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KR20100116765A - 파킨슨병 치료제 스크리닝 방법 - Google Patents

파킨슨병 치료제 스크리닝 방법 Download PDF

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KR20100116765A
KR20100116765A KR1020090035344A KR20090035344A KR20100116765A KR 20100116765 A KR20100116765 A KR 20100116765A KR 1020090035344 A KR1020090035344 A KR 1020090035344A KR 20090035344 A KR20090035344 A KR 20090035344A KR 20100116765 A KR20100116765 A KR 20100116765A
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설원기
김시현
허헤영
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인제대학교 산학협력단
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Abstract

본 발명은 파킨스병 치료 물질을 스크리닝하는 방법에 관한 것으로 보다 구체적으로 세포에 LRRK2(leucine rich repeat kinase 2) 돌연변이 단백질을 발현하고, 상기 세포에 산화스트레스 또는 미토콘드리아 독성 유발 물질을 가한 다음 상기 세포에 시험 물질을 접촉시켜서 상기 시험 물질과 접촉된 세포와 상기 시험 물질과 접촉되지 않은 세포를 비교하여 상기 시험 물질의 접촉에 의한 세포 사멸의 감소여부를 측정하거나 상기 세포에 시험 유전자를 형질전환시키고 시험 유전자로 형질전환된 세포와 상기 시험 유전자로 형질전환되지 않은 세포를 비교하여 상기 시험 유전자의 형질전환에 의한 세포 사멸의 감소여부를 측정함으로써 파킨스병 치료 물질을 스크리닝하는 방법 및 파킨슨병 치료 물질 스크리닝 키트에 관한 것이다. 본 발명에 따르면 파킨슨병 치료제로 가능성이 있는 화합물을 간편하고 경제적으로 검색할 수 있어 본 발명으로 검색한 화합물은 파킨슨병을 치료하는 선도물질로 이용할 수 있으며 본 발명으로 검색한 유전자는 파킨슨병 치료제 검색을 위한 표적유전자로 이용할 수 있다.
LRRK2(leucine rich repeat kinase 2), 파킨슨병, 산화스트레스, SN4741 세포, 화합물 스크리닝, 유전자 스크리닝

Description

파킨슨병 치료제 스크리닝 방법{Methods to screen materials to inhibit Parkinson's disease}
본 발명은 세포에 LRRK2(leucine rich repeat kinase 2) 돌연변이 단백질을 발현하고, 상기 세포에 산화스트레스 또는 미토콘드리아 독성 유발 물질을 가한 다음 상기 세포에 시험 물질을 접촉시켜서 상기 시험 물질과 접촉된 세포와 상기 시험 물질과 접촉되지 않은 세포를 비교하여 상기 시험 물질의 접촉에 의한 세포 사멸의 감소여부를 측정하거나 상기 세포에 시험 유전자를 형질전환시키고 시험 유전자로 형질전환된 세포와 상기 시험 유전자로 형질전환되지 않은 세포를 비교하여 상기 시험 유전자의 형질전환에 의한 세포 사멸의 감소여부를 측정함으로써 파킨스병 치료 물질을 스크리닝하는 방법 및 파킨슨병 치료 물질 스크리닝 키트에 관한 것이다.
파킨슨병은 알츠하이머 치매와 더불어 노년기에 나타나는 대표적인 퇴행성 신경질환이다. 65세 인구에서 1 % 정도가 발병하며 나이가 들수록 그 발병률이 증 가한다 (Gasser 2007; Thomas and Beal 2007}. 파킨슨병은 운동성장애를 나타내어 안정시 떨림, 경직, 느린 동작, 자세의 불안정이 대표적인 증후이며 병리학적으로는 중뇌의 흑뇌에 있는 도파민성 신경세포가 점진적으로 사멸하여 도파민의 분비 감소로 인하여 생기는 질병이다 (Olanow and Tatton 1999).
파킨슨병은 대부분이 산발적으로 일어나지만 5-10%의 환자는 가족력을 가지는데 이 들 환자 시료의 연구로부터 PARK 1-13의 유전자자리가 현재까지 밝혀졌으며, 그 중 몇 개의 유전자자리에서 돌연변이에 의해 파킨슨병을 유발하는 유전자가 확인되었다 (Lewthwaite and Nicholl 2005; Gasser 2007). 돌연변이에 의해 파킨슨병을 일으키는 파킨슨병 원인 유전자는 parkin, PINK1, DJ-1, α-synuclein, LRRK2 등이 알려져있다. (Moore, West et al. 2005; Gasser 2007; Thomas and Beal 2007)
이 중 LRRK2 유전자는, α-synuclein처럼 상동염색체의 우성 유전자로 2004년에 최초로 보고되었다 (Paisan-Ruiz, Jain et al. 2004; Zimprich, Biskup et al. 2004). LRRK2 돌연변이에 의한 파킨슨병 환자는, 다른 파킨슨병 원인 유전자와는 달리, 그 증상이 산발적 파킨슨병 환자와 아주 유사하다 (Mata, Wedemeyer et al. 2006). 또한 LRRK2 돌연변이는 가족력이 있는 파킨슨병 환자뿐 아니라 산발적 파킨슨병의 환자에서도 발견되므로 이 유전자의 돌연변이에 의한 파킨슨병 발병 기작을 밝히면 파킨슨병의 발병 기작 이해와 치료제 개발에 큰 도움이 될 것이다. LRRK2 단백질은 세포 신호 전달에 관여하는 GTPase와 인산화효소의 기능적 도메인과, 단백질 상호결합에 관여하는 WD40, LRR (leucine-rich repeat)의 도메인을 포 함한다 (도 1, (Paisan-Ruiz, Jain et al. 2004; Zimprich, Biskup et al. 2004)). 파킨슨병을 일으키는 LRRK2 돌연변이는 GTPase 부분에 있는 R1441G, R1441C, 인산화효소 부분에 있는 G2019S, I2020T, GTPase와 인산화효소 도메인 사이에 있는 Y1699C가 보고되었으며 (Paisan-Ruiz, Jain et al. 2004; Zimprich, Biskup et al. 2004) 그 외에도 많은 수의 polymorphism이 보고되었다 (Mata, Wedemeyer et al. 2006).
G2019S 돌연변이는 그 과발현이 인산화효소 활성을 증가시키며, 세포 독성을 유발하고, 신경축삭의 길이를 감소시키는데 (Smith, Pei et al. 2005; Smith, Pei et al. 2006; West, Moore et al. 2007; MacLeod et al. 2006), 특이하게도 LRRK2 돌연변이로 인한 파킨슨병 환자의 85%를 차지한다 (Healy, Falchi et al. 2008).
이러한 이유 때문에 LRRK2의 돌연변이 유전자, 특히 G2019S에 의해 일어나는 현상 (증가된 인산화효소 활성, 감소된 신경축삭의 길이 등)을 제거하거나 감소시키는 화합물을 검색하려는 특허들이 등록되었다. WO/2008/091799 (PCT/US2008/051485)는 LRRK2 돌연변이 단백질이 과발현되면 이 단백질에 의해 필라멘트가 형성된다는 점을 이용하여 LRRK2의 다양한 돌연변이 단백질을 과발현시킨 뒤 그 필라멘트 형성을 감소시키는 화합물을 다양한 배양세포에서 검색하는 방법에 관한 특허이다. 또한, WO/2008/122789 (PCT/GB2008/001211)는 LRRK2 단백질이 Ezrin/Radixin/Moesin (ERM) 단백질 들을 그 인산화효소 기질로 사용한다는 점을 이용하여 LRRK2 단백질에 의한 ERM 단백질의 인산화를 조절하는 화합물을 검색하는 방법에 관한 특허이다. 또한, WO/2007/124096 (PCT/US2007/009736)는 LRRK2의 파킨슨병 유발 돌연변이 단백질이 세포에서 발현되면 그 세포의 신경축삭의 길이와 가지 수를 감소시킨다는 점을 이용하여 LRRK2 돌연변이 단백질을 과발현한 세포에서 신경축삭의 길이, 가지 수 등 그 형상을 관찰하여 길이나 가지 수를 감소시키지 않은 화합물을 검색하는 방법에 관한 특허이다.
그러나 이들 특허는 형광현미경이나 고배율현미경 등의 고가 장비로 각 세포를 관찰해야 하거나(WO/2008/091799, WO/2007/124096), 방사성 동위원소나 형광물질로 반응을 진행해야 하는(WO/2008/122789) 단점이 있다.
또한, 파킨슨병 관련 유전자의 신경세포 독성을 이용한 파킨슨병 치료제 검색을 위해 alpha-synuclein을 이용한 발명이 있다 (WO/2008/063779). 그러나 alpha-synucelin 유전자의 돌연변이나 과발현에 의한 유전적인 파킨슨병 환자의 수가, LRRK2 유전자 돌연변이 환자 수에 비해 아주 작은 점으로 미루어 볼 때, alpha-synucelin을 이용한 방법보다는 LRRK2를 이용한 검색 방법이 더 효과적이라고 할 것이다. 또한, LRRK2는 그 돌연변이가 가족력이 있는 유전적인 환자뿐만 아니라 산발적인 환자에서도 1-2 % 관찰되며 (Gilks, Abou-Sleiman et al. 2005, Mata, Wedemeyer et al. 2006), 그 단백질의 기능이 세포내 신호 전달과 조절에 중요한 기능을 하는 GTPase와 인산화효소인 점을 감안할 때, alpha-synuclein보다는 LRRK2 단백질을 대상으로 치료제용 화합물을 검색하는 것이 보다 효율적이다.
이에 본 발명자들은 LRRK2 돌연변이 단백질의 세포독성을 그 독성을 저해하는 화합물 또는 유전자를 검색하는 스크리닝 방법에 응용하면 상기 단점들을 해결할 수 있음을 발견하고 본원 발명을 완성하였다.
본 발명의 목적은 파킨스병 치료 물질을 스크리닝하는 방법 및 파킨슨병 치료 물질 스크리닝 키트를 제공하기 위한 것이다.
일 양태로 본 발명은 세포에 LRRK2(leucine rich repeat kinase 2) 돌연변이 단백질을 발현하는 단계; 상기 세포에 산화스트레스 또는 미토콘드리아 독성 유발 물질을 처리하는 단계; 상기 세포에 시험 물질을 접촉시키는 단계; 상기 시험 물질과 접촉된 세포와 상기 시험 물질과 접촉되지 않은 세포를 비교하는 단계; 및 상기 시험 물질의 접촉에 의한 세포 사멸의 감소여부를 측정하는 단계를 포함하여 파킨스병 치료 물질을 스크리닝하는 방법을 제공한다.
다른 양태로 본 발명은 세포에 LRRK2 돌연변이 단백질을 발현하는 단계; 상기 세포에 산화스트레스 또는 미토콘드리아 독성 유발 물질을 처리하는 단계; 상기 세포에 시험 유전자를 형질전환시키는 단계; 상기 시험 유전자로 형질전환된 세포와 상기 시험 유전자로 형질전환되지 않은 세포를 비교하는 단계; 및 상기 시험 유전자의 형질전환에 의한 세포 사멸의 감소여부를 측정하는 단계를 포함하여 파킨스병 치료 물질을 스크리닝하는 방법을 제공한다.
어떤 특정 목적을 가진 화합물을 화합물 라이브러리에서 검색하고자 할 때는 high-throughput으로 목적에 맞는 변화를 일으키는 특정 화합물을 검색할 수 있는 간편하고 가격이 저렴한 방법이 필요하다.
파킨슨병 치료제를 효과적으로 스크리닝하기 위해서는 LRRK2 돌연변이 단백질의 과발현에 의한 신경세포 독성을 이용하여 대다수의 세포에 돌연변이 단백질이 과발현 되도록 하여야 하고, 발현된 세포의 대부분이 사멸되도록 한다. 전자의 조건을 만족시키기 위해서 형질전환률이 높은 도파민성 신경세포주를 사용하는 것이 바람직하고 특히, SN4741 또는 MN9D을 이용하는 것이 바람직하고, 후자의 조건을 만족시키기 위해서 세포에 일정 정도의 산화스트레스 또는 미토콘드리아 독성 물질을 처리하여 세포의 산화스트레스 또는 미토콘드리아 독성 물질에 대한 감수성을 증가시키는 것이 바람직하다. 두 조건 하의 세포사멸도는 단순히 두 조건을 동시에 적용함으로써 유도되는 세포사멸도를 넘어서는 시너지 효과를 보이는 세포사멸도이다. 이 때 더욱 바람직하게는 LRRK2 돌연변이 단백질의 발현없이 산화스트레스(미토콘드리아 독성 물질) 단독 처리만으로 사멸하는 세포 수를 최소화하고, LRRK2 돌연변이 단백질의 발현과 산화스트레스(미토콘드리아 독성 유발 물질) 처리의 두 조건에 의해 사멸하는 세포 수를 최대화하여야 한다.
본 발명의 구체적인 실시예에서 나타나듯이 대조군 벡터나 LRRK2 야생종 단백질에 비하여 돌연변이 단백질의 발현은 산화스트레스(미토콘드리아 독성 유발 물질)의 존재하에 현저히 상승된 세포 치사율을 보였다. 본 발명의 구체적인 실시예에서는, SN4741 세포주를 대상으로 G2019S의 형질전환에 의한 발현만이나 산화스트 레스만을 처리한 경우에 비해, G2019S를 형질 전환하여 발현하고 산화스트레스(예를 들면 과산화수소)를 처리한 경우에 세포사멸도가 현저히 증가하는 조건 하에서 LRRK2 돌연변이의 세포독성을 방해하는 화합물을 검색하였다.
LRRK2(leucine rich repeat kinase 2)는 가족성 파킨슨병 환자에서 그 돌연변이들이 발견된 파킨슨병 원인 유전자이다. LRRK2 돌연변이 단백질을 발현하기 위해서 당업계에 공지된 다양한 방법이 응용될 수 있으나 본 발명의 구체적인 실시예에서는 LRRK2 유전자를 형질전환하여 돌연변이 단백질을 발현하였는데 이 경우 돌연변이 단백질의 발현도가 높다는 장점이 있다.
세포에서 LRRK2 돌연변이 단백질을 발현한 뒤, 산화스트레스나 미토콘드리아 독성 유발 물질을 처리하면 세포주가 야생종이거나 대조군 벡터를 발현한 세포주에 비해 더 높은 세포 사멸도를 보인다.
바람직하게는 본 발명의 스크리닝 방법을 사용하여 파킨슨병 치료제를 검색하기 전에 먼저, LRRK2 돌연변이 단백질 발현 세포주를 대상으로 파킨슨병 치료제를 검색한 후 세포사멸도에 차이를 보이는 것을 먼저 일차 시험물질로 선택한다. 그 다음에 이들 시험물질들 중에서 산화스트레스(미토콘드리아 독성 유발 물질) 또는 LRRK2 야생종 발현 등의 단독 조건만으로는 세포사멸도의 차이를 보이지 않고, 산화스트레스(미토콘드리아 독성 유발 물질)와 G2019S 발현의 존재, 두 조건이 동시에 존재하는 경우, 그 외의 경우에 비해 세포사멸도에 차이를 보이는 경우를 시 험물질로 선택하는 것이 바람직하다.
상기 세포는 MN9D, SN4741, SH-SY5Y, SK-N-BE2C, 및 PC12로 구성된 도파민을 분비하는 세포군 또는 HEK293T, HeLa, 및 COS-7 세포로 구성된 도파민을 분비하지 않는 세포군 중에서 선택되는 것이 바람직하나, 더욱 바람직하게는 도파민을 많이 분비하는 도파민성 신경세포인 MN9D 또는 SN4741이다. 본 발명의 구체적인 실시예에서는 파킨슨병에서 일어나는 선조체의 도파민 신경세포의 사멸에 유사한 생리적인 조건을 사용하기 위해 실험에 SN4741 세포주를 사용하였다.
상기 LRRK2 돌연변이 단백질은 서열번호 2로 표시되는 G2019S, 서열번호 4로 표시되는 R1441C, 서열번호 6으로 표시되는 R1441G, 서열번호 8로 표시되는 Y1699C, 서열번호 10으로 표시되는 I2020T로 구성된 군에서 선택되는 1이상의 단백질인 것이 바람직하다.
LRRK2 G2019S 유전자 서열은 서열번호 1, LRRK2 R1441C 유전자 서열은 서열번호 3, LRRK2 R1441G 유전자 서열은 서열번호 5, LRRK2 Y1699C 유전자 서열은 서열번호 7, LRRK2 I2020T 유전자 서열은 서열번호 9호 표시한다.
상기 G2019S는 2019번째 아미노산 글라이신(glycin)이 세린(serine)으로 치환되었음을 의미하고, R1441C은 1441번째 아미노산 아르기닌(arginine)이 시스테인(cysteine)으로 치환되었음을 의미하며, R1441G은 1441번째 아미노산 아르기닌 (arginine)이 글리신(glycin)으로 치환되었음을 의미하고, Y1699C는 1699번째 아미 노산 티로신(tyrosine)이 시스테인(cysteine)으로 치환되었음을 의미하고, I2020T은 2020번째 아미노산 이소루이신(isoleucine)이 트레오닌(threonine)으로 치환되었음을 의미한다.
상기 산화스트레스는 당업계에 공지된 다양한 방법으로 유발될 수 있으나 바람직하게는 활성산소종을 발생하는 과산화수소로 유발한다. 상기 산화스트레스란 정상세포의 불안정한 분자인 활성산소가 체내에 있는 산소화합물과 반응, 세포와 조직에 염증을 일으키는 현상을 말한다.
또한 상기 미토콘드리아의 독성 역시 당업계에 공지된 다양한 방법으로 유발될 수 있으나 바람직하게는 파라쿼트(paraquat)로 유발한다.
상기 시험물질은 기존 화합물, 천연 화합물, 신약 후보물질 등 당업자가 세포 사멸을 저해할 것으로 기대할 수 있는 모든 물질을 사용하는 것이 가능하다.
또한 화합물 라이브러리 대신 유전자 라이브러리를 이용하여 동일한 방법으로 검색하면 LRRK2 돌연변이 유전가 세포사멸을 일으키는 세포 내 기작의 하위에 있는 유전자를 검색하는 방법을 제공할 수 있다. 상기 시험 유전자는 기존 유전자, 새로운 유전자, 유전자의 발현을 저해하는 siRNA 등 당업자가 세포 사멸을 저해할 것으로 기대할 수 있는 모든 유전자를 사용하는 것이 가능하다.
다른 양태로 본 발명은 LRRK2 돌연변이 단백질이 발현된 세포, 세포 사멸의 감소여부 측정 장치를 포함하는 파킨스병 치료제 스크리닝 키트를 제공한다.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.
실시예 1. SN4741 세포의 형질전환률
녹색형광단백질 (GFP)을 SN4741에 발현하여 형광현미경으로 그 발현도를 관찰하였다. SN4741 세포주는 생쥐의 선조체의 세포를 이용하여 만든 도파민 신경세포주이다 (Son, Chun et al. 1999). 본 발명에서는 파킨슨병에서 일어나는 선조체의 도파민성 신경세포의 사멸에 유사한 생리적인 조건을 사용하기 위해 실험에 SN4741 세포주를 사용하였다. 12 well plate에 cover slip을 넣고 SN4741 세포를 1X105/well의 조건으로 깐 다음 10 % fetal bovine serum (FBS) 을 포함한 Dubecco's modified minimal medium (DMEM)에서 하루 배양한 뒤 GFP 유전자를 포함한 플라스미드를 0.5 μg/well을 염화칼슘법으로 형질전환하였다. 2일 배양한 후 그 발현도를 GFP에 대한 항체를 이용하여 염색하여 관찰하였다.
도 2에는 그 결과를 도시하고 있는 바, 1x105 cell/well을 12 well plate에 깔은 다음 0.5 μg을 형질전환한 후 2일 후 GFP 에 대한 항체(b)로 면역염색한 것을 나타낸 것이다. a는 핵 염색물질인 Hoechst H33258을 같이 염색한 도면이며, c는 a, b를 merge한 것이다. 각 도 밑의 bar는 150 μm이다. 도 2에서 보인 바와 같이 그 형질 전환률은 약 20 %였다.
실시예 2. LRRK2 야생종이나 돌연변이 단백질을 발현한 SN4741 세포에 과산화수소를 처리한 후 SN4741세포의 생존률
SN4741 세포를 48 well plate에 5X104/well의 조건으로 seeding 한 다음 실시예1과 같은 조건으로 하루 배양한 뒤 대조군 empty vector (pcDNA3.1/HisMyc, Invitrogen Co. 미국), LRRK2 야생종이나 G2019S 돌연변이 유전자를 포함한 pcDNA3.1/HisMyc 플라스미드를 1 μg/well을 염화칼슘법으로 각 well에 형질전환하였다. 각 sample마다 3개의 well을 사용하였다. 2일 배양한 후 과산화수소를 100 μM 처리하고 24시간 후에 crystal violet 염색법으로 세포생존률을 각 well의 흡광도로 측정하였다.
crystal violet 염색은 다음과 같이 행하였다. 배양배지를 제거한 후, 50% 메탄올로 0.5% crystal violet 용액을 만들어 well당 100μl를 넣어 주고 30분간 실온에서 반응시킨다. 각 well을 물로 3번 가볍게 씻어주고 물기를 제거한 후 50% 메탄올 400μl를 넣고 30분간 실온에서 반응시켜 세포내 염색액이 완전히 녹도록 한 뒤 96 well plate에 용액을 옮겨 540nm에서 흡광도를 측정하여 세포 생존률을 결정하였다.
대조군 벡터인 pcDNA3.1/HisMyc을 형질전환한 세포의 생존률을 100으로 하여 각 경우의 세포생존률을 도 3에 서로 비교하였다. 이 실험조건에서 LRRK2 야생종보다 G2019S 돌연변이의 세포독성이 더 큰 것을 관찰하였다.
실시예 3. 과산화수소 처리 하에서 LRRK2 단백질의 과발현 유무에 따른 독성의 차이를 최대화하기 위한 최적화 조건
LRRK2 G2019S를 형질전환하고 과산화수소를 처리한 경우의 세포 치사율을 vector 대조군과 비교하여 최대화시키기 위하여 형질전환한 후 배양한 시간과 과산화수소 처리 농도를 변화시켜 세포 생존률을 조사하였다. 도 4에 보인 것처럼 각 sample의 세포생존률이 과산화수소의 농도에 따라 대조군과 비교하여 약간의 차이는 있으나 실시예 2에서의 차이와 비교하여 뚜렸한 차이가 없기에 스크리닝 등 다른 실험에 실시예 2의 조건을 이용하였다.
실시예 4. LRRK2 야생종이나 G2019S를 안정적으로 발현하는 세포주 확립
LRRK2 세포주의 돌연변이, 특히 G2019S가 세포독성이 있으므로 필요할 때만 LRRK2 단백질을 조건적으로, 안정적으로 발현하는 (conditionally and stably induced expression) 세포주를 구축하였다. 이를 위하여, 도파민성 신경세포주인 MN9D 세포주와 Rheo-switch mammalian inducible expression system (New England Biolab Co. 미국 매사추세츠주)을 이용하였다.
MN9D 세포주 배양에는 DMEM medium을 사용하였다. 먼저 MN9D 세포에 NEBR-R1 plasmid를 형질전환하여 G418을 900μg/ml로 3주간 처리하여 각 colony를 한 개씩 96 well plate의 각 well에 분리하였다. 이들 colony를 각각 계속 배양한 뒤, ligand인 RSL1에 가장 잘 반응하는 colony를 선택하기 위하여 NEBR-gluc plasmid (대조군 단백질인 루시퍼라제 발현 플라스미드)로 형질전환하고, 이 system의 ligand인 RSL1을 500nM/well으로 처리한 뒤 NEBR-gluc에 의해 발현하는 루시퍼라제 활성을 측정하였다. 이 방법을 통하여 RSL1 ligand에 의해 luciferase를 가장 많이 발현하는 colony를 선택하고 L14로 명명하였다. L14 세포주에 LRRK2 야생종이나 G2019S 돌연변이 유전자가 클론된 NEBR-X1 플라스미드나 대조군으로 공벡터인 NEBR-X1을 각각 형질전환하여 hygromycin 600μg/ml로 3주간 처리하여 colony를 96 well plate의 각 well에 분리하였다. 이들 colony를 계속 배양한 뒤, ligand인 RSL1을 500nM/well로 각 colony에 처리한 뒤 24시간 만에 LRRK2 단백질의 발현 정도를 western blot을 통해 분석하였다. 이 때 ligand에 의해 LRRK2 야생종, G2019S 단백질을 가장 많이 발현하는 colony를 각각 선택하고 HL2, HMG15로 명명하였다 (도 5).
도 5의 a에서는 LRRK2 단백질을 Myc tag에 대한 항체(윗 도)나 LRRK2 항체(중간 도)로 염색한 western blot 분석 결과를 나타내었다. HV, HL, HMG는 각각 대조군 vector를 삽입하거나 (HV), LRRK2 야생종이나 (HL), G2019S 돌연변이 단백질(HMG)을 발현하는 플라스미드를 삽입한 세포주를 지칭한다. Myc tag은 G2019S 단백질에만 융합되었으므로 HMG 세포주에서만 나타난다. 사용된 단백질 양을 확인하 기 위하여 같은 blot을 beta-actin 항체로 염색하였다 (아래 도). 왼쪽의 숫자는 marker로 사용한 단백질의 분자량(kd)이다. 또한 도 5의 b에서는 각각의 LRRK2 발현양 (a 중간 도)을 beta-actin 발현양으로 나눠서 보정한, LRRK2의 상대적인 발현도를 나타낸 것이다.
또 이들 LRRK2 유전자가 해당 세포에서 염색체에 삽입되어 발현함을 각 세포의 RNA를 분리하여 삽입된 유전자에 특이적인 프라이머쌍을 이용하여 RT-PCR로 확인하였다. RNA분리는 trizol (Invitrogen Co.)을 사용하였고, 일반적인 방법에 의해 reverse transcriptase를 이용하여 cDNA를 만든 다음 해당 프라이머쌍으로 PCR을 행하여 agarose gel에서 전기영동하여 분석하였다 (도 6).
도 6에서는 HL2, HMG15에 RSL1을 500 nM 처리하고 3일 후에 세포를 모아서 전체 RNA를 분리하고 일반적인 방법에 의해 역전사를 행하여 cDNA를 만들고 만들어진 cDNA를 주형으로 하여, d에 표시된 프라이머쌍으로 PCR을 수행함. 그 PCR 산물을 agarose gel 전기영동으로 분석한 결과를 a, b, c에 해당 프라이머 쌍과 함께 보였다. HL2, HMG15은 도 5에서 설명한 각clon을 지칭하며 숫자는 실험에 사용하려고 선택한 클론 번호이다. M은 size marker DNA, P는 해당 플라스미드를 주형으로 하여 동일한 PCR을 진행한 결과이다. 동량의 cDNA가 사용되었음을 확인하기 위하여 GAPDH에 대한 PCR을 병행하였다. 각 PCR의 조건은 아래와 같다. a: 95도 5분 반응 후 95도 30초, 45도 30초, 72도 30초 40cycles, 72도 7분 반응. b: 95도 5분 반응 후 95도 30초, 48도 30초, 72도 1분 40cycles, 72도 7분 반응. c: 95도 5분 반응 후 95도 30초, 59도 30초, 72도 30초 26cycles, 72도 7분 반응 또한 각 PCR에 사용된 프라이머 서열은 다음과 같다.
LRRK2-F: GTCATGATGACAGCACAGC, pNEBR-R: TAATACGACTCACTATAGGC, LRRK2-R: CTTCATTCTCATTCTTTTCCTC, pNEBR-F: GCCAAGCTTCTCTGCAGGATATC, GAPDH-F: GCCCACTGAAGGGCATCTTG, GAPDH-R: AGGCCATGTAGGCCATGAGG.
이러한 방법으로 구축한 세포주에 RSL1을 처리하여 각 경우의 세포생존률을 비교하였다. 각 해당 세포를 48 well plate에 깐 뒤 24시간 후에 RSL1을 처리하고 2-4일 후에 crystal violet assay로 생존률을 결정하였다 (도 7). 각 sample마다 3개의 well을 사용하였고 RSL1을 처리하지 않고 2일 간 배양한 HV sample의 세포 생존률을 100%로 하여 다른 sample의 생존률을 환산하였다.
실시예 7. LRRK2 G2019S의 세포 독성을 저해하는 유전자를 검색하는 방법
G2019S 유전자를 안정적으로 발현하는 MN9D 세포주를 100mm dish에 깔아준 뒤 하루 뒤에 인간 유전자의 cDNA 라이브러리와 GFP(green fluorescence protein) 유전자를 가진 plasmid를 4:1로 섞어서 같이 형질 전환한 후 상기 실시예 6에서 확립된 조건에 따라 세포 사멸을 촉진시킨다. 이 때, GFP와 유전자 라이브러리 플라스미드의 항생제 저항성 마커를 각각 kanamycin과 ampicillin으로 사용한다. 살아 남은 세포중에서 형질전환된 세포를 FACS (fluorecence-activated cell sorting)로 분리하여 플라스미드를 포함한 total genomic DNA를 이들 세포로부터 분리한다.
유전자 라이브러리를 증폭시키기 위하여, 분리된 플라스미드를 대장균에 형질전환하고 GFP가 아닌 유전자 라이브러리만 증폭시키는 조건인 ampicillin을 처리하여 배양한다. 하루 뒤에 나온 콜로니를 다 같이 섞어서 플라스미드 라이브러리를 분리한다.
이들 플라스미드 라이브러리 DNA를 준비된 G2019S 유전자를 안정적으로 발현하는 MN9D 세포주에 다시 형질전환하여 상기 방법을 되풀이하여 살아 남은 세포에서 유전자 플라스미드를 분리하여 대장균에서 증폭시킨다. 이러한 검색 방법을 5-10회 거쳐서 G2019S 독성을 줄여 주는 특정 유전자들을 점차 증폭시킨다.
이 때 GFP 플라스미드를 이용한 FACS 대신 MACS (magnetic-activated cell sorting)를 이용하는 플라스미드를 사용하여 자장에 의한 세포분리법을 이용할 수도 있다. 또한 G2019S 유전자를 안정적으로 발현하는 MN9D 세포주 대신에 G2019S를 발현하는 플라스미드를 유전자 라이브러리와 같이 SN4741 세포주에 임시적으로 형질전환하여 사용할 수도 있다. 이러한 방법을 거쳐, 유전자 플라스미드 조합의 형질전환을 거친 G2019S 발현 세포주의 세포사멸도가, 유전자가 없는 대조군 벡터를 형질전환한 G2019S 발현 세포주의 세포사멸도에 비해 충분히 높은 차이가 날 때, 대장균에서 각 콜로니로부터 플라스미드를 각각 분리한다. 분리한 플라스미드를 48 well plate에 깐 G2019S 발현세포주를 이용하여 각 플라스미드에 대해 같은 방법으로 세포사멸도를 대조군 벡터를 형질전환한 경우와 비교한다. 분리한 유전자 플라스미드를 형질전환한 경우가 대조군 플라스미드를 형질전환한 경우와 의미있는 생존률 차이가 나타나면 그 유전자 염기 서열을 읽어서 유전자를 동정한다. 또한 유 전자 라이브러리 대신 특정 유전자에 대해 미리 선별된 siRNA 라이브러리가 이용 가능하면, 이 라이브러리를 96 well 에 미리 깐 stable 세포주에 각각 형질전환하여 crystal violet assay를 통해 세포사멸을 저해하는 siRNA를 직접적으로 검색할 수도 있다.
실시예 8. LRRK2 G2019S의 세포 독성을 저해하는 화합물을 검색하는 방법
실시예 7과 같이 세포주를 키우고, 유전자 라이브러리대신 검색하고자 하는 화합물 라이브러리를 well당 한 종류씩 처리해 준 다음 세포 사멸도를 대조군의 세포사멸도와 비교하여 의미있는 차이가 나는 경우의 화합물을 선택한다.
이 실시예를 검증하기 위하여 LRRK2의 G2019S에 의한 세포사멸을 저해하는 화합물로 보고된 ERK (extraccellular signal-regulated kinase) inhibitor (Liou et al. 2008)를 사용하였다. 도 8에서와 같이 G2019S를 발현하고 과산화수소를 처리한 경우에 ERK inhibitor PD98059 (Calbiochem Co. 미국 캘리포니아주)를 처리한 sample이 ERK inhibitor를 처리하지 않은 sample에 비해 더 높은 세포 생존률을 보일 뿐만 아니라, G2019S를 발현하지 않은 대조군 벡터만 형질전환한 경우에 비해서도 약간 높거나 거의 비슷한 생존률을 보여 ERK inhibitor가 G2019S와 과산화수소에 의한 SN4741 세포 독성을 거의 회복시키는 걸 알 수 있다. 다만 ERK inhibitor는 그 작용점이 LRRK2가 아니라 세포의 여러 신호전달 회로에 관여하는 ERK이기 때문에 본 특허의 목적인 파킨슨병 치료를 위한 특이적인 화합물은 될 수 없을 것이다. 실제로 대조군 벡터만 형질전환한 경우에는 과산화수소를 처리하면 ERK inhibitor 처리가 세포사멸을 더 촉진시킨 것을 볼 수 있다.
도 8에서는 LRRK2 야생종이나 G2019S 단백질을 발현하는 플라스미드나, 대조군 벡터 플라스미드를 SN4741 세포주에 형질전환한 후 48시간 뒤에 과산화수소 100 μM을 24시간 처리하고 crystal violet assay를 실시하였다. ERK inhibitor PD98059 (Calbiochem Co. 캘리포니아주, 미국)는 과산화수소 처리하기 1시간 전에 5 μM로 처리하였고, crystal violet assay 결과를, 대조군 플라스미드에 과산화수소를 처리하지 않은 경우를 100 %로 하여 각 sample의 생존률을 환산하였다.함. 각 sample마다 3개의 well을 사용하였다.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.
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도 1은 2527개의 아미노산으로 구성된 LRRK2 단백질의 기능에 따른 도메인 모식도를 나타낸 것이다. 파킨슨병 환자에서 발견되는 돌연변이가 표시되어 있다. LRR: leucine rich repeat, Roc:Ras of complex, COR: C-terminal of Roc, MAPKKK:mitogen-activated protein kinase kinase kinase.
도 2는 녹색형광단백질 (green fluorescence protein: GFP)을 형질 전환한 SN4741 세포주의 GFP 단백질 발현 양상을 나타낸 것이다.
도 3은 LRRK2 돌연변이 단백질과 야생종을 발현하고 과산화수소를 처리한 SN4741세포의 생존률을 나타낸 것이다.
도 4는 과산화수소 처리 조건에서 LRRK2 단백질의 과발현 유무에 따른 독성의 차이를 최대화하기 위한 최적화 조건을 나타낸 것이다.
도 5는 LRRK2 야생종과 G2019S 단백질을 안정적으로 발현하는 MN9D 세포주의 LRRK2발현도를 나타낸 것이다.
도 6은 구축한 stable cell line에 삽입된 plasmid로부터 전사된 LRRK2 mRNA를 reverse transcription (RT)-PCR로 확인한 것이다.
도 7 LRRK2 단백질을 발현하는 stable cell line을 1x105 cell/well로 48 well plate에 깔은 다음 24시간 후에 RSL1을 500 nM로 처리한 결과를 나타낸 것이다.
도 8은 LRRK2 야생종이나 G2019S 단백질을 발현하는 플라스미드나, 대조군 벡터 플라스미드를 SN4741 세포주에 형질전환한 후 47시간 뒤에 ERK저해제 PD98059를 5 μM로 처리하고 그 1시간 뒤에 과산화수소수 100 μM을 24시간 처리하고 crystal violet assay를 실시한 결과를 나타낸 것이다.
<110> Inje University Industry-Academic Cooperation Foundation <120> Methods to screen materials to inhibit Parkinson's disease <160> 10 <170> KopatentIn 1.71 <210> 1 <211> 7584 <212> DNA <213> Homo sapiens <400> 1 atggctagtg gcagctgtca ggggtgcgaa gaggacgagg aaactctgaa gaagttgata 60 gtcaggctga acaatgtcca ggaaggaaaa cagatagaaa cgctggtcca aatcctggag 120 gatctgctgg tgttcacgta ctccgagcac gcctccaagt tatttcaagg caaaaatatc 180 catgtgcctc tgttgatcgt cttggactcc tatatgagag tcgcgagtgt gcagcaggtg 240 ggttggtcac ttctgtgcaa attaatagaa gtctgtccag gtacaatgca aagcttaatg 300 ggaccccagg atgttggaaa tgattgggaa gtccttggtg ttcaccaatt gattcttaaa 360 atgctaacag ttcataatgc cagtgtaaac ttgtcagtga ttggactgaa gaccttagat 420 ctcctcctaa cttcaggtaa aatcaccttg ctgatactgg atgaagaaag tgatattttc 480 atgttaattt ttgatgccat gcactcattt ccagccaatg atgaagtcca gaaacttgga 540 tgcaaagctt tacatgtgct gtttgagaga gtctcagagg agcaactgac tgaatttgtt 600 gagaacaaag attatatgat attgttaagt gcgtcaacaa attttaaaga tgaagaggaa 660 attgtgcttc atgtgctgca ttgtttacat tccctagcga ttccttgcaa taatgtggaa 720 gtcctcatga gtggcaatgt caggtgttat aatattgtgg tggaagctat gaaagcattc 780 cctatgagtg aaagaattca agaagtgagt tgctgtttgc tccataggct tacattaggt 840 aattttttca atatcctggt attaaacgaa gtccatgagt ttgtggtgaa agctgtgcag 900 cagtacccag agaatgcagc attgcagatc tcagcgctca gctgtttggc cctcctcact 960 gagactattt tcttaaatca agatttagag gaaaagaatg agaatcaaga gaatgatgat 1020 gagggggaag aagataaatt gttttggctg gaagcctgtt acaaagcatt aacgtggcat 1080 agaaagaaca agcacgtgca ggaggccgca tgctgggcac taaataatct ccttatgtac 1140 caaaacagtt tacatgagaa gattggagat gaagatggcc atttcccagc tcatagggaa 1200 gtgatgctct ccatgctgat gcattcttca tcaaaggaag ttttccaggc atctgcgaat 1260 gcattgtcaa ctctcttaga acaaaatgtt aatttcagaa aaatactgtt atcaaaagga 1320 atacacctga atgttttgga gttaatgcag aagcatatac attctcctga agtggctgaa 1380 agtggctgta aaatgctaaa tcatcttttt gaaggaagca acacttccct ggatataatg 1440 gcagcagtgg tccccaaaat actaacagtt atgaaacgtc atgagacatc attaccagtg 1500 cagctggagg cgcttcgagc tattttacat tttatagtgc ctggcatgcc agaagaatcc 1560 agggaggata cagaatttca tcataagcta aatatggtta aaaaacagtg tttcaagaat 1620 gatattcaca aactggtcct agcagctttg aacaggttca ttggaaatcc tgggattcag 1680 aaatgtggat taaaagtaat ttcttctatt gtacattttc ctgatgcatt agagatgtta 1740 tccctggaag gtgctatgga ttcagtgctt cacacactgc agatgtatcc agatgaccaa 1800 gaaattcagt gtctgggttt aagtcttata ggatacttga ttacaaagaa gaatgtgttc 1860 ataggaactg gacatctgct ggcaaaaatt ctggtttcca gcttataccg atttaaggat 1920 gttgctgaaa tacagactaa aggatttcag acaatcttag caatcctcaa attgtcagca 1980 tctttttcta agctgctggt gcatcattca tttgacttag taatattcca tcaaatgtct 2040 tccaatatca tggaacaaaa ggatcaacag tttctaaacc tctgttgcaa gtgttttgca 2100 aaagtagcta tggatgatta cttaaaaaat gtgatgctag agagagcgtg tgatcagaat 2160 aacagcatca tggttgaatg cttgcttcta ttgggagcag atgccaatca agcaaaggag 2220 ggatcttctt taatttgtca ggtatgtgag aaagagagca gtcccaaatt ggtggaactc 2280 ttactgaata gtggatctcg tgaacaagat gtacgaaaag cgttgacgat aagcattggg 2340 aaaggtgaca gccagatcat cagcttgctc ttaaggaggc tggccctgga tgtggccaac 2400 aatagcattt gccttggagg attttgtata ggaaaagttg aaccttcttg gcttggtcct 2460 ttatttccag ataagacttc taatttaagg aaacaaacaa atatagcatc tacactagca 2520 agaatggtga tcagatatca gatgaaaagt gctgtggaag aaggaacagc ctcaggcagc 2580 gatggaaatt tttctgaaga tgtgctgtct aaatttgatg aatggacctt tattcctgac 2640 tcttctatgg acagtgtgtt tgctcaaagt gatgacctgg atagtgaagg aagtgaaggc 2700 tcatttcttg tgaaaaagaa atctaattca attagtgtag gagaatttta ccgagatgcc 2760 gtattacagc gttgctcacc aaatttgcaa agacattcca attccttggg gcccattttt 2820 gatcatgaag atttactgaa gcgaaaaaga aaaatactat cttcagatga ttcactcagg 2880 tcatcaaaac ttcaatccca tatgaggcat tcagacagca tttcttctct ggcttctgag 2940 agagaatata ttacatcact agacctttca gcaaatgaac taagagatat tgatgcccta 3000 agccagaaat gctgtataag tgttcatttg gagcatcttg aaaagctgga gcttcaccag 3060 aatgcactca cgagctttcc acaacagcta tgtgaaactc tgaagagttt gacacatttg 3120 gacttgcaca gtaataaatt tacatcattt ccttcttatt tgttgaaaat gagttgtatt 3180 gctaatcttg atgtctctcg aaatgacatt ggaccctcag tggttttaga tcctacagtg 3240 aaatgtccaa ctctgaaaca gtttaacctg tcatataacc agctgtcttt tgtacctgag 3300 aacctcactg atgtggtaga gaaactggag cagctcattt tagaaggaaa taaaatatca 3360 gggatatgct cccccttgag actgaaggaa ctgaagattt taaaccttag taagaaccac 3420 atttcatccc tatcagagaa ctttcttgag gcttgtccta aagtggagag tttcagtgcc 3480 agaatgaatt ttcttgctgc tatgcctttc ttgcctcctt ctatgacaat cctaaaatta 3540 tctcagaaca aattttcctg tattccagaa gcaattttaa atcttccaca cttgcggtct 3600 ttagatatga gcagcaatga tattcagtac ctaccaggtc ccgcacactg gaaatctttg 3660 aacttaaggg aactcttatt tagccataat cagatcagca tcttggactt gagtgaaaaa 3720 gcatatttat ggtctagagt agagaaactg catctttctc acaataaact gaaagagatt 3780 cctcctgaga ttggctgtct tgaaaatctg acatctctgg atgtcagtta caacttggaa 3840 ctaagatcct ttcccaatga aatggggaaa ttaagcaaaa tatgggatct tcctttggat 3900 gaactgcatc ttaactttga ttttaaacat ataggatgta aagccaaaga catcataagg 3960 tttcttcaac agcgattaaa aaaggctgtg ccttataacc gaatgaaact tatgattgtg 4020 ggaaatactg ggagtggtaa aaccacctta ttgcagcaat taatgaaaac caagaaatca 4080 gatcttggaa tgcaaagtgc cacagttggc atagatgtga aagactggcc tatccaaata 4140 agagacaaaa gaaagagaga tctcgtccta aatgtgtggg attttgcagg tcgtgaggaa 4200 ttctatagta ctcatcccca ttttatgacg cagcgagcat tgtaccttgc tgtctatgac 4260 ctcagcaagg gacaggctga agttgatgcc atgaagcctt ggctcttcaa tataaaggct 4320 cgcgcttctt cttcccctgt gattctcgtt ggcacacatt tggatgtttc tgatgagaag 4380 caacgcaaag cctgcatgag taaaatcacc aaggaactcc tgaataagcg agggttccct 4440 gccatacgag attaccactt tgtgaatgcc accgaggaat ctgatgcttt ggcaaaactt 4500 cggaaaacca tcataaacga gagccttaat ttcaagatcc gagatcagct tgttgttgga 4560 cagctgattc cagactgcta tgtagaactt gaaaaaatca ttttatcgga gcgtaaaaat 4620 gtgccaattg aatttcccgt aattgaccgg aaacgattat tacaactagt gagagaaaat 4680 cagctgcagt tagatgaaaa tgagcttcct cacgcagttc actttctaaa tgaatcagga 4740 gtccttcttc attttcaaga cccagcactg cagttaagtg acttgtactt tgtggaaccc 4800 aagtggcttt gtaaaatcat ggcacagatt ttgacagtga aagtggaagg ttgtccaaaa 4860 caccctaagg gcattatttc gcgtagagat gtggaaaaat ttctttcaaa aaaaaggaaa 4920 tttccaaaga actacatgtc acagtatttt aagctcctag aaaaattcca gattgctttg 4980 ccaataggag aagaatattt gctggttcca agcagtttgt ctgaccacag gcctgtgata 5040 gagcttcccc attgtgagaa ctctgaaatt atcatccgac tatatgaaat gccttatttt 5100 ccaatgggat tttggtcaag attaatcaat cgattacttg agatttcacc ttacatgctt 5160 tcagggagag aacgagcact tcgcccaaac agaatgtatt ggcgacaagg catttactta 5220 aattggtctc ctgaagctta ttgtctggta ggatctgaag tcttagacaa tcatccagag 5280 agtttcttaa aaattacagt tccttcttgt agaaaaggct gtattctttt gggccaagtt 5340 gtggaccaca ttgattctct catggaagaa tggtttcctg ggttgctgga gattgatatt 5400 tgtggtgaag gagaaactct gttgaagaaa tgggcattat atagttttaa tgatggcgaa 5460 gaacatcaaa aaatcttact tgatgacttg atgaagaaag cagaggaagg agatctctta 5520 gtaaatccag atcaaccaag gctcaccatt ccaatatctc agattgcccc tgacttgatt 5580 ttggctgacc tgcctagaaa tattatgttg aataatgatg agttggaatt tgaacaagct 5640 ccagagtttc tcctaggtga tggcagtttt ggatcagttt accgagcagc ctatgaagga 5700 gaagaagtgg ctgtgaagat ttttaataaa catacatcac tcaggctgtt aagacaagag 5760 cttgtggtgc tttgccacct ccaccacccc agtttgatat ctttgctggc agctgggatt 5820 cgtccccgga tgttggtgat ggagttagcc tccaagggtt ccttggatcg cctgcttcag 5880 caggacaaag ccagcctcac tagaacccta cagcacagga ttgcactcca cgtagctgat 5940 ggtttgagat acctccactc agccatgatt atataccgag acctgaaacc ccacaatgtg 6000 ctgcttttca cactgtatcc caatgctgcc atcattgcaa agattgctga ctacagcatt 6060 gctcagtact gctgtagaat ggggataaaa acatcagagg gcacaccagg gtttcgtgca 6120 cctgaagttg ccagaggaaa tgtcatttat aaccaacagg ctgatgttta ttcatttggt 6180 ttactactct atgacatttt gacaactgga ggtagaatag tagagggttt gaagtttcca 6240 aatgagtttg atgaattaga aatacaagga aaattacctg atccagttaa agaatatggt 6300 tgtgccccat ggcctatggt tgagaaatta attaaacagt gtttgaaaga aaatcctcaa 6360 gaaaggccta cttctgccca ggtctttgac attttgaatt cagctgaatt agtctgtctg 6420 acgagacgca ttttattacc taaaaacgta attgttgaat gcatggttgc tacacatcac 6480 aacagcagga atgcaagcat ttggctgggc tgtgggcaca ccgacagagg acagctctca 6540 tttcttgact taaatactga aggatacact tctgaggaag ttgctgatag tagaatattg 6600 tgcttagcct tggtgcatct tcctgttgaa aaggaaagct ggattgtgtc tgggacacag 6660 tctggtactc tcctggtcat caataccgaa gatgggaaaa agagacatac cctagaaaag 6720 atgactgatt ctgtcacttg tttgtattgc aattcctttt ccaagcaaag caaacaaaaa 6780 aattttcttt tggttggaac cgctgatggc aagttagcaa tttttgaaga taagactgtt 6840 aagcttaaag gagctgctcc tttgaagata ctaaatatag gaaatgtcag tactccattg 6900 atgtgtttga gtgaatccac aaattcaacg gaaagaaatg taatgtgggg aggatgtggc 6960 acaaagattt tctccttttc taatgatttc accattcaga aactcattga gacaagaaca 7020 agccaactgt tttcttatgc agctttcagt gattccaaca tcataacagt ggtggtagac 7080 actgctctct atattgctaa gcaaaatagc cctgttgtgg aagtgtggga taagaaaact 7140 gaaaaactct gtggactaat agactgcgtg cactttttaa gggaggtaat ggtaaaagaa 7200 aacaaggaat caaaacacaa aatgtcttat tctgggagag tgaaaaccct ctgccttcag 7260 aagaacactg ctctttggat aggaactgga ggaggccata ttttactcct ggatctttca 7320 actcgtcgac ttatacgtgt aatttacaac ttttgtaatt cggtcagagt catgatgaca 7380 gcacagctag gaagccttaa aaatgtcatg ctggtattgg gctacaaccg gaaaaatact 7440 gaaggtacac aaaagcagaa agagatacaa tcttgcttga ccgtttggga catcaatctt 7500 ccacatgaag tgcaaaattt agaaaaacac attgaagtga gaaaagaatt agctgaaaaa 7560 atgagacgaa catctgttga gtaa 7584 <210> 2 <211> 2527 <212> PRT <213> Homo sapiens <400> 2 Met Ala Ser Gly Ser Cys Gln Gly Cys Glu Glu Asp Glu Glu Thr Leu 1 5 10 15 Lys Lys Leu Ile Val Arg Leu Asn Asn Val Gln Glu Gly Lys Gln Ile 20 25 30 Glu Thr Leu Val Gln Ile Leu Glu Asp Leu Leu Val Phe Thr Tyr Ser 35 40 45 Glu His Ala Ser Lys Leu Phe Gln Gly Lys Asn Ile His Val Pro Leu 50 55 60 Leu Ile Val Leu Asp Ser Tyr Met Arg Val Ala Ser Val Gln Gln Val 65 70 75 80 Gly Trp Ser Leu Leu Cys Lys Leu Ile Glu Val Cys Pro Gly Thr Met 85 90 95 Gln Ser Leu Met Gly Pro Gln Asp Val Gly Asn Asp Trp Glu Val Leu 100 105 110 Gly Val His Gln Leu Ile Leu Lys Met Leu Thr Val His Asn Ala Ser 115 120 125 Val Asn Leu Ser Val Ile Gly Leu Lys Thr Leu Asp Leu Leu Leu Thr 130 135 140 Ser Gly Lys Ile Thr Leu Leu Ile Leu Asp Glu Glu Ser Asp Ile Phe 145 150 155 160 Met Leu Ile Phe Asp Ala Met His Ser Phe Pro Ala Asn Asp Glu Val 165 170 175 Gln Lys Leu Gly Cys Lys Ala Leu His Val Leu Phe Glu Arg Val Ser 180 185 190 Glu Glu Gln Leu Thr Glu Phe Val Glu Asn Lys Asp Tyr Met Ile Leu 195 200 205 Leu Ser Ala Leu Thr Asn Phe Lys Asp Glu Glu Glu Ile Val Leu His 210 215 220 Val Leu His Cys Leu His Ser Leu Ala Ile Pro Cys Asn Asn Val Glu 225 230 235 240 Val Leu Met Ser Gly Asn Val Arg Cys Tyr Asn Ile Val Val Glu Ala 245 250 255 Met Lys Ala Phe Pro Met Ser Glu Arg Ile Gln Glu Val Ser Cys Cys 260 265 270 Leu Leu His Arg Leu Thr Leu Gly Asn Phe Phe Asn Ile Leu Val Leu 275 280 285 Asn Glu Val His Glu Phe Val Val Lys Ala Val Gln Gln Tyr Pro Glu 290 295 300 Asn Ala Ala Leu Gln Ile Ser Ala Leu Ser Cys Leu Ala Leu Leu Thr 305 310 315 320 Glu Thr Ile Phe Leu Asn Gln Asp Leu Glu Glu Lys Asn Glu Asn Gln 325 330 335 Glu Asn Asp Asp Glu Gly Glu Glu Asp Lys Leu Phe Trp Leu Glu Ala 340 345 350 Cys Tyr Lys Ala Leu Thr Trp His Arg Lys Asn Lys His Val Gln Glu 355 360 365 Ala Ala Cys Trp Ala Leu Asn Asn Leu Leu Met Tyr Gln Asn Ser Leu 370 375 380 His Glu Lys Ile Gly Asp Glu Asp Gly His Phe Pro Ala His Arg Glu 385 390 395 400 Val Met Leu Ser Met Leu Met His Ser Ser Ser Lys Glu Val Phe Gln 405 410 415 Ala Ser Ala Asn Ala Leu Ser Thr Leu Leu Glu Gln Asn Val Asn Phe 420 425 430 Arg Lys Ile Leu Leu Ser Lys Gly Ile His Leu Asn Val Leu Glu Leu 435 440 445 Met Gln Lys His Ile His Ser Pro Glu Val Ala Glu Ser Gly Cys Lys 450 455 460 Met Leu Asn His Leu Phe Glu Gly Ser Asn Thr Ser Leu Asp Ile Met 465 470 475 480 Ala Ala Val Val Pro Lys Ile Leu Thr Val Met Lys Arg His Glu Thr 485 490 495 Ser Leu Pro Val Gln Leu Glu Ala Leu Arg Ala Ile Leu His Phe Ile 500 505 510 Val Pro Gly Met Pro Glu Glu Ser Arg Glu Asp Thr Glu Phe His His 515 520 525 Lys Leu Asn Met Val Lys Lys Gln Cys Phe Lys Asn Asp Ile His Lys 530 535 540 Leu Val Leu Ala Ala Leu Asn Arg Phe Ile Gly Asn Pro Gly Ile Gln 545 550 555 560 Lys Cys Gly Leu Lys Val Ile Ser Ser Ile Val His Phe Pro Asp Ala 565 570 575 Leu Glu Met Leu Ser Leu Glu Gly Ala Met Asp Ser Val Leu His Thr 580 585 590 Leu Gln Met Tyr Pro Asp Asp Gln Glu Ile Gln Cys Leu Gly Leu Ser 595 600 605 Leu Ile Gly Tyr Leu Ile Thr Lys Lys Asn Val Phe Ile Gly Thr Gly 610 615 620 His Leu Leu Ala Lys Ile Leu Val Ser Ser Leu Tyr Arg Phe Lys Asp 625 630 635 640 Val Ala Glu Ile Gln Thr Lys Gly Phe Gln Thr Ile Leu Ala Ile Leu 645 650 655 Lys Leu Ser Ala Ser Phe Ser Lys Leu Leu Val His His Ser Phe Asp 660 665 670 Leu Val Ile Phe His Gln Met Ser Ser Asn Ile Met Glu Gln Lys Asp 675 680 685 Gln Gln Phe Leu Asn Leu Cys Cys Lys Cys Phe Ala Lys Val Ala Met 690 695 700 Asp Asp Tyr Leu Lys Asn Val Met Leu Glu Arg Ala Cys Asp Gln Asn 705 710 715 720 Asn Ser Ile Met Val Glu Cys Leu Leu Leu Leu Gly Ala Asp Ala Asn 725 730 735 Gln Ala Lys Glu Gly Ser Ser Leu Ile Cys Gln Val Cys Glu Lys Glu 740 745 750 Ser Ser Pro Lys Leu Val Glu Leu Leu Leu Asn Ser Gly Ser Arg Glu 755 760 765 Gln Asp Val Arg Lys Ala Leu Thr Ile Ser Ile Gly Lys Gly Asp Ser 770 775 780 Gln Ile Ile Ser Leu Leu Leu Arg Arg Leu Ala Leu Asp Val Ala Asn 785 790 795 800 Asn Ser Ile Cys Leu Gly Gly Phe Cys Ile Gly Lys Val Glu Pro Ser 805 810 815 Trp Leu Gly Pro Leu Phe Pro Asp Lys Thr Ser Asn Leu Arg Lys Gln 820 825 830 Thr Asn Ile Ala Ser Thr Leu Ala Arg Met Val Ile Arg Tyr Gln Met 835 840 845 Lys Ser Ala Val Glu Glu Gly Thr Ala Ser Gly Ser Asp Gly Asn Phe 850 855 860 Ser Glu Asp Val Leu Ser Lys Phe Asp Glu Trp Thr Phe Ile Pro Asp 865 870 875 880 Ser Ser Met Asp Ser Val Phe Ala Gln Ser Asp Asp Leu Asp Ser Glu 885 890 895 Gly Ser Glu Gly Ser Phe Leu Val Lys Lys Lys Ser Asn Ser Ile Ser 900 905 910 Val Gly Glu Phe Tyr Arg Asp Ala Val Leu Gln Arg Cys Ser Pro Asn 915 920 925 Leu Gln Arg His Ser Asn Ser Leu Gly Pro Ile Phe Asp His Glu Asp 930 935 940 Leu Leu Lys Arg Lys Arg Lys Ile Leu Ser Ser Asp Asp Ser Leu Arg 945 950 955 960 Ser Ser Lys Leu Gln Ser His Met Arg His Ser Asp Ser Ile Ser Ser 965 970 975 Leu Ala Ser Glu Arg Glu Tyr Ile Thr Ser Leu Asp Leu Ser Ala Asn 980 985 990 Glu Leu Arg Asp Ile Asp Ala Leu Ser Gln Lys Cys Cys Ile Ser Val 995 1000 1005 His Leu Glu His Leu Glu Lys Leu Glu Leu His Gln Asn Ala Leu Thr 1010 1015 1020 Ser Phe Pro Gln Gln Leu Cys Glu Thr Leu Lys Ser Leu Thr His Leu 1025 1030 1035 1040 Asp Leu His Ser Asn Lys Phe Thr Ser Phe Pro Ser Tyr Leu Leu Lys 1045 1050 1055 Met Ser Cys Ile Ala Asn Leu Asp Val Ser Arg Asn Asp Ile Gly Pro 1060 1065 1070 Ser Val Val Leu Asp Pro Thr Val Lys Cys Pro Thr Leu Lys Gln Phe 1075 1080 1085 Asn Leu Ser Tyr Asn Gln Leu Ser Phe Val Pro Glu Asn Leu Thr Asp 1090 1095 1100 Val Val Glu Lys Leu Glu Gln Leu Ile Leu Glu Gly Asn Lys Ile Ser 1105 1110 1115 1120 Gly Ile Cys Ser Pro Leu Arg Leu Lys Glu Leu Lys Ile Leu Asn Leu 1125 1130 1135 Ser Lys Asn His Ile Ser Ser Leu Ser Glu Asn Phe Leu Glu Ala Cys 1140 1145 1150 Pro Lys Val Glu Ser Phe Ser Ala Arg Met Asn Phe Leu Ala Ala Met 1155 1160 1165 Pro Phe Leu Pro Pro Ser Met Thr Ile Leu Lys Leu Ser Gln Asn Lys 1170 1175 1180 Phe Ser Cys Ile Pro Glu Ala Ile Leu Asn Leu Pro His Leu Arg Ser 1185 1190 1195 1200 Leu Asp Met Ser Ser Asn Asp Ile Gln Tyr Leu Pro Gly Pro Ala His 1205 1210 1215 Trp Lys Ser Leu Asn Leu Arg Glu Leu Leu Phe Ser His Asn Gln Ile 1220 1225 1230 Ser Ile Leu Asp Leu Ser Glu Lys Ala Tyr Leu Trp Ser Arg Val Glu 1235 1240 1245 Lys Leu His Leu Ser His Asn Lys Leu Lys Glu Ile Pro Pro Glu Ile 1250 1255 1260 Gly Cys Leu Glu Asn Leu Thr Ser Leu Asp Val Ser Tyr Asn Leu Glu 1265 1270 1275 1280 Leu Arg Ser Phe Pro Asn Glu Met Gly Lys Leu Ser Lys Ile Trp Asp 1285 1290 1295 Leu Pro Leu Asp Glu Leu His Leu Asn Phe Asp Phe Lys His Ile Gly 1300 1305 1310 Cys Lys Ala Lys Asp Ile Ile Arg Phe Leu Gln Gln Arg Leu Lys Lys 1315 1320 1325 Ala Val Pro Tyr Asn Arg Met Lys Leu Met Ile Val Gly Asn Thr Gly 1330 1335 1340 Ser Gly Lys Thr Thr Leu Leu Gln Gln Leu Met Lys Thr Lys Lys Ser 1345 1350 1355 1360 Asp Leu Gly Met Gln Ser Ala Thr Val Gly Ile Asp Val Lys Asp Trp 1365 1370 1375 Pro Ile Gln Ile Arg Asp Lys Arg Lys Arg Asp Leu Val Leu Asn Val 1380 1385 1390 Trp Asp Phe Ala Gly Arg Glu Glu Phe Tyr Ser Thr His Pro His Phe 1395 1400 1405 Met Thr Gln Arg Ala Leu Tyr Leu Ala Val Tyr Asp Leu Ser Lys Gly 1410 1415 1420 Gln Ala Glu Val Asp Ala Met Lys Pro Trp Leu Phe Asn Ile Lys Ala 1425 1430 1435 1440 Arg Ala Ser Ser Ser Pro Val Ile Leu Val Gly Thr His Leu Asp Val 1445 1450 1455 Ser Asp Glu Lys Gln Arg Lys Ala Cys Met Ser Lys Ile Thr Lys Glu 1460 1465 1470 Leu Leu Asn Lys Arg Gly Phe Pro Ala Ile Arg Asp Tyr His Phe Val 1475 1480 1485 Asn Ala Thr Glu Glu Ser Asp Ala Leu Ala Lys Leu Arg Lys Thr Ile 1490 1495 1500 Ile Asn Glu Ser Leu Asn Phe Lys Ile Arg Asp Gln Leu Val Val Gly 1505 1510 1515 1520 Gln Leu Ile Pro Asp Cys Tyr Val Glu Leu Glu Lys Ile Ile Leu Ser 1525 1530 1535 Glu Arg Lys Asn Val Pro Ile Glu Phe Pro Val Ile Asp Arg Lys Arg 1540 1545 1550 Leu Leu Gln Leu Val Arg Glu Asn Gln Leu Gln Leu Asp Glu Asn Glu 1555 1560 1565 Leu Pro His Ala Val His Phe Leu Asn Glu Ser Gly Val Leu Leu His 1570 1575 1580 Phe Gln Asp Pro Ala Leu Gln Leu Ser Asp Leu Tyr Phe Val Glu Pro 1585 1590 1595 1600 Lys Trp Leu Cys Lys Ile Met Ala Gln Ile Leu Thr Val Lys Val Glu 1605 1610 1615 Gly Cys Pro Lys His Pro Lys Gly Ile Ile Ser Arg Arg Asp Val Glu 1620 1625 1630 Lys Phe Leu Ser Lys Lys Arg Lys Phe Pro Lys Asn Tyr Met Ser Gln 1635 1640 1645 Tyr Phe Lys Leu Leu Glu Lys Phe Gln Ile Ala Leu Pro Ile Gly Glu 1650 1655 1660 Glu Tyr Leu Leu Val Pro Ser Ser Leu Ser Asp His Arg Pro Val Ile 1665 1670 1675 1680 Glu Leu Pro His Cys Glu Asn Ser Glu Ile Ile Ile Arg Leu Tyr Glu 1685 1690 1695 Met Pro Tyr Phe Pro Met Gly Phe Trp Ser Arg Leu Ile Asn Arg Leu 1700 1705 1710 Leu Glu Ile Ser Pro Tyr Met Leu Ser Gly Arg Glu Arg Ala Leu Arg 1715 1720 1725 Pro Asn Arg Met Tyr Trp Arg Gln Gly Ile Tyr Leu Asn Trp Ser Pro 1730 1735 1740 Glu Ala Tyr Cys Leu Val Gly Ser Glu Val Leu Asp Asn His Pro Glu 1745 1750 1755 1760 Ser Phe Leu Lys Ile Thr Val Pro Ser Cys Arg Lys Gly Cys Ile Leu 1765 1770 1775 Leu Gly Gln Val Val Asp His Ile Asp Ser Leu Met Glu Glu Trp Phe 1780 1785 1790 Pro Gly Leu Leu Glu Ile Asp Ile Cys Gly Glu Gly Glu Thr Leu Leu 1795 1800 1805 Lys Lys Trp Ala Leu Tyr Ser Phe Asn Asp Gly Glu Glu His Gln Lys 1810 1815 1820 Ile Leu Leu Asp Asp Leu Met Lys Lys Ala Glu Glu Gly Asp Leu Leu 1825 1830 1835 1840 Val Asn Pro Asp Gln Pro Arg Leu Thr Ile Pro Ile Ser Gln Ile Ala 1845 1850 1855 Pro Asp Leu Ile Leu Ala Asp Leu Pro Arg Asn Ile Met Leu Asn Asn 1860 1865 1870 Asp Glu Leu Glu Phe Glu Gln Ala Pro Glu Phe Leu Leu Gly Asp Gly 1875 1880 1885 Ser Phe Gly Ser Val Tyr Arg Ala Ala Tyr Glu Gly Glu Glu Val Ala 1890 1895 1900 Val Lys Ile Phe Asn Lys His Thr Ser Leu Arg Leu Leu Arg Gln Glu 1905 1910 1915 1920 Leu Val Val Leu Cys His Leu His His Pro Ser Leu Ile Ser Leu Leu 1925 1930 1935 Ala Ala Gly Ile Arg Pro Arg Met Leu Val Met Glu Leu Ala Ser Lys 1940 1945 1950 Gly Ser Leu Asp Arg Leu Leu Gln Gln Asp Lys Ala Ser Leu Thr Arg 1955 1960 1965 Thr Leu Gln His Arg Ile Ala Leu His Val Ala Asp Gly Leu Arg Tyr 1970 1975 1980 Leu His Ser Ala Met Ile Ile Tyr Arg Asp Leu Lys Pro His Asn Val 1985 1990 1995 2000 Leu Leu Phe Thr Leu Tyr Pro Asn Ala Ala Ile Ile Ala Lys Ile Ala 2005 2010 2015 Asp Tyr Ser Ile Ala Gln Tyr Cys Cys Arg Met Gly Ile Lys Thr Ser 2020 2025 2030 Glu Gly Thr Pro Gly Phe Arg Ala Pro Glu Val Ala Arg Gly Asn Val 2035 2040 2045 Ile Tyr Asn Gln Gln Ala Asp Val Tyr Ser Phe Gly Leu Leu Leu Tyr 2050 2055 2060 Asp Ile Leu Thr Thr Gly Gly Arg Ile Val Glu Gly Leu Lys Phe Pro 2065 2070 2075 2080 Asn Glu Phe Asp Glu Leu Glu Ile Gln Gly Lys Leu Pro Asp Pro Val 2085 2090 2095 Lys Glu Tyr Gly Cys Ala Pro Trp Pro Met Val Glu Lys Leu Ile Lys 2100 2105 2110 Gln Cys Leu Lys Glu Asn Pro Gln Glu Arg Pro Thr Ser Ala Gln Val 2115 2120 2125 Phe Asp Ile Leu Asn Ser Ala Glu Leu Val Cys Leu Thr Arg Arg Ile 2130 2135 2140 Leu Leu Pro Lys Asn Val Ile Val Glu Cys Met Val Ala Thr His His 2145 2150 2155 2160 Asn Ser Arg Asn Ala Ser Ile Trp Leu Gly Cys Gly His Thr Asp Arg 2165 2170 2175 Gly Gln Leu Ser Phe Leu Asp Leu Asn Thr Glu Gly Tyr Thr Ser Glu 2180 2185 2190 Glu Val Ala Asp Ser Arg Ile Leu Cys Leu Ala Leu Val His Leu Pro 2195 2200 2205 Val Glu Lys Glu Ser Trp Ile Val Ser Gly Thr Gln Ser Gly Thr Leu 2210 2215 2220 Leu Val Ile Asn Thr Glu Asp Gly Lys Lys Arg His Thr Leu Glu Lys 2225 2230 2235 2240 Met Thr Asp Ser Val Thr Cys Leu Tyr Cys Asn Ser Phe Ser Lys Gln 2245 2250 2255 Ser Lys Gln Lys Asn Phe Leu Leu Val Gly Thr Ala Asp Gly Lys Leu 2260 2265 2270 Ala Ile Phe Glu Asp Lys Thr Val Lys Leu Lys Gly Ala Ala Pro Leu 2275 2280 2285 Lys Ile Leu Asn Ile Gly Asn Val Ser Thr Pro Leu Met Cys Leu Ser 2290 2295 2300 Glu Ser Thr Asn Ser Thr Glu Arg Asn Val Met Trp Gly Gly Cys Gly 2305 2310 2315 2320 Thr Lys Ile Phe Ser Phe Ser Asn Asp Phe Thr Ile Gln Lys Leu Ile 2325 2330 2335 Glu Thr Arg Thr Ser Gln Leu Phe Ser Tyr Ala Ala Phe Ser Asp Ser 2340 2345 2350 Asn Ile Ile Thr Val Val Val Asp Thr Ala Leu Tyr Ile Ala Lys Gln 2355 2360 2365 Asn Ser Pro Val Val Glu Val Trp Asp Lys Lys Thr Glu Lys Leu Cys 2370 2375 2380 Gly Leu Ile Asp Cys Val His Phe Leu Arg Glu Val Met Val Lys Glu 2385 2390 2395 2400 Asn Lys Glu Ser Lys His Lys Met Ser Tyr Ser Gly Arg Val Lys Thr 2405 2410 2415 Leu Cys Leu Gln Lys Asn Thr Ala Leu Trp Ile Gly Thr Gly Gly Gly 2420 2425 2430 His Ile Leu Leu Leu Asp Leu Ser Thr Arg Arg Leu Ile Arg Val Ile 2435 2440 2445 Tyr Asn Phe Cys Asn Ser Val Arg Val Met Met Thr Ala Gln Leu Gly 2450 2455 2460 Ser Leu Lys Asn Val Met Leu Val Leu Gly Tyr Asn Arg Lys Asn Thr 2465 2470 2475 2480 Glu Gly Thr Gln Lys Gln Lys Glu Ile Gln Ser Cys Leu Thr Val Trp 2485 2490 2495 Asp Ile Asn Leu Pro His Glu Val Gln Asn Leu Glu Lys His Ile Glu 2500 2505 2510 Val Arg Lys Glu Leu Ala Glu Lys Met Arg Arg Thr Ser Val Glu 2515 2520 2525 <210> 3 <211> 7584 <212> DNA <213> Homo sapiens <400> 3 atggctagtg gcagctgtca ggggtgcgaa gaggacgagg aaactctgaa gaagttgata 60 gtcaggctga acaatgtcca ggaaggaaaa cagatagaaa cgctggtcca aatcctggag 120 gatctgctgg tgttcacgta ctccgagcac gcctccaagt tatttcaagg caaaaatatc 180 catgtgcctc tgttgatcgt cttggactcc tatatgagag tcgcgagtgt gcagcaggtg 240 ggttggtcac ttctgtgcaa attaatagaa gtctgtccag gtacaatgca aagcttaatg 300 ggaccccagg atgttggaaa tgattgggaa gtccttggtg ttcaccaatt gattcttaaa 360 atgctaacag ttcataatgc cagtgtaaac ttgtcagtga ttggactgaa gaccttagat 420 ctcctcctaa cttcaggtaa aatcaccttg ctgatactgg atgaagaaag tgatattttc 480 atgttaattt ttgatgccat gcactcattt ccagccaatg atgaagtcca gaaacttgga 540 tgcaaagctt tacatgtgct gtttgagaga gtctcagagg agcaactgac tgaatttgtt 600 gagaacaaag attatatgat attgttaagt gcgtcaacaa attttaaaga tgaagaggaa 660 attgtgcttc atgtgctgca ttgtttacat tccctagcga ttccttgcaa taatgtggaa 720 gtcctcatga gtggcaatgt caggtgttat aatattgtgg tggaagctat gaaagcattc 780 cctatgagtg aaagaattca agaagtgagt tgctgtttgc tccataggct tacattaggt 840 aattttttca atatcctggt attaaacgaa gtccatgagt ttgtggtgaa agctgtgcag 900 cagtacccag agaatgcagc attgcagatc tcagcgctca gctgtttggc cctcctcact 960 gagactattt tcttaaatca agatttagag gaaaagaatg agaatcaaga gaatgatgat 1020 gagggggaag aagataaatt gttttggctg gaagcctgtt acaaagcatt aacgtggcat 1080 agaaagaaca agcacgtgca ggaggccgca tgctgggcac taaataatct ccttatgtac 1140 caaaacagtt tacatgagaa gattggagat gaagatggcc atttcccagc tcatagggaa 1200 gtgatgctct ccatgctgat gcattcttca tcaaaggaag ttttccaggc atctgcgaat 1260 gcattgtcaa ctctcttaga acaaaatgtt aatttcagaa aaatactgtt atcaaaagga 1320 atacacctga atgttttgga gttaatgcag aagcatatac attctcctga agtggctgaa 1380 agtggctgta aaatgctaaa tcatcttttt gaaggaagca acacttccct ggatataatg 1440 gcagcagtgg tccccaaaat actaacagtt atgaaacgtc atgagacatc attaccagtg 1500 cagctggagg cgcttcgagc tattttacat tttatagtgc ctggcatgcc agaagaatcc 1560 agggaggata cagaatttca tcataagcta aatatggtta aaaaacagtg tttcaagaat 1620 gatattcaca aactggtcct agcagctttg aacaggttca ttggaaatcc tgggattcag 1680 aaatgtggat taaaagtaat ttcttctatt gtacattttc ctgatgcatt agagatgtta 1740 tccctggaag gtgctatgga ttcagtgctt cacacactgc agatgtatcc agatgaccaa 1800 gaaattcagt gtctgggttt aagtcttata ggatacttga ttacaaagaa gaatgtgttc 1860 ataggaactg gacatctgct ggcaaaaatt ctggtttcca gcttataccg atttaaggat 1920 gttgctgaaa tacagactaa aggatttcag acaatcttag caatcctcaa attgtcagca 1980 tctttttcta agctgctggt gcatcattca tttgacttag taatattcca tcaaatgtct 2040 tccaatatca tggaacaaaa ggatcaacag tttctaaacc tctgttgcaa gtgttttgca 2100 aaagtagcta tggatgatta cttaaaaaat gtgatgctag agagagcgtg tgatcagaat 2160 aacagcatca tggttgaatg cttgcttcta ttgggagcag atgccaatca agcaaaggag 2220 ggatcttctt taatttgtca ggtatgtgag aaagagagca gtcccaaatt ggtggaactc 2280 ttactgaata gtggatctcg tgaacaagat gtacgaaaag cgttgacgat aagcattggg 2340 aaaggtgaca gccagatcat cagcttgctc ttaaggaggc tggccctgga tgtggccaac 2400 aatagcattt gccttggagg attttgtata ggaaaagttg aaccttcttg gcttggtcct 2460 ttatttccag ataagacttc taatttaagg aaacaaacaa atatagcatc tacactagca 2520 agaatggtga tcagatatca gatgaaaagt gctgtggaag aaggaacagc ctcaggcagc 2580 gatggaaatt tttctgaaga tgtgctgtct aaatttgatg aatggacctt tattcctgac 2640 tcttctatgg acagtgtgtt tgctcaaagt gatgacctgg atagtgaagg aagtgaaggc 2700 tcatttcttg tgaaaaagaa atctaattca attagtgtag gagaatttta ccgagatgcc 2760 gtattacagc gttgctcacc aaatttgcaa agacattcca attccttggg gcccattttt 2820 gatcatgaag atttactgaa gcgaaaaaga aaaatactat cttcagatga ttcactcagg 2880 tcatcaaaac ttcaatccca tatgaggcat tcagacagca tttcttctct ggcttctgag 2940 agagaatata ttacatcact agacctttca gcaaatgaac taagagatat tgatgcccta 3000 agccagaaat gctgtataag tgttcatttg gagcatcttg aaaagctgga gcttcaccag 3060 aatgcactca cgagctttcc acaacagcta tgtgaaactc tgaagagttt gacacatttg 3120 gacttgcaca gtaataaatt tacatcattt ccttcttatt tgttgaaaat gagttgtatt 3180 gctaatcttg atgtctctcg aaatgacatt ggaccctcag tggttttaga tcctacagtg 3240 aaatgtccaa ctctgaaaca gtttaacctg tcatataacc agctgtcttt tgtacctgag 3300 aacctcactg atgtggtaga gaaactggag cagctcattt tagaaggaaa taaaatatca 3360 gggatatgct cccccttgag actgaaggaa ctgaagattt taaaccttag taagaaccac 3420 atttcatccc tatcagagaa ctttcttgag gcttgtccta aagtggagag tttcagtgcc 3480 agaatgaatt ttcttgctgc tatgcctttc ttgcctcctt ctatgacaat cctaaaatta 3540 tctcagaaca aattttcctg tattccagaa gcaattttaa atcttccaca cttgcggtct 3600 ttagatatga gcagcaatga tattcagtac ctaccaggtc ccgcacactg gaaatctttg 3660 aacttaaggg aactcttatt tagccataat cagatcagca tcttggactt gagtgaaaaa 3720 gcatatttat ggtctagagt agagaaactg catctttctc acaataaact gaaagagatt 3780 cctcctgaga ttggctgtct tgaaaatctg acatctctgg atgtcagtta caacttggaa 3840 ctaagatcct ttcccaatga aatggggaaa ttaagcaaaa tatgggatct tcctttggat 3900 gaactgcatc ttaactttga ttttaaacat ataggatgta aagccaaaga catcataagg 3960 tttcttcaac agcgattaaa aaaggctgtg ccttataacc gaatgaaact tatgattgtg 4020 ggaaatactg ggagtggtaa aaccacctta ttgcagcaat taatgaaaac caagaaatca 4080 gatcttggaa tgcaaagtgc cacagttggc atagatgtga aagactggcc tatccaaata 4140 agagacaaaa gaaagagaga tctcgtccta aatgtgtggg attttgcagg tcgtgaggaa 4200 ttctatagta ctcatcccca ttttatgacg cagcgagcat tgtaccttgc tgtctatgac 4260 ctcagcaagg gacaggctga agttgatgcc atgaagcctt ggctcttcaa tataaaggct 4320 tgcgcttctt cttcccctgt gattctcgtt ggcacacatt tggatgtttc tgatgagaag 4380 caacgcaaag cctgcatgag taaaatcacc aaggaactcc tgaataagcg agggttccct 4440 gccatacgag attaccactt tgtgaatgcc accgaggaat ctgatgcttt ggcaaaactt 4500 cggaaaacca tcataaacga gagccttaat ttcaagatcc gagatcagct tgttgttgga 4560 cagctgattc cagactgcta tgtagaactt gaaaaaatca ttttatcgga gcgtaaaaat 4620 gtgccaattg aatttcccgt aattgaccgg aaacgattat tacaactagt gagagaaaat 4680 cagctgcagt tagatgaaaa tgagcttcct cacgcagttc actttctaaa tgaatcagga 4740 gtccttcttc attttcaaga cccagcactg cagttaagtg acttgtactt tgtggaaccc 4800 aagtggcttt gtaaaatcat ggcacagatt ttgacagtga aagtggaagg ttgtccaaaa 4860 caccctaagg gcattatttc gcgtagagat gtggaaaaat ttctttcaaa aaaaaggaaa 4920 tttccaaaga actacatgtc acagtatttt aagctcctag aaaaattcca gattgctttg 4980 ccaataggag aagaatattt gctggttcca agcagtttgt ctgaccacag gcctgtgata 5040 gagcttcccc attgtgagaa ctctgaaatt atcatccgac tatatgaaat gccttatttt 5100 ccaatgggat tttggtcaag attaatcaat cgattacttg agatttcacc ttacatgctt 5160 tcagggagag aacgagcact tcgcccaaac agaatgtatt ggcgacaagg catttactta 5220 aattggtctc ctgaagctta ttgtctggta ggatctgaag tcttagacaa tcatccagag 5280 agtttcttaa aaattacagt tccttcttgt agaaaaggct gtattctttt gggccaagtt 5340 gtggaccaca ttgattctct catggaagaa tggtttcctg ggttgctgga gattgatatt 5400 tgtggtgaag gagaaactct gttgaagaaa tgggcattat atagttttaa tgatggcgaa 5460 gaacatcaaa aaatcttact tgatgacttg atgaagaaag cagaggaagg agatctctta 5520 gtaaatccag atcaaccaag gctcaccatt ccaatatctc agattgcccc tgacttgatt 5580 ttggctgacc tgcctagaaa tattatgttg aataatgatg agttggaatt tgaacaagct 5640 ccagagtttc tcctaggtga tggcagtttt ggatcagttt accgagcagc ctatgaagga 5700 gaagaagtgg ctgtgaagat ttttaataaa catacatcac tcaggctgtt aagacaagag 5760 cttgtggtgc tttgccacct ccaccacccc agtttgatat ctttgctggc agctgggatt 5820 cgtccccgga tgttggtgat ggagttagcc tccaagggtt ccttggatcg cctgcttcag 5880 caggacaaag ccagcctcac tagaacccta cagcacagga ttgcactcca cgtagctgat 5940 ggtttgagat acctccactc agccatgatt atataccgag acctgaaacc ccacaatgtg 6000 ctgcttttca cactgtatcc caatgctgcc atcattgcaa agattgctga ctacggcatt 6060 gctcagtact gctgtagaat ggggataaaa acatcagagg gcacaccagg gtttcgtgca 6120 cctgaagttg ccagaggaaa tgtcatttat aaccaacagg ctgatgttta ttcatttggt 6180 ttactactct atgacatttt gacaactgga ggtagaatag tagagggttt gaagtttcca 6240 aatgagtttg atgaattaga aatacaagga aaattacctg atccagttaa agaatatggt 6300 tgtgccccat ggcctatggt tgagaaatta attaaacagt gtttgaaaga aaatcctcaa 6360 gaaaggccta cttctgccca ggtctttgac attttgaatt cagctgaatt agtctgtctg 6420 acgagacgca ttttattacc taaaaacgta attgttgaat gcatggttgc tacacatcac 6480 aacagcagga atgcaagcat ttggctgggc tgtgggcaca ccgacagagg acagctctca 6540 tttcttgact taaatactga aggatacact tctgaggaag ttgctgatag tagaatattg 6600 tgcttagcct tggtgcatct tcctgttgaa aaggaaagct ggattgtgtc tgggacacag 6660 tctggtactc tcctggtcat caataccgaa gatgggaaaa agagacatac cctagaaaag 6720 atgactgatt ctgtcacttg tttgtattgc aattcctttt ccaagcaaag caaacaaaaa 6780 aattttcttt tggttggaac cgctgatggc aagttagcaa tttttgaaga taagactgtt 6840 aagcttaaag gagctgctcc tttgaagata ctaaatatag gaaatgtcag tactccattg 6900 atgtgtttga gtgaatccac aaattcaacg gaaagaaatg taatgtgggg aggatgtggc 6960 acaaagattt tctccttttc taatgatttc accattcaga aactcattga gacaagaaca 7020 agccaactgt tttcttatgc agctttcagt gattccaaca tcataacagt ggtggtagac 7080 actgctctct atattgctaa gcaaaatagc cctgttgtgg aagtgtggga taagaaaact 7140 gaaaaactct gtggactaat agactgcgtg cactttttaa gggaggtaat ggtaaaagaa 7200 aacaaggaat caaaacacaa aatgtcttat tctgggagag tgaaaaccct ctgccttcag 7260 aagaacactg ctctttggat aggaactgga ggaggccata ttttactcct ggatctttca 7320 actcgtcgac ttatacgtgt aatttacaac ttttgtaatt cggtcagagt catgatgaca 7380 gcacagctag gaagccttaa aaatgtcatg ctggtattgg gctacaaccg gaaaaatact 7440 gaaggtacac aaaagcagaa agagatacaa tcttgcttga ccgtttggga catcaatctt 7500 ccacatgaag tgcaaaattt agaaaaacac attgaagtga gaaaagaatt agctgaaaaa 7560 atgagacgaa catctgttga gtaa 7584 <210> 4 <211> 2527 <212> PRT <213> Homo sapiens <400> 4 Met Ala Ser Gly Ser Cys Gln Gly Cys Glu Glu Asp Glu Glu Thr Leu 1 5 10 15 Lys Lys Leu Ile Val Arg Leu Asn Asn Val Gln Glu Gly Lys Gln Ile 20 25 30 Glu Thr Leu Val Gln Ile Leu Glu Asp Leu Leu Val Phe Thr Tyr Ser 35 40 45 Glu His Ala Ser Lys Leu Phe Gln Gly Lys Asn Ile His Val Pro Leu 50 55 60 Leu Ile Val Leu Asp Ser Tyr Met Arg Val Ala Ser Val Gln Gln Val 65 70 75 80 Gly Trp Ser Leu Leu Cys Lys Leu Ile Glu Val Cys Pro Gly Thr Met 85 90 95 Gln Ser Leu Met Gly Pro Gln Asp Val Gly Asn Asp Trp Glu Val Leu 100 105 110 Gly Val His Gln Leu Ile Leu Lys Met Leu Thr Val His Asn Ala Ser 115 120 125 Val Asn Leu Ser Val Ile Gly Leu Lys Thr Leu Asp Leu Leu Leu Thr 130 135 140 Ser Gly Lys Ile Thr Leu Leu Ile Leu Asp Glu Glu Ser Asp Ile Phe 145 150 155 160 Met Leu Ile Phe Asp Ala Met His Ser Phe Pro Ala Asn Asp Glu Val 165 170 175 Gln Lys Leu Gly Cys Lys Ala Leu His Val Leu Phe Glu Arg Val Ser 180 185 190 Glu Glu Gln Leu Thr Glu Phe Val Glu Asn Lys Asp Tyr Met Ile Leu 195 200 205 Leu Ser Ala Leu Thr Asn Phe Lys Asp Glu Glu Glu Ile Val Leu His 210 215 220 Val Leu His Cys Leu His Ser Leu Ala Ile Pro Cys Asn Asn Val Glu 225 230 235 240 Val Leu Met Ser Gly Asn Val Arg Cys Tyr Asn Ile Val Val Glu Ala 245 250 255 Met Lys Ala Phe Pro Met Ser Glu Arg Ile Gln Glu Val Ser Cys Cys 260 265 270 Leu Leu His Arg Leu Thr Leu Gly Asn Phe Phe Asn Ile Leu Val Leu 275 280 285 Asn Glu Val His Glu Phe Val Val Lys Ala Val Gln Gln Tyr Pro Glu 290 295 300 Asn Ala Ala Leu Gln Ile Ser Ala Leu Ser Cys Leu Ala Leu Leu Thr 305 310 315 320 Glu Thr Ile Phe Leu Asn Gln Asp Leu Glu Glu Lys Asn Glu Asn Gln 325 330 335 Glu Asn Asp Asp Glu Gly Glu Glu Asp Lys Leu Phe Trp Leu Glu Ala 340 345 350 Cys Tyr Lys Ala Leu Thr Trp His Arg Lys Asn Lys His Val Gln Glu 355 360 365 Ala Ala Cys Trp Ala Leu Asn Asn Leu Leu Met Tyr Gln Asn Ser Leu 370 375 380 His Glu Lys Ile Gly Asp Glu Asp Gly His Phe Pro Ala His Arg Glu 385 390 395 400 Val Met Leu Ser Met Leu Met His Ser Ser Ser Lys Glu Val Phe Gln 405 410 415 Ala Ser Ala Asn Ala Leu Ser Thr Leu Leu Glu Gln Asn Val Asn Phe 420 425 430 Arg Lys Ile Leu Leu Ser Lys Gly Ile His Leu Asn Val Leu Glu Leu 435 440 445 Met Gln Lys His Ile His Ser Pro Glu Val Ala Glu Ser Gly Cys Lys 450 455 460 Met Leu Asn His Leu Phe Glu Gly Ser Asn Thr Ser Leu Asp Ile Met 465 470 475 480 Ala Ala Val Val Pro Lys Ile Leu Thr Val Met Lys Arg His Glu Thr 485 490 495 Ser Leu Pro Val Gln Leu Glu Ala Leu Arg Ala Ile Leu His Phe Ile 500 505 510 Val Pro Gly Met Pro Glu Glu Ser Arg Glu Asp Thr Glu Phe His His 515 520 525 Lys Leu Asn Met Val Lys Lys Gln Cys Phe Lys Asn Asp Ile His Lys 530 535 540 Leu Val Leu Ala Ala Leu Asn Arg Phe Ile Gly Asn Pro Gly Ile Gln 545 550 555 560 Lys Cys Gly Leu Lys Val Ile Ser Ser Ile Val His Phe Pro Asp Ala 565 570 575 Leu Glu Met Leu Ser Leu Glu Gly Ala Met Asp Ser Val Leu His Thr 580 585 590 Leu Gln Met Tyr Pro Asp Asp Gln Glu Ile Gln Cys Leu Gly Leu Ser 595 600 605 Leu Ile Gly Tyr Leu Ile Thr Lys Lys Asn Val Phe Ile Gly Thr Gly 610 615 620 His Leu Leu Ala Lys Ile Leu Val Ser Ser Leu Tyr Arg Phe Lys Asp 625 630 635 640 Val Ala Glu Ile Gln Thr Lys Gly Phe Gln Thr Ile Leu Ala Ile Leu 645 650 655 Lys Leu Ser Ala Ser Phe Ser Lys Leu Leu Val His His Ser Phe Asp 660 665 670 Leu Val Ile Phe His Gln Met Ser Ser Asn Ile Met Glu Gln Lys Asp 675 680 685 Gln Gln Phe Leu Asn Leu Cys Cys Lys Cys Phe Ala Lys Val Ala Met 690 695 700 Asp Asp Tyr Leu Lys Asn Val Met Leu Glu Arg Ala Cys Asp Gln Asn 705 710 715 720 Asn Ser Ile Met Val Glu Cys Leu Leu Leu Leu Gly Ala Asp Ala Asn 725 730 735 Gln Ala Lys Glu Gly Ser Ser Leu Ile Cys Gln Val Cys Glu Lys Glu 740 745 750 Ser Ser Pro Lys Leu Val Glu Leu Leu Leu Asn Ser Gly Ser Arg Glu 755 760 765 Gln Asp Val Arg Lys Ala Leu Thr Ile Ser Ile Gly Lys Gly Asp Ser 770 775 780 Gln Ile Ile Ser Leu Leu Leu Arg Arg Leu Ala Leu Asp Val Ala Asn 785 790 795 800 Asn Ser Ile Cys Leu Gly Gly Phe Cys Ile Gly Lys Val Glu Pro Ser 805 810 815 Trp Leu Gly Pro Leu Phe Pro Asp Lys Thr Ser Asn Leu Arg Lys Gln 820 825 830 Thr Asn Ile Ala Ser Thr Leu Ala Arg Met Val Ile Arg Tyr Gln Met 835 840 845 Lys Ser Ala Val Glu Glu Gly Thr Ala Ser Gly Ser Asp Gly Asn Phe 850 855 860 Ser Glu Asp Val Leu Ser Lys Phe Asp Glu Trp Thr Phe Ile Pro Asp 865 870 875 880 Ser Ser Met Asp Ser Val Phe Ala Gln Ser Asp Asp Leu Asp Ser Glu 885 890 895 Gly Ser Glu Gly Ser Phe Leu Val Lys Lys Lys Ser Asn Ser Ile Ser 900 905 910 Val Gly Glu Phe Tyr Arg Asp Ala Val Leu Gln Arg Cys Ser Pro Asn 915 920 925 Leu Gln Arg His Ser Asn Ser Leu Gly Pro Ile Phe Asp His Glu Asp 930 935 940 Leu Leu Lys Arg Lys Arg Lys Ile Leu Ser Ser Asp Asp Ser Leu Arg 945 950 955 960 Ser Ser Lys Leu Gln Ser His Met Arg His Ser Asp Ser Ile Ser Ser 965 970 975 Leu Ala Ser Glu Arg Glu Tyr Ile Thr Ser Leu Asp Leu Ser Ala Asn 980 985 990 Glu Leu Arg Asp Ile Asp Ala Leu Ser Gln Lys Cys Cys Ile Ser Val 995 1000 1005 His Leu Glu His Leu Glu Lys Leu Glu Leu His Gln Asn Ala Leu Thr 1010 1015 1020 Ser Phe Pro Gln Gln Leu Cys Glu Thr Leu Lys Ser Leu Thr His Leu 1025 1030 1035 1040 Asp Leu His Ser Asn Lys Phe Thr Ser Phe Pro Ser Tyr Leu Leu Lys 1045 1050 1055 Met Ser Cys Ile Ala Asn Leu Asp Val Ser Arg Asn Asp Ile Gly Pro 1060 1065 1070 Ser Val Val Leu Asp Pro Thr Val Lys Cys Pro Thr Leu Lys Gln Phe 1075 1080 1085 Asn Leu Ser Tyr Asn Gln Leu Ser Phe Val Pro Glu Asn Leu Thr Asp 1090 1095 1100 Val Val Glu Lys Leu Glu Gln Leu Ile Leu Glu Gly Asn Lys Ile Ser 1105 1110 1115 1120 Gly Ile Cys Ser Pro Leu Arg Leu Lys Glu Leu Lys Ile Leu Asn Leu 1125 1130 1135 Ser Lys Asn His Ile Ser Ser Leu Ser Glu Asn Phe Leu Glu Ala Cys 1140 1145 1150 Pro Lys Val Glu Ser Phe Ser Ala Arg Met Asn Phe Leu Ala Ala Met 1155 1160 1165 Pro Phe Leu Pro Pro Ser Met Thr Ile Leu Lys Leu Ser Gln Asn Lys 1170 1175 1180 Phe Ser Cys Ile Pro Glu Ala Ile Leu Asn Leu Pro His Leu Arg Ser 1185 1190 1195 1200 Leu Asp Met Ser Ser Asn Asp Ile Gln Tyr Leu Pro Gly Pro Ala His 1205 1210 1215 Trp Lys Ser Leu Asn Leu Arg Glu Leu Leu Phe Ser His Asn Gln Ile 1220 1225 1230 Ser Ile Leu Asp Leu Ser Glu Lys Ala Tyr Leu Trp Ser Arg Val Glu 1235 1240 1245 Lys Leu His Leu Ser His Asn Lys Leu Lys Glu Ile Pro Pro Glu Ile 1250 1255 1260 Gly Cys Leu Glu Asn Leu Thr Ser Leu Asp Val Ser Tyr Asn Leu Glu 1265 1270 1275 1280 Leu Arg Ser Phe Pro Asn Glu Met Gly Lys Leu Ser Lys Ile Trp Asp 1285 1290 1295 Leu Pro Leu Asp Glu Leu His Leu Asn Phe Asp Phe Lys His Ile Gly 1300 1305 1310 Cys Lys Ala Lys Asp Ile Ile Arg Phe Leu Gln Gln Arg Leu Lys Lys 1315 1320 1325 Ala Val Pro Tyr Asn Arg Met Lys Leu Met Ile Val Gly Asn Thr Gly 1330 1335 1340 Ser Gly Lys Thr Thr Leu Leu Gln Gln Leu Met Lys Thr Lys Lys Ser 1345 1350 1355 1360 Asp Leu Gly Met Gln Ser Ala Thr Val Gly Ile Asp Val Lys Asp Trp 1365 1370 1375 Pro Ile Gln Ile Arg Asp Lys Arg Lys Arg Asp Leu Val Leu Asn Val 1380 1385 1390 Trp Asp Phe Ala Gly Arg Glu Glu Phe Tyr Ser Thr His Pro His Phe 1395 1400 1405 Met Thr Gln Arg Ala Leu Tyr Leu Ala Val Tyr Asp Leu Ser Lys Gly 1410 1415 1420 Gln Ala Glu Val Asp Ala Met Lys Pro Trp Leu Phe Asn Ile Lys Ala 1425 1430 1435 1440 Cys Ala Ser Ser Ser Pro Val Ile Leu Val Gly Thr His Leu Asp Val 1445 1450 1455 Ser Asp Glu Lys Gln Arg Lys Ala Cys Met Ser Lys Ile Thr Lys Glu 1460 1465 1470 Leu Leu Asn Lys Arg Gly Phe Pro Ala Ile Arg Asp Tyr His Phe Val 1475 1480 1485 Asn Ala Thr Glu Glu Ser Asp Ala Leu Ala Lys Leu Arg Lys Thr Ile 1490 1495 1500 Ile Asn Glu Ser Leu Asn Phe Lys Ile Arg Asp Gln Leu Val Val Gly 1505 1510 1515 1520 Gln Leu Ile Pro Asp Cys Tyr Val Glu Leu Glu Lys Ile Ile Leu Ser 1525 1530 1535 Glu Arg Lys Asn Val Pro Ile Glu Phe Pro Val Ile Asp Arg Lys Arg 1540 1545 1550 Leu Leu Gln Leu Val Arg Glu Asn Gln Leu Gln Leu Asp Glu Asn Glu 1555 1560 1565 Leu Pro His Ala Val His Phe Leu Asn Glu Ser Gly Val Leu Leu His 1570 1575 1580 Phe Gln Asp Pro Ala Leu Gln Leu Ser Asp Leu Tyr Phe Val Glu Pro 1585 1590 1595 1600 Lys Trp Leu Cys Lys Ile Met Ala Gln Ile Leu Thr Val Lys Val Glu 1605 1610 1615 Gly Cys Pro Lys His Pro Lys Gly Ile Ile Ser Arg Arg Asp Val Glu 1620 1625 1630 Lys Phe Leu Ser Lys Lys Arg Lys Phe Pro Lys Asn Tyr Met Ser Gln 1635 1640 1645 Tyr Phe Lys Leu Leu Glu Lys Phe Gln Ile Ala Leu Pro Ile Gly Glu 1650 1655 1660 Glu Tyr Leu Leu Val Pro Ser Ser Leu Ser Asp His Arg Pro Val Ile 1665 1670 1675 1680 Glu Leu Pro His Cys Glu Asn Ser Glu Ile Ile Ile Arg Leu Tyr Glu 1685 1690 1695 Met Pro Tyr Phe Pro Met Gly Phe Trp Ser Arg Leu Ile Asn Arg Leu 1700 1705 1710 Leu Glu Ile Ser Pro Tyr Met Leu Ser Gly Arg Glu Arg Ala Leu Arg 1715 1720 1725 Pro Asn Arg Met Tyr Trp Arg Gln Gly Ile Tyr Leu Asn Trp Ser Pro 1730 1735 1740 Glu Ala Tyr Cys Leu Val Gly Ser Glu Val Leu Asp Asn His Pro Glu 1745 1750 1755 1760 Ser Phe Leu Lys Ile Thr Val Pro Ser Cys Arg Lys Gly Cys Ile Leu 1765 1770 1775 Leu Gly Gln Val Val Asp His Ile Asp Ser Leu Met Glu Glu Trp Phe 1780 1785 1790 Pro Gly Leu Leu Glu Ile Asp Ile Cys Gly Glu Gly Glu Thr Leu Leu 1795 1800 1805 Lys Lys Trp Ala Leu Tyr Ser Phe Asn Asp Gly Glu Glu His Gln Lys 1810 1815 1820 Ile Leu Leu Asp Asp Leu Met Lys Lys Ala Glu Glu Gly Asp Leu Leu 1825 1830 1835 1840 Val Asn Pro Asp Gln Pro Arg Leu Thr Ile Pro Ile Ser Gln Ile Ala 1845 1850 1855 Pro Asp Leu Ile Leu Ala Asp Leu Pro Arg Asn Ile Met Leu Asn Asn 1860 1865 1870 Asp Glu Leu Glu Phe Glu Gln Ala Pro Glu Phe Leu Leu Gly Asp Gly 1875 1880 1885 Ser Phe Gly Ser Val Tyr Arg Ala Ala Tyr Glu Gly Glu Glu Val Ala 1890 1895 1900 Val Lys Ile Phe Asn Lys His Thr Ser Leu Arg Leu Leu Arg Gln Glu 1905 1910 1915 1920 Leu Val Val Leu Cys His Leu His His Pro Ser Leu Ile Ser Leu Leu 1925 1930 1935 Ala Ala Gly Ile Arg Pro Arg Met Leu Val Met Glu Leu Ala Ser Lys 1940 1945 1950 Gly Ser Leu Asp Arg Leu Leu Gln Gln Asp Lys Ala Ser Leu Thr Arg 1955 1960 1965 Thr Leu Gln His Arg Ile Ala Leu His Val Ala Asp Gly Leu Arg Tyr 1970 1975 1980 Leu His Ser Ala Met Ile Ile Tyr Arg Asp Leu Lys Pro His Asn Val 1985 1990 1995 2000 Leu Leu Phe Thr Leu Tyr Pro Asn Ala Ala Ile Ile Ala Lys Ile Ala 2005 2010 2015 Asp Tyr Gly Ile Ala Gln Tyr Cys Cys Arg Met Gly Ile Lys Thr Ser 2020 2025 2030 Glu Gly Thr Pro Gly Phe Arg Ala Pro Glu Val Ala Arg Gly Asn Val 2035 2040 2045 Ile Tyr Asn Gln Gln Ala Asp Val Tyr Ser Phe Gly Leu Leu Leu Tyr 2050 2055 2060 Asp Ile Leu Thr Thr Gly Gly Arg Ile Val Glu Gly Leu Lys Phe Pro 2065 2070 2075 2080 Asn Glu Phe Asp Glu Leu Glu Ile Gln Gly Lys Leu Pro Asp Pro Val 2085 2090 2095 Lys Glu Tyr Gly Cys Ala Pro Trp Pro Met Val Glu Lys Leu Ile Lys 2100 2105 2110 Gln Cys Leu Lys Glu Asn Pro Gln Glu Arg Pro Thr Ser Ala Gln Val 2115 2120 2125 Phe Asp Ile Leu Asn Ser Ala Glu Leu Val Cys Leu Thr Arg Arg Ile 2130 2135 2140 Leu Leu Pro Lys Asn Val Ile Val Glu Cys Met Val Ala Thr His His 2145 2150 2155 2160 Asn Ser Arg Asn Ala Ser Ile Trp Leu Gly Cys Gly His Thr Asp Arg 2165 2170 2175 Gly Gln Leu Ser Phe Leu Asp Leu Asn Thr Glu Gly Tyr Thr Ser Glu 2180 2185 2190 Glu Val Ala Asp Ser Arg Ile Leu Cys Leu Ala Leu Val His Leu Pro 2195 2200 2205 Val Glu Lys Glu Ser Trp Ile Val Ser Gly Thr Gln Ser Gly Thr Leu 2210 2215 2220 Leu Val Ile Asn Thr Glu Asp Gly Lys Lys Arg His Thr Leu Glu Lys 2225 2230 2235 2240 Met Thr Asp Ser Val Thr Cys Leu Tyr Cys Asn Ser Phe Ser Lys Gln 2245 2250 2255 Ser Lys Gln Lys Asn Phe Leu Leu Val Gly Thr Ala Asp Gly Lys Leu 2260 2265 2270 Ala Ile Phe Glu Asp Lys Thr Val Lys Leu Lys Gly Ala Ala Pro Leu 2275 2280 2285 Lys Ile Leu Asn Ile Gly Asn Val Ser Thr Pro Leu Met Cys Leu Ser 2290 2295 2300 Glu Ser Thr Asn Ser Thr Glu Arg Asn Val Met Trp Gly Gly Cys Gly 2305 2310 2315 2320 Thr Lys Ile Phe Ser Phe Ser Asn Asp Phe Thr Ile Gln Lys Leu Ile 2325 2330 2335 Glu Thr Arg Thr Ser Gln Leu Phe Ser Tyr Ala Ala Phe Ser Asp Ser 2340 2345 2350 Asn Ile Ile Thr Val Val Val Asp Thr Ala Leu Tyr Ile Ala Lys Gln 2355 2360 2365 Asn Ser Pro Val Val Glu Val Trp Asp Lys Lys Thr Glu Lys Leu Cys 2370 2375 2380 Gly Leu Ile Asp Cys Val His Phe Leu Arg Glu Val Met Val Lys Glu 2385 2390 2395 2400 Asn Lys Glu Ser Lys His Lys Met Ser Tyr Ser Gly Arg Val Lys Thr 2405 2410 2415 Leu Cys Leu Gln Lys Asn Thr Ala Leu Trp Ile Gly Thr Gly Gly Gly 2420 2425 2430 His Ile Leu Leu Leu Asp Leu Ser Thr Arg Arg Leu Ile Arg Val Ile 2435 2440 2445 Tyr Asn Phe Cys Asn Ser Val Arg Val Met Met Thr Ala Gln Leu Gly 2450 2455 2460 Ser Leu Lys Asn Val Met Leu Val Leu Gly Tyr Asn Arg Lys Asn Thr 2465 2470 2475 2480 Glu Gly Thr Gln Lys Gln Lys Glu Ile Gln Ser Cys Leu Thr Val Trp 2485 2490 2495 Asp Ile Asn Leu Pro His Glu Val Gln Asn Leu Glu Lys His Ile Glu 2500 2505 2510 Val Arg Lys Glu Leu Ala Glu Lys Met Arg Arg Thr Ser Val Glu 2515 2520 2525 <210> 5 <211> 7584 <212> DNA <213> Homo sapiens <400> 5 atggctagtg gcagctgtca ggggtgcgaa gaggacgagg aaactctgaa gaagttgata 60 gtcaggctga acaatgtcca ggaaggaaaa cagatagaaa cgctggtcca aatcctggag 120 gatctgctgg tgttcacgta ctccgagcac gcctccaagt tatttcaagg caaaaatatc 180 catgtgcctc tgttgatcgt cttggactcc tatatgagag tcgcgagtgt gcagcaggtg 240 ggttggtcac ttctgtgcaa attaatagaa gtctgtccag gtacaatgca aagcttaatg 300 ggaccccagg atgttggaaa tgattgggaa gtccttggtg ttcaccaatt gattcttaaa 360 atgctaacag ttcataatgc cagtgtaaac ttgtcagtga ttggactgaa gaccttagat 420 ctcctcctaa cttcaggtaa aatcaccttg ctgatactgg atgaagaaag tgatattttc 480 atgttaattt ttgatgccat gcactcattt ccagccaatg atgaagtcca gaaacttgga 540 tgcaaagctt tacatgtgct gtttgagaga gtctcagagg agcaactgac tgaatttgtt 600 gagaacaaag attatatgat attgttaagt gcgtcaacaa attttaaaga tgaagaggaa 660 attgtgcttc atgtgctgca ttgtttacat tccctagcga ttccttgcaa taatgtggaa 720 gtcctcatga gtggcaatgt caggtgttat aatattgtgg tggaagctat gaaagcattc 780 cctatgagtg aaagaattca agaagtgagt tgctgtttgc tccataggct tacattaggt 840 aattttttca atatcctggt attaaacgaa gtccatgagt ttgtggtgaa agctgtgcag 900 cagtacccag agaatgcagc attgcagatc tcagcgctca gctgtttggc cctcctcact 960 gagactattt tcttaaatca agatttagag gaaaagaatg agaatcaaga gaatgatgat 1020 gagggggaag aagataaatt gttttggctg gaagcctgtt acaaagcatt aacgtggcat 1080 agaaagaaca agcacgtgca ggaggccgca tgctgggcac taaataatct ccttatgtac 1140 caaaacagtt tacatgagaa gattggagat gaagatggcc atttcccagc tcatagggaa 1200 gtgatgctct ccatgctgat gcattcttca tcaaaggaag ttttccaggc atctgcgaat 1260 gcattgtcaa ctctcttaga acaaaatgtt aatttcagaa aaatactgtt atcaaaagga 1320 atacacctga atgttttgga gttaatgcag aagcatatac attctcctga agtggctgaa 1380 agtggctgta aaatgctaaa tcatcttttt gaaggaagca acacttccct ggatataatg 1440 gcagcagtgg tccccaaaat actaacagtt atgaaacgtc atgagacatc attaccagtg 1500 cagctggagg cgcttcgagc tattttacat tttatagtgc ctggcatgcc agaagaatcc 1560 agggaggata cagaatttca tcataagcta aatatggtta aaaaacagtg tttcaagaat 1620 gatattcaca aactggtcct agcagctttg aacaggttca ttggaaatcc tgggattcag 1680 aaatgtggat taaaagtaat ttcttctatt gtacattttc ctgatgcatt agagatgtta 1740 tccctggaag gtgctatgga ttcagtgctt cacacactgc agatgtatcc agatgaccaa 1800 gaaattcagt gtctgggttt aagtcttata ggatacttga ttacaaagaa gaatgtgttc 1860 ataggaactg gacatctgct ggcaaaaatt ctggtttcca gcttataccg atttaaggat 1920 gttgctgaaa tacagactaa aggatttcag acaatcttag caatcctcaa attgtcagca 1980 tctttttcta agctgctggt gcatcattca tttgacttag taatattcca tcaaatgtct 2040 tccaatatca tggaacaaaa ggatcaacag tttctaaacc tctgttgcaa gtgttttgca 2100 aaagtagcta tggatgatta cttaaaaaat gtgatgctag agagagcgtg tgatcagaat 2160 aacagcatca tggttgaatg cttgcttcta ttgggagcag atgccaatca agcaaaggag 2220 ggatcttctt taatttgtca ggtatgtgag aaagagagca gtcccaaatt ggtggaactc 2280 ttactgaata gtggatctcg tgaacaagat gtacgaaaag cgttgacgat aagcattggg 2340 aaaggtgaca gccagatcat cagcttgctc ttaaggaggc tggccctgga tgtggccaac 2400 aatagcattt gccttggagg attttgtata ggaaaagttg aaccttcttg gcttggtcct 2460 ttatttccag ataagacttc taatttaagg aaacaaacaa atatagcatc tacactagca 2520 agaatggtga tcagatatca gatgaaaagt gctgtggaag aaggaacagc ctcaggcagc 2580 gatggaaatt tttctgaaga tgtgctgtct aaatttgatg aatggacctt tattcctgac 2640 tcttctatgg acagtgtgtt tgctcaaagt gatgacctgg atagtgaagg aagtgaaggc 2700 tcatttcttg tgaaaaagaa atctaattca attagtgtag gagaatttta ccgagatgcc 2760 gtattacagc gttgctcacc aaatttgcaa agacattcca attccttggg gcccattttt 2820 gatcatgaag atttactgaa gcgaaaaaga aaaatactat cttcagatga ttcactcagg 2880 tcatcaaaac ttcaatccca tatgaggcat tcagacagca tttcttctct ggcttctgag 2940 agagaatata ttacatcact agacctttca gcaaatgaac taagagatat tgatgcccta 3000 agccagaaat gctgtataag tgttcatttg gagcatcttg aaaagctgga gcttcaccag 3060 aatgcactca cgagctttcc acaacagcta tgtgaaactc tgaagagttt gacacatttg 3120 gacttgcaca gtaataaatt tacatcattt ccttcttatt tgttgaaaat gagttgtatt 3180 gctaatcttg atgtctctcg aaatgacatt ggaccctcag tggttttaga tcctacagtg 3240 aaatgtccaa ctctgaaaca gtttaacctg tcatataacc agctgtcttt tgtacctgag 3300 aacctcactg atgtggtaga gaaactggag cagctcattt tagaaggaaa taaaatatca 3360 gggatatgct cccccttgag actgaaggaa ctgaagattt taaaccttag taagaaccac 3420 atttcatccc tatcagagaa ctttcttgag gcttgtccta aagtggagag tttcagtgcc 3480 agaatgaatt ttcttgctgc tatgcctttc ttgcctcctt ctatgacaat cctaaaatta 3540 tctcagaaca aattttcctg tattccagaa gcaattttaa atcttccaca cttgcggtct 3600 ttagatatga gcagcaatga tattcagtac ctaccaggtc ccgcacactg gaaatctttg 3660 aacttaaggg aactcttatt tagccataat cagatcagca tcttggactt gagtgaaaaa 3720 gcatatttat ggtctagagt agagaaactg catctttctc acaataaact gaaagagatt 3780 cctcctgaga ttggctgtct tgaaaatctg acatctctgg atgtcagtta caacttggaa 3840 ctaagatcct ttcccaatga aatggggaaa ttaagcaaaa tatgggatct tcctttggat 3900 gaactgcatc ttaactttga ttttaaacat ataggatgta aagccaaaga catcataagg 3960 tttcttcaac agcgattaaa aaaggctgtg ccttataacc gaatgaaact tatgattgtg 4020 ggaaatactg ggagtggtaa aaccacctta ttgcagcaat taatgaaaac caagaaatca 4080 gatcttggaa tgcaaagtgc cacagttggc atagatgtga aagactggcc tatccaaata 4140 agagacaaaa gaaagagaga tctcgtccta aatgtgtggg attttgcagg tcgtgaggaa 4200 ttctatagta ctcatcccca ttttatgacg cagcgagcat tgtaccttgc tgtctatgac 4260 ctcagcaagg gacaggctga agttgatgcc atgaagcctt ggctcttcaa tataaaggct 4320 ggcgcttctt cttcccctgt gattctcgtt ggcacacatt tggatgtttc tgatgagaag 4380 caacgcaaag cctgcatgag taaaatcacc aaggaactcc tgaataagcg agggttccct 4440 gccatacgag attaccactt tgtgaatgcc accgaggaat ctgatgcttt ggcaaaactt 4500 cggaaaacca tcataaacga gagccttaat ttcaagatcc gagatcagct tgttgttgga 4560 cagctgattc cagactgcta tgtagaactt gaaaaaatca ttttatcgga gcgtaaaaat 4620 gtgccaattg aatttcccgt aattgaccgg aaacgattat tacaactagt gagagaaaat 4680 cagctgcagt tagatgaaaa tgagcttcct cacgcagttc actttctaaa tgaatcagga 4740 gtccttcttc attttcaaga cccagcactg cagttaagtg acttgtactt tgtggaaccc 4800 aagtggcttt gtaaaatcat ggcacagatt ttgacagtga aagtggaagg ttgtccaaaa 4860 caccctaagg gcattatttc gcgtagagat gtggaaaaat ttctttcaaa aaaaaggaaa 4920 tttccaaaga actacatgtc acagtatttt aagctcctag aaaaattcca gattgctttg 4980 ccaataggag aagaatattt gctggttcca agcagtttgt ctgaccacag gcctgtgata 5040 gagcttcccc attgtgagaa ctctgaaatt atcatccgac tatatgaaat gccttatttt 5100 ccaatgggat tttggtcaag attaatcaat cgattacttg agatttcacc ttacatgctt 5160 tcagggagag aacgagcact tcgcccaaac agaatgtatt ggcgacaagg catttactta 5220 aattggtctc ctgaagctta ttgtctggta ggatctgaag tcttagacaa tcatccagag 5280 agtttcttaa aaattacagt tccttcttgt agaaaaggct gtattctttt gggccaagtt 5340 gtggaccaca ttgattctct catggaagaa tggtttcctg ggttgctgga gattgatatt 5400 tgtggtgaag gagaaactct gttgaagaaa tgggcattat atagttttaa tgatggcgaa 5460 gaacatcaaa aaatcttact tgatgacttg atgaagaaag cagaggaagg agatctctta 5520 gtaaatccag atcaaccaag gctcaccatt ccaatatctc agattgcccc tgacttgatt 5580 ttggctgacc tgcctagaaa tattatgttg aataatgatg agttggaatt tgaacaagct 5640 ccagagtttc tcctaggtga tggcagtttt ggatcagttt accgagcagc ctatgaagga 5700 gaagaagtgg ctgtgaagat ttttaataaa catacatcac tcaggctgtt aagacaagag 5760 cttgtggtgc tttgccacct ccaccacccc agtttgatat ctttgctggc agctgggatt 5820 cgtccccgga tgttggtgat ggagttagcc tccaagggtt ccttggatcg cctgcttcag 5880 caggacaaag ccagcctcac tagaacccta cagcacagga ttgcactcca cgtagctgat 5940 ggtttgagat acctccactc agccatgatt atataccgag acctgaaacc ccacaatgtg 6000 ctgcttttca cactgtatcc caatgctgcc atcattgcaa agattgctga ctacggcatt 6060 gctcagtact gctgtagaat ggggataaaa acatcagagg gcacaccagg gtttcgtgca 6120 cctgaagttg ccagaggaaa tgtcatttat aaccaacagg ctgatgttta ttcatttggt 6180 ttactactct atgacatttt gacaactgga ggtagaatag tagagggttt gaagtttcca 6240 aatgagtttg atgaattaga aatacaagga aaattacctg atccagttaa agaatatggt 6300 tgtgccccat ggcctatggt tgagaaatta attaaacagt gtttgaaaga aaatcctcaa 6360 gaaaggccta cttctgccca ggtctttgac attttgaatt cagctgaatt agtctgtctg 6420 acgagacgca ttttattacc taaaaacgta attgttgaat gcatggttgc tacacatcac 6480 aacagcagga atgcaagcat ttggctgggc tgtgggcaca ccgacagagg acagctctca 6540 tttcttgact taaatactga aggatacact tctgaggaag ttgctgatag tagaatattg 6600 tgcttagcct tggtgcatct tcctgttgaa aaggaaagct ggattgtgtc tgggacacag 6660 tctggtactc tcctggtcat caataccgaa gatgggaaaa agagacatac cctagaaaag 6720 atgactgatt ctgtcacttg tttgtattgc aattcctttt ccaagcaaag caaacaaaaa 6780 aattttcttt tggttggaac cgctgatggc aagttagcaa tttttgaaga taagactgtt 6840 aagcttaaag gagctgctcc tttgaagata ctaaatatag gaaatgtcag tactccattg 6900 atgtgtttga gtgaatccac aaattcaacg gaaagaaatg taatgtgggg aggatgtggc 6960 acaaagattt tctccttttc taatgatttc accattcaga aactcattga gacaagaaca 7020 agccaactgt tttcttatgc agctttcagt gattccaaca tcataacagt ggtggtagac 7080 actgctctct atattgctaa gcaaaatagc cctgttgtgg aagtgtggga taagaaaact 7140 gaaaaactct gtggactaat agactgcgtg cactttttaa gggaggtaat ggtaaaagaa 7200 aacaaggaat caaaacacaa aatgtcttat tctgggagag tgaaaaccct ctgccttcag 7260 aagaacactg ctctttggat aggaactgga ggaggccata ttttactcct ggatctttca 7320 actcgtcgac ttatacgtgt aatttacaac ttttgtaatt cggtcagagt catgatgaca 7380 gcacagctag gaagccttaa aaatgtcatg ctggtattgg gctacaaccg gaaaaatact 7440 gaaggtacac aaaagcagaa agagatacaa tcttgcttga ccgtttggga catcaatctt 7500 ccacatgaag tgcaaaattt agaaaaacac attgaagtga gaaaagaatt agctgaaaaa 7560 atgagacgaa catctgttga gtaa 7584 <210> 6 <211> 2527 <212> PRT <213> Homo sapiens <400> 6 Met Ala Ser Gly Ser Cys Gln Gly Cys Glu Glu Asp Glu Glu Thr Leu 1 5 10 15 Lys Lys Leu Ile Val Arg Leu Asn Asn Val Gln Glu Gly Lys Gln Ile 20 25 30 Glu Thr Leu Val Gln Ile Leu Glu Asp Leu Leu Val Phe Thr Tyr Ser 35 40 45 Glu His Ala Ser Lys Leu Phe Gln Gly Lys Asn Ile His Val Pro Leu 50 55 60 Leu Ile Val Leu Asp Ser Tyr Met Arg Val Ala Ser Val Gln Gln Val 65 70 75 80 Gly Trp Ser Leu Leu Cys Lys Leu Ile Glu Val Cys Pro Gly Thr Met 85 90 95 Gln Ser Leu Met Gly Pro Gln Asp Val Gly Asn Asp Trp Glu Val Leu 100 105 110 Gly Val His Gln Leu Ile Leu Lys Met Leu Thr Val His Asn Ala Ser 115 120 125 Val Asn Leu Ser Val Ile Gly Leu Lys Thr Leu Asp Leu Leu Leu Thr 130 135 140 Ser Gly Lys Ile Thr Leu Leu Ile Leu Asp Glu Glu Ser Asp Ile Phe 145 150 155 160 Met Leu Ile Phe Asp Ala Met His Ser Phe Pro Ala Asn Asp Glu Val 165 170 175 Gln Lys Leu Gly Cys Lys Ala Leu His Val Leu Phe Glu Arg Val Ser 180 185 190 Glu Glu Gln Leu Thr Glu Phe Val Glu Asn Lys Asp Tyr Met Ile Leu 195 200 205 Leu Ser Ala Leu Thr Asn Phe Lys Asp Glu Glu Glu Ile Val Leu His 210 215 220 Val Leu His Cys Leu His Ser Leu Ala Ile Pro Cys Asn Asn Val Glu 225 230 235 240 Val Leu Met Ser Gly Asn Val Arg Cys Tyr Asn Ile Val Val Glu Ala 245 250 255 Met Lys Ala Phe Pro Met Ser Glu Arg Ile Gln Glu Val Ser Cys Cys 260 265 270 Leu Leu His Arg Leu Thr Leu Gly Asn Phe Phe Asn Ile Leu Val Leu 275 280 285 Asn Glu Val His Glu Phe Val Val Lys Ala Val Gln Gln Tyr Pro Glu 290 295 300 Asn Ala Ala Leu Gln Ile Ser Ala Leu Ser Cys Leu Ala Leu Leu Thr 305 310 315 320 Glu Thr Ile Phe Leu Asn Gln Asp Leu Glu Glu Lys Asn Glu Asn Gln 325 330 335 Glu Asn Asp Asp Glu Gly Glu Glu Asp Lys Leu Phe Trp Leu Glu Ala 340 345 350 Cys Tyr Lys Ala Leu Thr Trp His Arg Lys Asn Lys His Val Gln Glu 355 360 365 Ala Ala Cys Trp Ala Leu Asn Asn Leu Leu Met Tyr Gln Asn Ser Leu 370 375 380 His Glu Lys Ile Gly Asp Glu Asp Gly His Phe Pro Ala His Arg Glu 385 390 395 400 Val Met Leu Ser Met Leu Met His Ser Ser Ser Lys Glu Val Phe Gln 405 410 415 Ala Ser Ala Asn Ala Leu Ser Thr Leu Leu Glu Gln Asn Val Asn Phe 420 425 430 Arg Lys Ile Leu Leu Ser Lys Gly Ile His Leu Asn Val Leu Glu Leu 435 440 445 Met Gln Lys His Ile His Ser Pro Glu Val Ala Glu Ser Gly Cys Lys 450 455 460 Met Leu Asn His Leu Phe Glu Gly Ser Asn Thr Ser Leu Asp Ile Met 465 470 475 480 Ala Ala Val Val Pro Lys Ile Leu Thr Val Met Lys Arg His Glu Thr 485 490 495 Ser Leu Pro Val Gln Leu Glu Ala Leu Arg Ala Ile Leu His Phe Ile 500 505 510 Val Pro Gly Met Pro Glu Glu Ser Arg Glu Asp Thr Glu Phe His His 515 520 525 Lys Leu Asn Met Val Lys Lys Gln Cys Phe Lys Asn Asp Ile His Lys 530 535 540 Leu Val Leu Ala Ala Leu Asn Arg Phe Ile Gly Asn Pro Gly Ile Gln 545 550 555 560 Lys Cys Gly Leu Lys Val Ile Ser Ser Ile Val His Phe Pro Asp Ala 565 570 575 Leu Glu Met Leu Ser Leu Glu Gly Ala Met Asp Ser Val Leu His Thr 580 585 590 Leu Gln Met Tyr Pro Asp Asp Gln Glu Ile Gln Cys Leu Gly Leu Ser 595 600 605 Leu Ile Gly Tyr Leu Ile Thr Lys Lys Asn Val Phe Ile Gly Thr Gly 610 615 620 His Leu Leu Ala Lys Ile Leu Val Ser Ser Leu Tyr Arg Phe Lys Asp 625 630 635 640 Val Ala Glu Ile Gln Thr Lys Gly Phe Gln Thr Ile Leu Ala Ile Leu 645 650 655 Lys Leu Ser Ala Ser Phe Ser Lys Leu Leu Val His His Ser Phe Asp 660 665 670 Leu Val Ile Phe His Gln Met Ser Ser Asn Ile Met Glu Gln Lys Asp 675 680 685 Gln Gln Phe Leu Asn Leu Cys Cys Lys Cys Phe Ala Lys Val Ala Met 690 695 700 Asp Asp Tyr Leu Lys Asn Val Met Leu Glu Arg Ala Cys Asp Gln Asn 705 710 715 720 Asn Ser Ile Met Val Glu Cys Leu Leu Leu Leu Gly Ala Asp Ala Asn 725 730 735 Gln Ala Lys Glu Gly Ser Ser Leu Ile Cys Gln Val Cys Glu Lys Glu 740 745 750 Ser Ser Pro Lys Leu Val Glu Leu Leu Leu Asn Ser Gly Ser Arg Glu 755 760 765 Gln Asp Val Arg Lys Ala Leu Thr Ile Ser Ile Gly Lys Gly Asp Ser 770 775 780 Gln Ile Ile Ser Leu Leu Leu Arg Arg Leu Ala Leu Asp Val Ala Asn 785 790 795 800 Asn Ser Ile Cys Leu Gly Gly Phe Cys Ile Gly Lys Val Glu Pro Ser 805 810 815 Trp Leu Gly Pro Leu Phe Pro Asp Lys Thr Ser Asn Leu Arg Lys Gln 820 825 830 Thr Asn Ile Ala Ser Thr Leu Ala Arg Met Val Ile Arg Tyr Gln Met 835 840 845 Lys Ser Ala Val Glu Glu Gly Thr Ala Ser Gly Ser Asp Gly Asn Phe 850 855 860 Ser Glu Asp Val Leu Ser Lys Phe Asp Glu Trp Thr Phe Ile Pro Asp 865 870 875 880 Ser Ser Met Asp Ser Val Phe Ala Gln Ser Asp Asp Leu Asp Ser Glu 885 890 895 Gly Ser Glu Gly Ser Phe Leu Val Lys Lys Lys Ser Asn Ser Ile Ser 900 905 910 Val Gly Glu Phe Tyr Arg Asp Ala Val Leu Gln Arg Cys Ser Pro Asn 915 920 925 Leu Gln Arg His Ser Asn Ser Leu Gly Pro Ile Phe Asp His Glu Asp 930 935 940 Leu Leu Lys Arg Lys Arg Lys Ile Leu Ser Ser Asp Asp Ser Leu Arg 945 950 955 960 Ser Ser Lys Leu Gln Ser His Met Arg His Ser Asp Ser Ile Ser Ser 965 970 975 Leu Ala Ser Glu Arg Glu Tyr Ile Thr Ser Leu Asp Leu Ser Ala Asn 980 985 990 Glu Leu Arg Asp Ile Asp Ala Leu Ser Gln Lys Cys Cys Ile Ser Val 995 1000 1005 His Leu Glu His Leu Glu Lys Leu Glu Leu His Gln Asn Ala Leu Thr 1010 1015 1020 Ser Phe Pro Gln Gln Leu Cys Glu Thr Leu Lys Ser Leu Thr His Leu 1025 1030 1035 1040 Asp Leu His Ser Asn Lys Phe Thr Ser Phe Pro Ser Tyr Leu Leu Lys 1045 1050 1055 Met Ser Cys Ile Ala Asn Leu Asp Val Ser Arg Asn Asp Ile Gly Pro 1060 1065 1070 Ser Val Val Leu Asp Pro Thr Val Lys Cys Pro Thr Leu Lys Gln Phe 1075 1080 1085 Asn Leu Ser Tyr Asn Gln Leu Ser Phe Val Pro Glu Asn Leu Thr Asp 1090 1095 1100 Val Val Glu Lys Leu Glu Gln Leu Ile Leu Glu Gly Asn Lys Ile Ser 1105 1110 1115 1120 Gly Ile Cys Ser Pro Leu Arg Leu Lys Glu Leu Lys Ile Leu Asn Leu 1125 1130 1135 Ser Lys Asn His Ile Ser Ser Leu Ser Glu Asn Phe Leu Glu Ala Cys 1140 1145 1150 Pro Lys Val Glu Ser Phe Ser Ala Arg Met Asn Phe Leu Ala Ala Met 1155 1160 1165 Pro Phe Leu Pro Pro Ser Met Thr Ile Leu Lys Leu Ser Gln Asn Lys 1170 1175 1180 Phe Ser Cys Ile Pro Glu Ala Ile Leu Asn Leu Pro His Leu Arg Ser 1185 1190 1195 1200 Leu Asp Met Ser Ser Asn Asp Ile Gln Tyr Leu Pro Gly Pro Ala His 1205 1210 1215 Trp Lys Ser Leu Asn Leu Arg Glu Leu Leu Phe Ser His Asn Gln Ile 1220 1225 1230 Ser Ile Leu Asp Leu Ser Glu Lys Ala Tyr Leu Trp Ser Arg Val Glu 1235 1240 1245 Lys Leu His Leu Ser His Asn Lys Leu Lys Glu Ile Pro Pro Glu Ile 1250 1255 1260 Gly Cys Leu Glu Asn Leu Thr Ser Leu Asp Val Ser Tyr Asn Leu Glu 1265 1270 1275 1280 Leu Arg Ser Phe Pro Asn Glu Met Gly Lys Leu Ser Lys Ile Trp Asp 1285 1290 1295 Leu Pro Leu Asp Glu Leu His Leu Asn Phe Asp Phe Lys His Ile Gly 1300 1305 1310 Cys Lys Ala Lys Asp Ile Ile Arg Phe Leu Gln Gln Arg Leu Lys Lys 1315 1320 1325 Ala Val Pro Tyr Asn Arg Met Lys Leu Met Ile Val Gly Asn Thr Gly 1330 1335 1340 Ser Gly Lys Thr Thr Leu Leu Gln Gln Leu Met Lys Thr Lys Lys Ser 1345 1350 1355 1360 Asp Leu Gly Met Gln Ser Ala Thr Val Gly Ile Asp Val Lys Asp Trp 1365 1370 1375 Pro Ile Gln Ile Arg Asp Lys Arg Lys Arg Asp Leu Val Leu Asn Val 1380 1385 1390 Trp Asp Phe Ala Gly Arg Glu Glu Phe Tyr Ser Thr His Pro His Phe 1395 1400 1405 Met Thr Gln Arg Ala Leu Tyr Leu Ala Val Tyr Asp Leu Ser Lys Gly 1410 1415 1420 Gln Ala Glu Val Asp Ala Met Lys Pro Trp Leu Phe Asn Ile Lys Ala 1425 1430 1435 1440 Gly Ala Ser Ser Ser Pro Val Ile Leu Val Gly Thr His Leu Asp Val 1445 1450 1455 Ser Asp Glu Lys Gln Arg Lys Ala Cys Met Ser Lys Ile Thr Lys Glu 1460 1465 1470 Leu Leu Asn Lys Arg Gly Phe Pro Ala Ile Arg Asp Tyr His Phe Val 1475 1480 1485 Asn Ala Thr Glu Glu Ser Asp Ala Leu Ala Lys Leu Arg Lys Thr Ile 1490 1495 1500 Ile Asn Glu Ser Leu Asn Phe Lys Ile Arg Asp Gln Leu Val Val Gly 1505 1510 1515 1520 Gln Leu Ile Pro Asp Cys Tyr Val Glu Leu Glu Lys Ile Ile Leu Ser 1525 1530 1535 Glu Arg Lys Asn Val Pro Ile Glu Phe Pro Val Ile Asp Arg Lys Arg 1540 1545 1550 Leu Leu Gln Leu Val Arg Glu Asn Gln Leu Gln Leu Asp Glu Asn Glu 1555 1560 1565 Leu Pro His Ala Val His Phe Leu Asn Glu Ser Gly Val Leu Leu His 1570 1575 1580 Phe Gln Asp Pro Ala Leu Gln Leu Ser Asp Leu Tyr Phe Val Glu Pro 1585 1590 1595 1600 Lys Trp Leu Cys Lys Ile Met Ala Gln Ile Leu Thr Val Lys Val Glu 1605 1610 1615 Gly Cys Pro Lys His Pro Lys Gly Ile Ile Ser Arg Arg Asp Val Glu 1620 1625 1630 Lys Phe Leu Ser Lys Lys Arg Lys Phe Pro Lys Asn Tyr Met Ser Gln 1635 1640 1645 Tyr Phe Lys Leu Leu Glu Lys Phe Gln Ile Ala Leu Pro Ile Gly Glu 1650 1655 1660 Glu Tyr Leu Leu Val Pro Ser Ser Leu Ser Asp His Arg Pro Val Ile 1665 1670 1675 1680 Glu Leu Pro His Cys Glu Asn Ser Glu Ile Ile Ile Arg Leu Tyr Glu 1685 1690 1695 Met Pro Tyr Phe Pro Met Gly Phe Trp Ser Arg Leu Ile Asn Arg Leu 1700 1705 1710 Leu Glu Ile Ser Pro Tyr Met Leu Ser Gly Arg Glu Arg Ala Leu Arg 1715 1720 1725 Pro Asn Arg Met Tyr Trp Arg Gln Gly Ile Tyr Leu Asn Trp Ser Pro 1730 1735 1740 Glu Ala Tyr Cys Leu Val Gly Ser Glu Val Leu Asp Asn His Pro Glu 1745 1750 1755 1760 Ser Phe Leu Lys Ile Thr Val Pro Ser Cys Arg Lys Gly Cys Ile Leu 1765 1770 1775 Leu Gly Gln Val Val Asp His Ile Asp Ser Leu Met Glu Glu Trp Phe 1780 1785 1790 Pro Gly Leu Leu Glu Ile Asp Ile Cys Gly Glu Gly Glu Thr Leu Leu 1795 1800 1805 Lys Lys Trp Ala Leu Tyr Ser Phe Asn Asp Gly Glu Glu His Gln Lys 1810 1815 1820 Ile Leu Leu Asp Asp Leu Met Lys Lys Ala Glu Glu Gly Asp Leu Leu 1825 1830 1835 1840 Val Asn Pro Asp Gln Pro Arg Leu Thr Ile Pro Ile Ser Gln Ile Ala 1845 1850 1855 Pro Asp Leu Ile Leu Ala Asp Leu Pro Arg Asn Ile Met Leu Asn Asn 1860 1865 1870 Asp Glu Leu Glu Phe Glu Gln Ala Pro Glu Phe Leu Leu Gly Asp Gly 1875 1880 1885 Ser Phe Gly Ser Val Tyr Arg Ala Ala Tyr Glu Gly Glu Glu Val Ala 1890 1895 1900 Val Lys Ile Phe Asn Lys His Thr Ser Leu Arg Leu Leu Arg Gln Glu 1905 1910 1915 1920 Leu Val Val Leu Cys His Leu His His Pro Ser Leu Ile Ser Leu Leu 1925 1930 1935 Ala Ala Gly Ile Arg Pro Arg Met Leu Val Met Glu Leu Ala Ser Lys 1940 1945 1950 Gly Ser Leu Asp Arg Leu Leu Gln Gln Asp Lys Ala Ser Leu Thr Arg 1955 1960 1965 Thr Leu Gln His Arg Ile Ala Leu His Val Ala Asp Gly Leu Arg Tyr 1970 1975 1980 Leu His Ser Ala Met Ile Ile Tyr Arg Asp Leu Lys Pro His Asn Val 1985 1990 1995 2000 Leu Leu Phe Thr Leu Tyr Pro Asn Ala Ala Ile Ile Ala Lys Ile Ala 2005 2010 2015 Asp Tyr Gly Ile Ala Gln Tyr Cys Cys Arg Met Gly Ile Lys Thr Ser 2020 2025 2030 Glu Gly Thr Pro Gly Phe Arg Ala Pro Glu Val Ala Arg Gly Asn Val 2035 2040 2045 Ile Tyr Asn Gln Gln Ala Asp Val Tyr Ser Phe Gly Leu Leu Leu Tyr 2050 2055 2060 Asp Ile Leu Thr Thr Gly Gly Arg Ile Val Glu Gly Leu Lys Phe Pro 2065 2070 2075 2080 Asn Glu Phe Asp Glu Leu Glu Ile Gln Gly Lys Leu Pro Asp Pro Val 2085 2090 2095 Lys Glu Tyr Gly Cys Ala Pro Trp Pro Met Val Glu Lys Leu Ile Lys 2100 2105 2110 Gln Cys Leu Lys Glu Asn Pro Gln Glu Arg Pro Thr Ser Ala Gln Val 2115 2120 2125 Phe Asp Ile Leu Asn Ser Ala Glu Leu Val Cys Leu Thr Arg Arg Ile 2130 2135 2140 Leu Leu Pro Lys Asn Val Ile Val Glu Cys Met Val Ala Thr His His 2145 2150 2155 2160 Asn Ser Arg Asn Ala Ser Ile Trp Leu Gly Cys Gly His Thr Asp Arg 2165 2170 2175 Gly Gln Leu Ser Phe Leu Asp Leu Asn Thr Glu Gly Tyr Thr Ser Glu 2180 2185 2190 Glu Val Ala Asp Ser Arg Ile Leu Cys Leu Ala Leu Val His Leu Pro 2195 2200 2205 Val Glu Lys Glu Ser Trp Ile Val Ser Gly Thr Gln Ser Gly Thr Leu 2210 2215 2220 Leu Val Ile Asn Thr Glu Asp Gly Lys Lys Arg His Thr Leu Glu Lys 2225 2230 2235 2240 Met Thr Asp Ser Val Thr Cys Leu Tyr Cys Asn Ser Phe Ser Lys Gln 2245 2250 2255 Ser Lys Gln Lys Asn Phe Leu Leu Val Gly Thr Ala Asp Gly Lys Leu 2260 2265 2270 Ala Ile Phe Glu Asp Lys Thr Val Lys Leu Lys Gly Ala Ala Pro Leu 2275 2280 2285 Lys Ile Leu Asn Ile Gly Asn Val Ser Thr Pro Leu Met Cys Leu Ser 2290 2295 2300 Glu Ser Thr Asn Ser Thr Glu Arg Asn Val Met Trp Gly Gly Cys Gly 2305 2310 2315 2320 Thr Lys Ile Phe Ser Phe Ser Asn Asp Phe Thr Ile Gln Lys Leu Ile 2325 2330 2335 Glu Thr Arg Thr Ser Gln Leu Phe Ser Tyr Ala Ala Phe Ser Asp Ser 2340 2345 2350 Asn Ile Ile Thr Val Val Val Asp Thr Ala Leu Tyr Ile Ala Lys Gln 2355 2360 2365 Asn Ser Pro Val Val Glu Val Trp Asp Lys Lys Thr Glu Lys Leu Cys 2370 2375 2380 Gly Leu Ile Asp Cys Val His Phe Leu Arg Glu Val Met Val Lys Glu 2385 2390 2395 2400 Asn Lys Glu Ser Lys His Lys Met Ser Tyr Ser Gly Arg Val Lys Thr 2405 2410 2415 Leu Cys Leu Gln Lys Asn Thr Ala Leu Trp Ile Gly Thr Gly Gly Gly 2420 2425 2430 His Ile Leu Leu Leu Asp Leu Ser Thr Arg Arg Leu Ile Arg Val Ile 2435 2440 2445 Tyr Asn Phe Cys Asn Ser Val Arg Val Met Met Thr Ala Gln Leu Gly 2450 2455 2460 Ser Leu Lys Asn Val Met Leu Val Leu Gly Tyr Asn Arg Lys Asn Thr 2465 2470 2475 2480 Glu Gly Thr Gln Lys Gln Lys Glu Ile Gln Ser Cys Leu Thr Val Trp 2485 2490 2495 Asp Ile Asn Leu Pro His Glu Val Gln Asn Leu Glu Lys His Ile Glu 2500 2505 2510 Val Arg Lys Glu Leu Ala Glu Lys Met Arg Arg Thr Ser Val Glu 2515 2520 2525 <210> 7 <211> 7584 <212> DNA <213> Homo sapiens <400> 7 atggctagtg gcagctgtca ggggtgcgaa gaggacgagg aaactctgaa gaagttgata 60 gtcaggctga acaatgtcca ggaaggaaaa cagatagaaa cgctggtcca aatcctggag 120 gatctgctgg tgttcacgta ctccgagcac gcctccaagt tatttcaagg caaaaatatc 180 catgtgcctc tgttgatcgt cttggactcc tatatgagag tcgcgagtgt gcagcaggtg 240 ggttggtcac ttctgtgcaa attaatagaa gtctgtccag gtacaatgca aagcttaatg 300 ggaccccagg atgttggaaa tgattgggaa gtccttggtg ttcaccaatt gattcttaaa 360 atgctaacag ttcataatgc cagtgtaaac ttgtcagtga ttggactgaa gaccttagat 420 ctcctcctaa cttcaggtaa aatcaccttg ctgatactgg atgaagaaag tgatattttc 480 atgttaattt ttgatgccat gcactcattt ccagccaatg atgaagtcca gaaacttgga 540 tgcaaagctt tacatgtgct gtttgagaga gtctcagagg agcaactgac tgaatttgtt 600 gagaacaaag attatatgat attgttaagt gcgtcaacaa attttaaaga tgaagaggaa 660 attgtgcttc atgtgctgca ttgtttacat tccctagcga ttccttgcaa taatgtggaa 720 gtcctcatga gtggcaatgt caggtgttat aatattgtgg tggaagctat gaaagcattc 780 cctatgagtg aaagaattca agaagtgagt tgctgtttgc tccataggct tacattaggt 840 aattttttca atatcctggt attaaacgaa gtccatgagt ttgtggtgaa agctgtgcag 900 cagtacccag agaatgcagc attgcagatc tcagcgctca gctgtttggc cctcctcact 960 gagactattt tcttaaatca agatttagag gaaaagaatg agaatcaaga gaatgatgat 1020 gagggggaag aagataaatt gttttggctg gaagcctgtt acaaagcatt aacgtggcat 1080 agaaagaaca agcacgtgca ggaggccgca tgctgggcac taaataatct ccttatgtac 1140 caaaacagtt tacatgagaa gattggagat gaagatggcc atttcccagc tcatagggaa 1200 gtgatgctct ccatgctgat gcattcttca tcaaaggaag ttttccaggc atctgcgaat 1260 gcattgtcaa ctctcttaga acaaaatgtt aatttcagaa aaatactgtt atcaaaagga 1320 atacacctga atgttttgga gttaatgcag aagcatatac attctcctga agtggctgaa 1380 agtggctgta aaatgctaaa tcatcttttt gaaggaagca acacttccct ggatataatg 1440 gcagcagtgg tccccaaaat actaacagtt atgaaacgtc atgagacatc attaccagtg 1500 cagctggagg cgcttcgagc tattttacat tttatagtgc ctggcatgcc agaagaatcc 1560 agggaggata cagaatttca tcataagcta aatatggtta aaaaacagtg tttcaagaat 1620 gatattcaca aactggtcct agcagctttg aacaggttca ttggaaatcc tgggattcag 1680 aaatgtggat taaaagtaat ttcttctatt gtacattttc ctgatgcatt agagatgtta 1740 tccctggaag gtgctatgga ttcagtgctt cacacactgc agatgtatcc agatgaccaa 1800 gaaattcagt gtctgggttt aagtcttata ggatacttga ttacaaagaa gaatgtgttc 1860 ataggaactg gacatctgct ggcaaaaatt ctggtttcca gcttataccg atttaaggat 1920 gttgctgaaa tacagactaa aggatttcag acaatcttag caatcctcaa attgtcagca 1980 tctttttcta agctgctggt gcatcattca tttgacttag taatattcca tcaaatgtct 2040 tccaatatca tggaacaaaa ggatcaacag tttctaaacc tctgttgcaa gtgttttgca 2100 aaagtagcta tggatgatta cttaaaaaat gtgatgctag agagagcgtg tgatcagaat 2160 aacagcatca tggttgaatg cttgcttcta ttgggagcag atgccaatca agcaaaggag 2220 ggatcttctt taatttgtca ggtatgtgag aaagagagca gtcccaaatt ggtggaactc 2280 ttactgaata gtggatctcg tgaacaagat gtacgaaaag cgttgacgat aagcattggg 2340 aaaggtgaca gccagatcat cagcttgctc ttaaggaggc tggccctgga tgtggccaac 2400 aatagcattt gccttggagg attttgtata ggaaaagttg aaccttcttg gcttggtcct 2460 ttatttccag ataagacttc taatttaagg aaacaaacaa atatagcatc tacactagca 2520 agaatggtga tcagatatca gatgaaaagt gctgtggaag aaggaacagc ctcaggcagc 2580 gatggaaatt tttctgaaga tgtgctgtct aaatttgatg aatggacctt tattcctgac 2640 tcttctatgg acagtgtgtt tgctcaaagt gatgacctgg atagtgaagg aagtgaaggc 2700 tcatttcttg tgaaaaagaa atctaattca attagtgtag gagaatttta ccgagatgcc 2760 gtattacagc gttgctcacc aaatttgcaa agacattcca attccttggg gcccattttt 2820 gatcatgaag atttactgaa gcgaaaaaga aaaatactat cttcagatga ttcactcagg 2880 tcatcaaaac ttcaatccca tatgaggcat tcagacagca tttcttctct ggcttctgag 2940 agagaatata ttacatcact agacctttca gcaaatgaac taagagatat tgatgcccta 3000 agccagaaat gctgtataag tgttcatttg gagcatcttg aaaagctgga gcttcaccag 3060 aatgcactca cgagctttcc acaacagcta tgtgaaactc tgaagagttt gacacatttg 3120 gacttgcaca gtaataaatt tacatcattt ccttcttatt tgttgaaaat gagttgtatt 3180 gctaatcttg atgtctctcg aaatgacatt ggaccctcag tggttttaga tcctacagtg 3240 aaatgtccaa ctctgaaaca gtttaacctg tcatataacc agctgtcttt tgtacctgag 3300 aacctcactg atgtggtaga gaaactggag cagctcattt tagaaggaaa taaaatatca 3360 gggatatgct cccccttgag actgaaggaa ctgaagattt taaaccttag taagaaccac 3420 atttcatccc tatcagagaa ctttcttgag gcttgtccta aagtggagag tttcagtgcc 3480 agaatgaatt ttcttgctgc tatgcctttc ttgcctcctt ctatgacaat cctaaaatta 3540 tctcagaaca aattttcctg tattccagaa gcaattttaa atcttccaca cttgcggtct 3600 ttagatatga gcagcaatga tattcagtac ctaccaggtc ccgcacactg gaaatctttg 3660 aacttaaggg aactcttatt tagccataat cagatcagca tcttggactt gagtgaaaaa 3720 gcatatttat ggtctagagt agagaaactg catctttctc acaataaact gaaagagatt 3780 cctcctgaga ttggctgtct tgaaaatctg acatctctgg atgtcagtta caacttggaa 3840 ctaagatcct ttcccaatga aatggggaaa ttaagcaaaa tatgggatct tcctttggat 3900 gaactgcatc ttaactttga ttttaaacat ataggatgta aagccaaaga catcataagg 3960 tttcttcaac agcgattaaa aaaggctgtg ccttataacc gaatgaaact tatgattgtg 4020 ggaaatactg ggagtggtaa aaccacctta ttgcagcaat taatgaaaac caagaaatca 4080 gatcttggaa tgcaaagtgc cacagttggc atagatgtga aagactggcc tatccaaata 4140 agagacaaaa gaaagagaga tctcgtccta aatgtgtggg attttgcagg tcgtgaggaa 4200 ttctatagta ctcatcccca ttttatgacg cagcgagcat tgtaccttgc tgtctatgac 4260 ctcagcaagg gacaggctga agttgatgcc atgaagcctt ggctcttcaa tataaaggct 4320 cgcgcttctt cttcccctgt gattctcgtt ggcacacatt tggatgtttc tgatgagaag 4380 caacgcaaag cctgcatgag taaaatcacc aaggaactcc tgaataagcg agggttccct 4440 gccatacgag attaccactt tgtgaatgcc accgaggaat ctgatgcttt ggcaaaactt 4500 cggaaaacca tcataaacga gagccttaat ttcaagatcc gagatcagct tgttgttgga 4560 cagctgattc cagactgcta tgtagaactt gaaaaaatca ttttatcgga gcgtaaaaat 4620 gtgccaattg aatttcccgt aattgaccgg aaacgattat tacaactagt gagagaaaat 4680 cagctgcagt tagatgaaaa tgagcttcct cacgcagttc actttctaaa tgaatcagga 4740 gtccttcttc attttcaaga cccagcactg cagttaagtg acttgtactt tgtggaaccc 4800 aagtggcttt gtaaaatcat ggcacagatt ttgacagtga aagtggaagg ttgtccaaaa 4860 caccctaagg gcattatttc gcgtagagat gtggaaaaat ttctttcaaa aaaaaggaaa 4920 tttccaaaga actacatgtc acagtatttt aagctcctag aaaaattcca gattgctttg 4980 ccaataggag aagaatattt gctggttcca agcagtttgt ctgaccacag gcctgtgata 5040 gagcttcccc attgtgagaa ctctgaaatt atcatccgac tatatgaaat gccttgtttt 5100 ccaatgggat tttggtcaag attaatcaat cgattacttg agatttcacc ttacatgctt 5160 tcagggagag aacgagcact tcgcccaaac agaatgtatt ggcgacaagg catttactta 5220 aattggtctc ctgaagctta ttgtctggta ggatctgaag tcttagacaa tcatccagag 5280 agtttcttaa aaattacagt tccttcttgt agaaaaggct gtattctttt gggccaagtt 5340 gtggaccaca ttgattctct catggaagaa tggtttcctg ggttgctgga gattgatatt 5400 tgtggtgaag gagaaactct gttgaagaaa tgggcattat atagttttaa tgatggcgaa 5460 gaacatcaaa aaatcttact tgatgacttg atgaagaaag cagaggaagg agatctctta 5520 gtaaatccag atcaaccaag gctcaccatt ccaatatctc agattgcccc tgacttgatt 5580 ttggctgacc tgcctagaaa tattatgttg aataatgatg agttggaatt tgaacaagct 5640 ccagagtttc tcctaggtga tggcagtttt ggatcagttt accgagcagc ctatgaagga 5700 gaagaagtgg ctgtgaagat ttttaataaa catacatcac tcaggctgtt aagacaagag 5760 cttgtggtgc tttgccacct ccaccacccc agtttgatat ctttgctggc agctgggatt 5820 cgtccccgga tgttggtgat ggagttagcc tccaagggtt ccttggatcg cctgcttcag 5880 caggacaaag ccagcctcac tagaacccta cagcacagga ttgcactcca cgtagctgat 5940 ggtttgagat acctccactc agccatgatt atataccgag acctgaaacc ccacaatgtg 6000 ctgcttttca cactgtatcc caatgctgcc atcattgcaa agattgctga ctacggcatt 6060 gctcagtact gctgtagaat ggggataaaa acatcagagg gcacaccagg gtttcgtgca 6120 cctgaagttg ccagaggaaa tgtcatttat aaccaacagg ctgatgttta ttcatttggt 6180 ttactactct atgacatttt gacaactgga ggtagaatag tagagggttt gaagtttcca 6240 aatgagtttg atgaattaga aatacaagga aaattacctg atccagttaa agaatatggt 6300 tgtgccccat ggcctatggt tgagaaatta attaaacagt gtttgaaaga aaatcctcaa 6360 gaaaggccta cttctgccca ggtctttgac attttgaatt cagctgaatt agtctgtctg 6420 acgagacgca ttttattacc taaaaacgta attgttgaat gcatggttgc tacacatcac 6480 aacagcagga atgcaagcat ttggctgggc tgtgggcaca ccgacagagg acagctctca 6540 tttcttgact taaatactga aggatacact tctgaggaag ttgctgatag tagaatattg 6600 tgcttagcct tggtgcatct tcctgttgaa aaggaaagct ggattgtgtc tgggacacag 6660 tctggtactc tcctggtcat caataccgaa gatgggaaaa agagacatac cctagaaaag 6720 atgactgatt ctgtcacttg tttgtattgc aattcctttt ccaagcaaag caaacaaaaa 6780 aattttcttt tggttggaac cgctgatggc aagttagcaa tttttgaaga taagactgtt 6840 aagcttaaag gagctgctcc tttgaagata ctaaatatag gaaatgtcag tactccattg 6900 atgtgtttga gtgaatccac aaattcaacg gaaagaaatg taatgtgggg aggatgtggc 6960 acaaagattt tctccttttc taatgatttc accattcaga aactcattga gacaagaaca 7020 agccaactgt tttcttatgc agctttcagt gattccaaca tcataacagt ggtggtagac 7080 actgctctct atattgctaa gcaaaatagc cctgttgtgg aagtgtggga taagaaaact 7140 gaaaaactct gtggactaat agactgcgtg cactttttaa gggaggtaat ggtaaaagaa 7200 aacaaggaat caaaacacaa aatgtcttat tctgggagag tgaaaaccct ctgccttcag 7260 aagaacactg ctctttggat aggaactgga ggaggccata ttttactcct ggatctttca 7320 actcgtcgac ttatacgtgt aatttacaac ttttgtaatt cggtcagagt catgatgaca 7380 gcacagctag gaagccttaa aaatgtcatg ctggtattgg gctacaaccg gaaaaatact 7440 gaaggtacac aaaagcagaa agagatacaa tcttgcttga ccgtttggga catcaatctt 7500 ccacatgaag tgcaaaattt agaaaaacac attgaagtga gaaaagaatt agctgaaaaa 7560 atgagacgaa catctgttga gtaa 7584 <210> 8 <211> 2527 <212> PRT <213> Homo sapiens <400> 8 Met Ala Ser Gly Ser Cys Gln Gly Cys Glu Glu Asp Glu Glu Thr Leu 1 5 10 15 Lys Lys Leu Ile Val Arg Leu Asn Asn Val Gln Glu Gly Lys Gln Ile 20 25 30 Glu Thr Leu Val Gln Ile Leu Glu Asp Leu Leu Val Phe Thr Tyr Ser 35 40 45 Glu His Ala Ser Lys Leu Phe Gln Gly Lys Asn Ile His Val Pro Leu 50 55 60 Leu Ile Val Leu Asp Ser Tyr Met Arg Val Ala Ser Val Gln Gln Val 65 70 75 80 Gly Trp Ser Leu Leu Cys Lys Leu Ile Glu Val Cys Pro Gly Thr Met 85 90 95 Gln Ser Leu Met Gly Pro Gln Asp Val Gly Asn Asp Trp Glu Val Leu 100 105 110 Gly Val His Gln Leu Ile Leu Lys Met Leu Thr Val His Asn Ala Ser 115 120 125 Val Asn Leu Ser Val Ile Gly Leu Lys Thr Leu Asp Leu Leu Leu Thr 130 135 140 Ser Gly Lys Ile Thr Leu Leu Ile Leu Asp Glu Glu Ser Asp Ile Phe 145 150 155 160 Met Leu Ile Phe Asp Ala Met His Ser Phe Pro Ala Asn Asp Glu Val 165 170 175 Gln Lys Leu Gly Cys Lys Ala Leu His Val Leu Phe Glu Arg Val Ser 180 185 190 Glu Glu Gln Leu Thr Glu Phe Val Glu Asn Lys Asp Tyr Met Ile Leu 195 200 205 Leu Ser Ala Leu Thr Asn Phe Lys Asp Glu Glu Glu Ile Val Leu His 210 215 220 Val Leu His Cys Leu His Ser Leu Ala Ile Pro Cys Asn Asn Val Glu 225 230 235 240 Val Leu Met Ser Gly Asn Val Arg Cys Tyr Asn Ile Val Val Glu Ala 245 250 255 Met Lys Ala Phe Pro Met Ser Glu Arg Ile Gln Glu Val Ser Cys Cys 260 265 270 Leu Leu His Arg Leu Thr Leu Gly Asn Phe Phe Asn Ile Leu Val Leu 275 280 285 Asn Glu Val His Glu Phe Val Val Lys Ala Val Gln Gln Tyr Pro Glu 290 295 300 Asn Ala Ala Leu Gln Ile Ser Ala Leu Ser Cys Leu Ala Leu Leu Thr 305 310 315 320 Glu Thr Ile Phe Leu Asn Gln Asp Leu Glu Glu Lys Asn Glu Asn Gln 325 330 335 Glu Asn Asp Asp Glu Gly Glu Glu Asp Lys Leu Phe Trp Leu Glu Ala 340 345 350 Cys Tyr Lys Ala Leu Thr Trp His Arg Lys Asn Lys His Val Gln Glu 355 360 365 Ala Ala Cys Trp Ala Leu Asn Asn Leu Leu Met Tyr Gln Asn Ser Leu 370 375 380 His Glu Lys Ile Gly Asp Glu Asp Gly His Phe Pro Ala His Arg Glu 385 390 395 400 Val Met Leu Ser Met Leu Met His Ser Ser Ser Lys Glu Val Phe Gln 405 410 415 Ala Ser Ala Asn Ala Leu Ser Thr Leu Leu Glu Gln Asn Val Asn Phe 420 425 430 Arg Lys Ile Leu Leu Ser Lys Gly Ile His Leu Asn Val Leu Glu Leu 435 440 445 Met Gln Lys His Ile His Ser Pro Glu Val Ala Glu Ser Gly Cys Lys 450 455 460 Met Leu Asn His Leu Phe Glu Gly Ser Asn Thr Ser Leu Asp Ile Met 465 470 475 480 Ala Ala Val Val Pro Lys Ile Leu Thr Val Met Lys Arg His Glu Thr 485 490 495 Ser Leu Pro Val Gln Leu Glu Ala Leu Arg Ala Ile Leu His Phe Ile 500 505 510 Val Pro Gly Met Pro Glu Glu Ser Arg Glu Asp Thr Glu Phe His His 515 520 525 Lys Leu Asn Met Val Lys Lys Gln Cys Phe Lys Asn Asp Ile His Lys 530 535 540 Leu Val Leu Ala Ala Leu Asn Arg Phe Ile Gly Asn Pro Gly Ile Gln 545 550 555 560 Lys Cys Gly Leu Lys Val Ile Ser Ser Ile Val His Phe Pro Asp Ala 565 570 575 Leu Glu Met Leu Ser Leu Glu Gly Ala Met Asp Ser Val Leu His Thr 580 585 590 Leu Gln Met Tyr Pro Asp Asp Gln Glu Ile Gln Cys Leu Gly Leu Ser 595 600 605 Leu Ile Gly Tyr Leu Ile Thr Lys Lys Asn Val Phe Ile Gly Thr Gly 610 615 620 His Leu Leu Ala Lys Ile Leu Val Ser Ser Leu Tyr Arg Phe Lys Asp 625 630 635 640 Val Ala Glu Ile Gln Thr Lys Gly Phe Gln Thr Ile Leu Ala Ile Leu 645 650 655 Lys Leu Ser Ala Ser Phe Ser Lys Leu Leu Val His His Ser Phe Asp 660 665 670 Leu Val Ile Phe His Gln Met Ser Ser Asn Ile Met Glu Gln Lys Asp 675 680 685 Gln Gln Phe Leu Asn Leu Cys Cys Lys Cys Phe Ala Lys Val Ala Met 690 695 700 Asp Asp Tyr Leu Lys Asn Val Met Leu Glu Arg Ala Cys Asp Gln Asn 705 710 715 720 Asn Ser Ile Met Val Glu Cys Leu Leu Leu Leu Gly Ala Asp Ala Asn 725 730 735 Gln Ala Lys Glu Gly Ser Ser Leu Ile Cys Gln Val Cys Glu Lys Glu 740 745 750 Ser Ser Pro Lys Leu Val Glu Leu Leu Leu Asn Ser Gly Ser Arg Glu 755 760 765 Gln Asp Val Arg Lys Ala Leu Thr Ile Ser Ile Gly Lys Gly Asp Ser 770 775 780 Gln Ile Ile Ser Leu Leu Leu Arg Arg Leu Ala Leu Asp Val Ala Asn 785 790 795 800 Asn Ser Ile Cys Leu Gly Gly Phe Cys Ile Gly Lys Val Glu Pro Ser 805 810 815 Trp Leu Gly Pro Leu Phe Pro Asp Lys Thr Ser Asn Leu Arg Lys Gln 820 825 830 Thr Asn Ile Ala Ser Thr Leu Ala Arg Met Val Ile Arg Tyr Gln Met 835 840 845 Lys Ser Ala Val Glu Glu Gly Thr Ala Ser Gly Ser Asp Gly Asn Phe 850 855 860 Ser Glu Asp Val Leu Ser Lys Phe Asp Glu Trp Thr Phe Ile Pro Asp 865 870 875 880 Ser Ser Met Asp Ser Val Phe Ala Gln Ser Asp Asp Leu Asp Ser Glu 885 890 895 Gly Ser Glu Gly Ser Phe Leu Val Lys Lys Lys Ser Asn Ser Ile Ser 900 905 910 Val Gly Glu Phe Tyr Arg Asp Ala Val Leu Gln Arg Cys Ser Pro Asn 915 920 925 Leu Gln Arg His Ser Asn Ser Leu Gly Pro Ile Phe Asp His Glu Asp 930 935 940 Leu Leu Lys Arg Lys Arg Lys Ile Leu Ser Ser Asp Asp Ser Leu Arg 945 950 955 960 Ser Ser Lys Leu Gln Ser His Met Arg His Ser Asp Ser Ile Ser Ser 965 970 975 Leu Ala Ser Glu Arg Glu Tyr Ile Thr Ser Leu Asp Leu Ser Ala Asn 980 985 990 Glu Leu Arg Asp Ile Asp Ala Leu Ser Gln Lys Cys Cys Ile Ser Val 995 1000 1005 His Leu Glu His Leu Glu Lys Leu Glu Leu His Gln Asn Ala Leu Thr 1010 1015 1020 Ser Phe Pro Gln Gln Leu Cys Glu Thr Leu Lys Ser Leu Thr His Leu 1025 1030 1035 1040 Asp Leu His Ser Asn Lys Phe Thr Ser Phe Pro Ser Tyr Leu Leu Lys 1045 1050 1055 Met Ser Cys Ile Ala Asn Leu Asp Val Ser Arg Asn Asp Ile Gly Pro 1060 1065 1070 Ser Val Val Leu Asp Pro Thr Val Lys Cys Pro Thr Leu Lys Gln Phe 1075 1080 1085 Asn Leu Ser Tyr Asn Gln Leu Ser Phe Val Pro Glu Asn Leu Thr Asp 1090 1095 1100 Val Val Glu Lys Leu Glu Gln Leu Ile Leu Glu Gly Asn Lys Ile Ser 1105 1110 1115 1120 Gly Ile Cys Ser Pro Leu Arg Leu Lys Glu Leu Lys Ile Leu Asn Leu 1125 1130 1135 Ser Lys Asn His Ile Ser Ser Leu Ser Glu Asn Phe Leu Glu Ala Cys 1140 1145 1150 Pro Lys Val Glu Ser Phe Ser Ala Arg Met Asn Phe Leu Ala Ala Met 1155 1160 1165 Pro Phe Leu Pro Pro Ser Met Thr Ile Leu Lys Leu Ser Gln Asn Lys 1170 1175 1180 Phe Ser Cys Ile Pro Glu Ala Ile Leu Asn Leu Pro His Leu Arg Ser 1185 1190 1195 1200 Leu Asp Met Ser Ser Asn Asp Ile Gln Tyr Leu Pro Gly Pro Ala His 1205 1210 1215 Trp Lys Ser Leu Asn Leu Arg Glu Leu Leu Phe Ser His Asn Gln Ile 1220 1225 1230 Ser Ile Leu Asp Leu Ser Glu Lys Ala Tyr Leu Trp Ser Arg Val Glu 1235 1240 1245 Lys Leu His Leu Ser His Asn Lys Leu Lys Glu Ile Pro Pro Glu Ile 1250 1255 1260 Gly Cys Leu Glu Asn Leu Thr Ser Leu Asp Val Ser Tyr Asn Leu Glu 1265 1270 1275 1280 Leu Arg Ser Phe Pro Asn Glu Met Gly Lys Leu Ser Lys Ile Trp Asp 1285 1290 1295 Leu Pro Leu Asp Glu Leu His Leu Asn Phe Asp Phe Lys His Ile Gly 1300 1305 1310 Cys Lys Ala Lys Asp Ile Ile Arg Phe Leu Gln Gln Arg Leu Lys Lys 1315 1320 1325 Ala Val Pro Tyr Asn Arg Met Lys Leu Met Ile Val Gly Asn Thr Gly 1330 1335 1340 Ser Gly Lys Thr Thr Leu Leu Gln Gln Leu Met Lys Thr Lys Lys Ser 1345 1350 1355 1360 Asp Leu Gly Met Gln Ser Ala Thr Val Gly Ile Asp Val Lys Asp Trp 1365 1370 1375 Pro Ile Gln Ile Arg Asp Lys Arg Lys Arg Asp Leu Val Leu Asn Val 1380 1385 1390 Trp Asp Phe Ala Gly Arg Glu Glu Phe Tyr Ser Thr His Pro His Phe 1395 1400 1405 Met Thr Gln Arg Ala Leu Tyr Leu Ala Val Tyr Asp Leu Ser Lys Gly 1410 1415 1420 Gln Ala Glu Val Asp Ala Met Lys Pro Trp Leu Phe Asn Ile Lys Ala 1425 1430 1435 1440 Arg Ala Ser Ser Ser Pro Val Ile Leu Val Gly Thr His Leu Asp Val 1445 1450 1455 Ser Asp Glu Lys Gln Arg Lys Ala Cys Met Ser Lys Ile Thr Lys Glu 1460 1465 1470 Leu Leu Asn Lys Arg Gly Phe Pro Ala Ile Arg Asp Tyr His Phe Val 1475 1480 1485 Asn Ala Thr Glu Glu Ser Asp Ala Leu Ala Lys Leu Arg Lys Thr Ile 1490 1495 1500 Ile Asn Glu Ser Leu Asn Phe Lys Ile Arg Asp Gln Leu Val Val Gly 1505 1510 1515 1520 Gln Leu Ile Pro Asp Cys Tyr Val Glu Leu Glu Lys Ile Ile Leu Ser 1525 1530 1535 Glu Arg Lys Asn Val Pro Ile Glu Phe Pro Val Ile Asp Arg Lys Arg 1540 1545 1550 Leu Leu Gln Leu Val Arg Glu Asn Gln Leu Gln Leu Asp Glu Asn Glu 1555 1560 1565 Leu Pro His Ala Val His Phe Leu Asn Glu Ser Gly Val Leu Leu His 1570 1575 1580 Phe Gln Asp Pro Ala Leu Gln Leu Ser Asp Leu Tyr Phe Val Glu Pro 1585 1590 1595 1600 Lys Trp Leu Cys Lys Ile Met Ala Gln Ile Leu Thr Val Lys Val Glu 1605 1610 1615 Gly Cys Pro Lys His Pro Lys Gly Ile Ile Ser Arg Arg Asp Val Glu 1620 1625 1630 Lys Phe Leu Ser Lys Lys Arg Lys Phe Pro Lys Asn Tyr Met Ser Gln 1635 1640 1645 Tyr Phe Lys Leu Leu Glu Lys Phe Gln Ile Ala Leu Pro Ile Gly Glu 1650 1655 1660 Glu Tyr Leu Leu Val Pro Ser Ser Leu Ser Asp His Arg Pro Val Ile 1665 1670 1675 1680 Glu Leu Pro His Cys Glu Asn Ser Glu Ile Ile Ile Arg Leu Tyr Glu 1685 1690 1695 Met Pro Cys Phe Pro Met Gly Phe Trp Ser Arg Leu Ile Asn Arg Leu 1700 1705 1710 Leu Glu Ile Ser Pro Tyr Met Leu Ser Gly Arg Glu Arg Ala Leu Arg 1715 1720 1725 Pro Asn Arg Met Tyr Trp Arg Gln Gly Ile Tyr Leu Asn Trp Ser Pro 1730 1735 1740 Glu Ala Tyr Cys Leu Val Gly Ser Glu Val Leu Asp Asn His Pro Glu 1745 1750 1755 1760 Ser Phe Leu Lys Ile Thr Val Pro Ser Cys Arg Lys Gly Cys Ile Leu 1765 1770 1775 Leu Gly Gln Val Val Asp His Ile Asp Ser Leu Met Glu Glu Trp Phe 1780 1785 1790 Pro Gly Leu Leu Glu Ile Asp Ile Cys Gly Glu Gly Glu Thr Leu Leu 1795 1800 1805 Lys Lys Trp Ala Leu Tyr Ser Phe Asn Asp Gly Glu Glu His Gln Lys 1810 1815 1820 Ile Leu Leu Asp Asp Leu Met Lys Lys Ala Glu Glu Gly Asp Leu Leu 1825 1830 1835 1840 Val Asn Pro Asp Gln Pro Arg Leu Thr Ile Pro Ile Ser Gln Ile Ala 1845 1850 1855 Pro Asp Leu Ile Leu Ala Asp Leu Pro Arg Asn Ile Met Leu Asn Asn 1860 1865 1870 Asp Glu Leu Glu Phe Glu Gln Ala Pro Glu Phe Leu Leu Gly Asp Gly 1875 1880 1885 Ser Phe Gly Ser Val Tyr Arg Ala Ala Tyr Glu Gly Glu Glu Val Ala 1890 1895 1900 Val Lys Ile Phe Asn Lys His Thr Ser Leu Arg Leu Leu Arg Gln Glu 1905 1910 1915 1920 Leu Val Val Leu Cys His Leu His His Pro Ser Leu Ile Ser Leu Leu 1925 1930 1935 Ala Ala Gly Ile Arg Pro Arg Met Leu Val Met Glu Leu Ala Ser Lys 1940 1945 1950 Gly Ser Leu Asp Arg Leu Leu Gln Gln Asp Lys Ala Ser Leu Thr Arg 1955 1960 1965 Thr Leu Gln His Arg Ile Ala Leu His Val Ala Asp Gly Leu Arg Tyr 1970 1975 1980 Leu His Ser Ala Met Ile Ile Tyr Arg Asp Leu Lys Pro His Asn Val 1985 1990 1995 2000 Leu Leu Phe Thr Leu Tyr Pro Asn Ala Ala Ile Ile Ala Lys Ile Ala 2005 2010 2015 Asp Tyr Gly Ile Ala Gln Tyr Cys Cys Arg Met Gly Ile Lys Thr Ser 2020 2025 2030 Glu Gly Thr Pro Gly Phe Arg Ala Pro Glu Val Ala Arg Gly Asn Val 2035 2040 2045 Ile Tyr Asn Gln Gln Ala Asp Val Tyr Ser Phe Gly Leu Leu Leu Tyr 2050 2055 2060 Asp Ile Leu Thr Thr Gly Gly Arg Ile Val Glu Gly Leu Lys Phe Pro 2065 2070 2075 2080 Asn Glu Phe Asp Glu Leu Glu Ile Gln Gly Lys Leu Pro Asp Pro Val 2085 2090 2095 Lys Glu Tyr Gly Cys Ala Pro Trp Pro Met Val Glu Lys Leu Ile Lys 2100 2105 2110 Gln Cys Leu Lys Glu Asn Pro Gln Glu Arg Pro Thr Ser Ala Gln Val 2115 2120 2125 Phe Asp Ile Leu Asn Ser Ala Glu Leu Val Cys Leu Thr Arg Arg Ile 2130 2135 2140 Leu Leu Pro Lys Asn Val Ile Val Glu Cys Met Val Ala Thr His His 2145 2150 2155 2160 Asn Ser Arg Asn Ala Ser Ile Trp Leu Gly Cys Gly His Thr Asp Arg 2165 2170 2175 Gly Gln Leu Ser Phe Leu Asp Leu Asn Thr Glu Gly Tyr Thr Ser Glu 2180 2185 2190 Glu Val Ala Asp Ser Arg Ile Leu Cys Leu Ala Leu Val His Leu Pro 2195 2200 2205 Val Glu Lys Glu Ser Trp Ile Val Ser Gly Thr Gln Ser Gly Thr Leu 2210 2215 2220 Leu Val Ile Asn Thr Glu Asp Gly Lys Lys Arg His Thr Leu Glu Lys 2225 2230 2235 2240 Met Thr Asp Ser Val Thr Cys Leu Tyr Cys Asn Ser Phe Ser Lys Gln 2245 2250 2255 Ser Lys Gln Lys Asn Phe Leu Leu Val Gly Thr Ala Asp Gly Lys Leu 2260 2265 2270 Ala Ile Phe Glu Asp Lys Thr Val Lys Leu Lys Gly Ala Ala Pro Leu 2275 2280 2285 Lys Ile Leu Asn Ile Gly Asn Val Ser Thr Pro Leu Met Cys Leu Ser 2290 2295 2300 Glu Ser Thr Asn Ser Thr Glu Arg Asn Val Met Trp Gly Gly Cys Gly 2305 2310 2315 2320 Thr Lys Ile Phe Ser Phe Ser Asn Asp Phe Thr Ile Gln Lys Leu Ile 2325 2330 2335 Glu Thr Arg Thr Ser Gln Leu Phe Ser Tyr Ala Ala Phe Ser Asp Ser 2340 2345 2350 Asn Ile Ile Thr Val Val Val Asp Thr Ala Leu Tyr Ile Ala Lys Gln 2355 2360 2365 Asn Ser Pro Val Val Glu Val Trp Asp Lys Lys Thr Glu Lys Leu Cys 2370 2375 2380 Gly Leu Ile Asp Cys Val His Phe Leu Arg Glu Val Met Val Lys Glu 2385 2390 2395 2400 Asn Lys Glu Ser Lys His Lys Met Ser Tyr Ser Gly Arg Val Lys Thr 2405 2410 2415 Leu Cys Leu Gln Lys Asn Thr Ala Leu Trp Ile Gly Thr Gly Gly Gly 2420 2425 2430 His Ile Leu Leu Leu Asp Leu Ser Thr Arg Arg Leu Ile Arg Val Ile 2435 2440 2445 Tyr Asn Phe Cys Asn Ser Val Arg Val Met Met Thr Ala Gln Leu Gly 2450 2455 2460 Ser Leu Lys Asn Val Met Leu Val Leu Gly Tyr Asn Arg Lys Asn Thr 2465 2470 2475 2480 Glu Gly Thr Gln Lys Gln Lys Glu Ile Gln Ser Cys Leu Thr Val Trp 2485 2490 2495 Asp Ile Asn Leu Pro His Glu Val Gln Asn Leu Glu Lys His Ile Glu 2500 2505 2510 Val Arg Lys Glu Leu Ala Glu Lys Met Arg Arg Thr Ser Val Glu 2515 2520 2525 <210> 9 <211> 7584 <212> DNA <213> Homo sapiens <400> 9 atggctagtg gcagctgtca ggggtgcgaa gaggacgagg aaactctgaa gaagttgata 60 gtcaggctga acaatgtcca ggaaggaaaa cagatagaaa cgctggtcca aatcctggag 120 gatctgctgg tgttcacgta ctccgagcac gcctccaagt tatttcaagg caaaaatatc 180 catgtgcctc tgttgatcgt cttggactcc tatatgagag tcgcgagtgt gcagcaggtg 240 ggttggtcac ttctgtgcaa attaatagaa gtctgtccag gtacaatgca aagcttaatg 300 ggaccccagg atgttggaaa tgattgggaa gtccttggtg ttcaccaatt gattcttaaa 360 atgctaacag ttcataatgc cagtgtaaac ttgtcagtga ttggactgaa gaccttagat 420 ctcctcctaa cttcaggtaa aatcaccttg ctgatactgg atgaagaaag tgatattttc 480 atgttaattt ttgatgccat gcactcattt ccagccaatg atgaagtcca gaaacttgga 540 tgcaaagctt tacatgtgct gtttgagaga gtctcagagg agcaactgac tgaatttgtt 600 gagaacaaag attatatgat attgttaagt gcgtcaacaa attttaaaga tgaagaggaa 660 attgtgcttc atgtgctgca ttgtttacat tccctagcga ttccttgcaa taatgtggaa 720 gtcctcatga gtggcaatgt caggtgttat aatattgtgg tggaagctat gaaagcattc 780 cctatgagtg aaagaattca agaagtgagt tgctgtttgc tccataggct tacattaggt 840 aattttttca atatcctggt attaaacgaa gtccatgagt ttgtggtgaa agctgtgcag 900 cagtacccag agaatgcagc attgcagatc tcagcgctca gctgtttggc cctcctcact 960 gagactattt tcttaaatca agatttagag gaaaagaatg agaatcaaga gaatgatgat 1020 gagggggaag aagataaatt gttttggctg gaagcctgtt acaaagcatt aacgtggcat 1080 agaaagaaca agcacgtgca ggaggccgca tgctgggcac taaataatct ccttatgtac 1140 caaaacagtt tacatgagaa gattggagat gaagatggcc atttcccagc tcatagggaa 1200 gtgatgctct ccatgctgat gcattcttca tcaaaggaag ttttccaggc atctgcgaat 1260 gcattgtcaa ctctcttaga acaaaatgtt aatttcagaa aaatactgtt atcaaaagga 1320 atacacctga atgttttgga gttaatgcag aagcatatac attctcctga agtggctgaa 1380 agtggctgta aaatgctaaa tcatcttttt gaaggaagca acacttccct ggatataatg 1440 gcagcagtgg tccccaaaat actaacagtt atgaaacgtc atgagacatc attaccagtg 1500 cagctggagg cgcttcgagc tattttacat tttatagtgc ctggcatgcc agaagaatcc 1560 agggaggata cagaatttca tcataagcta aatatggtta aaaaacagtg tttcaagaat 1620 gatattcaca aactggtcct agcagctttg aacaggttca ttggaaatcc tgggattcag 1680 aaatgtggat taaaagtaat ttcttctatt gtacattttc ctgatgcatt agagatgtta 1740 tccctggaag gtgctatgga ttcagtgctt cacacactgc agatgtatcc agatgaccaa 1800 gaaattcagt gtctgggttt aagtcttata ggatacttga ttacaaagaa gaatgtgttc 1860 ataggaactg gacatctgct ggcaaaaatt ctggtttcca gcttataccg atttaaggat 1920 gttgctgaaa tacagactaa aggatttcag acaatcttag caatcctcaa attgtcagca 1980 tctttttcta agctgctggt gcatcattca tttgacttag taatattcca tcaaatgtct 2040 tccaatatca tggaacaaaa ggatcaacag tttctaaacc tctgttgcaa gtgttttgca 2100 aaagtagcta tggatgatta cttaaaaaat gtgatgctag agagagcgtg tgatcagaat 2160 aacagcatca tggttgaatg cttgcttcta ttgggagcag atgccaatca agcaaaggag 2220 ggatcttctt taatttgtca ggtatgtgag aaagagagca gtcccaaatt ggtggaactc 2280 ttactgaata gtggatctcg tgaacaagat gtacgaaaag cgttgacgat aagcattggg 2340 aaaggtgaca gccagatcat cagcttgctc ttaaggaggc tggccctgga tgtggccaac 2400 aatagcattt gccttggagg attttgtata ggaaaagttg aaccttcttg gcttggtcct 2460 ttatttccag ataagacttc taatttaagg aaacaaacaa atatagcatc tacactagca 2520 agaatggtga tcagatatca gatgaaaagt gctgtggaag aaggaacagc ctcaggcagc 2580 gatggaaatt tttctgaaga tgtgctgtct aaatttgatg aatggacctt tattcctgac 2640 tcttctatgg acagtgtgtt tgctcaaagt gatgacctgg atagtgaagg aagtgaaggc 2700 tcatttcttg tgaaaaagaa atctaattca attagtgtag gagaatttta ccgagatgcc 2760 gtattacagc gttgctcacc aaatttgcaa agacattcca attccttggg gcccattttt 2820 gatcatgaag atttactgaa gcgaaaaaga aaaatactat cttcagatga ttcactcagg 2880 tcatcaaaac ttcaatccca tatgaggcat tcagacagca tttcttctct ggcttctgag 2940 agagaatata ttacatcact agacctttca gcaaatgaac taagagatat tgatgcccta 3000 agccagaaat gctgtataag tgttcatttg gagcatcttg aaaagctgga gcttcaccag 3060 aatgcactca cgagctttcc acaacagcta tgtgaaactc tgaagagttt gacacatttg 3120 gacttgcaca gtaataaatt tacatcattt ccttcttatt tgttgaaaat gagttgtatt 3180 gctaatcttg atgtctctcg aaatgacatt ggaccctcag tggttttaga tcctacagtg 3240 aaatgtccaa ctctgaaaca gtttaacctg tcatataacc agctgtcttt tgtacctgag 3300 aacctcactg atgtggtaga gaaactggag cagctcattt tagaaggaaa taaaatatca 3360 gggatatgct cccccttgag actgaaggaa ctgaagattt taaaccttag taagaaccac 3420 atttcatccc tatcagagaa ctttcttgag gcttgtccta aagtggagag tttcagtgcc 3480 agaatgaatt ttcttgctgc tatgcctttc ttgcctcctt ctatgacaat cctaaaatta 3540 tctcagaaca aattttcctg tattccagaa gcaattttaa atcttccaca cttgcggtct 3600 ttagatatga gcagcaatga tattcagtac ctaccaggtc ccgcacactg gaaatctttg 3660 aacttaaggg aactcttatt tagccataat cagatcagca tcttggactt gagtgaaaaa 3720 gcatatttat ggtctagagt agagaaactg catctttctc acaataaact gaaagagatt 3780 cctcctgaga ttggctgtct tgaaaatctg acatctctgg atgtcagtta caacttggaa 3840 ctaagatcct ttcccaatga aatggggaaa ttaagcaaaa tatgggatct tcctttggat 3900 gaactgcatc ttaactttga ttttaaacat ataggatgta aagccaaaga catcataagg 3960 tttcttcaac agcgattaaa aaaggctgtg ccttataacc gaatgaaact tatgattgtg 4020 ggaaatactg ggagtggtaa aaccacctta ttgcagcaat taatgaaaac caagaaatca 4080 gatcttggaa tgcaaagtgc cacagttggc atagatgtga aagactggcc tatccaaata 4140 agagacaaaa gaaagagaga tctcgtccta aatgtgtggg attttgcagg tcgtgaggaa 4200 ttctatagta ctcatcccca ttttatgacg cagcgagcat tgtaccttgc tgtctatgac 4260 ctcagcaagg gacaggctga agttgatgcc atgaagcctt ggctcttcaa tataaaggct 4320 cgcgcttctt cttcccctgt gattctcgtt ggcacacatt tggatgtttc tgatgagaag 4380 caacgcaaag cctgcatgag taaaatcacc aaggaactcc tgaataagcg agggttccct 4440 gccatacgag attaccactt tgtgaatgcc accgaggaat ctgatgcttt ggcaaaactt 4500 cggaaaacca tcataaacga gagccttaat ttcaagatcc gagatcagct tgttgttgga 4560 cagctgattc cagactgcta tgtagaactt gaaaaaatca ttttatcgga gcgtaaaaat 4620 gtgccaattg aatttcccgt aattgaccgg aaacgattat tacaactagt gagagaaaat 4680 cagctgcagt tagatgaaaa tgagcttcct cacgcagttc actttctaaa tgaatcagga 4740 gtccttcttc attttcaaga cccagcactg cagttaagtg acttgtactt tgtggaaccc 4800 aagtggcttt gtaaaatcat ggcacagatt ttgacagtga aagtggaagg ttgtccaaaa 4860 caccctaagg gcattatttc gcgtagagat gtggaaaaat ttctttcaaa aaaaaggaaa 4920 tttccaaaga actacatgtc acagtatttt aagctcctag aaaaattcca gattgctttg 4980 ccaataggag aagaatattt gctggttcca agcagtttgt ctgaccacag gcctgtgata 5040 gagcttcccc attgtgagaa ctctgaaatt atcatccgac tatatgaaat gccttatttt 5100 ccaatgggat tttggtcaag attaatcaat cgattacttg agatttcacc ttacatgctt 5160 tcagggagag aacgagcact tcgcccaaac agaatgtatt ggcgacaagg catttactta 5220 aattggtctc ctgaagctta ttgtctggta ggatctgaag tcttagacaa tcatccagag 5280 agtttcttaa aaattacagt tccttcttgt agaaaaggct gtattctttt gggccaagtt 5340 gtggaccaca ttgattctct catggaagaa tggtttcctg ggttgctgga gattgatatt 5400 tgtggtgaag gagaaactct gttgaagaaa tgggcattat atagttttaa tgatggcgaa 5460 gaacatcaaa aaatcttact tgatgacttg atgaagaaag cagaggaagg agatctctta 5520 gtaaatccag atcaaccaag gctcaccatt ccaatatctc agattgcccc tgacttgatt 5580 ttggctgacc tgcctagaaa tattatgttg aataatgatg agttggaatt tgaacaagct 5640 ccagagtttc tcctaggtga tggcagtttt ggatcagttt accgagcagc ctatgaagga 5700 gaagaagtgg ctgtgaagat ttttaataaa catacatcac tcaggctgtt aagacaagag 5760 cttgtggtgc tttgccacct ccaccacccc agtttgatat ctttgctggc agctgggatt 5820 cgtccccgga tgttggtgat ggagttagcc tccaagggtt ccttggatcg cctgcttcag 5880 caggacaaag ccagcctcac tagaacccta cagcacagga ttgcactcca cgtagctgat 5940 ggtttgagat acctccactc agccatgatt atataccgag acctgaaacc ccacaatgtg 6000 ctgcttttca cactgtatcc caatgctgcc atcattgcaa agattgctga ctacggcact 6060 gctcagtact gctgtagaat ggggataaaa acatcagagg gcacaccagg gtttcgtgca 6120 cctgaagttg ccagaggaaa tgtcatttat aaccaacagg ctgatgttta ttcatttggt 6180 ttactactct atgacatttt gacaactgga ggtagaatag tagagggttt gaagtttcca 6240 aatgagtttg atgaattaga aatacaagga aaattacctg atccagttaa agaatatggt 6300 tgtgccccat ggcctatggt tgagaaatta attaaacagt gtttgaaaga aaatcctcaa 6360 gaaaggccta cttctgccca ggtctttgac attttgaatt cagctgaatt agtctgtctg 6420 acgagacgca ttttattacc taaaaacgta attgttgaat gcatggttgc tacacatcac 6480 aacagcagga atgcaagcat ttggctgggc tgtgggcaca ccgacagagg acagctctca 6540 tttcttgact taaatactga aggatacact tctgaggaag ttgctgatag tagaatattg 6600 tgcttagcct tggtgcatct tcctgttgaa aaggaaagct ggattgtgtc tgggacacag 6660 tctggtactc tcctggtcat caataccgaa gatgggaaaa agagacatac cctagaaaag 6720 atgactgatt ctgtcacttg tttgtattgc aattcctttt ccaagcaaag caaacaaaaa 6780 aattttcttt tggttggaac cgctgatggc aagttagcaa tttttgaaga taagactgtt 6840 aagcttaaag gagctgctcc tttgaagata ctaaatatag gaaatgtcag tactccattg 6900 atgtgtttga gtgaatccac aaattcaacg gaaagaaatg taatgtgggg aggatgtggc 6960 acaaagattt tctccttttc taatgatttc accattcaga aactcattga gacaagaaca 7020 agccaactgt tttcttatgc agctttcagt gattccaaca tcataacagt ggtggtagac 7080 actgctctct atattgctaa gcaaaatagc cctgttgtgg aagtgtggga taagaaaact 7140 gaaaaactct gtggactaat agactgcgtg cactttttaa gggaggtaat ggtaaaagaa 7200 aacaaggaat caaaacacaa aatgtcttat tctgggagag tgaaaaccct ctgccttcag 7260 aagaacactg ctctttggat aggaactgga ggaggccata ttttactcct ggatctttca 7320 actcgtcgac ttatacgtgt aatttacaac ttttgtaatt cggtcagagt catgatgaca 7380 gcacagctag gaagccttaa aaatgtcatg ctggtattgg gctacaaccg gaaaaatact 7440 gaaggtacac aaaagcagaa agagatacaa tcttgcttga ccgtttggga catcaatctt 7500 ccacatgaag tgcaaaattt agaaaaacac attgaagtga gaaaagaatt agctgaaaaa 7560 atgagacgaa catctgttga gtaa 7584 <210> 10 <211> 2527 <212> PRT <213> Homo sapiens <400> 10 Met Ala Ser Gly Ser Cys Gln Gly Cys Glu Glu Asp Glu Glu Thr Leu 1 5 10 15 Lys Lys Leu Ile Val Arg Leu Asn Asn Val Gln Glu Gly Lys Gln Ile 20 25 30 Glu Thr Leu Val Gln Ile Leu Glu Asp Leu Leu Val Phe Thr Tyr Ser 35 40 45 Glu His Ala Ser Lys Leu Phe Gln Gly Lys Asn Ile His Val Pro Leu 50 55 60 Leu Ile Val Leu Asp Ser Tyr Met Arg Val Ala Ser Val Gln Gln Val 65 70 75 80 Gly Trp Ser Leu Leu Cys Lys Leu Ile Glu Val Cys Pro Gly Thr Met 85 90 95 Gln Ser Leu Met Gly Pro Gln Asp Val Gly Asn Asp Trp Glu Val Leu 100 105 110 Gly Val His Gln Leu Ile Leu Lys Met Leu Thr Val His Asn Ala Ser 115 120 125 Val Asn Leu Ser Val Ile Gly Leu Lys Thr Leu Asp Leu Leu Leu Thr 130 135 140 Ser Gly Lys Ile Thr Leu Leu Ile Leu Asp Glu Glu Ser Asp Ile Phe 145 150 155 160 Met Leu Ile Phe Asp Ala Met His Ser Phe Pro Ala Asn Asp Glu Val 165 170 175 Gln Lys Leu Gly Cys Lys Ala Leu His Val Leu Phe Glu Arg Val Ser 180 185 190 Glu Glu Gln Leu Thr Glu Phe Val Glu Asn Lys Asp Tyr Met Ile Leu 195 200 205 Leu Ser Ala Leu Thr Asn Phe Lys Asp Glu Glu Glu Ile Val Leu His 210 215 220 Val Leu His Cys Leu His Ser Leu Ala Ile Pro Cys Asn Asn Val Glu 225 230 235 240 Val Leu Met Ser Gly Asn Val Arg Cys Tyr Asn Ile Val Val Glu Ala 245 250 255 Met Lys Ala Phe Pro Met Ser Glu Arg Ile Gln Glu Val Ser Cys Cys 260 265 270 Leu Leu His Arg Leu Thr Leu Gly Asn Phe Phe Asn Ile Leu Val Leu 275 280 285 Asn Glu Val His Glu Phe Val Val Lys Ala Val Gln Gln Tyr Pro Glu 290 295 300 Asn Ala Ala Leu Gln Ile Ser Ala Leu Ser Cys Leu Ala Leu Leu Thr 305 310 315 320 Glu Thr Ile Phe Leu Asn Gln Asp Leu Glu Glu Lys Asn Glu Asn Gln 325 330 335 Glu Asn Asp Asp Glu Gly Glu Glu Asp Lys Leu Phe Trp Leu Glu Ala 340 345 350 Cys Tyr Lys Ala Leu Thr Trp His Arg Lys Asn Lys His Val Gln Glu 355 360 365 Ala Ala Cys Trp Ala Leu Asn Asn Leu Leu Met Tyr Gln Asn Ser Leu 370 375 380 His Glu Lys Ile Gly Asp Glu Asp Gly His Phe Pro Ala His Arg Glu 385 390 395 400 Val Met Leu Ser Met Leu Met His Ser Ser Ser Lys Glu Val Phe Gln 405 410 415 Ala Ser Ala Asn Ala Leu Ser Thr Leu Leu Glu Gln Asn Val Asn Phe 420 425 430 Arg Lys Ile Leu Leu Ser Lys Gly Ile His Leu Asn Val Leu Glu Leu 435 440 445 Met Gln Lys His Ile His Ser Pro Glu Val Ala Glu Ser Gly Cys Lys 450 455 460 Met Leu Asn His Leu Phe Glu Gly Ser Asn Thr Ser Leu Asp Ile Met 465 470 475 480 Ala Ala Val Val Pro Lys Ile Leu Thr Val Met Lys Arg His Glu Thr 485 490 495 Ser Leu Pro Val Gln Leu Glu Ala Leu Arg Ala Ile Leu His Phe Ile 500 505 510 Val Pro Gly Met Pro Glu Glu Ser Arg Glu Asp Thr Glu Phe His His 515 520 525 Lys Leu Asn Met Val Lys Lys Gln Cys Phe Lys Asn Asp Ile His Lys 530 535 540 Leu Val Leu Ala Ala Leu Asn Arg Phe Ile Gly Asn Pro Gly Ile Gln 545 550 555 560 Lys Cys Gly Leu Lys Val Ile Ser Ser Ile Val His Phe Pro Asp Ala 565 570 575 Leu Glu Met Leu Ser Leu Glu Gly Ala Met Asp Ser Val Leu His Thr 580 585 590 Leu Gln Met Tyr Pro Asp Asp Gln Glu Ile Gln Cys Leu Gly Leu Ser 595 600 605 Leu Ile Gly Tyr Leu Ile Thr Lys Lys Asn Val Phe Ile Gly Thr Gly 610 615 620 His Leu Leu Ala Lys Ile Leu Val Ser Ser Leu Tyr Arg Phe Lys Asp 625 630 635 640 Val Ala Glu Ile Gln Thr Lys Gly Phe Gln Thr Ile Leu Ala Ile Leu 645 650 655 Lys Leu Ser Ala Ser Phe Ser Lys Leu Leu Val His His Ser Phe Asp 660 665 670 Leu Val Ile Phe His Gln Met Ser Ser Asn Ile Met Glu Gln Lys Asp 675 680 685 Gln Gln Phe Leu Asn Leu Cys Cys Lys Cys Phe Ala Lys Val Ala Met 690 695 700 Asp Asp Tyr Leu Lys Asn Val Met Leu Glu Arg Ala Cys Asp Gln Asn 705 710 715 720 Asn Ser Ile Met Val Glu Cys Leu Leu Leu Leu Gly Ala Asp Ala Asn 725 730 735 Gln Ala Lys Glu Gly Ser Ser Leu Ile Cys Gln Val Cys Glu Lys Glu 740 745 750 Ser Ser Pro Lys Leu Val Glu Leu Leu Leu Asn Ser Gly Ser Arg Glu 755 760 765 Gln Asp Val Arg Lys Ala Leu Thr Ile Ser Ile Gly Lys Gly Asp Ser 770 775 780 Gln Ile Ile Ser Leu Leu Leu Arg Arg Leu Ala Leu Asp Val Ala Asn 785 790 795 800 Asn Ser Ile Cys Leu Gly Gly Phe Cys Ile Gly Lys Val Glu Pro Ser 805 810 815 Trp Leu Gly Pro Leu Phe Pro Asp Lys Thr Ser Asn Leu Arg Lys Gln 820 825 830 Thr Asn Ile Ala Ser Thr Leu Ala Arg Met Val Ile Arg Tyr Gln Met 835 840 845 Lys Ser Ala Val Glu Glu Gly Thr Ala Ser Gly Ser Asp Gly Asn Phe 850 855 860 Ser Glu Asp Val Leu Ser Lys Phe Asp Glu Trp Thr Phe Ile Pro Asp 865 870 875 880 Ser Ser Met Asp Ser Val Phe Ala Gln Ser Asp Asp Leu Asp Ser Glu 885 890 895 Gly Ser Glu Gly Ser Phe Leu Val Lys Lys Lys Ser Asn Ser Ile Ser 900 905 910 Val Gly Glu Phe Tyr Arg Asp Ala Val Leu Gln Arg Cys Ser Pro Asn 915 920 925 Leu Gln Arg His Ser Asn Ser Leu Gly Pro Ile Phe Asp His Glu Asp 930 935 940 Leu Leu Lys Arg Lys Arg Lys Ile Leu Ser Ser Asp Asp Ser Leu Arg 945 950 955 960 Ser Ser Lys Leu Gln Ser His Met Arg His Ser Asp Ser Ile Ser Ser 965 970 975 Leu Ala Ser Glu Arg Glu Tyr Ile Thr Ser Leu Asp Leu Ser Ala Asn 980 985 990 Glu Leu Arg Asp Ile Asp Ala Leu Ser Gln Lys Cys Cys Ile Ser Val 995 1000 1005 His Leu Glu His Leu Glu Lys Leu Glu Leu His Gln Asn Ala Leu Thr 1010 1015 1020 Ser Phe Pro Gln Gln Leu Cys Glu Thr Leu Lys Ser Leu Thr His Leu 1025 1030 1035 1040 Asp Leu His Ser Asn Lys Phe Thr Ser Phe Pro Ser Tyr Leu Leu Lys 1045 1050 1055 Met Ser Cys Ile Ala Asn Leu Asp Val Ser Arg Asn Asp Ile Gly Pro 1060 1065 1070 Ser Val Val Leu Asp Pro Thr Val Lys Cys Pro Thr Leu Lys Gln Phe 1075 1080 1085 Asn Leu Ser Tyr Asn Gln Leu Ser Phe Val Pro Glu Asn Leu Thr Asp 1090 1095 1100 Val Val Glu Lys Leu Glu Gln Leu Ile Leu Glu Gly Asn Lys Ile Ser 1105 1110 1115 1120 Gly Ile Cys Ser Pro Leu Arg Leu Lys Glu Leu Lys Ile Leu Asn Leu 1125 1130 1135 Ser Lys Asn His Ile Ser Ser Leu Ser Glu Asn Phe Leu Glu Ala Cys 1140 1145 1150 Pro Lys Val Glu Ser Phe Ser Ala Arg Met Asn Phe Leu Ala Ala Met 1155 1160 1165 Pro Phe Leu Pro Pro Ser Met Thr Ile Leu Lys Leu Ser Gln Asn Lys 1170 1175 1180 Phe Ser Cys Ile Pro Glu Ala Ile Leu Asn Leu Pro His Leu Arg Ser 1185 1190 1195 1200 Leu Asp Met Ser Ser Asn Asp Ile Gln Tyr Leu Pro Gly Pro Ala His 1205 1210 1215 Trp Lys Ser Leu Asn Leu Arg Glu Leu Leu Phe Ser His Asn Gln Ile 1220 1225 1230 Ser Ile Leu Asp Leu Ser Glu Lys Ala Tyr Leu Trp Ser Arg Val Glu 1235 1240 1245 Lys Leu His Leu Ser His Asn Lys Leu Lys Glu Ile Pro Pro Glu Ile 1250 1255 1260 Gly Cys Leu Glu Asn Leu Thr Ser Leu Asp Val Ser Tyr Asn Leu Glu 1265 1270 1275 1280 Leu Arg Ser Phe Pro Asn Glu Met Gly Lys Leu Ser Lys Ile Trp Asp 1285 1290 1295 Leu Pro Leu Asp Glu Leu His Leu Asn Phe Asp Phe Lys His Ile Gly 1300 1305 1310 Cys Lys Ala Lys Asp Ile Ile Arg Phe Leu Gln Gln Arg Leu Lys Lys 1315 1320 1325 Ala Val Pro Tyr Asn Arg Met Lys Leu Met Ile Val Gly Asn Thr Gly 1330 1335 1340 Ser Gly Lys Thr Thr Leu Leu Gln Gln Leu Met Lys Thr Lys Lys Ser 1345 1350 1355 1360 Asp Leu Gly Met Gln Ser Ala Thr Val Gly Ile Asp Val Lys Asp Trp 1365 1370 1375 Pro Ile Gln Ile Arg Asp Lys Arg Lys Arg Asp Leu Val Leu Asn Val 1380 1385 1390 Trp Asp Phe Ala Gly Arg Glu Glu Phe Tyr Ser Thr His Pro His Phe 1395 1400 1405 Met Thr Gln Arg Ala Leu Tyr Leu Ala Val Tyr Asp Leu Ser Lys Gly 1410 1415 1420 Gln Ala Glu Val Asp Ala Met Lys Pro Trp Leu Phe Asn Ile Lys Ala 1425 1430 1435 1440 Arg Ala Ser Ser Ser Pro Val Ile Leu Val Gly Thr His Leu Asp Val 1445 1450 1455 Ser Asp Glu Lys Gln Arg Lys Ala Cys Met Ser Lys Ile Thr Lys Glu 1460 1465 1470 Leu Leu Asn Lys Arg Gly Phe Pro Ala Ile Arg Asp Tyr His Phe Val 1475 1480 1485 Asn Ala Thr Glu Glu Ser Asp Ala Leu Ala Lys Leu Arg Lys Thr Ile 1490 1495 1500 Ile Asn Glu Ser Leu Asn Phe Lys Ile Arg Asp Gln Leu Val Val Gly 1505 1510 1515 1520 Gln Leu Ile Pro Asp Cys Tyr Val Glu Leu Glu Lys Ile Ile Leu Ser 1525 1530 1535 Glu Arg Lys Asn Val Pro Ile Glu Phe Pro Val Ile Asp Arg Lys Arg 1540 1545 1550 Leu Leu Gln Leu Val Arg Glu Asn Gln Leu Gln Leu Asp Glu Asn Glu 1555 1560 1565 Leu Pro His Ala Val His Phe Leu Asn Glu Ser Gly Val Leu Leu His 1570 1575 1580 Phe Gln Asp Pro Ala Leu Gln Leu Ser Asp Leu Tyr Phe Val Glu Pro 1585 1590 1595 1600 Lys Trp Leu Cys Lys Ile Met Ala Gln Ile Leu Thr Val Lys Val Glu 1605 1610 1615 Gly Cys Pro Lys His Pro Lys Gly Ile Ile Ser Arg Arg Asp Val Glu 1620 1625 1630 Lys Phe Leu Ser Lys Lys Arg Lys Phe Pro Lys Asn Tyr Met Ser Gln 1635 1640 1645 Tyr Phe Lys Leu Leu Glu Lys Phe Gln Ile Ala Leu Pro Ile Gly Glu 1650 1655 1660 Glu Tyr Leu Leu Val Pro Ser Ser Leu Ser Asp His Arg Pro Val Ile 1665 1670 1675 1680 Glu Leu Pro His Cys Glu Asn Ser Glu Ile Ile Ile Arg Leu Tyr Glu 1685 1690 1695 Met Pro Tyr Phe Pro Met Gly Phe Trp Ser Arg Leu Ile Asn Arg Leu 1700 1705 1710 Leu Glu Ile Ser Pro Tyr Met Leu Ser Gly Arg Glu Arg Ala Leu Arg 1715 1720 1725 Pro Asn Arg Met Tyr Trp Arg Gln Gly Ile Tyr Leu Asn Trp Ser Pro 1730 1735 1740 Glu Ala Tyr Cys Leu Val Gly Ser Glu Val Leu Asp Asn His Pro Glu 1745 1750 1755 1760 Ser Phe Leu Lys Ile Thr Val Pro Ser Cys Arg Lys Gly Cys Ile Leu 1765 1770 1775 Leu Gly Gln Val Val Asp His Ile Asp Ser Leu Met Glu Glu Trp Phe 1780 1785 1790 Pro Gly Leu Leu Glu Ile Asp Ile Cys Gly Glu Gly Glu Thr Leu Leu 1795 1800 1805 Lys Lys Trp Ala Leu Tyr Ser Phe Asn Asp Gly Glu Glu His Gln Lys 1810 1815 1820 Ile Leu Leu Asp Asp Leu Met Lys Lys Ala Glu Glu Gly Asp Leu Leu 1825 1830 1835 1840 Val Asn Pro Asp Gln Pro Arg Leu Thr Ile Pro Ile Ser Gln Ile Ala 1845 1850 1855 Pro Asp Leu Ile Leu Ala Asp Leu Pro Arg Asn Ile Met Leu Asn Asn 1860 1865 1870 Asp Glu Leu Glu Phe Glu Gln Ala Pro Glu Phe Leu Leu Gly Asp Gly 1875 1880 1885 Ser Phe Gly Ser Val Tyr Arg Ala Ala Tyr Glu Gly Glu Glu Val Ala 1890 1895 1900 Val Lys Ile Phe Asn Lys His Thr Ser Leu Arg Leu Leu Arg Gln Glu 1905 1910 1915 1920 Leu Val Val Leu Cys His Leu His His Pro Ser Leu Ile Ser Leu Leu 1925 1930 1935 Ala Ala Gly Ile Arg Pro Arg Met Leu Val Met Glu Leu Ala Ser Lys 1940 1945 1950 Gly Ser Leu Asp Arg Leu Leu Gln Gln Asp Lys Ala Ser Leu Thr Arg 1955 1960 1965 Thr Leu Gln His Arg Ile Ala Leu His Val Ala Asp Gly Leu Arg Tyr 1970 1975 1980 Leu His Ser Ala Met Ile Ile Tyr Arg Asp Leu Lys Pro His Asn Val 1985 1990 1995 2000 Leu Leu Phe Thr Leu Tyr Pro Asn Ala Ala Ile Ile Ala Lys Ile Ala 2005 2010 2015 Asp Tyr Gly Thr Ala Gln Tyr Cys Cys Arg Met Gly Ile Lys Thr Ser 2020 2025 2030 Glu Gly Thr Pro Gly Phe Arg Ala Pro Glu Val Ala Arg Gly Asn Val 2035 2040 2045 Ile Tyr Asn Gln Gln Ala Asp Val Tyr Ser Phe Gly Leu Leu Leu Tyr 2050 2055 2060 Asp Ile Leu Thr Thr Gly Gly Arg Ile Val Glu Gly Leu Lys Phe Pro 2065 2070 2075 2080 Asn Glu Phe Asp Glu Leu Glu Ile Gln Gly Lys Leu Pro Asp Pro Val 2085 2090 2095 Lys Glu Tyr Gly Cys Ala Pro Trp Pro Met Val Glu Lys Leu Ile Lys 2100 2105 2110 Gln Cys Leu Lys Glu Asn Pro Gln Glu Arg Pro Thr Ser Ala Gln Val 2115 2120 2125 Phe Asp Ile Leu Asn Ser Ala Glu Leu Val Cys Leu Thr Arg Arg Ile 2130 2135 2140 Leu Leu Pro Lys Asn Val Ile Val Glu Cys Met Val Ala Thr His His 2145 2150 2155 2160 Asn Ser Arg Asn Ala Ser Ile Trp Leu Gly Cys Gly His Thr Asp Arg 2165 2170 2175 Gly Gln Leu Ser Phe Leu Asp Leu Asn Thr Glu Gly Tyr Thr Ser Glu 2180 2185 2190 Glu Val Ala Asp Ser Arg Ile Leu Cys Leu Ala Leu Val His Leu Pro 2195 2200 2205 Val Glu Lys Glu Ser Trp Ile Val Ser Gly Thr Gln Ser Gly Thr Leu 2210 2215 2220 Leu Val Ile Asn Thr Glu Asp Gly Lys Lys Arg His Thr Leu Glu Lys 2225 2230 2235 2240 Met Thr Asp Ser Val Thr Cys Leu Tyr Cys Asn Ser Phe Ser Lys Gln 2245 2250 2255 Ser Lys Gln Lys Asn Phe Leu Leu Val Gly Thr Ala Asp Gly Lys Leu 2260 2265 2270 Ala Ile Phe Glu Asp Lys Thr Val Lys Leu Lys Gly Ala Ala Pro Leu 2275 2280 2285 Lys Ile Leu Asn Ile Gly Asn Val Ser Thr Pro Leu Met Cys Leu Ser 2290 2295 2300 Glu Ser Thr Asn Ser Thr Glu Arg Asn Val Met Trp Gly Gly Cys Gly 2305 2310 2315 2320 Thr Lys Ile Phe Ser Phe Ser Asn Asp Phe Thr Ile Gln Lys Leu Ile 2325 2330 2335 Glu Thr Arg Thr Ser Gln Leu Phe Ser Tyr Ala Ala Phe Ser Asp Ser 2340 2345 2350 Asn Ile Ile Thr Val Val Val Asp Thr Ala Leu Tyr Ile Ala Lys Gln 2355 2360 2365 Asn Ser Pro Val Val Glu Val Trp Asp Lys Lys Thr Glu Lys Leu Cys 2370 2375 2380 Gly Leu Ile Asp Cys Val His Phe Leu Arg Glu Val Met Val Lys Glu 2385 2390 2395 2400 Asn Lys Glu Ser Lys His Lys Met Ser Tyr Ser Gly Arg Val Lys Thr 2405 2410 2415 Leu Cys Leu Gln Lys Asn Thr Ala Leu Trp Ile Gly Thr Gly Gly Gly 2420 2425 2430 His Ile Leu Leu Leu Asp Leu Ser Thr Arg Arg Leu Ile Arg Val Ile 2435 2440 2445 Tyr Asn Phe Cys Asn Ser Val Arg Val Met Met Thr Ala Gln Leu Gly 2450 2455 2460 Ser Leu Lys Asn Val Met Leu Val Leu Gly Tyr Asn Arg Lys Asn Thr 2465 2470 2475 2480 Glu Gly Thr Gln Lys Gln Lys Glu Ile Gln Ser Cys Leu Thr Val Trp 2485 2490 2495 Asp Ile Asn Leu Pro His Glu Val Gln Asn Leu Glu Lys His Ile Glu 2500 2505 2510 Val Arg Lys Glu Leu Ala Glu Lys Met Arg Arg Thr Ser Val Glu 2515 2520 2525

Claims (7)

  1. 세포에 LRRK2(leucine rich repeat kinase 2) 돌연변이 단백질을 발현하는 단계;
    상기 세포에 산화스트레스 또는 미토콘드리아 독성 유발 물질을 처리하는 단계;
    상기 세포에 시험 물질을 접촉시키는 단계;
    상기 시험 물질과 접촉된 세포와 상기 시험 물질과 접촉되지 않은 세포를 비교하는 단계; 및
    상기 시험 물질의 접촉에 의한 세포 사멸의 감소여부를 측정하는 단계를 포함하여 파킨스병 치료제를 스크리닝하는 방법.
  2. 세포에 LRRK2 돌연변이 단백질을 발현하는 단계;
    상기 세포에 산화스트레스 또는 미토콘드리아 독성 유발 물질을 가하는 단계;
    상기 세포에 시험 유전자를 형질전환시키는 단계;
    상기 시험 유전자로 형질전환된 세포와 상기 시험 유전자로 형질전환되지 않은 세포를 비교하는 단계; 및
    상기 시험 유전자의 형질전환에 의한 세포 사멸의 감소여부를 측정하는 단계를 포함하여 파킨스병 치료제를 스크리닝하는 방법.
  3. 제1항 또는 제2항에 있어서, 상기 LRRK2 돌연변이 단백질은 서열번호 2로 표시되는 G2019S, 서열번호 4로 표시되는 R1441C, 서열번호 6으로 표시되는 R1441G, 서열번호 8로 표시되는 Y1699C, 서열번호 10로 표시되는 I2020T로 구성된 군에서 선택되는 1이상의 단백질인 것을 특징으로 하는 파킨스병 치료제를 스크리닝하는 방법.
  4. 제1항 또는 제2항에 있어서, 상기 세포는 MN9D, SN4741, SH-SY5Y, SK-N-BE2C, 및 PC12로 구성된 도파민을 분비하는 세포군 또는 HEK293T, HeLa, 및 COS-7 세포로 구성된 도파민을 분비하지 않는 세포군 중에서 선택되는 1이상의 세포인 것을 특징으로 하는 파킨스병 치료제를 스크리닝하는 방법.
  5. 제1항 또는 제2항에 있어서, 상기 산화스트레스는 과산화수소로 유발한 것을 특징으로 하는 파킨스병 치료제를 스크리닝하는 방법.
  6. 제1항 또는 제2항에 있어서, 상기 미토콘드리아 독성 유발 물질은 파라쿼트(paraquat)인 것을 특징으로 하는 파킨스병 치료제를 스크리닝하는 방법.
  7. LRRK2 돌연변이 단백질이 발현된 세포, 세포 사멸의 감소여부 측정 장치를 포함하는 파킨스병 치료제 스크리닝 키트.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9156845B2 (en) 2012-06-29 2015-10-13 Pfizer Inc. 4-(substituted amino)-7H-pyrrolo[2,3-d] pyrimidines as LRRK2 inhibitors
US9695171B2 (en) 2013-12-17 2017-07-04 Pfizer Inc. 3,4-disubstituted-1 H-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazines as LRRK2 inhibitors
US10039753B2 (en) 2015-09-14 2018-08-07 Pfizer Inc. Imidazo[4,5-c]quinoline and imidazo[4,5-c][1,5]naphthyridine derivatives as LRRK2 inhibitors

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9156845B2 (en) 2012-06-29 2015-10-13 Pfizer Inc. 4-(substituted amino)-7H-pyrrolo[2,3-d] pyrimidines as LRRK2 inhibitors
US9642855B2 (en) 2012-06-29 2017-05-09 Pfizer Inc. Substituted pyrrolo[2,3-d]pyrimidines as LRRK2 inhibitors
US9695171B2 (en) 2013-12-17 2017-07-04 Pfizer Inc. 3,4-disubstituted-1 H-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazines as LRRK2 inhibitors
US10039753B2 (en) 2015-09-14 2018-08-07 Pfizer Inc. Imidazo[4,5-c]quinoline and imidazo[4,5-c][1,5]naphthyridine derivatives as LRRK2 inhibitors

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