475 480
aga aat aaa gga gag ttt aca aat ctt cag ggg gta gct gca tct aca 1488
Arg Asn Lys Gly Glu Phe Thr Asn Leu Gln Gly Val Ala Ala Ser Thr
485 490 495
aat gga aag ata tta att gca gac agt aac aac caa tgt gtg cag ata 1536
Asn Gly Lys Ile Leu Ile Ala Asp Ser Asn Asn Gln Cys Val Gln Ile
500 505 510
ttt tcc aat gat ggc cag ttc aaa agt cgt ttt ggc ata cgg gga cgc 1584
Phe Ser Asn Asp Gly Gln Phe Lys Ser Arg Phe Gly Ile Arg Gly Arg
515 520 525
tct ccg ggg cag ctg cag cgg ccc aca gga gtg gct gta cat ccc agt 1632
Ser Pro Gly Gln Leu Gln Arg Pro Thr Gly Val Ala Val His Pro Ser
530 535 540
ggg gac ata atc att gcc gat tat gat aat aaa tgg gtc agc att ttc 1680
Gly Asp Ile Ile Ile Ala Asp Tyr Asp Asn Lys Trp Val Ser Ile Phe
545 550 555 560
tcc tcc gat ggg aaa ttt aag aca aaa att gga tca gga aag ctg atg 1728
Ser Ser Asp Gly Lys Phe Lys Thr Lys Ile Gly Ser Gly Lys Leu Met
565 570 575
gga ccc aaa gga gtt tct gtg gac cgc aat ggg cac att att gtt gtg 1776
Gly Pro Lys Gly Val Ser Val Asp Arg Asn Gly His Ile Ile Val Val
580 585 590
gac aac aag gcg tgc tgc gtg ttt atc ttc cag cca aac ggg aaa ata 1824
Asp Asn Lys Ala Cys Cys Val Phe Ile Phe Gln Pro Asn Gly Lys Ile
595 600 605
gtc acc agg ttt ggt agc cga gga aat ggg gac agg cag ttt gca ggt 1872
Val Thr Arg Phe Gly Ser Arg Gly Asn Gly Asp Arg Gln Phe Ala Gly
610 615 620
ccc cat ttt gca gct gta aat agc aat aat gag att att att aca gat 1920
Pro His Phe Ala Ala Val Asn Ser Asn Asn Glu Ile Ile Ile Thr Asp
625 630 635 640
ttc cat aat cat tct gtc aag gtg ttt aat cag gaa gga gaa ttc atg 1968
Phe His Asn His Ser Val Lys Val Phe Asn Gln Glu Gly Glu Phe Met
645 650 655
ttg aag ttt ggc tca aat gga gaa gga aat ggg cag ttt aat gct cca 2016
Leu Lys Phe Gly Ser Asn Gly Glu Gly Asn Gly Gln Phe Asn Ala Pro
660 665 670
aca ggt gta gca gtg gat tca aat gga aac atc att gtg gcc gac tgg 2064
Thr Gly Val Ala Val Asp Ser Asn Gly Asn Ile Ile Val Ala Asp Trp
675 680 685
gga aac agc agg atc cag gtt ttt gat ggg agt gga tca ttt ttg tcc 2112
Gly Asn Ser Arg Ile Gln Val Phe Asp Gly Ser Gly Ser Phe Leu Ser
690 695 700
tac att aac aca tct gct gac cca ctc tat ggc ccc caa ggc ctg gcc 2160
Tyr Ile Asn Thr Ser Ala Asp Pro Leu Tyr Gly Pro Gln Gly Leu Ala
705 710 715 720
cta act tca gat ggt cat gtt gtg gtt gca gac tct gga aat cac tgt 2208
Leu Thr Ser Asp Gly His Val Val Val Ala Asp Ser Gly Asn His Cys
725 730 735
ttc aaa gtc tat cga tac tta cag taa 2235
Phe Lys Val Tyr Arg Tyr Leu Gln
740
<210> 40
<211> 744
<212> PRT
<213> Homo sapiens
<400> 40
Met Ala Ser Glu Gly Thr Asn Ile Pro Ser Pro Val Val Arg Gln Ile
1 5 10 15
Asp Lys Gln Phe Leu Ile Cys Ser Ile Cys Leu Glu Arg Tyr Lys Asn
20 25 30
Pro Lys Val Leu Pro Cys Leu His Thr Phe Cys Glu Arg Cys Leu Gln
35 40 45
Asn Tyr Ile Pro Ala His Ser Leu Thr Leu Ser Cys Pro Val Cys Arg
50 55 60
Gln Thr Ser Ile Leu Pro Glu Lys Gly Val Ala Ala Leu Gln Asn Asn
65 70 75 80
Phe Phe Ile Thr Asn Leu Met Asp Val Leu Gln Arg Thr Pro Gly Ser
85 90 95
Asn Ala Glu Glu Ser Ser Ile Leu Glu Thr Val Thr Ala Val Ala Ala
100 105 110
Gly Lys Pro Leu Ser Cys Pro Asn His Asp Gly Asn Val Met Glu Phe
115 120 125
Tyr Cys Gln Ser Cys Glu Thr Ala Met Cys Arg Glu Cys Thr Glu Gly
130 135 140
Glu His Ala Glu His Pro Thr Val Pro Leu Lys Asp Val Val Glu Gln
145 150 155 160
His Lys Ala Ser Leu Gln Val Gln Leu Asp Ala Val Asn Lys Arg Leu
165 170 175
Pro Glu Ile Asp Ser Ala Leu Gln Phe Ile Ser Glu Ile Ile His Gln
180 185 190
Leu Thr Asn Gln Lys Ala Ser Ile Val Asp Asp Ile His Ser Thr Phe
195 200 205
Asp Glu Leu Gln Lys Thr Leu Asn Val Arg Lys Ser Val Leu Leu Met
210 215 220
Glu Leu Glu Val Asn Tyr Gly Leu Lys His Lys Val Leu Gln Ser Gln
225 230 235 240
Leu Asp Thr Leu Leu Gln Gly Gln Glu Ser Ile Lys Ser Cys Ser Asn
245 250 255
Phe Thr Ala Gln Ala Leu Asn His Gly Thr Glu Thr Glu Val Leu Leu
260 265 270
Val Lys Lys Gln Met Ser Glu Lys Leu Asn Glu Leu Ala Asp Gln Asp
275 280 285
Phe Pro Leu His Pro Arg Glu Asn Asp Gln Leu Asp Phe Ile Val Glu
290 295 300
Thr Glu Gly Leu Lys Lys Ser Ile His Asn Leu Gly Thr Ile Leu Thr
305 310 315 320
Thr Asn Ala Val Ala Ser Glu Thr Val Ala Thr Gly Glu Gly Leu Arg
325 330 335
Gln Thr Ile Ile Gly Gln Pro Met Ser Val Thr Ile Thr Thr Lys Asp
340 345 350
Lys Asp Gly Glu Leu Cys Lys Thr Gly Asn Ala Tyr Leu Thr Ala Glu
355 360 365
Leu Ser Thr Pro Asp Gly Ser Val Ala Asp Gly Glu Ile Leu Asp Asn
370 375 380
Lys Asn Gly Thr Tyr Glu Phe Leu Tyr Thr Val Gln Lys Glu Gly Asp
385 390 395 400
Phe Thr Leu Ser Leu Arg Leu Tyr Asp Gln His Ile Arg Gly Ser Pro
405 410 415
Phe Lys Leu Lys Val Ile Arg Ser Ala Asp Val Ser Pro Thr Thr Glu
420 425 430
Gly Val Lys Arg Arg Val Lys Ser Pro Gly Ser Gly His Val Lys Gln
435 440 445
Lys Ala Val Lys Arg Pro Ala Ser Met Tyr Ser Thr Gly Lys Arg Lys
450 455 460
Glu Asn Pro Ile Glu Asp Asp Leu Ile Phe Arg Val Gly Thr Lys Gly
465 470 475 480
Arg Asn Lys Gly Glu Phe Thr Asn Leu Gln Gly Val Ala Ala Ser Thr
485 490 495
Asn Gly Lys Ile Leu Ile Ala Asp Ser Asn Asn Gln Cys Val Gln Ile
500 505 510
Phe Ser Asn Asp Gly Gln Phe Lys Ser Arg Phe Gly Ile Arg Gly Arg
515 520 525
Ser Pro Gly Gln Leu Gln Arg Pro Thr Gly Val Ala Val His Pro Ser
530 535 540
Gly Asp Ile Ile Ile Ala Asp Tyr Asp Asn Lys Trp Val Ser Ile Phe
545 550 555 560
Ser Ser Asp Gly Lys Phe Lys Thr Lys Ile Gly Ser Gly Lys Leu Met
565 570 575
Gly Pro Lys Gly Val Ser Val Asp Arg Asn Gly His Ile Ile Val Val
580 585 590
Asp Asn Lys Ala Cys Cys Val Phe Ile Phe Gln Pro Asn Gly Lys Ile
595 600 605
Val Thr Arg Phe Gly Ser Arg Gly Asn Gly Asp Arg Gln Phe Ala Gly
610 615 620
Pro His Phe Ala Ala Val Asn Ser Asn Asn Glu Ile Ile Ile Thr Asp
625 630 635 640
Phe His Asn His Ser Val Lys Val Phe Asn Gln Glu Gly Glu Phe Met
645 650 655
Leu Lys Phe Gly Ser Asn Gly Glu Gly Asn Gly Gln Phe Asn Ala Pro
660 665 670
Thr Gly Val Ala Val Asp Ser Asn Gly Asn Ile Ile Val Ala Asp Trp
675 680 685
Gly Asn Ser Arg Ile Gln Val Phe Asp Gly Ser Gly Ser Phe Leu Ser
690 695 700
Tyr Ile Asn Thr Ser Ala Asp Pro Leu Tyr Gly Pro Gln Gly Leu Ala
705 710 715 720
Leu Thr Ser Asp Gly His Val Val Val Ala Asp Ser Gly Asn His Cys
725 730 735
Phe Lys Val Tyr Arg Tyr Leu Gln
740
<210> 41
<211> 1944
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(1944)
<400> 41
atg gcc acg ttt gtt ccc ttt gtt act tgt ctt gat aca ggt ttt tgg 48
Met Ala Thr Phe Val Pro Phe Val Thr Cys Leu Asp Thr Gly Phe Trp
1 5 10 15
aac gaa gtg aac aag aaa aag ctc aat gat tgg aaa ctc gat gag acg 96
Asn Glu Val Asn Lys Lys Lys Leu Asn Asp Trp Lys Leu Asp Glu Thr
20 25 30
cca aag tgt atc tca agt caa tta tcg ctt cat caa acc gaa ggt ttt 144
Pro Lys Cys Ile Ser Ser Gln Leu Ser Leu His Gln Thr Glu Gly Phe
35 40 45
aaa tgt cat cta tcc tta agt tac gac agt ttg agc agt ttg gag agc 192
Lys Cys His Leu Ser Leu Ser Tyr Asp Ser Leu Ser Ser Leu Glu Ser
50 55 60
aca act gga ttg tca atg tcc ggt acc ctt ctt ctg tac aat aca att 240
Thr Thr Gly Leu Ser Met Ser Gly Thr Leu Leu Leu Tyr Asn Thr Ile
65 70 75 80
gaa agt ttc aag atg gtt gac aaa agt gat ttg ata aga agt gaa gca 288
Glu Ser Phe Lys Met Val Asp Lys Ser Asp Leu Ile Arg Ser Glu Ala
85 90 95
gaa aag atc tgg gaa tct atc aca act cga aaa tgg ctc caa aat cct 336
Glu Lys Ile Trp Glu Ser Ile Thr Thr Arg Lys Trp Leu Gln Asn Pro
100 105 110
cgt ctt ctg tcg caa ttc ttc atc atc gct ttt gct gat ttg aaa aaa 384
Arg Leu Leu Ser Gln Phe Phe Ile Ile Ala Phe Ala Asp Leu Lys Lys
115 120 125
ttc aaa tat tat tat tgg aca tgt gtt cct gct ttg gta tat cct agt 432
Phe Lys Tyr Tyr Tyr Trp Thr Cys Val Pro Ala Leu Val Tyr Pro Ser
130 135 140
gaa ata aaa caa gag atc aca cca cta tca tct ctc gga gcc gat cac 480
Glu Ile Lys Gln Glu Ile Thr Pro Leu Ser Ser Leu Gly Ala Asp His
145 150 155 160
aag atc ctg ttc gac ttt tat agg aaa aac aat ttt ccg atc ttc cta 528
Lys Ile Leu Phe Asp Phe Tyr Arg Lys Asn Asn Phe Pro Ile Phe Leu
165 170 175
tac tcc aaa caa tct tca aaa atg ctc gaa ctg tca gaa ttg gaa aac 576
Tyr Ser Lys Gln Ser Ser Lys Met Leu Glu Leu Ser Glu Leu Glu Asn
180 185 190
aac aca aat cct gac gaa ata tgt gtt gtt gtc gct gat cct tct cct 624
Asn Thr Asn Pro Asp Glu Ile Cys Val Val Val Ala Asp Pro Ser Pro
195 200 205
gtt gcg tat tct gca gga tgg atg gtt cgc aac gtt ctt gcc gca gtg 672
Val Ala Tyr Ser Ala Gly Trp Met Val Arg Asn Val Leu Ala Ala Val
210 215 220
gca cat ctt cat cct acg tgg aag cat tgt cat atc atc agt ctt cgt 720
Ala His Leu His Pro Thr Trp Lys His Cys His Ile Ile Ser Leu Arg
225 230 235 240
tca gct gac agt atc gga ata aaa tac aca tgg acc ttg ccg agt gct 768
Ser Ala Asp Ser Ile Gly Ile Lys Tyr Thr Trp Thr Leu Pro Ser Ala
245 250 255
gaa tgc tca gca gat gga gct cag aat gct gtt cca aaa gct gtg gga 816
Glu Cys Ser Ala Asp Gly Ala Gln Asn Ala Val Pro Lys Ala Val Gly
260 265 270
tgg gaa aga aat gca aat gat aag ttg cag ccg att tca gta gac tta 864
Trp Glu Arg Asn Ala Asn Asp Lys Leu Gln Pro Ile Ser Val Asp Leu
275 280 285
agt aaa gag ttc gat cca aaa ata tta atg gaa aga tct gtg gat ctt 912
Ser Lys Glu Phe Asp Pro Lys Ile Leu Met Glu Arg Ser Val Asp Leu
290 295 300
aat tta tca tta atc aaa tgg aga ttg cac cca gat att caa ttg gaa 960
Asn Leu Ser Leu Ile Lys Trp Arg Leu His Pro Asp Ile Gln Leu Glu
305 310 315 320
aga tac tca cag ctg aag gtt ctc att ctt ggt gct gga acg ctt gga 1008
Arg Tyr Ser Gln Leu Lys Val Leu Ile Leu Gly Ala Gly Thr Leu Gly
325 330 335
tgt aac att gcc cgt tgt ctt atc gga tgg gga gtt cgt cac att tcg 1056
Cys Asn Ile Ala Arg Cys Leu Ile Gly Trp Gly Val Arg His Ile Ser
340 345 350
ttt ctt gat aat tca act gtc agc tac aat aac ccc gtt cgc cag agt 1104
Phe Leu Asp Asn Ser Thr Val Ser Tyr Asn Asn Pro Val Arg Gln Ser
355 360 365
ctc tca gaa ttt gaa gat gca cgc ctg ggt cgt gga aaa gcc gaa aca 1152
Leu Ser Glu Phe Glu Asp Ala Arg Leu Gly Arg Gly Lys Ala Glu Thr
370 375 380
gca caa gct gct atc caa cgc att ttc cca tcg att caa gca act gct 1200
Ala Gln Ala Ala Ile Gln Arg Ile Phe Pro Ser Ile Gln Ala Thr Ala
385 390 395 400
cat cgt ctc act gtt cca atg cct gga cat tct atc gat gaa aaa gat 1248
His Arg Leu Thr Val Pro Met Pro Gly His Ser Ile Asp Glu Lys Asp
405 410 415
gta cca gag ctg gaa aaa gat att gca aaa ttg gag caa ctt gtg aaa 1296
Val Pro Glu Leu Glu Lys Asp Ile Ala Lys Leu Glu Gln Leu Val Lys
420 425 430
gat cat gat gtt gtt ttc cta gca tta gat tca agg gaa gct cgc tgg 1344
Asp His Asp Val Val Phe Leu Ala Leu Asp Ser Arg Glu Ala Arg Trp
435 440 445
ctt cca aca gtt ttg gct agt aga cat aag aag att gca att agt gtc 1392
Leu Pro Thr Val Leu Ala Ser Arg His Lys Lys Ile Ala Ile Ser Val
450 455 460
gcg att gga ttc gat acc tac gtc atc att cgg cat gga att ggt tct 1440
Ala Ile Gly Phe Asp Thr Tyr Val Ile Ile Arg His Gly Ile Gly Ser
465 470 475 480
aga agc gaa agt gtt tca gat gtt tca tca tca gat tcc gta cca tac 1488
Arg Ser Glu Ser Val Ser Asp Val Ser Ser Ser Asp Ser Val Pro Tyr
485 490 495
tct cag ctt tct tgc tat ttc tgc agt gat gta act gct cca gga aat 1536
Ser Gln Leu Ser Cys Tyr Phe Cys Ser Asp Val Thr Ala Pro Gly Asn
500 505 510
tct act ttc gat aga aca ttg gac caa cag tgc act gtt gca cga cca 1584
Ser Thr Phe Asp Arg Thr Leu Asp Gln Gln Cys Thr Val Ala Arg Pro
515 520 525
gga aca tct atg att gca tct gga att gcc gtt gaa ctc tta tcg tct 1632
Gly Thr Ser Met Ile Ala Ser Gly Ile Ala Val Glu Leu Leu Ser Ser
530 535 540
gtt tta caa tac cct gat cca ctc aag aca cca gcc agc cac gac gat 1680
Val Leu Gln Tyr Pro Asp Pro Leu Lys Thr Pro Ala Ser His Asp Asp
545 550 555 560
aat aca aca gtc ctt gga gct gct cca cat caa att cgc ggt ttt ctg 1728
Asn Thr Thr Val Leu Gly Ala Ala Pro His Gln Ile Arg Gly Phe Leu
565 570 575
gga aga ttc cag cag att ctt cct tct gta aaa cga ttc gat caa tgt 1776
Gly Arg Phe Gln Gln Ile Leu Pro Ser Val Lys Arg Phe Asp Gln Cys
580 585 590
gtt gct tgt gga gac gct atc gct gca cag ttt cag caa aat ggc tgg 1824
Val Ala Cys Gly Asp Ala Ile Ala Ala Gln Phe Gln Gln Asn Gly Trp
595 600 605
aag ttt gtt cgc gac gtt atg aac tcg cca ggt cgt ctc gaa gaa gtc 1872
Lys Phe Val Arg Asp Val Met Asn Ser Pro Gly Arg Leu Glu Glu Val
610 615 620
acc ggg ctc gac gag ctt cag aac tct gtt aat gct att gat atc gat 1920
Thr Gly Leu Asp Glu Leu Gln Asn Ser Val Asn Ala Ile Asp Ile Asp
625 630 635 640
ttt gag gat gat gaa gat ttc tga 1944
Phe Glu Asp Asp Glu Asp Phe
645
<210> 42
<211> 647
<212> PRT
<213> Caenorhabditis elegans
<400> 42
Met Ala Thr Phe Val Pro Phe Val Thr Cys Leu Asp Thr Gly Phe Trp
1 5 10 15
Asn Glu Val Asn Lys Lys Lys Leu Asn Asp Trp Lys Leu Asp Glu Thr
20 25 30
Pro Lys Cys Ile Ser Ser Gln Leu Ser Leu His Gln Thr Glu Gly Phe
35 40 45
Lys Cys His Leu Ser Leu Ser Tyr Asp Ser Leu Ser Ser Leu Glu Ser
50 55 60
Thr Thr Gly Leu Ser Met Ser Gly Thr Leu Leu Leu Tyr Asn Thr Ile
65 70 75 80
Glu Ser Phe Lys Met Val Asp Lys Ser Asp Leu Ile Arg Ser Glu Ala
85 90 95
Glu Lys Ile Trp Glu Ser Ile Thr Thr Arg Lys Trp Leu Gln Asn Pro
100 105 110
Arg Leu Leu Ser Gln Phe Phe Ile Ile Ala Phe Ala Asp Leu Lys Lys
115 120 125
Phe Lys Tyr Tyr Tyr Trp Thr Cys Val Pro Ala Leu Val Tyr Pro Ser
130 135 140
Glu Ile Lys Gln Glu Ile Thr Pro Leu Ser Ser Leu Gly Ala Asp His
145 150 155 160
Lys Ile Leu Phe Asp Phe Tyr Arg Lys Asn Asn Phe Pro Ile Phe Leu
165 170 175
Tyr Ser Lys Gln Ser Ser Lys Met Leu Glu Leu Ser Glu Leu Glu Asn
180 185 190
Asn Thr Asn Pro Asp Glu Ile Cys Val Val Val Ala Asp Pro Ser Pro
195 200 205
Val Ala Tyr Ser Ala Gly Trp Met Val Arg Asn Val Leu Ala Ala Val
210 215 220
Ala His Leu His Pro Thr Trp Lys His Cys His Ile Ile Ser Leu Arg
225 230 235 240
Ser Ala Asp Ser Ile Gly Ile Lys Tyr Thr Trp Thr Leu Pro Ser Ala
245 250 255
Glu Cys Ser Ala Asp Gly Ala Gln Asn Ala Val Pro Lys Ala Val Gly
260 265 270
Trp Glu Arg Asn Ala Asn Asp Lys Leu Gln Pro Ile Ser Val Asp Leu
275 280 285
Ser Lys Glu Phe Asp Pro Lys Ile Leu Met Glu Arg Ser Val Asp Leu
290 295 300
Asn Leu Ser Leu Ile Lys Trp Arg Leu His Pro Asp Ile Gln Leu Glu
305 310 315 320
Arg Tyr Ser Gln Leu Lys Val Leu Ile Leu Gly Ala Gly Thr Leu Gly
325 330 335
Cys Asn Ile Ala Arg Cys Leu Ile Gly Trp Gly Val Arg His Ile Ser
340 345 350
Phe Leu Asp Asn Ser Thr Val Ser Tyr Asn Asn Pro Val Arg Gln Ser
355 360 365
Leu Ser Glu Phe Glu Asp Ala Arg Leu Gly Arg Gly Lys Ala Glu Thr
370 375 380
Ala Gln Ala Ala Ile Gln Arg Ile Phe Pro Ser Ile Gln Ala Thr Ala
385 390 395 400
His Arg Leu Thr Val Pro Met Pro Gly His Ser Ile Asp Glu Lys Asp
405 410 415
Val Pro Glu Leu Glu Lys Asp Ile Ala Lys Leu Glu Gln Leu Val Lys
420 425 430
Asp His Asp Val Val Phe Leu Ala Leu Asp Ser Arg Glu Ala Arg Trp
435 440 445
Leu Pro Thr Val Leu Ala Ser Arg His Lys Lys Ile Ala Ile Ser Val
450 455 460
Ala Ile Gly Phe Asp Thr Tyr Val Ile Ile Arg His Gly Ile Gly Ser
465 470 475 480
Arg Ser Glu Ser Val Ser Asp Val Ser Ser Ser Asp Ser Val Pro Tyr
485 490 495
Ser Gln Leu Ser Cys Tyr Phe Cys Ser Asp Val Thr Ala Pro Gly Asn
500 505 510
Ser Thr Phe Asp Arg Thr Leu Asp Gln Gln Cys Thr Val Ala Arg Pro
515 520 525
Gly Thr Ser Met Ile Ala Ser Gly Ile Ala Val Glu Leu Leu Ser Ser
530 535 540
Val Leu Gln Tyr Pro Asp Pro Leu Lys Thr Pro Ala Ser His Asp Asp
545 550 555 560
Asn Thr Thr Val Leu Gly Ala Ala Pro His Gln Ile Arg Gly Phe Leu
565 570 575
Gly Arg Phe Gln Gln Ile Leu Pro Ser Val Lys Arg Phe Asp Gln Cys
580 585 590
Val Ala Cys Gly Asp Ala Ile Ala Ala Gln Phe Gln Gln Asn Gly Trp
595 600 605
Lys Phe Val Arg Asp Val Met Asn Ser Pro Gly Arg Leu Glu Glu Val
610 615 620
Thr Gly Leu Asp Glu Leu Gln Asn Ser Val Asn Ala Ile Asp Ile Asp
625 630 635 640
Phe Glu Asp Asp Glu Asp Phe
645
<210> 43
<211> 2112
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(2112)
<400> 43
atg gcg gca gct acg ggg gat cct gga ctc tct aaa ctg cag ttt gcc 48
Met Ala Ala Ala Thr Gly Asp Pro Gly Leu Ser Lys Leu Gln Phe Ala
1 5 10 15
cct ttt agt agt gcc ttg gat gtt ggg ttt tgg cat gag ttg acc cag 96
Pro Phe Ser Ser Ala Leu Asp Val Gly Phe Trp His Glu Leu Thr Gln
20 25 30
aag aag ctg aac gag tat cgg ctg gat gaa gct ccc aag gac att aag 144
Lys Lys Leu Asn Glu Tyr Arg Leu Asp Glu Ala Pro Lys Asp Ile Lys
35 40 45
ggt tat tac tac aat ggt gac tct gct ggg ctg cca gct cgc tta aca 192
Gly Tyr Tyr Tyr Asn Gly Asp Ser Ala Gly Leu Pro Ala Arg Leu Thr
50 55 60
ttg gag ttc agt gct ttt gac atg agt gct ccc acc cca gcc cgt tgc 240
Leu Glu Phe Ser Ala Phe Asp Met Ser Ala Pro Thr Pro Ala Arg Cys
65 70 75 80
tgc cca gct att gga aca ctg tat aac acc aac aca ctc gag tct ttc 288
Cys Pro Ala Ile Gly Thr Leu Tyr Asn Thr Asn Thr Leu Glu Ser Phe
85 90 95
aag act gca gat aag aag ctc ctt ttg gaa caa gca gca aat gag ata 336
Lys Thr Ala Asp Lys Lys Leu Leu Leu Glu Gln Ala Ala Asn Glu Ile
100 105 110
tgg gaa tcc ata aaa tca ggc act gct ctt gaa aac cct gta ctc ctc 384
Trp Glu Ser Ile Lys Ser Gly Thr Ala Leu Glu Asn Pro Val Leu Leu
115 120 125
aac aag ttc ctc ctc ttg aca ttt gca gat cta aag aag tac cac ttc 432
Asn Lys Phe Leu Leu Leu Thr Phe Ala Asp Leu Lys Lys Tyr His Phe
130 135 140
tac tat tgg ttt tgc tat cct gcc ctc tgt ctt cca gag agt tta cct 480
Tyr Tyr Trp Phe Cys Tyr Pro Ala Leu Cys Leu Pro Glu Ser Leu Pro
145 150 155 160
ctc att cag ggg cca gtg ggt ttg gat caa agg ttt tca cta aaa cag 528
Leu Ile Gln Gly Pro Val Gly Leu Asp Gln Arg Phe Ser Leu Lys Gln
165 170 175
att gaa gca cta gag tgt gca tat gat aat ctt tgt caa aca gaa gga 576
Ile Glu Ala Leu Glu Cys Ala Tyr Asp Asn Leu Cys Gln Thr Glu Gly
180 185 190
gtc aca gct ctt cct tac ttc tta atc aag tat gat gag aac atg gtg 624
Val Thr Ala Leu Pro Tyr Phe Leu Ile Lys Tyr Asp Glu Asn Met Val
195 200 205
ctg gtt tcc ttg ctt aaa cac tac agt gat ttc ttc caa ggt caa agg 672
Leu Val Ser Leu Leu Lys His Tyr Ser Asp Phe Phe Gln Gly Gln Arg
210 215 220
acg aag ata aca att ggt gta tat gat ccc tgt aac tta gcc cag tac 720
Thr Lys Ile Thr Ile Gly Val Tyr Asp Pro Cys Asn Leu Ala Gln Tyr
225 230 235 240
cct gga tgg cct ttg agg aat ttt ttg gtc cta gca gcc cac aga tgg 768
Pro Gly Trp Pro Leu Arg Asn Phe Leu Val Leu Ala Ala His Arg Trp
245 250 255
agt agc agt ttc cag tct gtt gaa gtt gtt tgc ttc cgt gac cgt acc 816
Ser Ser Ser Phe Gln Ser Val Glu Val Val Cys Phe Arg Asp Arg Thr
260 265 270
atg cag ggg gcg aga gac gtt gcc cac agc atc atc ttc gaa gtg aag 864
Met Gln Gly Ala Arg Asp Val Ala His Ser Ile Ile Phe Glu Val Lys
275 280 285
ctt cca gaa atg gca ttt agc cca gat tgt cct aaa gca gtt gga tgg 912
Leu Pro Glu Met Ala Phe Ser Pro Asp Cys Pro Lys Ala Val Gly Trp
290 295 300
gaa aag aac cag aaa gga ggc atg gga cca agg atg gtg aac ctc agt 960
Glu Lys Asn Gln Lys Gly Gly Met Gly Pro Arg Met Val Asn Leu Ser
305 310 315 320
gaa tgt atg gac cct aaa agg tta gct gag tca tca gtg gat cta aat 1008
Glu Cys Met Asp Pro Lys Arg Leu Ala Glu Ser Ser Val Asp Leu Asn
325 330 335
ctc aaa ctg atg tgt tgg aga ttg gtt cct act tta gac ttg gac aag 1056
Leu Lys Leu Met Cys Trp Arg Leu Val Pro Thr Leu Asp Leu Asp Lys
340 345 350
gtt gtg tct gtc aaa tgt ctg ctg ctt gga gcc ggc acc ttg ggt tgc 1104
Val Val Ser Val Lys Cys Leu Leu Leu Gly Ala Gly Thr Leu Gly Cys
355 360 365
aat gta gct agg acg ttg atg ggt tgg ggc gtg aga cac atc aca ttt 1152
Asn Val Ala Arg Thr Leu Met Gly Trp Gly Val Arg His Ile Thr Phe
370 375 380
gtg gac aat gcc aag atc tcc tac tcc aat cct gtg agg cag cct ctc 1200
Val Asp Asn Ala Lys Ile Ser Tyr Ser Asn Pro Val Arg Gln Pro Leu
385 390 395 400
tat gag ttt gaa gat tgc cta ggg ggt ggt aag ccc aag gct ctg gca 1248
Tyr Glu Phe Glu Asp Cys Leu Gly Gly Gly Lys Pro Lys Ala Leu Ala
405 410 415
gca gcg gac cgg ctc cag aaa ata ttc ccc ggt gtg aat gcc aga gga 1296
Ala Ala Asp Arg Leu Gln Lys Ile Phe Pro Gly Val Asn Ala Arg Gly
420 425 430
ttc aac atg agc ata cct atg cct ggg cat cca gtg aac ttc tcc agt 1344
Phe Asn Met Ser Ile Pro Met Pro Gly His Pro Val Asn Phe Ser Ser
435 440 445
gtc act ctg gag caa gcc cgc aga gat gtg gag caa ctg gag cag ctc 1392
Val Thr Leu Glu Gln Ala Arg Arg Asp Val Glu Gln Leu Glu Gln Leu
450 455 460
atc gaa agc cat gat gtc gtc ttc cta ttg atg gac acc agg gag agc 1440
Ile Glu Ser His Asp Val Val Phe Leu Leu Met Asp Thr Arg Glu Ser
465 470 475 480
cgg tgg ctt cct gcc gtc att gct gca agc aag aga aag ctg gtc atc 1488
Arg Trp Leu Pro Ala Val Ile Ala Ala Ser Lys Arg Lys Leu Val Ile
485 490 495
aat gct gct ttg gga ttt gac aca ttt gtt gtc atg aga cat ggt ctg 1536
Asn Ala Ala Leu Gly Phe Asp Thr Phe Val Val Met Arg His Gly Leu
500 505 510
aag aaa cca aag cag caa gga gct ggg gac ttg tgt cca aac cac cct 1584
Lys Lys Pro Lys Gln Gln Gly Ala Gly Asp Leu Cys Pro Asn His Pro
515 520 525
gtg gca tct gct gac ctc ctg ggc tca tcg ctt ttt gcc aac atc cct 1632
Val Ala Ser Ala Asp Leu Leu Gly Ser Ser Leu Phe Ala Asn Ile Pro
530 535 540
ggt tac aag ctt ggc tgc tac ttc tgc aat gat gtg gtg gcc cca gga 1680
Gly Tyr Lys Leu Gly Cys Tyr Phe Cys Asn Asp Val Val Ala Pro Gly
545 550 555 560
gat tca acc aga gac cgg acc ttg gac cag cag tgc act gtg agt cgt 1728
Asp Ser Thr Arg Asp Arg Thr Leu Asp Gln Gln Cys Thr Val Ser Arg
565 570 575
cca gga ctg gcc gtg att gca gga gcc ctg gcc gtg gaa ttg atg gta 1776
Pro Gly Leu Ala Val Ile Ala Gly Ala Leu Ala Val Glu Leu Met Val
580 585 590
tct gtt ttg cag cat cca gaa ggg ggc tat gcc att gcc agc agc agt 1824
Ser Val Leu Gln His Pro Glu Gly Gly Tyr Ala Ile Ala Ser Ser Ser
595 600 605
gac gat cgg atg aat gag cct cca acc tct ctt ggg ctt gtg cct cac 1872
Asp Asp Arg Met Asn Glu Pro Pro Thr Ser Leu Gly Leu Val Pro His
610 615 620
cag atc cgg gga ttt ctt tca cgg ttt gat aat gtc ctt ccc gtc agc 1920
Gln Ile Arg Gly Phe Leu Ser Arg Phe Asp Asn Val Leu Pro Val Ser
625 630 635 640
ctg gca ttt gac aaa tgt aca gct tgt tct tcc aaa gtt ctt gat caa 1968
Leu Ala Phe Asp Lys Cys Thr Ala Cys Ser Ser Lys Val Leu Asp Gln
645 650 655
tat gaa cga gaa gga ttt aac ttc cta gcc aag gtg ttt aat tct tca 2016
Tyr Glu Arg Glu Gly Phe Asn Phe Leu Ala Lys Val Phe Asn Ser Ser
660 665 670
cat tcc ttc tta gaa gac ttg act ggt ctt aca ttg ctg cat caa gaa 2064
His Ser Phe Leu Glu Asp Leu Thr Gly Leu Thr Leu Leu His Gln Glu
675 680 685
acc caa gct gct gag atc tgg gac atg agc gat gat gag acc atc tga 2112
Thr Gln Ala Ala Glu Ile Trp Asp Met Ser Asp Asp Glu Thr Ile
690 695 700
<210> 44
<211> 703
<212> PRT
<213> Homo sapiens
<400> 44
Met Ala Ala Ala Thr Gly Asp Pro Gly Leu Ser Lys Leu Gln Phe Ala
1 5 10 15
Pro Phe Ser Ser Ala Leu Asp Val Gly Phe Trp His Glu Leu Thr Gln
20 25 30
Lys Lys Leu Asn Glu Tyr Arg Leu Asp Glu Ala Pro Lys Asp Ile Lys
35 40 45
Gly Tyr Tyr Tyr Asn Gly Asp Ser Ala Gly Leu Pro Ala Arg Leu Thr
50 55 60
Leu Glu Phe Ser Ala Phe Asp Met Ser Ala Pro Thr Pro Ala Arg Cys
65 70 75 80
Cys Pro Ala Ile Gly Thr Leu Tyr Asn Thr Asn Thr Leu Glu Ser Phe
85 90 95
Lys Thr Ala Asp Lys Lys Leu Leu Leu Glu Gln Ala Ala Asn Glu Ile
100 105 110
Trp Glu Ser Ile Lys Ser Gly Thr Ala Leu Glu Asn Pro Val Leu Leu
115 120 125
Asn Lys Phe Leu Leu Leu Thr Phe Ala Asp Leu Lys Lys Tyr His Phe
130 135 140
Tyr Tyr Trp Phe Cys Tyr Pro Ala Leu Cys Leu Pro Glu Ser Leu Pro
145 150 155 160
Leu Ile Gln Gly Pro Val Gly Leu Asp Gln Arg Phe Ser Leu Lys Gln
165 170 175
Ile Glu Ala Leu Glu Cys Ala Tyr Asp Asn Leu Cys Gln Thr Glu Gly
180 185 190
Val Thr Ala Leu Pro Tyr Phe Leu Ile Lys Tyr Asp Glu Asn Met Val
195 200 205
Leu Val Ser Leu Leu Lys His Tyr Ser Asp Phe Phe Gln Gly Gln Arg
210 215 220
Thr Lys Ile Thr Ile Gly Val Tyr Asp Pro Cys Asn Leu Ala Gln Tyr
225 230 235 240
Pro Gly Trp Pro Leu Arg Asn Phe Leu Val Leu Ala Ala His Arg Trp
245 250 255
Ser Ser Ser Phe Gln Ser Val Glu Val Val Cys Phe Arg Asp Arg Thr
260 265 270
Met Gln Gly Ala Arg Asp Val Ala His Ser Ile Ile Phe Glu Val Lys
275 280 285
Leu Pro Glu Met Ala Phe Ser Pro Asp Cys Pro Lys Ala Val Gly Trp
290 295 300
Glu Lys Asn Gln Lys Gly Gly Met Gly Pro Arg Met Val Asn Leu Ser
305 310 315 320
Glu Cys Met Asp Pro Lys Arg Leu Ala Glu Ser Ser Val Asp Leu Asn
325 330 335
Leu Lys Leu Met Cys Trp Arg Leu Val Pro Thr Leu Asp Leu Asp Lys
340 345 350
Val Val Ser Val Lys Cys Leu Leu Leu Gly Ala Gly Thr Leu Gly Cys
355 360 365
Asn Val Ala Arg Thr Leu Met Gly Trp Gly Val Arg His Ile Thr Phe
370 375 380
Val Asp Asn Ala Lys Ile Ser Tyr Ser Asn Pro Val Arg Gln Pro Leu
385 390 395 400
Tyr Glu Phe Glu Asp Cys Leu Gly Gly Gly Lys Pro Lys Ala Leu Ala
405 410 415
Ala Ala Asp Arg Leu Gln Lys Ile Phe Pro Gly Val Asn Ala Arg Gly
420 425 430
Phe Asn Met Ser Ile Pro Met Pro Gly His Pro Val Asn Phe Ser Ser
435 440 445
Val Thr Leu Glu Gln Ala Arg Arg Asp Val Glu Gln Leu Glu Gln Leu
450 455 460
Ile Glu Ser His Asp Val Val Phe Leu Leu Met Asp Thr Arg Glu Ser
465 470 475 480
Arg Trp Leu Pro Ala Val Ile Ala Ala Ser Lys Arg Lys Leu Val Ile
485 490 495
Asn Ala Ala Leu Gly Phe Asp Thr Phe Val Val Met Arg His Gly Leu
500 505 510
Lys Lys Pro Lys Gln Gln Gly Ala Gly Asp Leu Cys Pro Asn His Pro
515 520 525
Val Ala Ser Ala Asp Leu Leu Gly Ser Ser Leu Phe Ala Asn Ile Pro
530 535 540
Gly Tyr Lys Leu Gly Cys Tyr Phe Cys Asn Asp Val Val Ala Pro Gly
545 550 555 560
Asp Ser Thr Arg Asp Arg Thr Leu Asp Gln Gln Cys Thr Val Ser Arg
565 570 575
Pro Gly Leu Ala Val Ile Ala Gly Ala Leu Ala Val Glu Leu Met Val
580 585 590
Ser Val Leu Gln His Pro Glu Gly Gly Tyr Ala Ile Ala Ser Ser Ser
595 600 605
Asp Asp Arg Met Asn Glu Pro Pro Thr Ser Leu Gly Leu Val Pro His
610 615 620
Gln Ile Arg Gly Phe Leu Ser Arg Phe Asp Asn Val Leu Pro Val Ser
625 630 635 640
Leu Ala Phe Asp Lys Cys Thr Ala Cys Ser Ser Lys Val Leu Asp Gln
645 650 655
Tyr Glu Arg Glu Gly Phe Asn Phe Leu Ala Lys Val Phe Asn Ser Ser
660 665 670
His Ser Phe Leu Glu Asp Leu Thr Gly Leu Thr Leu Leu His Gln Glu
675 680 685
Thr Gln Ala Ala Glu Ile Trp Asp Met Ser Asp Asp Glu Thr Ile
690 695 700
<210> 45
<211> 288
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(288)
<400> 45
atg tct ttg gtg cca gct tca ttc tat caa aat gtg gat att att cga 48
Met Ser Leu Val Pro Ala Ser Phe Tyr Gln Asn Val Asp Ile Ile Arg
1 5 10 15
gat gtg aag ttt aat atg aag cca acg tgt tcg att tgt atg gaa gaa 96
Asp Val Lys Phe Asn Met Lys Pro Thr Cys Ser Ile Cys Met Glu Glu
20 25 30
ttc gat gca aat tct cat att ccg aag gtt ctc att tgt ggc cac tcg 144
Phe Asp Ala Asn Ser His Ile Pro Lys Val Leu Ile Cys Gly His Ser
35 40 45
ttt tgc att att tgc atc gaa aaa cat ttg aga tca tca aat ctc aca 192
Phe Cys Ile Ile Cys Ile Glu Lys His Leu Arg Ser Ser Asn Leu Thr
50 55 60
ttc tgg cga tgg gga tgt ttt cag tca tta tac atg ctc tac ttg ccg 240
Phe Trp Arg Trp Gly Cys Phe Gln Ser Leu Tyr Met Leu Tyr Leu Pro
65 70 75 80
cac aac gat gga aat tcc tgt caa cgg agc agc tgg att ttc cac taa 288
His Asn Asp Gly Asn Ser Cys Gln Arg Ser Ser Trp Ile Phe His
85 90 95
<210> 46
<211> 95
<212> PRT
<213> Caenorhabditis elegans
<400> 46
Met Ser Leu Val Pro Ala Ser Phe Tyr Gln Asn Val Asp Ile Ile Arg
1 5 10 15
Asp Val Lys Phe Asn Met Lys Pro Thr Cys Ser Ile Cys Met Glu Glu
20 25 30
Phe Asp Ala Asn Ser His Ile Pro Lys Val Leu Ile Cys Gly His Ser
35 40 45
Phe Cys Ile Ile Cys Ile Glu Lys His Leu Arg Ser Ser Asn Leu Thr
50 55 60
Phe Trp Arg Trp Gly Cys Phe Gln Ser Leu Tyr Met Leu Tyr Leu Pro
65 70 75 80
His Asn Asp Gly Asn Ser Cys Gln Arg Ser Ser Trp Ile Phe His
85 90 95
<210> 47
<211> 1962
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(1962)
<400> 47
atg gct gca gca gca gct tct cac ctg aac ctg gat gcc ctc cgg gaa 48
Met Ala Ala Ala Ala Ala Ser His Leu Asn Leu Asp Ala Leu Arg Glu
1 5 10 15
gtg cta gaa tgc ccc atc tgc atg gag tcc ttc aca gaa gag cag ctg 96
Val Leu Glu Cys Pro Ile Cys Met Glu Ser Phe Thr Glu Glu Gln Leu
20 25 30
cgt ccc aag ctt ctg cac tgt ggc cat acc atc tgc cgc cag tgc ctg 144
Arg Pro Lys Leu Leu His Cys Gly His Thr Ile Cys Arg Gln Cys Leu
35 40 45
gag aag cta ttg gcc agt agc atc aat ggt gtc cgc tgt ccc ttt tgc 192
Glu Lys Leu Leu Ala Ser Ser Ile Asn Gly Val Arg Cys Pro Phe Cys
50 55 60
agc aag att acc cgc ata acc agc ttg acc cag ctg aca gac aat ctg 240
Ser Lys Ile Thr Arg Ile Thr Ser Leu Thr Gln Leu Thr Asp Asn Leu
65 70 75 80
aca gtg cta aag atc att gat aca gct ggg ctc agc gag gct gtg ggg 288
Thr Val Leu Lys Ile Ile Asp Thr Ala Gly Leu Ser Glu Ala Val Gly
85 90 95
ctg ctc atg tgt cgg tcc tgt ggg cgg cgt ctg ccc cgg caa ttc tgc 336
Leu Leu Met Cys Arg Ser Cys Gly Arg Arg Leu Pro Arg Gln Phe Cys
100 105 110
cgg agc tgt ggt ttg gtg tta tgt gag ccc tgc cgg gag gca gac cat 384
Arg Ser Cys Gly Leu Val Leu Cys Glu Pro Cys Arg Glu Ala Asp His
115 120 125
cag cct cct ggc cac tgt aca ctc cct gtc aaa gaa gca gct gag gag 432
Gln Pro Pro Gly His Cys Thr Leu Pro Val Lys Glu Ala Ala Glu Glu
130 135 140
cgg cgt cgg gac ttt gga gag aag tta act cgt ctg cgg gaa ctt atg 480
Arg Arg Arg Asp Phe Gly Glu Lys Leu Thr Arg Leu Arg Glu Leu Met
145 150 155 160
ggg gag ctg cag cgg cgg aag gca gcc ttg gaa ggt gtc tcc aag gac 528
Gly Glu Leu Gln Arg Arg Lys Ala Ala Leu Glu Gly Val Ser Lys Asp
165 170 175
ctt cag gca agg tat aaa gca gtt ctc cag gag tat ggg cat gag gag 576
Leu Gln Ala Arg Tyr Lys Ala Val Leu Gln Glu Tyr Gly His Glu Glu
180 185 190
cgc agg gtc cag gat gag ctg gct cgc tct cgg aag ttc ttc aca ggc 624
Arg Arg Val Gln Asp Glu Leu Ala Arg Ser Arg Lys Phe Phe Thr Gly
195 200 205
tct ttg gct gaa gtt gag aag tcc aat agt caa gtg gta gag gag cag 672
Ser Leu Ala Glu Val Glu Lys Ser Asn Ser Gln Val Val Glu Glu Gln
210 215 220
agt tac ctg ctt aac att gca gag gtg cag gct gtg tct cgc tgt gac 720
Ser Tyr Leu Leu Asn Ile Ala Glu Val Gln Ala Val Ser Arg Cys Asp
225 230 235 240
tac ttc ctg gcc aag atc aag cag gca gat gta gca cta ctg gag gag 768
Tyr Phe Leu Ala Lys Ile Lys Gln Ala Asp Val Ala Leu Leu Glu Glu
245 250 255
aca gct gat gag gag gag cca gag ctc act gcc agc ttg cct cgg gag 816
Thr Ala Asp Glu Glu Glu Pro Glu Leu Thr Ala Ser Leu Pro Arg Glu
260 265 270
ctc acc ctg caa gat gtg gag ctc ctt aag gta ggt cat gtt ggc ccc 864
Leu Thr Leu Gln Asp Val Glu Leu Leu Lys Val Gly His Val Gly Pro
275 280 285
ctc caa att gga caa gct gtt aag aag ccc cgg aca gtt aac gtg gaa 912
Leu Gln Ile Gly Gln Ala Val Lys Lys Pro Arg Thr Val Asn Val Glu
290 295 300
gat tcc tgg gcc atg gag gcc aca gcg tct gct gcc tct acc tct gtt 960
Asp Ser Trp Ala Met Glu Ala Thr Ala Ser Ala Ala Ser Thr Ser Val
305 310 315 320
act ttt aga gag atg gac atg agc ccg gag gaa gtg gtt gcc agc cct 1008
Thr Phe Arg Glu Met Asp Met Ser Pro Glu Glu Val Val Ala Ser Pro
325 330 335
agg gcc tca cct gct aaa cag cgg ggt cct gag gca gcc tcc aat atc 1056
Arg Ala Ser Pro Ala Lys Gln Arg Gly Pro Glu Ala Ala Ser Asn Ile
340 345 350
cag cag tgc ctc ttt ctc aag aag atg ggg gcc aaa ggc agc act cca 1104
Gln Gln Cys Leu Phe Leu Lys Lys Met Gly Ala Lys Gly Ser Thr Pro
355 360 365
gga atg ttc aat ctt cca gtc agt ctc tac gtg acc agt caa ggt gaa 1152
Gly Met Phe Asn Leu Pro Val Ser Leu Tyr Val Thr Ser Gln Gly Glu
370 375 380
gta cta gtc gct gac cgt ggt aac tat cgt ata caa gtc ttt acc cgc 1200
Val Leu Val Ala Asp Arg Gly Asn Tyr Arg Ile Gln Val Phe Thr Arg
385 390 395 400
aaa ggc ttt ttg aag gaa atc cgc cgc agc ccc agt ggc att gat agc 1248
Lys Gly Phe Leu Lys Glu Ile Arg Arg Ser Pro Ser Gly Ile Asp Ser
405 410 415
ttt gtg cta agc ttc ctt ggg gca gat cta ccc aac ctc act cct ctc 1296
Phe Val Leu Ser Phe Leu Gly Ala Asp Leu Pro Asn Leu Thr Pro Leu
420 425 430
tca gtg gca atg aac tgc cag ggg ctg att ggt gtg act gac agc tat 1344
Ser Val Ala Met Asn Cys Gln Gly Leu Ile Gly Val Thr Asp Ser Tyr
435 440 445
gat aac tcc ctc aag gta tat acc ttg gat ggc cac tgc gtg gcc tgt 1392
Asp Asn Ser Leu Lys Val Tyr Thr Leu Asp Gly His Cys Val Ala Cys
450 455 460
cac agg agc cag ctg agc aaa cca tgg ggt atc aca gcc ttg cca tct 1440
His Arg Ser Gln Leu Ser Lys Pro Trp Gly Ile Thr Ala Leu Pro Ser
465 470 475 480
ggc cag ttt gta gta acc gat gtg gaa ggt gga aag ctt tgg tgt ttc 1488
Gly Gln Phe Val Val Thr Asp Val Glu Gly Gly Lys Leu Trp Cys Phe
485 490 495
aca gtt gat cga gga tca ggg gtg gtc aaa tac agc tgc cta tgt agt 1536
Thr Val Asp Arg Gly Ser Gly Val Val Lys Tyr Ser Cys Leu Cys Ser
500 505 510
gct gtg cgg ccc aaa ttt gtc acc tgt gat gct gag ggc acc gtc tac 1584
Ala Val Arg Pro Lys Phe Val Thr Cys Asp Ala Glu Gly Thr Val Tyr
515 520 525
ttc acc cag ggc tta ggc ctc aat ctg gag aat cgg cag aat gag cac 1632
Phe Thr Gln Gly Leu Gly Leu Asn Leu Glu Asn Arg Gln Asn Glu His
530 535 540
cac ctg gag ggt ggc ttt tcc att ggc tct gta ggc cct gat ggg cag 1680
His Leu Glu Gly Gly Phe Ser Ile Gly Ser Val Gly Pro Asp Gly Gln
545 550 555 560
ctg ggt cgc cag att agc cac ttc ttc tcg gag aat gag gat ttc cgc 1728
Leu Gly Arg Gln Ile Ser His Phe Phe Ser Glu Asn Glu Asp Phe Arg
565 570 575
tgc att gct ggc atg tgt gtg gat gct cgt ggt gat ctc atc gtg gct 1776
Cys Ile Ala Gly Met Cys Val Asp Ala Arg Gly Asp Leu Ile Val Ala
580 585 590
gac agt agt cgc aag gaa att ctc cat ttt cct aag ggt ggg ggc tat 1824
Asp Ser Ser Arg Lys Glu Ile Leu His Phe Pro Lys Gly Gly Gly Tyr
595 600 605
agt gtc ctt att cga gag gga ctt acc tgt ccg gtg ggc ata gcc cta 1872
Ser Val Leu Ile Arg Glu Gly Leu Thr Cys Pro Val Gly Ile Ala Leu
610 615 620
act cct aag ggg cag ctg ctg gtc ttg gac tgt tgg gat cat tgc atc 1920
Thr Pro Lys Gly Gln Leu Leu Val Leu Asp Cys Trp Asp His Cys Ile
625 630 635 640
aag atc tac agc tac cat ctg aga aga tat tcc acc cca tag 1962
Lys Ile Tyr Ser Tyr His Leu Arg Arg Tyr Ser Thr Pro
645 650
<210> 48
<211> 653
<212> PRT
<213> Homo sapiens
<400> 48
Met Ala Ala Ala Ala Ala Ser His Leu Asn Leu Asp Ala Leu Arg Glu
1 5 10 15
Val Leu Glu Cys Pro Ile Cys Met Glu Ser Phe Thr Glu Glu Gln Leu
20 25 30
Arg Pro Lys Leu Leu His Cys Gly His Thr Ile Cys Arg Gln Cys Leu
35 40 45
Glu Lys Leu Leu Ala Ser Ser Ile Asn Gly Val Arg Cys Pro Phe Cys
50 55 60
Ser Lys Ile Thr Arg Ile Thr Ser Leu Thr Gln Leu Thr Asp Asn Leu
65 70 75 80
Thr Val Leu Lys Ile Ile Asp Thr Ala Gly Leu Ser Glu Ala Val Gly
85 90 95
Leu Leu Met Cys Arg Ser Cys Gly Arg Arg Leu Pro Arg Gln Phe Cys
100 105 110
Arg Ser Cys Gly Leu Val Leu Cys Glu Pro Cys Arg Glu Ala Asp His
115 120 125
Gln Pro Pro Gly His Cys Thr Leu Pro Val Lys Glu Ala Ala Glu Glu
130 135 140
Arg Arg Arg Asp Phe Gly Glu Lys Leu Thr Arg Leu Arg Glu Leu Met
145 150 155 160
Gly Glu Leu Gln Arg Arg Lys Ala Ala Leu Glu Gly Val Ser Lys Asp
165 170 175
Leu Gln Ala Arg Tyr Lys Ala Val Leu Gln Glu Tyr Gly His Glu Glu
180 185 190
Arg Arg Val Gln Asp Glu Leu Ala Arg Ser Arg Lys Phe Phe Thr Gly
195 200 205
Ser Leu Ala Glu Val Glu Lys Ser Asn Ser Gln Val Val Glu Glu Gln
210 215 220
Ser Tyr Leu Leu Asn Ile Ala Glu Val Gln Ala Val Ser Arg Cys Asp
225 230 235 240
Tyr Phe Leu Ala Lys Ile Lys Gln Ala Asp Val Ala Leu Leu Glu Glu
245 250 255
Thr Ala Asp Glu Glu Glu Pro Glu Leu Thr Ala Ser Leu Pro Arg Glu
260 265 270
Leu Thr Leu Gln Asp Val Glu Leu Leu Lys Val Gly His Val Gly Pro
275 280 285
Leu Gln Ile Gly Gln Ala Val Lys Lys Pro Arg Thr Val Asn Val Glu
290 295 300
Asp Ser Trp Ala Met Glu Ala Thr Ala Ser Ala Ala Ser Thr Ser Val
305 310 315 320
Thr Phe Arg Glu Met Asp Met Ser Pro Glu Glu Val Val Ala Ser Pro
325 330 335
Arg Ala Ser Pro Ala Lys Gln Arg Gly Pro Glu Ala Ala Ser Asn Ile
340 345 350
Gln Gln Cys Leu Phe Leu Lys Lys Met Gly Ala Lys Gly Ser Thr Pro
355 360 365
Gly Met Phe Asn Leu Pro Val Ser Leu Tyr Val Thr Ser Gln Gly Glu
370 375 380
Val Leu Val Ala Asp Arg Gly Asn Tyr Arg Ile Gln Val Phe Thr Arg
385 390 395 400
Lys Gly Phe Leu Lys Glu Ile Arg Arg Ser Pro Ser Gly Ile Asp Ser
405 410 415
Phe Val Leu Ser Phe Leu Gly Ala Asp Leu Pro Asn Leu Thr Pro Leu
420 425 430
Ser Val Ala Met Asn Cys Gln Gly Leu Ile Gly Val Thr Asp Ser Tyr
435 440 445
Asp Asn Ser Leu Lys Val Tyr Thr Leu Asp Gly His Cys Val Ala Cys
450 455 460
His Arg Ser Gln Leu Ser Lys Pro Trp Gly Ile Thr Ala Leu Pro Ser
465 470 475 480
Gly Gln Phe Val Val Thr Asp Val Glu Gly Gly Lys Leu Trp Cys Phe
485 490 495
Thr Val Asp Arg Gly Ser Gly Val Val Lys Tyr Ser Cys Leu Cys Ser
500 505 510
Ala Val Arg Pro Lys Phe Val Thr Cys Asp Ala Glu Gly Thr Val Tyr
515 520 525
Phe Thr Gln Gly Leu Gly Leu Asn Leu Glu Asn Arg Gln Asn Glu His
530 535 540
His Leu Glu Gly Gly Phe Ser Ile Gly Ser Val Gly Pro Asp Gly Gln
545 550 555 560
Leu Gly Arg Gln Ile Ser His Phe Phe Ser Glu Asn Glu Asp Phe Arg
565 570 575
Cys Ile Ala Gly Met Cys Val Asp Ala Arg Gly Asp Leu Ile Val Ala
580 585 590
Asp Ser Ser Arg Lys Glu Ile Leu His Phe Pro Lys Gly Gly Gly Tyr
595 600 605
Ser Val Leu Ile Arg Glu Gly Leu Thr Cys Pro Val Gly Ile Ala Leu
610 615 620
Thr Pro Lys Gly Gln Leu Leu Val Leu Asp Cys Trp Asp His Cys Ile
625 630 635 640
Lys Ile Tyr Ser Tyr His Leu Arg Arg Tyr Ser Thr Pro
645 650
<210> 49
<211> 1125
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(1125)
<400> 49
atg ggg caa gcg aag ttg cgg ctg acg cgt tat tgg atg ctg gcg cgt 48
Met Gly Gln Ala Lys Leu Arg Leu Thr Arg Tyr Trp Met Leu Ala Arg
1 5 10 15
ttc gcg acc agc gtt ggt ttt atc gag aat ttt ctc tgc agt aca aag 96
Phe Ala Thr Ser Val Gly Phe Ile Glu Asn Phe Leu Cys Ser Thr Lys
20 25 30
tcc caa att cgg tgg ttt ttt atc gat ttg acg cgc gtt tgc tca att 144
Ser Gln Ile Arg Trp Phe Phe Ile Asp Leu Thr Arg Val Cys Ser Ile
35 40 45
tct cga ttt tcc gcg ttt ttt att cag ttc tca tta att aac gtt cga 192
Ser Arg Phe Ser Ala Phe Phe Ile Gln Phe Ser Leu Ile Asn Val Arg
50 55 60
tgc ttg ttc aca aaa ttc agt ttt tgt ttt cac ttg ctc gtt ggt gtc 240
Cys Leu Phe Thr Lys Phe Ser Phe Cys Phe His Leu Leu Val Gly Val
65 70 75 80
gtt cgt tgt aat atg ttt gga ggt gga agt agt ggt ccc gtg gac acc 288
Val Arg Cys Asn Met Phe Gly Gly Gly Ser Ser Gly Pro Val Asp Thr
85 90 95
act tta tac aca aca ctc aat gtg aga cca gac gct tcg cag gcc gac 336
Thr Leu Tyr Thr Thr Leu Asn Val Arg Pro Asp Ala Ser Gln Ala Asp
100 105 110
att aag aaa tct tac ttc aaa ctt gct aaa gaa tac cat cca gat aaa 384
Ile Lys Lys Ser Tyr Phe Lys Leu Ala Lys Glu Tyr His Pro Asp Lys
115 120 125
aac ccg gac cat gga gat aaa ttc aaa gag atc agt ttt gcc tat gaa 432
Asn Pro Asp His Gly Asp Lys Phe Lys Glu Ile Ser Phe Ala Tyr Glu
130 135 140
gtt ctt tcg agc cct gaa aaa cga cgc ttg tat gac gcc aga ggt ttg 480
Val Leu Ser Ser Pro Glu Lys Arg Arg Leu Tyr Asp Ala Arg Gly Leu
145 150 155 160
gaa gga gtt caa gga gga gga gct ggt ggt ggt gga gga ggc ttt cct 528
Glu Gly Val Gln Gly Gly Gly Ala Gly Gly Gly Gly Gly Gly Phe Pro
165 170 175
gga ggt ctg ttc tct cac ttc ttc ggc ggt gct ggc ggt gat gac gat 576
Gly Gly Leu Phe Ser His Phe Phe Gly Gly Ala Gly Gly Asp Asp Asp
180 185 190
gac gac gat gat gat atg ggt ggt cat cca ttt ggt ggc ttg ttc ggt 624
Asp Asp Asp Asp Asp Met Gly Gly His Pro Phe Gly Gly Leu Phe Gly
195 200 205
gga atg ggt gga atg gga cga ggt ggc cca cgt cgg cgg aaa ttc caa 672
Gly Met Gly Gly Met Gly Arg Gly Gly Pro Arg Arg Arg Lys Phe Gln
210 215 220
gat act gtt cat ccc ctc aat gtt aca ctc gaa gag ctt tac gtc gga 720
Asp Thr Val His Pro Leu Asn Val Thr Leu Glu Glu Leu Tyr Val Gly
225 230 235 240
aaa aca tca aag ctg aag ctt tcc aaa aag gca ctc tgt aaa act tgc 768
Lys Thr Ser Lys Leu Lys Leu Ser Lys Lys Ala Leu Cys Lys Thr Cys
245 250 255
gaa ggg tca ggt gga aag aag gga gaa aaa tat aag tgt gat gca tgc 816
Glu Gly Ser Gly Gly Lys Lys Gly Glu Lys Tyr Lys Cys Asp Ala Cys
260 265 270
cgt ggt cgt gga gtg aag acg atc gtt cag caa att ggc ccc gga atg 864
Arg Gly Arg Gly Val Lys Thr Ile Val Gln Gln Ile Gly Pro Gly Met
275 280 285
ctc caa caa atg cag gtt cac tgt gat gct tgt aag ggt tct gga ggc 912
Leu Gln Gln Met Gln Val His Cys Asp Ala Cys Lys Gly Ser Gly Gly
290 295 300
aaa gtt cca gca ggt gat aag tgc aaa gga tgc cat gga gaa aag tac 960
Lys Val Pro Ala Gly Asp Lys Cys Lys Gly Cys His Gly Glu Lys Tyr
305 310 315 320
gaa aac gtt tcg aaa ata ttg gag gtt cac gtt ctt cct ggc atg aaa 1008
Glu Asn Val Ser Lys Ile Leu Glu Val His Val Leu Pro Gly Met Lys
325 330 335
cat aac gat aaa att aca ttc aaa gga gat gga gac caa tct gac cca 1056
His Asn Asp Lys Ile Thr Phe Lys Gly Asp Gly Asp Gln Ser Asp Pro
340 345 350
gat ggt gag cca gga gat gtt gtc att gtt att caa cag aaa gat cca 1104
Asp Gly Glu Pro Gly Asp Val Val Ile Val Ile Gln Gln Lys Asp Pro
355 360 365
tct ctg ata tgt tct gaa tga 1125
Ser Leu Ile Cys Ser Glu
370
<210> 50
<211> 374
<212> PRT
<213> Caenorhabditis elegans
<400> 50
Met Gly Gln Ala Lys Leu Arg Leu Thr Arg Tyr Trp Met Leu Ala Arg
1 5 10 15
Phe Ala Thr Ser Val Gly Phe Ile Glu Asn Phe Leu Cys Ser Thr Lys
20 25 30
Ser Gln Ile Arg Trp Phe Phe Ile Asp Leu Thr Arg Val Cys Ser Ile
35 40 45
Ser Arg Phe Ser Ala Phe Phe Ile Gln Phe Ser Leu Ile Asn Val Arg
50 55 60
Cys Leu Phe Thr Lys Phe Ser Phe Cys Phe His Leu Leu Val Gly Val
65 70 75 80
Val Arg Cys Asn Met Phe Gly Gly Gly Ser Ser Gly Pro Val Asp Thr
85 90 95
Thr Leu Tyr Thr Thr Leu Asn Val Arg Pro Asp Ala Ser Gln Ala Asp
100 105 110
Ile Lys Lys Ser Tyr Phe Lys Leu Ala Lys Glu Tyr His Pro Asp Lys
115 120 125
Asn Pro Asp His Gly Asp Lys Phe Lys Glu Ile Ser Phe Ala Tyr Glu
130 135 140
Val Leu Ser Ser Pro Glu Lys Arg Arg Leu Tyr Asp Ala Arg Gly Leu
145 150 155 160
Glu Gly Val Gln Gly Gly Gly Ala Gly Gly Gly Gly Gly Gly Phe Pro
165 170 175
Gly Gly Leu Phe Ser His Phe Phe Gly Gly Ala Gly Gly Asp Asp Asp
180 185 190
Asp Asp Asp Asp Asp Met Gly Gly His Pro Phe Gly Gly Leu Phe Gly
195 200 205
Gly Met Gly Gly Met Gly Arg Gly Gly Pro Arg Arg Arg Lys Phe Gln
210 215 220
Asp Thr Val His Pro Leu Asn Val Thr Leu Glu Glu Leu Tyr Val Gly
225 230 235 240
Lys Thr Ser Lys Leu Lys Leu Ser Lys Lys Ala Leu Cys Lys Thr Cys
245 250 255
Glu Gly Ser Gly Gly Lys Lys Gly Glu Lys Tyr Lys Cys Asp Ala Cys
260 265 270
Arg Gly Arg Gly Val Lys Thr Ile Val Gln Gln Ile Gly Pro Gly Met
275 280 285
Leu Gln Gln Met Gln Val His Cys Asp Ala Cys Lys Gly Ser Gly Gly
290 295 300
Lys Val Pro Ala Gly Asp Lys Cys Lys Gly Cys His Gly Glu Lys Tyr
305 310 315 320
Glu Asn Val Ser Lys Ile Leu Glu Val His Val Leu Pro Gly Met Lys
325 330 335
His Asn Asp Lys Ile Thr Phe Lys Gly Asp Gly Asp Gln Ser Asp Pro
340 345 350
Asp Gly Glu Pro Gly Asp Val Val Ile Val Ile Gln Gln Lys Asp Pro
355 360 365
Ser Leu Ile Cys Ser Glu
370
<210> 51
<211> 1239
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(1239)
<400> 51
atg gct aac gtg gct gac acg aag ctg tac gac atc ctg ggc gtc ccg 48
Met Ala Asn Val Ala Asp Thr Lys Leu Tyr Asp Ile Leu Gly Val Pro
1 5 10 15
ccc ggc gcc agc gag aac gag ctg aag aag gca tac aga aag tta gcc 96
Pro Gly Ala Ser Glu Asn Glu Leu Lys Lys Ala Tyr Arg Lys Leu Ala
20 25 30
aag gaa tat cat cct gat aag aat cca aat gca gga gac aaa ttt aaa 144
Lys Glu Tyr His Pro Asp Lys Asn Pro Asn Ala Gly Asp Lys Phe Lys
35 40 45
gaa ata agt ttt gca tat gaa gta cta tca aat cct gag aag cgt gag 192
Glu Ile Ser Phe Ala Tyr Glu Val Leu Ser Asn Pro Glu Lys Arg Glu
50 55 60
tta tat gac aga tac gga gag caa ggt ctt cgg gaa ggc agc ggc gga 240
Leu Tyr Asp Arg Tyr Gly Glu Gln Gly Leu Arg Glu Gly Ser Gly Gly
65 70 75 80
ggt ggt ggc atg gat gat att ttc tct cac att ttt ggt ggg gga ttg 288
Gly Gly Gly Met Asp Asp Ile Phe Ser His Ile Phe Gly Gly Gly Leu
85 90 95
ttc ggc ttc atg ggc aat cag agt aga agt cga aat ggc aga aga aga 336
Phe Gly Phe Met Gly Asn Gln Ser Arg Ser Arg Asn Gly Arg Arg Arg
100 105 110
gga gag gac atg atg cat cca ctc aaa gta tct tta gaa gat ctg tat 384
Gly Glu Asp Met Met His Pro Leu Lys Val Ser Leu Glu Asp Leu Tyr
115 120 125
aat ggc aag aca acc aaa cta caa ctt agc aag aat gtg ctc tgt agt 432
Asn Gly Lys Thr Thr Lys Leu Gln Leu Ser Lys Asn Val Leu Cys Ser
130 135 140
gca tgc agt ggc caa ggc gga aag tct gga gct gtc caa aag tgt agt 480
Ala Cys Ser Gly Gln Gly Gly Lys Ser Gly Ala Val Gln Lys Cys Ser
145 150 155 160
gct tgt cga ggt cga ggt gtg cgc atc atg atc aga cag ctg gct cca 528
Ala Cys Arg Gly Arg Gly Val Arg Ile Met Ile Arg Gln Leu Ala Pro
165 170 175
ggg atg gta caa cag atg cag tct gtg tgc tct gat tgt aat gga gaa 576
Gly Met Val Gln Gln Met Gln Ser Val Cys Ser Asp Cys Asn Gly Glu
180 185 190
gga gag gta att aat gaa aaa gac cgc tgt aaa aaa tgt gaa ggg aag 624
Gly Glu Val Ile Asn Glu Lys Asp Arg Cys Lys Lys Cys Glu Gly Lys
195 200 205
aag gtg att aaa gaa gtc aag att ctt gaa gtc cac gta gac aaa ggc 672
Lys Val Ile Lys Glu Val Lys Ile Leu Glu Val His Val Asp Lys Gly
210 215 220
atg aaa cat gga cag aga att aca ttc act ggg gaa gca gac cag gcc 720
Met Lys His Gly Gln Arg Ile Thr Phe Thr Gly Glu Ala Asp Gln Ala
225 230 235 240
cca gga gtg gaa ccc gga gac att gtt ctt ttg cta cag gag aaa gaa 768
Pro Gly Val Glu Pro Gly Asp Ile Val Leu Leu Leu Gln Glu Lys Glu
245 250 255
cat gag gta ttt cag aga gat ggg aat gat ttg cac atg aca tat aaa 816
His Glu Val Phe Gln Arg Asp Gly Asn Asp Leu His Met Thr Tyr Lys
260 265 270
ata gga ctt gtt gaa gct cta tgt gga ttt cag ttc aca ttt aag cac 864
Ile Gly Leu Val Glu Ala Leu Cys Gly Phe Gln Phe Thr Phe Lys His
275 280 285
ctt gat gga cgt cag att gtg gtg aaa tac ccc cct ggc aaa gta att 912
Leu Asp Gly Arg Gln Ile Val Val Lys Tyr Pro Pro Gly Lys Val Ile
290 295 300
gaa cca ggg tgt gtt cgt gta gtt cga ggt gaa ggg atg ccg cag tat 960
Glu Pro Gly Cys Val Arg Val Val Arg Gly Glu Gly Met Pro Gln Tyr
305 310 315 320
cgt aat ccc ttt gaa aaa ggt gat ctt tac ata aag ttt gat gtg cag 1008
Arg Asn Pro Phe Glu Lys Gly Asp Leu Tyr Ile Lys Phe Asp Val Gln
325 330 335
ttt cct gaa aac aac tgg atc aac cca gac aag ctt tct gaa cta gaa 1056
Phe Pro Glu Asn Asn Trp Ile Asn Pro Asp Lys Leu Ser Glu Leu Glu
340 345 350
gat ctt ctg cca tct aga ccg gaa gtt cct aac ata att gga gaa aca 1104
Asp Leu Leu Pro Ser Arg Pro Glu Val Pro Asn Ile Ile Gly Glu Thr
355 360 365
gag gag gta gag ctt cag gaa ttt gat agc act cga ggc tca gga ggt 1152
Glu Glu Val Glu Leu Gln Glu Phe Asp Ser Thr Arg Gly Ser Gly Gly
370 375 380
ggt cag agg cgt gaa gcc tat aat gat agc tct gat gaa gaa agc agc 1200
Gly Gln Arg Arg Glu Ala Tyr Asn Asp Ser Ser Asp Glu Glu Ser Ser
385 390 395 400
agc cat cat gga cct gga gtg cag tgt gcc cat cag taa 1239
Ser His His Gly Pro Gly Val Gln Cys Ala His Gln
405 410
<210> 52
<211> 412
<212> PRT
<213> Homo sapiens
<400> 52
Met Ala Asn Val Ala Asp Thr Lys Leu Tyr Asp Ile Leu Gly Val Pro
1 5 10 15
Pro Gly Ala Ser Glu Asn Glu Leu Lys Lys Ala Tyr Arg Lys Leu Ala
20 25 30
Lys Glu Tyr His Pro Asp Lys Asn Pro Asn Ala Gly Asp Lys Phe Lys
35 40 45
Glu Ile Ser Phe Ala Tyr Glu Val Leu Ser Asn Pro Glu Lys Arg Glu
50 55 60
Leu Tyr Asp Arg Tyr Gly Glu Gln Gly Leu Arg Glu Gly Ser Gly Gly
65 70 75 80
Gly Gly Gly Met Asp Asp Ile Phe Ser His Ile Phe Gly Gly Gly Leu
85 90 95
Phe Gly Phe Met Gly Asn Gln Ser Arg Ser Arg Asn Gly Arg Arg Arg
100 105 110
Gly Glu Asp Met Met His Pro Leu Lys Val Ser Leu Glu Asp Leu Tyr
115 120 125
Asn Gly Lys Thr Thr Lys Leu Gln Leu Ser Lys Asn Val Leu Cys Ser
130 135 140
Ala Cys Ser Gly Gln Gly Gly Lys Ser Gly Ala Val Gln Lys Cys Ser
145 150 155 160
Ala Cys Arg Gly Arg Gly Val Arg Ile Met Ile Arg Gln Leu Ala Pro
165 170 175
Gly Met Val Gln Gln Met Gln Ser Val Cys Ser Asp Cys Asn Gly Glu
180 185 190
Gly Glu Val Ile Asn Glu Lys Asp Arg Cys Lys Lys Cys Glu Gly Lys
195 200 205
Lys Val Ile Lys Glu Val Lys Ile Leu Glu Val His Val Asp Lys Gly
210 215 220
Met Lys His Gly Gln Arg Ile Thr Phe Thr Gly Glu Ala Asp Gln Ala
225 230 235 240
Pro Gly Val Glu Pro Gly Asp Ile Val Leu Leu Leu Gln Glu Lys Glu
245 250 255
His Glu Val Phe Gln Arg Asp Gly Asn Asp Leu His Met Thr Tyr Lys
260 265 270
Ile Gly Leu Val Glu Ala Leu Cys Gly Phe Gln Phe Thr Phe Lys His
275 280 285
Leu Asp Gly Arg Gln Ile Val Val Lys Tyr Pro Pro Gly Lys Val Ile
290 295 300
Glu Pro Gly Cys Val Arg Val Val Arg Gly Glu Gly Met Pro Gln Tyr
305 310 315 320
Arg Asn Pro Phe Glu Lys Gly Asp Leu Tyr Ile Lys Phe Asp Val Gln
325 330 335
Phe Pro Glu Asn Asn Trp Ile Asn Pro Asp Lys Leu Ser Glu Leu Glu
340 345 350
Asp Leu Leu Pro Ser Arg Pro Glu Val Pro Asn Ile Ile Gly Glu Thr
355 360 365
Glu Glu Val Glu Leu Gln Glu Phe Asp Ser Thr Arg Gly Ser Gly Gly
370 375 380
Gly Gln Arg Arg Glu Ala Tyr Asn Asp Ser Ser Asp Glu Glu Ser Ser
385 390 395 400
Ser His His Gly Pro Gly Val Gln Cys Ala His Gln
405 410
<210> 53
<211> 867
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(867)
<400> 53
atg ccc gac ttc acc aac aag caa att ata tta gat gaa aaa tac gag 48
Met Pro Asp Phe Thr Asn Lys Gln Ile Ile Leu Asp Glu Lys Tyr Glu
1 5 10 15
tat atg gat tca gtg gac gcc atg att ggg atg gga gca ttt gga gca 96
Tyr Met Asp Ser Val Asp Ala Met Ile Gly Met Gly Ala Phe Gly Ala
20 25 30
gtg ttc aag ggg agc ttg aag gat tct agc aat tcg att gcc ata aaa 144
Val Phe Lys Gly Ser Leu Lys Asp Ser Ser Asn Ser Ile Ala Ile Lys
35 40 45
agg atg ctc aaa gtg cac gtg aag gag agc gaa ttg aaa atg atc aaa 192
Arg Met Leu Lys Val His Val Lys Glu Ser Glu Leu Lys Met Ile Lys
50 55 60
gaa ctc aac agt gaa tat cta gtc gga gta cta gac att tgc aat ttc 240
Glu Leu Asn Ser Glu Tyr Leu Val Gly Val Leu Asp Ile Cys Asn Phe
65 70 75 80
gac gac ttt ttc tgc tgt tta ata atg gaa ctc tgc gat tgt gat ctt 288
Asp Asp Phe Phe Cys Cys Leu Ile Met Glu Leu Cys Asp Cys Asp Leu
85 90 95
gac cat cac atg cgc aat att tcg gtc aaa gga aga ttg aat ccg tcg 336
Asp His His Met Arg Asn Ile Ser Val Lys Gly Arg Leu Asn Pro Ser
100 105 110
aat ttc agg ctt ctt ctt gac aac att gcc cga gga tac aaa gcg ctt 384
Asn Phe Arg Leu Leu Leu Asp Asn Ile Ala Arg Gly Tyr Lys Ala Leu
115 120 125
tat gag ttg aaa att gta cat cgg gac att aaa ccc caa aac ata ctg 432
Tyr Glu Leu Lys Ile Val His Arg Asp Ile Lys Pro Gln Asn Ile Leu
130 135 140
atc act tat aca gat gca tcg aaa caa att gct tgt gct cgg atc aca 480
Ile Thr Tyr Thr Asp Ala Ser Lys Gln Ile Ala Cys Ala Arg Ile Thr
145 150 155 160
gac ttt gga att tcg aga acc ctt gat aac gag gga gaa gag ctg tgc 528
Asp Phe Gly Ile Ser Arg Thr Leu Asp Asn Glu Gly Glu Glu Leu Cys
165 170 175
aac gtt gcg ggt aca ttt tat tac atg gct cca gaa gtt gga gcg aac 576
Asn Val Ala Gly Thr Phe Tyr Tyr Met Ala Pro Glu Val Gly Ala Asn
180 185 190
ctt tta aaa act tgt cag tat gac tca aaa gtt gat atg tgg agc atc 624
Leu Leu Lys Thr Cys Gln Tyr Asp Ser Lys Val Asp Met Trp Ser Ile
195 200 205
gga tgc ctt ctc tac caa tgc gtt aca gga gag gtc cca ttc gat gag 672
Gly Cys Leu Leu Tyr Gln Cys Val Thr Gly Glu Val Pro Phe Asp Glu
210 215 220
tgc agt ttg tgt aag ctc ttc ctg tat gtg gca ggg gct aac ttc gac 720
Cys Ser Leu Cys Lys Leu Phe Leu Tyr Val Ala Gly Ala Asn Phe Asp
225 230 235 240
gcc tac gac ccg cct gag ctg ccc gac gag ctg agt caa gag gtt tcg 768
Ala Tyr Asp Pro Pro Glu Leu Pro Asp Glu Leu Ser Gln Glu Val Ser
245 250 255
ggg att att caa tca ctg ctg cag ctc gat acc act caa aga tgc aca 816
Gly Ile Ile Gln Ser Leu Leu Gln Leu Asp Thr Thr Gln Arg Cys Thr
260 265 270
cct act cag ttt tat gac aaa gca atc aac tgg agt caa caa ata tgt 864
Pro Thr Gln Phe Tyr Asp Lys Ala Ile Asn Trp Ser Gln Gln Ile Cys
275 280 285
tag 867
<210> 54
<211> 288
<212> PRT
<213> Caenorhabditis elegans
<400> 54
Met Pro Asp Phe Thr Asn Lys Gln Ile Ile Leu Asp Glu Lys Tyr Glu
1 5 10 15
Tyr Met Asp Ser Val Asp Ala Met Ile Gly Met Gly Ala Phe Gly Ala
20 25 30
Val Phe Lys Gly Ser Leu Lys Asp Ser Ser Asn Ser Ile Ala Ile Lys
35 40 45
Arg Met Leu Lys Val His Val Lys Glu Ser Glu Leu Lys Met Ile Lys
50 55 60
Glu Leu Asn Ser Glu Tyr Leu Val Gly Val Leu Asp Ile Cys Asn Phe
65 70 75 80
Asp Asp Phe Phe Cys Cys Leu Ile Met Glu Leu Cys Asp Cys Asp Leu
85 90 95
Asp His His Met Arg Asn Ile Ser Val Lys Gly Arg Leu Asn Pro Ser
100 105 110
Asn Phe Arg Leu Leu Leu Asp Asn Ile Ala Arg Gly Tyr Lys Ala Leu
115 120 125
Tyr Glu Leu Lys Ile Val His Arg Asp Ile Lys Pro Gln Asn Ile Leu
130 135 140
Ile Thr Tyr Thr Asp Ala Ser Lys Gln Ile Ala Cys Ala Arg Ile Thr
145 150 155 160
Asp Phe Gly Ile Ser Arg Thr Leu Asp Asn Glu Gly Glu Glu Leu Cys
165 170 175
Asn Val Ala Gly Thr Phe Tyr Tyr Met Ala Pro Glu Val Gly Ala Asn
180 185 190
Leu Leu Lys Thr Cys Gln Tyr Asp Ser Lys Val Asp Met Trp Ser Ile
195 200 205
Gly Cys Leu Leu Tyr Gln Cys Val Thr Gly Glu Val Pro Phe Asp Glu
210 215 220
Cys Ser Leu Cys Lys Leu Phe Leu Tyr Val Ala Gly Ala Asn Phe Asp
225 230 235 240
Ala Tyr Asp Pro Pro Glu Leu Pro Asp Glu Leu Ser Gln Glu Val Ser
245 250 255
Gly Ile Ile Gln Ser Leu Leu Gln Leu Asp Thr Thr Gln Arg Cys Thr
260 265 270
Pro Thr Gln Phe Tyr Asp Lys Ala Ile Asn Trp Ser Gln Gln Ile Cys
275 280 285
<210> 55
<211> 3111
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(3111)
<400> 55
atg gag gtg gtg ggt gac ttc gag tac agc aag agg gat ctc gtg gga 48
Met Glu Val Val Gly Asp Phe Glu Tyr Ser Lys Arg Asp Leu Val Gly
1 5 10 15
cac ggg gcc ttc gcc gtg gtc ttc cgg ggg cgg cac cgc cag aaa act 96
His Gly Ala Phe Ala Val Val Phe Arg Gly Arg His Arg Gln Lys Thr
20 25 30
gat tgg gag gta gct att aaa agt att aat aaa aag aac ttg tca aaa 144
Asp Trp Glu Val Ala Ile Lys Ser Ile Asn Lys Lys Asn Leu Ser Lys
35 40 45
tca caa ata ctg ctt gga aag gaa att aaa atc tta aag gaa ctt cag 192
Ser Gln Ile Leu Leu Gly Lys Glu Ile Lys Ile Leu Lys Glu Leu Gln
50 55 60
cat gaa aat att gta gca ctc tat gat gtt cag gaa tta ccc aac tct 240
His Glu Asn Ile Val Ala Leu Tyr Asp Val Gln Glu Leu Pro Asn Ser
65 70 75 80
gtc ttt ttg gtg atg gag tat tgc aat ggt gga gac ctc gca gat tat 288
Val Phe Leu Val Met Glu Tyr Cys Asn Gly Gly Asp Leu Ala Asp Tyr
85 90 95
ttg caa gcg aaa ggg act ctc agt gaa gac acg atc aga gtg ttt ctg 336
Leu Gln Ala Lys Gly Thr Leu Ser Glu Asp Thr Ile Arg Val Phe Leu
100 105 110
cat cag att gct gct gcc atg cga atc ctg cac agc aaa gga atc atc 384
His Gln Ile Ala Ala Ala Met Arg Ile Leu His Ser Lys Gly Ile Ile
115 120 125
cac aga gat ctc aaa cca cag aac atc ttg ctg tcc tat gcc aat cgc 432
His Arg Asp Leu Lys Pro Gln Asn Ile Leu Leu Ser Tyr Ala Asn Arg
130 135 140
aga aaa tca agt gtc agt ggt att cgc atc aaa ata gcg gat ttt ggt 480
Arg Lys Ser Ser Val Ser Gly Ile Arg Ile Lys Ile Ala Asp Phe Gly
145 150 155 160
ttt gct cgt tac cta cat agt aac atg atg gct gca aca ctg tgt gga 528
Phe Ala Arg Tyr Leu His Ser Asn Met Met Ala Ala Thr Leu Cys Gly
165 170 175
tcc ccg atg tac atg gct cct gag gtt att atg tct caa cat tat gat 576
Ser Pro Met Tyr Met Ala Pro Glu Val Ile Met Ser Gln His Tyr Asp
180 185 190
gct aag gct gac ttg tgg agc ata gga aca gtg ata tac caa tgc cta 624
Ala Lys Ala Asp Leu Trp Ser Ile Gly Thr Val Ile Tyr Gln Cys Leu
195 200 205
gtt gga aaa cca cct ttt cag gcc aat agt cct caa gac tta agg atg 672
Val Gly Lys Pro Pro Phe Gln Ala Asn Ser Pro Gln Asp Leu Arg Met
210 215 220
ttt tat gaa aaa aac agg agc tta atg cct agt att ccc aga gaa aca 720
Phe Tyr Glu Lys Asn Arg Ser Leu Met Pro Ser Ile Pro Arg Glu Thr
225 230 235 240
tca cct tat ttg gct aat ctc ctt ttg ggt ttg ctt cag aga aac caa 768
Ser Pro Tyr Leu Ala Asn Leu Leu Leu Gly Leu Leu Gln Arg Asn Gln
245 250 255
aaa gat aga atg gac ttt gaa gca ttt ttt agc cat cct ttt ctt gag 816
Lys Asp Arg Met Asp Phe Glu Ala Phe Phe Ser His Pro Phe Leu Glu
260 265 270
caa ggt cca gta aaa aaa tct tgc cca gtt cca gtg ccc atg tat tct 864
Gln Gly Pro Val Lys Lys Ser Cys Pro Val Pro Val Pro Met Tyr Ser
275 280 285
ggt tct gtc tct gga agc tcc tgt ggc agc tct cca tct tgt cgt ttt 912
Gly Ser Val Ser Gly Ser Ser Cys Gly Ser Ser Pro Ser Cys Arg Phe
290 295 300
gct tct cca cca tcc ctt cca gat atg cag cat att cag gaa gaa aac 960
Ala Ser Pro Pro Ser Leu Pro Asp Met Gln His Ile Gln Glu Glu Asn
305 310 315 320
tta tct tcc cca cca ttg ggt cct ccc aac tat cta caa gtt tcc aaa 1008
Leu Ser Ser Pro Pro Leu Gly Pro Pro Asn Tyr Leu Gln Val Ser Lys
325 330 335
gat tct gcc agt act agt agc aag aac tct tct tgt gac acg gat gac 1056
Asp Ser Ala Ser Thr Ser Ser Lys Asn Ser Ser Cys Asp Thr Asp Asp
340 345 350
ttt gtt ttg gtg cca cac aac atc tcg tca gac cac tca tgt gat atg 1104
Phe Val Leu Val Pro His Asn Ile Ser Ser Asp His Ser Cys Asp Met
355 360 365
cca gtg ggg act gct ggc aga cgt gct tca aat gaa ttc ttg gtg tgt 1152
Pro Val Gly Thr Ala Gly Arg Arg Ala Ser Asn Glu Phe Leu Val Cys
370 375 380
gga ggg cag tgt cag cct act gtg tca cct cac agc gaa aca gca cca 1200
Gly Gly Gln Cys Gln Pro Thr Val Ser Pro His Ser Glu Thr Ala Pro
385 390 395 400
att cca gtt cct act caa ata agg aat tat cag cgc ata gag cag aat 1248
Ile Pro Val Pro Thr Gln Ile Arg Asn Tyr Gln Arg Ile Glu Gln Asn
405 410 415
ctt aca tct act gcc agc tca ggc aca aat gta cat ggt tct cca aga 1296
Leu Thr Ser Thr Ala Ser Ser Gly Thr Asn Val His Gly Ser Pro Arg
420 425 430
tct gca gtg gta cga agg tcc aac acc agc ccc atg ggc ttc ctc cgg 1344
Ser Ala Val Val Arg Arg Ser Asn Thr Ser Pro Met Gly Phe Leu Arg
435 440 445
ccg gga tca tgc tcc cca gta cca gca gac aca gca cag aca gtt gga 1392
Pro Gly Ser Cys Ser Pro Val Pro Ala Asp Thr Ala Gln Thr Val Gly
450 455 460
cga agg ctc tcc act ggg tct tct agg cct tac tca cct tcc cct ttg 1440
Arg Arg Leu Ser Thr Gly Ser Ser Arg Pro Tyr Ser Pro Ser Pro Leu
465 470 475 480
gtt ggt acc att cct gag caa ttc agt cag tgc tgc tgt ggg cat cct 1488
Val Gly Thr Ile Pro Glu Gln Phe Ser Gln Cys Cys Cys Gly His Pro
485 490 495
cag ggc cat gac tcc agg agt aga aac tcc tca ggt tct cca gtg cca 1536
Gln Gly His Asp Ser Arg Ser Arg Asn Ser Ser Gly Ser Pro Val Pro
500 505 510
caa gct cag tcc cca cag tct ctc tta tcg ggt gct aga ctg cag agc 1584
Gln Ala Gln Ser Pro Gln Ser Leu Leu Ser Gly Ala Arg Leu Gln Ser
515 520 525
gcc ccc acc ctc act gac atc tat cag aac aag cag aag ctc aga aaa 1632
Ala Pro Thr Leu Thr Asp Ile Tyr Gln Asn Lys Gln Lys Leu Arg Lys
530 535 540
cag cac tct gac ccc gtg tgc cca tcc cat act ggg gct ggg tac agc 1680
Gln His Ser Asp Pro Val Cys Pro Ser His Thr Gly Ala Gly Tyr Ser
545 550 555 560
tac tcg cct cag ccc agt cgg cct ggc agc ctt gga act tct ccc acc 1728
Tyr Ser Pro Gln Pro Ser Arg Pro Gly Ser Leu Gly Thr Ser Pro Thr
565 570 575
aag cac ttg ggg tcc tct cca cgg agt tct gac tgg ttc ttt aaa act 1776
Lys His Leu Gly Ser Ser Pro Arg Ser Ser Asp Trp Phe Phe Lys Thr
580 585 590
cct ttg cca aca atc att ggc tct cct act aag acc aca gct cct ttc 1824
Pro Leu Pro Thr Ile Ile Gly Ser Pro Thr Lys Thr Thr Ala Pro Phe
595 600 605
aaa atc cct aaa act caa gca tct tcc aac ctg tta gcc ttg gtt act 1872
Lys Ile Pro Lys Thr Gln Ala Ser Ser Asn Leu Leu Ala Leu Val Thr
610 615 620
cgt cat ggg cct gct gaa gaa cag tcg aaa gat ggg aat gag cca cgg 1920
Arg His Gly Pro Ala Glu Glu Gln Ser Lys Asp Gly Asn Glu Pro Arg
625 630 635 640
gaa tgt gcc cat tgc ctc tta gtg caa gga agt gag agg cag cgg gcc 1968
Glu Cys Ala His Cys Leu Leu Val Gln Gly Ser Glu Arg Gln Arg Ala
645 650 655
gag cag cag agc aag gca gtg ttt ggc aga tct gtc agt acc ggg aag 2016
Glu Gln Gln Ser Lys Ala Val Phe Gly Arg Ser Val Ser Thr Gly Lys
660 665 670
tta tca gat caa caa gga aag act cct ata tgt cga cat cag ggc agc 2064
Leu Ser Asp Gln Gln Gly Lys Thr Pro Ile Cys Arg His Gln Gly Ser
675 680 685
aca gac agt tta aat aca gaa cga cca atg gat ata gct ccg gca gga 2112
Thr Asp Ser Leu Asn Thr Glu Arg Pro Met Asp Ile Ala Pro Ala Gly
690 695 700
gcc tgt ggt ggt gtt ctg gca cct cct gca ggt aca gca gca agt tcc 2160
Ala Cys Gly Gly Val Leu Ala Pro Pro Ala Gly Thr Ala Ala Ser Ser
705 710 715 720
aag gct gtc ctc ttc act gta ggg tct cct cca cac agt gcg gca gcc 2208
Lys Ala Val Leu Phe Thr Val Gly Ser Pro Pro His Ser Ala Ala Ala
725 730 735
ccc act tgt acc cac atg ttc ctt cga aca aga aca acc tca gtg ggg 2256
Pro Thr Cys Thr His Met Phe Leu Arg Thr Arg Thr Thr Ser Val Gly
740 745 750
ccc agc aac tcc ggg ggc tct ctt tgt gcc atg agt ggc cgc gtg tgc 2304
Pro Ser Asn Ser Gly Gly Ser Leu Cys Ala Met Ser Gly Arg Val Cys
755 760 765
gtg ggg tcc ccg cct ggc cca ggc ttc ggc tct tcc cct cca gga gca 2352
Val Gly Ser Pro Pro Gly Pro Gly Phe Gly Ser Ser Pro Pro Gly Ala
770 775 780
gag gca gct ccc agc ctg aga tac gtg cct tac ggt gct tca ccc ccc 2400
Glu Ala Ala Pro Ser Leu Arg Tyr Val Pro Tyr Gly Ala Ser Pro Pro
785 790 795 800
agc cta gag ggg ctc atc acc ttt gaa gcc cct gaa ctg ccg gag gag 2448
Ser Leu Glu Gly Leu Ile Thr Phe Glu Ala Pro Glu Leu Pro Glu Glu
805 810 815
acg ctg atg gag cgg gaa cac aca gac acc tta cgc cat ctg aat gtg 2496
Thr Leu Met Glu Arg Glu His Thr Asp Thr Leu Arg His Leu Asn Val
820 825 830
atg ctg atg ttc act gag tgt gtg ctg gac ctg aca gcc atg agg gga 2544
Met Leu Met Phe Thr Glu Cys Val Leu Asp Leu Thr Ala Met Arg Gly
835 840 845
gga aac cct gag ctg tgc aca tct gct gtg tcc ttg tac cag atc cag 2592
Gly Asn Pro Glu Leu Cys Thr Ser Ala Val Ser Leu Tyr Gln Ile Gln
850 855 860
gag agt gtg gtg gtg gac cag atc agt cag ctg agc aaa gac tgg ggg 2640
Glu Ser Val Val Val Asp Gln Ile Ser Gln Leu Ser Lys Asp Trp Gly
865 870 875 880
cgg gtg gag cag ctg gtg ttg tac atg aaa gca gca cag ctg ctt gcg 2688
Arg Val Glu Gln Leu Val Leu Tyr Met Lys Ala Ala Gln Leu Leu Ala
885 890 895
gct tct ctg cat ctt gcc aaa gcc cag atc aag tcc ggg aaa ctg agc 2736
Ala Ser Leu His Leu Ala Lys Ala Gln Ile Lys Ser Gly Lys Leu Ser
900 905 910
cca tcc aca gct gtg aaa caa gtt gtc aag aat ctg aac gaa cga tat 2784
Pro Ser Thr Ala Val Lys Gln Val Val Lys Asn Leu Asn Glu Arg Tyr
915 920 925
aaa ttc tgc atc acc atg tgc aag aaa ctt aca gaa aag ctg aat cga 2832
Lys Phe Cys Ile Thr Met Cys Lys Lys Leu Thr Glu Lys Leu Asn Arg
930 935 940
ttc ttc tct gac aaa cag agg ttt att gat gaa atc aac agt gtg act 2880
Phe Phe Ser Asp Lys Gln Arg Phe Ile Asp Glu Ile Asn Ser Val Thr
945 950 955 960
gca gag aaa ctc atc tat aat tgt gct gta gaa atg gtt cag tct gca 2928
Ala Glu Lys Leu Ile Tyr Asn Cys Ala Val Glu Met Val Gln Ser Ala
965 970 975
gcc ctg gat gag atg ttt cag cag acc gaa gat att gtt tat cgc tat 2976
Ala Leu Asp Glu Met Phe Gln Gln Thr Glu Asp Ile Val Tyr Arg Tyr
980 985 990
cat aag gca gcc ctt ctt ttg gaa ggc cta agt agg att cta cag gac 3024
His Lys Ala Ala Leu Leu Leu Glu Gly Leu Ser Arg Ile Leu Gln Asp
995 1000 1005
cct gca gat att gaa aat gtg cat aaa tat aaa tgt agt att gag 3069
Pro Ala Asp Ile Glu Asn Val His Lys Tyr Lys Cys Ser Ile Glu
1010 1015 1020
aga aga ctg tcg gcg ctc tgc cat agc acc gca acc gtg tga 3111
Arg Arg Leu Ser Ala Leu Cys His Ser Thr Ala Thr Val
1025 1030 1035
<210> 56
<211> 1036
<212> PRT
<213> Homo sapiens
<400> 56
Met Glu Val Val Gly Asp Phe Glu Tyr Ser Lys Arg Asp Leu Val Gly
1 5 10 15
His Gly Ala Phe Ala Val Val Phe Arg Gly Arg His Arg Gln Lys Thr
20 25 30
Asp Trp Glu Val Ala Ile Lys Ser Ile Asn Lys Lys Asn Leu Ser Lys
35 40 45
Ser Gln Ile Leu Leu Gly Lys Glu Ile Lys Ile Leu Lys Glu Leu Gln
50 55 60
His Glu Asn Ile Val Ala Leu Tyr Asp Val Gln Glu Leu Pro Asn Ser
65 70 75 80
Val Phe Leu Val Met Glu Tyr Cys Asn Gly Gly Asp Leu Ala Asp Tyr
85 90 95
Leu Gln Ala Lys Gly Thr Leu Ser Glu Asp Thr Ile Arg Val Phe Leu
100 105 110
His Gln Ile Ala Ala Ala Met Arg Ile Leu His Ser Lys Gly Ile Ile
115 120 125
His Arg Asp Leu Lys Pro Gln Asn Ile Leu Leu Ser Tyr Ala Asn Arg
130 135 140
Arg Lys Ser Ser Val Ser Gly Ile Arg Ile Lys Ile Ala Asp Phe Gly
145 150 155 160
Phe Ala Arg Tyr Leu His Ser Asn Met Met Ala Ala Thr Leu Cys Gly
165 170 175
Ser Pro Met Tyr Met Ala Pro Glu Val Ile Met Ser Gln His Tyr Asp
180 185 190
Ala Lys Ala Asp Leu Trp Ser Ile Gly Thr Val Ile Tyr Gln Cys Leu
195 200 205
Val Gly Lys Pro Pro Phe Gln Ala Asn Ser Pro Gln Asp Leu Arg Met
210 215 220
Phe Tyr Glu Lys Asn Arg Ser Leu Met Pro Ser Ile Pro Arg Glu Thr
225 230 235 240
Ser Pro Tyr Leu Ala Asn Leu Leu Leu Gly Leu Leu Gln Arg Asn Gln
245 250 255
Lys Asp Arg Met Asp Phe Glu Ala Phe Phe Ser His Pro Phe Leu Glu
260 265 270
Gln Gly Pro Val Lys Lys Ser Cys Pro Val Pro Val Pro Met Tyr Ser
275 280 285
Gly Ser Val Ser Gly Ser Ser Cys Gly Ser Ser Pro Ser Cys Arg Phe
290 295 300
Ala Ser Pro Pro Ser Leu Pro Asp Met Gln His Ile Gln Glu Glu Asn
305 310 315 320
Leu Ser Ser Pro Pro Leu Gly Pro Pro Asn Tyr Leu Gln Val Ser Lys
325 330 335
Asp Ser Ala Ser Thr Ser Ser Lys Asn Ser Ser Cys Asp Thr Asp Asp
340 345 350
Phe Val Leu Val Pro His Asn Ile Ser Ser Asp His Ser Cys Asp Met
355 360 365
Pro Val Gly Thr Ala Gly Arg Arg Ala Ser Asn Glu Phe Leu Val Cys
370 375 380
Gly Gly Gln Cys Gln Pro Thr Val Ser Pro His Ser Glu Thr Ala Pro
385 390 395 400
Ile Pro Val Pro Thr Gln Ile Arg Asn Tyr Gln Arg Ile Glu Gln Asn
405 410 415
Leu Thr Ser Thr Ala Ser Ser Gly Thr Asn Val His Gly Ser Pro Arg
420 425 430
Ser Ala Val Val Arg Arg Ser Asn Thr Ser Pro Met Gly Phe Leu Arg
435 440 445
Pro Gly Ser Cys Ser Pro Val Pro Ala Asp Thr Ala Gln Thr Val Gly
450 455 460
Arg Arg Leu Ser Thr Gly Ser Ser Arg Pro Tyr Ser Pro Ser Pro Leu
465 470 475 480
Val Gly Thr Ile Pro Glu Gln Phe Ser Gln Cys Cys Cys Gly His Pro
485 490 495
Gln Gly His Asp Ser Arg Ser Arg Asn Ser Ser Gly Ser Pro Val Pro
500 505 510
Gln Ala Gln Ser Pro Gln Ser Leu Leu Ser Gly Ala Arg Leu Gln Ser
515 520 525
Ala Pro Thr Leu Thr Asp Ile Tyr Gln Asn Lys Gln Lys Leu Arg Lys
530 535 540
Gln His Ser Asp Pro Val Cys Pro Ser His Thr Gly Ala Gly Tyr Ser
545 550 555 560
Tyr Ser Pro Gln Pro Ser Arg Pro Gly Ser Leu Gly Thr Ser Pro Thr
565 570 575
Lys His Leu Gly Ser Ser Pro Arg Ser Ser Asp Trp Phe Phe Lys Thr
580 585 590
Pro Leu Pro Thr Ile Ile Gly Ser Pro Thr Lys Thr Thr Ala Pro Phe
595 600 605
Lys Ile Pro Lys Thr Gln Ala Ser Ser Asn Leu Leu Ala Leu Val Thr
610 615 620
Arg His Gly Pro Ala Glu Glu Gln Ser Lys Asp Gly Asn Glu Pro Arg
625 630 635 640
Glu Cys Ala His Cys Leu Leu Val Gln Gly Ser Glu Arg Gln Arg Ala
645 650 655
Glu Gln Gln Ser Lys Ala Val Phe Gly Arg Ser Val Ser Thr Gly Lys
660 665 670
Leu Ser Asp Gln Gln Gly Lys Thr Pro Ile Cys Arg His Gln Gly Ser
675 680 685
Thr Asp Ser Leu Asn Thr Glu Arg Pro Met Asp Ile Ala Pro Ala Gly
690 695 700
Ala Cys Gly Gly Val Leu Ala Pro Pro Ala Gly Thr Ala Ala Ser Ser
705 710 715 720
Lys Ala Val Leu Phe Thr Val Gly Ser Pro Pro His Ser Ala Ala Ala
725 730 735
Pro Thr Cys Thr His Met Phe Leu Arg Thr Arg Thr Thr Ser Val Gly
740 745 750
Pro Ser Asn Ser Gly Gly Ser Leu Cys Ala Met Ser Gly Arg Val Cys
755 760 765
Val Gly Ser Pro Pro Gly Pro Gly Phe Gly Ser Ser Pro Pro Gly Ala
770 775 780
Glu Ala Ala Pro Ser Leu Arg Tyr Val Pro Tyr Gly Ala Ser Pro Pro
785 790 795 800
Ser Leu Glu Gly Leu Ile Thr Phe Glu Ala Pro Glu Leu Pro Glu Glu
805 810 815
Thr Leu Met Glu Arg Glu His Thr Asp Thr Leu Arg His Leu Asn Val
820 825 830
Met Leu Met Phe Thr Glu Cys Val Leu Asp Leu Thr Ala Met Arg Gly
835 840 845
Gly Asn Pro Glu Leu Cys Thr Ser Ala Val Ser Leu Tyr Gln Ile Gln
850 855 860
Glu Ser Val Val Val Asp Gln Ile Ser Gln Leu Ser Lys Asp Trp Gly
865 870 875 880
Arg Val Glu Gln Leu Val Leu Tyr Met Lys Ala Ala Gln Leu Leu Ala
885 890 895
Ala Ser Leu His Leu Ala Lys Ala Gln Ile Lys Ser Gly Lys Leu Ser
900 905 910
Pro Ser Thr Ala Val Lys Gln Val Val Lys Asn Leu Asn Glu Arg Tyr
915 920 925
Lys Phe Cys Ile Thr Met Cys Lys Lys Leu Thr Glu Lys Leu Asn Arg
930 935 940
Phe Phe Ser Asp Lys Gln Arg Phe Ile Asp Glu Ile Asn Ser Val Thr
945 950 955 960
Ala Glu Lys Leu Ile Tyr Asn Cys Ala Val Glu Met Val Gln Ser Ala
965 970 975
Ala Leu Asp Glu Met Phe Gln Gln Thr Glu Asp Ile Val Tyr Arg Tyr
980 985 990
His Lys Ala Ala Leu Leu Leu Glu Gly Leu Ser Arg Ile Leu Gln Asp
995 1000 1005
Pro Ala Asp Ile Glu Asn Val His Lys Tyr Lys Cys Ser Ile Glu
1010 1015 1020
Arg Arg Leu Ser Ala Leu Cys His Ser Thr Ala Thr Val
1025 1030 1035
<210> 57
<211> 2280
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(2280)
<400> 57
atg cca aag tct ata tat ttt tcc cct gac ttt atc cga cag caa tcc 48
Met Pro Lys Ser Ile Tyr Phe Ser Pro Asp Phe Ile Arg Gln Gln Ser
1 5 10 15
ggc cac tgc ttc atc atg gga gag cgg aac ctg gtt ctt tat gag aaa 96
Gly His Cys Phe Ile Met Gly Glu Arg Asn Leu Val Leu Tyr Glu Lys
20 25 30
aga atg ttt caa tac aaa gct tcg agt ctg tac tct gga tcc gaa aga 144
Arg Met Phe Gln Tyr Lys Ala Ser Ser Leu Tyr Ser Gly Ser Glu Arg
35 40 45
gat ggt ttt atc cac tgt tgt tct tgg aat gag aat ctc att gcg ttc 192
Asp Gly Phe Ile His Cys Cys Ser Trp Asn Glu Asn Leu Ile Ala Phe
50 55 60
aca aat gat acc gga aca aga gtc tac gaa aga ggc gca gag aga atc 240
Thr Asn Asp Thr Gly Thr Arg Val Tyr Glu Arg Gly Ala Glu Arg Ile
65 70 75 80
atc aca agt gtt cag cca tca cat gac gtg gat cgc gtc cga tca tct 288
Ile Thr Ser Val Gln Pro Ser His Asp Val Asp Arg Val Arg Ser Ser
85 90 95
cgc tca cca ccg aaa cac act tgg atg cct gag aac aac tta gtg att 336
Arg Ser Pro Pro Lys His Thr Trp Met Pro Glu Asn Asn Leu Val Ile
100 105 110
ggt tgg gca gac acg gtt acc atc ctc aaa att cgt gat gat gat gga 384
Gly Trp Ala Asp Thr Val Thr Ile Leu Lys Ile Arg Asp Asp Asp Gly
115 120 125
gta aaa aaa gga gag gtt cat cat att ttc cac gta tca atg ttc att 432
Val Lys Lys Gly Glu Val His His Ile Phe His Val Ser Met Phe Ile
130 135 140
tgt gga atc tcc tac atc ccg gaa agc ggc atc gac aat atg gag ctg 480
Cys Gly Ile Ser Tyr Ile Pro Glu Ser Gly Ile Asp Asn Met Glu Leu
145 150 155 160
ttc cta gtt ggg ttg cag ttg gaa ggg gag gac ttt gat gat tgt gcg 528
Phe Leu Val Gly Leu Gln Leu Glu Gly Glu Asp Phe Asp Asp Cys Ala
165 170 175
tca gtt att tcc act gtg aca aca ttg acc gca ttg gaa agt agt gca 576
Ser Val Ile Ser Thr Val Thr Thr Leu Thr Ala Leu Glu Ser Ser Ala
180 185 190
tgc aca atc ctg aag acg tct gtg atc cgg cca ctt gga ttg aaa gaa 624
Cys Thr Ile Leu Lys Thr Ser Val Ile Arg Pro Leu Gly Leu Lys Glu
195 200 205
ttt gag ctt cag tca gag gat atg att gaa agc gtc aaa ctc tcc aac 672
Phe Glu Leu Gln Ser Glu Asp Met Ile Glu Ser Val Lys Leu Ser Asn
210 215 220
cat act ttg cca tac atg att cac ggt ctt gga att cct tac ctt gcc 720
His Thr Leu Pro Tyr Met Ile His Gly Leu Gly Ile Pro Tyr Leu Ala
225 230 235 240
aca tac ttt ata ttg aca acg aag cac att att atg gcg gta cca tat 768
Thr Tyr Phe Ile Leu Thr Thr Lys His Ile Ile Met Ala Val Pro Tyr
245 250 255
ggc ccg gaa gac ggc att cgt tgg aga ttg aag tat aaa ctc tac gat 816
Gly Pro Glu Asp Gly Ile Arg Trp Arg Leu Lys Tyr Lys Leu Tyr Asp
260 265 270
gaa gcg ttg gat atg gca aag cac aat gcc gac tta ctc tcc aaa act 864
Glu Ala Leu Asp Met Ala Lys His Asn Ala Asp Leu Leu Ser Lys Thr
275 280 285
gat ctc agt ccg aag aaa gtg ggg agg atg att atc gag gga tac ctg 912
Asp Leu Ser Pro Lys Lys Val Gly Arg Met Ile Ile Glu Gly Tyr Leu
290 295 300
act gga aaa cga gca aga gca gct gct tcc cgc ctt cca ttg atc tgt 960
Thr Gly Lys Arg Ala Arg Ala Ala Ala Ser Arg Leu Pro Leu Ile Cys
305 310 315 320
gga gaa tgc aag gag gag tgg gaa tgg gca gtg aat cag ttt gag gaa 1008
Gly Glu Cys Lys Glu Glu Trp Glu Trp Ala Val Asn Gln Phe Glu Glu
325 330 335
gtc aaa tta tgc act cta cta gcg gag gtc ctg ccc gat ggc act ccg 1056
Val Lys Leu Cys Thr Leu Leu Ala Glu Val Leu Pro Asp Gly Thr Pro
340 345 350
aca ttg gat cca gag tgc tac cag aaa gtt ctt att gct tgt ctg ttc 1104
Thr Leu Asp Pro Glu Cys Tyr Gln Lys Val Leu Ile Ala Cys Leu Phe
355 360 365
aac aat gtg aag cag ttc cgg aaa ttg gta cag acg tgg agt ccg gat 1152
Asn Asn Val Lys Gln Phe Arg Lys Leu Val Gln Thr Trp Ser Pro Asp
370 375 380
ctc tat atg acc agt ttt ata atc gat cgg act caa tgg cgc att caa 1200
Leu Tyr Met Thr Ser Phe Ile Ile Asp Arg Thr Gln Trp Arg Ile Gln
385 390 395 400
caa atc agc aaa tcg ggc aat cta gca gac gtt gac gag act gag cga 1248
Gln Ile Ser Lys Ser Gly Asn Leu Ala Asp Val Asp Glu Thr Glu Arg
405 410 415
gtt ttg atg gac gct ttg gca cat ttg tat ctc tac gag aga aag tac 1296
Val Leu Met Asp Ala Leu Ala His Leu Tyr Leu Tyr Glu Arg Lys Tyr
420 425 430
gag agc gca ctg aaa atc ctt atg tcg tgt caa gat ttt caa att ttc 1344
Glu Ser Ala Leu Lys Ile Leu Met Ser Cys Gln Asp Phe Gln Ile Phe
435 440 445
aat gtt att gac aag cat caa ctc ttc gat ctt gtc aag gat caa atc 1392
Asn Val Ile Asp Lys His Gln Leu Phe Asp Leu Val Lys Asp Gln Ile
450 455 460
acc gaa ctg atg aac atc aac tct gaa cgt gct ctt cgg ctg ttg ctc 1440
Thr Glu Leu Met Asn Ile Asn Ser Glu Arg Ala Leu Arg Leu Leu Leu
465 470 475 480
gac aac gct gat tcg gtg gag cca tca ttt gtg atg gag aaa att ggg 1488
Asp Asn Ala Asp Ser Val Glu Pro Ser Phe Val Met Glu Lys Ile Gly
485 490 495
cga cag ccg aaa ctg caa ctc gcg tat ctc aca aaa ctg atg agc aga 1536
Arg Gln Pro Lys Leu Gln Leu Ala Tyr Leu Thr Lys Leu Met Ser Arg
500 505 510
aac gag gga act gag ttt gct gac aaa gct gtc cag ttg tat gct gaa 1584
Asn Glu Gly Thr Glu Phe Ala Asp Lys Ala Val Gln Leu Tyr Ala Glu
515 520 525
tac gac cag aag aag ctt ctt cca ttt ttg aga aag aat gca aac tac 1632
Tyr Asp Gln Lys Lys Leu Leu Pro Phe Leu Arg Lys Asn Ala Asn Tyr
530 535 540
aat gtg aac aag gca cga aag ttg tgc tcg gat aag gga tat att gaa 1680
Asn Val Asn Lys Ala Arg Lys Leu Cys Ser Asp Lys Gly Tyr Ile Glu
545 550 555 560
gag aca atc tat ctt ctt gcc aaa agt gga aat cat tat gat gct gtg 1728
Glu Thr Ile Tyr Leu Leu Ala Lys Ser Gly Asn His Tyr Asp Ala Val
565 570 575
aaa atg atg gtt cga gag tat cgg aac atg gaa aaa gtc atc gat tac 1776
Lys Met Met Val Arg Glu Tyr Arg Asn Met Glu Lys Val Ile Asp Tyr
580 585 590
tgc aaa gat caa aat gac ccc gat tta tgg att cac ctt cta gga gta 1824
Cys Lys Asp Gln Asn Asp Pro Asp Leu Trp Ile His Leu Leu Gly Val
595 600 605
gtt gcc gag ttt cct gct cat ttt tcg cag ctt atc att gaa gcg tca 1872
Val Ala Glu Phe Pro Ala His Phe Ser Gln Leu Ile Ile Glu Ala Ser
610 615 620
aac tgc ctc gat cct ctc ctg att atg gac aaa cta ccg gac gat tcg 1920
Asn Cys Leu Asp Pro Leu Leu Ile Met Asp Lys Leu Pro Asp Asp Ser
625 630 635 640
gat att cct aac ttg agt gaa gcg ctc gac aaa ctt ctc gtt gac tat 1968
Asp Ile Pro Asn Leu Ser Glu Ala Leu Asp Lys Leu Leu Val Asp Tyr
645 650 655
aca aat cat gca gag ctt cag caa tgt tgc tac gac tca acc ttg aac 2016
Thr Asn His Ala Glu Leu Gln Gln Cys Cys Tyr Asp Ser Thr Leu Asn
660 665 670
gat ctg aat gtt ctc act caa gga ctg ata tcg gca gct gat gaa tca 2064
Asp Leu Asn Val Leu Thr Gln Gly Leu Ile Ser Ala Ala Asp Glu Ser
675 680 685
gtt tcc gtg aac ata gta tcc aga tgt tca tta tgt gct caa atc atc 2112
Val Ser Val Asn Ile Val Ser Arg Cys Ser Leu Cys Ala Gln Ile Ile
690 695 700
atc aat tct aac caa gaa aca aca aaa aag ttt tcg gat ata aaa gtg 2160
Ile Asn Ser Asn Gln Glu Thr Thr Lys Lys Phe Ser Asp Ile Lys Val
705 710 715 720
ttc aaa tgc gga cac att ttt cac ttg gct tgt tct act tct gag atg 2208
Phe Lys Cys Gly His Ile Phe His Leu Ala Cys Ser Thr Ser Glu Met
725 730 735
gaa cgc cgt caa tca att gag gag ggc ctc tgc att gcg tgc tct gat 2256
Glu Arg Arg Gln Ser Ile Glu Glu Gly Leu Cys Ile Ala Cys Ser Asp
740 745 750
caa atc gaa ctc atc aac gtg taa 2280
Gln Ile Glu Leu Ile Asn Val
755
<210> 58
<211> 759
<212> PRT
<213> Caenorhabditis elegans
<400> 58
Met Pro Lys Ser Ile Tyr Phe Ser Pro Asp Phe Ile Arg Gln Gln Ser
1 5 10 15
Gly His Cys Phe Ile Met Gly Glu Arg Asn Leu Val Leu Tyr Glu Lys
20 25 30
Arg Met Phe Gln Tyr Lys Ala Ser Ser Leu Tyr Ser Gly Ser Glu Arg
35 40 45
Asp Gly Phe Ile His Cys Cys Ser Trp Asn Glu Asn Leu Ile Ala Phe
50 55 60
Thr Asn Asp Thr Gly Thr Arg Val Tyr Glu Arg Gly Ala Glu Arg Ile
65 70 75 80
Ile Thr Ser Val Gln Pro Ser His Asp Val Asp Arg Val Arg Ser Ser
85 90 95
Arg Ser Pro Pro Lys His Thr Trp Met Pro Glu Asn Asn Leu Val Ile
100 105 110
Gly Trp Ala Asp Thr Val Thr Ile Leu Lys Ile Arg Asp Asp Asp Gly
115 120 125
Val Lys Lys Gly Glu Val His His Ile Phe His Val Ser Met Phe Ile
130 135 140
Cys Gly Ile Ser Tyr Ile Pro Glu Ser Gly Ile Asp Asn Met Glu Leu
145 150 155 160
Phe Leu Val Gly Leu Gln Leu Glu Gly Glu Asp Phe Asp Asp Cys Ala
165 170 175
Ser Val Ile Ser Thr Val Thr Thr Leu Thr Ala Leu Glu Ser Ser Ala
180 185 190
Cys Thr Ile Leu Lys Thr Ser Val Ile Arg Pro Leu Gly Leu Lys Glu
195 200 205
Phe Glu Leu Gln Ser Glu Asp Met Ile Glu Ser Val Lys Leu Ser Asn
210 215 220
His Thr Leu Pro Tyr Met Ile His Gly Leu Gly Ile Pro Tyr Leu Ala
225 230 235 240
Thr Tyr Phe Ile Leu Thr Thr Lys His Ile Ile Met Ala Val Pro Tyr
245 250 255
Gly Pro Glu Asp Gly Ile Arg Trp Arg Leu Lys Tyr Lys Leu Tyr Asp
260 265 270
Glu Ala Leu Asp Met Ala Lys His Asn Ala Asp Leu Leu Ser Lys Thr
275 280 285
Asp Leu Ser Pro Lys Lys Val Gly Arg Met Ile Ile Glu Gly Tyr Leu
290 295 300
Thr Gly Lys Arg Ala Arg Ala Ala Ala Ser Arg Leu Pro Leu Ile Cys
305 310 315 320
Gly Glu Cys Lys Glu Glu Trp Glu Trp Ala Val Asn Gln Phe Glu Glu
325 330 335
Val Lys Leu Cys Thr Leu Leu Ala Glu Val Leu Pro Asp Gly Thr Pro
340 345 350
Thr Leu Asp Pro Glu Cys Tyr Gln Lys Val Leu Ile Ala Cys Leu Phe
355 360 365
Asn Asn Val Lys Gln Phe Arg Lys Leu Val Gln Thr Trp Ser Pro Asp
370 375 380
Leu Tyr Met Thr Ser Phe Ile Ile Asp Arg Thr Gln Trp Arg Ile Gln
385 390 395 400
Gln Ile Ser Lys Ser Gly Asn Leu Ala Asp Val Asp Glu Thr Glu Arg
405 410 415
Val Leu Met Asp Ala Leu Ala His Leu Tyr Leu Tyr Glu Arg Lys Tyr
420 425 430
Glu Ser Ala Leu Lys Ile Leu Met Ser Cys Gln Asp Phe Gln Ile Phe
435 440 445
Asn Val Ile Asp Lys His Gln Leu Phe Asp Leu Val Lys Asp Gln Ile
450 455 460
Thr Glu Leu Met Asn Ile Asn Ser Glu Arg Ala Leu Arg Leu Leu Leu
465 470 475 480
Asp Asn Ala Asp Ser Val Glu Pro Ser Phe Val Met Glu Lys Ile Gly
485 490 495
Arg Gln Pro Lys Leu Gln Leu Ala Tyr Leu Thr Lys Leu Met Ser Arg
500 505 510
Asn Glu Gly Thr Glu Phe Ala Asp Lys Ala Val Gln Leu Tyr Ala Glu
515 520 525
Tyr Asp Gln Lys Lys Leu Leu Pro Phe Leu Arg Lys Asn Ala Asn Tyr
530 535 540
Asn Val Asn Lys Ala Arg Lys Leu Cys Ser Asp Lys Gly Tyr Ile Glu
545 550 555 560
Glu Thr Ile Tyr Leu Leu Ala Lys Ser Gly Asn His Tyr Asp Ala Val
565 570 575
Lys Met Met Val Arg Glu Tyr Arg Asn Met Glu Lys Val Ile Asp Tyr
580 585 590
Cys Lys Asp Gln Asn Asp Pro Asp Leu Trp Ile His Leu Leu Gly Val
595 600 605
Val Ala Glu Phe Pro Ala His Phe Ser Gln Leu Ile Ile Glu Ala Ser
610 615 620
Asn Cys Leu Asp Pro Leu Leu Ile Met Asp Lys Leu Pro Asp Asp Ser
625 630 635 640
Asp Ile Pro Asn Leu Ser Glu Ala Leu Asp Lys Leu Leu Val Asp Tyr
645 650 655
Thr Asn His Ala Glu Leu Gln Gln Cys Cys Tyr Asp Ser Thr Leu Asn
660 665 670
Asp Leu Asn Val Leu Thr Gln Gly Leu Ile Ser Ala Ala Asp Glu Ser
675 680 685
Val Ser Val Asn Ile Val Ser Arg Cys Ser Leu Cys Ala Gln Ile Ile
690 695 700
Ile Asn Ser Asn Gln Glu Thr Thr Lys Lys Phe Ser Asp Ile Lys Val
705 710 715 720
Phe Lys Cys Gly His Ile Phe His Leu Ala Cys Ser Thr Ser Glu Met
725 730 735
Glu Arg Arg Gln Ser Ile Glu Glu Gly Leu Cys Ile Ala Cys Ser Asp
740 745 750
Gln Ile Glu Leu Ile Asn Val
755
<210> 59
<211> 2565
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(2565)
<400> 59
atg gcg gaa gca gag gag cag gaa act ggg tcc ctt gaa gaa tct aca 48
Met Ala Glu Ala Glu Glu Gln Glu Thr Gly Ser Leu Glu Glu Ser Thr
1 5 10 15
gat gag tct gag gaa gaa gag agc gaa gag gaa ccc aag ctg aag tat 96
Asp Glu Ser Glu Glu Glu Glu Ser Glu Glu Glu Pro Lys Leu Lys Tyr
20 25 30
gaa agg ctt tcc aat ggg gta act gaa ata ctt cag aag gat gca gct 144
Glu Arg Leu Ser Asn Gly Val Thr Glu Ile Leu Gln Lys Asp Ala Ala
35 40 45
agc tgc atg aca gtc cat gac aag ttt ttg gca ttg ggc aca cat tat 192
Ser Cys Met Thr Val His Asp Lys Phe Leu Ala Leu Gly Thr His Tyr
50 55 60
ggc aag gtt tat tta ctt gat gtc cag ggg aac atc act cag aag ttt 240
Gly Lys Val Tyr Leu Leu Asp Val Gln Gly Asn Ile Thr Gln Lys Phe
65 70 75 80
gat gta agt cct gtg aag ata aat cag att agc ttg gat gaa agt gga 288
Asp Val Ser Pro Val Lys Ile Asn Gln Ile Ser Leu Asp Glu Ser Gly
85 90 95
gag cac atg ggt gtg tgt tca gag gat ggc aag gtg cag gta ttt gga 336
Glu His Met Gly Val Cys Ser Glu Asp Gly Lys Val Gln Val Phe Gly
100 105 110
ctg tat tct gga gaa gaa ttt cac gag act ttt gac tgt ccc att aaa 384
Leu Tyr Ser Gly Glu Glu Phe His Glu Thr Phe Asp Cys Pro Ile Lys
115 120 125
att att gct gtg cac cca cat ttc gtg aga tcc agt tgc aag cag ttt 432
Ile Ile Ala Val His Pro His Phe Val Arg Ser Ser Cys Lys Gln Phe
130 135 140
gtg acc gga ggg aag aag ctg cta ctg ttt gaa cgg tct tgg atg aac 480
Val Thr Gly Gly Lys Lys Leu Leu Leu Phe Glu Arg Ser Trp Met Asn
145 150 155 160
aga tgg aag tct gct gtt ctg cat gaa ggg gaa ggg aac ata agg agt 528
Arg Trp Lys Ser Ala Val Leu His Glu Gly Glu Gly Asn Ile Arg Ser
165 170 175
gtg aag tgg aga ggc cat ctg att gct tgg gcc aat aat atg ggt gtg 576
Val Lys Trp Arg Gly His Leu Ile Ala Trp Ala Asn Asn Met Gly Val
180 185 190
aag att ttt gac atc atc tca aag caa aga atc acc aat gtg ccc cgg 624
Lys Ile Phe Asp Ile Ile Ser Lys Gln Arg Ile Thr Asn Val Pro Arg
195 200 205
gat gat ata agt ctt cgc cca gac atg tat ccc tgc agc ctc tgc tgg 672
Asp Asp Ile Ser Leu Arg Pro Asp Met Tyr Pro Cys Ser Leu Cys Trp
210 215 220
aag gac aat gtg aca ctg att att ggc tgg ggg act tct gtc aag gtg 720
Lys Asp Asn Val Thr Leu Ile Ile Gly Trp Gly Thr Ser Val Lys Val
225 230 235 240
tgc tca gtg aag gaa cgg cat gcc agt gaa atg agg gat ttg cca agt 768
Cys Ser Val Lys Glu Arg His Ala Ser Glu Met Arg Asp Leu Pro Ser
245 250 255
cga tat gtt gaa ata gtg tct cag ttt gaa act gaa ttc tac atc agt 816
Arg Tyr Val Glu Ile Val Ser Gln Phe Glu Thr Glu Phe Tyr Ile Ser
260 265 270
gga ctt gca cct ctc tgt gat cag ctt gtt gta ctt tcg tat gta aag 864
Gly Leu Ala Pro Leu Cys Asp Gln Leu Val Val Leu Ser Tyr Val Lys
275 280 285
gag att tca gaa aaa acg gaa aga gaa tac tgt gcc agg cct aga ctg 912
Glu Ile Ser Glu Lys Thr Glu Arg Glu Tyr Cys Ala Arg Pro Arg Leu
290 295 300
gac atc atc cag cca ctt tct gag act tgt gaa gag atc tct tct gat 960
Asp Ile Ile Gln Pro Leu Ser Glu Thr Cys Glu Glu Ile Ser Ser Asp
305 310 315 320
gct ttg aca gtc aga ggc ttt cag gag aat gaa tgt aga gat tat cat 1008
Ala Leu Thr Val Arg Gly Phe Gln Glu Asn Glu Cys Arg Asp Tyr His
325 330 335
tta gaa tac tct gaa ggg gaa tca ctt ttt tac atc gtg agt ccg aga 1056
Leu Glu Tyr Ser Glu Gly Glu Ser Leu Phe Tyr Ile Val Ser Pro Arg
340 345 350
gat gtt gta gtg gcc aag gaa cga gac caa gat gat cac att gac tgg 1104
Asp Val Val Val Ala Lys Glu Arg Asp Gln Asp Asp His Ile Asp Trp
355 360 365
ctc ctt gaa aag aag aaa tat gaa gaa gca ttg atg gca gct gaa att 1152
Leu Leu Glu Lys Lys Lys Tyr Glu Glu Ala Leu Met Ala Ala Glu Ile
370 375 380
agc caa aaa aat att aaa aga cat aag att ctg gat att ggc ttg gca 1200
Ser Gln Lys Asn Ile Lys Arg His Lys Ile Leu Asp Ile Gly Leu Ala
385 390 395 400
tat ata aat cac ctg gtg gag aga gga gac tat gac ata gca gca cgc 1248
Tyr Ile Asn His Leu Val Glu Arg Gly Asp Tyr Asp Ile Ala Ala Arg
405 410 415
aaa tgc cag aaa att ctt ggg aaa aat gca gca ctc tgg gaa tat gaa 1296
Lys Cys Gln Lys Ile Leu Gly Lys Asn Ala Ala Leu Trp Glu Tyr Glu
420 425 430
gtt tat aaa ttt aaa gaa att gga cag ctt aag gct att agt cct tat 1344
Val Tyr Lys Phe Lys Glu Ile Gly Gln Leu Lys Ala Ile Ser Pro Tyr
435 440 445
ttg cca aga ggt gat cca gtt ctg aaa cca ctc atc tat gaa atg atc 1392
Leu Pro Arg Gly Asp Pro Val Leu Lys Pro Leu Ile Tyr Glu Met Ile
450 455 460
tta cat gaa ttt ttg gag agt gat tat gag ggt ttt gcc aca ttg atc 1440
Leu His Glu Phe Leu Glu Ser Asp Tyr Glu Gly Phe Ala Thr Leu Ile
465 470 475 480
cga gaa tgg cct gga gat ctg tat aat aat tca gtc ata gtt caa gca 1488
Arg Glu Trp Pro Gly Asp Leu Tyr Asn Asn Ser Val Ile Val Gln Ala
485 490 495
gtt cgg gat cat ttg aag aaa gat agt cag aac aag act tta ctt aaa 1536
Val Arg Asp His Leu Lys Lys Asp Ser Gln Asn Lys Thr Leu Leu Lys
500 505 510
acc ctg gca gaa ttg tac acc tat gac aag aac tat ggc aat gct ctg 1584
Thr Leu Ala Glu Leu Tyr Thr Tyr Asp Lys Asn Tyr Gly Asn Ala Leu
515 520 525
gaa ata tac tta aca tta aga cat aaa gac gtt ttt cag ttg atc cac 1632
Glu Ile Tyr Leu Thr Leu Arg His Lys Asp Val Phe Gln Leu Ile His
530 535 540
aag cat aat ctt ttc agt tct atc aag gat aaa att gtt tta tta atg 1680
Lys His Asn Leu Phe Ser Ser Ile Lys Asp Lys Ile Val Leu Leu Met
545 550 555 560
gat ttt gat tca gag aaa gct gtt gac atg ctt ttg gac aat gaa gat 1728
Asp Phe Asp Ser Glu Lys Ala Val Asp Met Leu Leu Asp Asn Glu Asp
565 570 575
aaa att tca att aaa aag gta gtg gaa gaa ttg gaa gac aga cca gag 1776
Lys Ile Ser Ile Lys Lys Val Val Glu Glu Leu Glu Asp Arg Pro Glu
580 585 590
cta cag cat gtg tat ttg cat aag ctt ttc aag aga gac cac cat aag 1824
Leu Gln His Val Tyr Leu His Lys Leu Phe Lys Arg Asp His His Lys
595 600 605
ggg cag cgt tac cat gaa aaa cag atc agt ctt tat gct gaa tat gat 1872
Gly Gln Arg Tyr His Glu Lys Gln Ile Ser Leu Tyr Ala Glu Tyr Asp
610 615 620
cga cca aac tta ctt ccc ttt ctc cga gac agt acc cat tgc cca ctt 1920
Arg Pro Asn Leu Leu Pro Phe Leu Arg Asp Ser Thr His Cys Pro Leu
625 630 635 640
gaa aag gct ctt gag atc tgt caa cag aga aac ttt gta gaa gag aca 1968
Glu Lys Ala Leu Glu Ile Cys Gln Gln Arg Asn Phe Val Glu Glu Thr
645 650 655
gtt tat ctt ctg agc cga atg ggt aat agc cga agt gcc ctg aag atg 2016
Val Tyr Leu Leu Ser Arg Met Gly Asn Ser Arg Ser Ala Leu Lys Met
660 665 670
att atg gag gaa tta cat gat gtt gat aaa gca atc gaa ttt gcc aag 2064
Ile Met Glu Glu Leu His Asp Val Asp Lys Ala Ile Glu Phe Ala Lys
675 680 685
gag caa gat gat gga gag ctg tgg gaa gat ttg att tta tat tcc att 2112
Glu Gln Asp Asp Gly Glu Leu Trp Glu Asp Leu Ile Leu Tyr Ser Ile
690 695 700
gac aaa cca cca ttt att act ggc ttg tta aac aac att ggc aca cat 2160
Asp Lys Pro Pro Phe Ile Thr Gly Leu Leu Asn Asn Ile Gly Thr His
705 710 715 720
gtt gac cca att cta ctg att cac cgt att aag gaa gga atg gag atc 2208
Val Asp Pro Ile Leu Leu Ile His Arg Ile Lys Glu Gly Met Glu Ile
725 730 735
ccc aat ttg aga gat tcc ttg gtt aaa att ctg caa gac tac aat ttg 2256
Pro Asn Leu Arg Asp Ser Leu Val Lys Ile Leu Gln Asp Tyr Asn Leu
740 745 750
caa att ctg ctt cgt gaa ggc tgc aag aag att ctc gta gct gac tct 2304
Gln Ile Leu Leu Arg Glu Gly Cys Lys Lys Ile Leu Val Ala Asp Ser
755 760 765
ttg tcc tta ctg aag aaa atg cac cga act caa atg aaa ggt gtt ctt 2352
Leu Ser Leu Leu Lys Lys Met His Arg Thr Gln Met Lys Gly Val Leu
770 775 780
gtt gat gag gag aac atc tgt gag tcg tgc ctt tcc cct att ctt cca 2400
Val Asp Glu Glu Asn Ile Cys Glu Ser Cys Leu Ser Pro Ile Leu Pro
785 790 795 800
tca gat gca gct aag ccc ttc agc gtg gtg gtc ttc cat tgc cgg cac 2448
Ser Asp Ala Ala Lys Pro Phe Ser Val Val Val Phe His Cys Arg His
805 810 815
atg ttc cac aag gag tgc ctg ccc atg ccc agc atg aac tct gct gca 2496
Met Phe His Lys Glu Cys Leu Pro Met Pro Ser Met Asn Ser Ala Ala
820 825 830
cag ttc tgc aac atc tgc agt gct aag aac cgt gga cca gga agt gca 2544
Gln Phe Cys Asn Ile Cys Ser Ala Lys Asn Arg Gly Pro Gly Ser Ala
835 840 845
att ttg gag atg aaa aaa tag 2565
Ile Leu Glu Met Lys Lys
850
<210> 60
<211> 854
<212> PRT
<213> Homo sapiens
<400> 60
Met Ala Glu Ala Glu Glu Gln Glu Thr Gly Ser Leu Glu Glu Ser Thr
1 5 10 15
Asp Glu Ser Glu Glu Glu Glu Ser Glu Glu Glu Pro Lys Leu Lys Tyr
20 25 30
Glu Arg Leu Ser Asn Gly Val Thr Glu Ile Leu Gln Lys Asp Ala Ala
35 40 45
Ser Cys Met Thr Val His Asp Lys Phe Leu Ala Leu Gly Thr His Tyr
50 55 60
Gly Lys Val Tyr Leu Leu Asp Val Gln Gly Asn Ile Thr Gln Lys Phe
65 70 75 80
Asp Val Ser Pro Val Lys Ile Asn Gln Ile Ser Leu Asp Glu Ser Gly
85 90 95
Glu His Met Gly Val Cys Ser Glu Asp Gly Lys Val Gln Val Phe Gly
100 105 110
Leu Tyr Ser Gly Glu Glu Phe His Glu Thr Phe Asp Cys Pro Ile Lys
115 120 125
Ile Ile Ala Val His Pro His Phe Val Arg Ser Ser Cys Lys Gln Phe
130 135 140
Val Thr Gly Gly Lys Lys Leu Leu Leu Phe Glu Arg Ser Trp Met Asn
145 150 155 160
Arg Trp Lys Ser Ala Val Leu His Glu Gly Glu Gly Asn Ile Arg Ser
165 170 175
Val Lys Trp Arg Gly His Leu Ile Ala Trp Ala Asn Asn Met Gly Val
180 185 190
Lys Ile Phe Asp Ile Ile Ser Lys Gln Arg Ile Thr Asn Val Pro Arg
195 200 205
Asp Asp Ile Ser Leu Arg Pro Asp Met Tyr Pro Cys Ser Leu Cys Trp
210 215 220
Lys Asp Asn Val Thr Leu Ile Ile Gly Trp Gly Thr Ser Val Lys Val
225 230 235 240
Cys Ser Val Lys Glu Arg His Ala Ser Glu Met Arg Asp Leu Pro Ser
245 250 255
Arg Tyr Val Glu Ile Val Ser Gln Phe Glu Thr Glu Phe Tyr Ile Ser
260 265 270
Gly Leu Ala Pro Leu Cys Asp Gln Leu Val Val Leu Ser Tyr Val Lys
275 280 285
Glu Ile Ser Glu Lys Thr Glu Arg Glu Tyr Cys Ala Arg Pro Arg Leu
290 295 300
Asp Ile Ile Gln Pro Leu Ser Glu Thr Cys Glu Glu Ile Ser Ser Asp
305 310 315 320
Ala Leu Thr Val Arg Gly Phe Gln Glu Asn Glu Cys Arg Asp Tyr His
325 330 335
Leu Glu Tyr Ser Glu Gly Glu Ser Leu Phe Tyr Ile Val Ser Pro Arg
340 345 350
Asp Val Val Val Ala Lys Glu Arg Asp Gln Asp Asp His Ile Asp Trp
355 360 365
Leu Leu Glu Lys Lys Lys Tyr Glu Glu Ala Leu Met Ala Ala Glu Ile
370 375 380
Ser Gln Lys Asn Ile Lys Arg His Lys Ile Leu Asp Ile Gly Leu Ala
385 390 395 400
Tyr Ile Asn His Leu Val Glu Arg Gly Asp Tyr Asp Ile Ala Ala Arg
405 410 415
Lys Cys Gln Lys Ile Leu Gly Lys Asn Ala Ala Leu Trp Glu Tyr Glu
420 425 430
Val Tyr Lys Phe Lys Glu Ile Gly Gln Leu Lys Ala Ile Ser Pro Tyr
435 440 445
Leu Pro Arg Gly Asp Pro Val Leu Lys Pro Leu Ile Tyr Glu Met Ile
450 455 460
Leu His Glu Phe Leu Glu Ser Asp Tyr Glu Gly Phe Ala Thr Leu Ile
465 470 475 480
Arg Glu Trp Pro Gly Asp Leu Tyr Asn Asn Ser Val Ile Val Gln Ala
485 490 495
Val Arg Asp His Leu Lys Lys Asp Ser Gln Asn Lys Thr Leu Leu Lys
500 505 510
Thr Leu Ala Glu Leu Tyr Thr Tyr Asp Lys Asn Tyr Gly Asn Ala Leu
515 520 525
Glu Ile Tyr Leu Thr Leu Arg His Lys Asp Val Phe Gln Leu Ile His
530 535 540
Lys His Asn Leu Phe Ser Ser Ile Lys Asp Lys Ile Val Leu Leu Met
545 550 555 560
Asp Phe Asp Ser Glu Lys Ala Val Asp Met Leu Leu Asp Asn Glu Asp
565 570 575
Lys Ile Ser Ile Lys Lys Val Val Glu Glu Leu Glu Asp Arg Pro Glu
580 585 590
Leu Gln His Val Tyr Leu His Lys Leu Phe Lys Arg Asp His His Lys
595 600 605
Gly Gln Arg Tyr His Glu Lys Gln Ile Ser Leu Tyr Ala Glu Tyr Asp
610 615 620
Arg Pro Asn Leu Leu Pro Phe Leu Arg Asp Ser Thr His Cys Pro Leu
625 630 635 640
Glu Lys Ala Leu Glu Ile Cys Gln Gln Arg Asn Phe Val Glu Glu Thr
645 650 655
Val Tyr Leu Leu Ser Arg Met Gly Asn Ser Arg Ser Ala Leu Lys Met
660 665 670
Ile Met Glu Glu Leu His Asp Val Asp Lys Ala Ile Glu Phe Ala Lys
675 680 685
Glu Gln Asp Asp Gly Glu Leu Trp Glu Asp Leu Ile Leu Tyr Ser Ile
690 695 700
Asp Lys Pro Pro Phe Ile Thr Gly Leu Leu Asn Asn Ile Gly Thr His
705 710 715 720
Val Asp Pro Ile Leu Leu Ile His Arg Ile Lys Glu Gly Met Glu Ile
725 730 735
Pro Asn Leu Arg Asp Ser Leu Val Lys Ile Leu Gln Asp Tyr Asn Leu
740 745 750
Gln Ile Leu Leu Arg Glu Gly Cys Lys Lys Ile Leu Val Ala Asp Ser
755 760 765
Leu Ser Leu Leu Lys Lys Met His Arg Thr Gln Met Lys Gly Val Leu
770 775 780
Val Asp Glu Glu Asn Ile Cys Glu Ser Cys Leu Ser Pro Ile Leu Pro
785 790 795 800
Ser Asp Ala Ala Lys Pro Phe Ser Val Val Val Phe His Cys Arg His
805 810 815
Met Phe His Lys Glu Cys Leu Pro Met Pro Ser Met Asn Ser Ala Ala
820 825 830
Gln Phe Cys Asn Ile Cys Ser Ala Lys Asn Arg Gly Pro Gly Ser Ala
835 840 845
Ile Leu Glu Met Lys Lys
850
<210> 61
<211> 1305
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(1305)
<400> 61
atg tac tat aaa atc tct tat tta tta tct atc agt att cta tta ttt 48
Met Tyr Tyr Lys Ile Ser Tyr Leu Leu Ser Ile Ser Ile Leu Leu Phe
1 5 10 15
ttc gcg aaa tgt gaa aaa gta aaa aat aag gca gtg gag aag aaa gat 96
Phe Ala Lys Cys Glu Lys Val Lys Asn Lys Ala Val Glu Lys Lys Asp
20 25 30
gat cga aat gaa cga gaa ctg gca aag cac tta ctt gat gat tac tac 144
Asp Arg Asn Glu Arg Glu Leu Ala Lys His Leu Leu Asp Asp Tyr Tyr
35 40 45
caa tat act cga ccg gtt cgg aat tat tcc agt gtg ctc aat gtg acg 192
Gln Tyr Thr Arg Pro Val Arg Asn Tyr Ser Ser Val Leu Asn Val Thr
50 55 60
gta cag cca caa att tac aac ttg gta gag gtg aat gaa caa aat gag 240
Val Gln Pro Gln Ile Tyr Asn Leu Val Glu Val Asn Glu Gln Asn Glu
65 70 75 80
caa atc aaa ata ttg ctc tgg ttc ccc caa agt tgg aaa gac gat tat 288
Gln Ile Lys Ile Leu Leu Trp Phe Pro Gln Ser Trp Lys Asp Asp Tyr
85 90 95
cta aca tgg gat cct aag gaa tgg aac gga ata gag aga ata ata ata 336
Leu Thr Trp Asp Pro Lys Glu Trp Asn Gly Ile Glu Arg Ile Ile Ile
100 105 110
ccc aaa tcg caa att tgg att cca gat gga tat ata ttt aat aca gta 384
Pro Lys Ser Gln Ile Trp Ile Pro Asp Gly Tyr Ile Phe Asn Thr Val
115 120 125
gaa gaa act gaa ccg tta gaa aac cac aat gca aga gta aga tac gat 432
Glu Glu Thr Glu Pro Leu Glu Asn His Asn Ala Arg Val Arg Tyr Asp
130 135 140
ggg cga gtg gaa gtt gat ttc aat aaa ctc gtc gac ttg acg tgc cct 480
Gly Arg Val Glu Val Asp Phe Asn Lys Leu Val Asp Leu Thr Cys Pro
145 150 155 160
atg tca gtg ctc tct ttc cca ttt gat gtt caa tta tgt gcc ctc cag 528
Met Ser Val Leu Ser Phe Pro Phe Asp Val Gln Leu Cys Ala Leu Gln
165 170 175
ttt ggc tcc tgg tcg tat caa gct cat gcg att agc ttc aac gta ctc 576
Phe Gly Ser Trp Ser Tyr Gln Ala His Ala Ile Ser Phe Asn Val Leu
180 185 190
gac aca ttt gtc cca aag aaa agc aag aat tct gaa tgg gac att gta 624
Asp Thr Phe Val Pro Lys Lys Ser Lys Asn Ser Glu Trp Asp Ile Val
195 200 205
tcg ttt aat gct aca aag atg aca aca aaa tat ggt gac acg ctt gga 672
Ser Phe Asn Ala Thr Lys Met Thr Thr Lys Tyr Gly Asp Thr Leu Gly
210 215 220
gga ttc aat gtt tat gaa gag att ttc tat tac ttg gaa ctt cgc cga 720
Gly Phe Asn Val Tyr Glu Glu Ile Phe Tyr Tyr Leu Glu Leu Arg Arg
225 230 235 240
aag cca ttg tat tac att gta gtc att ctg ctc cca tca ttt tta att 768
Lys Pro Leu Tyr Tyr Ile Val Val Ile Leu Leu Pro Ser Phe Leu Ile
245 250 255
gtt acc gtc tca aac att gga ctg ttt acg cct cat gga gtt cac gga 816
Val Thr Val Ser Asn Ile Gly Leu Phe Thr Pro His Gly Val His Gly
260 265 270
gac aga gaa gag cat gtg tca ttg ggt ctc act aca atg ctt acc atg 864
Asp Arg Glu Glu His Val Ser Leu Gly Leu Thr Thr Met Leu Thr Met
275 280 285
gct gtt atc tta gac atg gtc aca gga caa atg cca aga agt agt gaa 912
Ala Val Ile Leu Asp Met Val Thr Gly Gln Met Pro Arg Ser Ser Glu
290 295 300
gga ata cca cta ttg gga atg tat gtg ctg att gaa ttt gtt ata tct 960
Gly Ile Pro Leu Leu Gly Met Tyr Val Leu Ile Glu Phe Val Ile Ser
305 310 315 320
gta att gct gta tta gta tca gtt gta ata att ttt gca cac gaa agg 1008
Val Ile Ala Val Leu Val Ser Val Val Ile Ile Phe Ala His Glu Arg
325 330 335
atg cta tat ctc gat gca act cct ccg tac tgg gtg tgc aaa ttg ttt 1056
Met Leu Tyr Leu Asp Ala Thr Pro Pro Tyr Trp Val Cys Lys Leu Phe
340 345 350
tca gat gac tgc aaa atg tca ttg gaa gaa ata gaa gaa gat ttt tgt 1104
Ser Asp Asp Cys Lys Met Ser Leu Glu Glu Ile Glu Glu Asp Phe Cys
355 360 365
tca aaa cca gct gat ctg gtg caa gag tta agg ttt tgt atg gag gaa 1152
Ser Lys Pro Ala Asp Leu Val Gln Glu Leu Arg Phe Cys Met Glu Glu
370 375 380
atc aaa cga tat ctt gac gaa cag gat tcg aca gag aag aac cga att 1200
Ile Lys Arg Tyr Leu Asp Glu Gln Asp Ser Thr Glu Lys Asn Arg Ile
385 390 395 400
ata tgg cag agg ttt ttc tcg tgg aca gat att ata ttc agt ata ttc 1248
Ile Trp Gln Arg Phe Phe Ser Trp Thr Asp Ile Ile Phe Ser Ile Phe
405 410 415
ttt ttt gtt gtt aat tgt ctt gtg aca ttt tac atg ttt atg gag ttt 1296
Phe Phe Val Val Asn Cys Leu Val Thr Phe Tyr Met Phe Met Glu Phe
420 425 430
atg ttt tga 1305
Met Phe
<210> 62
<211> 434
<212> PRT
<213> Caenorhabditis elegans
<400> 62
Met Tyr Tyr Lys Ile Ser Tyr Leu Leu Ser Ile Ser Ile Leu Leu Phe
1 5 10 15
Phe Ala Lys Cys Glu Lys Val Lys Asn Lys Ala Val Glu Lys Lys Asp
20 25 30
Asp Arg Asn Glu Arg Glu Leu Ala Lys His Leu Leu Asp Asp Tyr Tyr
35 40 45
Gln Tyr Thr Arg Pro Val Arg Asn Tyr Ser Ser Val Leu Asn Val Thr
50 55 60
Val Gln Pro Gln Ile Tyr Asn Leu Val Glu Val Asn Glu Gln Asn Glu
65 70 75 80
Gln Ile Lys Ile Leu Leu Trp Phe Pro Gln Ser Trp Lys Asp Asp Tyr
85 90 95
Leu Thr Trp Asp Pro Lys Glu Trp Asn Gly Ile Glu Arg Ile Ile Ile
100 105 110
Pro Lys Ser Gln Ile Trp Ile Pro Asp Gly Tyr Ile Phe Asn Thr Val
115 120 125
Glu Glu Thr Glu Pro Leu Glu Asn His Asn Ala Arg Val Arg Tyr Asp
130 135 140
Gly Arg Val Glu Val Asp Phe Asn Lys Leu Val Asp Leu Thr Cys Pro
145 150 155 160
Met Ser Val Leu Ser Phe Pro Phe Asp Val Gln Leu Cys Ala Leu Gln
165 170 175
Phe Gly Ser Trp Ser Tyr Gln Ala His Ala Ile Ser Phe Asn Val Leu
180 185 190
Asp Thr Phe Val Pro Lys Lys Ser Lys Asn Ser Glu Trp Asp Ile Val
195 200 205
Ser Phe Asn Ala Thr Lys Met Thr Thr Lys Tyr Gly Asp Thr Leu Gly
210 215 220
Gly Phe Asn Val Tyr Glu Glu Ile Phe Tyr Tyr Leu Glu Leu Arg Arg
225 230 235 240
Lys Pro Leu Tyr Tyr Ile Val Val Ile Leu Leu Pro Ser Phe Leu Ile
245 250 255
Val Thr Val Ser Asn Ile Gly Leu Phe Thr Pro His Gly Val His Gly
260 265 270
Asp Arg Glu Glu His Val Ser Leu Gly Leu Thr Thr Met Leu Thr Met
275 280 285
Ala Val Ile Leu Asp Met Val Thr Gly Gln Met Pro Arg Ser Ser Glu
290 295 300
Gly Ile Pro Leu Leu Gly Met Tyr Val Leu Ile Glu Phe Val Ile Ser
305 310 315 320
Val Ile Ala Val Leu Val Ser Val Val Ile Ile Phe Ala His Glu Arg
325 330 335
Met Leu Tyr Leu Asp Ala Thr Pro Pro Tyr Trp Val Cys Lys Leu Phe
340 345 350
Ser Asp Asp Cys Lys Met Ser Leu Glu Glu Ile Glu Glu Asp Phe Cys
355 360 365
Ser Lys Pro Ala Asp Leu Val Gln Glu Leu Arg Phe Cys Met Glu Glu
370 375 380
Ile Lys Arg Tyr Leu Asp Glu Gln Asp Ser Thr Glu Lys Asn Arg Ile
385 390 395 400
Ile Trp Gln Arg Phe Phe Ser Trp Thr Asp Ile Ile Phe Ser Ile Phe
405 410 415
Phe Phe Val Val Asn Cys Leu Val Thr Phe Tyr Met Phe Met Glu Phe
420 425 430
Met Phe
<210> 63
<211> 1440
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(1440)
<400> 63
atg aac tgg tcc cat tcc tgc atc tcc ttt tgc tgg atc tac ttt gct 48
Met Asn Trp Ser His Ser Cys Ile Ser Phe Cys Trp Ile Tyr Phe Ala
1 5 10 15
gct tcc aga ctg aga gct gca gag acg gca gat gga aaa tat gct cag 96
Ala Ser Arg Leu Arg Ala Ala Glu Thr Ala Asp Gly Lys Tyr Ala Gln
20 25 30
aag ttg ttt aat gac ctt ttt gaa gat tat tct aat gct ctt cgt cca 144
Lys Leu Phe Asn Asp Leu Phe Glu Asp Tyr Ser Asn Ala Leu Arg Pro
35 40 45
gtg gaa gat aca gat aaa gtc ctg aat gtg acc ctg cag att acg ctc 192
Val Glu Asp Thr Asp Lys Val Leu Asn Val Thr Leu Gln Ile Thr Leu
50 55 60
tct cag att aag gat atg gat gaa aga aac caa att ctg act gct tat 240
Ser Gln Ile Lys Asp Met Asp Glu Arg Asn Gln Ile Leu Thr Ala Tyr
65 70 75 80
ttg tgg atc cgc caa atc tgg cac gat gcc tat ctc acg tgg gac cga 288
Leu Trp Ile Arg Gln Ile Trp His Asp Ala Tyr Leu Thr Trp Asp Arg
85 90 95
gat cag tac gat ggc cta gac tcc atc agg atc ccc agt gac ctc gtg 336
Asp Gln Tyr Asp Gly Leu Asp Ser Ile Arg Ile Pro Ser Asp Leu Val
100 105 110
tgg agg cca gac atc gtc tta tat aac aag gct gat gat gaa tct tca 384
Trp Arg Pro Asp Ile Val Leu Tyr Asn Lys Ala Asp Asp Glu Ser Ser
115 120 125
gag cct gtg aac acc aat gtg gtc ctg cgg tat gat ggg ctg atc acc 432
Glu Pro Val Asn Thr Asn Val Val Leu Arg Tyr Asp Gly Leu Ile Thr
130 135 140
tgg gat gca ccg gcc atc acc aaa agc tcc tgt gtg gtg gat gtc acc 480
Trp Asp Ala Pro Ala Ile Thr Lys Ser Ser Cys Val Val Asp Val Thr
145 150 155 160
tac ttc cct ttt gac aac cag cag tgc aac ctg act ttt ggt tcc tgg 528
Tyr Phe Pro Phe Asp Asn Gln Gln Cys Asn Leu Thr Phe Gly Ser Trp
165 170 175
acc tac aat ggc aat cag gtg gac ata ttc aac gcc ttg gac agc gga 576
Thr Tyr Asn Gly Asn Gln Val Asp Ile Phe Asn Ala Leu Asp Ser Gly
180 185 190
gat ctc tct gac ttc att gaa gat gtg gaa tgg gag gtc cat ggc atg 624
Asp Leu Ser Asp Phe Ile Glu Asp Val Glu Trp Glu Val His Gly Met
195 200 205
ccc gct gtg aag aat gtg atc tcc tat ggc tgc tgc tct gag cct tac 672
Pro Ala Val Lys Asn Val Ile Ser Tyr Gly Cys Cys Ser Glu Pro Tyr
210 215 220
ccg gat gtc aca ttc acc ctc ctt ctg aag agg agg tcc tcg ttc tat 720
Pro Asp Val Thr Phe Thr Leu Leu Leu Lys Arg Arg Ser Ser Phe Tyr
225 230 235 240
atc gtc aac ctc ctc atc cca tgc gtc ctc ata tct ttt ctg gct cct 768
Ile Val Asn Leu Leu Ile Pro Cys Val Leu Ile Ser Phe Leu Ala Pro
245 250 255
ctg agt ttt tat ctc cca gca gcc tcc gga gaa aag gtc tcc ctg gga 816
Leu Ser Phe Tyr Leu Pro Ala Ala Ser Gly Glu Lys Val Ser Leu Gly
260 265 270
gtg acc atc ctg ttg gcc atg act gta ttt cag cta atg gtg gca gaa 864
Val Thr Ile Leu Leu Ala Met Thr Val Phe Gln Leu Met Val Ala Glu
275 280 285
atc atg ccg gcc tca gaa aat gtg ccc ctg ata ggt aaa tac tac ata 912
Ile Met Pro Ala Ser Glu Asn Val Pro Leu Ile Gly Lys Tyr Tyr Ile
290 295 300
gcc acg atg gcc ctg atc aca gcc tcc act gcg ttg acc atc atg gtg 960
Ala Thr Met Ala Leu Ile Thr Ala Ser Thr Ala Leu Thr Ile Met Val
305 310 315 320
atg aat atc cac ttc tgt ggg gcc gag gcc cgg ccg gtg cca cac tgg 1008
Met Asn Ile His Phe Cys Gly Ala Glu Ala Arg Pro Val Pro His Trp
325 330 335
gcc agg gtg gtc atc ctg aaa tac atg tcc agg gtc ttg ttt gtc tat 1056
Ala Arg Val Val Ile Leu Lys Tyr Met Ser Arg Val Leu Phe Val Tyr
340 345 350
gat gtg ggt gaa agc tgc ctc agc ccg cac cac agt aga gag cgg gac 1104
Asp Val Gly Glu Ser Cys Leu Ser Pro His His Ser Arg Glu Arg Asp
355 360 365
cac ctc acg aaa gtt tat agc aaa ctc cca gag tct aac ctg aaa gca 1152
His Leu Thr Lys Val Tyr Ser Lys Leu Pro Glu Ser Asn Leu Lys Ala
370 375 380
gcc agg aac aaa gac ctt tcc aga aag aag gac atg aac aaa cgc tta 1200
Ala Arg Asn Lys Asp Leu Ser Arg Lys Lys Asp Met Asn Lys Arg Leu
385 390 395 400
aag aac gac ctg ggc tgc cag ggt aag aac cct cag gag gcc gag agt 1248
Lys Asn Asp Leu Gly Cys Gln Gly Lys Asn Pro Gln Glu Ala Glu Ser
405 410 415
tac tgt gca cag tac aaa gtg ctg acg agg aat att gag tac atc gcc 1296
Tyr Cys Ala Gln Tyr Lys Val Leu Thr Arg Asn Ile Glu Tyr Ile Ala
420 425 430
aag tgc ctc aaa gac cac aag gcc acc aat tcc aag ggg agt gaa tgg 1344
Lys Cys Leu Lys Asp His Lys Ala Thr Asn Ser Lys Gly Ser Glu Trp
435 440 445
aag aag gtg gcg aaa gtc ata gac cga ttc ttc atg tgg att ttt ttc 1392
Lys Lys Val Ala Lys Val Ile Asp Arg Phe Phe Met Trp Ile Phe Phe
450 455 460
att atg gtg ttt gtg atg act att ttg atc ata gca aga gcg gat tag 1440
Ile Met Val Phe Val Met Thr Ile Leu Ile Ile Ala Arg Ala Asp
465 470 475
<210> 64
<211> 479
<212> PRT
<213> Homo sapiens
<400> 64
Met Asn Trp Ser His Ser Cys Ile Ser Phe Cys Trp Ile Tyr Phe Ala
1 5 10 15
Ala Ser Arg Leu Arg Ala Ala Glu Thr Ala Asp Gly Lys Tyr Ala Gln
20 25 30
Lys Leu Phe Asn Asp Leu Phe Glu Asp Tyr Ser Asn Ala Leu Arg Pro
35 40 45
Val Glu Asp Thr Asp Lys Val Leu Asn Val Thr Leu Gln Ile Thr Leu
50 55 60
Ser Gln Ile Lys Asp Met Asp Glu Arg Asn Gln Ile Leu Thr Ala Tyr
65 70 75 80
Leu Trp Ile Arg Gln Ile Trp His Asp Ala Tyr Leu Thr Trp Asp Arg
85 90 95
Asp Gln Tyr Asp Gly Leu Asp Ser Ile Arg Ile Pro Ser Asp Leu Val
100 105 110
Trp Arg Pro Asp Ile Val Leu Tyr Asn Lys Ala Asp Asp Glu Ser Ser
115 120 125
Glu Pro Val Asn Thr Asn Val Val Leu Arg Tyr Asp Gly Leu Ile Thr
130 135 140
Trp Asp Ala Pro Ala Ile Thr Lys Ser Ser Cys Val Val Asp Val Thr
145 150 155 160
Tyr Phe Pro Phe Asp Asn Gln Gln Cys Asn Leu Thr Phe Gly Ser Trp
165 170 175
Thr Tyr Asn Gly Asn Gln Val Asp Ile Phe Asn Ala Leu Asp Ser Gly
180 185 190
Asp Leu Ser Asp Phe Ile Glu Asp Val Glu Trp Glu Val His Gly Met
195 200 205
Pro Ala Val Lys Asn Val Ile Ser Tyr Gly Cys Cys Ser Glu Pro Tyr
210 215 220
Pro Asp Val Thr Phe Thr Leu Leu Leu Lys Arg Arg Ser Ser Phe Tyr
225 230 235 240
Ile Val Asn Leu Leu Ile Pro Cys Val Leu Ile Ser Phe Leu Ala Pro
245 250 255
Leu Ser Phe Tyr Leu Pro Ala Ala Ser Gly Glu Lys Val Ser Leu Gly
260 265 270
Val Thr Ile Leu Leu Ala Met Thr Val Phe Gln Leu Met Val Ala Glu
275 280 285
Ile Met Pro Ala Ser Glu Asn Val Pro Leu Ile Gly Lys Tyr Tyr Ile
290 295 300
Ala Thr Met Ala Leu Ile Thr Ala Ser Thr Ala Leu Thr Ile Met Val
305 310 315 320
Met Asn Ile His Phe Cys Gly Ala Glu Ala Arg Pro Val Pro His Trp
325 330 335
Ala Arg Val Val Ile Leu Lys Tyr Met Ser Arg Val Leu Phe Val Tyr
340 345 350
Asp Val Gly Glu Ser Cys Leu Ser Pro His His Ser Arg Glu Arg Asp
355 360 365
His Leu Thr Lys Val Tyr Ser Lys Leu Pro Glu Ser Asn Leu Lys Ala
370 375 380
Ala Arg Asn Lys Asp Leu Ser Arg Lys Lys Asp Met Asn Lys Arg Leu
385 390 395 400
Lys Asn Asp Leu Gly Cys Gln Gly Lys Asn Pro Gln Glu Ala Glu Ser
405 410 415
Tyr Cys Ala Gln Tyr Lys Val Leu Thr Arg Asn Ile Glu Tyr Ile Ala
420 425 430
Lys Cys Leu Lys Asp His Lys Ala Thr Asn Ser Lys Gly Ser Glu Trp
435 440 445
Lys Lys Val Ala Lys Val Ile Asp Arg Phe Phe Met Trp Ile Phe Phe
450 455 460
Ile Met Val Phe Val Met Thr Ile Leu Ile Ile Ala Arg Ala Asp
465 470 475
<210> 65
<211> 1674
<212> DNA
<213> Caenorhabditis elegans
<220>
<221> CDS
<222> (1)..(1674)
<400> 65
atg gca tcg tct aat aac gat ggt ccc att gag cct gag gct gaa ccg 48
Met Ala Ser Ser Asn Asn Asp Gly Pro Ile Glu Pro Glu Ala Glu Pro
1 5 10 15
tgg cga ata aca caa aac gat cat ctc gag caa gat ctt ttg gaa gaa 96
Trp Arg Ile Thr Gln Asn Asp His Leu Glu Gln Asp Leu Leu Glu Glu
20 25 30
gat gca gag agt cag gag aga gtt gat att cca gtt gat gat gtg gaa 144
Asp Ala Glu Ser Gln Glu Arg Val Asp Ile Pro Val Asp Asp Val Glu
35 40 45
aaa gcg ttc tcc ttc aaa aaa tta tgg gcg ttc aca ggg ccc gga ttt 192
Lys Ala Phe Ser Phe Lys Lys Leu Trp Ala Phe Thr Gly Pro Gly Phe
50 55 60
ctc atg agt att gcc tat ttg gac cca gga aac att gaa agc gac ctt 240
Leu Met Ser Ile Ala Tyr Leu Asp Pro Gly Asn Ile Glu Ser Asp Leu
65 70 75 80
cag tct ggc gca caa gcg gct tac aaa ctt ttg tgg gtt ttg ctc tca 288
Gln Ser Gly Ala Gln Ala Ala Tyr Lys Leu Leu Trp Val Leu Leu Ser
85 90 95
gct cat att atc gga atg ttg ctc caa cga atg tct gca aga ctt gga 336
Ala His Ile Ile Gly Met Leu Leu Gln Arg Met Ser Ala Arg Leu Gly
100 105 110
gtt gtc agt gga aaa cat atg gca gag gtt gcc tac caa ttt tac cca 384
Val Val Ser Gly Lys His Met Ala Glu Val Ala Tyr Gln Phe Tyr Pro
115 120 125
aga ctt cct cgc atc att ctc tgg ctt atg atc gag att gca att gtg 432
Arg Leu Pro Arg Ile Ile Leu Trp Leu Met Ile Glu Ile Ala Ile Val
130 135 140
tgt agt gat atg caa gaa gtt att gga aca gca att gcc att ttc ttg 480
Cys Ser Asp Met Gln Glu Val Ile Gly Thr Ala Ile Ala Ile Phe Leu
145 150 155 160
ctc tct aaa gga ttc gtt cca ctc tac gtt gga gtt ttc atc aca att 528
Leu Ser Lys Gly Phe Val Pro Leu Tyr Val Gly Val Phe Ile Thr Ile
165 170 175
ctt gac acc ttc aca ttt ttg ctg atc gac cgg tac gga atc cga aaa 576
Leu Asp Thr Phe Thr Phe Leu Leu Ile Asp Arg Tyr Gly Ile Arg Lys
180 185 190
ctg gaa tta atc ttt gga ttt ctt att tta aca atg aca gtg tca ttt 624
Leu Glu Leu Ile Phe Gly Phe Leu Ile Leu Thr Met Thr Val Ser Phe
195 200 205
ggc tat gag ttt gtc gtt gtg aaa cct cca att ggt gaa gtt ata tct 672
Gly Tyr Glu Phe Val Val Val Lys Pro Pro Ile Gly Glu Val Ile Ser
210 215 220
gga atg gtg gta cct tgg tgc gct gga tgt gga aaa gga gag ttt atg 720
Gly Met Val Val Pro Trp Cys Ala Gly Cys Gly Lys Gly Glu Phe Met
225 230 235 240
caa gcg ata tca gtt gtc gga gct gtc atc atg ccg cac aat ttg tac 768
Gln Ala Ile Ser Val Val Gly Ala Val Ile Met Pro His Asn Leu Tyr
245 250 255
ctt cat tcg gct cta gtg aag tct cgc cgt gta gat cgt aaa gac cgt 816
Leu His Ser Ala Leu Val Lys Ser Arg Arg Val Asp Arg Lys Asp Arg
260 265 270
cgt cgt gtg gct gag gcc aac aaa tat ttc aca ctt gag tcg gca att 864
Arg Arg Val Ala Glu Ala Asn Lys Tyr Phe Thr Leu Glu Ser Ala Ile
275 280 285
gct ctt ttc ctc agc ttc ttc atc aac ctt ttt gtg gtc gcc gtt ttc 912
Ala Leu Phe Leu Ser Phe Phe Ile Asn Leu Phe Val Val Ala Val Phe
290 295 300
gca cat gga ctt tac cag aaa aca aat gcg gat gtt aga gaa atg tgc 960
Ala His Gly Leu Tyr Gln Lys Thr Asn Ala Asp Val Arg Glu Met Cys
305 310 315 320
ata gcc aga cac gac atc ccg gat gca gat ata ttc cca aat aac act 1008
Ile Ala Arg His Asp Ile Pro Asp Ala Asp Ile Phe Pro Asn Asn Thr
325 330 335
gaa cca gtt gag ggt gga att tat ctc gga tgc cag ttt gga gct att 1056
Glu Pro Val Glu Gly Gly Ile Tyr Leu Gly Cys Gln Phe Gly Ala Ile
340 345 350
gca atg ttt atc tgg gga att gga ata ttc gca gct gga cag tca tca 1104
Ala Met Phe Ile Trp Gly Ile Gly Ile Phe Ala Ala Gly Gln Ser Ser
355 360 365
aca atg aca gga aca tat aca gga cag ttt gtg atg gaa gga ttt gtg 1152
Thr Met Thr Gly Thr Tyr Thr Gly Gln Phe Val Met Glu Gly Phe Val
370 375 380
aaa att gag tgg ccc aaa tgg aag aga gtt cta att aca aga gcg att 1200
Lys Ile Glu Trp Pro Lys Trp Lys Arg Val Leu Ile Thr Arg Ala Ile
385 390 395 400
gca atc act cca acc ctc gtg ctc acg ttt tat tcg caa gga gtt caa 1248
Ala Ile Thr Pro Thr Leu Val Leu Thr Phe Tyr Ser Gln Gly Val Gln
405 410 415
aac tta aca gga atg aat gat ttc tta aat tgt gtt caa atg att caa 1296
Asn Leu Thr Gly Met Asn Asp Phe Leu Asn Cys Val Gln Met Ile Gln
420 425 430
ctt ccg ttt gca cta att cca atc atc aca ttt acc tcg agc cga aaa 1344
Leu Pro Phe Ala Leu Ile Pro Ile Ile Thr Phe Thr Ser Ser Arg Lys
435 440 445
ata atg cac gac ttc aga agc tct aaa gtt ttt caa att ttt gct ctg 1392
Ile Met His Asp Phe Arg Ser Ser Lys Val Phe Gln Ile Phe Ala Leu
450 455 460
atc act tct gcg tta att tta tcg att aac gtt tat ttt att tct gac 1440
Ile Thr Ser Ala Leu Ile Leu Ser Ile Asn Val Tyr Phe Ile Ser Asp
465 470 475 480
tac gtg ttt tct cga ctt ggt agt gag tgg tat atc ata atg gtt ctt 1488
Tyr Val Phe Ser Arg Leu Gly Ser Glu Trp Tyr Ile Ile Met Val Leu
485 490 495
gct ccg atc acc ttt gca tac gtg ctc ttt gtg tta tat cta gca cta 1536
Ala Pro Ile Thr Phe Ala Tyr Val Leu Phe Val Leu Tyr Leu Ala Leu
500 505 510
tac tgt ttg gtc tct tgt gaa att atc cca gac acc gtt tcc atc cga 1584
Tyr Cys Leu Val Ser Cys Glu Ile Ile Pro Asp Thr Val Ser Ile Arg
515 520 525
gga ttc agc ttt aac aag tca tac gaa aac gat gct ccg tgg ttg gcg 1632
Gly Phe Ser Phe Asn Lys Ser Tyr Glu Asn Asp Ala Pro Trp Leu Ala
530 535 540
gtt gat tca tca gca gtc cat gac aat gca gga tat caa taa 1674
Val Asp Ser Ser Ala Val His Asp Asn Ala Gly Tyr Gln
545 550 555
<210> 66
<211> 557
<212> PRT
<213> Caenorhabditis elegans
<400> 66
Met Ala Ser Ser Asn Asn Asp Gly Pro Ile Glu Pro Glu Ala Glu Pro
1 5 10 15
Trp Arg Ile Thr Gln Asn Asp His Leu Glu Gln Asp Leu Leu Glu Glu
20 25 30
Asp Ala Glu Ser Gln Glu Arg Val Asp Ile Pro Val Asp Asp Val Glu
35 40 45
Lys Ala Phe Ser Phe Lys Lys Leu Trp Ala Phe Thr Gly Pro Gly Phe
50 55 60
Leu Met Ser Ile Ala Tyr Leu Asp Pro Gly Asn Ile Glu Ser Asp Leu
65 70 75 80
Gln Ser Gly Ala Gln Ala Ala Tyr Lys Leu Leu Trp Val Leu Leu Ser
85 90 95
Ala His Ile Ile Gly Met Leu Leu Gln Arg Met Ser Ala Arg Leu Gly
100 105 110
Val Val Ser Gly Lys His Met Ala Glu Val Ala Tyr Gln Phe Tyr Pro
115 120 125
Arg Leu Pro Arg Ile Ile Leu Trp Leu Met Ile Glu Ile Ala Ile Val
130 135 140
Cys Ser Asp Met Gln Glu Val Ile Gly Thr Ala Ile Ala Ile Phe Leu
145 150 155 160
Leu Ser Lys Gly Phe Val Pro Leu Tyr Val Gly Val Phe Ile Thr Ile
165 170 175
Leu Asp Thr Phe Thr Phe Leu Leu Ile Asp Arg Tyr Gly Ile Arg Lys
180 185 190
Leu Glu Leu Ile Phe Gly Phe Leu Ile Leu Thr Met Thr Val Ser Phe
195 200 205
Gly Tyr Glu Phe Val Val Val Lys Pro Pro Ile Gly Glu Val Ile Ser
210 215 220
Gly Met Val Val Pro Trp Cys Ala Gly Cys Gly Lys Gly Glu Phe Met
225 230 235 240
Gln Ala Ile Ser Val Val Gly Ala Val Ile Met Pro His Asn Leu Tyr
245 250 255
Leu His Ser Ala Leu Val Lys Ser Arg Arg Val Asp Arg Lys Asp Arg
260 265 270
Arg Arg Val Ala Glu Ala Asn Lys Tyr Phe Thr Leu Glu Ser Ala Ile
275 280 285
Ala Leu Phe Leu Ser Phe Phe Ile Asn Leu Phe Val Val Ala Val Phe
290 295 300
Ala His Gly Leu Tyr Gln Lys Thr Asn Ala Asp Val Arg Glu Met Cys
305 310 315 320
Ile Ala Arg His Asp Ile Pro Asp Ala Asp Ile Phe Pro Asn Asn Thr
325 330 335
Glu Pro Val Glu Gly Gly Ile Tyr Leu Gly Cys Gln Phe Gly Ala Ile
340 345 350
Ala Met Phe Ile Trp Gly Ile Gly Ile Phe Ala Ala Gly Gln Ser Ser
355 360 365
Thr Met Thr Gly Thr Tyr Thr Gly Gln Phe Val Met Glu Gly Phe Val
370 375 380
Lys Ile Glu Trp Pro Lys Trp Lys Arg Val Leu Ile Thr Arg Ala Ile
385 390 395 400
Ala Ile Thr Pro Thr Leu Val Leu Thr Phe Tyr Ser Gln Gly Val Gln
405 410 415
Asn Leu Thr Gly Met Asn Asp Phe Leu Asn Cys Val Gln Met Ile Gln
420 425 430
Leu Pro Phe Ala Leu Ile Pro Ile Ile Thr Phe Thr Ser Ser Arg Lys
435 440 445
Ile Met His Asp Phe Arg Ser Ser Lys Val Phe Gln Ile Phe Ala Leu
450 455 460
Ile Thr Ser Ala Leu Ile Leu Ser Ile Asn Val Tyr Phe Ile Ser Asp
465 470 475 480
Tyr Val Phe Ser Arg Leu Gly Ser Glu Trp Tyr Ile Ile Met Val Leu
485 490 495
Ala Pro Ile Thr Phe Ala Tyr Val Leu Phe Val Leu Tyr Leu Ala Leu
500 505 510
Tyr Cys Leu Val Ser Cys Glu Ile Ile Pro Asp Thr Val Ser Ile Arg
515 520 525
Gly Phe Ser Phe Asn Lys Ser Tyr Glu Asn Asp Ala Pro Trp Leu Ala
530 535 540
Val Asp Ser Ser Ala Val His Asp Asn Ala Gly Tyr Gln
545 550 555
<210> 67
<211> 1707
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(1707)
<400> 67
atg gtg ctg ggt cct gaa cag aag atg tca gat gac agt gtt tct gga 48
Met Val Leu Gly Pro Glu Gln Lys Met Ser Asp Asp Ser Val Ser Gly
1 5 10 15
gat cat ggg gag tct gcc agt ctt ggt aac atc aac cct gcc tat agt 96
Asp His Gly Glu Ser Ala Ser Leu Gly Asn Ile Asn Pro Ala Tyr Ser
20 25 30
aat ccc tct ctt tca cag tcc cct ggg gac tca gag gag tac ttc gcc 144
Asn Pro Ser Leu Ser Gln Ser Pro Gly Asp Ser Glu Glu Tyr Phe Ala
35 40 45
act tac ttt aat gag aag atc tcc att cct gag gag gag tac tct tgt 192
Thr Tyr Phe Asn Glu Lys Ile Ser Ile Pro Glu Glu Glu Tyr Ser Cys
50 55 60
ttt agc ttt cgt aaa ctc tgg gct ttc acc gga cca ggt ttt ctt atg 240
Phe Ser Phe Arg Lys Leu Trp Ala Phe Thr Gly Pro Gly Phe Leu Met
65 70 75 80
agc att gcc tac ctg gat cca gga aat att gaa tcc gat ttg cag tct 288
Ser Ile Ala Tyr Leu Asp Pro Gly Asn Ile Glu Ser Asp Leu Gln Ser
85 90 95
gga gca gtg gct gga ttt aag ttg ctc tgg atc ctt ctg ttg gcc acc 336
Gly Ala Val Ala Gly Phe Lys Leu Leu Trp Ile Leu Leu Leu Ala Thr
100 105 110
ctt gtg ggg ctg ctg ctc cag cgg ctt gca gct aga ctg gga gtg gtt 384
Leu Val Gly Leu Leu Leu Gln Arg Leu Ala Ala Arg Leu Gly Val Val
115 120 125
act ggg ctg cat ctt gct gaa gta tgt cac cgt cag tat ccc aag gtc 432
Thr Gly Leu His Leu Ala Glu Val Cys His Arg Gln Tyr Pro Lys Val
130 135 140
cca cga gtc atc ctg tgg ctg atg gtg gag ttg gct atc atc ggc tca 480
Pro Arg Val Ile Leu Trp Leu Met Val Glu Leu Ala Ile Ile Gly Ser
145 150 155 160
gac atg caa gaa gtc att ggc tca gcc att gct atc aat ctt ctg tct 528
Asp Met Gln Glu Val Ile Gly Ser Ala Ile Ala Ile Asn Leu Leu Ser
165 170 175
gta gga aga att cct ctg tgg ggt ggc gtt ctc atc acc att gca gat 576
Val Gly Arg Ile Pro Leu Trp Gly Gly Val Leu Ile Thr Ile Ala Asp
180 185 190
act ttt gta ttt ctc ttc ttg gac aaa tat ggc ttg cgg aag cta gaa 624
Thr Phe Val Phe Leu Phe Leu Asp Lys Tyr Gly Leu Arg Lys Leu Glu
195 200 205
gca ttt ttt ggc ttt ctc atc act att atg gcc ctc aca ttt gga tat 672
Ala Phe Phe Gly Phe Leu Ile Thr Ile Met Ala Leu Thr Phe Gly Tyr
210 215 220
gag tat gtt aca gtg aaa ccc agc cag agc cag gta ctc aag ggc atg 720
Glu Tyr Val Thr Val Lys Pro Ser Gln Ser Gln Val Leu Lys Gly Met
225 230 235 240
ttc gta cca tcc tgt tca ggc tgt cgc act cca cag att gaa cag gct 768
Phe Val Pro Ser Cys Ser Gly Cys Arg Thr Pro Gln Ile Glu Gln Ala
245 250 255
gtg ggc atc gtg gga gct gtc atc atg cca cac aac atg tac ctg cat 816
Val Gly Ile Val Gly Ala Val Ile Met Pro His Asn Met Tyr Leu His
260 265 270
tct gcc tta gtc aag tct aga cag gta aac cgg aac aat aag cag gaa 864
Ser Ala Leu Val Lys Ser Arg Gln Val Asn Arg Asn Asn Lys Gln Glu
275 280 285
gtt cga gaa gcc aat aag tac ttt ttc att gaa tcc tgc att gca ctc 912
Val Arg Glu Ala Asn Lys Tyr Phe Phe Ile Glu Ser Cys Ile Ala Leu
290 295 300
ttt gtt tcc ttc atc atc aat gtc ttt gtt gtc tca gtc ttt gct gaa 960
Phe Val Ser Phe Ile Ile Asn Val Phe Val Val Ser Val Phe Ala Glu
305 310 315 320
gca ttt ttt ggg aaa acc aac gag cag gtg gtt gaa gtc tgt aca aat 1008
Ala Phe Phe Gly Lys Thr Asn Glu Gln Val Val Glu Val Cys Thr Asn
325 330 335
acc agc agt cct cat gct ggc ctc ttt cct aaa gat aac tcg aca ctg 1056
Thr Ser Ser Pro His Ala Gly Leu Phe Pro Lys Asp Asn Ser Thr Leu
340 345 350
gct gtg gac atc tac aaa ggg ggt gtt gtg ctg gga tgt tac ttt ggg 1104
Ala Val Asp Ile Tyr Lys Gly Gly Val Val Leu Gly Cys Tyr Phe Gly
355 360 365
cct gct gca ctc tac att tgg gca gtg ggg atc ctg gct gca gga cag 1152
Pro Ala Ala Leu Tyr Ile Trp Ala Val Gly Ile Leu Ala Ala Gly Gln
370 375 380
agc tcc acc atg aca gga acc tat tct ggc cag ttt gtc atg gag gga 1200
Ser Ser Thr Met Thr Gly Thr Tyr Ser Gly Gln Phe Val Met Glu Gly
385 390 395 400
ttc ctg aac cta aag tgg tca cgc ttt gcc cga gtg gtt ctg act cgc 1248
Phe Leu Asn Leu Lys Trp Ser Arg Phe Ala Arg Val Val Leu Thr Arg
405 410 415
tct att gcc atc atc ccc act ctg ctt gtt gct gtc ttc caa gat gta 1296
Ser Ile Ala Ile Ile Pro Thr Leu Leu Val Ala Val Phe Gln Asp Val
420 425 430
gag cat cta aca ggg atg aat gac ttt ctg aat gtt cta cag agc tta 1344
Glu His Leu Thr Gly Met Asn Asp Phe Leu Asn Val Leu Gln Ser Leu
435 440 445
cag ctt ccc ttt gct ctc ata ccc atc ctc aca ttt acg agc ttg cgg 1392
Gln Leu Pro Phe Ala Leu Ile Pro Ile Leu Thr Phe Thr Ser Leu Arg
450 455 460
cca gta atg agt gac ttt gcc aat gga cta ggc tgg cgg att gca gga 1440
Pro Val Met Ser Asp Phe Ala Asn Gly Leu Gly Trp Arg Ile Ala Gly
465 470 475 480
gga atc ttg gtc ctt atc atc tgt tcc atc aat atg tac ttt gta gtg 1488
Gly Ile Leu Val Leu Ile Ile Cys Ser Ile Asn Met Tyr Phe Val Val
485 490 495
gtt tat gtc cgg gac cta ggg cat gtg gca tta tat gtg gtg gct gct 1536
Val Tyr Val Arg Asp Leu Gly His Val Ala Leu Tyr Val Val Ala Ala
500 505 510
gtg gtc agc gtg gct tat ctg ggc ttt gtg ttc tac ttg ggt tgg caa 1584
Val Val Ser Val Ala Tyr Leu Gly Phe Val Phe Tyr Leu Gly Trp Gln
515 520 525
tgt ttg att gca ctg ggc atg tcc ttc ctg gac tgt ggg cat acg tgc 1632
Cys Leu Ile Ala Leu Gly Met Ser Phe Leu Asp Cys Gly His Thr Cys
530 535 540
cat ctg gga ttg aca gct cag cct gaa ctc tat ctt ctg aac acc atg 1680
His Leu Gly Leu Thr Ala Gln Pro Glu Leu Tyr Leu Leu Asn Thr Met
545 550 555 560
gac gct gac tca ctt gtg tct aga tga 1707
Asp Ala Asp Ser Leu Val Ser Arg
565
<210> 68
<211> 568
<212> PRT
<213> Homo sapiens
<400> 68
Met Val Leu Gly Pro Glu Gln Lys Met Ser Asp Asp Ser Val Ser Gly
1 5 10 15
Asp His Gly Glu Ser Ala Ser Leu Gly Asn Ile Asn Pro Ala Tyr Ser
20 25 30
Asn Pro Ser Leu Ser Gln Ser Pro Gly Asp Ser Glu Glu Tyr Phe Ala
35 40 45
Thr Tyr Phe Asn Glu Lys Ile Ser Ile Pro Glu Glu Glu Tyr Ser Cys
50 55 60
Phe Ser Phe Arg Lys Leu Trp Ala Phe Thr Gly Pro Gly Phe Leu Met
65 70 75 80
Ser Ile Ala Tyr Leu Asp Pro Gly Asn Ile Glu Ser Asp Leu Gln Ser
85 90 95
Gly Ala Val Ala Gly Phe Lys Leu Leu Trp Ile Leu Leu Leu Ala Thr
100 105 110
Leu Val Gly Leu Leu Leu Gln Arg Leu Ala Ala Arg Leu Gly Val Val
115 120 125
Thr Gly Leu His Leu Ala Glu Val Cys His Arg Gln Tyr Pro Lys Val
130 135 140
Pro Arg Val Ile Leu Trp Leu Met Val Glu Leu Ala Ile Ile Gly Ser
145 150 155 160
Asp Met Gln Glu Val Ile Gly Ser Ala Ile Ala Ile Asn Leu Leu Ser
165 170 175
Val Gly Arg Ile Pro Leu Trp Gly Gly Val Leu Ile Thr Ile Ala Asp
180 185 190
Thr Phe Val Phe Leu Phe Leu Asp Lys Tyr Gly Leu Arg Lys Leu Glu
195 200 205
Ala Phe Phe Gly Phe Leu Ile Thr Ile Met Ala Leu Thr Phe Gly Tyr
210 215 220
Glu Tyr Val Thr Val Lys Pro Ser Gln Ser Gln Val Leu Lys Gly Met
225 230 235 240
Phe Val Pro Ser Cys Ser Gly Cys Arg Thr Pro Gln Ile Glu Gln Ala
245 250 255
Val Gly Ile Val Gly Ala Val Ile Met Pro His Asn Met Tyr Leu His
260 265 270
Ser Ala Leu Val Lys Ser Arg Gln Val Asn Arg Asn Asn Lys Gln Glu
275 280 285
Val Arg Glu Ala Asn Lys Tyr Phe Phe Ile Glu Ser Cys Ile Ala Leu
290 295 300
Phe Val Ser Phe Ile Ile Asn Val Phe Val Val Ser Val Phe Ala Glu
305 310 315 320
Ala Phe Phe Gly Lys Thr Asn Glu Gln Val Val Glu Val Cys Thr Asn
325 330 335
Thr Ser Ser Pro His Ala Gly Leu Phe Pro Lys Asp Asn Ser Thr Leu
340 345 350
Ala Val Asp Ile Tyr Lys Gly Gly Val Val Leu Gly Cys Tyr Phe Gly
355 360 365
Pro Ala Ala Leu Tyr Ile Trp Ala Val Gly Ile Leu Ala Ala Gly Gln
370 375 380
Ser Ser Thr Met Thr Gly Thr Tyr Ser Gly Gln Phe Val Met Glu Gly
385 390 395 400
Phe Leu Asn Leu Lys Trp Ser Arg Phe Ala Arg Val Val Leu Thr Arg
405 410 415
Ser Ile Ala Ile Ile Pro Thr Leu Leu Val Ala Val Phe Gln Asp Val
420 425 430
Glu His Leu Thr Gly Met Asn Asp Phe Leu Asn Val Leu Gln Ser Leu
435 440 445
Gln Leu Pro Phe Ala Leu Ile Pro Ile Leu Thr Phe Thr Ser Leu Arg
450 455 460
Pro Val Met Ser Asp Phe Ala Asn Gly Leu Gly Trp Arg Ile Ala Gly
465 470 475 480
Gly Ile Leu Val Leu Ile Ile Cys Ser Ile Asn Met Tyr Phe Val Val
485 490 495
Val Tyr Val Arg Asp Leu Gly His Val Ala Leu Tyr Val Val Ala Ala
500 505 510
Val Val Ser Val Ala Tyr Leu Gly Phe Val Phe Tyr Leu Gly Trp Gln
515 520 525
Cys Leu Ile Ala Leu Gly Met Ser Phe Leu Asp Cys Gly His Thr Cys
530 535 540
His Leu Gly Leu Thr Ala Gln Pro Glu Leu Tyr Leu Leu Asn Thr Met
545 550 555 560
Asp Ala Asp Ser Leu Val Ser Arg
565
<210> 69
<211> 1521
<212> DNA
<213> Drosophila sp.
<220>
<221> CDS
<222> (1)..(1521)
<400> 69
atg gtg gtg cgt ccg tac aac gat gag ctc cgg tac ctg gag aaa gtg 48
Met Val Val Arg Pro Tyr Asn Asp Glu Leu Arg Tyr Leu Glu Lys Val
1 5 10 15
agc gac cac tgc tgg cgc atc aag aag ggc ttc cag cca aat atg aat 96
Ser Asp His Cys Trp Arg Ile Lys Lys Gly Phe Gln Pro Asn Met Asn
20 25 30
gtg gag ggg tgt ttc tat gtg aac agc cgg ctg gag cgc ctg atg ctg 144
Val Glu Gly Cys Phe Tyr Val Asn Ser Arg Leu Glu Arg Leu Met Leu
35 40 45
gag gag ctg aag aac tcc tgt cgc ccg ggc gca gtg ggt ggc ttc ctg 192
Glu Glu Leu Lys Asn Ser Cys Arg Pro Gly Ala Val Gly Gly Phe Leu
50 55 60
cct ggc gtc aag cag ata gcc aat gtg gcc gcg ttg ccg ggc atc gtg 240
Pro Gly Val Lys Gln Ile Ala Asn Val Ala Ala Leu Pro Gly Ile Val
65 70 75 80
ggc agg tcc att gga ctg ccc gac att cat tcc ggc tac gga ttt gcc 288
Gly Arg Ser Ile Gly Leu Pro Asp Ile His Ser Gly Tyr Gly Phe Ala
85 90 95
atc ggg aac atg gct gct ttc gac atg aac gat ccg ctg tcc gtt gta 336
Ile Gly Asn Met Ala Ala Phe Asp Met Asn Asp Pro Leu Ser Val Val
100 105 110
agt ccc ggc ggc gtg ggt ttc gac atc aac tgt ggc gtg cgt ctg ctg 384
Ser Pro Gly Gly Val Gly Phe Asp Ile Asn Cys Gly Val Arg Leu Leu
115 120 125
cgc acg aat ctg tac gag aag gat gtg cag ccg gtg aag gag caa ctg 432
Arg Thr Asn Leu Tyr Glu Lys Asp Val Gln Pro Val Lys Glu Gln Leu
130 135 140
gcg cag tcc ctg ttc gat cac ata ccc gtg ggt gtg ggc tcc aag ggc 480
Ala Gln Ser Leu Phe Asp His Ile Pro Val Gly Val Gly Ser Lys Gly
145 150 155 160
atc ata ccc atg aat gcc cgc gat ctg gag gag gcc ctc gaa atg ggc 528
Ile Ile Pro Met Asn Ala Arg Asp Leu Glu Glu Ala Leu Glu Met Gly
165 170 175
atg gac tgg tcg ctg cgc gag gga tac gtg tgg gcg gag gac aag gag 576
Met Asp Trp Ser Leu Arg Glu Gly Tyr Val Trp Ala Glu Asp Lys Glu
180 185 190
cat tgc gag gag tac ggc cgc atg ctg aac gcc gat ccc gcc aag gtg 624
His Cys Glu Glu Tyr Gly Arg Met Leu Asn Ala Asp Pro Ala Lys Val
195 200 205
agc atg cgg gcc aag aag cga ggg ctg ccc cag ctg ggc act ctg ggt 672
Ser Met Arg Ala Lys Lys Arg Gly Leu Pro Gln Leu Gly Thr Leu Gly
210 215 220
gcg ggc aat cac tac gcc gag atc cag gtg gtg gac gaa atc tac gac 720
Ala Gly Asn His Tyr Ala Glu Ile Gln Val Val Asp Glu Ile Tyr Asp
225 230 235 240
aag tgg agc gcc tcc aag atg ggc atc gag gag aag ggc cag gtg gtg 768
Lys Trp Ser Ala Ser Lys Met Gly Ile Glu Glu Lys Gly Gln Val Val
245 250 255
gtg atg att cac tcg ggc agt cgt ggc ttc ggc cac cag gtc gct acc 816
Val Met Ile His Ser Gly Ser Arg Gly Phe Gly His Gln Val Ala Thr
260 265 270
gac gcc ctg gtc cag atg gag aag gcc atg aag cgg gac aag atc gag 864
Asp Ala Leu Val Gln Met Glu Lys Ala Met Lys Arg Asp Lys Ile Glu
275 280 285
acc aat gac cgg cag ctg gcc tgc gcc agg atc aat tcg gtg gag gga 912
Thr Asn Asp Arg Gln Leu Ala Cys Ala Arg Ile Asn Ser Val Glu Gly
290 295 300
cag gac tac ttg aag gcc atg gcg gcg gct gcg aac ttt gcc tgg gtg 960
Gln Asp Tyr Leu Lys Ala Met Ala Ala Ala Ala Asn Phe Ala Trp Val
305 310 315 320
aat cgc agc tcc atg aca ttc ctc acc cgt caa gcg ttt gcc aag atg 1008
Asn Arg Ser Ser Met Thr Phe Leu Thr Arg Gln Ala Phe Ala Lys Met
325 330 335
ttt aac acc aca ccc gat gat ctc gac atg cac gtt atc tat gac gtt 1056
Phe Asn Thr Thr Pro Asp Asp Leu Asp Met His Val Ile Tyr Asp Val
340 345 350
tcg cac aat att gcc aag gtg gag aac cac atg gtg gac ggc aag gag 1104
Ser His Asn Ile Ala Lys Val Glu Asn His Met Val Asp Gly Lys Glu
355 360 365
cgg aag ctg ttg gtt cac cgg aag ggc tcc acg cgc gcc ttc ccg cca 1152
Arg Lys Leu Leu Val His Arg Lys Gly Ser Thr Arg Ala Phe Pro Pro
370 375 380
cac cat ccc ctg atc cca gtg gac tat cag ctt acc ggg cag cca gtc 1200
His His Pro Leu Ile Pro Val Asp Tyr Gln Leu Thr Gly Gln Pro Val
385 390 395 400
ctc gtc ggt gga acc atg ggc act tgc agt tac gtg cta act gga acg 1248
Leu Val Gly Gly Thr Met Gly Thr Cys Ser Tyr Val Leu Thr Gly Thr
405 410 415
gag cag ggc atg cag gag acg ttc ggt agc act tgc cac gga gcg ggt 1296
Glu Gln Gly Met Gln Glu Thr Phe Gly Ser Thr Cys His Gly Ala Gly
420 425 430
cgt gca cta tct cga gcc aaa tcc cgg cgc aat ctg gac tac aag gat 1344
Arg Ala Leu Ser Arg Ala Lys Ser Arg Arg Asn Leu Asp Tyr Lys Asp
435 440 445
gtg ctg gac aag ctg gac cag ttg ggc atc gcc ata cgc gtg gcc tcg 1392
Val Leu Asp Lys Leu Asp Gln Leu Gly Ile Ala Ile Arg Val Ala Ser
450 455 460
ccc aaa ctg gtc atg gag gag gca ccc gaa tct tac aag gac gtg acc 1440
Pro Lys Leu Val Met Glu Glu Ala Pro Glu Ser Tyr Lys Asp Val Thr
465 470 475 480
gat gtg gtc gac acc tgt cac gca gct ggc atc agc aaa aag tgc atc 1488
Asp Val Val Asp Thr Cys His Ala Ala Gly Ile Ser Lys Lys Cys Ile
485 490 495
aag atg cgc cca att gca gtt atc aag ggc taa 1521
Lys Met Arg Pro Ile Ala Val Ile Lys Gly
500 505
<210> 70
<211> 506
<212> PRT
<213> Drosophila sp.
<400> 70
Met Val Val Arg Pro Tyr Asn Asp Glu Leu Arg Tyr Leu Glu Lys Val
1 5 10 15
Ser Asp His Cys Trp Arg Ile Lys Lys Gly Phe Gln Pro Asn Met Asn
20 25 30
Val Glu Gly Cys Phe Tyr Val Asn Ser Arg Leu Glu Arg Leu Met Leu
35 40 45
Glu Glu Leu Lys Asn Ser Cys Arg Pro Gly Ala Val Gly Gly Phe Leu
50 55 60
Pro Gly Val Lys Gln Ile Ala Asn Val Ala Ala Leu Pro Gly Ile Val
65 70 75 80
Gly Arg Ser Ile Gly Leu Pro Asp Ile His Ser Gly Tyr Gly Phe Ala
85 90 95
Ile Gly Asn Met Ala Ala Phe Asp Met Asn Asp Pro Leu Ser Val Val
100 105 110
Ser Pro Gly Gly Val Gly Phe Asp Ile Asn Cys Gly Val Arg Leu Leu
115 120 125
Arg Thr Asn Leu Tyr Glu Lys Asp Val Gln Pro Val Lys Glu Gln Leu
130 135 140
Ala Gln Ser Leu Phe Asp His Ile Pro Val Gly Val Gly Ser Lys Gly
145 150 155 160
Ile Ile Pro Met Asn Ala Arg Asp Leu Glu Glu Ala Leu Glu Met Gly
165 170 175
Met Asp Trp Ser Leu Arg Glu Gly Tyr Val Trp Ala Glu Asp Lys Glu
180 185 190
His Cys Glu Glu Tyr Gly Arg Met Leu Asn Ala Asp Pro Ala Lys Val
195 200 205
Ser Met Arg Ala Lys Lys Arg Gly Leu Pro Gln Leu Gly Thr Leu Gly
210 215 220
Ala Gly Asn His Tyr Ala Glu Ile Gln Val Val Asp Glu Ile Tyr Asp
225 230 235 240
Lys Trp Ser Ala Ser Lys Met Gly Ile Glu Glu Lys Gly Gln Val Val
245 250 255
Val Met Ile His Ser Gly Ser Arg Gly Phe Gly His Gln Val Ala Thr
260 265 270
Asp Ala Leu Val Gln Met Glu Lys Ala Met Lys Arg Asp Lys Ile Glu
275 280 285
Thr Asn Asp Arg Gln Leu Ala Cys Ala Arg Ile Asn Ser Val Glu Gly
290 295 300
Gln Asp Tyr Leu Lys Ala Met Ala Ala Ala Ala Asn Phe Ala Trp Val
305 310 315 320
Asn Arg Ser Ser Met Thr Phe Leu Thr Arg Gln Ala Phe Ala Lys Met
325 330 335
Phe Asn Thr Thr Pro Asp Asp Leu Asp Met His Val Ile Tyr Asp Val
340 345 350
Ser His Asn Ile Ala Lys Val Glu Asn His Met Val Asp Gly Lys Glu
355 360 365
Arg Lys Leu Leu Val His Arg Lys Gly Ser Thr Arg Ala Phe Pro Pro
370 375 380
His His Pro Leu Ile Pro Val Asp Tyr Gln Leu Thr Gly Gln Pro Val
385 390 395 400
Leu Val Gly Gly Thr Met Gly Thr Cys Ser Tyr Val Leu Thr Gly Thr
405 410 415
Glu Gln Gly Met Gln Glu Thr Phe Gly Ser Thr Cys His Gly Ala Gly
420 425 430
Arg Ala Leu Ser Arg Ala Lys Ser Arg Arg Asn Leu Asp Tyr Lys Asp
435 440 445
Val Leu Asp Lys Leu Asp Gln Leu Gly Ile Ala Ile Arg Val Ala Ser
450 455 460
Pro Lys Leu Val Met Glu Glu Ala Pro Glu Ser Tyr Lys Asp Val Thr
465 470 475 480
Asp Val Val Asp Thr Cys His Ala Ala Gly Ile Ser Lys Lys Cys Ile
485 490 495
Lys Met Arg Pro Ile Ala Val Ile Lys Gly
500 505
<210> 71
<211> 1518
<212> DNA
<213> Danio sp.
<220>
<221> CDS
<222> (1)..(1518)
<400> 71
atg agt cgc tct tac aac gat gag ctc cag tat ctg gat aaa ata cac 48
Met Ser Arg Ser Tyr Asn Asp Glu Leu Gln Tyr Leu Asp Lys Ile His
1 5 10 15
aaa aac tgc tgg cgg atc aag aag ggt ttc gtg ccg aat atg ctg gtg 96
Lys Asn Cys Trp Arg Ile Lys Lys Gly Phe Val Pro Asn Met Leu Val
20 25 30
gaa gga gtg ttt tat gtc aat gac ccg ctg gaa aag ctg atg ttc gag 144
Glu Gly Val Phe Tyr Val Asn Asp Pro Leu Glu Lys Leu Met Phe Glu
35 40 45
gag ctg aga aac gcc tgt cgc gga gga ggg ttt gga ggt ttc tta cct 192
Glu Leu Arg Asn Ala Cys Arg Gly Gly Gly Phe Gly Gly Phe Leu Pro
50 55 60
gcg atg aag cag att ggg aat gtg gcc gct ctg cca gga atc gtg cac 240
Ala Met Lys Gln Ile Gly Asn Val Ala Ala Leu Pro Gly Ile Val His
65 70 75 80
cgg tcg atc ggt tta ccg gac gtt cac tca gga tac gga ttc gct atc 288
Arg Ser Ile Gly Leu Pro Asp Val His Ser Gly Tyr Gly Phe Ala Ile
85 90 95
ggg aac atg gca gcg ttc gac atg gag aat ccg gac gca gtc gtc tct 336
Gly Asn Met Ala Ala Phe Asp Met Glu Asn Pro Asp Ala Val Val Ser
100 105 110
cca ggc ggt gtg ggt ttc gat att aac tgt ggt gtt cgt ctg ctg cgc 384
Pro Gly Gly Val Gly Phe Asp Ile Asn Cys Gly Val Arg Leu Leu Arg
115 120 125
aca aac ctg gat gag ggc gac gtt cag ccg gtg aag gag cag ctg gca 432
Thr Asn Leu Asp Glu Gly Asp Val Gln Pro Val Lys Glu Gln Leu Ala
130 135 140
cag tct ctc ttc gac cac atc cct gtc gga gtc ggc tcc aag ggc gtc 480
Gln Ser Leu Phe Asp His Ile Pro Val Gly Val Gly Ser Lys Gly Val
145 150 155 160
att cct atg ggt gca aag gac ctg gag gag gcg ttg gag atg ggt gtg 528
Ile Pro Met Gly Ala Lys Asp Leu Glu Glu Ala Leu Glu Met Gly Val
165 170 175
gac tgg tct ctg agg gag gga tat gcc tgg gcg gag gat aaa gag cac 576
Asp Trp Ser Leu Arg Glu Gly Tyr Ala Trp Ala Glu Asp Lys Glu His
180 185 190
tgt gag gag tac gga cgc atg ctg cag gcc gac cca aac aaa gtc tcc 624
Cys Glu Glu Tyr Gly Arg Met Leu Gln Ala Asp Pro Asn Lys Val Ser
195 200 205
tcc aaa gcc aag aag aga gga ctg cca cag ttg gga act ctg ggt gca 672
Ser Lys Ala Lys Lys Arg Gly Leu Pro Gln Leu Gly Thr Leu Gly Ala
210 215 220
gga aac cac tac gca gag att cag gtg gtg gac gag atc tac aat gat 720
Gly Asn His Tyr Ala Glu Ile Gln Val Val Asp Glu Ile Tyr Asn Asp
225 230 235 240
tac gcc gcc aag aag atg ggc atc gat cat aaa ggg cag gtg tgt gtg 768
Tyr Ala Ala Lys Lys Met Gly Ile Asp His Lys Gly Gln Val Cys Val
245 250 255
atg atc cac agc ggc agc cga gga ctc gga cat cag gtg gcc acc gac 816
Met Ile His Ser Gly Ser Arg Gly Leu Gly His Gln Val Ala Thr Asp
260 265 270
gct ctg gtg gcg atg gag aag gcc atg aag cgc gac cgc atc aca gta 864
Ala Leu Val Ala Met Glu Lys Ala Met Lys Arg Asp Arg Ile Thr Val
275 280 285
aac gac cgg cag cta gcg tgc gcg cgc atc acg tca gaa gag gga cag 912
Asn Asp Arg Gln Leu Ala Cys Ala Arg Ile Thr Ser Glu Glu Gly Gln
290 295 300
gat tat ctg aag gga atg gcg gca gca gga aac tac gcc tgg gtc aac 960
Asp Tyr Leu Lys Gly Met Ala Ala Ala Gly Asn Tyr Ala Trp Val Asn
305 310 315 320
cga tcc tcc atg acc ttc ctc aca cga cag gcg ttc tcc aaa gtg ttc 1008
Arg Ser Ser Met Thr Phe Leu Thr Arg Gln Ala Phe Ser Lys Val Phe
325 330 335
agc acc aca cca gat gat ctg gac atg cac gtg atc tac gac gtc tcg 1056
Ser Thr Thr Pro Asp Asp Leu Asp Met His Val Ile Tyr Asp Val Ser
340 345 350
cac aac atc gcc aaa gtg gag gag cac atg gtg gac ggc cgg cag aaa 1104
His Asn Ile Ala Lys Val Glu Glu His Met Val Asp Gly Arg Gln Lys
355 360 365
aca ctg ctg gtg cat agg aag ggc tcc acc aga gcg ttt cct cca cac 1152
Thr Leu Leu Val His Arg Lys Gly Ser Thr Arg Ala Phe Pro Pro His
370 375 380
cat cca ctc ata cct gta gac tat cag ctg acc ggt cag cca gtc ctg 1200
His Pro Leu Ile Pro Val Asp Tyr Gln Leu Thr Gly Gln Pro Val Leu
385 390 395 400
att gga gga acc atg ggc acc tgc agt tac gtg ctc aca ggc aca gag 1248
Ile Gly Gly Thr Met Gly Thr Cys Ser Tyr Val Leu Thr Gly Thr Glu
405 410 415
cag ggc atg aca gag acg ttc ggc acc aca tgt cac ggc gct ggc cga 1296
Gln Gly Met Thr Glu Thr Phe Gly Thr Thr Cys His Gly Ala Gly Arg
420 425 430
gct tta tcc aga gcc aaa tcc aga cgc aac ctg gac ttc cag gat gtt 1344
Ala Leu Ser Arg Ala Lys Ser Arg Arg Asn Leu Asp Phe Gln Asp Val
435 440 445
ctg gat aaa ctg gca gac atg ggc atc gct att aga gtg gcg tca ccg 1392
Leu Asp Lys Leu Ala Asp Met Gly Ile Ala Ile Arg Val Ala Ser Pro
450 455 460
aag ctg gtg atg gag gag gct ccc gag tcc tac aag aac gtg aca gac 1440
Lys Leu Val Met Glu Glu Ala Pro Glu Ser Tyr Lys Asn Val Thr Asp
465 470 475 480
gtg gtg aac aca tgc cat gat gcc ggc atc agc aaa aaa gcc atc aaa 1488
Val Val Asn Thr Cys His Asp Ala Gly Ile Ser Lys Lys Ala Ile Lys
485 490 495
ctc aga ccc atc gct gtg att aaa ggt taa 1518
Leu Arg Pro Ile Ala Val Ile Lys Gly
500 505
<210> 72
<211> 505
<212> PRT
<213> Danio sp.
<400> 72
Met Ser Arg Ser Tyr Asn Asp Glu Leu Gln Tyr Leu Asp Lys Ile His
1 5 10 15
Lys Asn Cys Trp Arg Ile Lys Lys Gly Phe Val Pro Asn Met Leu Val
20 25 30
Glu Gly Val Phe Tyr Val Asn Asp Pro Leu Glu Lys Leu Met Phe Glu
35 40 45
Glu Leu Arg Asn Ala Cys Arg Gly Gly Gly Phe Gly Gly Phe Leu Pro
50 55 60
Ala Met Lys Gln Ile Gly Asn Val Ala Ala Leu Pro Gly Ile Val His
65 70 75 80
Arg Ser Ile Gly Leu Pro Asp Val His Ser Gly Tyr Gly Phe Ala Ile
85 90 95
Gly Asn Met Ala Ala Phe Asp Met Glu Asn Pro Asp Ala Val Val Ser
100 105 110
Pro Gly Gly Val Gly Phe Asp Ile Asn Cys Gly Val Arg Leu Leu Arg
115 120 125
Thr Asn Leu Asp Glu Gly Asp Val Gln Pro Val Lys Glu Gln Leu Ala
130 135 140
Gln Ser Leu Phe Asp His Ile Pro Val Gly Val Gly Ser Lys Gly Val
145 150 155 160
Ile Pro Met Gly Ala Lys Asp Leu Glu Glu Ala Leu Glu Met Gly Val
165 170 175
Asp Trp Ser Leu Arg Glu Gly Tyr Ala Trp Ala Glu Asp Lys Glu His
180 185 190
Cys Glu Glu Tyr Gly Arg Met Leu Gln Ala Asp Pro Asn Lys Val Ser
195 200 205
Ser Lys Ala Lys Lys Arg Gly Leu Pro Gln Leu Gly Thr Leu Gly Ala
210 215 220
Gly Asn His Tyr Ala Glu Ile Gln Val Val Asp Glu Ile Tyr Asn Asp
225 230 235 240
Tyr Ala Ala Lys Lys Met Gly Ile Asp His Lys Gly Gln Val Cys Val
245 250 255
Met Ile His Ser Gly Ser Arg Gly Leu Gly His Gln Val Ala Thr Asp
260 265 270
Ala Leu Val Ala Met Glu Lys Ala Met Lys Arg Asp Arg Ile Thr Val
275 280 285
Asn Asp Arg Gln Leu Ala Cys Ala Arg Ile Thr Ser Glu Glu Gly Gln
290 295 300
Asp Tyr Leu Lys Gly Met Ala Ala Ala Gly Asn Tyr Ala Trp Val Asn
305 310 315 320
Arg Ser Ser Met Thr Phe Leu Thr Arg Gln Ala Phe Ser Lys Val Phe
325 330 335
Ser Thr Thr Pro Asp Asp Leu Asp Met His Val Ile Tyr Asp Val Ser
340 345 350
His Asn Ile Ala Lys Val Glu Glu His Met Val Asp Gly Arg Gln Lys
355 360 365
Thr Leu Leu Val His Arg Lys Gly Ser Thr Arg Ala Phe Pro Pro His
370 375 380
His Pro Leu Ile Pro Val Asp Tyr Gln Leu Thr Gly Gln Pro Val Leu
385 390 395 400
Ile Gly Gly Thr Met Gly Thr Cys Ser Tyr Val Leu Thr Gly Thr Glu
405 410 415
Gln Gly Met Thr Glu Thr Phe Gly Thr Thr Cys His Gly Ala Gly Arg
420 425 430
Ala Leu Ser Arg Ala Lys Ser Arg Arg Asn Leu Asp Phe Gln Asp Val
435 440 445
Leu Asp Lys Leu Ala Asp Met Gly Ile Ala Ile Arg Val Ala Ser Pro
450 455 460
Lys Leu Val Met Glu Glu Ala Pro Glu Ser Tyr Lys Asn Val Thr Asp
465 470 475 480
Val Val Asn Thr Cys His Asp Ala Gly Ile Ser Lys Lys Ala Ile Lys
485 490 495
Leu Arg Pro Ile Ala Val Ile Lys Gly
500 505
<210> 73
<211> 1518
<212> DNA
<213> Bos sp.
<220>
<221> CDS
<222> (1)..(1518)
<400> 73
atg agt cgc agt tat aat gat gag ctg cag ttc ttg gaa aag atc agt 48
Met Ser Arg Ser Tyr Asn Asp Glu Leu Gln Phe Leu Glu Lys Ile Ser
1 5 10 15
aag aac tgc tgg aga atc aag aag ggc ttc gtg ccc aac atg cag gtt 96
Lys Asn Cys Trp Arg Ile Lys Lys Gly Phe Val Pro Asn Met Gln Val
20 25 30
gaa gga gtt ttc tat gtg aat gat tct ctg gaa aaa tta atg ttt gaa 144
Glu Gly Val Phe Tyr Val Asn Asp Ser Leu Glu Lys Leu Met Phe Glu
35 40 45
gaa tta agg aat gcc tgt cga ggt ggt ggt gtt ggt ggc ttc ctg cca 192
Glu Leu Arg Asn Ala Cys Arg Gly Gly Gly Val Gly Gly Phe Leu Pro
50 55 60
gcc atg aaa caa att ggc aat gtg gcc gcc ctg cct ggg att gtt cat 240
Ala Met Lys Gln Ile Gly Asn Val Ala Ala Leu Pro Gly Ile Val His
65 70 75 80
cga tcc atc ggt ctt cct gat gtc cat tca ggt tat ggg ttt gct att 288
Arg Ser Ile Gly Leu Pro Asp Val His Ser Gly Tyr Gly Phe Ala Ile
85 90 95
gga aat atg gca gcc ttt gat atg aac gac cct gaa gca gtg gta tcc 336
Gly Asn Met Ala Ala Phe Asp Met Asn Asp Pro Glu Ala Val Val Ser
100 105 110
cca ggt ggt gtt ggg ttt gac att aac tgt ggt gtc cgc ttg ctg aga 384
Pro Gly Gly Val Gly Phe Asp Ile Asn Cys Gly Val Arg Leu Leu Arg
115 120 125
acc aat tta gat gaa agt gat gtt cag cct gtg aaa gag caa ctt gcc 432
Thr Asn Leu Asp Glu Ser Asp Val Gln Pro Val Lys Glu Gln Leu Ala
130 135 140
caa gct atg ttt gac cac att cct gtg gga gtg ggg tca aaa ggt gtc 480
Gln Ala Met Phe Asp His Ile Pro Val Gly Val Gly Ser Lys Gly Val
145 150 155 160
atc cca atg aat gcc aaa gac ttg gag gag gcc ttg gag atg ggt gtg 528
Ile Pro Met Asn Ala Lys Asp Leu Glu Glu Ala Leu Glu Met Gly Val
165 170 175
gac tgg tcc ctg aga gaa ggc tat gcc tgg gca gag gac aag gag cac 576
Asp Trp Ser Leu Arg Glu Gly Tyr Ala Trp Ala Glu Asp Lys Glu His
180 185 190
tgt gag gag tat gga agg atg ctg caa gct gat ccc aat aaa gtc tca 624
Cys Glu Glu Tyr Gly Arg Met Leu Gln Ala Asp Pro Asn Lys Val Ser
195 200 205
gcc agg gct aaa aaa aga ggc ctt ccc cag ttg ggg act ctg gga gca 672
Ala Arg Ala Lys Lys Arg Gly Leu Pro Gln Leu Gly Thr Leu Gly Ala
210 215 220
ggc aac cac tat gca gaa atc cag gtt gtg gat gag att ttc aac gag 720
Gly Asn His Tyr Ala Glu Ile Gln Val Val Asp Glu Ile Phe Asn Glu
225 230 235 240
tat gct gct aag aaa atg ggc att gac cat aag gga cag gtg tgt gtg 768
Tyr Ala Ala Lys Lys Met Gly Ile Asp His Lys Gly Gln Val Cys Val
245 250 255
atg atc cac agt gga agc aga ggc ttg ggc cac caa gtt gcc aca gat 816
Met Ile His Ser Gly Ser Arg Gly Leu Gly His Gln Val Ala Thr Asp
260 265 270
gca ctt gta gct atg gaa aaa gcc atg aag aga gac aag att ata gtc 864
Ala Leu Val Ala Met Glu Lys Ala Met Lys Arg Asp Lys Ile Ile Val
275 280 285
aat gac cgt cag ttg gct tgt gct cga att gct tcc cca gag ggt cag 912
Asn Asp Arg Gln Leu Ala Cys Ala Arg Ile Ala Ser Pro Glu Gly Gln
290 295 300
gac tac ctg aag gga atg gca gcg gct ggg aac tat gcc tgg gtc aac 960
Asp Tyr Leu Lys Gly Met Ala Ala Ala Gly Asn Tyr Ala Trp Val Asn
305 310 315 320
cgc tct tcc atg acc ttc tta acc cgt cag gct ttt gcc aag gtc ttc 1008
Arg Ser Ser Met Thr Phe Leu Thr Arg Gln Ala Phe Ala Lys Val Phe
325 330 335
aac aca acc cct gat gac ttg gac ctg cat gtg atc tat gat gtt tct 1056
Asn Thr Thr Pro Asp Asp Leu Asp Leu His Val Ile Tyr Asp Val Ser
340 345 350
cac aat att gcc aaa gta gaa cag cat gtg gtg gac ggg aag gag cgg 1104
His Asn Ile Ala Lys Val Glu Gln His Val Val Asp Gly Lys Glu Arg
355 360 365
act ctg tta gta cac agg aag ggg tcc acc cga gcc ttc cct cct cac 1152
Thr Leu Leu Val His Arg Lys Gly Ser Thr Arg Ala Phe Pro Pro His
370 375 380
cat ccc ctc att gcg gtt gat tac caa ctt acc gga caa cca gtg ctc 1200
His Pro Leu Ile Ala Val Asp Tyr Gln Leu Thr Gly Gln Pro Val Leu
385 390 395 400
att ggt ggc acc atg gga acc tgt agc tat gtt ctt act ggt act gag 1248
Ile Gly Gly Thr Met Gly Thr Cys Ser Tyr Val Leu Thr Gly Thr Glu
405 410 415
cag ggc atg act gaa acc ttt gga aca act tgt cat gga gcg ggc cgt 1296
Gln Gly Met Thr Glu Thr Phe Gly Thr Thr Cys His Gly Ala Gly Arg
420 425 430
gca ctg tcc cga gca aag tca aga cgt aat tta gat ttc cag gat gtc 1344
Ala Leu Ser Arg Ala Lys Ser Arg Arg Asn Leu Asp Phe Gln Asp Val
435 440 445
ctc gac aaa ttg gca gac atg gga att gca atc cgt gtc gcc tca ccc 1392
Leu Asp Lys Leu Ala Asp Met Gly Ile Ala Ile Arg Val Ala Ser Pro
450 455 460
aag ctg gta atg gaa gag gcc cct gag tcc tat aag aac gtg acg gat 1440
Lys Leu Val Met Glu Glu Ala Pro Glu Ser Tyr Lys Asn Val Thr Asp
465 470 475 480
gtg gtg aac acc tgc cat gat gcc gga atc agc aag aag gcc att aaa 1488
Val Val Asn Thr Cys His Asp Ala Gly Ile Ser Lys Lys Ala Ile Lys
485 490 495
ctg agg cca att gct gtt atc aaa gga tag 1518
Leu Arg Pro Ile Ala Val Ile Lys Gly
500 505
<210> 74
<211> 505
<212> PRT
<213> Bos sp.
<400> 74
Met Ser Arg Ser Tyr Asn Asp Glu Leu Gln Phe Leu Glu Lys Ile Ser
1 5 10 15
Lys Asn Cys Trp Arg Ile Lys Lys Gly Phe Val Pro Asn Met Gln Val
20 25 30
Glu Gly Val Phe Tyr Val Asn Asp Ser Leu Glu Lys Leu Met Phe Glu
35 40 45
Glu Leu Arg Asn Ala Cys Arg Gly Gly Gly Val Gly Gly Phe Leu Pro
50 55 60
Ala Met Lys Gln Ile Gly Asn Val Ala Ala Leu Pro Gly Ile Val His
65 70 75 80
Arg Ser Ile Gly Leu Pro Asp Val His Ser Gly Tyr Gly Phe Ala Ile
85 90 95
Gly Asn Met Ala Ala Phe Asp Met Asn Asp Pro Glu Ala Val Val Ser
100 105 110
Pro Gly Gly Val Gly Phe Asp Ile Asn Cys Gly Val Arg Leu Leu Arg
115 120 125
Thr Asn Leu Asp Glu Ser Asp Val Gln Pro Val Lys Glu Gln Leu Ala
130 135 140
Gln Ala Met Phe Asp His Ile Pro Val Gly Val Gly Ser Lys Gly Val
145 150 155 160
Ile Pro Met Asn Ala Lys Asp Leu Glu Glu Ala Leu Glu Met Gly Val
165 170 175
Asp Trp Ser Leu Arg Glu Gly Tyr Ala Trp Ala Glu Asp Lys Glu His
180 185 190
Cys Glu Glu Tyr Gly Arg Met Leu Gln Ala Asp Pro Asn Lys Val Ser
195 200 205
Ala Arg Ala Lys Lys Arg Gly Leu Pro Gln Leu Gly Thr Leu Gly Ala
210 215 220
Gly Asn His Tyr Ala Glu Ile Gln Val Val Asp Glu Ile Phe Asn Glu
225 230 235 240
Tyr Ala Ala Lys Lys Met Gly Ile Asp His Lys Gly Gln Val Cys Val
245 250 255
Met Ile His Ser Gly Ser Arg Gly Leu Gly His Gln Val Ala Thr Asp
260 265 270
Ala Leu Val Ala Met Glu Lys Ala Met Lys Arg Asp Lys Ile Ile Val
275 280 285
Asn Asp Arg Gln Leu Ala Cys Ala Arg Ile Ala Ser Pro Glu Gly Gln
290 295 300
Asp Tyr Leu Lys Gly Met Ala Ala Ala Gly Asn Tyr Ala Trp Val Asn
305 310 315 320
Arg Ser Ser Met Thr Phe Leu Thr Arg Gln Ala Phe Ala Lys Val Phe
325 330 335
Asn Thr Thr Pro Asp Asp Leu Asp Leu His Val Ile Tyr Asp Val Ser
340 345 350
His Asn Ile Ala Lys Val Glu Gln His Val Val Asp Gly Lys Glu Arg
355 360 365
Thr Leu Leu Val His Arg Lys Gly Ser Thr Arg Ala Phe Pro Pro His
370 375 380
His Pro Leu Ile Ala Val Asp Tyr Gln Leu Thr Gly Gln Pro Val Leu
385 390 395 400
Ile Gly Gly Thr Met Gly Thr Cys Ser Tyr Val Leu Thr Gly Thr Glu
405 410 415
Gln Gly Met Thr Glu Thr Phe Gly Thr Thr Cys His Gly Ala Gly Arg
420 425 430
Ala Leu Ser Arg Ala Lys Ser Arg Arg Asn Leu Asp Phe Gln Asp Val
435 440 445
Leu Asp Lys Leu Ala Asp Met Gly Ile Ala Ile Arg Val Ala Ser Pro
450 455 460
Lys Leu Val Met Glu Glu Ala Pro Glu Ser Tyr Lys Asn Val Thr Asp
465 470 475 480
Val Val Asn Thr Cys His Asp Ala Gly Ile Ser Lys Lys Ala Ile Lys
485 490 495
Leu Arg Pro Ile Ala Val Ile Lys Gly
500 505
<210> 75
<211> 1518
<212> DNA
<213> Mus sp.
<220>
<221> CDS
<222> (1)..(1518)
<400> 75
atg agt cgt aac tac aac gat gag cta cag ttc ttg gac aag atc aat 48
Met Ser Arg Asn Tyr Asn Asp Glu Leu Gln Phe Leu Asp Lys Ile Asn
1 5 10 15
aaa aac tgc tgg agg atc aag aag ggc ttt gtg ccc aac atg cag gtt 96
Lys Asn Cys Trp Arg Ile Lys Lys Gly Phe Val Pro Asn Met Gln Val
20 25 30
gaa gga gtg ttt tat gtg aat gat gct ctg gaa aaa cta atg ttt gag 144
Glu Gly Val Phe Tyr Val Asn Asp Ala Leu Glu Lys Leu Met Phe Glu
35 40 45
gaa tta agg aac gcc tgt cga ggt ggt ggt gtt ggt ggc ttt ctg cca 192
Glu Leu Arg Asn Ala Cys Arg Gly Gly Gly Val Gly Gly Phe Leu Pro
50 55 60
gcc atg aag cag att ggc aat gtg gca gcc ctg cct gga ata gtt cat 240
Ala Met Lys Gln Ile Gly Asn Val Ala Ala Leu Pro Gly Ile Val His
65 70 75 80
cgg tct atc ggg ctt cct gat gtc cat tca ggc tat ggg ttt gcc ata 288
Arg Ser Ile Gly Leu Pro Asp Val His Ser Gly Tyr Gly Phe Ala Ile
85 90 95
ggg aac atg gct gcc ttt gat atg aat gac cct gag gcc gtt gta tcc 336
Gly Asn Met Ala Ala Phe Asp Met Asn Asp Pro Glu Ala Val Val Ser
100 105 110
cca ggt ggt gtc gga ttt gat att aac tgt ggt gtc cgc ttg cta aga 384
Pro Gly Gly Val Gly Phe Asp Ile Asn Cys Gly Val Arg Leu Leu Arg
115 120 125
acc aat tta gat gag agc gat gta cag cct gtg aag gaa caa ctt gcc 432
Thr Asn Leu Asp Glu Ser Asp Val Gln Pro Val Lys Glu Gln Leu Ala
130 135 140
caa gct atg ttt gac cac atc cct gtt ggg gtg gga tca aaa ggt gtc 480
Gln Ala Met Phe Asp His Ile Pro Val Gly Val Gly Ser Lys Gly Val
145 150 155 160
att cca atg aat gcc aaa gac ttg gag gag gca ttg gag atg ggg gtg 528
Ile Pro Met Asn Ala Lys Asp Leu Glu Glu Ala Leu Glu Met Gly Val
165 170 175
gac tgg tcc ctg agg gaa ggc tat gcc tgg gct gaa gac aag gag cac 576
Asp Trp Ser Leu Arg Glu Gly Tyr Ala Trp Ala Glu Asp Lys Glu His
180 185 190
tgt gag gag tat gga agg atg ctg caa gcc gac ccc aat aag gtc tca 624
Cys Glu Glu Tyr Gly Arg Met Leu Gln Ala Asp Pro Asn Lys Val Ser
195 200 205
ccc agg gca aag aaa agg ggc ctt cct cag ttg ggg acc ctg gga gca 672
Pro Arg Ala Lys Lys Arg Gly Leu Pro Gln Leu Gly Thr Leu Gly Ala
210 215 220
ggc aac cat tat gca gaa atc cag gtt gta gat gag att ttc aat gag 720
Gly Asn His Tyr Ala Glu Ile Gln Val Val Asp Glu Ile Phe Asn Glu
225 230 235 240
tat gcc gcc aag aag atg ggc atc gac cat aag gga cag gtg tgt gtg 768
Tyr Ala Ala Lys Lys Met Gly Ile Asp His Lys Gly Gln Val Cys Val
245 250 255
atg atc cac agt gga agc aga ggc ttg ggc cac caa gta gct aca gat 816
Met Ile His Ser Gly Ser Arg Gly Leu Gly His Gln Val Ala Thr Asp
260 265 270
gca ctg gta gct atg gaa aag gcc atg aag aga gac aag att ata gtc 864
Ala Leu Val Ala Met Glu Lys Ala Met Lys Arg Asp Lys Ile Ile Val
275 280 285
aat gac cgg cag ttg gct tgt gct cgg att gca tcc cca gag gga caa 912
Asn Asp Arg Gln Leu Ala Cys Ala Arg Ile Ala Ser Pro Glu Gly Gln
290 295 300
gac tat cta aag gga atg gct gca gct gga aac tac gcc tgg gtt aac 960
Asp Tyr Leu Lys Gly Met Ala Ala Ala Gly Asn Tyr Ala Trp Val Asn
305 310 315 320
cgc tcc tct atg acc ttc tta acc cgt cag gct ttt gcc aaa gtc ttc 1008
Arg Ser Ser Met Thr Phe Leu Thr Arg Gln Ala Phe Ala Lys Val Phe
325 330 335
aac aca acc cct gat gac ctg gac ctg cat gtg atc tat gat gtg tcg 1056
Asn Thr Thr Pro Asp Asp Leu Asp Leu His Val Ile Tyr Asp Val Ser
340 345 350
cac aat atc gcc aaa gtg gag cag cac gtg gtg gat ggg aag gaa cgg 1104
His Asn Ile Ala Lys Val Glu Gln His Val Val Asp Gly Lys Glu Arg
355 360 365
acg ctg ctg gtg cac agg aag gga tcc acc cgt gct ttc ccg cct cac 1152
Thr Leu Leu Val His Arg Lys Gly Ser Thr Arg Ala Phe Pro Pro His
370 375 380
cac ccc ctc att gct gtg gat tat caa ctc aca gga caa cca gtg ctt 1200
His Pro Leu Ile Ala Val Asp Tyr Gln Leu Thr Gly Gln Pro Val Leu
385 390 395 400
att ggt ggc acc atg ggg acc tgt agt tac gtt ctg act ggc act gaa 1248
Ile Gly Gly Thr Met Gly Thr Cys Ser Tyr Val Leu Thr Gly Thr Glu
405 410 415
caa ggc atg act gag acc ttt gga aca acc tgt cat gga gcg ggc cgt 1296
Gln Gly Met Thr Glu Thr Phe Gly Thr Thr Cys His Gly Ala Gly Arg
420 425 430
gct ttg tcc aga gca aaa tca cgt cgt aac tta gat ttc caa gat gtc 1344
Ala Leu Ser Arg Ala Lys Ser Arg Arg Asn Leu Asp Phe Gln Asp Val
435 440 445
tta gac aaa ctg gca gac atg gga att gca atc cgg gtt gct tcc ccc 1392
Leu Asp Lys Leu Ala Asp Met Gly Ile Ala Ile Arg Val Ala Ser Pro
450 455 460
aag ctg gtt atg gaa gag gca cca gag tcc tat aag aat gtg aca gac 1440
Lys Leu Val Met Glu Glu Ala Pro Glu Ser Tyr Lys Asn Val Thr Asp
465 470 475 480
gtc gtg aac acc tgc cat gat gct ggg atc agc aag aag gcc att aaa 1488
Val Val Asn Thr Cys His Asp Ala Gly Ile Ser Lys Lys Ala Ile Lys
485 490 495
ctg aga cca att gct gtt att aaa ggg tag 1518
Leu Arg Pro Ile Ala Val Ile Lys Gly
500 505
<210> 76
<211> 505
<212> PRT
<213> Mus sp.
<400> 76
Met Ser Arg Asn Tyr Asn Asp Glu Leu Gln Phe Leu Asp Lys Ile Asn
1 5 10 15
Lys Asn Cys Trp Arg Ile Lys Lys Gly Phe Val Pro Asn Met Gln Val
20 25 30
Glu Gly Val Phe Tyr Val Asn Asp Ala Leu Glu Lys Leu Met Phe Glu
35 40 45
Glu Leu Arg Asn Ala Cys Arg Gly Gly Gly Val Gly Gly Phe Leu Pro
50 55 60
Ala Met Lys Gln Ile Gly Asn Val Ala Ala Leu Pro Gly Ile Val His
65 70 75 80
Arg Ser Ile Gly Leu Pro Asp Val His Ser Gly Tyr Gly Phe Ala Ile
85 90 95
Gly Asn Met Ala Ala Phe Asp Met Asn Asp Pro Glu Ala Val Val Ser
100 105 110
Pro Gly Gly Val Gly Phe Asp Ile Asn Cys Gly Val Arg Leu Leu Arg
115 120 125
Thr Asn Leu Asp Glu Ser Asp Val Gln Pro Val Lys Glu Gln Leu Ala
130 135 140
Gln Ala Met Phe Asp His Ile Pro Val Gly Val Gly Ser Lys Gly Val
145 150 155 160
Ile Pro Met Asn Ala Lys Asp Leu Glu Glu Ala Leu Glu Met Gly Val
165 170 175
Asp Trp Ser Leu Arg Glu Gly Tyr Ala Trp Ala Glu Asp Lys Glu His
180 185 190
Cys Glu Glu Tyr Gly Arg Met Leu Gln Ala Asp Pro Asn Lys Val Ser
195 200 205
Pro Arg Ala Lys Lys Arg Gly Leu Pro Gln Leu Gly Thr Leu Gly Ala
210 215 220
Gly Asn His Tyr Ala Glu Ile Gln Val Val Asp Glu Ile Phe Asn Glu
225 230 235 240
Tyr Ala Ala Lys Lys Met Gly Ile Asp His Lys Gly Gln Val Cys Val
245 250 255
Met Ile His Ser Gly Ser Arg Gly Leu Gly His Gln Val Ala Thr Asp
260 265 270
Ala Leu Val Ala Met Glu Lys Ala Met Lys Arg Asp Lys Ile Ile Val
275 280 285
Asn Asp Arg Gln Leu Ala Cys Ala Arg Ile Ala Ser Pro Glu Gly Gln
290 295 300
Asp Tyr Leu Lys Gly Met Ala Ala Ala Gly Asn Tyr Ala Trp Val Asn
305 310 315 320
Arg Ser Ser Met Thr Phe Leu Thr Arg Gln Ala Phe Ala Lys Val Phe
325 330 335
Asn Thr Thr Pro Asp Asp Leu Asp Leu His Val Ile Tyr Asp Val Ser
340 345 350
His Asn Ile Ala Lys Val Glu Gln His Val Val Asp Gly Lys Glu Arg
355 360 365
Thr Leu Leu Val His Arg Lys Gly Ser Thr Arg Ala Phe Pro Pro His
370 375 380
His Pro Leu Ile Ala Val Asp Tyr Gln Leu Thr Gly Gln Pro Val Leu
385 390 395 400
Ile Gly Gly Thr Met Gly Thr Cys Ser Tyr Val Leu Thr Gly Thr Glu
405 410 415
Gln Gly Met Thr Glu Thr Phe Gly Thr Thr Cys His Gly Ala Gly Arg
420 425 430
Ala Leu Ser Arg Ala Lys Ser Arg Arg Asn Leu Asp Phe Gln Asp Val
435 440 445
Leu Asp Lys Leu Ala Asp Met Gly Ile Ala Ile Arg Val Ala Ser Pro
450 455 460
Lys Leu Val Met Glu Glu Ala Pro Glu Ser Tyr Lys Asn Val Thr Asp
465 470 475 480
Val Val Asn Thr Cys His Asp Ala Gly Ile Ser Lys Lys Ala Ile Lys
485 490 495
Leu Arg Pro Ile Ala Val Ile Lys Gly
500 505
<210> 77
<211> 1518
<212> DNA
<213> Rattus sp.
<220>
<221> CDS
<222> (1)..(1518)
<400> 77
atg agt cgt aac tac aac gat gag cta cag ttc ttg gac aag atc aat 48
Met Ser Arg Asn Tyr Asn Asp Glu Leu Gln Phe Leu Asp Lys Ile Asn
1 5 10 15
aag aac tgc tgg agg atc aag aag ggc ttt gtg ccc aac atg cag gtt 96
Lys Asn Cys Trp Arg Ile Lys Lys Gly Phe Val Pro Asn Met Gln Val
20 25 30
gaa ggg gtg ttt tat gtg aat gac gct ctg gaa aag ctc atg ttt gag 144
Glu Gly Val Phe Tyr Val Asn Asp Ala Leu Glu Lys Leu Met Phe Glu
35 40 45
gag tta cgg aat gcc tgt cga ggt ggt ggt gtt ggt ggc ttc ctg cca 192
Glu Leu Arg Asn Ala Cys Arg Gly Gly Gly Val Gly Gly Phe Leu Pro
50 55 60
gcc atg aag cag att ggc aat gtg gca gcc ctg cct gga ata gtt cat 240
Ala Met Lys Gln Ile Gly Asn Val Ala Ala Leu Pro Gly Ile Val His
65 70 75 80
cgg tct att ggg ctt cct gat gtc cac tca ggc tac ggg ttt gcc ata 288
Arg Ser Ile Gly Leu Pro Asp Val His Ser Gly Tyr Gly Phe Ala Ile
85 90 95
ggg aac atg gct gcc ttt gat atg aat gac cct gag gca gtt gta tcc 336
Gly Asn Met Ala Ala Phe Asp Met Asn Asp Pro Glu Ala Val Val Ser
100 105 110
cca ggt ggt gtc gga ttt gat att aac tgt ggt gtc cgc ttg cta agg 384
Pro Gly Gly Val Gly Phe Asp Ile Asn Cys Gly Val Arg Leu Leu Arg
115 120 125
acc aat tta gat gag agc gat gta cag cct gtg aag gaa caa ctt gcc 432
Thr Asn Leu Asp Glu Ser Asp Val Gln Pro Val Lys Glu Gln Leu Ala
130 135 140
caa gct atg ttt gac cac atc cct gtc ggg gtg gga tcg aaa ggt gtc 480
Gln Ala Met Phe Asp His Ile Pro Val Gly Val Gly Ser Lys Gly Val
145 150 155 160
att cca atg aat gcc aaa gac ttg gag gag gca ttg gag atg ggt gtg 528
Ile Pro Met Asn Ala Lys Asp Leu Glu Glu Ala Leu Glu Met Gly Val
165 170 175
gac tgg tcc cta aga gaa ggc tat gcc tgg gct gag gac aag gag cac 576
Asp Trp Ser Leu Arg Glu Gly Tyr Ala Trp Ala Glu Asp Lys Glu His
180 185 190
tgt gag gag tat gga agg atg ctc caa gcc gac ccc aat aag gtc tca 624
Cys Glu Glu Tyr Gly Arg Met Leu Gln Ala Asp Pro Asn Lys Val Ser
195 200 205
ccc aga gca aag aaa agg ggc ctt cct cag ttg ggg acc ctg gga gca 672
Pro Arg Ala Lys Lys Arg Gly Leu Pro Gln Leu Gly Thr Leu Gly Ala
210 215 220
ggc aac cat tat gca gag atc cag gtt gta gat gag att ttc aac gag 720
Gly Asn His Tyr Ala Glu Ile Gln Val Val Asp Glu Ile Phe Asn Glu
225 230 235 240
tat gct gcc aag aag atg ggc atc gac cat aag gga cag gtg tgc gtg 768
Tyr Ala Ala Lys Lys Met Gly Ile Asp His Lys Gly Gln Val Cys Val
245 250 255
atg atc cac agc ggg agc aga ggc ttg ggc cat caa gta gct aca gac 816
Met Ile His Ser Gly Ser Arg Gly Leu Gly His Gln Val Ala Thr Asp
260 265 270
gca ctg gta gct atg gag aaa gcc atg aag aga gac aag att ata gtc 864
Ala Leu Val Ala Met Glu Lys Ala Met Lys Arg Asp Lys Ile Ile Val
275 280 285
aat gac cgg cag ctg gcg tgt gct cgg att gca tcc cca gag gga caa 912
Asn Asp Arg Gln Leu Ala Cys Ala Arg Ile Ala Ser Pro Glu Gly Gln
290 295 300
gac tat cta aag gga atg gct gcc gct gga aac tgt gcc tgg gtt aac 960
Asp Tyr Leu Lys Gly Met Ala Ala Ala Gly Asn Cys Ala Trp Val Asn
305 310 315 320
cgc tcg tct atg acc ttc tta acc cgt cag gct ttt gcc aaa gtc ttc 1008
Arg Ser Ser Met Thr Phe Leu Thr Arg Gln Ala Phe Ala Lys Val Phe
325 330 335
aac aca acc cct gac gac ctg gac ctg cat gtg att tat gat gtt tct 1056
Asn Thr Thr Pro Asp Asp Leu Asp Leu His Val Ile Tyr Asp Val Ser
340 345 350
cac aac atc gcc aaa gtg gag cag cac gtg gta gac gga aag gag cgg 1104
His Asn Ile Ala Lys Val Glu Gln His Val Val Asp Gly Lys Glu Arg
355 360 365
acg ctg ttg gtg cac agg aaa ggg tcc acc cgc gct ttc cct cct cac 1152
Thr Leu Leu Val His Arg Lys Gly Ser Thr Arg Ala Phe Pro Pro His
370 375 380
cat ccc ctc att gct gtt gat tac cag ctc act gga caa cca gtg ctt 1200
His Pro Leu Ile Ala Val Asp Tyr Gln Leu Thr Gly Gln Pro Val Leu
385 390 395 400
atc ggt ggc acc atg ggg acc tgt agt tat gtt ctg act ggc act gaa 1248
Ile Gly Gly Thr Met Gly Thr Cys Ser Tyr Val Leu Thr Gly Thr Glu
405 410 415
caa ggc atg act gag acc ttt gga aca acc tgt cat gga gcg ggc cgt 1296
Gln Gly Met Thr Glu Thr Phe Gly Thr Thr Cys His Gly Ala Gly Arg
420 425 430
gct ttg tcc aga gca aaa tca cgt cgt aat tta gat ttc caa gat gtc 1344
Ala Leu Ser Arg Ala Lys Ser Arg Arg Asn Leu Asp Phe Gln Asp Val
435 440 445
tta gac aag ctg gca gac atg gga atc gcc atc cgg gtt gcg tcc ccc 1392
Leu Asp Lys Leu Ala Asp Met Gly Ile Ala Ile Arg Val Ala Ser Pro
450 455 460
aag ctg gtt atg gaa gag gct cca gaa tca tat aag aat gtg aca gac 1440
Lys Leu Val Met Glu Glu Ala Pro Glu Ser Tyr Lys Asn Val Thr Asp
465 470 475 480
gtc gtg aac act tgc cat gat gct ggg atc agc aag aag gcc att aaa 1488
Val Val Asn Thr Cys His Asp Ala Gly Ile Ser Lys Lys Ala Ile Lys
485 490 495
ctg aga cca att gct gtt att aaa gga tag 1518
Leu Arg Pro Ile Ala Val Ile Lys Gly
500 505
<210> 78
<211> 505
<212> PRT
<213> Rattus sp.
<400> 78
Met Ser Arg Asn Tyr Asn Asp Glu Leu Gln Phe Leu Asp Lys Ile Asn
1 5 10 15
Lys Asn Cys Trp Arg Ile Lys Lys Gly Phe Val Pro Asn Met Gln Val
20 25 30
Glu Gly Val Phe Tyr Val Asn Asp Ala Leu Glu Lys Leu Met Phe Glu
35 40 45
Glu Leu Arg Asn Ala Cys Arg Gly Gly Gly Val Gly Gly Phe Leu Pro
50 55 60
Ala Met Lys Gln Ile Gly Asn Val Ala Ala Leu Pro Gly Ile Val His
65 70 75 80
Arg Ser Ile Gly Leu Pro Asp Val His Ser Gly Tyr Gly Phe Ala Ile
85 90 95
Gly Asn Met Ala Ala Phe Asp Met Asn Asp Pro Glu Ala Val Val Ser
100 105 110
Pro Gly Gly Val Gly Phe Asp Ile Asn Cys Gly Val Arg Leu Leu Arg
115 120 125
Thr Asn Leu Asp Glu Ser Asp Val Gln Pro Val Lys Glu Gln Leu Ala
130 135 140
Gln Ala Met Phe Asp His Ile Pro Val Gly Val Gly Ser Lys Gly Val
145 150 155 160
Ile Pro Met Asn Ala Lys Asp Leu Glu Glu Ala Leu Glu Met Gly Val
165 170 175
Asp Trp Ser Leu Arg Glu Gly Tyr Ala Trp Ala Glu Asp Lys Glu His
180 185 190
Cys Glu Glu Tyr Gly Arg Met Leu Gln Ala Asp Pro Asn Lys Val Ser
195 200 205
Pro Arg Ala Lys Lys Arg Gly Leu Pro Gln Leu Gly Thr Leu Gly Ala
210 215 220
Gly Asn His Tyr Ala Glu Ile Gln Val Val Asp Glu Ile Phe Asn Glu
225 230 235 240
Tyr Ala Ala Lys Lys Met Gly Ile Asp His Lys Gly Gln Val Cys Val
245 250 255
Met Ile His Ser Gly Ser Arg Gly Leu Gly His Gln Val Ala Thr Asp
260 265 270
Ala Leu Val Ala Met Glu Lys Ala Met Lys Arg Asp Lys Ile Ile Val
275 280 285
Asn Asp Arg Gln Leu Ala Cys Ala Arg Ile Ala Ser Pro Glu Gly Gln
290 295 300
Asp Tyr Leu Lys Gly Met Ala Ala Ala Gly Asn Cys Ala Trp Val Asn
305 310 315 320
Arg Ser Ser Met Thr Phe Leu Thr Arg Gln Ala Phe Ala Lys Val Phe
325 330 335
Asn Thr Thr Pro Asp Asp Leu Asp Leu His Val Ile Tyr Asp Val Ser
340 345 350
His Asn Ile Ala Lys Val Glu Gln His Val Val Asp Gly Lys Glu Arg
355 360 365
Thr Leu Leu Val His Arg Lys Gly Ser Thr Arg Ala Phe Pro Pro His
370 375 380
His Pro Leu Ile Ala Val Asp Tyr Gln Leu Thr Gly Gln Pro Val Leu
385 390 395 400
Ile Gly Gly Thr Met Gly Thr Cys Ser Tyr Val Leu Thr Gly Thr Glu
405 410 415
Gln Gly Met Thr Glu Thr Phe Gly Thr Thr Cys His Gly Ala Gly Arg
420 425 430
Ala Leu Ser Arg Ala Lys Ser Arg Arg Asn Leu Asp Phe Gln Asp Val
435 440 445
Leu Asp Lys Leu Ala Asp Met Gly Ile Ala Ile Arg Val Ala Ser Pro
450 455 460
Lys Leu Val Met Glu Glu Ala Pro Glu Ser Tyr Lys Asn Val Thr Asp
465 470 475 480
Val Val Asn Thr Cys His Asp Ala Gly Ile Ser Lys Lys Ala Ile Lys
485 490 495
Leu Arg Pro Ile Ala Val Ile Lys Gly
500 505
Claims (30)
- 적어도 하나의 제2 단백질의 미스폴딩(misfolding) 또는 응집에 대하여 선별하는 단계를 포함하는 제1 단백질에서의 변화를 검출하는 방법으로서, 상기 제1 단백질은 유비퀴틴-프로테아좀 분해 시스템 단백질, 자가포식(autophagy) 단백질, 분자 샤페론, 전사 인자, 소낭 수송(trafficking) 단백질, Mn2 +/Fe2 + 수송체, HSPC117 단백질, 아세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질로부터 선택되는 것인 제1 단백질에서의 변화를 검출하는 방법,
- 제1항에 있어서, 상기 변화가 제1 단백질의 발현 증가 또는 감소를 포함하는 것인 방법.
- 제1항에 있어서, 상기 변화가 제1 단백질에서의 돌연변이를 포함하는 것인 방법.
- 개체로부터의 조직 샘플중, 유비퀴틴-프로테아좀 분해 시스템 단백질, 자가포식 단백질, 분자 샤페론, 전사 인자, 소낭 수송 단백질, Mn2 +/Fe2 + 수송체, HSPC117 단백질, 아세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질로부터 선택되는 단백질에서의 변화를 검출하는 단계를 포함하되,여기에서, 변화가 신경계 질병에 대한 소인(predisposition), 또는 그의 존재를 지시하는 것인, 신경계 질병을 진단하는 방법.
- 제4항에 있어서, 생체내 또는 시험관내 모델에서 단백질 미스폴딩 또는 응집의 양을 측정하는 단계를 추가로 포함하는 것인 방법.
- 제4항에 있어서, 상기 단백질이, 야생형 또는 변화된 형태의 단백질에 대하여 특이적인 항체로 검출되는 것인 방법.
- 제4항에 있어서, 상기 단백질이, 야생형 또는 변화된 형태의 단백질에 상응하는 폴리뉴클레오티드 또는 폴리펩티드 서열에 특이적인 검출가능한 표지로 검출되는 것인 방법.
- 제4항에 있어서, 단백질이, 야생형 또는 변화된 형태의 단백질을 코딩하는 폴리뉴클레오티드에 특이적인 프로브를 포함하는 마이크로어레이로 검출되는 것인 방법.
- 표적 화합물을 유비퀴틴-프로테아좀 분해 시스템 단백질, 자가포식 단백질, 분자 샤페론, 전사 인자, 소낭 수송 단백질, Mn2 +/Fe2 + 수송체, HSPC117 단백질, 아 세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질로부터 선택되는 단백질과 접촉시키는 단계, 및화합물 부재하에서의 단백질 활성 변화를 측정하는 단계를 포함하는, 신경계 질병을 치료하는 화합물에 대하여 선별하는 방법.
- 제9항에 있어서, 상기 활성 변화가 단백질 발현의 증가 또는 감소를 포함하는 것인 방법.
- 제9항에 있어서, 적어도 하나의 제2 단백질의 미스폴딩 또는 응집을 검출하는 단계를 추가로 포함하는 것인 방법.
- 제9항에 있어서, 신경계 질병의 동물 모델에 화합물을 투여하여 적어도 하나의 제2 단백질의 미스폴딩 또는 응집을 감소시키는 단계를 추가로 포함하는 방법.
- 제9항에 있어서, 신경계 질병의 동물 모델에 화합물을 투여하여 동물 모델에 신경보호를 제공하는 단계를 추가로 포함하는 방법.
- 제12항에 있어서, 상기 화합물이 토포아이소머라제 II 저해제, 세균성 트랜스펩티다제 저해제, 칼슘 채널 길항제, 사이클로옥시게나제 저해제, 엽산 합성 저해제 및 나트륨 채널 차단제로부터 선택되는 것인 방법.
- 제13항에 있어서, 상기 화합물이 엽산 합성 저해제, 세균성 트랜스펩티다제 저해제, 사이클로옥시게나제 저해제, 또는 나트륨 채널 차단제로부터 선택되는 것인 방법.
- 유비퀴틴-프로테아좀 분해 시스템 단백질, 자가포식 단백질, 분자 샤페론, 전사 인자, 소낭 수송 단백질, Mn2 +/Fe2 + 수송체, HSPC117 단백질, 아세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질로부터 선택되는 단백질의 신경계 질병을 치료하기 위한 의약 제조에서의 용도로서, 상기 의약은 신경계 질병 증상을 치료하기 위한 유효량의 상기 단백질을 포함하는 것인 용도.
- 치료를 필요로 하는 개체에서 유비퀴틴-프로테아좀 분해 시스템 단백질, 자가포식 단백질, 분자 샤페론, 전사 인자, 소낭 수송 단백질, Mn2 +/Fe2 + 수송체, HSPC117 단백질, 아세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질로부터 선택되는 제1 단백질의 활성을 변화시키는 단계를 포함하는, 신경계 질병을 치료하는 방법.
- 제17항에 있어서, 제1 단백질의 활성이, 치료를 필요로 하는 개체에게 유비퀴틴-프로테아좀 분해 시스템 단백질, 자가포식 단백질, 분자 샤페론, 전사 인자, 소낭 수송 단백질, Mn2 +/Fe2 + 수송체, HSPC117 단백질, 아세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질로부터 선택되는 제2 단백질을 발현시키는 벡터를 투여함으로써 변화되는 것인 방법.
- 제17항에 있어서, 상기 단백질이 신경세포를 기능장애, 변성 또는 사멸로부터 보호하는 것인 방법.
- 제17항에 있어서, 상기 제1 단백질의 활성이, 화합물의 부재하에서 제1 단백질의 활성을 변화시키는 화합물을 투여함으로써 변화되는 것인 방법.
- 제17항에 있어서, 상기 신경계 질병이 근위축성 측삭 경화증, 알츠하이머병, 파킨슨병, 프리온 질병, 폴리글루타민 확장증, 척수소뇌성 실조증, 척수 및 연수 근육위축, 해면뇌병증, 타우증(tauopathy), 헌팅톤병, 또는 근육긴장이상으로부터 선택되는 것인 방법.
- 제17항에 있어서, 상기 제1 단백질의 활성이, 신경계 질병에 걸리기 쉬운 개체에서 증상이 발병되기 이전에 변화되는 것인 방법.
- 제20항에 있어서, 상기 화합물이 토포아이소머라제 II 저해제, 세균성 트랜 스펩티다제 저해제, 칼슘 채널 길항제, 사이클로옥시게나제 저해제, 엽산 합성 저해제 및 나트륨 채널 차단제로부터 선택되는 것인 방법.
- 제20항에 있어서, 상기 화합물이 약제학적으로 허용되는 담체에서 투여되는 것인 방법.
- 제20항에 있어서, 상기 화합물이 흡인식, 경피, 경구, 직장, 경점막, 장내 또는 비경구 경로에 의해 투여되는 것인 방법.
- 제20항에 있어서, 상기 화합물이 신경계 질병에 걸리기 쉬운 개체에서 증상이 발병되기 이전에 투여되는 것인 방법.
- 야생형 동물에서보다는 활성이 변화된, 유비퀴틴-프로테아좀 분해 시스템 단백질, 자가포식 단백질, 분자 샤페론, 전사 인자, 소낭 수송 단백질, Mn2 +/Fe2 + 수송체, HSPC117 단백질, 아세틸콜린 수용체 서브유니트, DJ-1 단백질 및 PINK-1 단백질로부터 선택되는 단백질을 포함하는 트랜스제닉 동물.
- 제27항에 있어서, 상기 변화된 활성이 단백질 발현의 증가 또는 감소를 포함하는 것인 트랜스제닉 동물.
- 제27항에 있어서, 상기 변화된 활성이 단백질 서열내 돌연변이를 포함하는 것인 트랜스제닉 동물.
- 제1항, 제4항, 제9항 및 제17항 중 어느 한 항의 방법과 함께 사용하기 위한 키트.
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| US73876105P | 2005-11-21 | 2005-11-21 | |
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| US74991005P | 2005-12-12 | 2005-12-12 | |
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| AU (1) | AU2006216442A1 (ko) |
| CA (1) | CA2599182A1 (ko) |
| WO (1) | WO2006091964A2 (ko) |
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| JP2010535505A (ja) * | 2007-08-08 | 2010-11-25 | ザ・ボード・オブ・トラスティーズ・オブ・ザ・ユニバーシティー・オブ・アラバマ・フォー・アンド・オン・ビハーフ・オブ・ザ・ユニバーシティー・オブ・アラバマ | タンパク質のミスフォールディングおよび神経保護の制御および使用の方法 |
| EP2042592A1 (en) * | 2007-09-28 | 2009-04-01 | IMBA-Institut für Molekulare Biotechnologie GmbH | Methods for modulating the proliferation and differentiation potential of stem cells and progenitor cells |
| WO2011137486A1 (en) * | 2010-05-04 | 2011-11-10 | Monash University | Diagnostic and prognostic and therapeutic methods |
| EP2423304A1 (en) | 2010-08-30 | 2012-02-29 | IMBA-Institut für Molekulare Biotechnologie GmbH | Use of a RNA ligase |
| IT1405762B1 (it) | 2010-11-25 | 2014-01-24 | Icgeb | Proteine ricombinanti con attivita' di inattivazione selettiva di proteine bersaglio |
| US20130024954A1 (en) * | 2011-06-24 | 2013-01-24 | Jonathan Thomas Pierce-Shimomura | Human Age-Related Neurodegenerative Nematode Model and Methods |
| US9296994B2 (en) | 2012-04-23 | 2016-03-29 | Imba-Institut Für Molekulare Biotechnologie Gmbh | Archease as RNA ligaes complex member |
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| EP0989995A2 (en) * | 1997-06-19 | 2000-04-05 | The General Hospital Corporation | Torsin, torsin genes, and methods of use |
| US20050214763A1 (en) * | 2002-02-14 | 2005-09-29 | Rainer Hipfel | Diagnostic and therapeutic use of an activator protein for vesicle secretion for neurodegenerative diseases |
| US20030235823A1 (en) * | 2002-06-24 | 2003-12-25 | The University Of Alabama | Nucleotide sequences that code for torsin genes, torsin proteins, and methods of using the same to treat protein-aggregation |
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- 2006-02-27 US US11/364,612 patent/US20070204352A1/en not_active Abandoned
- 2006-02-27 EP EP06736344A patent/EP1856527A4/en not_active Withdrawn
- 2006-02-27 WO PCT/US2006/007002 patent/WO2006091964A2/en active Application Filing
- 2006-02-27 CA CA002599182A patent/CA2599182A1/en not_active Abandoned
- 2006-02-27 KR KR1020077021968A patent/KR20070110104A/ko not_active Application Discontinuation
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| WO2006091964A3 (en) | 2007-07-12 |
| CA2599182A1 (en) | 2006-08-31 |
| US20070204352A1 (en) | 2007-08-30 |
| EP1856527A4 (en) | 2010-09-01 |
| WO2006091964A8 (en) | 2007-03-22 |
| AU2006216442A1 (en) | 2006-08-31 |
| WO2006091964A2 (en) | 2006-08-31 |
| JP2008531019A (ja) | 2008-08-14 |
| EP1856527A2 (en) | 2007-11-21 |
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