KR100968838B1 - Composition for drug delivery comprising the polypeptide fragment of EGF-like domain repeat protein of stabilin-2 and use thereof - Google Patents
Composition for drug delivery comprising the polypeptide fragment of EGF-like domain repeat protein of stabilin-2 and use thereof Download PDFInfo
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- KR100968838B1 KR100968838B1 KR1020080016945A KR20080016945A KR100968838B1 KR 100968838 B1 KR100968838 B1 KR 100968838B1 KR 1020080016945 A KR1020080016945 A KR 1020080016945A KR 20080016945 A KR20080016945 A KR 20080016945A KR 100968838 B1 KR100968838 B1 KR 100968838B1
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Abstract
본 발명은 스태빌린-2의 EGF-유사 도메인의 반복부위 단편을 포함하는 폴리펩티드, 이를 포함하는 포스파티딜세린 검출용 조성물 및 이의 용도에 관한 것으로서, 보다 상세하게는 스태빌린-2(stabilin-2)의 EGF-유사 도메인의 반복부위(EGF-like domain repeat protein)에서 두 번째 비정형 EGF-유사 도메인 및 3개 이상의 EGF-유사도메인이 순차적으로 연결된 폴리펩티드가 포스파티딜세린과 특이적으로 결합한다는 점을 이용하여 상기 폴리펩티드, 상기 폴리펩티드를 포함하는 포스파티딜세린 검출용 조성물 및 이의 용도에 관한 것이다. 본 발명의 스태빌린-2(stabilin-2)의 EGF-유사 도메인의 반복부위(EGF-like domain repeat protein, EGFrp)에서 두 번째 비정형 EGF-유사 도메인 및 3개 이상의 EGF-유사도메인이 순차적으로 연결된 폴리펩티드는 세포 표면의 포스파티딜세린과 특이적으로 결합할 수 있다. 따라서, 본 발명은 포스파티딜세린을 세포 표면으로 발현하는 세포에 대한 약물 전달, 종양 세포에 대한 약물 또는 표지물질의 전달을 통한 종양성 질환의 예방, 치료 또는 영상화 등에 다양하게 사용될 수 있다.The present invention relates to a polypeptide comprising a repeat fragment of the EGF-like domain of Stabilin-2, a composition for detecting phosphatidylserine comprising the same, and more particularly, the use of stabilin-2 This is achieved by the fact that a polypeptide that is sequentially linked to a second atypical EGF-like domain and at least three EGF-like domains in an EGF-like domain repeat protein is specifically bound to phosphatidylserine. A polypeptide, a composition for detecting phosphatidylserine comprising the polypeptide, and a use thereof. The second atypical EGF-like domain and three or more EGF-like domains are sequentially linked in an EGF-like domain repeat protein (EGFrp) of stabilin-2 of the present invention. The polypeptide may specifically bind to phosphatidylserine on the cell surface. Therefore, the present invention can be used in various ways, such as drug delivery to cells expressing phosphatidylserine on the cell surface, prevention, treatment or imaging of tumor diseases through delivery of drugs or markers to tumor cells.
스태빌린-2, EGFrp, 포스파티딜세린, 사멸세포, 종양성질환 Stabilin-2, EGFrp, Phosphatidylserine, Killing Cells, Tumor Disease
Description
본 발명은 스태빌린-2의 EGF-유사 도메인의 반복부위 단편을 유효성분으로 포함하는 약물 전달용 조성물 및 이의 용도에 관한 것으로서, 보다 상세하게는 스태빌린-2(stabilin-2)의 EGF-유사 도메인의 반복부위(EGF-like domain repeat protein)에서 두 번째 비정형 EGF-유사 도메인 및 3개 이상의 EGF-유사도메인이 순차적으로 연결된 폴리펩티드가 포스파티딜세린과 특이적으로 결합한다는 점을 이용하여 상기 폴리펩티드를 포함하는 약물전달용 조성물 및 이의 용도에 관한 것이다.The present invention relates to a composition for drug delivery comprising a repeat region fragment of the EGF-like domain of Stabilin-2 as an active ingredient, and more specifically, to EGF-like of Stabilin-2. The polypeptide is exploited by the fact that a polypeptide that is sequentially linked to a second atypical EGF-like domain and at least three EGF-like domains in an EGF-like domain repeat protein is specifically bound to phosphatidylserine It relates to a composition for drug delivery and its use.
포스파티딜세린(phosphatidylserine, PS)은 대식세포가 사멸세포를 인식하여 제거하는 중요한 표지자이다(Schlegel, R.A. et al., Cell Death and Differentiation, 2001, 8:551-563; Lauber, K. et al., Mol Cell 2004, 14: 277-287 Henson, P.M. et al., Curr Biol 2001, 11: R795-805 Grimsley, C. et al.,Trends Cell Biol. 2003, 13: 648-656). 정상적으로 포스파티딜세린은 세포막의 내부에 존재하나 세포가 사멸신호를 받거나 적혈구가 노화되면 세포막의 외부로 노출되며(Fadeel, B. et al., Cell Mol Life Sci, 2003, 60:2575-2585), 이것을 대식세포가 세포표면의 수용체를 통해서 인식하여 탐식작용을 일으킨다(Fadok, V.A. et al., J immunol 1992, 148:2207-2216; Fadok, V. A. et al., Nature 2000, 405:85-90; Park, S.Y.et. al., Cell Death and Differentiation, in press). Phosphatidylserine (PS) is an important marker for macrophages to recognize and eliminate apoptosis (Schlegel, RA et al., Cell Death and Differentiation, 2001, 8: 551-563; Lauber, K. et al., Mol Cell 2004, 14: 277-287 Henson, PM et al., Curr Biol 2001, 11: R795-805 Grimsley, C. et al., Trends Cell Biol. 2003, 13: 648-656). Normally, phosphatidylserine is present inside the cell membrane but is exposed to the outside of the cell membrane when the cell receives a death signal or when erythrocytes age (Fadeel, B. et al., Cell Mol Life Sci, 2003, 60: 2575-2585). Macrophages are recognized through cell surface receptors to cause phagocytosis (Fadok, VA et al., J immunol 1992, 148: 2207-2216; Fadok, VA et al., Nature 2000, 405: 85-90; Park , SY et al., Cell Death and Differentiation, in press).
사멸세포 이외에도 포스파티딜세린은 또한 여러 가지 병적인 상황에서도 세포막의 외부로 노출된다(Zwaal, R.F.A. et al., Cell. Mol. Life Sci 2005, 62:971-988). 그 예로 스코트 증후군(Scott syndrome), 항인지질 증후군(antiphospholipid syndrome), 겸상 적혈구 빈혈증(sickle cell anemia), 탈라세미아(thalassemia), 스토마토싸이토시스(stomatocytosis), 요독증(uremia), 신장결석(kidney stone disease), 당뇨병(diabetes), 고혈당증(hyperglycemia), 바이러스 감염 및 미생물 감염, 말라리아(malaria), 전-자간증(pre-eclampsia), 고빌리루빈혈증(hyperbilirubinemia), 신생물 종양(neoplasia) 등이 있다. 특히, 많은 종양세포들이 세포막의 외부로 포스파티딜세린의 발현 증가를 나타나며(Utsugi, T. et al., Cancer Res. 1991, 15:3062-3066; Rao, L. et al., Thromb Res. 1992, 67:517-531; Sigimura, M. et al., Fibrinolysis. 1994, 5:365-373; Ran, S. et al., Cancer Res. 2002, 62:6132-6140; Woehlecke, H. et al., Biochem J. 2003, 376:489-495), 이것은 미분화성 발암성 세포(undifferentiated tumorigenic cell) 에서 더욱 저명하게 나타난다. 종양조직은 또한 포스파티딜세린을 세포막의 외부로 노출하는 소혈관을 방출한다(Ran, S. et al., Cancer Res. 2002, 62:6132-6140; Zwaal, R.F.A. et al., Blood. 1997, 89:1121-1132). In addition to killer cells, phosphatidylserine is also exposed to the outside of the cell membrane under various pathological conditions (Zwaal, R.F.A. et al., Cell.Mol.Life Sci 2005, 62: 971-988). Examples include Scott syndrome, antiphospholipid syndrome, sickle cell anemia, thalassemia, stomatocytosis, uremia, and kidney stones. kidney stone disease, diabetes, hyperglycemia, viral and microbial infections, malaria, pre-eclampsia, hyperbilirubinemia, neoplasia, etc. have. In particular, many tumor cells show increased expression of phosphatidylserine outside of the cell membrane (Utsugi, T. et al., Cancer Res. 1991, 15: 3062-3066; Rao, L. et al., Thromb Res. 1992, 67: 517-531; Sigimura, M. et al., Fibrinolysis. 1994, 5: 365-373; Ran, S. et al., Cancer Res. 2002, 62: 6132-6140; Woehlecke, H. et al. , Biochem J. 2003, 376: 489-495), which is more prominent in undifferentiated tumorigenic cells. Tumor tissue also releases small blood vessels that expose phosphatidylserine to the outside of the cell membrane (Ran, S. et al., Cancer Res. 2002, 62: 6132-6140; Zwaal, RFA et al., Blood. 1997, 89 : 1121-1132).
더욱이, 포스파티딜세린은 여러 가지 세포 내 생리학적 과정 중에서 비사멸세포에서도 또한 관찰된다. 그러한 예로는 혈소판의 활성화 과정, 근육세포의 융합과정, 합포체성 영양세포(syncytiotrophoblast)의 형성, 비만세포(mast cells)의 이뮤노글로불린 의존성 자극, 및 T 세포의 이동 등이 있다 (Fadeel, B. et al., Cell Death Differ 2006, 13:360-2 Ran, S. et al., Int J Radiat Oncol Biol Phys 2002, 54:1479-84 Schlegel, R. A. et al., Cell Death Differ 2001, 8:551-63.). 그 중에 특히 혈소판의 활성화 과정에서 발현되는 포스파티딜세린을 차단함은 동맥경화에 의해 형성될 수 있는 혈전형성(thrombosis)과정을 억제함으로써 그 치료효과를 나타낼 수도 있다(Cederholm, A. and Frosteg, J., Ann N Y Acad Sci. 2007, 1108:96-103 Cederholm, A. and Frosteg, J., Drug News Perspect. 2007 20(5):321-6). 따라서, 이러한 포스파티딜리세린의 역할들로 인해 특히 종양성 및 염증성 질환을 비롯한 여러 상황에서 포스파티딜세린은 진단, 치료, 및 치료추적을 위한 표적 물질로 제시되고 있다.Moreover, phosphatidylserine is also observed in non-killing cells among various intracellular physiological processes. Examples include platelet activation, muscle cell fusion, syncytiotrophoblast formation, immunoglobulin-dependent stimulation of mast cells, and T cell migration. (Fadeel, B. et al., Cell Death Differ 2006, 13: 360-2 Ran, S. et al., Int J Radiat Oncol Biol Phys 2002, 54: 1479-84 Schlegel, RA et al., Cell Death Differ 2001, 8: 551-63.). In particular, blocking phosphatidylserine, which is expressed during the activation of platelets, may have a therapeutic effect by inhibiting the thrombosis process that may be formed by atherosclerosis (Cederholm, A. and Frosteg, J.). , Ann NY Acad Sci. 2007, 1108: 96-103 Cederholm, A. and Frosteg, J., Drug News Perspect. 2007 20 (5): 321-6). Therefore, these roles of phosphatidylserine have been suggested as phosphatidylserine as a target material for diagnosis, treatment, and treatment tracking, especially in various situations including neoplastic and inflammatory diseases.
또한, 포스파티딜세린의 인식의 억제는 조사된 림프종(irradiated lymphoma)에서 세포의 면역성(immunogenicity)을 증가시킨다고 보고되었다(Bondanza, A. et al., J Exp Med 2004, 200:1157-65). 따라서, 포스파티딜세린에 효과적으로 결합할 수 있는 단백질은 사멸세포의 포스파티딜세린의 인식과 면역억제성 제거를 방해함으로써 아폽토틱 세포-기반 백신(apoptotic cell-based vaccines)의 효과를 증대시키는데도 사용될 수 있을 것이다. In addition, inhibition of the recognition of phosphatidylserine has been reported to increase the cell's immunogenicity in irradiated lymphoma (Bondanza, A. et al., J Exp Med 2004, 200: 1157-65). Thus, proteins that can effectively bind phosphatidylserine may also be used to augment the effects of apoptotic cell-based vaccines by interfering with phosphatidylserine recognition and immunosuppressive clearance of killer cells. .
이에 본 발명자들은 포스파티딜세린을 표적화할 수 있는 새로운 단백질 또는 그 단편을 탐색하고자 연구한 결과, 스태빌린-2(stabilin-2)의 EGF-유사 도메인의 반복부위(EGFrp)가 사멸세포의 표면에 발현되는 포스파티딜세린에 특이적으로 결합할 수 있음을 확인함으로써 본 발명을 완성하였다. Therefore, the present inventors have studied to search for a novel protein or fragment thereof capable of targeting phosphatidylserine. As a result, the repeat region (EGFrp) of the EGF-like domain of stabilin-2 is expressed on the surface of dead cells. The present invention was completed by confirming that it can specifically bind to phosphatidylserine.
따라서 본 발명의 목적은 포스파티딜세린에 특이적으로 결합하는 스태빌린-2의 EGFrp 단편을 포함하는 약물 전달용 조성물 및 이의 용도를 제공하는 것이다.It is therefore an object of the present invention to provide a composition for drug delivery comprising the EGFrp fragment of Stabilin-2 which specifically binds to phosphatidylserine and its use.
상기와 같은 목적을 달성하기 위하여, 본 발명은 스태빌린-2(stabilin-2)의 EGF-유사 도메인의 반복부위(EGF-like domain repeat protein)의 폴리펩티드를 유효성분으로 포함하는 약물 전달용 조성물을 제공한다.In order to achieve the above object, the present invention provides a drug delivery composition comprising a polypeptide of the EGF-like domain repeat protein of the stabilin-2 (stabilin-2) as an active ingredient to provide.
본 발명의 다른 목적을 달성하기 위하여, 본 발명은 상기 폴리펩티드 및 이와 결합된 항-종양성 질환 제제를 유효성분으로 포함하는 종양성 질환의 예방 및 치료용 약학적 조성물을 제공한다.In order to achieve the other object of the present invention, the present invention provides a pharmaceutical composition for the prevention and treatment of neoplastic diseases comprising the polypeptide and the anti-tumor disease agent coupled thereto as an active ingredient.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 스태빌린-2(stabilin-2)의 EGF-유사 도메인의 반복부위(EGF-like domain repeat protein)에서 두 번째 비정형 EGF-유사 도메인 및 3개 이상의 EGF-유사도메인이 순차적으로 연결된 폴리펩티드가 세포 표면에 노출되는 포스파티딜세린과 특이적으로 결합한다는 점에 착안하여 두 번째 비정형 EGF-유사 도메인 및 3개 이상의 EGF-유사도메인이 순차적으로 조합되어 연결된 새로운 서열의 폴리펩티 드를 유효성분으로 포함하는 약물 전달용 조성물 및 상기 폴리펩티드와 이와 결합된 항-종양성 질환 제제를 유효성분으로 포함하는 종양성 질환의 예방 및 치료용 약학적 조성물을 제공하는 것을 특징으로 한다.The present invention relates to a polypeptide in which a second atypical EGF-like domain and three or more EGF-like domains are sequentially linked in an EGF-like domain repeat protein of stabilin-2. In view of the specific binding to phosphatidylserine exposed to the cell surface, a second sequence of EGF-like domains and three or more EGF-like domains are sequentially combined to include a polypeptide of a new sequence linked thereto as an active ingredient. It provides a pharmaceutical delivery composition and a pharmaceutical composition for the prevention and treatment of tumor diseases comprising the polypeptide and an anti-tumor disease agent coupled thereto as an active ingredient.
본 발명의 스태빌린-2(stabilin-2, Genbank Accession No. MN_017564)는 랫트(rat)의 정맥동 내피세포(sinusoidal endothelial cells)에서 하이알루로난(hyaluronan) 수용체로서 기능을 통해 최초로 보고되었으며(McCourt, P.A. et al., Hepatology. 1999, 30:1276-1286; Politz, O. et al., Biochem J. 2002, 362:155-164; Zhou, B. et al., J Biol Chem. 2000, 275:37733-37741), 그 후 변형 LDL(modified LDL)과 글리케이션 엔드 프로덕트(glycation end products)의 탐식에 관여하며, Gram(-)와 Gram(+)박테리아에 대한 결합능을 가진다고 보고되었다(Adachi, H. et al., J Biol Chem. 2002, 277:34264-34270; Tamura, Y. et al., J Biol Chem. 2003, 278:12613-126). 더욱이 최근에 본 발명자들은 스태빌린-2가 사멸세포 및 노화된 적혈구의 탐식에 중요한 수용체임을 규명하였다(Park, S.Y. et al., Cell Death Differ. 2008, 15:192-201). 스태빌린-2의 세포외 부분은 7개의 FAS1 도메인과 4개의 EGF-유사 도메인의 반복부위(23개의 EGF-유사 도메인) 및 1개의 Link 도메인으로 구성되어 있으며, 그 중, EGF-유사 도메인의 반복부위(EGF-like domain repeat protein)는 5개 혹은 6개의 EGF-유사 도메인으로 구성되어 있다. EGF-유사 도메인은 그 기능이 정확하게 알려져 있지는 않지만 많은 세포막 수용체 단백질의 세포외 부분에서 반복부위로 존재하며 리간드-수용체 간의 상호작용 에 관여한다고 알려져 있으며(Campbell, I.D. and Bork, P. Curr Opin Struc Biol. 1993, 3:385-39), 그 길이와 구조에 따라 (1) 표준 EGF-유사도메인, (2) 칼슘 결합 EGF-유사 도메인, (3) 라미닌-타입 EGF-유사 도메인, 및 (4) 비정형 EGF-유사 도메인으로 분류될 수 있다.Stabilin-2 (Genbank Accession No. MN_017564) of the present invention was first reported through its function as a hyaluronan receptor in sinusoidal endothelial cells of rats (McCourt). , PA et al., Hepatology. 1999, 30: 1276-1286; Politz, O. et al., Biochem J. 2002, 362: 155-164; Zhou, B. et al., J Biol Chem. 2000, 275 (37733-37741), then involved in phagocytosis of modified LDL and glycation end products, and has been reported to have binding capacity to Gram (-) and Gram (+) bacteria (Adachi, H. et al., J Biol Chem. 2002, 277: 34264-34270; Tamura, Y. et al., J Biol Chem. 2003, 278: 12613-126). Furthermore, we have recently identified that Stabilin-2 is an important receptor for phagocytosis of dead cells and aged erythrocytes (Park, S.Y. et al., Cell Death Differ. 2008, 15: 192-201). The extracellular portion of Stabilin-2 consists of 7 FAS1 domains, 4 repeats of EGF-like domains (23 EGF-like domains) and 1 Link domain, among which repeats of EGF-like domains The region (EGF-like domain repeat protein) consists of five or six EGF-like domains. Although EGF-like domains are not known for their exact function, they exist as repeats in the extracellular portion of many membrane receptor proteins and are known to be involved in ligand-receptor interactions (Campbell, ID and Bork, P. Curr Opin Struc Biol). 1993, 3: 385-39), depending on its length and structure: (1) standard EGF-like domains, (2) calcium binding EGF-like domains, (3) laminin-type EGF-like domains, and (4) Can be classified as an atypical EGF-like domain.
본 발명에서의 폴리펩티드는 스태빌린-2의 EGF-유사 도메인의 반복 부위(EGF-like domain repeat protein, EGFrp) 중 두번째 비정형 EGF-유사 도메인 및3개 이상의 EGF-유사 도메인을 순차적으로 연결된 폴리펩티드를 말한다. 본 발명의 펩티드 단편은 모든 종류의 펩티드, 폴리펩티드, 단백질, 펩티드 모조물, 화합물 및 생물제제를 포함하며, 종양 세포 등의 세포의 표면에서 발현되는 포스파티딜세린에 특이적으로 결합할 수 있는 활성을 갖는 것을 말한다. 본 발명의 폴리펩티드가 유래되는 스태빌린-2의 EGF-유사 도메인의 반복 부위는 포유동물로부터 유래된 것일 수 있으며, 바람직하게는 인간, 랫트(rat) 및 마우스(mouse)로 이루어진 그룹 중에서 선택되는 어느 하나로부터 유래된 것일 수 있다. The polypeptide in the present invention refers to a polypeptide sequentially linked to a second atypical EGF-like domain and three or more EGF-like domains of an EGF-like domain repeat protein (EGFrp) of Stabilin-2. . Peptide fragments of the present invention include all kinds of peptides, polypeptides, proteins, peptide replicas, compounds and biologics, and have the activity of specifically binding to phosphatidylserine expressed on the surface of cells such as tumor cells. Say that. The repeating site of the EGF-like domain of Stabilin-2 from which the polypeptide of the present invention is derived may be from a mammal and is preferably any one selected from the group consisting of human, rat and mouse. It may be derived from one.
본 발명의 폴리펩티드, 스태빌린-2의 EGF-유사 도메인의 반복 부위(EGF-like domain repeat protein, EGFrp) 중 두 번째 비정형 EGF-유사 도메인은 공지된 스태빌린-2의 EGF-유사 도메인의 반복 부위의 두 번째 비정형 EGF-유사 도메인이라면 이에 제한되지는 않으나, 바람직하게는 서열번호 84, 서열번호 90, 서열번호 96 또는 서열번호 102로 이루어진 아미노산 서열을 가질 수 있다. The second atypical EGF-like domain of the polypeptide of the present invention, the EGF-like domain repeat protein (EGFrp) of Stabilin-2, is the repeat site of the known EGF-like domain of Stabilin-2. The second atypical EGF-like domain of may be, but is not limited to, having an amino acid sequence consisting of SEQ ID NO: 84, SEQ ID NO: 90, SEQ ID NO: 96, or SEQ ID NO: 102.
아울러, 본 발명의 폴리펩티드에서 두 번째 비정형 EGF-유사 도메인을 제외한 3개 이상의 EGF-유사 도메인을 이루는 EGF-유사 도메인은 공지된 스태빌린-2의 EGF-유사 도메인의 반복 부위의 EGF-유사 도메인이라면 이에 제한되지는 않으나, 바람직하게는 표준 EGF-유사 도메인(standard EGF-like domain) 또는 비정형 EGF-유사 도메인(atypical EGF-like domain)일 수 있다. 표준 EGF-유사 도메인은 바람직하게는 서열번호 85 내지 서열번호 88, 서열번호 91 내지 서열번호 94, 서열번호 97 내지 서열번호 100 및 서열번호 103 내지 서열번호 105로 이루어진 군에서 선택된 아미노산 서열을 가질 수 있으며, 비정형 EGF-유사 도메인은 바람직하게는 서열번호 83, 서열번호 84, 서열번호 89, 서열번호 90, 서열번호 95, 서열번호 96, 서열번호 101 및 서열번호 102로 이루어진 군에서 선택된 아미노산 서열을 가질 수 있다. In addition, the EGF-like domain constituting three or more EGF-like domains except the second atypical EGF-like domain in the polypeptide of the present invention may be an EGF-like domain of the repeat region of the known EGF-like domain of Stabilin-2. It may be, but not limited to, a standard EGF-like domain or an atypical EGF-like domain. The standard EGF-like domain may preferably have an amino acid sequence selected from the group consisting of SEQ ID NO: 85 to SEQ ID NO: 88, SEQ ID NO: 91 to SEQ ID NO: 94, SEQ ID NO: 97 to SEQ ID NO: 100, and SEQ ID NO: 103 to SEQ ID NO: 105. And the atypical EGF-like domain preferably comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 101, and SEQ ID NO: 102 Can have
본 발명의 폴리펩티드에 포함되는 상기 EGF-유사 도메인은 3개 이상, 바람직하게는 3개 내지 10개, 더 바람직하게는 3개 내지 5개의 EGF-유사 도메인을 포함할 수 있으며, 각각의 EGF-유사 도메인은 동일한 서열이 반복되어 조합, 예를 들어 서열번호 96의 아미노산 서열만으로도 이루어 질 수 있다. 아울러, 본 발명의 폴리펩티드는 상기 두 번째 비정형 EGF-유사 도메인이 본 발명의 폴리펩티드의 N말단, C말단 또는 가운데 어느 부위에도 위치하도록 조합될 수 있다. 바람직하게는 본 발명의 폴리펩티드는 서열번호 75 내지 서열번호 82 및 서열번호 106 내지 서열번호 116으로 이루어진 군에서 선택된 아미노산 서열을 가지는 폴리펩티드일 수 있다. The EGF-like domain included in the polypeptide of the present invention may comprise 3 or more, preferably 3 to 10, more preferably 3 to 5 EGF-like domains, each EGF-like The domain may be composed of the same sequence repeated and combined, for example, only the amino acid sequence of SEQ ID NO: 96. In addition, the polypeptide of the present invention may be combined such that the second atypical EGF-like domain is located at the N-terminus, C-terminus or any site of the polypeptide of the present invention. Preferably, the polypeptide of the present invention may be a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 75 to SEQ ID NO: 82 and SEQ ID NO: 106 to 116.
아울러, 본 발명은 본 발명의 폴리펩티드를 암호화하는 염기서열을 가지는 폴리뉴클레오티드를 제공한다. 본 발명의 폴리뉴클레오티드는 바람직하게는 상기 폴리뉴클레오티드는 서열번호 33 내지 서열번호 40 및 서열번호 64 내지 서열번호 73으로 이루어진 군에서 선택된 염기서열을 가질 수 있다.In addition, the present invention provides a polynucleotide having a nucleotide sequence encoding the polypeptide of the present invention. Preferably, the polynucleotide of the present invention may have a nucleotide sequence selected from the group consisting of SEQ ID NO: 33 to SEQ ID NO: 40 and SEQ ID NO: 64 to SEQ ID NO: 73.
아울러, 본 발명은 본 발명의 폴리펩티드를 암호화하는 염기서열을 가지는 벡터 및 상기 벡터로 형질전환된 형질전환체를 제공한다. In addition, the present invention provides a vector having a nucleotide sequence encoding a polypeptide of the present invention and a transformant transformed with the vector.
본 발명의 벡터는 플라스미드 벡터, 코즈미드 벡터, 박테리오파아지 벡터 및 바이러스 벡터 등을 포함하나 이에 제한되지 않는다. 본 발명의 벡터는 통상의 클로닝 벡터 또는 발현벡터일 수 있으며, 발현벡터는 프로모터, 오퍼레이터, 개시코돈, 종결코돈, 폴리아데닐화 시그널 및 인핸서(촉진유전자) 같은 발현 조절 서열 외에도 막 표적화 또는 분비를 위한 시그널 서열 또는 리더 서열을 포함하며 목적에 따라 다양하게 제조될 수 있다. 또한 상기 벡터는 벡터를 함유하는 숙주 세포를 선택하기 위한 선택 마커를 포함하고, 복제 가능한 벡터인 경우 복제 기원을 포함한다. Vectors of the invention include, but are not limited to, plasmid vectors, cosmid vectors, bacteriophage vectors, viral vectors, and the like. Vectors of the present invention may be conventional cloning vectors or expression vectors, which may be used for membrane targeting or secretion in addition to expression control sequences such as promoters, operators, initiation codons, termination codons, polyadenylation signals and enhancers (promoter). It includes a signal sequence or leader sequence and can be prepared in various ways depending on the purpose. The vector also includes a selection marker for selecting a host cell containing the vector and, in the case of a replicable vector, the origin of replication.
상기 벡터로 형질전환하는 것은 당업자에게 공지된 형질전환기술에 의해 수 행될 수 있다. 바람직하게는 미세사출법(microprojectile bombardment), 전기충격유전자전달법(electroporation), 인산 칼슘(CaPO4) 침전, 염화 칼슘(CaCl2) 침전, PEG-매개 융합법(PEG-mediated fusion), 미세주입법(microinjection) 및 리포좀 매개법(liposome-mediated method)를 이용할 수 있으며, 상기 형질전환체는 대장균(Escherichia coli), 바실러스 서브틸리스(Bacillus subtilis), 스트렙토마이세스(Streptomyces), 슈도모나스(Pseudomonas), 프로테우스 미라빌리스(Proteus mirabilis), 스타필로코쿠스( Staphylococcus), 아그로박테리움 투메파시엔스(Agrobacterium tumefaciens)일 수 있으나, 이로 제한되는 것은 아니다.Transformation with the vector can be carried out by transformation techniques known to those skilled in the art. Preferably, microprojectile bombardment, electroporation, electroporation, calcium phosphate (CaPO 4 ) precipitation, calcium chloride (CaCl 2 ) precipitation, PEG-mediated fusion, microinjection (microinjection) and liposome-mediated methods can be used, and the transformant is Escherichia coli ), Bacillus Subtilis ( Bacillus subtilis), Streptomyces (Streptomyces), Pseudomonas (Pseudomonas), Proteus Mira Billy's (Proteus mirabilis), Staphylococcus (Staphylococcus), Agrobacterium Tome Pacific Enschede (Agrobacterium tumefaciens ), but is not limited thereto.
본 발명자들은 상기 EGFrp의 기능을 확인하고자 다양한 실험을 수행한 결과, 상기 EGFrp가 노화된 세포 및 사멸 세포의 표면에서 발현되는 포스파티딜세린을 특이적으로 인식함으로써 상기 세포의 부착 및 탐식을 매개한다는 사실을 스태빌린-2 유전자로 형질전환된 섬유아세포(L/Stab-2세포)를 이용하여 확인하였다. 또한, 본 발명자들은 대식세포에 의한 노화된 세포 및 사멸 세포의 탐식도 역시 in vitro와 in vivo에서 EGFrp 단백질에 의해 저해됨을 확인하였다. 또한, 스태빌린-2 매개 탐식작용과 EGFrp에 의한 포스파티딜세린의 인식에 칼슘이 필요함을 확인하였다. 나아가, 본 발명자들은 EGFrp의 C-말단 및 N-말단 결손 단백질을 제작하여 EGFrp가 포스파티딜세린을 인식하기 위해서는 4개 이상의 EGF-유사 도메인이 필요로 하며, EGFrp내에 두 번째 비정형(atypical) EGF-유사 도메인이 칼슘 의존성 포스파티딜세 린의 인식에 중요함을 확인하였다. 이로부터 본 발명자들은 상기 EGFrp가 포스파티딜세린의 신규한 결합단백질임을 규명하였다. 따라서, 스태빌린-2의 EGFrp를 포스파티딜세린의 검출용 조성물로 이용할 수 있음을 알 수 있었으며, 더 나아가 종양조직 내에 포스파티딜세린을 인식하는 진단 또는 치료추적용 제제, 또는 별도의 종양 치료용 제제와 더불어 종양성 질환 예방 및 치료용 약학적 조성물로서 사용할 수 있음을 알 수 있었다.The inventors conducted various experiments to confirm the function of the EGFrp, and as a result, the EGFrp mediates the adhesion and phagocytosis of the cells by specifically recognizing phosphatidylserine expressed on the surface of aged and dead cells. Fibroblasts (L / Stab-2 cells) transformed with Stabilin-2 gene were identified. In addition, the present inventors confirmed that phagocytosis of aged and dead cells by macrophages was also inhibited by EGFrp protein in vitro and in vivo. In addition, it was confirmed that calcium is required for stabilin-2 mediated phagocytosis and recognition of phosphatidylserine by EGFrp. Furthermore, the present inventors have created four C-terminal and N-terminal deletion proteins of EGFrp so that EGFrp requires four or more EGF-like domains to recognize phosphatidylserine, and a second atypical EGF-like in EGFrp. It was confirmed that the domain is important for the recognition of calcium dependent phosphatidylserine. From this, the inventors have identified that EGFrp is a novel binding protein of phosphatidylserine. Therefore, it was found that EGFrp of Stabilin-2 can be used as a composition for detecting phosphatidylserine, and furthermore, together with a diagnostic or therapeutic tracking agent for recognizing phosphatidylserine in tumor tissue, or a separate tumor therapeutic agent. It can be seen that it can be used as a pharmaceutical composition for the prevention and treatment of tumor diseases.
보다 구체적으로 본 발명의 일 실시예에서는 스태빌린-2 단백질의 세포외 부분을 4개의 소단위로 나눈 후 이에 해당하는 재조합 단백질을 제조한 다음(실시예 1 참조), 이를 탐식능을 가지는 스태빌린-2가 과발현되는 마우스 섬유아세포인 L 세포(L/Stab-2 세포)에 전처치한 후 상기 세포의 노화된 세포의 탐식에 이들 단백질의 효과를 조사하였다(실시예 2 참조). 그 결과, L/Stab-2에 의한 노화된 적혈구의 탐식이 4개의 소단위에 해당하는 재조합단백질에 의해 억제되는 것을 확인할 수 있었다(도 2 및 도 3 참조). 따라서, 세포 탐식에 관여하는 모티프가 네 개의 소단위에 모두 존재한다는 것을 확인하였다. 나아가, 본 발명은 세포 탐식에 관여하는 도메인을 더 자세히 동정하기 위해 세번째 소단위를 구성하는 EGF-유사 도메인의 반복 부위(EGFrp, E3)와 FAS1 도메인(F5)에 대한 재조합 단백질을 제조하여(실시예 1 참조) 실험한 결과 EGF-유사 도메인의 반복 부위에 해당하는 단백질의 전 처치에 의해도 노화된 적혈구 및 사멸세포의 탐식이 억제됨을 확인할 수 있었다(도 4 및 도 5 참조). 또한 다른 소단위에 존재하는 4개의 EGF-유사 도메인의 반복부위들도 역시 노화된 적혈구의 탐식을 억제하였다(도 6 참조). 따라서 EGF-유사 도메인의 반복부위(EGF-like domain repeat protein, EGFrp)가 포스파티딜세린의 인식을 담당하는 부분임을 알 수 있었다.More specifically, in an embodiment of the present invention, after dividing the extracellular portion of the Stabilin-2 protein into four subunits to prepare a recombinant protein corresponding thereto (see Example 1), Stabilin-2 having a phagocytic ability After pretreatment to L cells (L / Stab-2 cells), which are overexpressed mouse fibroblasts, the effects of these proteins on phagocytosis of aged cells of the cells were examined (see Example 2). As a result, it was confirmed that phagocytosis of aged red blood cells by L / Stab-2 was inhibited by recombinant proteins corresponding to four subunits (see FIGS. 2 and 3). Thus, it was confirmed that the motifs involved in cell phagocytosis exist in all four subunits. Furthermore, the present invention is to prepare a recombinant protein for the repeat region (EGFrp, E3) and FAS1 domain (F5) of the EGF-like domain constituting the third subunit to further identify the domain involved in cell phagocytosis (Example As a result of the experiment, pretreatment of the protein corresponding to the repeat region of the EGF-like domain was confirmed that the phagocytosis of the aged red blood cells and the dead cells was suppressed (see FIGS. 4 and 5). In addition, repeat regions of four EGF-like domains present in other subunits also inhibited phagocytosis of aged erythrocytes (see FIG. 6). Therefore, it was found that the EGF-like domain repeat protein (EGFrp) is responsible for the recognition of phosphatidylserine.
나아가, 본 발명자들은 EGFrp 단백질과 포스파티딜세린이 직접적으로 결합하는지를 조사한 결과(실시예 2-2 참조), EGFrp 단백질은 포스파티딜세린과 직접적으로 결합을 하며, 포스파티딜세린이외의 포스포지질, 즉 포스파티딜콜린, 포스파티딜이노시톨 및 포스파티딜에탄올아민과는 결합하지 않음을 알 수 있었다(도 7 및 도 8 참조). 따라서, EGFrp 단백질이 특이적으로 포스파티딜세린과 직접적 결합을 하는 신규한 단백질임을 규명할 수 있었다.Furthermore, the present inventors examined whether the EGFrp protein and phosphatidylserine bind directly (see Example 2-2), and the EGFrp protein directly binds to phosphatidylserine and phospholipids other than phosphatidylserine, that is, phosphatidylcholine and phosphatidyl It can be seen that it does not bind to inositol and phosphatidylethanolamine (see FIGS. 7 and 8). Therefore, it was possible to identify that EGFrp protein is a novel protein that specifically binds directly to phosphatidylserine.
한편, 노화된 세포 및 자연사멸세포의 탐식을 위한 포스파티딜세린의 인식은 주로 대식세포에 표면에 존재하는 수용체에 의해 이루어지기 때문에 세포의 표면에 EGFrp만을 발현시키기 위해 스태빌린-2단백질의 세포외 부분을 EGFrp로 치환시킨 단백질(도 9 참조)을 만들기 위한 발현벡터를 제작하였다(실시예 3 참조). 그 후 섬유아세포를 형질전환하여 EGFrp가 세포표면에 발현되는 세포주(L/EGF3세포)를 제작하였다(도 10 참조). 상기의 세포를 이용하여 세포표면에 존재하는 EGFrp가 포스파티딜세린과 결합하는지를 조사하였다(실시예 4 참조). 그 결과, EGFrp가 발현되는 세포는 포스파티딜세린 리포좀에 결합하였고(도 11 참조), 포스파티딜세린이 코팅된 플레이트에 잘 부착하였다(도 12 참조). 또한, EGFrp가 발현되는 세포는 노화 된 적혈구의 부착을 매개하였으며(도 13 및 도 14 참조), 적혈구의 부착은 스태빌린-2 단클론 항체와 포스파티딜세린 리포좀에 의해 특이적으로 저해되었다(도 15 참조).On the other hand, the recognition of phosphatidylserine for phagocytosis of senescent cells and natural killer cells is mainly performed by receptors present on the surface of macrophages, so that the extracellular portion of the Stabilin-2 protein is used to express only EGFrp on the surface of cells. Was prepared an expression vector for making a protein substituted with EGFrp (see Fig. 9) (see Example 3). Thereafter, fibroblasts were transformed to prepare a cell line (L / EGF3 cells) in which EGFrp was expressed on the cell surface (see FIG. 10). The cells were used to examine whether EGFrp on the cell surface binds to phosphatidylserine (see Example 4). As a result, EGFrp-expressing cells bound to phosphatidylserine liposomes (see FIG. 11) and adhered well to phosphatidylserine coated plates (see FIG. 12). In addition, EGFrp-expressing cells mediated the attachment of aged erythrocytes (see FIGS. 13 and 14), and adhesion of erythrocytes was specifically inhibited by stabilin-2 monoclonal antibody and phosphatidylserine liposomes (see FIG. 15). ).
또한, EGFrp가 대식세포에 의한 탐식작용을 저해하는지 알아보기 위해 인간 단핵구 유래 대식세포를 분리하여 실험한 결과 EGFrp에 의해 노화된 적혈구의 탐식이 저해되었다(도 16 참조). 더욱이 in vivo 에서도 EGFrp 단백질이 탐식작용을 저해할 수 있는지 알아 보기 위해 쥐의 복강내에 대식세포를 유도한 동물모델을 이용하였다(실시예 5 참조). 그 결과, EGFrp 단백질은 쥐 복강 내에서 대식세포의 사멸세포 탐식을 저해하였다(도 17 및 도 18 참조).In addition, in order to determine whether EGFrp inhibits phagocytosis by macrophages, human monocyte-derived macrophages were separated and tested for aging of red blood cells by EGFrp (see FIG. 16). Furthermore, in order to determine whether EGFrp protein can inhibit phagocytosis in vivo, an animal model inducing macrophages intraperitoneally of rats was used (see Example 5). As a result, EGFrp protein inhibited macrophage phagocytic phagocytosis in rat abdominal cavity (see FIGS. 17 and 18).
한편, 세포내에 포스파티딜세린과 결합하는 단백질들은 칼슘 이온에 의존성 결합을 한다고 알려져 있다. 이에 본 발명자들은 스태빌린-2가 발현되는 세포(L/Stab-2 세포)를 이용하여 노화된 적혈구의 탐식에 칼슘의 효과를 조사하였다(실시예 6-1 참조). 그 결과, 혈청과 칼슘을 제거한 배지에서 거의 최소한의 노화적혈구의 탐식만이 관찰되었다. 그러나 칼슘이 추가됨에 따라 노화된 적혈구의 탐식은 증가되었다(도 19 참조). 따라서, 스태빌린-2에 의해 매개되는 탐식과정에 칼슘이 필요함을 알 수 있었다. 또한, EGFrp에 의한 포스파티딜세린의 인식에도 칼슘이 필요한지를 NBD형광의 소멸효과를 이용하여 조사하였다(실시예 6-2 참조). 그 결과, EGFrp는 PS 리포좀에 잘 부착하였으며, 이러한 부착은 칼슘 킬레이터에 의해 서 저해되었다(도 20 참조). 따라서, EGFrp에 의한 포스파티딜세린의 인식과정에도 칼슘이온이 관여됨을 알 수 있었다.On the other hand, proteins that bind to phosphatidylserine in the cell are known to be dependent on calcium ions. The present inventors investigated the effect of calcium on phagocytosis of aged erythrocytes using cells expressing Stabilin-2 (L / Stab-2 cells) (see Example 6-1). As a result, almost minimal aging of red blood cells was observed in serum and calcium-free medium. However, as calcium was added, the phagocytosis of aged erythrocytes increased (see FIG. 19). Therefore, it was found that calcium is required for the stabilization process mediated by Stabilin-2. In addition, whether calcium was required for the recognition of phosphatidylserine by EGFrp was investigated by using the extinction effect of NBD fluorescence (see Example 6-2). As a result, EGFrp adhered well to the PS liposomes, which were inhibited by calcium chelators (see FIG. 20). Therefore, it was found that calcium ion is involved in the recognition process of phosphatidylserine by EGFrp.
본 발명자들은 EGFrp단백질의 C-말단 및 N-말단 결손 단백질들(도 21 참조)을 제조하여 사멸세포의 포스파티딜세린을 인식하는 모티프를 조사하였다(실시예 7 참조). C-말단 결실 단백질을 사용한 실험에서 EGFrp가 포스파티딜세린을 인식하기 위해서는 4개 이상의 EGF-유사 도메인이 필요함을 알 수 있었으며(도 22 참조), N-말단 결실 단백질을 사용한 실험을 통하여 비정형(atypical) EGF-유사 도메인이 중요함을 알 수 있었다(도 23 참조). 상기의 결과는 L/Stab-2 세포를 이용한 탐식 저해 실험에서도 유사한 결과를 나타냈다(도 24 및 도 25 참조). 따라서, EGFrp가 포스파티딜세린을 인식하기 위해서는 비정형(atypical) EGF-유사 도메인을 포함하는 4개 이상의 EGF-유사 도메인으로 구성되어야 함을 알 수 있었다.We prepared C-terminal and N-terminal defective proteins (see FIG. 21) of the EGFrp protein to investigate motifs that recognize phosphatidylserine of dead cells (see Example 7). In experiments using the C-terminal deletion protein, it was found that four or more EGF-like domains are required for EGFrp to recognize phosphatidylserine (see FIG. 22), and atypical through experiments using the N-terminal deletion protein. It was found that the EGF-like domain is important (see FIG. 23). The results showed similar results in phagocytosis inhibition experiments using L / Stab-2 cells (see FIGS. 24 and 25). Therefore, it was found that EGFrp should be composed of four or more EGF-like domains including atypical EGF-like domains in order to recognize phosphatidylserine.
더욱이, 본 발명자들은 EGFrp내의 2개의 비정형(atypical) EGF-유사 도메인중에서 어느 비정형(atypical) EGF-유사 도메인이 중요한가를 조사하기 위해 각각의 비정형(atypical) EGF-유사 도메인이 결실된 단백질을 제조하였다(도 26 및 실시예 7 참조). 상기의 단백질에 대해서 포스파티딜세린에 대한 부착정도를 NBD형광의 소멸효과를 이용하여 조사한 결과 두번째 비정형(atypical) EGF-유사 도메인이 칼슘 의존성 포스파티딜세린의 인식에 중요함을 알 수 있었다(도 27 및 도 28 참조). 노화된 적혈구의 탐식에도 역시 두번째 비정형(atypical) EGF-유사 도메인이 중요한 역할을 함을 알 수 있었다(도 29 참조). Furthermore, the inventors have prepared proteins in which each atypical EGF-like domain is deleted to investigate which atypical EGF-like domain is important among the two atypical EGF-like domains in the EGFrp. (See FIG. 26 and Example 7). The degree of adhesion of phosphatidylserine to the protein was examined using the extinction effect of NBD fluorescence, indicating that the second atypical EGF-like domain was important for the recognition of calcium-dependent phosphatidylserine (Fig. 27 and Fig. 27). 28). A second atypical EGF-like domain also plays an important role in phagocytosis of aged erythrocytes (see FIG. 29).
결론적으로, 스태빌린-2의 EGFrp-유사 도메인 반복부위, 특히 스태빌린-2의 EGFrp-유사 도메인 반복 부위 중 두번째 비정형(atypical) EGF-유사 도메인 및 3개의 EGF-유사 도메인이 포스파티딜세린과 특이적으로 결합하여 생체내에서 사멸세포 및 노화된 적혈구의 인식과 탐식에 중요한 역할을 함을 알 수 있었다. In conclusion, the second atypical EGF-like domain and three EGF-like domains of the EGFrp-like domain repeat region of Stabilin-2, particularly the Stabilin-2, are specific for phosphatidylserine. In addition, it can be seen that it plays an important role in recognition and phagocytosis of dead cells and aged red blood cells in vivo.
참고로, 상기에서 언급한 뉴클레오티드 및 단백질 작업에는 다음의 문헌을 참조할 수 있다(Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.(1982); Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d Ed., Cold Spring Harbor Laboratory Press(1989); Deutscher, M., Guide to Protein Purification Methods Enzymology, vol. 182. Academic Press. Inc., San Diego, CA(1990)). For reference, reference may be made to the above-mentioned nucleotide and protein operations (Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (1982); Sambrook et al. ., Molecular Cloning: A Laboratory Manual, 2d Ed., Cold Spring Harbor Laboratory Press (1989); Deutscher, M., Guide to Protein Purification Methods Enzymology, vol. 182. Academic Press. Inc., San Diego, CA (1990). )).
따라서, 본 발명은 본 발명의 폴리펩티드, 즉 스태빌린-2(stabilin-2)의 EGF-유사 도메인의 반복부위(EGF-like domain repeat protein)에서 두 번째 비정형 EGF-유사 도메인 및 3개 이상의 EGF-유사도메인이 순차적으로 연결된 폴리펩티드를 포함하는 폴리펩티드를 유효성분으로 포함하는 포스파티딜세린(phosphatidylserine) 검출용 조성물을 제공한다.Thus, the present invention is directed to a second atypical EGF-like domain and at least three EGF-s in the EGF-like domain repeat protein of the polypeptide of the invention, ie, stabilin-2. Provided is a composition for detecting phosphatidylserine comprising a polypeptide including a polypeptide in which a pseudo domain is sequentially linked.
아울러, 본 발명의 폴리펩티드는 포스파티딜세린과 특이적으로 결합하므로 본 발명은 In addition, since the polypeptide of the present invention specifically binds to phosphatidylserine, the present invention
(a) 본 발명의 폴리펩티드, 즉 스태빌린-2(stabilin-2)의 EGF-유사 도메인의 반복부위(EGF-like domain repeat protein)에서 두 번째 비정형 EGF-유사 도메인 및 3개 이상의 EGF-유사도메인이 순차적으로 연결된 폴리펩티드를 시료와 혼합하는 단계;(a) a second atypical EGF-like domain and three or more EGF-like domains in the polypeptide of the invention, ie the EGF-like domain repeat protein of stabilin-2 Mixing the sequentially linked polypeptide with a sample;
(b) 미결합되거나 비특이적으로 결합된 상기 폴리펩티드를 제거하는 단계; 및(b) removing the unbound or nonspecifically bound polypeptide; And
(c) 상기 폴리펩티드의 결합 여부 및 위치를 확인하는 단계를 포함하는 포스파티딜세린의 검출 방법을 제공한다.(c) it provides a method for detecting phosphatidylserine comprising the step of confirming the binding and position of the polypeptide.
본 발명의 폴리펩티드의 결합 여부의 확인, 검출 및 정량을 용이하게 하기 위하여, 본 발명의 폴리펩티드는 표지된 상태로 제공될 수 있다. 즉, 검출가능한 표지에 링크(예: 공유 결합 또는 가교)되어 제공될 수 있다. 상기 검출가능한 표지는 발색효소(예: 퍼옥시다제, 알칼라인 포스파타제), 방사성 동위원소(예: 125I, 32P, 35S), 크로모포어(chromophore), 발광물질 또는 형광물질(예: FITC, RITC, 형광단백질(GFP(Green Fluorescent Protein); EGFP(Enhanced Green Fluorescent Protein), RFP(Red Fluorescent Protein); DsRed(Discosoma sp. red fluorescent protein); CFP(Cyan Fluorescent Protein), CGFP(Cyan Green Fluorescent Protein) 및 YFP(Yellow Fluorescent Protein)))일 수 있다.In order to facilitate identification, detection and quantification of binding of the polypeptide of the present invention, the polypeptide of the present invention may be provided in a labeled state. In other words, the detectable label may be provided in a link (eg, covalently bonded or crosslinked). The detectable label may be a colorase (e.g. peroxidase, alkaline phosphatase), radioisotope (e.g. 125 I, 32 P, 35 S), chromophore, luminescent or fluorescent material (e.g. FITC , RITC, Fluorescent Protein (GFP (Green Fluorescent Protein); EGFP (Enhanced Green Fluorescent Protein), RFP (Red Fluorescent Protein); DsRed (Discosoma sp. Red fluorescent protein); CFP (Cyan Fluorescent Protein), CGFP (Cyan Green Fluorescent) Protein) and YFP (Yellow Fluorescent Protein)).
표지에 따른 검출 방법은 당업계에 널리 알려져 있으나, 예를 들어 다음과 같은 방법에 의해 수행될 수 있다. 만약 검출가능한 표지로 형광물질을 이용하는 경우에는 면역형광염색법을 이용할 수 있다. 예컨대, 형광물질로 표지된 본 발명의 폴리펩티드를 시료와 반응시키고 미결합 또는 비특이적인 결합 산물을 제거한 다음 형광현미경 하에서 펩티드에 의한 형광을 관찰할 수 있다. 또한 검출가능한 표지로 효소를 이용하는 경우에는 효소반응을 통한 기질의 발색반응에 의해 흡광도를 측정하고, 방사선 물질인 경우에는 방사선 방출량을 측정함으로써 수행할 수 있다.Detection methods according to labels are well known in the art, but can be performed, for example, by the following method. If fluorescent material is used as a detectable label, immunofluorescence staining may be used. For example, a fluorescently labeled polypeptide of the present invention may be reacted with a sample to remove unbound or nonspecific binding products, and then fluorescence by peptides may be observed under a fluorescence microscope. In addition, in the case of using the enzyme as a detectable label, the absorbance may be measured by the color reaction of the substrate through the enzymatic reaction, and in the case of the radioactive substance, the radiation emission may be measured.
또한, 본 발명의 폴리펩티드는 포스파티딜세린을 세포 표면으로 노출하는 세포와 특이적으로 결합할 수 있으며, 사멸세포(apoptotic cell)에서 포스파티딜세린이 세포막으로 노출되므로 본 발명은 본 발명의 폴리펩티드를 유효성분으로 포함하는 사멸세포(apoptotic cell) 검출용 조성물을 제공한다. 상기에서 사멸세포의 검출은 이에 한정되지는 않으나, 예를 들어, 상기 포스파티딜세린의 검출시의 방법을 이용할 수 있으며, 상기에서 기재한 바와 같이 본 발명의 폴리펩티드의 결합 여부의 확인, 검출 및 정량을 용이하게 하기 위하여, 본 발명의 폴리펩티드는 표지된 상태로 제공될 수 있다. 검출된 결과는 검출표지에 따른 공지된 영상화 방법에 따라 영상화될 수도 있다.In addition, the polypeptide of the present invention can specifically bind to cells exposing phosphatidylserine to the cell surface, and since the phosphatidylserine is exposed to the cell membrane in apoptotic cells, the present invention provides the polypeptide of the present invention as an active ingredient. It provides a composition for detecting apoptotic cells comprising. The detection of dead cells in the above is not limited thereto. For example, a method for detecting phosphatidylserine may be used, and as described above, identification, detection, and quantification of binding of the polypeptide of the present invention may be performed. To facilitate, the polypeptides of the invention can be provided in a labeled state. The detected result may be imaged according to a known imaging method according to the detection label.
또한 본 발명의 폴리펩티드는 포스파티딜세린을 세포 표면으로 노출하는 세포와 특이적으로 결합할 수 있으므로 약물을 상기 세포에 선택적으로 전달하는 지능형 약물 전달체로서 사용할 수 있다. 따라서, 본 발명의 폴리펩티드, 즉 스태빌린-2(stabilin-2)의 EGF-유사 도메인의 반복부위(EGF-like domain repeat protein)에서 두 번째 비정형 EGF-유사 도메인 및 3개 이상의 EGF-유사도메인이 순차적으로 연결된 폴리펩티드를 유효성분으로 포함하는 약물 전달용 조성물을 제공한다.In addition, the polypeptide of the present invention can specifically bind to a cell exposing phosphatidylserine to a cell surface, and thus can be used as an intelligent drug carrier for selectively delivering a drug to the cell. Thus, the second atypical EGF-like domain and three or more EGF-like domains in the polypeptide of the present invention, ie, the EGF-like domain repeat protein of stabilin-2, It provides a drug delivery composition comprising a sequentially linked polypeptide as an active ingredient.
상기한 바와 같이, 세포막의 외부로 포스파티딜세린의 발현 증가는 흑색종 및 대장암 세포(Utsugi, T. et al., Cancer Res. 1991, 15:3062-3066), 난소암 세포(Rao, L. et al., Thromb Res. 1992, 67:517-531), 위암 및 간암 세포(Sugimura, M. et al., Blood Coagul. Fibrinolysis. 1994, 5:365-373; Woehlecke, H. et al., Biochem J. 2003, 376:489-495), 암조직의 내피세포(Ran, S. et al., Cancer Res. 2002, 62:6132-6140) 등 여러 종양세포에서 나타나며, 이것은 미분화성 발암성 세포(undifferentiated tumorigenic cell)에서 더욱 저명하게 나타난다. 종양조직은 또한 포스파티딜세린을 세포막의 외부로 노출하는 소혈관을 방출한다(Ran, S. et al., Cancer Res. 2002, 62:6132-6140; Zwaal, R.F.A. et al., Blood. 1997, 89:1121-1132).As noted above, increased expression of phosphatidylserine outside of the cell membrane has been associated with melanoma and colorectal cancer cells (Utsugi, T. et al., Cancer Res. 1991, 15: 3062-3066), ovarian cancer cells (Rao, L. et al. et al., Thromb Res. 1992, 67: 517-531), gastric and liver cancer cells (Sugimura, M. et al., Blood Coagul. Fibrinolysis. 1994, 5: 365-373; Woehlecke, H. et al., Biochem J. 2003, 376: 489-495), and endothelial cells of cancer tissues (Ran, S. et al., Cancer Res. 2002, 62: 6132-6140), which are found in undifferentiated carcinogenic cells. more pronounced in undifferentiated tumorigenic cells. Tumor tissue also releases small blood vessels that expose phosphatidylserine to the outside of the cell membrane (Ran, S. et al., Cancer Res. 2002, 62: 6132-6140; Zwaal, RFA et al., Blood. 1997, 89 : 1121-1132).
따라서, 상기 약물 전달용 조성물은 종양성 질환에 특이적일 수 있다. 종양성 질환이란 악성 종양에 의해 병리적 증상을 보이는 질환으로서, 그 예로는 이에 한정되지는 않으나, 대장암, 폐암, 위암, 식도암, 췌장암, 담낭암, 신장암, 방광암, 전립선암, 고환암, 자궁경부암, 자궁내막암, 융모암, 난소암, 유방암, 갑상선암, 뇌암, 두경부암, 악성흑색종, 피부암, 간암, 백혈병(leukemia), 림프종(lymphoma), 복합 골수종(multiple myeloma), 만성 골수성 백혈병(chronic myelogenous leukemia), 신경아종(neuroblastoma), 재생불량성 빈혈일 수 있다.Thus, the drug delivery composition may be specific for a neoplastic disease. Tumorous diseases are pathological symptoms caused by malignant tumors, but are not limited to, but are not limited to, colon cancer, lung cancer, stomach cancer, esophageal cancer, pancreatic cancer, gallbladder cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer , Endometrial cancer, chorionic cancer, ovarian cancer, breast cancer, thyroid cancer, brain cancer, head and neck cancer, malignant melanoma, skin cancer, liver cancer, leukemia, lymphoma, multiple myeloma, chronic myelogenous leukemia myelogenous leukemia, neuroblastoma, aplastic anemia.
본 발명의 약물 전달용 조성물에 포함되는 본 발명의 폴리펩티드를 종래 항-종양성 질환 제제와 연결하여 치료에 이용한다면 본 발명의 폴리펩티드에 의해 상기 제제가 종양 세포에만 선택적으로 전달되기 때문에 약의 효력을 증가시킬 수 있고 동시에 정상조직에 미치는 부작용을 현저히 줄일 수 있다.When the polypeptide of the present invention contained in the composition for drug delivery of the present invention is used for treatment in connection with a conventional anti-tumor disease agent, the effect of the drug may be exerted because the agent is selectively delivered only to tumor cells by the polypeptide of the present invention. It can increase and at the same time significantly reduce side effects on normal tissues.
본 발명의 폴리펩티드에 연결될 수 있는 항-종양성 질환 제제는 종래 종양 치료에 사용되는 것이라면 제한 없이 사용될 수 있다. 예컨대, 파클리탁셀, 독소루비신, 빈크리스틴, 다우노루비신(daunorubicin), 빈블라스틴(vinblastine), 액티노마이신-D(actinomycin-D), 도세탁셀(docetaxel), 에토포사이드(etoposide), 테니포사이드(teniposide), 비산트렌(bisantrene), 호모해링토닌(homoharringtonine), 글리벡(Gleevec; STI-571), 시스플라틴(cisplain), 5-플로오우라실(5-fluouracil), 아드리아마이신(adriamycin), 메토트렉세이트(methotrexate), 부설판(busulfan), 클로람부실(chlorambucil), 시클로포스파미드(cyclophosphamide), 멜팔란(melphalan), 니트로겐 무스타드(nitrogen mustard), 니트로소우레 아(nitrosourea) 등이 있다. 상기 제제와 본 발명의 폴리펩티드의 연결은 당업계에 공지된 방법, 예컨대, 공유 결합, 가교 등을 통해 수행될 수 있다. 이를 위해 본 발명의 펩티드는 필요하다면 그 활성이 소실되지 않는 범위에서 화학적으로 수식(modification)될 수 있다. 본 발명의 조성물에 포함되는 본 발명의 펩티드의 양은 결합되는 항암제의 종류 및 양에 따라 달라질 수 있다.Anti-tumor disease agents that can be linked to the polypeptides of the invention can be used without limitation as long as they are used in conventional tumor therapy. For example, paclitaxel, doxorubicin, vincristine, daunorubicin, vinblastine, actinomycin-D, docetaxel, etoposide, teniposide , Bisantrene, homomoharringtonine, Gleevec (STI-571), cisplain, 5-fluouracil, 5-fluouracil, adriamycin, methotrexate, Busulfan, chlorambucil, cyclophosphamide, melphalan, nitrogen mustard, nitrosourea, and the like. The linking of the agent with the polypeptide of the present invention may be carried out through methods known in the art, such as covalent bonds, crosslinking, and the like. To this end, the peptide of the present invention may be chemically modified if necessary so long as its activity is not lost. The amount of the peptide of the present invention included in the composition of the present invention may vary depending on the type and amount of the anticancer agent bound.
한편, 본 발명은 본 발명의 폴리펩티드, 즉 스태빌린-2(stabilin-2)의 EGF-유사 도메인의 반복부위(EGF-like domain repeat protein)에서 두 번째 비정형 EGF-유사 도메인 및 3개 이상의 EGF-유사도메인이 순차적으로 연결된 폴리펩티드 및 이와 결합된 항-종양성 질환 제제를 유효성분으로 종양성 질환의 예방 및 치료용 약학적 조성물을 제공한다. On the other hand, the present invention provides a polypeptide of the present invention, that is, a second atypical EGF-like domain and three or more EGF-s in the EGF-like domain repeat protein of stabilin-2. Provided is a pharmaceutical composition for the prevention and treatment of neoplastic diseases as an active ingredient using the polypeptide and the anti-tumor disease agent coupled to the similar domain sequentially.
이 때, 상기 약학적 조성물에서 항-종양성 질환 제제, 결합 방법 및 종양성 질환에 대해서는 상기에서 기재한 바와 같다.At this time, the anti-tumor disease agent, the binding method and the neoplastic disease in the pharmaceutical composition are as described above.
한편, 본 발명에 따른 약학적 조성물은 상기 폴리펩티드의 순수한 형태 또는 약학적으로 허용되는 담체와 함께 적합한 형태로 제형화함으로써 제공될 수 있다. '약학적으로 허용되는'이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증 등과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 비독성의 조성물을 말한다. 상기 담체로는 모든 종류의 용매, 분산매질, 수중 유 또는 유중수 에멀젼, 수성 조성물, 리포좀, 마이크로비드 및 마이크로좀이 포함된다. On the other hand, the pharmaceutical composition according to the present invention can be provided by formulating in a suitable form together with the pure form of the polypeptide or a pharmaceutically acceptable carrier. 'Pharmaceutically acceptable' refers to a nontoxic composition which, when administered to humans, is physiologically acceptable and typically does not cause allergic or similar reactions such as gastrointestinal disorders, dizziness and the like. Such carriers include all kinds of solvents, dispersion media, oil-in-water or water-in-oil emulsions, aqueous compositions, liposomes, microbeads and microsomes.
한편, 본 발명에 따른 약학적 조성물은 투여 경로에 따라 적합한 담체와 함께 제형화될 수 있다. 상기 본 발명에 따른 약학적 조성물의 투여 경로로는 이에 한정되지는 않으나 경구적 또는 비경구적으로 투여될 수 있다. 비경구적 투여 경로로는 예를 들면, 경피, 비강, 복강, 근육, 피하 또는 정맥 등의 여러 경로가 포함된다.On the other hand, the pharmaceutical composition according to the present invention can be formulated with a suitable carrier depending on the route of administration. The route of administration of the pharmaceutical composition according to the present invention is not limited thereto, but may be administered orally or parenterally. Parenteral routes of administration include, for example, several routes such as transdermal, nasal, abdominal, muscle, subcutaneous or intravenous.
본 발명의 약학적 조성물을 경구 투여하는 경우 본 발명의 약학적 조성물은 적합한 경구 투여용 담체와 함께 당 업계에 공지된 방법에 따라 분말, 과립, 정제, 환제, 당의정제, 캡슐제, 액제, 겔제, 시럽제, 현탁액, 웨이퍼 등의 형태로 제형화될 수 있다. 적합한 담체의 예로는 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨 및 말티톨 등을 포함하는 당류와 옥수수 전분, 밀 전분, 쌀 전분 및 감자 전분 등을 포함하는 전분류, 셀룰로즈, 메틸 셀룰로즈, 나트륨 카르복시메틸셀룰로오즈 및 하이드록시프로필메틸-셀룰로즈 등을 포함하는 셀룰로즈류, 젤라틴, 폴리비닐피롤리돈 등과 같은 충전제가 포함될 수 있다. 또한, 경우에 따라 가교결합 폴리비닐피롤리돈, 한천, 알긴산 또는 나트륨 알기네이트 등을 붕해제로 첨가할 수 있다. 나아가, 상기 약학적 조성물은 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.In the case of oral administration of the pharmaceutical composition of the present invention, the pharmaceutical composition of the present invention is prepared in powder, granule, tablet, pill, dragee, capsule, liquid, gel according to a method known in the art together with a suitable oral carrier. , Syrups, suspensions, wafers and the like. Examples of suitable carriers include sugars, including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol and starch, cellulose, starch including corn starch, wheat starch, rice starch and potato starch, and the like. Fillers such as cellulose, gelatin, polyvinylpyrrolidone, and the like, including methyl cellulose, sodium carboxymethylcellulose, hydroxypropylmethyl-cellulose, and the like. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid or sodium alginate and the like may optionally be added as a disintegrant. Furthermore, the pharmaceutical composition may further include an anticoagulant, a lubricant, a humectant, a perfume, an emulsifier, and a preservative.
또한, 비경구적으로 투여하는 경우 본 발명의 약학적 조성물은 적합한 비경구용 담체와 함께 주사제, 경피 투여제 및 비강 흡입제의 형태로 당 업계에 공지된 방법에 따라 제형화될 수 있다. 상기 주사제의 경우에는 반드시 멸균되어야 하며 박테리아 및 진균과 같은 미생물의 오염으로부터 보호되어야 한다. 주사제의 경우 적합한 담체의 예로는 이에 한정되지는 않으나, 물, 에탄올, 폴리올(예를 들어, 글리세롤, 프로필렌 글리콜 및 액체 폴리에틸렌 글리콜 등), 이들의 혼합물 및/또는 식물유를 포함하는 용매 또는 분산매질일 수 있다. 보다 바람직하게는, 적합한 담체로는 행크스 용액, 링거 용액, 트리에탄올 아민이 함유된 PBS(phosphate buffered saline) 또는 주사용 멸균수, 10% 에탄올, 40% 프로필렌 글리콜 및 5% 덱스트로즈와 같은 등장 용액 등을 사용할 수 있다. 상기 주사제를 미생물 오염으로부터 보호하기 위해서는 파라벤, 클로로부탄올, 페놀, 소르빈산, 티메로살 등과 같은 다양한 항균제 및 항진균제를 추가로 포함할 수 있다. 또한, 상기 주사제는 대부분의 경우 당 또는 나트륨 클로라이드와 같은 등장화제를 추가로 포함할 수 있다.In addition, when administered parenterally, the pharmaceutical compositions of the present invention may be formulated according to methods known in the art in the form of injections, transdermal and nasal inhalants together with suitable parenteral carriers. Such injections must be sterile and protected from contamination of microorganisms such as bacteria and fungi. Examples of suitable carriers for injections include, but are not limited to, solvents or dispersion media comprising water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycols, etc.), mixtures thereof and / or vegetable oils Can be. More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanol amine or sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose Etc. can be used. In order to protect the injection from microbial contamination, various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like may be further included. In addition, the injection may in most cases further comprise an isotonic agent such as sugar or sodium chloride.
경피 투여제의 경우 연고제, 크림제, 로션제, 겔제, 외용액제, 파스타제, 리니멘트제, 에어롤제 등의 형태가 포함된다. 상기에서 “경피 투여”는 약학적 조성물을 국소적으로 피부에 투여하여 약학적 조성물에 함유된 유효한 양의 활성성분이 피부 내로 전달되는 것을 의미한다. 이들 제형은 제약 화학에 일반적으로 공지된 처방서인 문헌(Remington's Pharmaceutical Science, 15th Edition, 1975, Mack Publishing Company, Easton, Pennsylvania)에 기술되어 있다.In the case of transdermal administrations, ointments, creams, lotions, gels, external preparations, pasta preparations, linen preparations, air rolls and the like are included. As used herein, "transdermal administration" means that the pharmaceutical composition is topically administered to the skin such that an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin. These formulations are formulated in Remington's , a commonly known formula in pharmaceutical chemistry. Pharmaceutical Science , 15th Edition, 1975, Mack Publishing Company, Easton, Pennsylvania.
흡입 투여제의 경우, 본 발명에 따라 사용되는 화합물은 적합한 추진제, 예를 들면, 디클로로플루오로메탄, 트리클로로플루오로메탄, 디클로로테트라플루오로에탄, 이산화탄소 또는 다른 적합한 기체를 사용하여, 가압 팩 또는 연무기로부터 에어로졸 스프레이 형태로 편리하게 전달 할 수 있다. 가압 에어로졸의 경우, 투약 단위는 계량된 양을 전달하는 밸브를 제공하여 결정할 수 있다. 예를 들면, 흡입기 또는 취입기에 사용되는 젤라틴 캡슐 및 카트리지는 화합물, 및 락토즈 또는 전분과 같은 적합한 분말 기제의 분말 혼합물을 함유하도록 제형화할 수 있다. In the case of inhaled dosages, the compounds used according to the invention may be pressurized packs or by means of suitable propellants, for example dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It can be delivered conveniently from the nebulizer in the form of an aerosol spray. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. For example, gelatin capsules and cartridges for use in inhalers or blowers can be formulated to contain a mixture of the compound and a suitable powder base such as lactose or starch.
그 밖의 약학적으로 허용되는 담체로는 다음의 문헌에 기재되어 있는 것을 참고로 할 수 있다(Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995). Other pharmaceutically acceptable carriers can be found in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995).
또한, 본 발명에 따른 약학적 조성물은 하나 이상의 완충제(예를 들어, 식염수 또는 PBS), 카보하이트레이트(예를 들어, 글루코스, 만노즈, 슈크로즈 또는 덱스트란), 안정화제(아황산수소나트륨, 아황산나트륨 또는 아스코르브산) 항산화제, 정균제, 킬레이트화제(예를 들어, EDTA 또는 글루타치온), 아쥬반트(예를 들어, 알루미늄 하이드록사이드), 현탁제, 농후제 및/또는 보존제(벤즈알코늄 클로라이드, 메틸- 또는 프로필-파라벤 및 클로로부탄올)를 추가로 포함할 수 있다.In addition, the pharmaceutical compositions according to the invention may contain one or more buffers (eg saline or PBS), carbohydrates (eg glucose, mannose, sucrose or dextran), stabilizers (sodium bisulfite, Sodium sulfite or ascorbic acid) antioxidants, bacteriostatic agents, chelating agents (eg EDTA or glutathione), adjuvants (eg aluminum hydroxide), suspending agents, thickening agents and / or preservatives (benzalkonium chloride , Methyl- or propyl-paraben and chlorobutanol).
또한, 본 발명의 약학적 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화될 수 있다.In addition, the pharmaceutical compositions of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
상기와 같은 방법으로 제형화된 약학적 조성물은 유효량으로 경구, 경피, 피하, 정맥 또는 근육을 포함한 여러 경로를 통해 투여될 수 있다. 상기에서 '유효량' 이란 환자에게 투여하였을 때, 진단 또는 치료 효과의 추적을 가능하게 하는 화합물 또는 추출물의 양을 말한다. 본 발명에 따른 약학적 조성물의 투여량은 투여 경로, 투여 대상, 대상 질환 및 이의 중증정도, 연령, 성별 체중, 개인차 및 질병 상태에 따라 적절히 선택할 수 있다. 바람직하게는, 본 발명의 폴리펩티드를 포함하는 약학적 조성물은 질환의 정도에 따라 유효성분의 함량을 달리할 수 있으나, 통상적으로 성인을 기준으로 할 때 1회 투여시 10 ㎍ 내지 10 ㎎의 유효용량으로 하루에 수 차례 반복 투여될 수 있다. Pharmaceutical compositions formulated in such a manner can be administered in a effective amount via several routes, including oral, transdermal, subcutaneous, intravenous or intramuscular. As used herein, an 'effective amount' refers to an amount of a compound or extract that, when administered to a patient, enables the tracking of a diagnostic or therapeutic effect. The dosage of the pharmaceutical composition according to the present invention may be appropriately selected according to the route of administration, the subject to be administered, the target disease and its severity, age, sex weight, individual difference, and disease state. Preferably, the pharmaceutical composition comprising the polypeptide of the present invention may vary in the amount of the active ingredient depending on the extent of the disease, but usually an effective dose of 10 μg to 10 mg per single dose based on an adult May be repeated several times a day.
아울러, 본 발명의 폴리펩티드, 즉 스태빌린-2(stabilin-2)의 EGF-유사 도메인의 반복부위(EGF-like domain repeat protein)에서 두 번째 비정형 EGF-유사 도메인 및 3개 이상의 EGF-유사도메인이 순차적으로 연결된 폴리펩티드는 포스파티딜세린과 특이적으로 결합하므로 종양성 질환의 발병 부위의 영상화에도 유용하게 사 용될 수 있다. 따라서, 본 발명은 상기 폴리펩티드를 유효성분으로 포함하는 종양성 질환의 영상화용 조성물을 제공한다. 상기 폴리펩티드는 결합 여부의 확인, 검출 및 정량을 용이하게 하기 위하여, 표지된 상태로 제공될 수 있으며, 이에 대해서는 상기에서 기술한 바와 같다.In addition, a second atypical EGF-like domain and three or more EGF-like domains of the polypeptide of the present invention, ie, the EGF-like domain repeat protein of stabilin-2, Sequentially linked polypeptides specifically bind to phosphatidylserine and thus may be useful for imaging the onset of neoplastic disease. Accordingly, the present invention provides a composition for imaging tumor disease comprising the polypeptide as an active ingredient. The polypeptide may be provided in a labeled state to facilitate identification, detection, and quantification of binding, as described above.
또한, 포스파티딜세린은 상기 종양성 질환 이외에도 여러 가지 병적인 상황에서도 세포막의 외부로 노출된다(Zwaal, R.F.A. et al., Cell. Mol. Life Sci. 2005, 62:971-988). 그 예로 스코트 증후군(Scott syndrome), 항인지질 증후군(antiphospholipid syndrome), 겸상 적혈구 빈혈증(sickle cell anemia), 탈라세미아(thalathemia), 스토마토싸이토시스(stomatocytosis), 요독증(uremia), 신장결석(kidney stone disease), 당뇨병(diabetes), 고혈당증(hyperglycemia), 바이러스 감염 및 미생물 감염, 말라리아(malaria), 전-자간증(pre-eclampsia), 고빌리루빈혈증(hyperbilirubinemia), 신생물 종양(neoplasia) 등이 있다. In addition, phosphatidylserine is exposed to the outside of the cell membrane in a variety of pathological conditions in addition to the tumor disease (Zwaal, R.F.A. et al., Cell.Mol.Life Sci. 2005, 62: 971-988). Examples include Scott syndrome, antiphospholipid syndrome, sickle cell anemia, thalathemia, stomatocytosis, uremia, and kidney stones ( kidney stone disease, diabetes, hyperglycemia, viral and microbial infections, malaria, pre-eclampsia, hyperbilirubinemia, neoplasia, etc. have.
따라서, 본 발명은 본 발명의 폴리펩티드, 즉 스태빌린-2(stabilin-2)의 EGF-유사 도메인의 반복부위(EGF-like domain repeat protein)에서 두 번째 비정형 EGF-유사 도메인 및 3개 이상의 EGF-유사도메인이 순차적으로 연결된 폴리펩티드를 유효성분으로 포함하는, 스코트 증후군(Scott syndrome), 항인지질 증후군(antiphospholipid syndrome), 겸상 적혈구 빈혈증(sickle cell anemia), 탈라세미아(thalathemia), 스토마토싸이토시스(stomatocytosis), 요독증(uremia), 신장결 석(kidney stone disease), 당뇨병(diabetes), 고혈당증(hyperglycemia), 바이러스 감염 및 미생물 감염, 말라리아(malaria), 전-자간증(pre-eclampsia), 고빌리루빈혈증(hyperbilirubinemia), 신생물 종양(neoplasia)으로 이루어진 군에서 선택된 질환의 진단용 조성물을 제공할 수 있다. Thus, the present invention is directed to a second atypical EGF-like domain and at least three EGF-s in the EGF-like domain repeat protein of the polypeptide of the invention, ie, stabilin-2. Scott syndrome, antiphospholipid syndrome, sickle cell anemia, thalathemia, stomatocytosis, comprising polypeptides with similar domains sequentially linked as active ingredients (stomatocytosis), uremia, kidney stone disease, diabetes mellitus, hyperglycemia, viral infections and microbial infections, malaria, pre-eclampsia, gobilirubin A diagnostic composition for a disease selected from the group consisting of hyperbilirubinemia and neoplasia can be provided.
한편, 본 발명에 기재된 스태빌린-2 내의 폴리펩티드 및 폴리뉴클레오티드에 관한 서열(서열번호 33 내지 서열번호 116)은 하기 표 1에 기재된 바와 같다. 아울러, 본 발명의 단편의 명칭은 EGFrp 및 EGF-유사 도메인의 위치에 따라 명명된 것으로, 예를 들어, 본 발명의 단편 E1-14는 스태빌린-2 내의 첫 번째 EGFrp의 첫 번째 EGF-유사 도메인부터 네 번째 EGF-유사 도메인까지의 아미노산 서열로 이루어진 단편을 의미하고, 본 발명의 단편 E3-25는 스태빌린-2 내의 세 번째 EGFrp의 두 번째 EGF-유사 도메인부터 다섯 번째 EGF-유사 도메인까지의 아미노산 서열로 이루어진 단편을 의미하는 것이다. 본 발명에서 소단위(Stab-U1 등), EGFrp 및 EGF-유사 도메인의 순서는 모두 N 말단에서의 위치에 따라 순서를 정한 것이다.On the other hand, the sequences (SEQ ID NO: 33 to SEQ ID NO: 116) relating to the polypeptide and polynucleotide in Stabilin-2 described in the present invention are as described in Table 1 below. In addition, the fragments of the present invention are named according to the positions of the EGFrp and EGF-like domains, for example, fragment E1-14 of the present invention is the first EGF-like domain of the first EGFrp in Stabilin-2. Refers to a fragment consisting of an amino acid sequence from the fourth EGF-like domain, wherein fragment E3-25 of the present invention is from the second EGF-like domain of the third EGFrp in Stabilin-2 to the fifth EGF-like domain. It means a fragment consisting of the amino acid sequence. In the present invention, the order of subunits (Stab-U1, etc.), EGFrp, and EGF-like domains are all ordered according to their position at the N terminus.
이상 살펴본 바와 같이, 본 발명의 스태빌린-2(stabilin-2)의 EGF-유사 도메인의 반복부위(EGF-like domain repeat protein)에서 두 번째 비정형 EGF-유사 도메인 및 3개 이상의 EGF-유사도메인이 순차적으로 연결된 폴리펩티드는 세포 표면의 포스파티딜세린과 특이적으로 결합할 수 있다. 따라서, 본 발명은 포스파티딜세린을 세포 표면으로 발현하는 세포에 대한 약물 전달, 종양 세포에 대한 약물 또는 표지물질의 전달을 통한 종양성 질환의 예방, 치료 또는 영상화 등에 다양하게 사용될 수 있다.As described above, the second atypical EGF-like domain and three or more EGF-like domains in the EGF-like domain repeat protein of stabilin-2 of the present invention. Sequentially linked polypeptides can specifically bind phosphatidylserine on the cell surface. Therefore, the present invention can be used in various ways, such as drug delivery to cells expressing phosphatidylserine on the cell surface, prevention, treatment or imaging of tumor diseases through delivery of drugs or markers to tumor cells.
이하. 본 발명을 실시예에 의해 상세히 설명한다.Below. The present invention will be described in detail by way of examples.
단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.
<< 실시예Example 1> 1>
스태빌린Stabilin -2(-2( stabilinstabilin -2)를 이용한 재조합 단백질의 제조-2) Preparation of Recombinant Protein
<1-1> 발현 벡터의 제조<1-1> Preparation of Expression Vector
스태빌린-2의 세포외 부분을 4개의 소단위로 구분하였으며, 이 때 상기 각 소단위는 1개의 EGF-유사 도메인의 반복 부위(EGFrp, EGF-like domain repeat protein)와 2개의 FAS-1 도메인을 포함하도록 하였다(도 1 참조).The extracellular portion of Stabilin-2 was divided into four subunits, each subunit comprising one EGF-like domain repeat protein (EGFrp, EGF-like domain repeat protein) and two FAS-1 domains. (See FIG. 1).
먼저 상기 소단위(Stab-U1, Stab-U2, Stab-U3 및 Stab-U4)를 각각 포함하는 재조합 발현 벡터를 제조하기 위하여, 인간 스태빌린-2 cDNA 서열(Genbank Accession No. NM_017564)을 기초로 하여 4쌍의 프라이머(서열번호 1 내지 서열번호 8)를 디자인하였다(표 2 참조). 상기에서 디자인된 각각의 프라이머 쌍을 사용하여 인간 스태빌린-2의 cDNA를 포함하고 있는 발현벡터(Park, S.Y. et al., Cell Death Differ. 2008, 15:192-201)를 주형으로 해서 중합효소연쇄반응(polymerase chain reaction, PCR)을 수행하였다. 구체적으로 상기에서 PCR 반응은 Pfu DNA 중 합효소(Promega)를 사용하여 95℃에서 2분 동안 반응시킨 후, 94℃에서 1분, 55℃에서 30초, 72℃에서 2분 동안의 반응을 35회 반복하여 수행하였다. 그 결과 4개의 소단위에 해당하는 각각의 cDNA를 수득하였다. 상기 수득된 증폭 산물 중 Stab-U1, Stab-U2, Stab-U3을 제한효소 BamHI 및 XhoI(TaKaRa)로, Stab-U4를 제한효소 BamHI 및 EcoRI으로 각각 절단한 후, pET43.1(Novagen) 벡터의 동일한 제한효소 자리에 T4 리가제(ligase, Invitrogen)를 사용하여 삽입함으로써 재조합 벡터 ‘pET-Stab-U1', ‘pET-Stab-U2', ‘pET-Stab-U3', 및 ‘pET-Stab-U4'를 각각 제조하였다. pET43.1(Novagen) 벡터는 재조합 단백질의 용해성(solubility)을 높이기 위해 N-말단에 Nus tag에 대한 코딩 서열을 포함하고 있다. First, to prepare a recombinant expression vector comprising the subunits (Stab-U1, Stab-U2, Stab-U3 and Stab-U4), based on the human Stabilin-2 cDNA sequence (Genbank Accession No. NM_017564) Four pairs of primers (SEQ ID NO: 1 to SEQ ID NO: 8) were designed (see Table 2). Using each primer pair designed above, the polymerase was expressed using an expression vector (Park, SY et al., Cell Death Differ. 2008, 15: 192-201) containing the cDNA of human Stabilin-2 as a template. Polymerase chain reaction (PCR) was performed. Specifically, the PCR reaction using Pfu DNA polymerase (Promega) for 2 minutes at 95 ℃, then 1 minute at 94 ℃, 30 seconds at 55 ℃, 2 minutes at 72 ℃ 35 It was performed repeatedly. As a result, each cDNA corresponding to four subunits was obtained. Obtained above Stab-U1, Stab-U2, and Stab-U3 in the amplification products were digested with restriction enzymes BamHI and XhoI (TaKaRa) and Stab-U4 with restriction enzymes BamHI and EcoRI, respectively, followed by the same restriction of the pET43.1 (Novagen) vector. Recombinant vectors 'pET-Stab-U1', 'pET-Stab-U2', 'pET-Stab-U3', and 'pET-Stab-U4' are inserted by inserting the T4 ligase (Invitrogen) into the enzyme site. Were prepared respectively. The pET43.1 (Novagen) vector contains a coding sequence for the Nus tag at the N-terminus to increase the solubility of the recombinant protein.
또한 상기 스태빌린-2의 각 소단위에 존재하는 EGF-유사 도메인의 반복 부위(EGFrp; E1, E2, E3 및 E4)를 각각 포함하는 재조합 발현 벡터를 제조하기 위하여, 인간 스태빌린-2 cDNA 서열을 기초로 하여 4쌍의 프라이머(서열번호 1, 3, 5, 7 및 서열번호 9 내지 서열번호 12)를 디자인하였다(표 2 참조). 상기에서 디자인된 각각의 프라이머 쌍을 사용하여 상기 스태빌린-2 cDNA를 포함하는 상기 발현벡터를 주형으로 해서 상기와 동일한 중합효소연쇄반응(polymerase chain reaction, PCR)을 수행하였다. 그 결과 수득된 증폭 산물을 BamHI 및 XhoI(TaKaRa)로 절단한 후, pET43.1(Novagen) 벡터의 동일한 제한효소 자리에 T4 리가제(ligase, Invitrogen)를 사용하여 삽입함으로써 재조합 벡터 ‘pET-E1', ‘pET-E2', ‘pET-E3', 및 ‘pET-E4'를 제조하였다.In addition, to prepare a recombinant expression vector comprising a repeating site (EGFrp; E1, E2, E3 and E4) of the EGF-like domain present in each subunit of Stabilin-2, a human Stabilin-2 cDNA sequence was prepared. Four pairs of primers (SEQ ID NOs: 1, 3, 5, 7 and SEQ ID NOs: 9 to 12) were designed on the basis (see Table 2). Using the primer pairs designed above, the same polymerase chain reaction (PCR) was carried out using the expression vector including the Stabilin-2 cDNA as a template. The resulting amplification product was digested with BamHI and XhoI (TaKaRa), and then inserted into the same restriction enzyme site of pET43.1 (Novagen) vector using T4 ligase (Invitrogen) to recombinant vector 'pET-E1. ',' pET-E2 ',' pET-E3 ', and' pET-E4 'were prepared.
한편 상기 스태빌린-2의 세 번째 소단위(Stab-U3)에 존재하는 FAS-1 도메인(F5)을 포함하는 재조합 발현 벡터를 제조하기 위하여, 인간 스태빌린-2 cDNA 서열을 기초로 하여 1쌍의 프라이머(서열번호 13 내지 서열번호 14)를 디자인하였다(표 2 참조). 상기에서 디자인된 각각의 프라이머 쌍을 사용하여 상기 스태빌린-2 cDNA를 포함하는 상기 발현벡터를 주형으로 해서 상기와 동일한 중합효소연쇄반응(polymerase chain reaction, PCR)을 수행하였다. 구체적으로 상기에서 PCR 반응은 Pfu DNA 중합효소(Promega)을 사용하여 95℃에서 2분간 반응시킨 후 94℃에서 1 분, 55℃에서 30초, 72℃에서 1 분 동안의 반응을 35회 반복하여 수행하였다. 그 결과 수득된 증폭 산물을 BamHI 및 XhoI(TaKaRa)로 절단한 후, pET43.1(Novagen) 벡터의 동일한 제한효소 자리에 T4 리가제(ligase, Invitrogen)를 사용하여 삽입함으로써 재조합 벡터‘pET-F5'를 제조하였다.Meanwhile, in order to prepare a recombinant expression vector comprising the FAS-1 domain (F5) present in the third subunit of Stabilin-2 (Stab-U3), a pair of pairs based on the human Stabilin-2 cDNA sequence Primers (SEQ ID NO: 13 to SEQ ID NO: 14) were designed (see Table 2). Using the primer pairs designed above, the same polymerase chain reaction (PCR) was carried out using the expression vector including the Stabilin-2 cDNA as a template. Specifically, the PCR reaction was performed by using Pfu DNA polymerase (Promega) for 2 minutes at 95 ° C., followed by 1 minute at 94 ° C., 30 seconds at 55 ° C., and 1 minute at 72 ° C. for 35 times. Was performed. The resulting amplification product was digested with BamHI and XhoI (TaKaRa), and then inserted into the same restriction enzyme site of pET43.1 (Novagen) vector using T4 ligase (Invitrogen) to recombinant vector'pET-F5 'Was prepared.
<1-2> <1-2> 스태빌린Stabilin -2(-2( stabilinstabilin -2)를 이용한 재조합 단백질의 제조-2) Preparation of Recombinant Protein
상기 <실시예 1-1>에서 제조된 각각의 발현 벡터를 사용하여 대장균 BL21(DE3)을 형질전환하였다. 상기 형질전환된 대장균을 50㎍/㎖의 카나마이신(kanamycin)을 포함하는 LB 배지에서 배양한 다음, 재조합 단백질의 발현을 유도하기 위하여 배양액의 흡광도가 600nm에서 0.5~0.6이 되었을 때 1mM의 IPTG (isopropyl-D-(-)-thiogalactopyranoside)를 첨가하여 37℃에서 4시간 동안 추가로 배양하였다.E. coli BL21 (DE3) was transformed using the respective expression vectors prepared in Example 1-1. The transformed Escherichia coli was cultured in LB medium containing 50 µg / ml kanamycin, and then, when the absorbance of the culture medium was 0.5 to 0.6 at 600 nm to induce the expression of recombinant protein, 1 mM IPTG (isopropyl) was used. -D-(-)-thiogalactopyranoside) was added and further incubated at 37 ° C for 4 hours.
상기 배양 후 발현된 재조합 단백질을 공지의 방법에 따라 정제하였다(Kim, J.-E. et al., J. Cell . Biochem., 77:169-187, 2000). 구체적으로 상기 형질전환된 대장균의 배양액을 원심 분리하여 세포를 수득한 후, 용해 완충용액(50mM Tris-HCl (pH 8.0), 100mM NaCl, 1mM EDTA, 1% Triton X-100, 1mM PMSF, 0.5mM DTT)에 재현탁하였다. 상기 세포 현탁액을 초음파로 분쇄한 후, 원심 분리하여 상층액을 Ni-NTA수지(resin, Qiagen)를 이용하여 재조합 단백질을 정제하였다. 상기 재조합 단백질을 200mM 이미다졸(imidazole) 용액에서 용리한 다음, SDS-PAGE에 의하여 재조합 단백질을 확인하였다(결과 미도시). The recombinant protein expressed after the culture was purified according to a known method (Kim, J.-E. et al., J. Cell . Biochem ., 77: 169-187, 2000). Specifically, after centrifuging the culture of the transformed E. coli to obtain the cells, lysis buffer (50mM Tris-HCl (pH 8.0), 100mM NaCl, 1mM EDTA, 1% Triton X-100, 1mM PMSF, 0.5mM Resuspended in DTT). The cell suspension was pulverized by ultrasonication and centrifuged to purify the recombinant protein using Ni-NTA resin (resin, Qiagen). The recombinant protein was eluted in 200mM imidazole solution, and the recombinant protein was identified by SDS-PAGE (result not shown).
그 결과 상기 스태빌린-2의 소단위를 각각 포함하는‘Stab-U1', ‘Stab-U2', ‘Stab-U3' 및 ‘Stab-U4'로 명명된 재조합 단백질을 제조하였고, 상기 스태빌린-2의 각 소단위에 존재하는 EGF-유사 도메인의 반복 부위(EGFrp)만을 각각 포함하는 'E1', ‘E2', ‘E3', ‘E4'로 명명된 재조합 단백질을 제조하였으며, 상기 스태빌린-2의 세 번째 소단위(Stab-U3)에 존재하는 FAS-1 도메인(F5)만을 포함하는 ‘F5' 로 명명되는 재조합 단백질을 제조하였다. As a result, a recombinant protein named 'Stab-U1', 'Stab-U2', 'Stab-U3' and 'Stab-U4' each containing the subunit of Stabilin-2 was prepared. Recombinant proteins named 'E1', 'E2', 'E3', and 'E4', each containing only the repetition site (EGFrp) of the EGF-like domain present in each subunit of, were prepared. A recombinant protein named 'F5' containing only the FAS-1 domain (F5) present in the third subunit (Stab-U3) was prepared.
<실시예 2><Example 2>
스태빌린-2 내에 포스파티딜세린(phosphatidylserine, PS)의 인식 부위 동정Identification of the recognition site of phosphatidylserine (PS) in stabilin-2
<2-1> 스태빌린-2의 소단위를 포함하는 재조합 단백질에 의한 탐식 억제 효과<2-1> Phagocytosis inhibitory effect by recombinant protein containing subunit of Stabilin-2
상기 <실시예 1-2>에서 스태빌린-2(stabilin-2)를 이용하여 제조된 재조합 단백질(Stab-U1, Stab-U2, Stab-U3 및 Stab-U4)이 탐식 활성이 있는 L/Stab-2 세포(Park, S.Y. et al., Cell Death Differ. 2008, 15:192-201)에 의한 노화된 적혈구의 탐식을 억제하는지 여부를 조사하였다(Park, S.Y. et al., Cell Death Differ. 2008, 15:192-201).The recombinant protein (Stab-U1, Stab-U2, Stab-U3, and Stab-U4) prepared using Stabilin-2 in <Example 1-2> has L / Stab having phagocytic activity Whether or not the inhibition of senescence of aged red blood cells by -2 cells (Park, SY et al., Cell Death Differ. 2008, 15: 192-201) was investigated (Park, SY et al., Cell Death Differ. 2008) , 15: 192-201).
구체적으로, 먼저 정상 성인에서 채혈한 정상 적혈구를 헤마토크릿 20%가 되도록 인산완충용액(PBS, phosphate buffered saline)으로 희석한 후 37℃에서 4일간 배양함으로써 노화된 적혈구 세포를 제조하고, 상기 <실시예 1-2>에서 제조된 각각의 재조합 단백질(Stab-U1, Stab-U2, Stab-U3 및 Stab-U4)을 헤마토크릿 1%의 상기 노화된 적혈구와 37℃에서 1시간 동안 전배양하였다. 이때 대조군으로 pET43.1벡터에 의해 만들어지는 Nus단백질을 상기 노화된 적혈구와 상기와 같이 전배양한 것을 사용하였다. 상기 전배양 후 L/Stab-2 세포를 첨가하고 37℃에서 1시간 동안 추가 배양하였다. 상기 배양이 완료된 후 L/Stab-2 세포와 결합하지 않은 적혈구를 제거하고, 인산완충용액으로 세포를 5회 세척한 후 물로 10초간 처리하여 탐식되지 않고 결합되어 있는 적혈구를 모두 용해시켰다. 상기 용해시킨 후 L/Stab-2 세포를 디프 퀵 염색용 킷트(Diff quick staining kit, IMEM Ins., San Marcos, CA, 미국)를 사용하여 제조사의 지침에 따라 염색하여 관찰한 사진을 도 3에 게재하였으며, 임의로 선택한 5군데에서 적혈구를 탐식한 세포의 수를 계수한 다음, 전체 L/Stab-2 세포 중에서 상기 적혈구를 탐식한 세포의 수를 백분율로 나타내어 탐식지표(%)를 계산하고 그 결과를 도 2에 나타내었다.Specifically, first, the normal red blood cells collected from normal adults were diluted with phosphate buffered solution (PBS, phosphate buffered saline) to 20% hematocrit, and then aged cells were prepared by culturing at 37 ° C. for 4 days. Recombinant proteins (Stab-U1, Stab-U2, Stab-U3 and Stab-U4) prepared in 1-2> were preincubated with
그 결과, 도 2 및 도 3에 나타낸 바와 같이, L/Stab-2 세포를 상기 스태빌린-2의 4개의 소단위로 구성된 재조합 단백질과 전배양한 경우, 노화된 적혈구의 탐식이 크게 저해됨을 알 수 있었으며, 이에 비해 대조군인 Nus단백질과 전배양한 경우는 전배양을 하지 않은 것과 마찬가지로 노화된 적혈구의 탐식에 큰 영향을 주지 않음을 알 수 있었다. 상기 결과로부터, 노화된 적혈구의 포스파티딜세린과 상호 작용하여 탐식에 관여하는 모티프는 네 개의 소단위에 모두 존재한다는 것을 확인하였다.As a result, as shown in Figures 2 and 3, when the L / Statab-2 cells pre-cultured with the recombinant protein consisting of the four subunits of the Stabilin-2, it can be seen that the phagocytosis of aged erythrocytes is significantly inhibited In contrast, the pre-culture with the control group Nus protein did not significantly affect the phagocytosis of aged erythrocytes, as did the pre-culture. From the above results, it was confirmed that the motifs involved in phagocytosis by interacting with phosphatidylserine of aged red blood cells are present in all four subunits.
<2-2> 스태빌린-2의 EGF-유사 도메인의 반복 부위(EGFrp)를 포함하는 재조합 단백질에 의한 탐식 억제 효과<2-2> Inhibition of phagocytosis by recombinant protein comprising repeat region (EGFrp) of EGF-like domain of Stabilin-2
상기 <실시예 2-1>과 같이 스태빌린-2에서 포스파티딜세린과 상호 작용하는 모티프를 좀 더 구체적으로 동정하기 위하여, 상기 <실시예 1-2>에서 스태빌린-2를 이용하여 제조된 재조합 단백질 중 세 번째 소단위에 대한 재조합 단백질(Stab-U3) 및 결실 재조합 단백질(E3, F5)이 탐식 활성이 있는지 여부를 추가 확인하였다.In order to more specifically identify the motif interacting with phosphatidylserine in Stabilin-2 as in <Example 2-1>, the recombinant prepared using Stabilin-2 in <Example 1-2> It was further confirmed whether the recombinant protein (Stab-U3) and the deleted recombinant protein (E3, F5) for the third subunit of the protein had phagocytic activity.
구체적으로 각각의 재조합 단백질(Stab-U3, E3, F5)을 각각 0.1, 1 및 10㎍의 농도로 하여 사멸 세포와 전배양한 후, 상기 재조합 단백질이 L/Stab-2 세포에 의한 사멸 세포의 탐식을 억제하는지 여부를 확인하였다. 이 때 상기 사멸 세포는 RPM-I1640 배지(10% 소 태아 혈청이 함유)에서 배양된 인간 백혈병 Jurkat T 세포(한국 세포주 은행)를 항-Fas 항체(CH-11) 100ng/㎎가 첨가된 배지에 접종하여 6시간 동안 배양함으로써 사멸을 유도하여 제조된 세포를 말하며(Oka, K. et al., Proc Natl Acad Sci USA, 95:9535-40, 1998), L/Stab-2 세포를 염색하기 위하여 아넥신-V 아폽토시스 디텍션 키트(Annexin V Apoptosis detection kit, Santa Cruz)를 사용하였으며, 그 외 상기 실험 방법은 상기 <실시예 2-1>과 동일하게 진행한 후 그 결과를 도 4 및 도 5에 나타내었다.Specifically, each recombinant protein (Stab-U3, E3, F5) is pre-incubated with the dead cells at concentrations of 0.1, 1, and 10 µg, respectively, and then the recombinant protein is separated from the dead cells by L / Stab-2 cells. It was confirmed whether or not to inhibit the eating. At this time, the dead cells were cultured in RPM-I1640 medium (containing 10% fetal bovine serum). Human leukemia Jurkat T cells (Korea Cell Line Bank) were added to a medium to which 100ng / mg of anti-Fas antibody (CH-11) was added. Refers to cells prepared by inducing death by incubating for 6 hours by inoculation (Oka, K. et al., Proc Natl Acad Sci USA , 95: 9535-40, 1998), to stain L / Stab-2 cells Annexin-V Apoptosis Detection Kit (Santa Cruz) was used, and the experimental method was performed in the same manner as in <Example 2-1>, and the results are shown in FIGS. 4 and 5. Indicated.
그 결과, 도 4 및 도 5에 나타낸 바와 같이, EGF-유사 도메인의 반복 부위(EGFrp)가 포함된 Stab-U3과 E3 단백질이 사멸세포의 탐식을 농도 의존적으로 저해함을 알 수 있었다. 상기 결과로부터 사멸세포의 포스파티딜세린과 상호 작용하여 탐식에 관여하는 모티프는 EGF-유사 도메인의 반복 부위(EGFrp)에 존재한다는 것을 확인하였다.As a result, as shown in Figures 4 and 5, it can be seen that Stab-U3 and E3 protein containing the repeat site (EGFrp) of the EGF-like domain inhibits the phagocytosis of the dead cells in a concentration-dependent manner. From the above results, it was confirmed that a motif involved in phagocytosis by interacting with phosphatidylserine of apoptotic cells is present at the repeating site (EGFrp) of the EGF-like domain.
한편 다른 소단위에서의 EGF-유사 도메인의 반복 부위(EGFrp)도 같은 효과를 보이는지 확인하기 위해, 상기 <실시예 1-2>에서 제조된 재조합 단백질(E1, E2 및 E4)에 대해서도 상기 <실시예 2-1>와 동일한 실험을 수행하고 그 결과를 도 6에 기재하였다.On the other hand, in order to confirm whether the repetition site (EGFrp) of the EGF-like domain in another subunit exhibits the same effect, the recombinant example (E1, E2 and E4) prepared in Example 1-2 may be used in the above <Example 2-1> the same experiment was carried out and the results are shown in FIG.
그 결과, 도 6에 나타낸 바와 같이, EGF-유사 도메인의 반복 부위(EGFrp)만을 포함하는 재조합 단백질들(E1, E2, E3 및 E4)이 모두 노화된 적혈구의 탐식을 농도 의존적으로 저해하는 것을 알 수 있었다. 상기 결과로부터 결국 노화된 적혈구 또는 사멸세포의 포스파티딜세린과 상호 작용하여 탐식에 관여하는 모티프는 EGF-유사 도메인의 반복 부위(EGFrp)에 존재한다는 것을 확인하였다. 즉 노화된 적혈구 및 사멸세포의 탐식은 재조합 단백질의 EGF-유사 도메인의 반복 부위(EGFrp)에 의해 경쟁적으로 억제됨을 알 수 있었으며, 이러한 결과는 스태빌린-2의 세포외 부분에 존재하는 EGF-유사 도메인의 반복 부위들이 노화된 적혈구 및 사멸세포의 인식을 매개한다는 사실을 알 수 있었다.As a result, as shown in FIG. 6, it was found that all of the recombinant proteins (E1, E2, E3 and E4) including only the repetition site (EGFrp) of the EGF-like domain all concentration-dependently inhibit the aging of aged red blood cells. Could. From the above results, it was confirmed that the motif involved in phagocytosis by interacting with phosphatidylserine of aged erythrocytes or apoptosis cells is present at the repeating site (EGFrp) of the EGF-like domain. In other words, it was found that phagocytosis of aged erythrocytes and apoptotic cells was competitively inhibited by the repetition site (EGFrp) of the EGF-like domain of the recombinant protein, and this result was EGF-like in the extracellular portion of Stabilin-2. It was found that repeat sites in the domain mediate the recognition of aged red blood cells and dead cells.
<2-3> 스태빌린-2의 EGF-유사 도메인의 반복 부위(EGFrp)를 포함하는 재조합 단백질과 포스파티딜세린과의 직접적 결합 확인<2-3> Confirmation of Direct Binding of Phosphatidylserine with Recombinant Protein Containing Repeating Site (EGFrp) of EGF-Like Domain of Stabilin-2
상기 <실시예 1-2>에서 제조된 재조합 단백질이 포스파티딜세린과 직접적으로 결합하는지 여부를 확인하기 위하여, 포스파티딜세린을 메탄올에 녹여서 3㎍/㎖의 농도로 만든 다음, ELISA 플레이트에 첨가한 후 공기 중으로 메탄올이 증발할 때까지 실온에 놓아두었다. 이 후 비특이적인 결합을 억제하기 위해 2% BSA(bovine serum albumin)를 각 웰에 추가하여 1시간 동안 실온에서 배양한 다음, 상기 <실시예 1-2>에서 제조된 Stab-U3, E3 및 F5, 그리고 대조군으로 Nus 단백질을 추가하여 1시간 동안 실온에서 추가 배양하였다. 상기 배양이 끝난 후 결합하지 않은 단백질을 인산완충용액으로 제거하고, 웰에 있는 포스파티딜세린에 결합한 단백질은 페록시다아제(peroxidase)가 붙어 있는 항-His 항체를 첨가하여 1시간동안 둔 후 과산화수소수와 o-페닐렌디아민(o-phenylenediamine)이 들어있는 발색시약을 첨가함으로써 <실시예 1-2>에서 제조된 재조합 단백질과 포스파티딜세린의 결합정도를 확인하고 그 결과를 도 7에 나타내었다.In order to confirm whether the recombinant protein prepared in Example 1-2 directly binds to phosphatidylserine, phosphatidylserine is dissolved in methanol to make a concentration of 3 µg / ml, and then added to an ELISA plate, followed by air. It was left at room temperature until methanol evaporated. Then, in order to inhibit nonspecific binding, 2% bovine serum albumin (BSA) was added to each well and incubated at room temperature for 1 hour, followed by Stab-U3, E3, and F5 prepared in Example 1-2. And, as a control, Nus protein was added and further incubated for 1 hour at room temperature. After the incubation, the unbound protein was removed with a phosphate buffer solution, and the protein bound to phosphatidylserine in the well was left for 1 hour by the addition of an anti-His antibody with peroxidase, followed by hydrogen peroxide solution. And by adding a coloring reagent containing o-phenylenediamine (o-phenylenediamine) was confirmed the binding degree of the recombinant protein prepared in <Example 1-2> and phosphatidylserine and the results are shown in FIG.
그 결과, 도 7에 나타낸 바와 같이, 상기 <실시예 2-2>의 실험결과와 동일하게 EGF-유사 도메인의 반복 부위(EGFrp)가 포함되어 있는 Stab-U3 및 E3 단백질이 포스파티딜세린과 직접적으로 결합함을 알 수 있었다.As a result, as shown in FIG. 7, Stab-U3 and E3 proteins containing the repeating site (EGFrp) of the EGF-like domain, as in the experimental results of <Example 2-2>, directly with phosphatidylserine Could be combined.
한편, 스태빌린-2에 존재하는 EGF-유사 도메인의 반복 부위(EGFrp)가 선택적으로 포스파티딜세린과 직접적으로 결합하는지를 알아보기 위하여, 상기와 동일한 ELISA 플레이트에 포스파티딜세린(PS), 포스파티딜콜린(PC), 포스파티딜이노시톨(PI), 포스파티딜에탄올라민(PE)를 코팅한 후에 상기 <실시예 1-2>에서 제조된 E3 단배질을 추가하여 상기와 동일한 실험을 진행하고 그 결과를 도 8에 기재하였다.On the other hand, to determine whether the repeat site (EGFrp) of the EGF-like domain present in Stabilin-2 selectively binds directly to phosphatidylserine, phosphatidylserine (PS), phosphatidylcholine (PC), After coating phosphatidylinositol (PI) and phosphatidyl ethanolamine (PE), the same experiment as above was performed by adding the E3 protein prepared in Example 1-2, and the results are shown in FIG. 8.
그 결과, 도 8에 나타낸 바와 같이, EGF-유사 도메인의 반복 부위(EGFrp)가 선택적으로 포스파티딜세린과 직접적으로 결합함을 알 수 있었다.As a result, as shown in Figure 8, it was found that the repeat site (EGFrp) of the EGF-like domain selectively binds directly to phosphatidylserine.
<실시예 3><Example 3>
스태빌린-2의 EGF-유사 도메인의 반복 부위만을 포함하는 재조합 단백질의 cDNA의 클로닝Cloning of cDNA of Recombinant Proteins Containing Only Repeat Sites of the EGF-Like Domain of Stabilin-2
<3-1> 발현벡터의 제조<3-1> Preparation of Expression Vector
EGF-유사 도메인의 반복 부위(EGFrp)가 실제로 세포 표면에서 사멸세포의 표면에 존재하는 포스파티딜세린을 인식하는지를 알아보기 위해 먼저 스태빌린-2의 세포외 부분을 세 번째 EGF-유사 도메인의 반복 부위(EGFrp)로 치환시킨 단백질(도 9 참조)을 발현시키기 위한 발현벡터를 제조하였다.To determine if the repeat site (EGFrp) of the EGF-like domain actually recognizes phosphatidylserine that is present on the surface of apoptotic cells at the cell surface, first the extracellular portion of Stabilin-2 is referred to as the repeat site of the third EGF-like domain ( An expression vector was prepared to express a protein (see FIG. 9) substituted with EGFrp).
우선 스태빌린-2의 신호 펩티드 부위에 해당하는 cDNA를 얻기 위해서, 스태빌린-2 cDNA를 포함하는 발현벡터를 주형으로 하고 하기 표 3에 나타난 프라이머(서열번호 15 및 서열번호 16)를 사용하여 중합효소연쇄반응(polymerase chain reaction, PCR)을 수행하였다. 구체적으로 상기 PCR 반응은 Pfu DNA 중합효소(Promega)를 사용하여 95℃에서 2분간 반응시킨 후 94℃에서 1 분, 55℃에서 30초, 72℃에서 1 분 동안의 반응을 35회 반복하여 수행하였다. 상기 PCR 결과 증폭된 산물을 NheI 및 XhoI(TaKaRa) 제한효소로 절단한 다음, pcDNA3.1/Myc-His(Invitrogen) 벡터의 동일한 제한효소 자리에 T4 리가제(ligase, Invitrogen)를 사용하여 삽입함으로써 재조합 벡터 ‘pcDNA-S'를 제조하였다.First, in order to obtain cDNA corresponding to the signal peptide region of Stabilin-2, an expression vector containing Stabilin-2 cDNA was used as a template, and the primers (SEQ ID NO: 15 and SEQ ID NO: 16) shown in Table 3 below were used. A polymerase chain reaction (PCR) was performed. Specifically, the PCR reaction was performed by using Pfu DNA polymerase (Promega) for 2 minutes at 95 ° C. and then repeating the reaction 35 times for 1 minute at 94 ° C., 30 seconds at 55 ° C., and 1 minute at 72 ° C. It was. The product amplified by the PCR was digested with NheI and XhoI (TaKaRa) restriction enzymes, and then inserted into the same restriction enzyme site of the pcDNA3.1 / Myc-His (Invitrogen) vector using T4 ligase (Invitrogen). Recombinant vector 'pcDNA-S' was prepared.
한편, 스태빌린-2의 막횡단부위와 세포내부위를 포함하는 cDNA를 얻기 위해서 스태빌린-2의 발현벡터를 주형으로 하고 하기 표 3에 나타난 프라이머(서열번호 17 및 서열번호 18)를 사용하여 상기와 동일한 중합효소연쇄반응(polymerase chain reaction, PCR)을 수행하였다. 상기 PCR 결과 증폭된 산물을 BamHI 및 HindIII(TaKaRa) 제한효소로 절단한 다음, 상기 pcDNA-S 벡터의 상기 제한효소 자리에 T4 리가제(ligase, Invitrogen)를 사용하여 삽입함으로써 재조합 벡터‘pcDNA-S-TMC'을 제조하였다.On the other hand, in order to obtain cDNA containing the transmembrane and intracellular site of Stabilin-2 as a template, the expression vector of Stabilin-2 was used as a template, and the primers shown in Table 3 (SEQ ID NO: 17 and SEQ ID NO: 18) were used. The same polymerase chain reaction (PCR) was performed. The product amplified by the PCR was digested with BamHI and HindIII (TaKaRa) restriction enzymes, and then inserted into the restriction enzyme site of the pcDNA-S vector using a T4 ligase (Invitrogen) to recombinant vector'pcDNA-S. -TMC 'was prepared.
또한 스태빌린-2의 EGF-유사 도메인의 반복 부위(EGFrp)에 해당하는 cDNA를 얻기 위해서 스태빌린-2의 발현벡터를 주형으로 하고 하기 표 3에 나타난 프라이머(서열번호 19 내지 서열번호 20)를 사용하여 상기 <실시예 1-1>와 동일한 중합효소연쇄반응(polymerase chain reaction, PCR)을 수행하였다. 상기 PCR 결과 증폭된 산물을 XhoI 및 BamHI(TaKaRa) 제한효소로 절단한 다음, 상기의 pcDNA-S-TMC 벡터의 동일한 제한효소 자리에 T4 리가제(ligase, Invitrogen)를 사용하여 삽입함으로써 스태빌린-2의 세포외 부분을 세 번째 EGF-유사 도메인의 반복 부위(EGFrp)로 치환시킨 재조합 벡터를 완성하였으며, 이를 ‘pcDNA-EGF3'라 명명하였다.In addition, in order to obtain a cDNA corresponding to the repeat site (EGFrp) of the EGF-like domain of Stabilin-2, the expression vector of Stabilin-2 was used as a template, and the primers shown in Table 3 (SEQ ID NOs: 19 to 20) were used. Using the same polymerase chain reaction (PCR) as in <Example 1-1>. The product amplified by the PCR was digested with XhoI and BamHI (TaKaRa) restriction enzymes, and then inserted into the same restriction enzyme site of the pcDNA-S-TMC vector using T4 ligase (Invitrogen) to stabilize the Stabilin- The recombinant vector was replaced by replacing the extracellular portion of 2 with the repeat site (EGFrp) of the third EGF-like domain, which was named 'pcDNA-EGF3'.
상기에서 제조된 플라스미드를 염기서열 분석기(Applied Biosystems AB13700)에서 분석하여 올바르게 클로닝이 되었는지를 확인하였다(결과미도시). The plasmids prepared above were analyzed in a sequencing analyzer (Applied Biosystems AB13700) to confirm that they were correctly cloned (results not shown).
<3-2> L 세포의 형질전환<3-2> Transformation of L Cells
상기 <실시예 3-1>에서 제조된 발현 벡터 pcDNA-EGF3로 마우스 섬유아세포인 L 세포(ATCC CCL-1, 동경대학의 생물물리학과 다케치 박사로부터 제공받음)를 형질전환하였다. 구체적으로 상기 L 세포를 10% 열불활성화 FBS(fetal bovine serum), 페니실린G 및 스트렙토마이신이 첨가된 DMEM(Dulbecco's modified Eagle's medium) 배지에서 배양하고 상기에서 선택된 L 세포를 재조합 벡터 pcDNA-EGF3로 형질전환하기 위하여 리포펙타민(Lipofectamine)을 사용하였으며 제조자가 지시하는 방법에 따라 형질전환하였다. 상기 형질전환한 후 36시간에 G418(400㎍/㎖)을 처리하여 10 내지 12일 동안 배양하면서 저항성을 나타내는 각각의 콜로니를 분리하였다. 상기와 같은 방법으로 형질전환된 세포를 ‘L/EGF3’로 명명하였으며, 음성 대조군으로는 EGF3 유전자가 포함되지 않은 벡터인 pcDNA3.1(-)/Myc-His로 형질전환된 세포를 사용하였으며 이를 ‘L/Mock’으로 명명하였다. The expression vector pcDNA-EGF3 prepared in <Example 3-1> was transformed into L cells (ATCC CCL-1, provided by Dr. Takechi, Department of Biophysics, University of Tokyo), which are mouse fibroblasts. Specifically, the L cells were cultured in DMEM (Dulbecco's modified Eagle's medium) medium containing 10% heat-inactivated fetal bovine serum (FBS), penicillin G and streptomycin, and the L cells selected above were transformed with recombinant vector pcDNA-EGF3. Lipofectamine was used for the transformation and transformed according to the manufacturer's instructions. 36 hours after the transformation, each colony exhibiting resistance was isolated by incubating for 10 to 12 days with G418 (400 µg / ml). The cells transformed in the above manner were named 'L / EGF3', and as the negative control, cells transformed with pcDNA3.1 (-) / Myc-His, which are vectors containing no EGF3 gene, were used. Named 'L / Mock'.
<3-3> 세포 표면에서 <3-3> at the cell surface EGF3EGF3 의 발현 여부 확인The expression of
상기 실시예 <3-2>에 제조된 L/EGF3 세포 표면에서 EGF3이 발현되는지를 확인하기 위하여, EGF3을 인식하는 단클론 항체(5G3)를 이용하여 유세포 분석기(flow cytometry)로 분석하였다.In order to confirm whether EGF3 is expressed on the L / EGF3 cell surface prepared in Example <3-2>, it was analyzed by flow cytometry using a monoclonal antibody (5G3) that recognizes EGF3.
구체적으로 상기 L/EGF3 세포를 DMEM(Dulbecco's modified Eagle's medium) 배지가 포함된 플레이트에서 완전히 배양(confluent)한 다음, 상기 플레이트에 0.25% 트립신과 0.05% EDTA를 함유하는 인산완충용액을 처리하여 플레이트 표면으로부터 세포를 분리하였다. 상기 분리된 세포를 인산완충용액으로 2회 세척한 후 다시 인산완충용액에 재현탁한 후, 스태빌린-2 단클론 항체(5G3)를 첨가하여 4℃에서 1시간 동안 배양하였다. 상기 배양물에 10㎍/㎖의 FITC(fluorescein isothiocyanate)와 결합된 이차 항-마우스 면역글로불린 G(Santa Cruz Biotechnology, Inc., CA)를 첨가하여 4℃에서 1시간 동안 추가 배양하였다. 상기 배양한 후, 5-와트 레이저가 장착된 유세포 분석기(Becton Dickinson, San Jose, CA)를 이용하여 488nm에서 분석하였으며 이때 대조군으로는 스태빌린-2 단클론 항체 대신 이와 아형이 일치하는 마우스 면역글로불린(IgG1)을 사용하였으며 그 결과를 도 10에 나타내었다.Specifically, the L / EGF3 cells were completely confluent in a plate containing DMEM (Dulbecco's modified Eagle's medium) medium, and then treated with a phosphate buffer solution containing 0.25% trypsin and 0.05% EDTA on the plate surface. Cells were isolated from. The separated cells were washed twice with phosphate buffer solution and then resuspended in phosphate buffer solution, and then added with Stabilin-2 monoclonal antibody (5G3) and incubated at 4 ° C. for 1 hour. Secondary anti-mouse immunoglobulin G (Santa Cruz Biotechnology, Inc., CA) coupled with 10 μg / ml of fluorescein isothiocyanate (FITC) was added to the culture and further incubated at 4 ° C. for 1 hour. After incubation, the cells were analyzed at 488 nm using a 5-watt laser-equipped flow cytometer (Becton Dickinson, San Jose, Calif.), In which a mouse immunoglobulin (subtype-matched subtype) instead of the Stabilin-2 monoclonal antibody was used as a control IgG1) was used and the results are shown in FIG.
그 결과, 도 10에 나타낸 바와 같이, L/EGF3 세포의 표면에 EGF3가 발현됨을 확인할 수 있었으며, 반면 L/Mock 세포의 표면에는 EGF3가 발현되지 않음을 알 수 있었다. 또한 스태빌린-2 단클론 항체 대신 마우스 면역글로불린을 사용한 경우에도 EGF3의 발현은 검출되지 않았다.As a result, as shown in Figure 10, it was confirmed that EGF3 is expressed on the surface of the L / EGF3 cells, while it was found that EGF3 is not expressed on the surface of the L / Mock cells. In addition, expression of EGF3 was not detected even when mouse immunoglobulins were used instead of the Stabilin-2 monoclonal antibody.
<< 실시예Example 4> 4>
스태빌린Stabilin -2의 -2 EGFEGF -유사 도메인의 반복 부위의 Of repeat regions of the analogous domain 포스파티딜세린의Phosphatidylserine 인식 및 이로 인한 노화된 적혈구의 부착 및 탐식 Recognition and the Attachment and Phagocytosis of Aged Red Blood Cells
<4-1> L/<4-1> L / EGF3EGF3 세포에 의한 By cell 포스파티딜세린의Phosphatidylserine 인식 recognition
L/EGF3 세포가 포스파티딜세린을 인식하는지 여부를 확인하기 위하여, 포스파티딜콜린 리포좀과 포스파티딜세린 리포좀에 대한 L/EGF3 세포의 부착 활성을 조사하였다.To determine whether L / EGF3 cells recognize phosphatidylserine, the adhesion activity of L / EGF3 cells to phosphatidylcholine liposomes and phosphatidylserine liposomes was examined.
구체적으로 포스파티딜콜린(phosphatidlycholine, PC) 또는 포스파티딜세린(phosphatidlyserine, PS)을 포함하는 리포좀을 공지된 방법을 이용하여 제조하였다(Oka, K. et al., Proc . Natl . Acad . Sci . USA. 95:9535-9540, 1998; Fadok, V. A. et al., Nature 405:85-90, 2000). 보다 구체적으로 포스파티딜세린:포스파티딜콜린을 각각 50:50의 몰 비율로 혼합하여 리포좀(이하 ‘포스파티딜세린 리포좀’이라 함)을 제조하고, 포스파티딜콜린만을 포함하는 리포좀(이하 ‘포스파티딜콜린 리포좀’이라 함)을 제조하였다. 상기 제조된 리포좀 혼합물을 클로로포름과 혼합하고 질소 기체 하에서 건조시킨 다음 최종 농도가 5mM이 되도록 인산완충용액에 재현탁하여 얼음 위에서 10분간 초음파 처리하였다. 또한 상기 리포좀 제조시 총 인지질에 대해 1% 농도의 N-(lissamin rhodamine B sulfonyl)-L-α-포스파티딜에탄올아민(Avanti Polar Lipids)을 첨가하여 형광 표지된 인지질 리포좀을 제조하였다.Specifically liposomes comprising phosphatidlycholine (PC) or phosphatidlyserine (PS) were prepared using known methods (Oka, K. et al., Proc . Natl . Acad . Sci . USA. 95: 9535-9540, 1998; Fadok, VA et al., Nature 405: 85-90, 2000). More specifically, phosphatidylserine: phosphatidylcholine was mixed at a molar ratio of 50:50, respectively, to prepare liposomes (hereinafter referred to as 'phosphatidylserine liposomes'), and liposomes containing only phosphatidylcholine (hereinafter referred to as 'phosphatidylcholine liposomes'). . The prepared liposome mixture was mixed with chloroform, dried under nitrogen gas, resuspended in phosphate buffer solution to a final concentration of 5 mM, and sonicated on ice for 10 minutes. In addition, the liposomes were prepared with fluorescently labeled phospholipid liposomes by adding 1% N- (lissamin rhodamine B sulfonyl) -L-α-phosphatidylethanolamine (Avanti Polar Lipids) to total phospholipids.
상기 <실시예 3-2>에 제조된 L/EGF3 세포를 DMEM 배지에서 완전히 배양한 후, 상기 제조된 여러 종류의 인지질 리포좀을 각각 0, 10, 100μM씩 첨가하고 37℃에서 1시간 동안 배양하였다. 배양이 완료된 후 인산완충용액으로 충분히 세척하고 L/EGF3에 대한 인지질 리포좀의 부착 정도를 유세포 분석기(Becton Dickinson, San Jose, CA)를 이용하여 분석하고 그 결과를 도 11에 나타내었다.After fully culturing the L / EGF3 cells prepared in <Example 3-2> in DMEM medium, various phospholipid liposomes prepared above were added to each of 0, 10, and 100 μM and incubated at 37 ° C. for 1 hour. . After the incubation was completed, the phosphate buffer solution was sufficiently washed and the degree of adhesion of phospholipid liposomes to L / EGF3 was analyzed using a flow cytometer (Becton Dickinson, San Jose, Calif.) And the results are shown in FIG. 11.
그 결과, 도 11에 나타낸 바와 같이, L/EGF3 세포는 포스파티딜세린 리포좀을 더 많이 첨가함에 따라 포스파티딜세린 리포좀과의 결합은 증가하였지만, 포스파티딜콜린 리포좀과는 고농도에서도 결합을 하지 않음을 알 수 있었다.As a result, as shown in FIG. 11, L / EGF3 cells were found to increase binding to phosphatidylserine liposomes by adding more phosphatidylserine liposomes, but did not bind to phosphatidylcholine liposomes even at high concentrations.
<4-2> <4-2> 스태빌린Stabilin -2의 -2 EGFEGF -유사 도메인의 반복 부위에 의한 By repeat regions of the analogous domain 포스파티딜세린의Phosphatidylserine 인식 recognition
스태빌린-2의 EGF-유사 도메인의 반복 부위(EGFrp)가 포스파티딜세린을 인식하는지를 알아보기 위해 하기와 같은 세포부착실험을 시행하였다.In order to determine whether the repeat region (EGFrp) of the EGF-like domain of Stabilin-2 recognizes phosphatidylserine, the following cell adhesion experiment was performed.
구체적으로 ELISA 플레이트에 포스파티딜세린과 대조군으로 포스파티딜콜린을 0.1, 1, 10, 100μM의 농도로 상기 <실시예2-3>와 동일한 방법으로 코팅하고, L/stab-2 및 상기 <실시예 3-2>에서 제조된 L/EGF3, 및 L/Mock 세포를 각 웰에 104개를 첨가하고 1시간 동안 배양하였다. 배양한 후, 인산완충액을 이용하여 플레이트 표면에 코팅된 포스포지질과 결합하지 않은 세포들을 제거한 후에 90㎕의 반응 완충액을 첨가하여 1시간동안 추가 배양하였다. 상기 추가 배양한 후, 60㎕의 중지 완충액을 첨가하여 발색반응을 중지시킨 다음 마이크로 플레이트 리더(BioRad)를 사용하여 405nm에서 흡광도를 측정하여 그 결과를 도 12에 나타내었다.Specifically, phosphatidylserine and phosphatidylcholine as a control group were coated on an ELISA plate at the concentrations of 0.1, 1, 10, and 100 μM in the same manner as in <Example 2-3>, L / stab-2 and <Example 3-2. L / EGF3 prepared in>, and L / Mock cells were added 10 4 to each well and incubated for 1 hour. After incubation, the cells that did not bind phospholipids coated on the plate surface were removed using phosphate buffer, followed by further incubation for 1 hour by adding 90 µl of reaction buffer. After the further incubation, 60 μl of stop buffer was added to stop the color reaction, and then the absorbance was measured at 405 nm using a microplate reader (BioRad). The results are shown in FIG. 12.
그 결과, 도 12에 나타낸 바와 같이, 스태빌린-2의 EGF-유사 도메인의 반복 부위(EGFrp)가 존재하는 L/EGF3 세포 및 L/Stab-2 세포는 포스파티딜세린에 잘 부착되었으나, 대조군으로 사용된 L/Mock 세포는 포스파티딜세린에 부착되지 않았다. 한편 포스파티딜콜린에는 어떤 세포도 부착되지 않았다. 상기 결과로부터 스태빌린-2의 EGF-유사 도메인의 반복 부위(EGFrp)가 포스파티딜세린을 인식한다는 사실을 확인 할 수 있었다.As a result, as shown in FIG. 12, L / EGF3 cells and L / Stab-2 cells having a repeat site (EGFrp) of the EGF-like domain of Stabilin-2 adhered well to phosphatidylserine, but were used as a control. L / Mock cells did not attach to phosphatidylserine. Meanwhile, no cells were attached to phosphatidylcholine. From the above results, it was confirmed that the repeat region (EGFrp) of the EGF-like domain of Stabilin-2 recognizes phosphatidylserine.
<4-3> L/<4-3> L / EGF3EGF3 세포에 의한 노화된 적혈구의 부착 및 탐식 Attachment and Phagocytosis of Aged Red Blood Cells by Cells
상기 <실시예 3-2>에서 제조된 L/EGF3 세포에서 노화된 적혈구가 부착 및 탐식되는지 여부를 대조군인 L/Mock 세포와 비교하여 실험하였다.In the L / EGF3 cells prepared in <Example 3-2>, whether the aged red blood cells were attached and phagocytic were compared with the control L / Mock cells.
구체적으로 상기 <실시예2-1>과 동일한 방법으로 노화된 적혈구를 제조한 후, 상기 <실시예 3-2>에서 제조된 L/EGF3 세포와 L/Mock 세포를 각각 DMEM 배지가 포함된 6-웰 플레이트에서 완전히 배양한 후 노화된 적혈구를 최종 헤마토크릿 1%가 되도록 첨가하고 37℃에서 1시간 동안 추가 배양하였다. 상기 추가 배양 후, 배양액을 인산완충용액으로 5회 세척하고 광학현미경으로 노화된 적혈구 및 정상 적혈구의 부착 정도를 관찰하여 그 결과를 도 13에 나타내었다.Specifically, after the aging red blood cells were prepared in the same manner as in <Example 2-1>, the L / EGF3 cells and L / Mock cells prepared in <Example 3-2> were each prepared with DMEM medium. Aged erythrocytes were added to 1% final hematocrit after further incubation in well plates and further incubated for 1 hour at 37 ° C. After the further incubation, the culture solution was washed five times with phosphate buffer solution, and the adhesion degree of aged red blood cells and normal red blood cells was observed with an optical microscope, and the results are shown in FIG. 13.
또한 상기 실험 결과 임의로 선택한 100개의 L/EGF3 세포에 부착된 적혈구의 수를 계수하여 평균값을 구하고 탐식 분석을 위하여 상기 세포를 인산완충용액으로 세척한 다음 물로 10초간 처리하여 탐식되지 않은 세포를 모두 용해시킨 후, L/EGF3 세포를 디프 퀵 염색용 킷트(Diff quick staining kit, IMEM Ins., San Marcos, CA, USA)를 사용하여 염색하고, 임의로 선택한 5 군데에서 적혈구를 탐식한 세포의 수를 계수하였다. 상기 계수 결과를 토대로 부착 및 탐식지표(%)는 전체 L/EGF3 세포 중에서 적혈구를 부착 및 탐식한 세포의 수를 백분율로 나타내어 계산하고 그 결과를 도 14에 나타내었다.As a result of the experiment, the average value was obtained by counting the number of red blood cells attached to 100 randomly selected L / EGF3 cells, and the cells were washed with phosphate buffer solution for phagocytosis, and then treated with water for 10 seconds to dissolve all unproven cells. After staining, the L / EGF3 cells were stained using a Diff quick staining kit (IMEM Ins., San Marcos, Calif., USA), and the number of cells that phagocytized erythrocytes in five randomly selected cells was counted. It was. Based on the counting results, the adhesion and phagocytic index (%) was calculated by expressing the number of cells attached and phagocytic with red blood cells in percentage in total L / EGF3 cells and the results are shown in FIG. 14.
그 결과, 도 13 및 도 14에 나타낸 바와 같이, 노화된 적혈구가 L/EGF3 세포에 부착되지만 L/EGF3세포에 의해서 노화된 적혈구의 탐식은 일어나지 않음을 알 수 있었으며 대조군인 L/Mock 세포에는 노화된 적혈구의 부착 및 탐식 어느 것도 일어나지 않음을 알 수 있었다.As a result, as shown in Figure 13 and 14, the aging red blood cells attached to the L / EGF3 cells, but it can be seen that the phagocytosis of the aged erythrocytes by the L / EGF3 cells does not occur, the aging in the control L / Mock cells It was found that neither attachment nor phagocytosis of the red blood cells occurred.
<4-4> <4-4> 스태빌린Stabilin -2의 -2 EGFEGF -유사 도메인의 반복 부위에 의한 노화된 적혈구의 부착Attachment of Aged Red Blood Cells by Repeat Sites of Similar Domains
상기 <실시예 4-3>에서 L/EGF3 세포에 의한 노화된 적혈구의 부착이 EGF-유사 도메인의 반복 부위(EGFrp)에 의한 것임을 확인하기 위하여 추가 실험을 진행하였다. In <Example 4-3>, further experiments were conducted to confirm that the adhesion of aged red blood cells by L / EGF3 cells was due to the repetition site (EGFrp) of the EGF-like domain.
구체적으로 L/EGF3 세포를 포스파티딜세린 리포좀 또는 포스파티딜콜린 리포좀 100μM, 스태빌린-2 단클론 항체(5G3) 및 마우스 면역글로불린(IgG) 100㎍/㎖ 씩을 각각 첨가하고, 37℃에서 1시간 동안 배양한 후 노화된 적혈구를 추가 첨가한 후 상기 <실시예 4-3>과 동일한 방법으로 부착정도를 조사하여 그 결과를 도 15에 나타내었다.Specifically, 100 μM of phosphatidylserine liposomes or phosphatidylcholine liposomes, stabilin-2 monoclonal antibody (5G3), and 100 μg / ml of mouse immunoglobulin (IgG) were respectively added to the L / EGF3 cells, and cultured at 37 ° C. for 1 hour, followed by aging. After adding the added red blood cells, the degree of adhesion was examined in the same manner as in <Example 4-3>, and the results are shown in FIG. 15.
그 결과, 도 15에 나타낸 바와 같이, L/EGF3세포에 의한 노화된 적혈구의 부착은 포스파티딜세린 리포좀(PC)과 스태빌린-2 단클론 항체(mAb 5G3)에 의해 저해됨을 알 수 있었으며, 상기 결과로부터 EGF-유사 도메인의 반복 부위(EGFrp)가 세포표면에 발현되는 상황에서 노화된 적혈구의 선택적인 부착을 매개함을 알 수 있었다.As a result, as shown in Figure 15, the adhesion of aged red blood cells by L / EGF3 cells was found to be inhibited by phosphatidylserine liposomes (PC) and Stabilin-2 monoclonal antibody (mAb 5G3), from the results It was found that the repetition site (EGFrp) of the EGF-like domain mediates the selective attachment of aged red blood cells in the context of expression on the cell surface.
<< 실시예Example 5> 5>
스태빌린Stabilin -2의 -2 EGFEGF -유사 도메인의 반복 부위에 의한 사멸세포 탐식 억제 효과Effect of Inhibiting Apoptotic Cell Phagocytosis by Repeat Sites of Similar Domains
<5-1> 생체 외(<5-1> ex vivo ( inin vitroin vitro )에서 )in EGFEGF -유사 도메인의 반복 부위에 의한 노화된 적혈구의 탐식 억제 효과Inhibition of Phagocytosis of Aged Erythrocytes by Repeated Sites of Similar Domains
스태빌린-2의 EGF-유사 도메인의 반복 부위(EGFrp)가 생체 외에서 노화된 적혈구의 탐식을 저해할 수 있는지 여부를 알아보기 위하여, 먼저 정상 성인의 자발적 공여자로부터 혈액을 채취하고 상기 혈액에서 단핵세포를 분리한 다음 10% 사람 혈청이 포함된 X-비보 10(Bio Whitaker)에서 7일 정도 배양하여 대식세포로 분화시킴으로써 인간 단핵세포에서 유래한 대식세포(human monocyte-derived macrophage, HMDM)를 제조하였다. 상기 제조 후, 상기 <실시예 1-2>에서 제조된 재조합단백질 Stab-U3, E3 및 F5 그리고 상기 <실시예 4-1>에서 제조된 포스파티딜세린 리포좀 100μM을 각각 첨가하여 전배양하였다. 상기 전배양한 후, 노화된 적혈구를 첨가하여 37℃에서 1시간 동안 추가로 배양하고 배양이 완료된 다음 인산완충용액으로 5회 세척하여 상기 <실시예 2-1>과 동일한 방법으로 탐식지표(%)를 구하였으며 그 결과를 도 16에 나타내었다.To determine whether the repeat site (EGFrp) of the EGF-like domain of Stabilin-2 can inhibit phagocytosis of aged erythrocytes in vitro, first blood was drawn from a spontaneous donor of a normal adult and the monocytes from the blood. Human monocyte-derived macrophage (HMDM) derived from human monocytes was prepared by culturing for 7 days and then incubating in X-Vivo 10 (Bio Whitaker) containing 10% human serum to differentiate into macrophages. . After the preparation, the recombinant proteins Stab-U3, E3 and F5 prepared in <Example 1-2> and 100 μM of the phosphatidylserine liposomes prepared in <Example 4-1> were added and pre-cultured, respectively. After the pre-incubation, aged erythrocytes were added, and further cultured at 37 ° C. for 1 hour, and the culture was completed, and then washed five times with phosphate buffer solution in the same manner as in <Example 2-1>. ) And the results are shown in FIG.
그 결과, 상기 도 16에 나타낸 바와 같이, 상기 대식세포에 의한 노화된 적혈구의 탐식은 EGF-유사 도메인의 반복 부위(EGFrp)가 포함되어 있는 Stab-U3 및 E3 단백질에 의해서 저해되었으며, 상기의 저해효과는 포스파티딜세린 리포좀에 의한 것과 유사한 결과를 나타냄을 알 수 있었다.As a result, as shown in FIG. 16, phagocytosis of aged erythrocytes by the macrophages was inhibited by Stab-U3 and E3 proteins containing repeat sites (EGFrp) of the EGF-like domain. The effect was found to show a similar result to that by phosphatidylserine liposomes.
<5-2> <5-2> 생체 내(In vivo ( inin vivovivo )에서 )in EGFEGF -유사 도메인의 반복 부위에 의한 사멸세포 탐식 억제 효과Effect of Inhibiting Apoptotic Cell Phagocytosis by Repeat Sites of Similar Domains
스태빌린-2의 EGF-유사 도메인의 반복 부위(EGFrp)가 생체 내에서 자연사멸세포의 탐식을 저해할 수 있는지 여부를 알아보기 위하여, 다음과 같이 실시하였다. 먼저 쥐의 복강에 대식세포를 공지된 방법을 이용하여 유도하였으며(Taylor, P.R. et al., J Exp Med . 192: 359-366, 2000), 구체적으로 실험 4일 전에 쥐의 복강 내로 3% 티오글리콜레이트 4㎖을 주사하여 대식세포를 유도하였다.To determine whether the repeat site (EGFrp) of the EGF-like domain of Stabilin-2 can inhibit phagocytosis of natural killer cells in vivo, it was performed as follows. First, macrophages were induced in the abdominal cavity of rats using known methods (Taylor, PR et al., J Exp Med . 192: 359-366, 2000), specifically, macrophages were induced by injecting 4 ml of 3% thioglycolate into the abdominal cavity of
한편 사멸세포로 사용될 쥐의 흉선세포를 분리하기 위해 쥐의 흉선을 분리하여 가위와 포셉을 가지고 RPMI-1640 배지가 들어있는 플레이트 위에서 잘게 자른 다음, 하루가 경과한 후 세포 여과체(cell strainer, BD Falcon)로 조직을 여과하였다. 상기 여과 후 1500rpm에서 3분 동안 원심 분리하여 세포를 가라앉힌 다음, 인산완충용액을 사용하여 세포를 여러 번 씻어 주었다. 상기와 같이 분리된 흉선세포를 배지 100㎕에 1× 106개의 세포가 들어가게 준비한 다음, 형광시약인 CFSE(Carboxyfluorescein diacetate succinimidyl ester, Invitrogen)을 3㎕을 넣고 30분간 37℃에서 배양하여 염색하였다. 상기 염색 후, 흉선세포의 사멸을 유도하기 위해 1× 107개의 세포가 들어있는 10㎖의 배지(혈청이 첨가되어 있지 않음)에 1μM의 덱사메타손(dexamethasone)을 넣고 4시간 동안 37℃에서 배양하여 세포의 사멸을 유도하였다.On the other hand, in order to separate the thymus cells of the rats to be used as dead cells, the rat thymus was separated, chopped with scissors and forceps on a plate containing RPMI-1640 medium, and after one day, the cell strainer (BD) The tissue was filtered with Falcon). After filtration, the cells were allowed to settle by centrifugation at 1500 rpm for 3 minutes, and the cells were washed several times using phosphate buffer solution. The prepared thymic cells were prepared to include 1 × 10 6 cells in 100 μl of medium, and then 3 μl of CFSE (Carboxyfluorescein diacetate succinimidyl ester, Invitrogen), a fluorescent reagent, was incubated at 37 ° C. for 30 minutes and stained. After the staining, 1 μM of dexamethasone (dexamethasone) was added to 10 ml of medium containing no 1 × 10 7 cells (no serum was added) to induce thymic cell death and cultured at 37 ° C. for 4 hours. Cell death was induced.
상기 사멸이 유도된 흉선세포를 상기 <실시예 1-2>에서 제조된 E3 재조합 단백질 5μM과 30분 동안 상온에서 전배양 한 후, 세포와 결합하지 않은 단백질은 인산완충용액으로 제거하고 쥐의 복강 내로 주사기를 이용해서 상기 배양물을 주입하였다. 이 때 대조군으로는 Nus 단백질을 같은 시간 동안 전배양한 것을 사용하였다. 상기 주입 후 5, 15, 30분에 다시 복강에 인산완충용액 5 ㎖을 주입한 후 즉시 세척액(lavage)을 이용하여 복강 내의 세포를 분리한다. 상기 분리된 세포를 1500rpm에서 10분간 원심 분리하여 인산완충용액으로 여러 번 씻은 후 이를 다시 인산완충용액에 재현탁하였다. 상기 세포 현탁액에 Cy5.5가 결합되어 있는 항 Mac-1 항체를 첨가하여 4℃에서 1시간 동안 배양한 후 5-와트 레이저가 장착된 유세포 분석기(Becton Dickinson, San Jose, CA)를 이용하여 분석하여 그 결과를 도 17 및 도 18에 나타내었다.After killing the induced
그 결과, 도 17에 나타낸 바와 같이, 스태빌린-2의 EGF-유사 도메인의 반복 부위(EGFrp)가 포함된 E3 재조합 단백질로 전처치한 군의 경우 사멸세포 주입 후 5분에서 쥐 복강 내에 사멸세포를 탐식한 대식세포의 비율이 감소되었으며, 그 효과는 30분 동안 지속됨을 알 수 있었다. 또한 도 18에 나타낸 바와 같이, 탐식되지 않은 사멸세포의 비율 역시 E3 재조합 단백질로 전처리한 군의 경우 증가되었음을 알 수 있었다.As a result, as shown in FIG. 17, in the group pretreated with the E3 recombinant protein containing the repeat site (EGFrp) of the Stabilin-2 EGF-like domain, dead cells in the mouse abdominal cavity at 5 minutes after the injection of the dead cells The percentage of macrophages phagocytic was reduced, and the effect lasted for 30 minutes. In addition, as shown in Figure 18, it was found that the proportion of undeveloped dead cells was also increased in the group pretreated with E3 recombinant protein.
상기 결과로부터 생체 내 및 외에서 EGF-유사 도메인의 반복 부위(EGFrp)에 의하여 대식세포의 노화된 적혈구 또는 사멸세포에 대한 탐식을 억제하는 활성이 있음을 알 수 있었다.From the above results, it can be seen that there is an activity of inhibiting phagocytosis of macrophages to aged erythrocytes or dead cells by the repetition site (EGFrp) of EGF-like domain in vivo and ex vivo.
<< 실시예Example 6> 6>
EGFEGF -유사 도메인의 반복 부위에 의한 By repeat regions of the analogous domain 포스파티딜세린을Phosphatidylserine 인식하는 과정에서 칼슘의 효과 Effects of Calcium in the Recognition Process
<6-1> <6-1> 스태빌린Stabilin -2에 의한 노화된 적혈구의 탐식 과정에서 칼슘의 효과Effect of Calcium on Phagocytosis of Aged Red Blood Cells by -2
세포내에 포스파티딜세린과 결합하는 단백질들은 칼슘 이온에 의존성 결합을 한다고 알려져 있어(Swairjo, M. A. et al., Nat Struct Biol, 2:968-74, 1995; Verdaguer, N. et al., Embo J, 18:6329-38, 1999), 이에 본 발명자들은 스태빌린-2에 의해 매개되는 탐식과정에서 칼슘의 효과를 조사하기 위하여 배지에 각각 칼슘을 0, 2, 5 및 10mM로 포함되도록 하여 상기 <실시예 2-1>과 동일한 방법을 이용하여 노화된 적혈구에 대한 탐식 정도를 측정하였고, 그 결과를 도 19에 나타내었다.Proteins that bind to phosphatidylserine are known to be dependent on calcium ions (Swairjo, MA et al., Nat Struct Biol , 2: 968-74, 1995; Verdaguer, N. et al., Embo J , 18: 6329-38, 1999), whereby the inventors of the present invention investigated the effect of calcium on the medium to investigate the effect of calcium on stabilin-2 mediated phagocytosis. , 5 and 10mM were measured to measure the degree of phagocytosis of aged erythrocytes using the same method as in Example 2-1, and the results are shown in FIG. 19.
그 결과, 도 19에 나타낸 바와 같이, 칼슘이 포함되지 않은 배지에서는 노화된 적혈구의 탐식은 거의 일어나지 않았으나, 칼슘이 2, 5 및 10mM로 포함되었을 때 탐식은 농도 의존적으로 증가하였다. 따라서 상기의 결과로부터 스태빌린-2에 의한 탐식과정은 칼슘 의존성 반응임을 알 수 있었다.As a result, as shown in FIG. 19, the aging of red blood cells was hardly observed in the medium containing no calcium, but the concentration increased depending on the concentration of 2, 5, and 10 mM calcium. Therefore, it can be seen from the results that the stabilization process by Stabilin-2 is a calcium-dependent reaction.
<6-2> <6-2> EGFEGF -유사 도메인의 반복 부위에 의한 By repeat regions of the analogous domain 포스파티딜세린을Phosphatidylserine 인식하는 과정에서 칼슘의 효과 Effects of Calcium in the Recognition Process
상기 <실시예 6-1>을 기초로 EGF-유사 도메인의 반복 부위(EGFrp)에 의한 포스파티딜세린을 인식하는 과정에서 칼슘이 관여하는지를 조사하였다.On the basis of the <Example 6-1> it was investigated whether calcium is involved in the process of recognizing phosphatidylserine by the repetition site (EGFrp) of the EGF-like domain.
구체적으로 클로로포름에 녹아있는 500㎍의 포스파티딜콜린과 포스파티딜콜린/포스파티딜세린(80/20)에 NBD-포스파티딜콜린과 NBD-포스파티딜세린(배합비:0.5mol%)을 혼합한 후, 클로로포름을 스피드백 건조기(Speed-Vac)를 사용하여 제거한 다음 300㎕의 인산완충용액에 현탁하고 초음파 분쇄기(10/50 duration cycle)로 3분 동안 분쇄하여 형광 리포좀을 제조하였다.Specifically, NBD-phosphatidylcholine and NBD-phosphatidylserine (mixture ratio: 0.5 mol%) are mixed with 500 µg of phosphatidylcholine and phosphatidylcholine / phosphatidylserine (80/20) dissolved in chloroform, and then chloroform is used for a speed-back dryer (Speed-Vac). ) And then suspended in 300 μl phosphate buffer solution and ground for 3 minutes in an ultrasonic grinder (10/50 duration cycle) to prepare a fluorescent liposome.
또한, Nus-tag이 포함되지 않은 EGF-유사 도메인의 반복 부위에 대한 재조합 단백질을 제조하기 위해 상기 실시예 <1-1>에서 사용된 스태빌린-2 cDNA를 포함하는 발현벡터를 주형으로 하고 하기 <표 4>의 서열번호 21 및 서열번호 22의 프라이머쌍을 이용하여 상기 실시예 <1-1>과 동일한 중합효소연쇄반응(polymerase chain reaction, PCR)을 수행하였다. 상기 수행결과, 증폭된 각각의 산물을 제한효소 BamHI 및 XhoI(TaKaRa)로 절단한 후, pET28a(Novagen) 벡터의 동일한 제한효소 자리에 T4 리가제(ligase, Invitrogen)를 사용하여 삽입함으로써 재조합 벡터 ‘pET-E3-16'를 제조하였다. 그 후, 상기 스태빌린-2의 세 번째 EGF-유사 도메인의 반복 부위(EGFrp)만을 각각 포함하는 ‘E3-16'으로 명명된 재조합 단백질을 제조하였다. In addition, an expression vector comprising Stabilin-2 cDNA used in Example <1-1> to prepare a recombinant protein for a repeating site of an EGF-like domain that does not contain a Nus-tag was used. The primer pairs of SEQ ID NO: 21 and SEQ ID NO: 22 of Table 4 are the same as in Example <1-1>. A polymerase chain reaction (PCR) was performed. As a result, each amplified product was digested with restriction enzymes BamHI and XhoI (TaKaRa), and then inserted into the same restriction enzyme site of the pET28a (Novagen) vector using T4 ligase (Invitrogen). pET-E3-16 'was prepared. Thereafter, a recombinant protein named 'E3-16' was prepared, each containing only the repeating site (EGFrp) of the third EGF-like domain of Stabilin-2.
상기 제조 후, E3-16 단백질을 0.0, 0.156, 0.032, 0.064, 0.126, 0.25, 0.5, 1μM의 농도로 500㎕의 반응액(50mM Hepes(pH 7.4), 100mM NaCl, 25mM KCl, 2.5mM CaCl2)에 넣고 2㎕의 상기 제조된 리포좀 용액을 혼합하여 형광 분광분석기(Perkin Elmer L55, excitation wavelength:460nm, excitation slits:5nm, emission slits:10nm)로 460nm에서 600nm까지 방출스펙트럼(emission spectrum)을 측정하고 그 결과를 도 20에 나타내었다.After the preparation, 500 μl of the reaction solution (50 mM Hepes (pH 7.4), 100 mM NaCl, 25 mM KCl, 2.5 mM CaCl 2 ) was prepared at a concentration of 0.0, 0.156, 0.032, 0.064, 0.126, 0.25, 0.5, 1 μM. ) And 2 μl of the prepared liposome solution were mixed to measure the emission spectrum from 460 nm to 600 nm with a fluorescence spectrometer (Perkin Elmer L55, excitation wavelength: 460 nm, excitation slits: 5 nm, emission slits: 10 nm). The results are shown in FIG. 20.
그 결과, 도 20에 나타낸 바와 같이, 상기 EGF-유사 도메인의 반복 부위만을 포함하는 E3 재조합 단백질은 포스파티딜콜린 리포좀 보다는 포스파티딜세린 리포좀에 상당히 많이 결합하는 것을 알 수 있었으며, 또한 반응액 내에 칼슘 킬레이터인 EGTA가 포함된 경우에는 포스파티딜세린 리포좀에 대한 결합이 저해되는 것을 알 수 있었다. 따라서 EGF-유사 도메인의 반복 부위에 의한 포스파티딜세린의 인식은 칼슘 의존성 반응임을 또한 알 수 있었다.As a result, as shown in FIG. 20, it was found that the E3 recombinant protein including only the repeating site of the EGF-like domain binds to phosphatidylserine liposome considerably more than phosphatidylcholine liposome, and also EGTA, which is a calcium chelator in the reaction solution. It was found that the binding to phosphatidylserine liposomes is inhibited. Thus, it was also found that the recognition of phosphatidylserine by the repeat site of the EGF-like domain was a calcium dependent response.
<< 실시예Example 7> 7>
EGFEGF -유사 도메인의 반복 -Repetition of similar domains 부위내에Within the site 포스파티딜세린과With phosphatidylserine 결합을 매개하는 모티프의 동정 Identification of motifs that mediate binding
<7-1> <7-1> EGFEGF -유사 도메인의 반복 부위를 이용한 C-말단 혹은 N-말단 결실 재조합 단백질의 제조Preparation of C-terminal or N-terminal Deletion Recombinant Protein Using Repeat Sites of Similar Domains
EGF-유사 도메인의 반복 부위(EGFrp)내에 사멸세포의 포스파티딜세린과 결합하는 모티프를 구체적으로 동정하기 위하여, 각 EGF-유사 도메인의 반복 부위(EGFrp)가 6개의 EGF-유사 도메인으로 이루어진 것을 알고(단, 네 번째 EGF-유사 도메인의 반복 부위는 5개의 EGF-유사 도메인으로 이루어짐.) EGF-유사 도메인의 반복 부위(EGFrp)를 이용하여 N-말단 혹은 C-말단이 결실된 재조합 단백질을 제조하였다. 구체적으로, 세 번째 EGF-유사 도메인의 반복 부위(EGFrp)에 존재하는 6개의 EGF-유사 도메인을 이용하여, 6개에서 1개까지 EGF-유사 도메인으로 구성된 C-말단 결실 재조합 단백질 또는 N-말단 결실 재조합 단백질을 다음과 같이 제조하였다(도 21 참조).In order to specifically identify motifs that bind to phosphatidylserine of apoptotic cells in the repeating site (EGFrp) of the EGF-like domain, it is known that the repeating site (EGFrp) of each EGF-like domain consists of 6 EGF-like domains ( However, the repetition site of the fourth EGF-like domain is composed of five EGF-like domains.) Using the repetition site (EGFrp) of the EGF-like domain, a recombinant protein having N- or C-terminal deletions was prepared. . Specifically, the C-terminal deletion recombinant protein or N-terminus consisting of 6 to 1 EGF-like domains, using 6 EGF-like domains present at the repeat site (EGFrp) of the third EGF-like domain. The deleted recombinant protein was prepared as follows (see FIG. 21).
먼저 5개에서 1개까지 EGF-유사 도메인으로 구성된 C-말단 결실 재조합 단백질을 위한 발현벡터를 제조하기 위해, 상기 실시예 <6-2>에서 사용된 pET-E3-16 발현벡터를 주형으로 하고 하기 서열번호 21 및 서열번호 23의 프라이머쌍(E3-15), 서열번호 21 및 서열번호 24의 프라이머쌍(E3-14), 서열번호 21 및 서열번호 25의 프라이머쌍(E3-13), 서열번호 21 및 서열번호 26의 프라이머쌍(E3-12) 및 서열번호 21 및 서열번호 27의 프라이머쌍(E3-1)(표 4 참조)을 이용하여 상기 <실시예 1-1>과 동일한 중합효소연쇄반응(polymerase chain reaction, PCR)을 수행하였다. 상기 수행결과, 증폭된 각각의 산물을 제한효소 BamHI 및 XhoI(TaKaRa)로 절단한 후, pET28a(Novagen) 벡터의 동일한 제한효소 자리에 T4 리가제(ligase, Invitrogen)를 사용하여 삽입함으로써 재조합 벡터 ‘pET-E3-15, ‘pET-E3-14', ‘pET-E3-13', ‘pET-E3-12', 및 ‘pET-E3-1'를 제조하였다.First, to prepare an expression vector for a C-terminal deletion recombinant protein composed of 5 to 1 EGF-like domains, the pET-E3-16 expression vector used in Example <6-2> was used as a template. The following primer pairs of SEQ ID NO: 21 and SEQ ID NO: 23 (E3-15), primer pairs of SEQ ID NO: 21 and SEQ ID NO: 24 (E3-14), primer pairs of SEQ ID NO: 21 and SEQ ID NO: 25 (E3-13), sequence The primer pair (E3-12) of SEQ ID NO: 21 and SEQ ID NO: 26 and the primer pair (E3-1) of SEQ ID NO: 21 and SEQ ID NO: 27 (see Table 4) are the same as those of <Example 1-1>. A polymerase chain reaction (PCR) was performed. As a result, each amplified product was digested with restriction enzymes BamHI and XhoI (TaKaRa), and then inserted into the same restriction enzyme site of the pET28a (Novagen) vector using T4 ligase (Invitrogen). pET-E3-15, 'pET-E3-14', 'pET-E3-13', 'pET-E3-12', and 'pET-E3-1' were prepared.
또한, 5개에서 1개까지 EGF-유사 도메인으로 구성된 N-말단 결실 재조합 단백질을 위한 발현벡터를 제조하기 위해, 서열번호 28 및 서열번호 22의 프라이머쌍(E3-26), 서열번호 29 및 서열번호 22의 프라이머쌍(E3-36), 서열번호 30 및 서열번호 22의 프라이머쌍(E3-46), 서열번호 31 및 서열번호 22의 프라이머쌍(E3-56) 및 서열번호 32 및 서열번호 22의 프라이머쌍(E3-6)(표 4 참조)를 이용하여 상기와 동일한 방법을 이용하였으며 그 결과 재조합 벡터 ‘pET-E3-26, ‘pET-E3-36', ‘pET-E3-46', ‘pET-E3-56', 및 ‘pET-E3-6'를 제조하였다.In addition, to prepare an expression vector for an N-terminal deletion recombinant protein consisting of 5 to 1 EGF-like domains, primer pairs of SEQ ID NO: 28 and SEQ ID NO: 22 (E3-26), SEQ ID NO: 29 and sequence Primer pair (E3-36) of SEQ ID NO: 22, primer pair (E3-46) of SEQ ID NO: 30 and SEQ ID NO: 22, primer pair (E3-56) of SEQ ID NO: 31 and SEQ ID NO: 22, and SEQ ID NO: 32 and SEQ ID NO: 22 Primer pairs (E3-6) (see Table 4) were used in the same manner as described above. As a result, the recombinant vectors' pET-E3-26, 'pET-E3-36', 'pET-E3-46', 'pET-E3-56', and 'pET-E3-6' were prepared.
상기의 발현벡터들을 이용하여 C-말단 결실 재조합 단백질 또는 N-말단 결실 재조합 단백질을 만들기 위하여, 상기 <실시예 1-2>와 동일한 방법을 이용하여 재조합 단백질을 분리 및 정제하였다. 상기와 같이 제조된 C-말단 결실 재조합 단백질들을 각각 ‘E3-15’, ‘E3-14’, ‘E3-13’, ‘E3-12’, ‘E3-1’로 명명하였으며, N-말단 단백질들을 각각 ‘E3-26’, ‘E3-36’, ‘E3-46’, ‘E3-56’, ‘E3-6’으로 명명하였다.In order to make a C-terminal deleted recombinant protein or N-terminal deleted recombinant protein using the expression vectors, the recombinant protein was isolated and purified using the same method as in <Example 1-2>. The C-terminal deletion recombinant proteins prepared as described above were named 'E3-15', 'E3-14', 'E3-13', 'E3-12', and 'E3-1', respectively, and the N-terminal protein. They were named 'E3-26', 'E3-36', 'E3-46', 'E3-56' and 'E3-6', respectively.
<7-2> <7-2> EGFEGF -유사 도메인의 반복 부위 내에 Within the repeat region of the pseudo domain 포스파티딜세린과With phosphatidylserine 결합을 매개하는 모티프의 동정 Identification of motifs that mediate binding
상기 실시예 <6-2>에서 제조된 E6-16 및 실시예 <7-1>에서 제조된 결실 재조합단백질과 포스파티딜세린과의 결합을 알아보기 위해, 상기 실시예 <6-2>에서처럼 NBD-포스파티딜콜린 및 NBD-포스파티딜세린을 이용한 형광의 소멸효과를 관찰하여 그 결과를 도 22 및 도 23에 나타내었다.In order to examine the binding of the deleted recombinant protein prepared in Example <6-2> and Example <7-1> with phosphatidylserine, as in Example <6-2>, NBD- The quenching effect of fluorescence using phosphatidylcholine and NBD-phosphatidylserine was observed and the results are shown in FIGS. 22 and 23.
그 결과, 도 22에 나타낸 바와 같이, C-말단 결실 단백질들을 사용한 실험에서는 야생형(wild-type)인 E3-16을 비롯하여 E3-15, E3-14 재조합 단백질이 포스파티딜세린과 잘 결합함을 알 수 있었다. 따라서 포스파티딜세린에 잘 결합하기 위해서는 4개 이상의 EGF-유사 도메인이 필요함을 알 수 있었다. As a result, as shown in Fig. 22, in the experiment using the C-terminal deletion proteins, it can be seen that E3-15 and E3-14 recombinant proteins including wild-type E3-16 bind well with phosphatidylserine. there was. Therefore, it can be seen that more than four EGF-like domains are required for binding to phosphatidylserine.
또한, 도 23에 나타낸 바와 같이, N-말단 결실 단백질들을 사용한 실험에서는 야생형(wild-type)인 E3-16과 E-26 재조합 단백질만이 포스파티딜세린과 잘 결합함을 알 수 있었다. 따라서 비정형(atypical) EGF-유사 도메인이 포스파티딜세린과의 결합에 중요한 역할을 함을 알 수 있었다.In addition, as shown in FIG. 23, in the experiment using N-terminal deletion proteins, only wild-type E3-16 and E-26 recombinant proteins were found to bind well with phosphatidylserine. Therefore, it was found that the atypical EGF-like domain plays an important role in binding to phosphatidylserine.
한편, 상기 <실시예7-1>에서 제조된 결실 재조합단백질을 이용하여 상기 <실시예2-1>과 동일한 방법으로 노화된 적혈구에 대한 탐식 실험을 수행하고 그 결과를 도 24 및 도 25에 나타내었다.On the other hand, using the deletion recombinant protein prepared in <Example 7-1> by performing a phagocytic experiment for aging red blood cells in the same manner as in <Example 2-1> and the results are shown in Figures 24 and 25 Indicated.
그 결과, 도 24에 나타낸 바와 같이, C-말단 결실 재조합단백질 중에서는 4개 이상의 EGF-유사 도메인을 가지고 있는 E-16, E-15, E-14 재조합 단백질이 노화된 적혈구의 탐식을 억제하는 것으로 나타났으며, 또한 도 25에 나타낸 바와 같이, N-말단 결실 재조합단백질 중에서는 비정형(atypical) EGF-유사 도메인을 가지고 있는 E3-16과 E3-26 재조합 단백질만이 노화된 적혈구의 탐식을 억제하는 것으로 나타났다.As a result, as shown in FIG. 24, among the C-terminal deletion recombinant proteins, E-16, E-15, and E-14 recombinant proteins having four or more EGF-like domains inhibited phagocytosis of aged red blood cells. In addition, as shown in FIG. 25, among the N-terminal deletion recombinant proteins, only E3-16 and E3-26 recombinant proteins having atypical EGF-like domains inhibited phagocytosis of aged erythrocytes. Appeared to be.
따라서 상기 실험결과를 토대로 비정형(atypical) EGF-유사 도메인을 가지면서 4개 이상의 EGF-유사 도메인을 가지는 EGF-유사 도메인의 반복 부위(EGFrp)가 포스파티딜세린의 인식에 중요한 역할을 한다는 사실을 알 수 있었다.Therefore, based on the experimental results, it can be seen that the repeat region (EGFrp) of the EGF-like domain having at least four EGF-like domains with atypical EGF-like domains plays an important role in the recognition of phosphatidylserine. there was.
<7-3> 비정형(<7-3> Atypical ( atypicalatypical ) ) EGFEGF -유사 도메인이 결핍된 결실 재조합 단백질의 제조Preparation of deleted recombinant protein lacking similar domains
EGF-유사 도메인의 반복 부위(EGFrp)내에 어느 비정형(atypical) EGF-유사 도메인이 포스파티딜세린과의 상호작용에 중요하는지를 동정하기 위하여 비정형(atypical) EGF-유사 도메인이 결핍된 결실 재조합 단백질을 제조하였다.A deletion recombinant protein lacking an atypical EGF-like domain was prepared to identify which atypical EGF-like domain is important for interaction with phosphatidylserine in the repeat region (EGFrp) of the EGF-like domain. .
구체적으로 우선 세 번째 EGF-유사 도메인의 반복 부위(EGFrp)내에 첫 번째 비정형(atypical) EGF-유사 도메인이 결실되어 있으면서 4개의 EGF-유사 도메인으로 구성된 재조합 단백질(도 26의 E3-25)을 제조하기 위한 발현 벡터를 제조하기 위해, 상기 표 4에 기재된 프라이머(서열번호 28 및 서열번호 23)를 사용하고 상기 <실시예 7-1>과 동일한 방법을 이용하여 재조합 벡터 ‘pET-E3-25'를 제조하였다.Specifically, a recombinant protein consisting of four EGF-like domains (E3-25 in FIG. 26) was prepared, in which the first atypical EGF-like domain was deleted in the repeat region (EGFrp) of the third EGF-like domain. In order to prepare an expression vector for use, the recombinant vector 'pET-E3-25' was prepared using the primers set forth in Table 4 (SEQ ID NO: 28 and SEQ ID NO: 23) and the same method as in <Example 7-1>. Was prepared.
또한 두 번째 비정형(atypical) EGF-유사 도메인이 결실되어 있으면서 4개의 EGF-유사 도메인으로 구성된 재조합 단백질(도 26의 E3-15Δ2)을 제조하기 위한 발현 벡터를 제조하기 위해, 상기 표 4에 기재된 서열번호 21 및 서열번호 27의 프라이머쌍(첫 번째 EGF-유사 도메인을 증폭) 및 서열번호 23 및 서열번호 29의 프라이머쌍(세 번째 내지 다섯 번째 EGF-유사 도메인을 증폭)을 사용하여 각각 상기 <실시예 1-1>과 동일한 중합효소연쇄반응(polymerase chain reaction, PCR)을 수행하였다. 상기 수행결과, 증폭된 산물 중 첫 번째 EGF-유사 도메인을 제한효소 BamHI 및 EcoRI(TaKaRa)로 절단한 후, pET28a(Novagen) 벡터의 동일한 제한효소 자리에 T4 리가제(ligase, Invitrogen)를 사용하여 삽입한 다음, 증폭된 산물 중 세 번째 내지 다섯 번째 EGF-유사 도메인을 제한효소 EcoRI(TaKaRa) 및 XhoI(TaKaRa)로 절단한 후, pET28a(Novagen) 벡터의 동일한 제한효소 자리에 T4 리가제(ligase, Invitrogen)를 사용하여 삽입함으로써 재조합 벡터 ‘pET-E3-15△2'를 제조하였다.In addition, to prepare an expression vector for preparing a recombinant protein consisting of four EGF-like domains (E3-15Δ2 in FIG. 26), which is deleted from a second atypical EGF-like domain, the sequence described in Table 4 above. The primer pairs of SEQ ID NO: 21 and SEQ ID NO: 27 (amplifying the first EGF-like domain) and primer pairs of SEQ ID NO: 23 and SEQ ID NO: 29 (amplifying the third to fifth EGF-like domains), respectively, Same as Example 1-1> A polymerase chain reaction (PCR) was performed. As a result, the first EGF-like domain of the amplified product was digested with restriction enzymes BamHI and EcoRI (TaKaRa), and then T4 ligase (Invitrogen) was used in the same restriction enzyme site of pET28a (Novagen) vector. After insertion, the third to fifth EGF-like domains of the amplified products were cleaved with restriction enzymes EcoRI (TaKaRa) and XhoI (TaKaRa), and then T4 ligase in the same restriction enzyme site of the pET28a (Novagen) vector. , Invitrogen) to prepare a recombinant vector 'pET-E3-15Δ2'.
상기의 발현벡터들을 이용하여 상기 <실시예1-2>와 동일한 방법을 이용하여 재조합 단백질을 분리 및 정제하여, 세 번째 EGF-유사 도메인의 반복 부위(EGFrp)내에 첫 번째 비정형(atypical) EGF-유사 도메인이 결실된 재조합 단백질인 ‘E3-25’를 제조하였으며 두 번째 비정형(atypical) EGF-유사 도메인이 결실된 재조합 단백질인 ‘E3-15△2'를 제조하였다.By using the expression vectors described above, the recombinant protein was isolated and purified using the same method as in <Example 1-2>, and the first atypical EGF- in the repeat region (EGFrp) of the third EGF-like domain. 'E3-25', a recombinant protein lacking a similar domain, was prepared and 'E3-15Δ2', a recombinant protein lacking a second atypical EGF-like domain, was prepared.
<7-4> 비정형(<7-4> Atypical ( atypicalatypical ) ) EGFEGF -유사 도메인 중 -Of similar domains 포스파티딜세린과With phosphatidylserine 결합을 매개하는 모티프의 동정 Identification of motifs that mediate binding
EGF-유사 도메인의 반복 부위(EGFrp)내에 어떤 비정형(atypical) EGF-유사 도메인이 포스파티딜세린과의 결합에 중요한 역할을 하는지를 알아보기 위하여 C-말단 결실 단백질인 E3-14와 N-말단 결실 단백질인 E3-36과 더불어 실시예<7-3>에서 제조한 재조합 단백질인 E3-25 및 E3-15△2를 이용하여 포스파티딜세린과의 결합을 조사하여 비교하였다. 이 때 재조합 단백질의 크기에 의해 생기는 오류를 방지하기 위해 상기 4가지 단백질은 모두 EGF-유사 도메인이 4개로 구성된 것을 사용하였다(도 26 참조).To determine which atypical EGF-like domain plays an important role in binding to phosphatidylserine in the repeat region (EGFrp) of the EGF-like domain, the C-terminal deletion proteins E3-14 and N-terminal deletion proteins In addition to E3-36, the binding to phosphatidylserine was compared using the recombinant proteins E3-25 and E3-15Δ2 prepared in Example <7-3>. At this time, in order to prevent the error caused by the size of the recombinant protein, the four proteins were used that consists of four EGF-like domains (see Fig. 26).
먼저 상기 재조합 단백질에 대해 상기 <실시예 6-2>와 동일한 방법을 이용하여 NBD-포스파티딜콜린 및 NBD-포스파티딜세린을 사용한 형광의 감쇄효과를 관찰하고 그 결과를 도 27에 나타내었다. First, the attenuation effect of fluorescence using NBD-phosphatidylcholine and NBD-phosphatidylserine was observed for the recombinant protein using the same method as in Example 6-2, and the results are shown in FIG. 27.
그 결과, 도 27에 나타낸 바와 같이 두 번째 비정형(atypical) EGF-유사 도메인이 결실된 E3-15△2에서 포스파티딜세린에 대한 결합이 현저하게 감소됨을 알 수 있었다.As a result, as shown in Figure 27 it can be seen that the binding to phosphatidylserine is significantly reduced in E3-15Δ2 where the second atypical EGF-like domain is deleted.
또한, 두 번째 비정형(atypical) EGF-유사 도메인이 칼슘-의존성 반응에 관여하는지 알아보기 위해, NBD-포스파티딜세린을 사용한 형광의 감쇄효과를 관찰한 실험을 칼슘 킬레이터인 EGTA의 존재하에서 시행하였으며 그 결과를 Stern-Volmer law Fo/(Fo-F)=1/fa+1/(faK[Mt])에 따라 다이나믹 퀀칭 컨스턴트(dynamic quenching constant(K))로 도시하였다. 그 결과 EGTA가 첨가되었을때 PS와 함에 의한 반응성이 현저히 감소하는 것을 관찰하였다. In addition, to investigate whether the second atypical EGF-like domain is involved in calcium-dependent reactions, an experiment was conducted in the presence of calcium chelator EGTA to observe the attenuation effect of fluorescence using NBD-phosphatidylserine. The results are shown as dynamic quenching constants (K) according to Stern-Volmer law Fo / (Fo-F) = 1 / fa + 1 / (faK [Mt]). As a result, when EGTA was added, it was observed that the reactivity with PS was significantly decreased.
그 결과, 도 28에 나타낸 바와 같이 두 번째 비정형(atypical) EGF-유사 도메인이 포스파티딜세린과의 결합과 그것의 칼슘 의존성에 중요한 역할을 함을 알 수 있었다.As a result, as shown in FIG. 28, it was found that the second atypical EGF-like domain plays an important role in binding to phosphatidylserine and its calcium dependency.
또한 상기 재조합단백질을 이용하여 상기 <실시예2-1>과 동일한 방법으로 노화된 적혈구에 대한 탐식 실험을 수행하고 그 결과를 도 29에 나타내었다. 상기 도 29에 나타낸 바와 같이 두 번째 비정형(atypical) EGF-유사 도메인이 결실된 E3-15△2에서 노화된 적혈구의 탐식에 대한 억제 효과가 현저하게 감소됨을 알 수 있었다.In addition, by using the recombinant protein in the same manner as in <Example 2-1> was carried out a phagocytic experiment for aging red blood cells and the results are shown in Figure 29. As shown in FIG. 29, the inhibitory effect on the phagocytosis of aged erythrocytes was significantly reduced in E3-15Δ2 in which the second atypical EGF-like domain was deleted.
상기의 결과를 통하여 EGF-유사 도메인의 반복 부위(EGFrp)내에 두 번째 비정형(atypical) EGF-유사 도메인이 포스파티딜세린과의 결합에 중요한 역할을 한다는 사실을 알 수 있었다.The results showed that the second atypical EGF-like domain in the repeating site (EGFrp) of the EGF-like domain plays an important role in binding to phosphatidylserine.
이상 살펴본 바와 같이, 본 발명의 스태빌린-2(stabilin-2)의 EGF-유사 도메인의 반복부위(EGF-like domain repeat protein)에서 두 번째 비정형 EGF-유사 도메인 및 3개 이상의 EGF-유사도메인이 순차적으로 연결된 폴리펩티드는 세포 표면의 포스파티딜세린과 특이적으로 결합할 수 있다. 따라서, 본 발명은 포스파티딜세린을 세포 표면으로 발현하는 세포에 대한 약물 전달, 종양 세포에 대한 약물 또는 표지물질의 전달을 통한 종양성 질환의 예방, 치료 또는 영상화 등에 다양하게 사용될 수 있다.As described above, the second atypical EGF-like domain and three or more EGF-like domains in the EGF-like domain repeat protein of stabilin-2 of the present invention. Sequentially linked polypeptides can specifically bind phosphatidylserine on the cell surface. Therefore, the present invention can be used in various ways, such as drug delivery to cells expressing phosphatidylserine on the cell surface, prevention, treatment or imaging of tumor diseases through delivery of drugs or markers to tumor cells.
도 1은 인간 스태빌린(stabilin-2) 단백질의 각 도메인과 스태빌린-2 단백질에서 유래한 의 재조합단백질의 구조를 도시화한 모식도이다. 1 is a schematic diagram showing the structure of the recombinant protein of derived from each domain of the stabilin-2 protein and the Stabilin-2 protein.
(Stab-U1, Stab-U2, Stab-U3, Stab-U4: 스태빌린-2 단백질의 각각의 세포외 부분에 대한 재조합 단백질;(Stab-U1, Stab-U2, Stab-U3, Stab-U4: recombinant protein for each extracellular portion of Stabilin-2 protein;
E1, E2, E3, E4: 스태빌린-2 단백질의 EGF-유사 도메인의 반복 부분(EGFrp)에 대한 재조합 단백질;E1, E2, E3, E4: recombinant proteins for the repeat portion (EGFrp) of the EGF-like domain of Stabilin-2 protein;
F1, F2, F3, F4, F5, F6, F7: 스태빌린-2 단백질의 FAS1 도메인에 대한 재조합 단백질;F1, F2, F3, F4, F5, F6, F7: recombinant proteins for the FAS1 domain of Stabilin-2 protein;
짙게 채워진 오각형 : 비정형 EGFrp, 옅게 채워진 오각형 : 표준 EGFrp, 사각형 : FAS1 도메인)Heavily filled pentagram: atypical EGFrp, lightly filled pentagram: standard EGFrp, square: FAS1 domain)
도 2는 Stab-U1, Stab-U2, Stab-U3, Stab-U4이 가지는 노화된 적혈구의 탐식에 대한 효과를 나타낸 그래프이다.Figure 2 is a graph showing the effect on the phagocytosis of the aged red blood cells of Stab-U1, Stab-U2, Stab-U3, Stab-U4.
(None: 미처리군; Nus: Nus 단백질만 있는 것(대조군))(None: untreated; Nus: containing only Nus protein (control))
도 3은 L/Stab-2 세포에서 Stab-U1, Stab-U2, Stab-U3, Stab-U4의 존재 하에서의 자연 사멸세포(apoptotic cell)의 탐식 정도를 관찰한 사진이다.Figure 3 is a photograph showing the degree of phagocytosis of apoptotic cells (apoptotic cells) in the presence of Stab-U1, Stab-U2, Stab-U3, Stab-U4 in L / Stab-2 cells.
도 4는 세 번째 소단위(Stab-U3) 및 이들의 단편(E3, F5)의 양을 달리하여(0.1, 1, 10 μg) 전처치한 경우 노화된 적혈구의 탐식에 대해 미치는 효과를 나타낸 그래프이다.4 is a graph showing the effect on the phagocytosis of aged erythrocytes when pretreated with different amounts of the third subunit (Stab-U3) and their fragments (E3, F5) (0.1, 1, 10 μg). .
도 5는 세 번째 소단위(Stab-U3) 및 이들의 단편(E3, F5)의 사멸세포의 탐식 에 대한 효과를 나타낸 사진이다.Figure 5 is a photograph showing the effect on the phagocytosis of dead cells of the third subunit (Stab-U3) and fragments thereof (E3, F5).
도 6은 노화된 적혈구의 탐식에 대한 스태빌린-2 단백질 내의 4개의 EGF-유사 도메인의 반복 부분들(EGFrp; E1, E2, E3, E4)의 효과를 나타낸 그래프이다. FIG. 6 is a graph showing the effect of repeating portions (EGFrp; E1, E2, E3, E4) of four EGF-like domains in Stabilin-2 protein on phagocytosis of aged erythrocytes.
도 7은 포스파티딜세린과 세 번째 소단위(Stab-U3) 및 이들의 단편(E3, F5)의 결합력을 조사한 그래프이다.Figure 7 is a graph of the binding force of the phosphatidylserine and the third subunit (Stab-U3) and their fragments (E3, F5).
도 8은 여러 종류의 인지질과 E3 단편간의 결합력을 조사한 그래프이다.(PS: 포스파티딜세린; PC: 포스파티딜콜린; PE: 포스파티딜에탄올아민; PI: 포스파티딜이노시톨)FIG. 8 is a graph illustrating the binding force between various kinds of phospholipids and E3 fragments (PS: phosphatidylserine; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PI: phosphatidylinositol)
도 9는 인간 스태빌린-2 단백질의 세번째 EGF-유사도메인의 반복 부분이 세포표면에 발현되는 막 단백질(Stab-EGF3)의 구조를 도시화한 모식도이다.9 is a schematic diagram showing the structure of the membrane protein (Stab-EGF3) in which the repeating portion of the third EGF-like domain of the human Stabilin-2 protein is expressed on the cell surface.
도 10은 L/EGF3 세포에서 Stab-EGF3 단백질의 발현 여부를 스태빌린-2 단클론 항체를 이용하여 유세포 분석기로 분석한 결과이다.10 is a result of analyzing the expression of Stab-EGF3 protein in L / EGF3 cells by flow cytometry using a Stabilin-2 monoclonal antibody.
도 11은 L/EGF3 세포가 포스파티딜세린(PS) 리포좀에 결합하는 정도를 유세포 분석기로 분석한 결과이다.11 is a result of analyzing the extent of L / EGF3 cells to phosphatidylserine (PS) liposomes by flow cytometry.
도 12는 L/Stab-2 세포, L/EGF3세포, 및 L/Mock세포들이 포스파티딜세린에 대한 부착 정도를 나타낸 그래프이다.12 is a graph showing the degree of adhesion of L / Stab-2 cells, L / EGF3 cells, and L / Mock cells to phosphatidylserine.
도 13은 L/EGF3 세포에 의한 노화된 적혈구의 부착 정도를 L/Mock세포와 비교한 사진이다.Figure 13 is a photograph comparing the degree of adhesion of aged red blood cells by L / EGF3 cells and L / Mock cells.
도 14는 L/EGF3 세포에 의한 노화된 적혈구의 부착 및 탐식 정도를 L/Mock세포와 비교한 그래프이다.14 is a graph comparing the degree of adhesion and phagocytosis of aged erythrocytes by L / EGF3 cells with L / Mock cells.
도 15는 포스파티딜세린 또는 스태빌린-2 단클론 항체 및 PS리포좀에 의한 L/EGF3 세포의 노화된 적혈구의 부착억제 정도를 나타낸 그래프이다.15 is a graph showing the degree of inhibition of adhesion of aged erythrocytes of L / EGF3 cells by phosphatidylserine or stabilin-2 monoclonal antibody and PS liposomes.
(None: 아무것도 처리하지 않음; PS: 포스파티딜세린 리포좀; PC: 포스파티딜콜린 리포좀; mAb 5G3: 스태빌린-2 단클론 항체; Isotype cont Ab: 아형이 일치하는 마우스 면역글로불린)(None: nothing processed; PS: phosphatidylserine liposomes; PC: phosphatidylcholine liposomes; mAb 5G3: Stabilin-2 monoclonal antibody; Isotype cont Ab: mouse immunoglobulin with matching subtypes)
도 16은 인간 단핵구에서 유래한 대식세포에 의한 노화된 적혈구의 탐식에 Stab-U3, E3, F5 단백질 및 포스파티딜세린 리포좀의 효과를 나타낸 그래프이다.16 is a graph showing the effects of Stab-U3, E3, F5 protein and phosphatidylserine liposomes on phagocytosis of aged erythrocytes by macrophages derived from human monocytes.
도 17은 동물모델에서 쥐 복강내의 대식세포에 의한 탐식작용에 E3 단편의 효과를 시간에 따라 나타낸 그래프이다.17 is a graph showing the effect of E3 fragments over time on phagocytosis by macrophages in rat intraperitoneal animals in an animal model.
도 18은 동물모델에서 쥐 복강내의 사멸세포의 제거에 E3 단편의 효과를 유세포 분석기로 분석한 결과이다. 18 is a result of analyzing the effect of the E3 fragment on the removal of dead cells in the rat abdominal cavity in the animal model by flow cytometry.
도 19는 L/Stab-2 세포에 의한 노화된 적혈구의 탐식에 대한 칼슘의 효과를 나타낸 그래프이다.19 is a graph showing the effect of calcium on phagocytosis of aged erythrocytes by L / Stab-2 cells.
도 20은 E3 단편과 포스파티딜세린과의 결합에 대한 칼슘의 영향을 NBD형광의 소멸을 이용해서 나타낸 그래프이다.20 is a graph showing the effect of calcium on the binding of E3 fragment and phosphatidylserine using the disappearance of NBD fluorescence.
도 21은 E3 단편의 N-말단 및 C-말단의 결손 단백질의 구조를 도시화한 모식도이다.Fig. 21 is a schematic diagram showing the structures of the N-terminal and C-terminal deleted proteins of the E3 fragment.
도 22는 E3 단편의 C-말단의 결손 단백질의 포스파티딜세린 리포좀에 대한 결합정도를 NBD형광의 소멸을 통해서 나타낸 그래프이다.Figure 22 is a graph showing the extent of binding of the E3 fragment to the phosphatidylserine liposome of the C-terminal deletion protein through the disappearance of NBD fluorescence.
도 23은 E3 단편의 N-말단의 결손 단백질의 포스파티딜세린 리포좀에 대한 결합 정도를 NBD형광소멸을 통해서 나타낸 그래프이다.Figure 23 is a graph showing the degree of binding of the N-terminal deletion protein of the E3 fragment to the phosphatidylserine liposome through NBD fluorescence extinction.
도 24는 L/Stab-2 세포에 의한 노화된 적혈구의 탐식에 대한 E3 단편의 C-말단 결손 단백질들의 효과를 나타낸 그래프이다.24 is a graph showing the effect of C-terminal defective proteins of the E3 fragment on phagocytosis of aged erythrocytes by L / Stab-2 cells.
도 25는 L/Stab-2 세포에 의한 노화된 적혈구의 탐식에 대한 E3 단편의 N-말단 결손 단백질들의 효과를 나타낸 그래프이다.25 is a graph showing the effect of N-terminal defective proteins of the E3 fragment on phagocytosis of aged erythrocytes by L / Stab-2 cells.
도 26은 4개의 EGF-유사 도메인으로 이루어진 EGFrp로서 비정형 EGF-유사 도메인이 결손된 재조합단백질의 구조를 도시화한 모식도이다.Fig. 26 is a schematic diagram showing the structure of a recombinant protein in which an atypical EGF-like domain is deleted as an EGFrp consisting of four EGF-like domains.
도 27은 비정형 EGF-유사 도메인이 결손된 EGFrp 단백질들의 포스파티딜세린 리포좀에 대한 결합 정도를 NBD형광의 소멸을 통해서 나타낸 그래프이다.Figure 27 is a graph showing the degree of binding of phosphatidylserine liposomes of EGFrp proteins lacking the atypical EGF-like domain through the disappearance of NBD fluorescence.
도 28은 비정형 EGF-유사 도메인이 결손된 EGFrp 단백질에 의한 NBD 형광의 소멸정도를 형광의 감소 비율[Fo/(Fo-F)]과 비례하는 K상수(dynamic quenching constant)로 나타낸 그래프이다.(K : K(dynamic quenching constant))FIG. 28 is a graph showing the disappearance of NBD fluorescence by EGFrp protein lacking an atypical EGF-like domain as a dynamic quenching constant proportional to the rate of fluorescence reduction [Fo / (Fo-F)]. K: K (dynamic quenching constant)
도 29는 L/Stab-2 세포에 의한 노화된 적혈구의 탐식에 비정형 EGF-유사 도메인이 결손된 EGFrp 단백질의 효과를 나타낸 그래프이다.29 is a graph showing the effect of EGFrp protein deficient in atypical EGF-like domains on phagocytosis of aged erythrocytes by L / Stab-2 cells.
<110> Kyungpook national university industry-academic cooperation foundation <120> Composition for drug delivery comprising the polypeptide fragment of EGF-like domain repeat protein of stabilin-2 and use thereof <130> NP08-0001 <160> 116 <170> KopatentIn 1.71 <210> 1 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Stab-U1 sense <400> 1 aaaaggatcc gtaggggttc gagattg 27 <210> 2 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> Stab-U1 antisense <400> 2 aaaactcgag tcagggagga atgagaac 28 <210> 3 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> Stab-U2 sense <400> 3 aaaaggatcc aactctgagc ccacag 26 <210> 4 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Stab-U2 antisense <400> 4 aaaactcgag tcactgaatt tccag 25 <210> 5 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Stab-U3 sense <400> 5 aaaaggatcc gagaagagga gatgc 25 <210> 6 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Stab-U3 antisense <400> 6 aaaactcgag tcaatcaatc agcagac 27 <210> 7 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> Stab-U4 sense <400> 7 aaaaggatcc aggtggagta aaccaaag 28 <210> 8 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> Stab-U4 antisense <400> 8 aaaactcgag tcagggtgct tttaaaggc 29 <210> 9 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> E1 antisense <400> 9 aaaaactcga gtcaataaca cgttaagcc 29 <210> 10 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> E2 antisense <400> 10 aaaaactcga gtcaatagca cagaaagcc 29 <210> 11 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> E3 antisense <400> 11 aaaaactcga gtcagcggca ggtaaatcc 29 <210> 12 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> E4 antisense <400> 12 aaaaactcga gtcactcaca gttcagccc 29 <210> 13 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> F5 sense <400> 13 aaaaggatcc actgtttttg cacc 24 <210> 14 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> F5 antisense <400> 14 aaaactcgag tcatttggga gatagcaa 28 <210> 15 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> signal sense <400> 15 aaaatgctag ctcagcctga caggtgc 27 <210> 16 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> signal antisense <400> 16 aaaatctcga gtcttgcctg ccctgtg 27 <210> 17 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> TMC sense <400> 17 aaaaaggatc cacccacact ggcttg 26 <210> 18 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> TMC antisense <400> 18 cccgtccaag cttgcacagt gtcct 25 <210> 19 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> EGF3 sense <400> 19 aaaacctcga gagatgtgat aataatgac 29 <210> 20 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> EGF3 antisense <400> 20 aaaaaggatc cgcggcaggt aaatcc 26 <210> 21 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> E3-16 sense <400> 21 aaaaaggatc cacgagagaa tgctgtgcc 29 <210> 22 <211> 31 <212> DNA <213> Artificial Sequence <220> <223> E3-16 antisense <400> 22 aaaactcgag tcagcggcag gtaaatccat c 31 <210> 23 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> E3-15 antisense <400> 23 gatctcgagt tatgtgcaga cctttccatc 30 <210> 24 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> E3-14 antisense <400> 24 gatctcgagt tacaggcaca caatgcc 27 <210> 25 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> E3-13 antisense <400> 25 gatctcgagt tatgtgcaga tggtccc 27 <210> 26 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> E3-12 antisense <400> 26 gatctcgagt taggttgcat tgtcac 26 <210> 27 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> E3-1 antisense <400> 27 gatctcgagt tagcaggctg tgccgc 26 <210> 28 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> E3-26 sense <400> 28 aaaaaggatc cgagacctgc accgag 26 <210> 29 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> E3-36 sense <400> 29 aaaaggatcc acagaagaca actgcaatg 29 <210> 30 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> E3-46 sense <400> 30 aaaaggatcc gcaatcaatg cctgtgag 28 <210> 31 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> E3-56 sense <400> 31 aaaaggatcc ggaatcaacc cgtgtttg 28 <210> 32 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> E3-6 sense <400> 32 aaaaggatcc ctcatcaatg tctgcttaac 30 <210> 33 <211> 1770 <212> DNA <213> Homo sapiens <400> 33 gtaggggttc gagattgcag gtacaccttt gaggtcagaa catactctct gtctctcccc 60 ggatgccgcc atatttgtag gaaggactat ctccaacctc ggtgttgtcc tggccgctgg 120 ggcccagact gtatagagtg cccaggtgga gcggggtcac cctgcaatgg cagaggcagt 180 tgtgctgaag gcatggaagg aaatggaacc tgctcctgcc aagaagggtt tggtggaaca 240 gcctgtgaaa cctgtgctga cgacaactta tttggaccca gctgttcatc agtgtgcaac 300 tgtgtgcatg gggtgtgcaa cagtggacta gatggcgatg gaacctgtga gtgctactct 360 gcgtacactg gccccaagtg tgacaagccc atccctgaat gtgcagcctt gctctgccca 420 gaaaattcca gatgttcgcc ttccactgaa gatgaaaaca aactggaatg caaatgcctt 480 cccaattacc gaggcgatgg caaatactgc gaccccatca atccatgttt acgaaaaatc 540 tgccaccctc atgctcattg tacgtacctg ggaccaaatc ggcacagttg tacatgccaa 600 gaaggctacc gtggggatgg ccaagtgtgc ttgcctgtgg acccctgcca aattaacttt 660 ggaaactgcc ctacaaagtc tacagtgtgc aaatatgatg ggcctggaca gtctcactgc 720 gagtgtaagg agcattacca gaatttcgta cctggagtgg ggtgcagtat gactgatata 780 tgtaaatcag ataacccgtg tcataggaat gcaaattgca ccaccgtcgc accaggccga 840 actgaatgca tttgccagaa aggttacgtg ggtgatggct taacgtgtta tggaaacatt 900 atggagcgac tcagagaatt aaatactgaa cccagaggaa aatggcaagg aaggctgacc 960 tctttcatct cactcctaga caaagcttat gcctggccac tgagtaagct gggacccttc 1020 acggtgctgt tacctacaga caagggactg aaaggattca atgtaaatga gcttttggtg 1080 gataataaag ctgctcaata ctttgtgaaa ctccacataa ttgctggtca gatgaacatc 1140 gaatatatga ataacacaga catgttctac accttgactg gaaagtcggg ggaaatcttc 1200 aacagcgata aggacaatca aataaagctt aaactccatg gaggcaaaaa gaaggtaaaa 1260 attatacaag gggacatcat tgcttccaat gggcttctgc acatccttga cagagccatg 1320 gacaagttag aacccacatt tgagagcaac aatgagcaaa ccataatgac aatgctacaa 1380 ccaaggtaca gcaagttcag atctttgtta gaggaaacca atttgggaca tgccttagat 1440 gaggatggag ttggtggacc atacaccatt tttgttccaa ataatgaagc attgaataac 1500 atgaaggacg gcactctcga ttacctcctt tctccagagg gatctcggaa gcttctggaa 1560 ctcgtcagat accacattgt cccatttacc cagcttgaag tggccactct catctccacc 1620 cctcacatca ggagcatggc caaccagctc atacagttca acaccaccga caatggacag 1680 attctggcaa atgatgtggc aatggaagaa attgagatca ctgccaaaaa tggccgaatt 1740 tacacactga caggagttct cattcctccc 1770 <210> 34 <211> 1734 <212> DNA <213> Homo sapiens <400> 34 aactctgagc ccacagcact cttcacacac agatgtgtct acagtggcag gtttgggagc 60 ctgaagagcg gctgtgcccg gtactgcaat gccactgtga agattccaaa gtgctgcaaa 120 ggcttctatg gacctgactg caaccagtgt ccaggaggct tctcaaatcc atgctcagga 180 aatggacagt gtgcagatag cctcggcggc aacgggacat gcatttgtga ggagggcttc 240 caaggctccc agtgtcagtt ctgctctgat cccaataaat acggacctcg gtgtaacaaa 300 aaatgcctgt gcgttcacgg aacatgcaat aacaggatag acagcgatgg ggcctgcctc 360 actggcacat gcagagacgg ctctgccggg agactctgtg ataagcagac ctcagcctgt 420 gggccctacg tgcagttctg tcacatccac gccacctgtg aatacagcaa tgggacagcc 480 agttgtattt gcaaagcagg atatgaagga gatggaactc tgtgttctga gatggaccct 540 tgcacaggac taactccagg aggctgtagc cgcaatgcag aatgcatcaa aactggcacg 600 ggcacccaca cctgcgtgtg tcagcagggt tggacaggga atgggagaga ctgctcggag 660 atcaacaact gcctgctgcc cagtgcaggc ggctgccacg acaacgcatc ctgtttgtat 720 gtgggtcccg ggcagaatga gtgtgagtgc aagaaaggat ttcgaggaaa tgggattgac 780 tgtgaaccaa taacttcatg cttggaacaa accgggaaat gtcatccatt ggcaagctgt 840 caatctactt cgtctggtgt ctggagctgt gtttgtcaag agggctatga aggagatggc 900 tttctgtgct atggaaacgc agcagtggaa ttgtcatttc tctccgaagc agctatattt 960 aaccgatgga taaataatgc ttctctacaa cccacactgt cagccacctc aaacctcact 1020 gtcctcgtgc cttcccaaca agctactgag gacatggacc aggatgagaa aagcttctgg 1080 ttgtcacaga gcaatattcc agccctaata aagtaccata tgctactagg cacatacaga 1140 gtggcagatc tgcagaccct gtcttcttct gacatgttgg caacatcttt gcagggcaac 1200 ttccttcact tggcaaaggt ggatgggaat atcacaattg aaggggcctc cattgtcgat 1260 ggggacaacg cagccacaaa tggagtgata cacatcatca acaaggtgct ggtcccacaa 1320 agacgtctaa ctggctcctt accaaacctg ctcatgcggc tggaacagat gcctgactat 1380 tccatcttcc ggggctacat cattcaatat aatctggcga atgcaattga ggctgccgat 1440 gcctacacag tgtttgctcc aaacaacaat gccatcgaga attacatcag ggagaagaaa 1500 gtcttgtctc tagaggagga cgtcctccgg tatcatgtgg tcctggagga gaaactcctg 1560 aagaatgacc tgcacaatgg catgcatcgt gagaccatgc tgggtttctc ctatttcctt 1620 agcttctttc tccataatga ccagctctat gtaaatgagg ctccaataaa ctacaccaat 1680 gtagccactg ataagggagt gatccatggc ttgggaaaag ttctggaaat tcag 1734 <210> 35 <211> 1743 <212> DNA <213> Homo sapiens <400> 35 gagaagagga gatgcatcta tacctcctat ttcatgggaa gacgaaccct gtttattggg 60 tgccagccaa aatgtgtgag aaccgtcatt acgagagaat gctgtgccgg cttctttggc 120 ccccaatgcc agccctgccc agggaatgcc cagaatgtct gctttggtaa tggcatctgt 180 ttggatggag tgaatggcac aggtgtgtgt gagtgtgggg agggcttcag cggcacagcc 240 tgcgagacct gcaccgaggg caagtacggc atccactgtg accaagcatg ttcttgtgtc 300 catgggagat gcaaccaagg acccttggga gatggctcct gtgactgtga tgttggctgg 360 cgaggagtgc attgtgacaa tgcaaccaca gaagacaact gcaatgggac atgccatacc 420 agcgccaact gcctcaccaa ctcagatggt acagcttcat gcaagtgtgc agcaggattc 480 caaggaaacg ggaccatctg cacagcaatc aatgcctgtg agatcagcaa tggaggttgc 540 tctgccaagg ctgactgtaa gagaaccacc ccaggaaggc gagtgtgcac gtgcaaagca 600 ggctacacgg gtgatggcat tgtgtgcctg gaaatcaacc cgtgtttgga gaaccatggt 660 ggctgtgaca agaatgcgga gtgcacacag acaggaccca accaggctgc ctgtaactgt 720 ttgccagcat acactggaga tggaaaggtc tgcacactca tcaatgtctg cttaactaaa 780 aatggcggct gtagtgaatt tgccatctgc aaccacactg ggcaagtaga aaggacttgt 840 acttgcaagc caaactacat tggagatgga tttacctgcc gcggcagcat ttatcaggag 900 cttcccaaga acccgaaaac ttcccagtat ttcttccagt tgcaggagca tttcgtgaaa 960 gatctggtcg gcccaggccc cttcactgtt tttgcacctt tatctgcagc ctttgatgag 1020 gaagctcggg ttaaagactg ggacaaatac ggtttaatgc cccaggttct tcggtaccat 1080 gtggtcgcct gccaccagct gcttctggaa aacctgaaat tgatctcaaa tgctacttcc 1140 ctccaaggag agccaatagt catctccgtc tctcagagca cggtgtatat aaacaataag 1200 gctaagatca tatccagtga tatcatcagt actaatggga ttgttcatat catagacaaa 1260 ttgctatctc ccaaaaattt gcttatcact cccaaagaca actctggaag aattctgcaa 1320 aatcttacga ctttggcaac aaacaatggc tacatcaaat ttagcaactt aatacaggac 1380 tcaggtttgc tgagtgtcat caccgatccc atccacaccc cagtcactct cttctggccc 1440 accgaccaag ccctccatgc cctacctgct gaacaacagg acttcctgtt caaccaagac 1500 aacaaggaca agctgaagga gtatttgaag tttcatgtga tacgagatgc caaggtttta 1560 gctgtggatc ttcccacatc cactgcctgg aagaccctgc aaggttcaga gctgagtgtg 1620 aaatgtggag ctggcaggga catcggtgac ctctttctga atggccaaac ctgcagaatt 1680 gtgcagcggg agctcttgtt tgacctgggt gtggcctacg gcattgactg tctgctgatt 1740 gat 1743 <210> 36 <211> 1611 <212> DNA <213> Homo sapiens <400> 36 aggtggagta aaccaaaggg tgtgaagcag aagtgtctct acaacctgcc cttcaagagg 60 aacctggaag gctgccggga gcggtgcagc ctggtgatac agatccccag gtgctgcaag 120 ggctacttcg ggcgagactg tcaggcctgc cctggaggac cagatgcccc gtgtaataac 180 cggggtgtct gccttgatca gtactcggcc accggagagt gtaaatgcaa caccggcttc 240 aatgggacgg cgtgtgagat gtgctggccg gggagattcg ggcctgattg tctgccctgt 300 ggctgctcag accacggaca gtgcgatgat ggcatcacgg gctccgggca gtgcctctgt 360 gaaacggggt ggacaggccc ctcgtgtgac actcaggcag ttttgcctgc agtgtgtacg 420 cctccttgtt ctgctcatgc cacctgtaag gagaacaaca cgtgtgagtg taacctggat 480 tatgaaggtg acggaatcac atgcacagtt gtggatttct gcaaacagga caacgggggc 540 tgtgcaaagg tggccagatg ctcccagaag ggcacgaagg tctcctgcag ctgccagaag 600 ggatacaaag gggacgggca cagctgcaca gagatagacc cctgtgcaga cggccttaac 660 ggagggtgtc acgagcacgc cacctgtaag atgacaggcc cgggcaagca caagtgtgag 720 tgtaaaagtc actatgtcgg agatgggctg aactgtgagc cggagcagct gcccattgac 780 cgctgcttac aggacaatgg gcagtgccat gcagacgcca aatgtgtcga cctccacttc 840 caggatacca ctgttggggt gttccatcta cgctccccac tgggccagta taagctgacc 900 tttgacaaag ccagagaggc ctgtgccaac gaagctgcga ccatggcaac ctacaaccag 960 ctctcctatg cccagaaggc caagtaccac ctgtgctcag caggctggct ggagaccggg 1020 cgggttgcct accccacagc cttcgcctcc cagaactgtg gctctggtgt ggttgggata 1080 gtggactatg gacctagacc caacaagagt gaaatgtggg atgtcttctg ctatcggatg 1140 aaagatgtga actgcacctg caaggtgggc tatgtgggag atggcttctc atgcagtggg 1200 aacctgctgc aggtcctgat gtccttcccc tcactcacaa acttcctgac ggaagtgctg 1260 gcctattcca acagctcagc tcgaggccgt gcatttctag aacacctgac tgacctgtcc 1320 atccgcggca ccctctttgt gccacagaac agtgggctgg gggagaatga gaccttgtct 1380 gggcgggaca tcgagcacca cctcgccaat gtcagcatgt ttttctacaa tgaccttgtc 1440 aatggcacca ccctgcaaac gaggctggga agcaagctgc tcatcactgc cagccaggac 1500 ccactccaac cgacggagac caggtttgtt gatggaagag ccattctgca gtgggacatc 1560 tttgcctcca atgggatcat tcatgtcatt tccaggcctt taaaagcacc c 1611 <210> 37 <211> 891 <212> DNA <213> Homo sapiens <400> 37 gtaggggttc gagattgcag gtacaccttt gaggtcagaa catactctct gtctctcccc 60 ggatgccgcc atatttgtag gaaggactat ctccaacctc ggtgttgtcc tggccgctgg 120 ggcccagact gtatagagtg cccaggtgga gcggggtcac cctgcaatgg cagaggcagt 180 tgtgctgaag gcatggaagg aaatggaacc tgctcctgcc aagaagggtt tggtggaaca 240 gcctgtgaaa cctgtgctga cgacaactta tttggaccca gctgttcatc agtgtgcaac 300 tgtgtgcatg gggtgtgcaa cagtggacta gatggcgatg gaacctgtga gtgctactct 360 gcgtacactg gccccaagtg tgacaagccc atccctgaat gtgcagcctt gctctgccca 420 gaaaattcca gatgttcgcc ttccactgaa gatgaaaaca aactggaatg caaatgcctt 480 cccaattacc gaggcgatgg caaatactgc gaccccatca atccatgttt acgaaaaatc 540 tgccaccctc atgctcattg tacgtacctg ggaccaaatc ggcacagttg tacatgccaa 600 gaaggctacc gtggggatgg ccaagtgtgc ttgcctgtgg acccctgcca aattaacttt 660 ggaaactgcc ctacaaagtc tacagtgtgc aaatatgatg ggcctggaca gtctcactgc 720 gagtgtaagg agcattacca gaatttcgta cctggagtgg ggtgcagtat gactgatata 780 tgtaaatcag ataacccgtg tcataggaat gcaaattgca ccaccgtcgc accaggccga 840 actgaatgca tttgccagaa aggttacgtg ggtgatggct taacgtgtta t 891 <210> 38 <211> 912 <212> DNA <213> Homo sapiens <400> 38 aactctgagc ccacagcact cttcacacac agatgtgtct acagtggcag gtttgggagc 60 ctgaagagcg gctgtgcccg gtactgcaat gccactgtga agattccaaa gtgctgcaaa 120 ggcttctatg gacctgactg caaccagtgt ccaggaggct tctcaaatcc atgctcagga 180 aatggacagt gtgcagatag cctcggcggc aacgggacat gcatttgtga ggagggcttc 240 caaggctccc agtgtcagtt ctgctctgat cccaataaat acggacctcg gtgtaacaaa 300 aaatgcctgt gcgttcacgg aacatgcaat aacaggatag acagcgatgg ggcctgcctc 360 actggcacat gcagagacgg ctctgccggg agactctgtg ataagcagac ctcagcctgt 420 gggccctacg tgcagttctg tcacatccac gccacctgtg aatacagcaa tgggacagcc 480 agttgtattt gcaaagcagg atatgaagga gatggaactc tgtgttctga gatggaccct 540 tgcacaggac taactccagg aggctgtagc cgcaatgcag aatgcatcaa aactggcacg 600 ggcacccaca cctgcgtgtg tcagcagggt tggacaggga atgggagaga ctgctcggag 660 atcaacaact gcctgctgcc cagtgcaggc ggctgccacg acaacgcatc ctgtttgtat 720 gtgggtcccg ggcagaatga gtgtgagtgc aagaaaggat ttcgaggaaa tgggattgac 780 tgtgaaccaa taacttcatg cttggaacaa accgggaaat gtcatccatt ggcaagctgt 840 caatctactt cgtctggtgt ctggagctgt gtttgtcaag agggctatga aggagatggc 900 tttctgtgct at 912 <210> 39 <211> 882 <212> DNA <213> Homo sapiens <400> 39 gagaagagga gatgcatcta tacctcctat ttcatgggaa gacgaaccct gtttattggg 60 tgccagccaa aatgtgtgag aaccgtcatt acgagagaat gctgtgccgg cttctttggc 120 ccccaatgcc agccctgccc agggaatgcc cagaatgtct gctttggtaa tggcatctgt 180 ttggatggag tgaatggcac aggtgtgtgt gagtgtgggg agggcttcag cggcacagcc 240 tgcgagacct gcaccgaggg caagtacggc atccactgtg accaagcatg ttcttgtgtc 300 catgggagat gcaaccaagg acccttggga gatggctcct gtgactgtga tgttggctgg 360 cgaggagtgc attgtgacaa tgcaaccaca gaagacaact gcaatgggac atgccatacc 420 agcgccaact gcctcaccaa ctcagatggt acagcttcat gcaagtgtgc agcaggattc 480 caaggaaacg ggaccatctg cacagcaatc aatgcctgtg agatcagcaa tggaggttgc 540 tctgccaagg ctgactgtaa gagaaccacc ccaggaaggc gagtgtgcac gtgcaaagca 600 ggctacacgg gtgatggcat tgtgtgcctg gaaatcaacc cgtgtttgga gaaccatggt 660 ggctgtgaca agaatgcgga gtgcacacag acaggaccca accaggctgc ctgtaactgt 720 ttgccagcat acactggaga tggaaaggtc tgcacactca tcaatgtctg cttaactaaa 780 aatggcggct gtagtgaatt tgccatctgc aaccacactg ggcaagtaga aaggacttgt 840 acttgcaagc caaactacat tggagatgga tttacctgcc gc 882 <210> 40 <211> 759 <212> DNA <213> Homo sapiens <400> 40 aggtggagta aaccaaaggg tgtgaagcag aagtgtctct acaacctgcc cttcaagagg 60 aacctggaag gctgccggga gcggtgcagc ctggtgatac agatccccag gtgctgcaag 120 ggctacttcg ggcgagactg tcaggcctgc cctggaggac cagatgcccc gtgtaataac 180 cggggtgtct gccttgatca gtactcggcc accggagagt gtaaatgcaa caccggcttc 240 aatgggacgg cgtgtgagat gtgctggccg gggagattcg ggcctgattg tctgccctgt 300 ggctgctcag accacggaca gtgcgatgat ggcatcacgg gctccgggca gtgcctctgt 360 gaaacggggt ggacaggccc ctcgtgtgac actcaggcag ttttgcctgc agtgtgtacg 420 cctccttgtt ctgctcatgc cacctgtaag gagaacaaca cgtgtgagtg taacctggat 480 tatgaaggtg acggaatcac atgcacagtt gtggatttct gcaaacagga caacgggggc 540 tgtgcaaagg tggccagatg ctcccagaag ggcacgaagg tctcctgcag ctgccagaag 600 ggatacaaag gggacgggca cagctgcaca gagatagacc cctgtgcaga cggccttaac 660 ggagggtgtc acgagcacgc cacctgtaag atgacaggcc cgggcaagca caagtgtgag 720 tgtaaaagtc actatgtcgg agatgggctg aactgtgag 759 <210> 41 <211> 153 <212> DNA <213> Homo sapiens <400> 41 caacctcggt gttgtcctgg ccgctggggc ccagactgta tagagtgccc aggtggagcg 60 gggtcaccct gcaatggcag aggcagttgt gctgaaggca tggaaggaaa tggaacctgc 120 tcctgccaag aagggtttgg tggaacagcc tgt 153 <210> 42 <211> 141 <212> DNA <213> Homo sapiens <400> 42 gaaacctgtg ctgacgacaa cttatttgga cccagctgtt catcagtgtg caactgtgtg 60 catggggtgt gcaacagtgg actagatggc gatggaacct gtgagtgcta ctctgcgtac 120 actggcccca agtgtgacaa g 141 <210> 43 <211> 126 <212> DNA <213> Homo sapiens <400> 43 cccatccctg aatgtgcagc cttgctctgc ccagaaaatt ccagatgttc gccttccact 60 gaagatgaaa acaaactgga atgcaaatgc cttcccaatt accgaggcga tggcaaatac 120 tgcgac 126 <210> 44 <211> 120 <212> DNA <213> Homo sapiens <400> 44 cccatcaatc catgtttacg aaaaatctgc caccctcatg ctcattgtac gtacctggga 60 ccaaatcggc acagttgtac atgccaagaa ggctaccgtg gggatggcca agtgtgcttg 120 120 <210> 45 <211> 135 <212> DNA <213> Homo sapiens <400> 45 cctgtggacc cctgccaaat taactttgga aactgcccta caaagtctac agtgtgcaaa 60 tatgatgggc ctggacagtc tcactgcgag tgtaaggagc attaccagaa tttcgtacct 120 ggagtggggt gcagt 135 <210> 46 <211> 123 <212> DNA <213> Homo sapiens <400> 46 atgactgata tatgtaaatc agataacccg tgtcatagga atgcaaattg caccaccgtc 60 gcaccaggcc gaactgaatg catttgccag aaaggttacg tgggtgatgg cttaacgtgt 120 tat 123 <210> 47 <211> 153 <212> DNA <213> Homo sapiens <400> 47 attccaaagt gctgcaaagg cttctatgga cctgactgca accagtgtcc aggaggcttc 60 tcaaatccat gctcaggaaa tggacagtgt gcagatagcc tcggcggcaa cgggacatgc 120 atttgtgagg agggcttcca aggctcccag tgt 153 <210> 48 <211> 150 <212> DNA <213> Homo sapiens <400> 48 cagttctgct ctgatcccaa taaatacgga cctcggtgta acaaaaaatg cctgtgcgtt 60 cacggaacat gcaataacag gatagacagc gatggggcct gcctcactgg cacatgcaga 120 gacggctctg ccgggagact ctgtgataag 150 <210> 49 <211> 123 <212> DNA <213> Homo sapiens <400> 49 cagacctcag cctgtgggcc ctacgtgcag ttctgtcaca tccacgccac ctgtgaatac 60 agcaatggga cagccagttg tatttgcaaa gcaggatatg aaggagatgg aactctgtgt 120 tct 123 <210> 50 <211> 129 <212> DNA <213> Homo sapiens <400> 50 gagatggacc cttgcacagg actaactcca ggaggctgta gccgcaatgc agaatgcatc 60 aaaactggca cgggcaccca cacctgcgtg tgtcagcagg gttggacagg gaatgggaga 120 gactgctcg 129 <210> 51 <211> 129 <212> DNA <213> Homo sapiens <400> 51 gagatcaaca actgcctgct gcccagtgca ggcggctgcc acgacaacgc atcctgtttg 60 tatgtgggtc ccgggcagaa tgagtgtgag tgcaagaaag gatttcgagg aaatgggatt 120 gactgtgaa 129 <210> 52 <211> 126 <212> DNA <213> Homo sapiens <400> 52 ccaataactt catgcttgga acaaaccggg aaatgtcatc cattggcaag ctgtcaatct 60 acttcgtctg gtgtctggag ctgtgtttgt caagagggct atgaaggaga tggctttctg 120 tgctat 126 <210> 53 <211> 153 <212> DNA <213> Homo sapiens <400> 53 acgagagaat gctgtgccgg cttctttggc ccccaatgcc agccctgccc agggaatgcc 60 cagaatgtct gctttggtaa tggcatctgt ttggatggag tgaatggcac aggtgtgtgt 120 gagtgtgggg agggcttcag cggcacagcc tgc 153 <210> 54 <211> 144 <212> DNA <213> Homo sapiens <400> 54 gagacctgca ccgagggcaa gtacggcatc cactgtgacc aagcatgttc ttgtgtccat 60 gggagatgca accaaggacc cttgggagat ggctcctgtg actgtgatgt tggctggcga 120 ggagtgcatt gtgacaatgc aacc 144 <210> 55 <211> 117 <212> DNA <213> Homo sapiens <400> 55 acagaagaca actgcaatgg gacatgccat accagcgcca actgcctcac caactcagat 60 ggtacagctt catgcaagtg tgcagcagga ttccaaggaa acgggaccat ctgcaca 117 <210> 56 <211> 126 <212> DNA <213> Homo sapiens <400> 56 gcaatcaatg cctgtgagat cagcaatgga ggttgctctg ccaaggctga ctgtaagaga 60 accaccccag gaaggcgagt gtgcacgtgc aaagcaggct acacgggtga tggcattgtg 120 tgcctg 126 <210> 57 <211> 126 <212> DNA <213> Homo sapiens <400> 57 gaaatcaacc cgtgtttgga gaaccatggt ggctgtgaca agaatgcgga gtgcacacag 60 acaggaccca accaggctgc ctgtaactgt ttgccagcat acactggaga tggaaaggtc 120 tgcaca 126 <210> 58 <211> 126 <212> DNA <213> Homo sapiens <400> 58 ctcatcaatg tctgcttaac taaaaatggc ggctgtagtg aatttgccat ctgcaaccac 60 actgggcaag tagaaaggac ttgtacttgc aagccaaact acattggaga tggatttacc 120 tgccgc 126 <210> 59 <211> 153 <212> DNA <213> Homo sapiens <400> 59 atccccaggt gctgcaaggg ctacttcggg cgagactgtc aggcctgccc tggaggacca 60 gatgccccgt gtaataaccg gggtgtctgc cttgatcagt actcggccac cggagagtgt 120 aaatgcaaca ccggcttcaa tgggacggcg tgt 153 <210> 60 <211> 147 <212> DNA <213> Homo sapiens <400> 60 gagatgtgct ggccggggag attcgggcct gattgtctgc cctgtggctg ctcagaccac 60 ggacagtgcg atgatggcat cacgggctcc gggcagtgcc tctgtgaaac ggggtggaca 120 ggcccctcgt gtgacactca ggcagtt 147 <210> 61 <211> 105 <212> DNA <213> Homo sapiens <400> 61 ttgcctgcag tgtgtacgcc tccttgttct gctcatgcca cctgtaagga gaacaacacg 60 tgtgagtgta acctggatta tgaaggtgac ggaatcacat gcaca 105 <210> 62 <211> 123 <212> DNA <213> Homo sapiens <400> 62 gttgtggatt tctgcaaaca ggacaacggg ggctgtgcaa aggtggccag atgctcccag 60 aagggcacga aggtctcctg cagctgccag aagggataca aaggggacgg gcacagctgc 120 aca 123 <210> 63 <211> 129 <212> DNA <213> Homo sapiens <400> 63 gagatagacc cctgtgcaga cggccttaac ggagggtgtc acgagcacgc cacctgtaag 60 atgacaggcc cgggcaagca caagtgtgag tgtaaaagtc actatgtcgg agatgggctg 120 aactgtgag 129 <210> 64 <211> 540 <212> DNA <213> Homo sapiens <400> 64 caacctcggt gttgtcctgg ccgctggggc ccagactgta tagagtgccc aggtggagcg 60 gggtcaccct gcaatggcag aggcagttgt gctgaaggca tggaaggaaa tggaacctgc 120 tcctgccaag aagggtttgg tggaacagcc tgtgaaacct gtgctgacga caacttattt 180 ggacccagct gttcatcagt gtgcaactgt gtgcatgggg tgtgcaacag tggactagat 240 ggcgatggaa cctgtgagtg ctactctgcg tacactggcc ccaagtgtga caagcccatc 300 cctgaatgtg cagccttgct ctgcccagaa aattccagat gttcgccttc cactgaagat 360 gaaaacaaac tggaatgcaa atgccttccc aattaccgag gcgatggcaa atactgcgac 420 cccatcaatc catgtttacg aaaaatctgc caccctcatg ctcattgtac gtacctggga 480 ccaaatcggc acagttgtac atgccaagaa ggctaccgtg gggatggcca agtgtgcttg 540 540 <210> 65 <211> 675 <212> DNA <213> Homo sapiens <400> 65 caacctcggt gttgtcctgg ccgctggggc ccagactgta tagagtgccc aggtggagcg 60 gggtcaccct gcaatggcag aggcagttgt gctgaaggca tggaaggaaa tggaacctgc 120 tcctgccaag aagggtttgg tggaacagcc tgtgaaacct gtgctgacga caacttattt 180 ggacccagct gttcatcagt gtgcaactgt gtgcatgggg tgtgcaacag tggactagat 240 ggcgatggaa cctgtgagtg ctactctgcg tacactggcc ccaagtgtga caagcccatc 300 cctgaatgtg cagccttgct ctgcccagaa aattccagat gttcgccttc cactgaagat 360 gaaaacaaac tggaatgcaa atgccttccc aattaccgag gcgatggcaa atactgcgac 420 cccatcaatc catgtttacg aaaaatctgc caccctcatg ctcattgtac gtacctggga 480 ccaaatcggc acagttgtac atgccaagaa ggctaccgtg gggatggcca agtgtgcttg 540 cctgtggacc cctgccaaat taactttgga aactgcccta caaagtctac agtgtgcaaa 600 tatgatgggc ctggacagtc tcactgcgag tgtaaggagc attaccagaa tttcgtacct 660 ggagtggggt gcagt 675 <210> 66 <211> 522 <212> DNA <213> Homo sapiens <400> 66 gaaacctgtg ctgacgacaa cttatttgga cccagctgtt catcagtgtg caactgtgtg 60 catggggtgt gcaacagtgg actagatggc gatggaacct gtgagtgcta ctctgcgtac 120 actggcccca agtgtgacaa gcccatccct gaatgtgcag ccttgctctg cccagaaaat 180 tccagatgtt cgccttccac tgaagatgaa aacaaactgg aatgcaaatg ccttcccaat 240 taccgaggcg atggcaaata ctgcgacccc atcaatccat gtttacgaaa aatctgccac 300 cctcatgctc attgtacgta cctgggacca aatcggcaca gttgtacatg ccaagaaggc 360 taccgtgggg atggccaagt gtgcttgcct gtggacccct gccaaattaa ctttggaaac 420 tgccctacaa agtctacagt gtgcaaatat gatgggcctg gacagtctca ctgcgagtgt 480 aaggagcatt accagaattt cgtacctgga gtggggtgca gt 522 <210> 67 <211> 555 <212> DNA <213> Homo sapiens <400> 67 attccaaagt gctgcaaagg cttctatgga cctgactgca accagtgtcc aggaggcttc 60 tcaaatccat gctcaggaaa tggacagtgt gcagatagcc tcggcggcaa cgggacatgc 120 atttgtgagg agggcttcca aggctcccag tgtcagttct gctctgatcc caataaatac 180 ggacctcggt gtaacaaaaa atgcctgtgc gttcacggaa catgcaataa caggatagac 240 agcgatgggg cctgcctcac tggcacatgc agagacggct ctgccgggag actctgtgat 300 aagcagacct cagcctgtgg gccctacgtg cagttctgtc acatccacgc cacctgtgaa 360 tacagcaatg ggacagccag ttgtatttgc aaagcaggat atgaaggaga tggaactctg 420 tgttctgaga tggacccttg cacaggacta actccaggag gctgtagccg caatgcagaa 480 tgcatcaaaa ctggcacggg cacccacacc tgcgtgtgtc agcagggttg gacagggaat 540 gggagagact gctcg 555 <210> 68 <211> 684 <212> DNA <213> Homo sapiens <400> 68 attccaaagt gctgcaaagg cttctatgga cctgactgca accagtgtcc aggaggcttc 60 tcaaatccat gctcaggaaa tggacagtgt gcagatagcc tcggcggcaa cgggacatgc 120 atttgtgagg agggcttcca aggctcccag tgtcagttct gctctgatcc caataaatac 180 ggacctcggt gtaacaaaaa atgcctgtgc gttcacggaa catgcaataa caggatagac 240 agcgatgggg cctgcctcac tggcacatgc agagacggct ctgccgggag actctgtgat 300 aagcagacct cagcctgtgg gccctacgtg cagttctgtc acatccacgc cacctgtgaa 360 tacagcaatg ggacagccag ttgtatttgc aaagcaggat atgaaggaga tggaactctg 420 tgttctgaga tggacccttg cacaggacta actccaggag gctgtagccg caatgcagaa 480 tgcatcaaaa ctggcacggg cacccacacc tgcgtgtgtc agcagggttg gacagggaat 540 gggagagact gctcggagat caacaactgc ctgctgccca gtgcaggcgg ctgccacgac 600 aacgcatcct gtttgtatgt gggtcccggg cagaatgagt gtgagtgcaa gaaaggattt 660 cgaggaaatg ggattgactg tgaa 684 <210> 69 <211> 531 <212> DNA <213> Homo sapiens <400> 69 cagttctgct ctgatcccaa taaatacgga cctcggtgta acaaaaaatg cctgtgcgtt 60 cacggaacat gcaataacag gatagacagc gatggggcct gcctcactgg cacatgcaga 120 gacggctctg ccgggagact ctgtgataag cagacctcag cctgtgggcc ctacgtgcag 180 ttctgtcaca tccacgccac ctgtgaatac agcaatggga cagccagttg tatttgcaaa 240 gcaggatatg aaggagatgg aactctgtgt tctgagatgg acccttgcac aggactaact 300 ccaggaggct gtagccgcaa tgcagaatgc atcaaaactg gcacgggcac ccacacctgc 360 gtgtgtcagc agggttggac agggaatggg agagactgct cggagatcaa caactgcctg 420 ctgcccagtg caggcggctg ccacgacaac gcatcctgtt tgtatgtggg tcccgggcag 480 aatgagtgtg agtgcaagaa aggatttcga ggaaatggga ttgactgtga a 531 <210> 70 <211> 540 <212> DNA <213> Homo sapiens <400> 70 acgagagaat gctgtgccgg cttctttggc ccccaatgcc agccctgccc agggaatgcc 60 cagaatgtct gctttggtaa tggcatctgt ttggatggag tgaatggcac aggtgtgtgt 120 gagtgtgggg agggcttcag cggcacagcc tgcgagacct gcaccgaggg caagtacggc 180 atccactgtg accaagcatg ttcttgtgtc catgggagat gcaaccaagg acccttggga 240 gatggctcct gtgactgtga tgttggctgg cgaggagtgc attgtgacaa tgcaaccaca 300 gaagacaact gcaatgggac atgccatacc agcgccaact gcctcaccaa ctcagatggt 360 acagcttcat gcaagtgtgc agcaggattc caaggaaacg ggaccatctg cacagcaatc 420 aatgcctgtg agatcagcaa tggaggttgc tctgccaagg ctgactgtaa gagaaccacc 480 ccaggaaggc gagtgtgcac gtgcaaagca ggctacacgg gtgatggcat tgtgtgcctg 540 540 <210> 71 <211> 666 <212> DNA <213> Homo sapiens <400> 71 acgagagaat gctgtgccgg cttctttggc ccccaatgcc agccctgccc agggaatgcc 60 cagaatgtct gctttggtaa tggcatctgt ttggatggag tgaatggcac aggtgtgtgt 120 gagtgtgggg agggcttcag cggcacagcc tgcgagacct gcaccgaggg caagtacggc 180 atccactgtg accaagcatg ttcttgtgtc catgggagat gcaaccaagg acccttggga 240 gatggctcct gtgactgtga tgttggctgg cgaggagtgc attgtgacaa tgcaaccaca 300 gaagacaact gcaatgggac atgccatacc agcgccaact gcctcaccaa ctcagatggt 360 acagcttcat gcaagtgtgc agcaggattc caaggaaacg ggaccatctg cacagcaatc 420 aatgcctgtg agatcagcaa tggaggttgc tctgccaagg ctgactgtaa gagaaccacc 480 ccaggaaggc gagtgtgcac gtgcaaagca ggctacacgg gtgatggcat tgtgtgcctg 540 gaaatcaacc cgtgtttgga gaaccatggt ggctgtgaca agaatgcgga gtgcacacag 600 acaggaccca accaggctgc ctgtaactgt ttgccagcat acactggaga tggaaaggtc 660 tgcaca 666 <210> 72 <211> 513 <212> DNA <213> Homo sapiens <400> 72 gagacctgca ccgagggcaa gtacggcatc cactgtgacc aagcatgttc ttgtgtccat 60 gggagatgca accaaggacc cttgggagat ggctcctgtg actgtgatgt tggctggcga 120 ggagtgcatt gtgacaatgc aaccacagaa gacaactgca atgggacatg ccataccagc 180 gccaactgcc tcaccaactc agatggtaca gcttcatgca agtgtgcagc aggattccaa 240 ggaaacggga ccatctgcac agcaatcaat gcctgtgaga tcagcaatgg aggttgctct 300 gccaaggctg actgtaagag aaccacccca ggaaggcgag tgtgcacgtg caaagcaggc 360 tacacgggtg atggcattgt gtgcctggaa atcaacccgt gtttggagaa ccatggtggc 420 tgtgacaaga atgcggagtg cacacagaca ggacccaacc aggctgcctg taactgtttg 480 ccagcataca ctggagatgg aaaggtctgc aca 513 <210> 73 <211> 528 <212> DNA <213> Homo sapiens <400> 73 atccccaggt gctgcaaggg ctacttcggg cgagactgtc aggcctgccc tggaggacca 60 gatgccccgt gtaataaccg gggtgtctgc cttgatcagt actcggccac cggagagtgt 120 aaatgcaaca ccggcttcaa tgggacggcg tgtgagatgt gctggccggg gagattcggg 180 cctgattgtc tgccctgtgg ctgctcagac cacggacagt gcgatgatgg catcacgggc 240 tccgggcagt gcctctgtga aacggggtgg acaggcccct cgtgtgacac tcaggcagtt 300 ttgcctgcag tgtgtacgcc tccttgttct gctcatgcca cctgtaagga gaacaacacg 360 tgtgagtgta acctggatta tgaaggtgac ggaatcacat gcacagttgt ggatttctgc 420 aaacaggaca acgggggctg tgcaaaggtg gccagatgct cccagaaggg cacgaaggtc 480 tcctgcagct gccagaaggg atacaaaggg gacgggcaca gctgcaca 528 <210> 74 <211> 504 <212> DNA <213> Homo sapiens <400> 74 gagatgtgct ggccggggag attcgggcct gattgtctgc cctgtggctg ctcagaccac 60 ggacagtgcg atgatggcat cacgggctcc gggcagtgcc tctgtgaaac ggggtggaca 120 ggcccctcgt gtgacactca ggcagttttg cctgcagtgt gtacgcctcc ttgttctgct 180 catgccacct gtaaggagaa caacacgtgt gagtgtaacc tggattatga aggtgacgga 240 atcacatgca cagttgtgga tttctgcaaa caggacaacg ggggctgtgc aaaggtggcc 300 agatgctccc agaagggcac gaaggtctcc tgcagctgcc agaagggata caaaggggac 360 gggcacagct gcacagagat agacccctgt gcagacggcc ttaacggagg gtgtcacgag 420 cacgccacct gtaagatgac aggcccgggc aagcacaagt gtgagtgtaa aagtcactat 480 gtcggagatg ggctgaactg tgag 504 <210> 75 <211> 590 <212> PRT <213> Homo sapiens <400> 75 Val Gly Val Arg Asp Cys Arg Tyr Thr Phe Glu Val Arg Thr Tyr Ser 1 5 10 15 Leu Ser Leu Pro Gly Cys Arg His Ile Cys Arg Lys Asp Tyr Leu Gln 20 25 30 Pro Arg Cys Cys Pro Gly Arg Trp Gly Pro Asp Cys Ile Glu Cys Pro 35 40 45 Gly Gly Ala Gly Ser Pro Cys Asn Gly Arg Gly Ser Cys Ala Glu Gly 50 55 60 Met Glu Gly Asn Gly Thr Cys Ser Cys Gln Glu Gly Phe Gly Gly Thr 65 70 75 80 Ala Cys Glu Thr Cys Ala Asp Asp Asn Leu Phe Gly Pro Ser Cys Ser 85 90 95 Ser Val Cys Asn Cys Val His Gly Val Cys Asn Ser Gly Leu Asp Gly 100 105 110 Asp Gly Thr Cys Glu Cys Tyr Ser Ala Tyr Thr Gly Pro Lys Cys Asp 115 120 125 Lys Pro Ile Pro Glu Cys Ala Ala Leu Leu Cys Pro Glu Asn Ser Arg 130 135 140 Cys Ser Pro Ser Thr Glu Asp Glu Asn Lys Leu Glu Cys Lys Cys Leu 145 150 155 160 Pro Asn Tyr Arg Gly Asp Gly Lys Tyr Cys Asp Pro Ile Asn Pro Cys 165 170 175 Leu Arg Lys Ile Cys His Pro His Ala His Cys Thr Tyr Leu Gly Pro 180 185 190 Asn Arg His Ser Cys Thr Cys Gln Glu Gly Tyr Arg Gly Asp Gly Gln 195 200 205 Val Cys Leu Pro Val Asp Pro Cys Gln Ile Asn Phe Gly Asn Cys Pro 210 215 220 Thr Lys Ser Thr Val Cys Lys Tyr Asp Gly Pro Gly Gln Ser His Cys 225 230 235 240 Glu Cys Lys Glu His Tyr Gln Asn Phe Val Pro Gly Val Gly Cys Ser 245 250 255 Met Thr Asp Ile Cys Lys Ser Asp Asn Pro Cys His Arg Asn Ala Asn 260 265 270 Cys Thr Thr Val Ala Pro Gly Arg Thr Glu Cys Ile Cys Gln Lys Gly 275 280 285 Tyr Val Gly Asp Gly Leu Thr Cys Tyr Gly Asn Ile Met Glu Arg Leu 290 295 300 Arg Glu Leu Asn Thr Glu Pro Arg Gly Lys Trp Gln Gly Arg Leu Thr 305 310 315 320 Ser Phe Ile Ser Leu Leu Asp Lys Ala Tyr Ala Trp Pro Leu Ser Lys 325 330 335 Leu Gly Pro Phe Thr Val Leu Leu Pro Thr Asp Lys Gly Leu Lys Gly 340 345 350 Phe Asn Val Asn Glu Leu Leu Val Asp Asn Lys Ala Ala Gln Tyr Phe 355 360 365 Val Lys Leu His Ile Ile Ala Gly Gln Met Asn Ile Glu Tyr Met Asn 370 375 380 Asn Thr Asp Met Phe Tyr Thr Leu Thr Gly Lys Ser Gly Glu Ile Phe 385 390 395 400 Asn Ser Asp Lys Asp Asn Gln Ile Lys Leu Lys Leu His Gly Gly Lys 405 410 415 Lys Lys Val Lys Ile Ile Gln Gly Asp Ile Ile Ala Ser Asn Gly Leu 420 425 430 Leu His Ile Leu Asp Arg Ala Met Asp Lys Leu Glu Pro Thr Phe Glu 435 440 445 Ser Asn Asn Glu Gln Thr Ile Met Thr Met Leu Gln Pro Arg Tyr Ser 450 455 460 Lys Phe Arg Ser Leu Leu Glu Glu Thr Asn Leu Gly His Ala Leu Asp 465 470 475 480 Glu Asp Gly Val Gly Gly Pro Tyr Thr Ile Phe Val Pro Asn Asn Glu 485 490 495 Ala Leu Asn Asn Met Lys Asp Gly Thr Leu Asp Tyr Leu Leu Ser Pro 500 505 510 Glu Gly Ser Arg Lys Leu Leu Glu Leu Val Arg Tyr His Ile Val Pro 515 520 525 Phe Thr Gln Leu Glu Val Ala Thr Leu Ile Ser Thr Pro His Ile Arg 530 535 540 Ser Met Ala Asn Gln Leu Ile Gln Phe Asn Thr Thr Asp Asn Gly Gln 545 550 555 560 Ile Leu Ala Asn Asp Val Ala Met Glu Glu Ile Glu Ile Thr Ala Lys 565 570 575 Asn Gly Arg Ile Tyr Thr Leu Thr Gly Val Leu Ile Pro Pro 580 585 590 <210> 76 <211> 578 <212> PRT <213> Homo sapiens <400> 76 Asn Ser Glu Pro Thr Ala Leu Phe Thr His Arg Cys Val Tyr Ser Gly 1 5 10 15 Arg Phe Gly Ser Leu Lys Ser Gly Cys Ala Arg Tyr Cys Asn Ala Thr 20 25 30 Val Lys Ile Pro Lys Cys Cys Lys Gly Phe Tyr Gly Pro Asp Cys Asn 35 40 45 Gln Cys Pro Gly Gly Phe Ser Asn Pro Cys Ser Gly Asn Gly Gln Cys 50 55 60 Ala Asp Ser Leu Gly Gly Asn Gly Thr Cys Ile Cys Glu Glu Gly Phe 65 70 75 80 Gln Gly Ser Gln Cys Gln Phe Cys Ser Asp Pro Asn Lys Tyr Gly Pro 85 90 95 Arg Cys Asn Lys Lys Cys Leu Cys Val His Gly Thr Cys Asn Asn Arg 100 105 110 Ile Asp Ser Asp Gly Ala Cys Leu Thr Gly Thr Cys Arg Asp Gly Ser 115 120 125 Ala Gly Arg Leu Cys Asp Lys Gln Thr Ser Ala Cys Gly Pro Tyr Val 130 135 140 Gln Phe Cys His Ile His Ala Thr Cys Glu Tyr Ser Asn Gly Thr Ala 145 150 155 160 Ser Cys Ile Cys Lys Ala Gly Tyr Glu Gly Asp Gly Thr Leu Cys Ser 165 170 175 Glu Met Asp Pro Cys Thr Gly Leu Thr Pro Gly Gly Cys Ser Arg Asn 180 185 190 Ala Glu Cys Ile Lys Thr Gly Thr Gly Thr His Thr Cys Val Cys Gln 195 200 205 Gln Gly Trp Thr Gly Asn Gly Arg Asp Cys Ser Glu Ile Asn Asn Cys 210 215 220 Leu Leu Pro Ser Ala Gly Gly Cys His Asp Asn Ala Ser Cys Leu Tyr 225 230 235 240 Val Gly Pro Gly Gln Asn Glu Cys Glu Cys Lys Lys Gly Phe Arg Gly 245 250 255 Asn Gly Ile Asp Cys Glu Pro Ile Thr Ser Cys Leu Glu Gln Thr Gly 260 265 270 Lys Cys His Pro Leu Ala Ser Cys Gln Ser Thr Ser Ser Gly Val Trp 275 280 285 Ser Cys Val Cys Gln Glu Gly Tyr Glu Gly Asp Gly Phe Leu Cys Tyr 290 295 300 Gly Asn Ala Ala Val Glu Leu Ser Phe Leu Ser Glu Ala Ala Ile Phe 305 310 315 320 Asn Arg Trp Ile Asn Asn Ala Ser Leu Gln Pro Thr Leu Ser Ala Thr 325 330 335 Ser Asn Leu Thr Val Leu Val Pro Ser Gln Gln Ala Thr Glu Asp Met 340 345 350 Asp Gln Asp Glu Lys Ser Phe Trp Leu Ser Gln Ser Asn Ile Pro Ala 355 360 365 Leu Ile Lys Tyr His Met Leu Leu Gly Thr Tyr Arg Val Ala Asp Leu 370 375 380 Gln Thr Leu Ser Ser Ser Asp Met Leu Ala Thr Ser Leu Gln Gly Asn 385 390 395 400 Phe Leu His Leu Ala Lys Val Asp Gly Asn Ile Thr Ile Glu Gly Ala 405 410 415 Ser Ile Val Asp Gly Asp Asn Ala Ala Thr Asn Gly Val Ile His Ile 420 425 430 Ile Asn Lys Val Leu Val Pro Gln Arg Arg Leu Thr Gly Ser Leu Pro 435 440 445 Asn Leu Leu Met Arg Leu Glu Gln Met Pro Asp Tyr Ser Ile Phe Arg 450 455 460 Gly Tyr Ile Ile Gln Tyr Asn Leu Ala Asn Ala Ile Glu Ala Ala Asp 465 470 475 480 Ala Tyr Thr Val Phe Ala Pro Asn Asn Asn Ala Ile Glu Asn Tyr Ile 485 490 495 Arg Glu Lys Lys Val Leu Ser Leu Glu Glu Asp Val Leu Arg Tyr His 500 505 510 Val Val Leu Glu Glu Lys Leu Leu Lys Asn Asp Leu His Asn Gly Met 515 520 525 His Arg Glu Thr Met Leu Gly Phe Ser Tyr Phe Leu Ser Phe Phe Leu 530 535 540 His Asn Asp Gln Leu Tyr Val Asn Glu Ala Pro Ile Asn Tyr Thr Asn 545 550 555 560 Val Ala Thr Asp Lys Gly Val Ile His Gly Leu Gly Lys Val Leu Glu 565 570 575 Ile Gln <210> 77 <211> 581 <212> PRT <213> Homo sapiens <400> 77 Glu Lys Arg Arg Cys Ile Tyr Thr Ser Tyr Phe Met Gly Arg Arg Thr 1 5 10 15 Leu Phe Ile Gly Cys Gln Pro Lys Cys Val Arg Thr Val Ile Thr Arg 20 25 30 Glu Cys Cys Ala Gly Phe Phe Gly Pro Gln Cys Gln Pro Cys Pro Gly 35 40 45 Asn Ala Gln Asn Val Cys Phe Gly Asn Gly Ile Cys Leu Asp Gly Val 50 55 60 Asn Gly Thr Gly Val Cys Glu Cys Gly Glu Gly Phe Ser Gly Thr Ala 65 70 75 80 Cys Glu Thr Cys Thr Glu Gly Lys Tyr Gly Ile His Cys Asp Gln Ala 85 90 95 Cys Ser Cys Val His Gly Arg Cys Asn Gln Gly Pro Leu Gly Asp Gly 100 105 110 Ser Cys Asp Cys Asp Val Gly Trp Arg Gly Val His Cys Asp Asn Ala 115 120 125 Thr Thr Glu Asp Asn Cys Asn Gly Thr Cys His Thr Ser Ala Asn Cys 130 135 140 Leu Thr Asn Ser Asp Gly Thr Ala Ser Cys Lys Cys Ala Ala Gly Phe 145 150 155 160 Gln Gly Asn Gly Thr Ile Cys Thr Ala Ile Asn Ala Cys Glu Ile Ser 165 170 175 Asn Gly Gly Cys Ser Ala Lys Ala Asp Cys Lys Arg Thr Thr Pro Gly 180 185 190 Arg Arg Val Cys Thr Cys Lys Ala Gly Tyr Thr Gly Asp Gly Ile Val 195 200 205 Cys Leu Glu Ile Asn Pro Cys Leu Glu Asn His Gly Gly Cys Asp Lys 210 215 220 Asn Ala Glu Cys Thr Gln Thr Gly Pro Asn Gln Ala Ala Cys Asn Cys 225 230 235 240 Leu Pro Ala Tyr Thr Gly Asp Gly Lys Val Cys Thr Leu Ile Asn Val 245 250 255 Cys Leu Thr Lys Asn Gly Gly Cys Ser Glu Phe Ala Ile Cys Asn His 260 265 270 Thr Gly Gln Val Glu Arg Thr Cys Thr Cys Lys Pro Asn Tyr Ile Gly 275 280 285 Asp Gly Phe Thr Cys Arg Gly Ser Ile Tyr Gln Glu Leu Pro Lys Asn 290 295 300 Pro Lys Thr Ser Gln Tyr Phe Phe Gln Leu Gln Glu His Phe Val Lys 305 310 315 320 Asp Leu Val Gly Pro Gly Pro Phe Thr Val Phe Ala Pro Leu Ser Ala 325 330 335 Ala Phe Asp Glu Glu Ala Arg Val Lys Asp Trp Asp Lys Tyr Gly Leu 340 345 350 Met Pro Gln Val Leu Arg Tyr His Val Val Ala Cys His Gln Leu Leu 355 360 365 Leu Glu Asn Leu Lys Leu Ile Ser Asn Ala Thr Ser Leu Gln Gly Glu 370 375 380 Pro Ile Val Ile Ser Val Ser Gln Ser Thr Val Tyr Ile Asn Asn Lys 385 390 395 400 Ala Lys Ile Ile Ser Ser Asp Ile Ile Ser Thr Asn Gly Ile Val His 405 410 415 Ile Ile Asp Lys Leu Leu Ser Pro Lys Asn Leu Leu Ile Thr Pro Lys 420 425 430 Asp Asn Ser Gly Arg Ile Leu Gln Asn Leu Thr Thr Leu Ala Thr Asn 435 440 445 Asn Gly Tyr Ile Lys Phe Ser Asn Leu Ile Gln Asp Ser Gly Leu Leu 450 455 460 Ser Val Ile Thr Asp Pro Ile His Thr Pro Val Thr Leu Phe Trp Pro 465 470 475 480 Thr Asp Gln Ala Leu His Ala Leu Pro Ala Glu Gln Gln Asp Phe Leu 485 490 495 Phe Asn Gln Asp Asn Lys Asp Lys Leu Lys Glu Tyr Leu Lys Phe His 500 505 510 Val Ile Arg Asp Ala Lys Val Leu Ala Val Asp Leu Pro Thr Ser Thr 515 520 525 Ala Trp Lys Thr Leu Gln Gly Ser Glu Leu Ser Val Lys Cys Gly Ala 530 535 540 Gly Arg Asp Ile Gly Asp Leu Phe Leu Asn Gly Gln Thr Cys Arg Ile 545 550 555 560 Val Gln Arg Glu Leu Leu Phe Asp Leu Gly Val Ala Tyr Gly Ile Asp 565 570 575 Cys Leu Leu Ile Asp 580 <210> 78 <211> 537 <212> PRT <213> Homo sapiens <400> 78 Arg Trp Ser Lys Pro Lys Gly Val Lys Gln Lys Cys Leu Tyr Asn Leu 1 5 10 15 Pro Phe Lys Arg Asn Leu Glu Gly Cys Arg Glu Arg Cys Ser Leu Val 20 25 30 Ile Gln Ile Pro Arg Cys Cys Lys Gly Tyr Phe Gly Arg Asp Cys Gln 35 40 45 Ala Cys Pro Gly Gly Pro Asp Ala Pro Cys Asn Asn Arg Gly Val Cys 50 55 60 Leu Asp Gln Tyr Ser Ala Thr Gly Glu Cys Lys Cys Asn Thr Gly Phe 65 70 75 80 Asn Gly Thr Ala Cys Glu Met Cys Trp Pro Gly Arg Phe Gly Pro Asp 85 90 95 Cys Leu Pro Cys Gly Cys Ser Asp His Gly Gln Cys Asp Asp Gly Ile 100 105 110 Thr Gly Ser Gly Gln Cys Leu Cys Glu Thr Gly Trp Thr Gly Pro Ser 115 120 125 Cys Asp Thr Gln Ala Val Leu Pro Ala Val Cys Thr Pro Pro Cys Ser 130 135 140 Ala His Ala Thr Cys Lys Glu Asn Asn Thr Cys Glu Cys Asn Leu Asp 145 150 155 160 Tyr Glu Gly Asp Gly Ile Thr Cys Thr Val Val Asp Phe Cys Lys Gln 165 170 175 Asp Asn Gly Gly Cys Ala Lys Val Ala Arg Cys Ser Gln Lys Gly Thr 180 185 190 Lys Val Ser Cys Ser Cys Gln Lys Gly Tyr Lys Gly Asp Gly His Ser 195 200 205 Cys Thr Glu Ile Asp Pro Cys Ala Asp Gly Leu Asn Gly Gly Cys His 210 215 220 Glu His Ala Thr Cys Lys Met Thr Gly Pro Gly Lys His Lys Cys Glu 225 230 235 240 Cys Lys Ser His Tyr Val Gly Asp Gly Leu Asn Cys Glu Pro Glu Gln 245 250 255 Leu Pro Ile Asp Arg Cys Leu Gln Asp Asn Gly Gln Cys His Ala Asp 260 265 270 Ala Lys Cys Val Asp Leu His Phe Gln Asp Thr Thr Val Gly Val Phe 275 280 285 His Leu Arg Ser Pro Leu Gly Gln Tyr Lys Leu Thr Phe Asp Lys Ala 290 295 300 Arg Glu Ala Cys Ala Asn Glu Ala Ala Thr Met Ala Thr Tyr Asn Gln 305 310 315 320 Leu Ser Tyr Ala Gln Lys Ala Lys Tyr His Leu Cys Ser Ala Gly Trp 325 330 335 Leu Glu Thr Gly Arg Val Ala Tyr Pro Thr Ala Phe Ala Ser Gln Asn 340 345 350 Cys Gly Ser Gly Val Val Gly Ile Val Asp Tyr Gly Pro Arg Pro Asn 355 360 365 Lys Ser Glu Met Trp Asp Val Phe Cys Tyr Arg Met Lys Asp Val Asn 370 375 380 Cys Thr Cys Lys Val Gly Tyr Val Gly Asp Gly Phe Ser Cys Ser Gly 385 390 395 400 Asn Leu Leu Gln Val Leu Met Ser Phe Pro Ser Leu Thr Asn Phe Leu 405 410 415 Thr Glu Val Leu Ala Tyr Ser Asn Ser Ser Ala Arg Gly Arg Ala Phe 420 425 430 Leu Glu His Leu Thr Asp Leu Ser Ile Arg Gly Thr Leu Phe Val Pro 435 440 445 Gln Asn Ser Gly Leu Gly Glu Asn Glu Thr Leu Ser Gly Arg Asp Ile 450 455 460 Glu His His Leu Ala Asn Val Ser Met Phe Phe Tyr Asn Asp Leu Val 465 470 475 480 Asn Gly Thr Thr Leu Gln Thr Arg Leu Gly Ser Lys Leu Leu Ile Thr 485 490 495 Ala Ser Gln Asp Pro Leu Gln Pro Thr Glu Thr Arg Phe Val Asp Gly 500 505 510 Arg Ala Ile Leu Gln Trp Asp Ile Phe Ala Ser Asn Gly Ile Ile His 515 520 525 Val Ile Ser Arg Pro Leu Lys Ala Pro 530 535 <210> 79 <211> 266 <212> PRT <213> Homo sapiens <400> 79 Gln Pro Arg Cys Cys Pro Gly Arg Trp Gly Pro Asp Cys Ile Glu Cys 1 5 10 15 Pro Gly Gly Ala Gly Ser Pro Cys Asn Gly Arg Gly Ser Cys Ala Glu 20 25 30 Gly Met Glu Gly Asn Gly Thr Cys Ser Cys Gln Glu Gly Phe Gly Gly 35 40 45 Thr Ala Cys Glu Thr Cys Ala Asp Asp Asn Leu Phe Gly Pro Ser Cys 50 55 60 Ser Ser Val Cys Asn Cys Val His Gly Val Cys Asn Ser Gly Leu Asp 65 70 75 80 Gly Asp Gly Thr Cys Glu Cys Tyr Ser Ala Tyr Thr Gly Pro Lys Cys 85 90 95 Asp Lys Pro Ile Pro Glu Cys Ala Ala Leu Leu Cys Pro Glu Asn Ser 100 105 110 Arg Cys Ser Pro Ser Thr Glu Asp Glu Asn Lys Leu Glu Cys Lys Cys 115 120 125 Leu Pro Asn Tyr Arg Gly Asp Gly Lys Tyr Cys Asp Pro Ile Asn Pro 130 135 140 Cys Leu Arg Lys Ile Cys His Pro His Ala His Cys Thr Tyr Leu Gly 145 150 155 160 Pro Asn Arg His Ser Cys Thr Cys Gln Glu Gly Tyr Arg Gly Asp Gly 165 170 175 Gln Val Cys Leu Pro Val Asp Pro Cys Gln Ile Asn Phe Gly Asn Cys 180 185 190 Pro Thr Lys Ser Thr Val Cys Lys Tyr Asp Gly Pro Gly Gln Ser His 195 200 205 Cys Glu Cys Lys Glu His Tyr Gln Asn Phe Val Pro Gly Val Gly Cys 210 215 220 Ser Met Thr Asp Ile Cys Lys Ser Asp Asn Pro Cys His Arg Asn Ala 225 230 235 240 Asn Cys Thr Thr Val Ala Pro Gly Arg Thr Glu Cys Ile Cys Gln Lys 245 250 255 Gly Tyr Val Gly Asp Gly Leu Thr Cys Tyr 260 265 <210> 80 <211> 270 <212> PRT <213> Homo sapiens <400> 80 Ile Pro Lys Cys Cys Lys Gly Phe Tyr Gly Pro Asp Cys Asn Gln Cys 1 5 10 15 Pro Gly Gly Phe Ser Asn Pro Cys Ser Gly Asn Gly Gln Cys Ala Asp 20 25 30 Ser Leu Gly Gly Asn Gly Thr Cys Ile Cys Glu Glu Gly Phe Gln Gly 35 40 45 Ser Gln Cys Gln Phe Cys Ser Asp Pro Asn Lys Tyr Gly Pro Arg Cys 50 55 60 Asn Lys Lys Cys Leu Cys Val His Gly Thr Cys Asn Asn Arg Ile Asp 65 70 75 80 Ser Asp Gly Ala Cys Leu Thr Gly Thr Cys Arg Asp Gly Ser Ala Gly 85 90 95 Arg Leu Cys Asp Lys Gln Thr Ser Ala Cys Gly Pro Tyr Val Gln Phe 100 105 110 Cys His Ile His Ala Thr Cys Glu Tyr Ser Asn Gly Thr Ala Ser Cys 115 120 125 Ile Cys Lys Ala Gly Tyr Glu Gly Asp Gly Thr Leu Cys Ser Glu Met 130 135 140 Asp Pro Cys Thr Gly Leu Thr Pro Gly Gly Cys Ser Arg Asn Ala Glu 145 150 155 160 Cys Ile Lys Thr Gly Thr Gly Thr His Thr Cys Val Cys Gln Gln Gly 165 170 175 Trp Thr Gly Asn Gly Arg Asp Cys Ser Glu Ile Asn Asn Cys Leu Leu 180 185 190 Pro Ser Ala Gly Gly Cys His Asp Asn Ala Ser Cys Leu Tyr Val Gly 195 200 205 Pro Gly Gln Asn Glu Cys Glu Cys Lys Lys Gly Phe Arg Gly Asn Gly 210 215 220 Ile Asp Cys Glu Pro Ile Thr Ser Cys Leu Glu Gln Thr Gly Lys Cys 225 230 235 240 His Pro Leu Ala Ser Cys Gln Ser Thr Ser Ser Gly Val Trp Ser Cys 245 250 255 Val Cys Gln Glu Gly Tyr Glu Gly Asp Gly Phe Leu Cys Tyr 260 265 270 <210> 81 <211> 264 <212> PRT <213> Homo sapiens <400> 81 Thr Arg Glu Cys Cys Ala Gly Phe Phe Gly Pro Gln Cys Gln Pro Cys 1 5 10 15 Pro Gly Asn Ala Gln Asn Val Cys Phe Gly Asn Gly Ile Cys Leu Asp 20 25 30 Gly Val Asn Gly Thr Gly Val Cys Glu Cys Gly Glu Gly Phe Ser Gly 35 40 45 Thr Ala Cys Glu Thr Cys Thr Glu Gly Lys Tyr Gly Ile His Cys Asp 50 55 60 Gln Ala Cys Ser Cys Val His Gly Arg Cys Asn Gln Gly Pro Leu Gly 65 70 75 80 Asp Gly Ser Cys Asp Cys Asp Val Gly Trp Arg Gly Val His Cys Asp 85 90 95 Asn Ala Thr Thr Glu Asp Asn Cys Asn Gly Thr Cys His Thr Ser Ala 100 105 110 Asn Cys Leu Thr Asn Ser Asp Gly Thr Ala Ser Cys Lys Cys Ala Ala 115 120 125 Gly Phe Gln Gly Asn Gly Thr Ile Cys Thr Ala Ile Asn Ala Cys Glu 130 135 140 Ile Ser Asn Gly Gly Cys Ser Ala Lys Ala Asp Cys Lys Arg Thr Thr 145 150 155 160 Pro Gly Arg Arg Val Cys Thr Cys Lys Ala Gly Tyr Thr Gly Asp Gly 165 170 175 Ile Val Cys Leu Glu Ile Asn Pro Cys Leu Glu Asn His Gly Gly Cys 180 185 190 Asp Lys Asn Ala Glu Cys Thr Gln Thr Gly Pro Asn Gln Ala Ala Cys 195 200 205 Asn Cys Leu Pro Ala Tyr Thr Gly Asp Gly Lys Val Cys Thr Leu Ile 210 215 220 Asn Val Cys Leu Thr Lys Asn Gly Gly Cys Ser Glu Phe Ala Ile Cys 225 230 235 240 Asn His Thr Gly Gln Val Glu Arg Thr Cys Thr Cys Lys Pro Asn Tyr 245 250 255 Ile Gly Asp Gly Phe Thr Cys Arg 260 <210> 82 <211> 219 <212> PRT <213> Homo sapiens <400> 82 Ile Pro Arg Cys Cys Lys Gly Tyr Phe Gly Arg Asp Cys Gln Ala Cys 1 5 10 15 Pro Gly Gly Pro Asp Ala Pro Cys Asn Asn Arg Gly Val Cys Leu Asp 20 25 30 Gln Tyr Ser Ala Thr Gly Glu Cys Lys Cys Asn Thr Gly Phe Asn Gly 35 40 45 Thr Ala Cys Glu Met Cys Trp Pro Gly Arg Phe Gly Pro Asp Cys Leu 50 55 60 Pro Cys Gly Cys Ser Asp His Gly Gln Cys Asp Asp Gly Ile Thr Gly 65 70 75 80 Ser Gly Gln Cys Leu Cys Glu Thr Gly Trp Thr Gly Pro Ser Cys Asp 85 90 95 Thr Gln Ala Val Leu Pro Ala Val Cys Thr Pro Pro Cys Ser Ala His 100 105 110 Ala Thr Cys Lys Glu Asn Asn Thr Cys Glu Cys Asn Leu Asp Tyr Glu 115 120 125 Gly Asp Gly Ile Thr Cys Thr Val Val Asp Phe Cys Lys Gln Asp Asn 130 135 140 Gly Gly Cys Ala Lys Val Ala Arg Cys Ser Gln Lys Gly Thr Lys Val 145 150 155 160 Ser Cys Ser Cys Gln Lys Gly Tyr Lys Gly Asp Gly His Ser Cys Thr 165 170 175 Glu Ile Asp Pro Cys Ala Asp Gly Leu Asn Gly Gly Cys His Glu His 180 185 190 Ala Thr Cys Lys Met Thr Gly Pro Gly Lys His Lys Cys Glu Cys Lys 195 200 205 Ser His Tyr Val Gly Asp Gly Leu Asn Cys Glu 210 215 <210> 83 <211> 51 <212> PRT <213> Homo sapiens <400> 83 Gln Pro Arg Cys Cys Pro Gly Arg Trp Gly Pro Asp Cys Ile Glu Cys 1 5 10 15 Pro Gly Gly Ala Gly Ser Pro Cys Asn Gly Arg Gly Ser Cys Ala Glu 20 25 30 Gly Met Glu Gly Asn Gly Thr Cys Ser Cys Gln Glu Gly Phe Gly Gly 35 40 45 Thr Ala Cys 50 <210> 84 <211> 47 <212> PRT <213> Homo sapiens <400> 84 Glu Thr Cys Ala Asp Asp Asn Leu Phe Gly Pro Ser Cys Ser Ser Val 1 5 10 15 Cys Asn Cys Val His Gly Val Cys Asn Ser Gly Leu Asp Gly Asp Gly 20 25 30 Thr Cys Glu Cys Tyr Ser Ala Tyr Thr Gly Pro Lys Cys Asp Lys 35 40 45 <210> 85 <211> 42 <212> PRT <213> Homo sapiens <400> 85 Pro Ile Pro Glu Cys Ala Ala Leu Leu Cys Pro Glu Asn Ser Arg Cys 1 5 10 15 Ser Pro Ser Thr Glu Asp Glu Asn Lys Leu Glu Cys Lys Cys Leu Pro 20 25 30 Asn Tyr Arg Gly Asp Gly Lys Tyr Cys Asp 35 40 <210> 86 <211> 40 <212> PRT <213> Homo sapiens <400> 86 Pro Ile Asn Pro Cys Leu Arg Lys Ile Cys His Pro His Ala His Cys 1 5 10 15 Thr Tyr Leu Gly Pro Asn Arg His Ser Cys Thr Cys Gln Glu Gly Tyr 20 25 30 Arg Gly Asp Gly Gln Val Cys Leu 35 40 <210> 87 <211> 45 <212> PRT <213> Homo sapiens <400> 87 Pro Val Asp Pro Cys Gln Ile Asn Phe Gly Asn Cys Pro Thr Lys Ser 1 5 10 15 Thr Val Cys Lys Tyr Asp Gly Pro Gly Gln Ser His Cys Glu Cys Lys 20 25 30 Glu His Tyr Gln Asn Phe Val Pro Gly Val Gly Cys Ser 35 40 45 <210> 88 <211> 41 <212> PRT <213> Homo sapiens <400> 88 Met Thr Asp Ile Cys Lys Ser Asp Asn Pro Cys His Arg Asn Ala Asn 1 5 10 15 Cys Thr Thr Val Ala Pro Gly Arg Thr Glu Cys Ile Cys Gln Lys Gly 20 25 30 Tyr Val Gly Asp Gly Leu Thr Cys Tyr 35 40 <210> 89 <211> 51 <212> PRT <213> Homo sapiens <400> 89 Ile Pro Lys Cys Cys Lys Gly Phe Tyr Gly Pro Asp Cys Asn Gln Cys 1 5 10 15 Pro Gly Gly Phe Ser Asn Pro Cys Ser Gly Asn Gly Gln Cys Ala Asp 20 25 30 Ser Leu Gly Gly Asn Gly Thr Cys Ile Cys Glu Glu Gly Phe Gln Gly 35 40 45 Ser Gln Cys 50 <210> 90 <211> 50 <212> PRT <213> Homo sapiens <400> 90 Gln Phe Cys Ser Asp Pro Asn Lys Tyr Gly Pro Arg Cys Asn Lys Lys 1 5 10 15 Cys Leu Cys Val His Gly Thr Cys Asn Asn Arg Ile Asp Ser Asp Gly 20 25 30 Ala Cys Leu Thr Gly Thr Cys Arg Asp Gly Ser Ala Gly Arg Leu Cys 35 40 45 Asp Lys 50 <210> 91 <211> 41 <212> PRT <213> Homo sapiens <400> 91 Gln Thr Ser Ala Cys Gly Pro Tyr Val Gln Phe Cys His Ile His Ala 1 5 10 15 Thr Cys Glu Tyr Ser Asn Gly Thr Ala Ser Cys Ile Cys Lys Ala Gly 20 25 30 Tyr Glu Gly Asp Gly Thr Leu Cys Ser 35 40 <210> 92 <211> 43 <212> PRT <213> Homo sapiens <400> 92 Glu Met Asp Pro Cys Thr Gly Leu Thr Pro Gly Gly Cys Ser Arg Asn 1 5 10 15 Ala Glu Cys Ile Lys Thr Gly Thr Gly Thr His Thr Cys Val Cys Gln 20 25 30 Gln Gly Trp Thr Gly Asn Gly Arg Asp Cys Ser 35 40 <210> 93 <211> 43 <212> PRT <213> Homo sapiens <400> 93 Glu Ile Asn Asn Cys Leu Leu Pro Ser Ala Gly Gly Cys His Asp Asn 1 5 10 15 Ala Ser Cys Leu Tyr Val Gly Pro Gly Gln Asn Glu Cys Glu Cys Lys 20 25 30 Lys Gly Phe Arg Gly Asn Gly Ile Asp Cys Glu 35 40 <210> 94 <211> 42 <212> PRT <213> Homo sapiens <400> 94 Pro Ile Thr Ser Cys Leu Glu Gln Thr Gly Lys Cys His Pro Leu Ala 1 5 10 15 Ser Cys Gln Ser Thr Ser Ser Gly Val Trp Ser Cys Val Cys Gln Glu 20 25 30 Gly Tyr Glu Gly Asp Gly Phe Leu Cys Tyr 35 40 <210> 95 <211> 51 <212> PRT <213> Homo sapiens <400> 95 Thr Arg Glu Cys Cys Ala Gly Phe Phe Gly Pro Gln Cys Gln Pro Cys 1 5 10 15 Pro Gly Asn Ala Gln Asn Val Cys Phe Gly Asn Gly Ile Cys Leu Asp 20 25 30 Gly Val Asn Gly Thr Gly Val Cys Glu Cys Gly Glu Gly Phe Ser Gly 35 40 45 Thr Ala Cys 50 <210> 96 <211> 48 <212> PRT <213> Homo sapiens <400> 96 Glu Thr Cys Thr Glu Gly Lys Tyr Gly Ile His Cys Asp Gln Ala Cys 1 5 10 15 Ser Cys Val His Gly Arg Cys Asn Gln Gly Pro Leu Gly Asp Gly Ser 20 25 30 Cys Asp Cys Asp Val Gly Trp Arg Gly Val His Cys Asp Asn Ala Thr 35 40 45 <210> 97 <211> 39 <212> PRT <213> Homo sapiens <400> 97 Thr Glu Asp Asn Cys Asn Gly Thr Cys His Thr Ser Ala Asn Cys Leu 1 5 10 15 Thr Asn Ser Asp Gly Thr Ala Ser Cys Lys Cys Ala Ala Gly Phe Gln 20 25 30 Gly Asn Gly Thr Ile Cys Thr 35 <210> 98 <211> 42 <212> PRT <213> Homo sapiens <400> 98 Ala Ile Asn Ala Cys Glu Ile Ser Asn Gly Gly Cys Ser Ala Lys Ala 1 5 10 15 Asp Cys Lys Arg Thr Thr Pro Gly Arg Arg Val Cys Thr Cys Lys Ala 20 25 30 Gly Tyr Thr Gly Asp Gly Ile Val Cys Leu 35 40 <210> 99 <211> 42 <212> PRT <213> Homo sapiens <400> 99 Glu Ile Asn Pro Cys Leu Glu Asn His Gly Gly Cys Asp Lys Asn Ala 1 5 10 15 Glu Cys Thr Gln Thr Gly Pro Asn Gln Ala Ala Cys Asn Cys Leu Pro 20 25 30 Ala Tyr Thr Gly Asp Gly Lys Val Cys Thr 35 40 <210> 100 <211> 42 <212> PRT <213> Homo sapiens <400> 100 Leu Ile Asn Val Cys Leu Thr Lys Asn Gly Gly Cys Ser Glu Phe Ala 1 5 10 15 Ile Cys Asn His Thr Gly Gln Val Glu Arg Thr Cys Thr Cys Lys Pro 20 25 30 Asn Tyr Ile Gly Asp Gly Phe Thr Cys Arg 35 40 <210> 101 <211> 51 <212> PRT <213> Homo sapiens <400> 101 Ile Pro Arg Cys Cys Lys Gly Tyr Phe Gly Arg Asp Cys Gln Ala Cys 1 5 10 15 Pro Gly Gly Pro Asp Ala Pro Cys Asn Asn Arg Gly Val Cys Leu Asp 20 25 30 Gln Tyr Ser Ala Thr Gly Glu Cys Lys Cys Asn Thr Gly Phe Asn Gly 35 40 45 Thr Ala Cys 50 <210> 102 <211> 49 <212> PRT <213> Homo sapiens <400> 102 Glu Met Cys Trp Pro Gly Arg Phe Gly Pro Asp Cys Leu Pro Cys Gly 1 5 10 15 Cys Ser Asp His Gly Gln Cys Asp Asp Gly Ile Thr Gly Ser Gly Gln 20 25 30 Cys Leu Cys Glu Thr Gly Trp Thr Gly Pro Ser Cys Asp Thr Gln Ala 35 40 45 Val <210> 103 <211> 35 <212> PRT <213> Homo sapiens <400> 103 Leu Pro Ala Val Cys Thr Pro Pro Cys Ser Ala His Ala Thr Cys Lys 1 5 10 15 Glu Asn Asn Thr Cys Glu Cys Asn Leu Asp Tyr Glu Gly Asp Gly Ile 20 25 30 Thr Cys Thr 35 <210> 104 <211> 41 <212> PRT <213> Homo sapiens <400> 104 Val Val Asp Phe Cys Lys Gln Asp Asn Gly Gly Cys Ala Lys Val Ala 1 5 10 15 Arg Cys Ser Gln Lys Gly Thr Lys Val Ser Cys Ser Cys Gln Lys Gly 20 25 30 Tyr Lys Gly Asp Gly His Ser Cys Thr 35 40 <210> 105 <211> 43 <212> PRT <213> Homo sapiens <400> 105 Glu Ile Asp Pro Cys Ala Asp Gly Leu Asn Gly Gly Cys His Glu His 1 5 10 15 Ala Thr Cys Lys Met Thr Gly Pro Gly Lys His Lys Cys Glu Cys Lys 20 25 30 Ser His Tyr Val Gly Asp Gly Leu Asn Cys Glu 35 40 <210> 106 <211> 180 <212> PRT <213> Homo sapiens <400> 106 Gln Pro Arg Cys Cys Pro Gly Arg Trp Gly Pro Asp Cys Ile Glu Cys 1 5 10 15 Pro Gly Gly Ala Gly Ser Pro Cys Asn Gly Arg Gly Ser Cys Ala Glu 20 25 30 Gly Met Glu Gly Asn Gly Thr Cys Ser Cys Gln Glu Gly Phe Gly Gly 35 40 45 Thr Ala Cys Glu Thr Cys Ala Asp Asp Asn Leu Phe Gly Pro Ser Cys 50 55 60 Ser Ser Val Cys Asn Cys Val His Gly Val Cys Asn Ser Gly Leu Asp 65 70 75 80 Gly Asp Gly Thr Cys Glu Cys Tyr Ser Ala Tyr Thr Gly Pro Lys Cys 85 90 95 Asp Lys Pro Ile Pro Glu Cys Ala Ala Leu Leu Cys Pro Glu Asn Ser 100 105 110 Arg Cys Ser Pro Ser Thr Glu Asp Glu Asn Lys Leu Glu Cys Lys Cys 115 120 125 Leu Pro Asn Tyr Arg Gly Asp Gly Lys Tyr Cys Asp Pro Ile Asn Pro 130 135 140 Cys Leu Arg Lys Ile Cys His Pro His Ala His Cys Thr Tyr Leu Gly 145 150 155 160 Pro Asn Arg His Ser Cys Thr Cys Gln Glu Gly Tyr Arg Gly Asp Gly 165 170 175 Gln Val Cys Leu 180 <210> 107 <211> 225 <212> PRT <213> Homo sapiens <400> 107 Gln Pro Arg Cys Cys Pro Gly Arg Trp Gly Pro Asp Cys Ile Glu Cys 1 5 10 15 Pro Gly Gly Ala Gly Ser Pro Cys Asn Gly Arg Gly Ser Cys Ala Glu 20 25 30 Gly Met Glu Gly Asn Gly Thr Cys Ser Cys Gln Glu Gly Phe Gly Gly 35 40 45 Thr Ala Cys Glu Thr Cys Ala Asp Asp Asn Leu Phe Gly Pro Ser Cys 50 55 60 Ser Ser Val Cys Asn Cys Val His Gly Val Cys Asn Ser Gly Leu Asp 65 70 75 80 Gly Asp Gly Thr Cys Glu Cys Tyr Ser Ala Tyr Thr Gly Pro Lys Cys 85 90 95 Asp Lys Pro Ile Pro Glu Cys Ala Ala Leu Leu Cys Pro Glu Asn Ser 100 105 110 Arg Cys Ser Pro Ser Thr Glu Asp Glu Asn Lys Leu Glu Cys Lys Cys 115 120 125 Leu Pro Asn Tyr Arg Gly Asp Gly Lys Tyr Cys Asp Pro Ile Asn Pro 130 135 140 Cys Leu Arg Lys Ile Cys His Pro His Ala His Cys Thr Tyr Leu Gly 145 150 155 160 Pro Asn Arg His Ser Cys Thr Cys Gln Glu Gly Tyr Arg Gly Asp Gly 165 170 175 Gln Val Cys Leu Pro Val Asp Pro Cys Gln Ile Asn Phe Gly Asn Cys 180 185 190 Pro Thr Lys Ser Thr Val Cys Lys Tyr Asp Gly Pro Gly Gln Ser His 195 200 205 Cys Glu Cys Lys Glu His Tyr Gln Asn Phe Val Pro Gly Val Gly Cys 210 215 220 Ser 225 <210> 108 <211> 174 <212> PRT <213> Homo sapiens <400> 108 Glu Thr Cys Ala Asp Asp Asn Leu Phe Gly Pro Ser Cys Ser Ser Val 1 5 10 15 Cys Asn Cys Val His Gly Val Cys Asn Ser Gly Leu Asp Gly Asp Gly 20 25 30 Thr Cys Glu Cys Tyr Ser Ala Tyr Thr Gly Pro Lys Cys Asp Lys Pro 35 40 45 Ile Pro Glu Cys Ala Ala Leu Leu Cys Pro Glu Asn Ser Arg Cys Ser 50 55 60 Pro Ser Thr Glu Asp Glu Asn Lys Leu Glu Cys Lys Cys Leu Pro Asn 65 70 75 80 Tyr Arg Gly Asp Gly Lys Tyr Cys Asp Pro Ile Asn Pro Cys Leu Arg 85 90 95 Lys Ile Cys His Pro His Ala His Cys Thr Tyr Leu Gly Pro Asn Arg 100 105 110 His Ser Cys Thr Cys Gln Glu Gly Tyr Arg Gly Asp Gly Gln Val Cys 115 120 125 Leu Pro Val Asp Pro Cys Gln Ile Asn Phe Gly Asn Cys Pro Thr Lys 130 135 140 Ser Thr Val Cys Lys Tyr Asp Gly Pro Gly Gln Ser His Cys Glu Cys 145 150 155 160 Lys Glu His Tyr Gln Asn Phe Val Pro Gly Val Gly Cys Ser 165 170 <210> 109 <211> 185 <212> PRT <213> Homo sapiens <400> 109 Ile Pro Lys Cys Cys Lys Gly Phe Tyr Gly Pro Asp Cys Asn Gln Cys 1 5 10 15 Pro Gly Gly Phe Ser Asn Pro Cys Ser Gly Asn Gly Gln Cys Ala Asp 20 25 30 Ser Leu Gly Gly Asn Gly Thr Cys Ile Cys Glu Glu Gly Phe Gln Gly 35 40 45 Ser Gln Cys Gln Phe Cys Ser Asp Pro Asn Lys Tyr Gly Pro Arg Cys 50 55 60 Asn Lys Lys Cys Leu Cys Val His Gly Thr Cys Asn Asn Arg Ile Asp 65 70 75 80 Ser Asp Gly Ala Cys Leu Thr Gly Thr Cys Arg Asp Gly Ser Ala Gly 85 90 95 Arg Leu Cys Asp Lys Gln Thr Ser Ala Cys Gly Pro Tyr Val Gln Phe 100 105 110 Cys His Ile His Ala Thr Cys Glu Tyr Ser Asn Gly Thr Ala Ser Cys 115 120 125 Ile Cys Lys Ala Gly Tyr Glu Gly Asp Gly Thr Leu Cys Ser Glu Met 130 135 140 Asp Pro Cys Thr Gly Leu Thr Pro Gly Gly Cys Ser Arg Asn Ala Glu 145 150 155 160 Cys Ile Lys Thr Gly Thr Gly Thr His Thr Cys Val Cys Gln Gln Gly 165 170 175 Trp Thr Gly Asn Gly Arg Asp Cys Ser 180 185 <210> 110 <211> 228 <212> PRT <213> Homo sapiens <400> 110 Ile Pro Lys Cys Cys Lys Gly Phe Tyr Gly Pro Asp Cys Asn Gln Cys 1 5 10 15 Pro Gly Gly Phe Ser Asn Pro Cys Ser Gly Asn Gly Gln Cys Ala Asp 20 25 30 Ser Leu Gly Gly Asn Gly Thr Cys Ile Cys Glu Glu Gly Phe Gln Gly 35 40 45 Ser Gln Cys Gln Phe Cys Ser Asp Pro Asn Lys Tyr Gly Pro Arg Cys 50 55 60 Asn Lys Lys Cys Leu Cys Val His Gly Thr Cys Asn Asn Arg Ile Asp 65 70 75 80 Ser Asp Gly Ala Cys Leu Thr Gly Thr Cys Arg Asp Gly Ser Ala Gly 85 90 95 Arg Leu Cys Asp Lys Gln Thr Ser Ala Cys Gly Pro Tyr Val Gln Phe 100 105 110 Cys His Ile His Ala Thr Cys Glu Tyr Ser Asn Gly Thr Ala Ser Cys 115 120 125 Ile Cys Lys Ala Gly Tyr Glu Gly Asp Gly Thr Leu Cys Ser Glu Met 130 135 140 Asp Pro Cys Thr Gly Leu Thr Pro Gly Gly Cys Ser Arg Asn Ala Glu 145 150 155 160 Cys Ile Lys Thr Gly Thr Gly Thr His Thr Cys Val Cys Gln Gln Gly 165 170 175 Trp Thr Gly Asn Gly Arg Asp Cys Ser Glu Ile Asn Asn Cys Leu Leu 180 185 190 Pro Ser Ala Gly Gly Cys His Asp Asn Ala Ser Cys Leu Tyr Val Gly 195 200 205 Pro Gly Gln Asn Glu Cys Glu Cys Lys Lys Gly Phe Arg Gly Asn Gly 210 215 220 Ile Asp Cys Glu 225 <210> 111 <211> 177 <212> PRT <213> Homo sapiens <400> 111 Gln Phe Cys Ser Asp Pro Asn Lys Tyr Gly Pro Arg Cys Asn Lys Lys 1 5 10 15 Cys Leu Cys Val His Gly Thr Cys Asn Asn Arg Ile Asp Ser Asp Gly 20 25 30 Ala Cys Leu Thr Gly Thr Cys Arg Asp Gly Ser Ala Gly Arg Leu Cys 35 40 45 Asp Lys Gln Thr Ser Ala Cys Gly Pro Tyr Val Gln Phe Cys His Ile 50 55 60 His Ala Thr Cys Glu Tyr Ser Asn Gly Thr Ala Ser Cys Ile Cys Lys 65 70 75 80 Ala Gly Tyr Glu Gly Asp Gly Thr Leu Cys Ser Glu Met Asp Pro Cys 85 90 95 Thr Gly Leu Thr Pro Gly Gly Cys Ser Arg Asn Ala Glu Cys Ile Lys 100 105 110 Thr Gly Thr Gly Thr His Thr Cys Val Cys Gln Gln Gly Trp Thr Gly 115 120 125 Asn Gly Arg Asp Cys Ser Glu Ile Asn Asn Cys Leu Leu Pro Ser Ala 130 135 140 Gly Gly Cys His Asp Asn Ala Ser Cys Leu Tyr Val Gly Pro Gly Gln 145 150 155 160 Asn Glu Cys Glu Cys Lys Lys Gly Phe Arg Gly Asn Gly Ile Asp Cys 165 170 175 Glu <210> 112 <211> 180 <212> PRT <213> Homo sapiens <400> 112 Thr Arg Glu Cys Cys Ala Gly Phe Phe Gly Pro Gln Cys Gln Pro Cys 1 5 10 15 Pro Gly Asn Ala Gln Asn Val Cys Phe Gly Asn Gly Ile Cys Leu Asp 20 25 30 Gly Val Asn Gly Thr Gly Val Cys Glu Cys Gly Glu Gly Phe Ser Gly 35 40 45 Thr Ala Cys Glu Thr Cys Thr Glu Gly Lys Tyr Gly Ile His Cys Asp 50 55 60 Gln Ala Cys Ser Cys Val His Gly Arg Cys Asn Gln Gly Pro Leu Gly 65 70 75 80 Asp Gly Ser Cys Asp Cys Asp Val Gly Trp Arg Gly Val His Cys Asp 85 90 95 Asn Ala Thr Thr Glu Asp Asn Cys Asn Gly Thr Cys His Thr Ser Ala 100 105 110 Asn Cys Leu Thr Asn Ser Asp Gly Thr Ala Ser Cys Lys Cys Ala Ala 115 120 125 Gly Phe Gln Gly Asn Gly Thr Ile Cys Thr Ala Ile Asn Ala Cys Glu 130 135 140 Ile Ser Asn Gly Gly Cys Ser Ala Lys Ala Asp Cys Lys Arg Thr Thr 145 150 155 160 Pro Gly Arg Arg Val Cys Thr Cys Lys Ala Gly Tyr Thr Gly Asp Gly 165 170 175 Ile Val Cys Leu 180 <210> 113 <211> 222 <212> PRT <213> Homo sapiens <400> 113 Thr Arg Glu Cys Cys Ala Gly Phe Phe Gly Pro Gln Cys Gln Pro Cys 1 5 10 15 Pro Gly Asn Ala Gln Asn Val Cys Phe Gly Asn Gly Ile Cys Leu Asp 20 25 30 Gly Val Asn Gly Thr Gly Val Cys Glu Cys Gly Glu Gly Phe Ser Gly 35 40 45 Thr Ala Cys Glu Thr Cys Thr Glu Gly Lys Tyr Gly Ile His Cys Asp 50 55 60 Gln Ala Cys Ser Cys Val His Gly Arg Cys Asn Gln Gly Pro Leu Gly 65 70 75 80 Asp Gly Ser Cys Asp Cys Asp Val Gly Trp Arg Gly Val His Cys Asp 85 90 95 Asn Ala Thr Thr Glu Asp Asn Cys Asn Gly Thr Cys His Thr Ser Ala 100 105 110 Asn Cys Leu Thr Asn Ser Asp Gly Thr Ala Ser Cys Lys Cys Ala Ala 115 120 125 Gly Phe Gln Gly Asn Gly Thr Ile Cys Thr Ala Ile Asn Ala Cys Glu 130 135 140 Ile Ser Asn Gly Gly Cys Ser Ala Lys Ala Asp Cys Lys Arg Thr Thr 145 150 155 160 Pro Gly Arg Arg Val Cys Thr Cys Lys Ala Gly Tyr Thr Gly Asp Gly 165 170 175 Ile Val Cys Leu Glu Ile Asn Pro Cys Leu Glu Asn His Gly Gly Cys 180 185 190 Asp Lys Asn Ala Glu Cys Thr Gln Thr Gly Pro Asn Gln Ala Ala Cys 195 200 205 Asn Cys Leu Pro Ala Tyr Thr Gly Asp Gly Lys Val Cys Thr 210 215 220 <210> 114 <211> 171 <212> PRT <213> Homo sapiens <400> 114 Glu Thr Cys Thr Glu Gly Lys Tyr Gly Ile His Cys Asp Gln Ala Cys 1 5 10 15 Ser Cys Val His Gly Arg Cys Asn Gln Gly Pro Leu Gly Asp Gly Ser 20 25 30 Cys Asp Cys Asp Val Gly Trp Arg Gly Val His Cys Asp Asn Ala Thr 35 40 45 Thr Glu Asp Asn Cys Asn Gly Thr Cys His Thr Ser Ala Asn Cys Leu 50 55 60 Thr Asn Ser Asp Gly Thr Ala Ser Cys Lys Cys Ala Ala Gly Phe Gln 65 70 75 80 Gly Asn Gly Thr Ile Cys Thr Ala Ile Asn Ala Cys Glu Ile Ser Asn 85 90 95 Gly Gly Cys Ser Ala Lys Ala Asp Cys Lys Arg Thr Thr Pro Gly Arg 100 105 110 Arg Val Cys Thr Cys Lys Ala Gly Tyr Thr Gly Asp Gly Ile Val Cys 115 120 125 Leu Glu Ile Asn Pro Cys Leu Glu Asn His Gly Gly Cys Asp Lys Asn 130 135 140 Ala Glu Cys Thr Gln Thr Gly Pro Asn Gln Ala Ala Cys Asn Cys Leu 145 150 155 160 Pro Ala Tyr Thr Gly Asp Gly Lys Val Cys Thr 165 170 <210> 115 <211> 176 <212> PRT <213> Homo sapiens <400> 115 Ile Pro Arg Cys Cys Lys Gly Tyr Phe Gly Arg Asp Cys Gln Ala Cys 1 5 10 15 Pro Gly Gly Pro Asp Ala Pro Cys Asn Asn Arg Gly Val Cys Leu Asp 20 25 30 Gln Tyr Ser Ala Thr Gly Glu Cys Lys Cys Asn Thr Gly Phe Asn Gly 35 40 45 Thr Ala Cys Glu Met Cys Trp Pro Gly Arg Phe Gly Pro Asp Cys Leu 50 55 60 Pro Cys Gly Cys Ser Asp His Gly Gln Cys Asp Asp Gly Ile Thr Gly 65 70 75 80 Ser Gly Gln Cys Leu Cys Glu Thr Gly Trp Thr Gly Pro Ser Cys Asp 85 90 95 Thr Gln Ala Val Leu Pro Ala Val Cys Thr Pro Pro Cys Ser Ala His 100 105 110 Ala Thr Cys Lys Glu Asn Asn Thr Cys Glu Cys Asn Leu Asp Tyr Glu 115 120 125 Gly Asp Gly Ile Thr Cys Thr Val Val Asp Phe Cys Lys Gln Asp Asn 130 135 140 Gly Gly Cys Ala Lys Val Ala Arg Cys Ser Gln Lys Gly Thr Lys Val 145 150 155 160 Ser Cys Ser Cys Gln Lys Gly Tyr Lys Gly Asp Gly His Ser Cys Thr 165 170 175 <210> 116 <211> 168 <212> PRT <213> Homo sapiens <400> 116 Glu Met Cys Trp Pro Gly Arg Phe Gly Pro Asp Cys Leu Pro Cys Gly 1 5 10 15 Cys Ser Asp His Gly Gln Cys Asp Asp Gly Ile Thr Gly Ser Gly Gln 20 25 30 Cys Leu Cys Glu Thr Gly Trp Thr Gly Pro Ser Cys Asp Thr Gln Ala 35 40 45 Val Leu Pro Ala Val Cys Thr Pro Pro Cys Ser Ala His Ala Thr Cys 50 55 60 Lys Glu Asn Asn Thr Cys Glu Cys Asn Leu Asp Tyr Glu Gly Asp Gly 65 70 75 80 Ile Thr Cys Thr Val Val Asp Phe Cys Lys Gln Asp Asn Gly Gly Cys 85 90 95 Ala Lys Val Ala Arg Cys Ser Gln Lys Gly Thr Lys Val Ser Cys Ser 100 105 110 Cys Gln Lys Gly Tyr Lys Gly Asp Gly His Ser Cys Thr Glu Ile Asp 115 120 125 Pro Cys Ala Asp Gly Leu Asn Gly Gly Cys His Glu His Ala Thr Cys 130 135 140 Lys Met Thr Gly Pro Gly Lys His Lys Cys Glu Cys Lys Ser His Tyr 145 150 155 160 Val Gly Asp Gly Leu Asn Cys Glu 165 <110> Kyungpook national university industry-academic cooperation foundation <120> Composition for drug delivery comprising the polypeptide fragment of EGF-like domain repeat protein of stabilin-2 and use <130> NP08-0001 <160> 116 <170> KopatentIn 1.71 <210> 1 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Stab-U1 sense <400> 1 aaaaggatcc gtaggggttc gagattg 27 <210> 2 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> Stab-U1 antisense <400> 2 aaaactcgag tcagggagga atgagaac 28 <210> 3 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> Stab-U2 sense <400> 3 aaaaggatcc aactctgagc ccacag 26 <210> 4 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Stab-U2 antisense <400> 4 aaaactcgag tcactgaatt tccag 25 <210> 5 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Stab-U3 sense <400> 5 aaaaggatcc gagaagagga gatgc 25 <210> 6 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Stab-U3 antisense <400> 6 aaaactcgag tcaatcaatc agcagac 27 <210> 7 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> Stab-U4 sense <400> 7 aaaaggatcc aggtggagta aaccaaag 28 <210> 8 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> Stab-U4 antisense <400> 8 aaaactcgag tcagggtgct tttaaaggc 29 <210> 9 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> E1 antisense <400> 9 aaaaactcga gtcaataaca cgttaagcc 29 <210> 10 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> E2 antisense <400> 10 aaaaactcga gtcaatagca cagaaagcc 29 <210> 11 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> E3 antisense <400> 11 aaaaactcga gtcagcggca ggtaaatcc 29 <210> 12 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> E4 antisense <400> 12 aaaaactcga gtcactcaca gttcagccc 29 <210> 13 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> F5 sense <400> 13 aaaaggatcc actgtttttg cacc 24 <210> 14 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> F5 antisense <400> 14 aaaactcgag tcatttggga gatagcaa 28 <210> 15 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> signal sense <400> 15 aaaatgctag ctcagcctga caggtgc 27 <210> 16 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> signal antisense <400> 16 aaaatctcga gtcttgcctg ccctgtg 27 <210> 17 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> TMC sense <400> 17 aaaaaggatc cacccacact ggcttg 26 <210> 18 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> TMC antisense <400> 18 cccgtccaag cttgcacagt gtcct 25 <210> 19 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> EGF3 sense <400> 19 aaaacctcga gagatgtgat aataatgac 29 <210> 20 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> EGF3 antisense <400> 20 aaaaaggatc cgcggcaggt aaatcc 26 <210> 21 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> E3-16 sense <400> 21 aaaaaggatc cacgagagaa tgctgtgcc 29 <210> 22 <211> 31 <212> DNA <213> Artificial Sequence <220> <223> E3-16 antisense <400> 22 aaaactcgag tcagcggcag gtaaatccat c 31 <210> 23 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> E3-15 antisense <400> 23 gatctcgagt tatgtgcaga cctttccatc 30 <210> 24 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> E3-14 antisense <400> 24 gatctcgagt tacaggcaca caatgcc 27 <210> 25 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> E3-13 antisense <400> 25 gatctcgagt tatgtgcaga tggtccc 27 <210> 26 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> E3-12 antisense <400> 26 gatctcgagt taggttgcat tgtcac 26 <210> 27 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> E3-1 antisense <400> 27 gatctcgagt tagcaggctg tgccgc 26 <210> 28 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> E3-26 sense <400> 28 aaaaaggatc cgagacctgc accgag 26 <210> 29 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> E3-36 sense <400> 29 aaaaggatcc acagaagaca actgcaatg 29 <210> 30 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> E3-46 sense <400> 30 aaaaggatcc gcaatcaatg cctgtgag 28 <210> 31 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> E3-56 sense <400> 31 aaaaggatcc ggaatcaacc cgtgtttg 28 <210> 32 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> E3-6 sense <400> 32 aaaaggatcc ctcatcaatg tctgcttaac 30 <210> 33 <211> 1770 <212> DNA <213> Homo sapiens <400> 33 gtaggggttc gagattgcag gtacaccttt gaggtcagaa catactctct gtctctcccc 60 ggatgccgcc atatttgtag gaaggactat ctccaacctc ggtgttgtcc tggccgctgg 120 ggcccagact gtatagagtg cccaggtgga gcggggtcac cctgcaatgg cagaggcagt 180 tgtgctgaag gcatggaagg aaatggaacc tgctcctgcc aagaagggtt tggtggaaca 240 gcctgtgaaa cctgtgctga cgacaactta tttggaccca gctgttcatc agtgtgcaac 300 tgtgtgcatg gggtgtgcaa cagtggacta gatggcgatg gaacctgtga gtgctactct 360 gcgtacactg gccccaagtg tgacaagccc atccctgaat gtgcagcctt gctctgccca 420 gaaaattcca gatgttcgcc ttccactgaa gatgaaaaca aactggaatg caaatgcctt 480 cccaattacc gaggcgatgg caaatactgc gaccccatca atccatgttt acgaaaaatc 540 tgccaccctc atgctcattg tacgtacctg ggaccaaatc ggcacagttg tacatgccaa 600 gaaggctacc gtggggatgg ccaagtgtgc ttgcctgtgg acccctgcca aattaacttt 660 ggaaactgcc ctacaaagtc tacagtgtgc aaatatgatg ggcctggaca gtctcactgc 720 gagtgtaagg agcattacca gaatttcgta cctggagtgg ggtgcagtat gactgatata 780 tgtaaatcag ataacccgtg tcataggaat gcaaattgca ccaccgtcgc accaggccga 840 actgaatgca tttgccagaa aggttacgtg ggtgatggct taacgtgtta tggaaacatt 900 atggagcgac tcagagaatt aaatactgaa cccagaggaa aatggcaagg aaggctgacc 960 tctttcatct cactcctaga caaagcttat gcctggccac tgagtaagct gggacccttc 1020 acggtgctgt tacctacaga caagggactg aaaggattca atgtaaatga gcttttggtg 1080 gataataaag ctgctcaata ctttgtgaaa ctccacataa ttgctggtca gatgaacatc 1140 gaatatatga ataacacaga catgttctac accttgactg gaaagtcggg ggaaatcttc 1200 aacagcgata aggacaatca aataaagctt aaactccatg gaggcaaaaa gaaggtaaaa 1260 attatacaag gggacatcat tgcttccaat gggcttctgc acatccttga cagagccatg 1320 gacaagttag aacccacatt tgagagcaac aatgagcaaa ccataatgac aatgctacaa 1380 ccaaggtaca gcaagttcag atctttgtta gaggaaacca atttgggaca tgccttagat 1440 gaggatggag ttggtggacc atacaccatt tttgttccaa ataatgaagc attgaataac 1500 atgaaggacg gcactctcga ttacctcctt tctccagagg gatctcggaa gcttctggaa 1560 ctcgtcagat accacattgt cccatttacc cagcttgaag tggccactct catctccacc 1620 cctcacatca ggagcatggc caaccagctc atacagttca acaccaccga caatggacag 1680 attctggcaa atgatgtggc aatggaagaa attgagatca ctgccaaaaa tggccgaatt 1740 tacacactga caggagttct cattcctccc 1770 <210> 34 <211> 1734 <212> DNA <213> Homo sapiens <400> 34 aactctgagc ccacagcact cttcacacac agatgtgtct acagtggcag gtttgggagc 60 ctgaagagcg gctgtgcccg gtactgcaat gccactgtga agattccaaa gtgctgcaaa 120 ggcttctatg gacctgactg caaccagtgt ccaggaggct tctcaaatcc atgctcagga 180 aatggacagt gtgcagatag cctcggcggc aacgggacat gcatttgtga ggagggcttc 240 caaggctccc agtgtcagtt ctgctctgat cccaataaat acggacctcg gtgtaacaaa 300 aaatgcctgt gcgttcacgg aacatgcaat aacaggatag acagcgatgg ggcctgcctc 360 actggcacat gcagagacgg ctctgccggg agactctgtg ataagcagac ctcagcctgt 420 gggccctacg tgcagttctg tcacatccac gccacctgtg aatacagcaa tgggacagcc 480 agttgtattt gcaaagcagg atatgaagga gatggaactc tgtgttctga gatggaccct 540 tgcacaggac taactccagg aggctgtagc cgcaatgcag aatgcatcaa aactggcacg 600 ggcacccaca cctgcgtgtg tcagcagggt tggacaggga atgggagaga ctgctcggag 660 atcaacaact gcctgctgcc cagtgcaggc ggctgccacg acaacgcatc ctgtttgtat 720 gtgggtcccg ggcagaatga gtgtgagtgc aagaaaggat ttcgaggaaa tgggattgac 780 tgtgaaccaa taacttcatg cttggaacaa accgggaaat gtcatccatt ggcaagctgt 840 caatctactt cgtctggtgt ctggagctgt gtttgtcaag agggctatga aggagatggc 900 tttctgtgct atggaaacgc agcagtggaa ttgtcatttc tctccgaagc agctatattt 960 aaccgatgga taaataatgc ttctctacaa cccacactgt cagccacctc aaacctcact 1020 gtcctcgtgc cttcccaaca agctactgag gacatggacc aggatgagaa aagcttctgg 1080 ttgtcacaga gcaatattcc agccctaata aagtaccata tgctactagg cacatacaga 1140 gtggcagatc tgcagaccct gtcttcttct gacatgttgg caacatcttt gcagggcaac 1200 ttccttcact tggcaaaggt ggatgggaat atcacaattg aaggggcctc cattgtcgat 1260 ggggacaacg cagccacaaa tggagtgata cacatcatca acaaggtgct ggtcccacaa 1320 agacgtctaa ctggctcctt accaaacctg ctcatgcggc tggaacagat gcctgactat 1380 tccatcttcc ggggctacat cattcaatat aatctggcga atgcaattga ggctgccgat 1440 gcctacacag tgtttgctcc aaacaacaat gccatcgaga attacatcag ggagaagaaa 1500 gtcttgtctc tagaggagga cgtcctccgg tatcatgtgg tcctggagga gaaactcctg 1560 aagaatgacc tgcacaatgg catgcatcgt gagaccatgc tgggtttctc ctatttcctt 1620 agcttctttc tccataatga ccagctctat gtaaatgagg ctccaataaa ctacaccaat 1680 gtagccactg ataagggagt gatccatggc ttgggaaaag ttctggaaat tcag 1734 <210> 35 <211> 1743 <212> DNA <213> Homo sapiens <400> 35 gagaagagga gatgcatcta tacctcctat ttcatgggaa gacgaaccct gtttattggg 60 tgccagccaa aatgtgtgag aaccgtcatt acgagagaat gctgtgccgg cttctttggc 120 ccccaatgcc agccctgccc agggaatgcc cagaatgtct gctttggtaa tggcatctgt 180 ttggatggag tgaatggcac aggtgtgtgt gagtgtgggg agggcttcag cggcacagcc 240 tgcgagacct gcaccgaggg caagtacggc atccactgtg accaagcatg ttcttgtgtc 300 catgggagat gcaaccaagg acccttggga gatggctcct gtgactgtga tgttggctgg 360 cgaggagtgc attgtgacaa tgcaaccaca gaagacaact gcaatgggac atgccatacc 420 agcgccaact gcctcaccaa ctcagatggt acagcttcat gcaagtgtgc agcaggattc 480 caaggaaacg ggaccatctg cacagcaatc aatgcctgtg agatcagcaa tggaggttgc 540 tctgccaagg ctgactgtaa gagaaccacc ccaggaaggc gagtgtgcac gtgcaaagca 600 ggctacacgg gtgatggcat tgtgtgcctg gaaatcaacc cgtgtttgga gaaccatggt 660 ggctgtgaca agaatgcgga gtgcacacag acaggaccca accaggctgc ctgtaactgt 720 ttgccagcat acactggaga tggaaaggtc tgcacactca tcaatgtctg cttaactaaa 780 aatggcggct gtagtgaatt tgccatctgc aaccacactg ggcaagtaga aaggacttgt 840 acttgcaagc caaactacat tggagatgga tttacctgcc gcggcagcat ttatcaggag 900 cttcccaaga acccgaaaac ttcccagtat ttcttccagt tgcaggagca tttcgtgaaa 960 gatctggtcg gcccaggccc cttcactgtt tttgcacctt tatctgcagc ctttgatgag 1020 gaagctcggg ttaaagactg ggacaaatac ggtttaatgc cccaggttct tcggtaccat 1080 gtggtcgcct gccaccagct gcttctggaa aacctgaaat tgatctcaaa tgctacttcc 1140 ctccaaggag agccaatagt catctccgtc tctcagagca cggtgtatat aaacaataag 1200 gctaagatca tatccagtga tatcatcagt actaatggga ttgttcatat catagacaaa 1260 ttgctatctc ccaaaaattt gcttatcact cccaaagaca actctggaag aattctgcaa 1320 aatcttacga ctttggcaac aaacaatggc tacatcaaat ttagcaactt aatacaggac 1380 tcaggtttgc tgagtgtcat caccgatccc atccacaccc cagtcactct cttctggccc 1440 accgaccaag ccctccatgc cctacctgct gaacaacagg acttcctgtt caaccaagac 1500 aacaaggaca agctgaagga gtatttgaag tttcatgtga tacgagatgc caaggtttta 1560 gctgtggatc ttcccacatc cactgcctgg aagaccctgc aaggttcaga gctgagtgtg 1620 aaatgtggag ctggcaggga catcggtgac ctctttctga atggccaaac ctgcagaatt 1680 gtgcagcggg agctcttgtt tgacctgggt gtggcctacg gcattgactg tctgctgatt 1740 gat 1743 <210> 36 <211> 1611 <212> DNA <213> Homo sapiens <400> 36 aggtggagta aaccaaaggg tgtgaagcag aagtgtctct acaacctgcc cttcaagagg 60 aacctggaag gctgccggga gcggtgcagc ctggtgatac agatccccag gtgctgcaag 120 ggctacttcg ggcgagactg tcaggcctgc cctggaggac cagatgcccc gtgtaataac 180 cggggtgtct gccttgatca gtactcggcc accggagagt gtaaatgcaa caccggcttc 240 aatgggacgg cgtgtgagat gtgctggccg gggagattcg ggcctgattg tctgccctgt 300 ggctgctcag accacggaca gtgcgatgat ggcatcacgg gctccgggca gtgcctctgt 360 gaaacggggt ggacaggccc ctcgtgtgac actcaggcag ttttgcctgc agtgtgtacg 420 cctccttgtt ctgctcatgc cacctgtaag gagaacaaca cgtgtgagtg taacctggat 480 tatgaaggtg acggaatcac atgcacagtt gtggatttct gcaaacagga caacgggggc 540 tgtgcaaagg tggccagatg ctcccagaag ggcacgaagg tctcctgcag ctgccagaag 600 ggatacaaag gggacgggca cagctgcaca gagatagacc cctgtgcaga cggccttaac 660 ggagggtgtc acgagcacgc cacctgtaag atgacaggcc cgggcaagca caagtgtgag 720 tgtaaaagtc actatgtcgg agatgggctg aactgtgagc cggagcagct gcccattgac 780 cgctgcttac aggacaatgg gcagtgccat gcagacgcca aatgtgtcga cctccacttc 840 caggatacca ctgttggggt gttccatcta cgctccccac tgggccagta taagctgacc 900 tttgacaaag ccagagaggc ctgtgccaac gaagctgcga ccatggcaac ctacaaccag 960 ctctcctatg cccagaaggc caagtaccac ctgtgctcag caggctggct ggagaccggg 1020 cgggttgcct accccacagc cttcgcctcc cagaactgtg gctctggtgt ggttgggata 1080 gtggactatg gacctagacc caacaagagt gaaatgtggg atgtcttctg ctatcggatg 1140 aaagatgtga actgcacctg caaggtgggc tatgtgggag atggcttctc atgcagtggg 1200 aacctgctgc aggtcctgat gtccttcccc tcactcacaa acttcctgac ggaagtgctg 1260 gcctattcca acagctcagc tcgaggccgt gcatttctag aacacctgac tgacctgtcc 1320 atccgcggca ccctctttgt gccacagaac agtgggctgg gggagaatga gaccttgtct 1380 gggcgggaca tcgagcacca cctcgccaat gtcagcatgt ttttctacaa tgaccttgtc 1440 aatggcacca ccctgcaaac gaggctggga agcaagctgc tcatcactgc cagccaggac 1500 ccactccaac cgacggagac caggtttgtt gatggaagag ccattctgca gtgggacatc 1560 tttgcctcca atgggatcat tcatgtcatt tccaggcctt taaaagcacc c 1611 <210> 37 <211> 891 <212> DNA <213> Homo sapiens <400> 37 gtaggggttc gagattgcag gtacaccttt gaggtcagaa catactctct gtctctcccc 60 ggatgccgcc atatttgtag gaaggactat ctccaacctc ggtgttgtcc tggccgctgg 120 ggcccagact gtatagagtg cccaggtgga gcggggtcac cctgcaatgg cagaggcagt 180 tgtgctgaag gcatggaagg aaatggaacc tgctcctgcc aagaagggtt tggtggaaca 240 gcctgtgaaa cctgtgctga cgacaactta tttggaccca gctgttcatc agtgtgcaac 300 tgtgtgcatg gggtgtgcaa cagtggacta gatggcgatg gaacctgtga gtgctactct 360 gcgtacactg gccccaagtg tgacaagccc atccctgaat gtgcagcctt gctctgccca 420 gaaaattcca gatgttcgcc ttccactgaa gatgaaaaca aactggaatg caaatgcctt 480 cccaattacc gaggcgatgg caaatactgc gaccccatca atccatgttt acgaaaaatc 540 tgccaccctc atgctcattg tacgtacctg ggaccaaatc ggcacagttg tacatgccaa 600 gaaggctacc gtggggatgg ccaagtgtgc ttgcctgtgg acccctgcca aattaacttt 660 ggaaactgcc ctacaaagtc tacagtgtgc aaatatgatg ggcctggaca gtctcactgc 720 gagtgtaagg agcattacca gaatttcgta cctggagtgg ggtgcagtat gactgatata 780 tgtaaatcag ataacccgtg tcataggaat gcaaattgca ccaccgtcgc accaggccga 840 actgaatgca tttgccagaa aggttacgtg ggtgatggct taacgtgtta t 891 <210> 38 <211> 912 <212> DNA <213> Homo sapiens <400> 38 aactctgagc ccacagcact cttcacacac agatgtgtct acagtggcag gtttgggagc 60 ctgaagagcg gctgtgcccg gtactgcaat gccactgtga agattccaaa gtgctgcaaa 120 ggcttctatg gacctgactg caaccagtgt ccaggaggct tctcaaatcc atgctcagga 180 aatggacagt gtgcagatag cctcggcggc aacgggacat gcatttgtga ggagggcttc 240 caaggctccc agtgtcagtt ctgctctgat cccaataaat acggacctcg gtgtaacaaa 300 aaatgcctgt gcgttcacgg aacatgcaat aacaggatag acagcgatgg ggcctgcctc 360 actggcacat gcagagacgg ctctgccggg agactctgtg ataagcagac ctcagcctgt 420 gggccctacg tgcagttctg tcacatccac gccacctgtg aatacagcaa tgggacagcc 480 agttgtattt gcaaagcagg atatgaagga gatggaactc tgtgttctga gatggaccct 540 tgcacaggac taactccagg aggctgtagc cgcaatgcag aatgcatcaa aactggcacg 600 ggcacccaca cctgcgtgtg tcagcagggt tggacaggga atgggagaga ctgctcggag 660 atcaacaact gcctgctgcc cagtgcaggc ggctgccacg acaacgcatc ctgtttgtat 720 gtgggtcccg ggcagaatga gtgtgagtgc aagaaaggat ttcgaggaaa tgggattgac 780 tgtgaaccaa taacttcatg cttggaacaa accgggaaat gtcatccatt ggcaagctgt 840 caatctactt cgtctggtgt ctggagctgt gtttgtcaag agggctatga aggagatggc 900 tttctgtgct at 912 <210> 39 <211> 882 <212> DNA <213> Homo sapiens <400> 39 gagaagagga gatgcatcta tacctcctat ttcatgggaa gacgaaccct gtttattggg 60 tgccagccaa aatgtgtgag aaccgtcatt acgagagaat gctgtgccgg cttctttggc 120 ccccaatgcc agccctgccc agggaatgcc cagaatgtct gctttggtaa tggcatctgt 180 ttggatggag tgaatggcac aggtgtgtgt gagtgtgggg agggcttcag cggcacagcc 240 tgcgagacct gcaccgaggg caagtacggc atccactgtg accaagcatg ttcttgtgtc 300 catgggagat gcaaccaagg acccttggga gatggctcct gtgactgtga tgttggctgg 360 cgaggagtgc attgtgacaa tgcaaccaca gaagacaact gcaatgggac atgccatacc 420 agcgccaact gcctcaccaa ctcagatggt acagcttcat gcaagtgtgc agcaggattc 480 caaggaaacg ggaccatctg cacagcaatc aatgcctgtg agatcagcaa tggaggttgc 540 tctgccaagg ctgactgtaa gagaaccacc ccaggaaggc gagtgtgcac gtgcaaagca 600 ggctacacgg gtgatggcat tgtgtgcctg gaaatcaacc cgtgtttgga gaaccatggt 660 ggctgtgaca agaatgcgga gtgcacacag acaggaccca accaggctgc ctgtaactgt 720 ttgccagcat acactggaga tggaaaggtc tgcacactca tcaatgtctg cttaactaaa 780 aatggcggct gtagtgaatt tgccatctgc aaccacactg ggcaagtaga aaggacttgt 840 acttgcaagc caaactacat tggagatgga tttacctgcc gc 882 <210> 40 <211> 759 <212> DNA <213> Homo sapiens <400> 40 aggtggagta aaccaaaggg tgtgaagcag aagtgtctct acaacctgcc cttcaagagg 60 aacctggaag gctgccggga gcggtgcagc ctggtgatac agatccccag gtgctgcaag 120 ggctacttcg ggcgagactg tcaggcctgc cctggaggac cagatgcccc gtgtaataac 180 cggggtgtct gccttgatca gtactcggcc accggagagt gtaaatgcaa caccggcttc 240 aatgggacgg cgtgtgagat gtgctggccg gggagattcg ggcctgattg tctgccctgt 300 ggctgctcag accacggaca gtgcgatgat ggcatcacgg gctccgggca gtgcctctgt 360 gaaacggggt ggacaggccc ctcgtgtgac actcaggcag ttttgcctgc agtgtgtacg 420 cctccttgtt ctgctcatgc cacctgtaag gagaacaaca cgtgtgagtg taacctggat 480 tatgaaggtg acggaatcac atgcacagtt gtggatttct gcaaacagga caacgggggc 540 tgtgcaaagg tggccagatg ctcccagaag ggcacgaagg tctcctgcag ctgccagaag 600 ggatacaaag gggacgggca cagctgcaca gagatagacc cctgtgcaga cggccttaac 660 ggagggtgtc acgagcacgc cacctgtaag atgacaggcc cgggcaagca caagtgtgag 720 tgtaaaagtc actatgtcgg agatgggctg aactgtgag 759 <210> 41 <211> 153 <212> DNA <213> Homo sapiens <400> 41 caacctcggt gttgtcctgg ccgctggggc ccagactgta tagagtgccc aggtggagcg 60 gggtcaccct gcaatggcag aggcagttgt gctgaaggca tggaaggaaa tggaacctgc 120 tcctgccaag aagggtttgg tggaacagcc tgt 153 <210> 42 <211> 141 <212> DNA <213> Homo sapiens <400> 42 gaaacctgtg ctgacgacaa cttatttgga cccagctgtt catcagtgtg caactgtgtg 60 catggggtgt gcaacagtgg actagatggc gatggaacct gtgagtgcta ctctgcgtac 120 actggcccca agtgtgacaa g 141 <210> 43 <211> 126 <212> DNA <213> Homo sapiens <400> 43 cccatccctg aatgtgcagc cttgctctgc ccagaaaatt ccagatgttc gccttccact 60 gaagatgaaa acaaactgga atgcaaatgc cttcccaatt accgaggcga tggcaaatac 120 tgcgac 126 <210> 44 <211> 120 <212> DNA <213> Homo sapiens <400> 44 cccatcaatc catgtttacg aaaaatctgc caccctcatg ctcattgtac gtacctggga 60 ccaaatcggc acagttgtac atgccaagaa ggctaccgtg gggatggcca agtgtgcttg 120 120 <210> 45 <211> 135 <212> DNA <213> Homo sapiens <400> 45 cctgtggacc cctgccaaat taactttgga aactgcccta caaagtctac agtgtgcaaa 60 tatgatgggc ctggacagtc tcactgcgag tgtaaggagc attaccagaa tttcgtacct 120 ggagtggggt gcagt 135 <210> 46 <211> 123 <212> DNA <213> Homo sapiens <400> 46 atgactgata tatgtaaatc agataacccg tgtcatagga atgcaaattg caccaccgtc 60 gcaccaggcc gaactgaatg catttgccag aaaggttacg tgggtgatgg cttaacgtgt 120 tat 123 <210> 47 <211> 153 <212> DNA <213> Homo sapiens <400> 47 attccaaagt gctgcaaagg cttctatgga cctgactgca accagtgtcc aggaggcttc 60 tcaaatccat gctcaggaaa tggacagtgt gcagatagcc tcggcggcaa cgggacatgc 120 atttgtgagg agggcttcca aggctcccag tgt 153 <210> 48 <211> 150 <212> DNA <213> Homo sapiens <400> 48 cagttctgct ctgatcccaa taaatacgga cctcggtgta acaaaaaatg cctgtgcgtt 60 cacggaacat gcaataacag gatagacagc gatggggcct gcctcactgg cacatgcaga 120 gacggctctg ccgggagact ctgtgataag 150 <210> 49 <211> 123 <212> DNA <213> Homo sapiens <400> 49 cagacctcag cctgtgggcc ctacgtgcag ttctgtcaca tccacgccac ctgtgaatac 60 agcaatggga cagccagttg tatttgcaaa gcaggatatg aaggagatgg aactctgtgt 120 tct 123 <210> 50 <211> 129 <212> DNA <213> Homo sapiens <400> 50 gagatggacc cttgcacagg actaactcca ggaggctgta gccgcaatgc agaatgcatc 60 aaaactggca cgggcaccca cacctgcgtg tgtcagcagg gttggacagg gaatgggaga 120 gactgctcg 129 <210> 51 <211> 129 <212> DNA <213> Homo sapiens <400> 51 gagatcaaca actgcctgct gcccagtgca ggcggctgcc acgacaacgc atcctgtttg 60 tatgtgggtc ccgggcagaa tgagtgtgag tgcaagaaag gatttcgagg aaatgggatt 120 gactgtgaa 129 <210> 52 <211> 126 <212> DNA <213> Homo sapiens <400> 52 ccaataactt catgcttgga acaaaccggg aaatgtcatc cattggcaag ctgtcaatct 60 acttcgtctg gtgtctggag ctgtgtttgt caagagggct atgaaggaga tggctttctg 120 tgctat 126 <210> 53 <211> 153 <212> DNA <213> Homo sapiens <400> 53 acgagagaat gctgtgccgg cttctttggc ccccaatgcc agccctgccc agggaatgcc 60 cagaatgtct gctttggtaa tggcatctgt ttggatggag tgaatggcac aggtgtgtgt 120 gagtgtgggg agggcttcag cggcacagcc tgc 153 <210> 54 <211> 144 <212> DNA <213> Homo sapiens <400> 54 gagacctgca ccgagggcaa gtacggcatc cactgtgacc aagcatgttc ttgtgtccat 60 gggagatgca accaaggacc cttgggagat ggctcctgtg actgtgatgt tggctggcga 120 ggagtgcatt gtgacaatgc aacc 144 <210> 55 <211> 117 <212> DNA <213> Homo sapiens <400> 55 acagaagaca actgcaatgg gacatgccat accagcgcca actgcctcac caactcagat 60 ggtacagctt catgcaagtg tgcagcagga ttccaaggaa acgggaccat ctgcaca 117 <210> 56 <211> 126 <212> DNA <213> Homo sapiens <400> 56 gcaatcaatg cctgtgagat cagcaatgga ggttgctctg ccaaggctga ctgtaagaga 60 accaccccag gaaggcgagt gtgcacgtgc aaagcaggct acacgggtga tggcattgtg 120 tgcctg 126 <210> 57 <211> 126 <212> DNA <213> Homo sapiens <400> 57 gaaatcaacc cgtgtttgga gaaccatggt ggctgtgaca agaatgcgga gtgcacacag 60 acaggaccca accaggctgc ctgtaactgt ttgccagcat acactggaga tggaaaggtc 120 tgcaca 126 <210> 58 <211> 126 <212> DNA <213> Homo sapiens <400> 58 ctcatcaatg tctgcttaac taaaaatggc ggctgtagtg aatttgccat ctgcaaccac 60 actgggcaag tagaaaggac ttgtacttgc aagccaaact acattggaga tggatttacc 120 tgccgc 126 <210> 59 <211> 153 <212> DNA <213> Homo sapiens <400> 59 atccccaggt gctgcaaggg ctacttcggg cgagactgtc aggcctgccc tggaggacca 60 gatgccccgt gtaataaccg gggtgtctgc cttgatcagt actcggccac cggagagtgt 120 aaatgcaaca ccggcttcaa tgggacggcg tgt 153 <210> 60 <211> 147 <212> DNA <213> Homo sapiens <400> 60 gagatgtgct ggccggggag attcgggcct gattgtctgc cctgtggctg ctcagaccac 60 ggacagtgcg atgatggcat cacgggctcc gggcagtgcc tctgtgaaac ggggtggaca 120 ggcccctcgt gtgacactca ggcagtt 147 <210> 61 <211> 105 <212> DNA <213> Homo sapiens <400> 61 ttgcctgcag tgtgtacgcc tccttgttct gctcatgcca cctgtaagga gaacaacacg 60 tgtgagtgta acctggatta tgaaggtgac ggaatcacat gcaca 105 <210> 62 <211> 123 <212> DNA <213> Homo sapiens <400> 62 gttgtggatt tctgcaaaca ggacaacggg ggctgtgcaa aggtggccag atgctcccag 60 aagggcacga aggtctcctg cagctgccag aagggataca aaggggacgg gcacagctgc 120 aca 123 <210> 63 <211> 129 <212> DNA <213> Homo sapiens <400> 63 gagatagacc cctgtgcaga cggccttaac ggagggtgtc acgagcacgc cacctgtaag 60 atgacaggcc cgggcaagca caagtgtgag tgtaaaagtc actatgtcgg agatgggctg 120 aactgtgag 129 <210> 64 <211> 540 <212> DNA <213> Homo sapiens <400> 64 caacctcggt gttgtcctgg ccgctggggc ccagactgta tagagtgccc aggtggagcg 60 gggtcaccct gcaatggcag aggcagttgt gctgaaggca tggaaggaaa tggaacctgc 120 tcctgccaag aagggtttgg tggaacagcc tgtgaaacct gtgctgacga caacttattt 180 ggacccagct gttcatcagt gtgcaactgt gtgcatgggg tgtgcaacag tggactagat 240 ggcgatggaa cctgtgagtg ctactctgcg tacactggcc ccaagtgtga caagcccatc 300 cctgaatgtg cagccttgct ctgcccagaa aattccagat gttcgccttc cactgaagat 360 gaaaacaaac tggaatgcaa atgccttccc aattaccgag gcgatggcaa atactgcgac 420 cccatcaatc catgtttacg aaaaatctgc caccctcatg ctcattgtac gtacctggga 480 ccaaatcggc acagttgtac atgccaagaa ggctaccgtg gggatggcca agtgtgcttg 540 540 <210> 65 <211> 675 <212> DNA <213> Homo sapiens <400> 65 caacctcggt gttgtcctgg ccgctggggc ccagactgta tagagtgccc aggtggagcg 60 gggtcaccct gcaatggcag aggcagttgt gctgaaggca tggaaggaaa tggaacctgc 120 tcctgccaag aagggtttgg tggaacagcc tgtgaaacct gtgctgacga caacttattt 180 ggacccagct gttcatcagt gtgcaactgt gtgcatgggg tgtgcaacag tggactagat 240 ggcgatggaa cctgtgagtg ctactctgcg tacactggcc ccaagtgtga caagcccatc 300 cctgaatgtg cagccttgct ctgcccagaa aattccagat gttcgccttc cactgaagat 360 gaaaacaaac tggaatgcaa atgccttccc aattaccgag gcgatggcaa atactgcgac 420 cccatcaatc catgtttacg aaaaatctgc caccctcatg ctcattgtac gtacctggga 480 ccaaatcggc acagttgtac atgccaagaa ggctaccgtg gggatggcca agtgtgcttg 540 cctgtggacc cctgccaaat taactttgga aactgcccta caaagtctac agtgtgcaaa 600 tatgatgggc ctggacagtc tcactgcgag tgtaaggagc attaccagaa tttcgtacct 660 ggagtggggt gcagt 675 <210> 66 <211> 522 <212> DNA <213> Homo sapiens <400> 66 gaaacctgtg ctgacgacaa cttatttgga cccagctgtt catcagtgtg caactgtgtg 60 catggggtgt gcaacagtgg actagatggc gatggaacct gtgagtgcta ctctgcgtac 120 actggcccca agtgtgacaa gcccatccct gaatgtgcag ccttgctctg cccagaaaat 180 tccagatgtt cgccttccac tgaagatgaa aacaaactgg aatgcaaatg ccttcccaat 240 taccgaggcg atggcaaata ctgcgacccc atcaatccat gtttacgaaa aatctgccac 300 cctcatgctc attgtacgta cctgggacca aatcggcaca gttgtacatg ccaagaaggc 360 taccgtgggg atggccaagt gtgcttgcct gtggacccct gccaaattaa ctttggaaac 420 tgccctacaa agtctacagt gtgcaaatat gatgggcctg gacagtctca ctgcgagtgt 480 aaggagcatt accagaattt cgtacctgga gtggggtgca gt 522 <210> 67 <211> 555 <212> DNA <213> Homo sapiens <400> 67 attccaaagt gctgcaaagg cttctatgga cctgactgca accagtgtcc aggaggcttc 60 tcaaatccat gctcaggaaa tggacagtgt gcagatagcc tcggcggcaa cgggacatgc 120 atttgtgagg agggcttcca aggctcccag tgtcagttct gctctgatcc caataaatac 180 ggacctcggt gtaacaaaaa atgcctgtgc gttcacggaa catgcaataa caggatagac 240 agcgatgggg cctgcctcac tggcacatgc agagacggct ctgccgggag actctgtgat 300 aagcagacct cagcctgtgg gccctacgtg cagttctgtc acatccacgc cacctgtgaa 360 tacagcaatg ggacagccag ttgtatttgc aaagcaggat atgaaggaga tggaactctg 420 tgttctgaga tggacccttg cacaggacta actccaggag gctgtagccg caatgcagaa 480 tgcatcaaaa ctggcacggg cacccacacc tgcgtgtgtc agcagggttg gacagggaat 540 gggagagact gctcg 555 <210> 68 <211> 684 <212> DNA <213> Homo sapiens <400> 68 attccaaagt gctgcaaagg cttctatgga cctgactgca accagtgtcc aggaggcttc 60 tcaaatccat gctcaggaaa tggacagtgt gcagatagcc tcggcggcaa cgggacatgc 120 atttgtgagg agggcttcca aggctcccag tgtcagttct gctctgatcc caataaatac 180 ggacctcggt gtaacaaaaa atgcctgtgc gttcacggaa catgcaataa caggatagac 240 agcgatgggg cctgcctcac tggcacatgc agagacggct ctgccgggag actctgtgat 300 aagcagacct cagcctgtgg gccctacgtg cagttctgtc acatccacgc cacctgtgaa 360 tacagcaatg ggacagccag ttgtatttgc aaagcaggat atgaaggaga tggaactctg 420 tgttctgaga tggacccttg cacaggacta actccaggag gctgtagccg caatgcagaa 480 tgcatcaaaa ctggcacggg cacccacacc tgcgtgtgtc agcagggttg gacagggaat 540 gggagagact gctcggagat caacaactgc ctgctgccca gtgcaggcgg ctgccacgac 600 aacgcatcct gtttgtatgt gggtcccggg cagaatgagt gtgagtgcaa gaaaggattt 660 cgaggaaatg ggattgactg tgaa 684 <210> 69 <211> 531 <212> DNA <213> Homo sapiens <400> 69 cagttctgct ctgatcccaa taaatacgga cctcggtgta acaaaaaatg cctgtgcgtt 60 cacggaacat gcaataacag gatagacagc gatggggcct gcctcactgg cacatgcaga 120 gacggctctg ccgggagact ctgtgataag cagacctcag cctgtgggcc ctacgtgcag 180 ttctgtcaca tccacgccac ctgtgaatac agcaatggga cagccagttg tatttgcaaa 240 gcaggatatg aaggagatgg aactctgtgt tctgagatgg acccttgcac aggactaact 300 ccaggaggct gtagccgcaa tgcagaatgc atcaaaactg gcacgggcac ccacacctgc 360 gtgtgtcagc agggttggac agggaatggg agagactgct cggagatcaa caactgcctg 420 ctgcccagtg caggcggctg ccacgacaac gcatcctgtt tgtatgtggg tcccgggcag 480 aatgagtgtg agtgcaagaa aggatttcga ggaaatggga ttgactgtga a 531 <210> 70 <211> 540 <212> DNA <213> Homo sapiens <400> 70 acgagagaat gctgtgccgg cttctttggc ccccaatgcc agccctgccc agggaatgcc 60 cagaatgtct gctttggtaa tggcatctgt ttggatggag tgaatggcac aggtgtgtgt 120 gagtgtgggg agggcttcag cggcacagcc tgcgagacct gcaccgaggg caagtacggc 180 atccactgtg accaagcatg ttcttgtgtc catgggagat gcaaccaagg acccttggga 240 gatggctcct gtgactgtga tgttggctgg cgaggagtgc attgtgacaa tgcaaccaca 300 gaagacaact gcaatgggac atgccatacc agcgccaact gcctcaccaa ctcagatggt 360 acagcttcat gcaagtgtgc agcaggattc caaggaaacg ggaccatctg cacagcaatc 420 aatgcctgtg agatcagcaa tggaggttgc tctgccaagg ctgactgtaa gagaaccacc 480 ccaggaaggc gagtgtgcac gtgcaaagca ggctacacgg gtgatggcat tgtgtgcctg 540 540 <210> 71 <211> 666 <212> DNA <213> Homo sapiens <400> 71 acgagagaat gctgtgccgg cttctttggc ccccaatgcc agccctgccc agggaatgcc 60 cagaatgtct gctttggtaa tggcatctgt ttggatggag tgaatggcac aggtgtgtgt 120 gagtgtgggg agggcttcag cggcacagcc tgcgagacct gcaccgaggg caagtacggc 180 atccactgtg accaagcatg ttcttgtgtc catgggagat gcaaccaagg acccttggga 240 gatggctcct gtgactgtga tgttggctgg cgaggagtgc attgtgacaa tgcaaccaca 300 gaagacaact gcaatgggac atgccatacc agcgccaact gcctcaccaa ctcagatggt 360 acagcttcat gcaagtgtgc agcaggattc caaggaaacg ggaccatctg cacagcaatc 420 aatgcctgtg agatcagcaa tggaggttgc tctgccaagg ctgactgtaa gagaaccacc 480 ccaggaaggc gagtgtgcac gtgcaaagca ggctacacgg gtgatggcat tgtgtgcctg 540 gaaatcaacc cgtgtttgga gaaccatggt ggctgtgaca agaatgcgga gtgcacacag 600 acaggaccca accaggctgc ctgtaactgt ttgccagcat acactggaga tggaaaggtc 660 tgcaca 666 <210> 72 <211> 513 <212> DNA <213> Homo sapiens <400> 72 gagacctgca ccgagggcaa gtacggcatc cactgtgacc aagcatgttc ttgtgtccat 60 gggagatgca accaaggacc cttgggagat ggctcctgtg actgtgatgt tggctggcga 120 ggagtgcatt gtgacaatgc aaccacagaa gacaactgca atgggacatg ccataccagc 180 gccaactgcc tcaccaactc agatggtaca gcttcatgca agtgtgcagc aggattccaa 240 ggaaacggga ccatctgcac agcaatcaat gcctgtgaga tcagcaatgg aggttgctct 300 gccaaggctg actgtaagag aaccacccca ggaaggcgag tgtgcacgtg caaagcaggc 360 tacacgggtg atggcattgt gtgcctggaa atcaacccgt gtttggagaa ccatggtggc 420 tgtgacaaga atgcggagtg cacacagaca ggacccaacc aggctgcctg taactgtttg 480 ccagcataca ctggagatgg aaaggtctgc aca 513 <210> 73 <211> 528 <212> DNA <213> Homo sapiens <400> 73 atccccaggt gctgcaaggg ctacttcggg cgagactgtc aggcctgccc tggaggacca 60 gatgccccgt gtaataaccg gggtgtctgc cttgatcagt actcggccac cggagagtgt 120 aaatgcaaca ccggcttcaa tgggacggcg tgtgagatgt gctggccggg gagattcggg 180 cctgattgtc tgccctgtgg ctgctcagac cacggacagt gcgatgatgg catcacgggc 240 tccgggcagt gcctctgtga aacggggtgg acaggcccct cgtgtgacac tcaggcagtt 300 ttgcctgcag tgtgtacgcc tccttgttct gctcatgcca cctgtaagga gaacaacacg 360 tgtgagtgta acctggatta tgaaggtgac ggaatcacat gcacagttgt ggatttctgc 420 aaacaggaca acgggggctg tgcaaaggtg gccagatgct cccagaaggg cacgaaggtc 480 tcctgcagct gccagaaggg atacaaaggg gacgggcaca gctgcaca 528 <210> 74 <211> 504 <212> DNA <213> Homo sapiens <400> 74 gagatgtgct ggccggggag attcgggcct gattgtctgc cctgtggctg ctcagaccac 60 ggacagtgcg atgatggcat cacgggctcc gggcagtgcc tctgtgaaac ggggtggaca 120 ggcccctcgt gtgacactca ggcagttttg cctgcagtgt gtacgcctcc ttgttctgct 180 catgccacct gtaaggagaa caacacgtgt gagtgtaacc tggattatga aggtgacgga 240 atcacatgca cagttgtgga tttctgcaaa caggacaacg ggggctgtgc aaaggtggcc 300 agatgctccc agaagggcac gaaggtctcc tgcagctgcc agaagggata caaaggggac 360 gggcacagct gcacagagat agacccctgt gcagacggcc ttaacggagg gtgtcacgag 420 cacgccacct gtaagatgac aggcccgggc aagcacaagt gtgagtgtaa aagtcactat 480 gtcggagatg ggctgaactg tgag 504 <210> 75 <211> 590 <212> PRT <213> Homo sapiens <400> 75 Val Gly Val Arg Asp Cys Arg Tyr Thr Phe Glu Val Arg Thr Tyr Ser 1 5 10 15 Leu Ser Leu Pro Gly Cys Arg His Ile Cys Arg Lys Asp Tyr Leu Gln 20 25 30 Pro Arg Cys Cys Pro Gly Arg Trp Gly Pro Asp Cys Ile Glu Cys Pro 35 40 45 Gly Gly Ala Gly Ser Pro Cys Asn Gly Arg Gly Ser Cys Ala Glu Gly 50 55 60 Met Glu Gly Asn Gly Thr Cys Ser Cys Gln Glu Gly Phe Gly Gly Thr 65 70 75 80 Ala Cys Glu Thr Cys Ala Asp Asp Asn Leu Phe Gly Pro Ser Cys Ser 85 90 95 Ser Val Cys Asn Cys Val His Gly Val Cys Asn Ser Gly Leu Asp Gly 100 105 110 Asp Gly Thr Cys Glu Cys Tyr Ser Ala Tyr Thr Gly Pro Lys Cys Asp 115 120 125 Lys Pro Ile Pro Glu Cys Ala Ala Leu Leu Cys Pro Glu Asn Ser Arg 130 135 140 Cys Ser Pro Ser Thr Glu Asp Glu Asn Lys Leu Glu Cys Lys Cys Leu 145 150 155 160 Pro Asn Tyr Arg Gly Asp Gly Lys Tyr Cys Asp Pro Ile Asn Pro Cys 165 170 175 Leu Arg Lys Ile Cys His Pro His Ala His Cys Thr Tyr Leu Gly Pro 180 185 190 Asn Arg His Ser Cys Thr Cys Gln Glu Gly Tyr Arg Gly Asp Gly Gln 195 200 205 Val Cys Leu Pro Val Asp Pro Cys Gln Ile Asn Phe Gly Asn Cys Pro 210 215 220 Thr Lys Ser Thr Val Cys Lys Tyr Asp Gly Pro Gly Gln Ser His Cys 225 230 235 240 Glu Cys Lys Glu His Tyr Gln Asn Phe Val Pro Gly Val Gly Cys Ser 245 250 255 Met Thr Asp Ile Cys Lys Ser Asp Asn Pro Cys His Arg Asn Ala Asn 260 265 270 Cys Thr Thr Val Ala Pro Gly Arg Thr Glu Cys Ile Cys Gln Lys Gly 275 280 285 Tyr Val Gly Asp Gly Leu Thr Cys Tyr Gly Asn Ile Met Glu Arg Leu 290 295 300 Arg Glu Leu Asn Thr Glu Pro Arg Gly Lys Trp Gln Gly Arg Leu Thr 305 310 315 320 Ser Phe Ile Ser Leu Leu Asp Lys Ala Tyr Ala Trp Pro Leu Ser Lys 325 330 335 Leu Gly Pro Phe Thr Val Leu Leu Pro Thr Asp Lys Gly Leu Lys Gly 340 345 350 Phe Asn Val Asn Glu Leu Leu Val Asp Asn Lys Ala Ala Gln Tyr Phe 355 360 365 Val Lys Leu His Ile Ile Ala Gly Gln Met Asn Ile Glu Tyr Met Asn 370 375 380 Asn Thr Asp Met Phe Tyr Thr Leu Thr Gly Lys Ser Gly Glu Ile Phe 385 390 395 400 Asn Ser Asp Lys Asp Asn Gln Ile Lys Leu Lys Leu His Gly Gly Lys 405 410 415 Lys Lys Val Lys Ile Ile Gln Gly Asp Ile Ile Ala Ser Asn Gly Leu 420 425 430 Leu His Ile Leu Asp Arg Ala Met Asp Lys Leu Glu Pro Thr Phe Glu 435 440 445 Ser Asn Asn Glu Gln Thr Ile Met Thr Met Leu Gln Pro Arg Tyr Ser 450 455 460 Lys Phe Arg Ser Leu Leu Glu Glu Thr Asn Leu Gly His Ala Leu Asp 465 470 475 480 Glu Asp Gly Val Gly Gly Pro Tyr Thr Ile Phe Val Pro Asn Asn Glu 485 490 495 Ala Leu Asn Asn Met Lys Asp Gly Thr Leu Asp Tyr Leu Leu Ser Pro 500 505 510 Glu Gly Ser Arg Lys Leu Leu Glu Leu Val Arg Tyr His Ile Val Pro 515 520 525 Phe Thr Gln Leu Glu Val Ala Thr Leu Ile Ser Thr Pro His Ile Arg 530 535 540 Ser Met Ala Asn Gln Leu Ile Gln Phe Asn Thr Thr Asp Asn Gly Gln 545 550 555 560 Ile Leu Ala Asn Asp Val Ala Met Glu Glu Ile Glu Ile Thr Ala Lys 565 570 575 Asn Gly Arg Ile Tyr Thr Leu Thr Gly Val Leu Ile Pro Pro 580 585 590 <210> 76 <211> 578 <212> PRT <213> Homo sapiens <400> 76 Asn Ser Glu Pro Thr Ala Leu Phe Thr His Arg Cys Val Tyr Ser Gly 1 5 10 15 Arg Phe Gly Ser Leu Lys Ser Gly Cys Ala Arg Tyr Cys Asn Ala Thr 20 25 30 Val Lys Ile Pro Lys Cys Cys Lys Gly Phe Tyr Gly Pro Asp Cys Asn 35 40 45 Gln Cys Pro Gly Gly Phe Ser Asn Pro Cys Ser Gly Asn Gly Gln Cys 50 55 60 Ala Asp Ser Leu Gly Gly Asn Gly Thr Cys Ile Cys Glu Glu Gly Phe 65 70 75 80 Gln Gly Ser Gln Cys Gln Phe Cys Ser Asp Pro Asn Lys Tyr Gly Pro 85 90 95 Arg Cys Asn Lys Lys Cys Leu Cys Val His Gly Thr Cys Asn Asn Arg 100 105 110 Ile Asp Ser Asp Gly Ala Cys Leu Thr Gly Thr Cys Arg Asp Gly Ser 115 120 125 Ala Gly Arg Leu Cys Asp Lys Gln Thr Ser Ala Cys Gly Pro Tyr Val 130 135 140 Gln Phe Cys His Ile His Ala Thr Cys Glu Tyr Ser Asn Gly Thr Ala 145 150 155 160 Ser Cys Ile Cys Lys Ala Gly Tyr Glu Gly Asp Gly Thr Leu Cys Ser 165 170 175 Glu Met Asp Pro Cys Thr Gly Leu Thr Pro Gly Gly Cys Ser Arg Asn 180 185 190 Ala Glu Cys Ile Lys Thr Gly Thr Gly Thr His Thr Cys Val Cys Gln 195 200 205 Gln Gly Trp Thr Gly Asn Gly Arg Asp Cys Ser Glu Ile Asn Asn Cys 210 215 220 Leu Leu Pro Ser Ala Gly Gly Cys His Asp Asn Ala Ser Cys Leu Tyr 225 230 235 240 Val Gly Pro Gly Gln Asn Glu Cys Glu Cys Lys Lys Gly Phe Arg Gly 245 250 255 Asn Gly Ile Asp Cys Glu Pro Ile Thr Ser Cys Leu Glu Gln Thr Gly 260 265 270 Lys Cys His Pro Leu Ala Ser Cys Gln Ser Thr Ser Ser Gly Val Trp 275 280 285 Ser Cys Val Cys Gln Glu Gly Tyr Glu Gly Asp Gly Phe Leu Cys Tyr 290 295 300 Gly Asn Ala Ala Val Glu Leu Ser Phe Leu Ser Glu Ala Ala Ile Phe 305 310 315 320 Asn Arg Trp Ile Asn Asn Ala Ser Leu Gln Pro Thr Leu Ser Ala Thr 325 330 335 Ser Asn Leu Thr Val Leu Val Pro Ser Gln Gln Ala Thr Glu Asp Met 340 345 350 Asp Gln Asp Glu Lys Ser Phe Trp Leu Ser Gln Ser Asn Ile Pro Ala 355 360 365 Leu Ile Lys Tyr His Met Leu Leu Gly Thr Tyr Arg Val Ala Asp Leu 370 375 380 Gln Thr Leu Ser Ser Ser Asp Met Leu Ala Thr Ser Leu Gln Gly Asn 385 390 395 400 Phe Leu His Leu Ala Lys Val Asp Gly Asn Ile Thr Ile Glu Gly Ala 405 410 415 Ser Ile Val Asp Gly Asp Asn Ala Ala Thr Asn Gly Val Ile His Ile 420 425 430 Ile Asn Lys Val Leu Val Pro Gln Arg Arg Leu Thr Gly Ser Leu Pro 435 440 445 Asn Leu Leu Met Arg Leu Glu Gln Met Pro Asp Tyr Ser Ile Phe Arg 450 455 460 Gly Tyr Ile Ile Gln Tyr Asn Leu Ala Asn Ala Ile Glu Ala Ala Asp 465 470 475 480 Ala Tyr Thr Val Phe Ala Pro Asn Asn Asn Ala Ile Glu Asn Tyr Ile 485 490 495 Arg Glu Lys Lys Val Leu Ser Leu Glu Glu Asp Val Leu Arg Tyr His 500 505 510 Val Val Leu Glu Glu Lys Leu Leu Lys Asn Asp Leu His Asn Gly Met 515 520 525 His Arg Glu Thr Met Leu Gly Phe Ser Tyr Phe Leu Ser Phe Phe Leu 530 535 540 His Asn Asp Gln Leu Tyr Val Asn Glu Ala Pro Ile Asn Tyr Thr Asn 545 550 555 560 Val Ala Thr Asp Lys Gly Val Ile His Gly Leu Gly Lys Val Leu Glu 565 570 575 Ile gln <210> 77 <211> 581 <212> PRT <213> Homo sapiens <400> 77 Glu Lys Arg Arg Cys Ile Tyr Thr Ser Tyr Phe Met Gly Arg Arg Thr 1 5 10 15 Leu Phe Ile Gly Cys Gln Pro Lys Cys Val Arg Thr Val Ile Thr Arg 20 25 30 Glu Cys Cys Ala Gly Phe Ghe Pro Gln Cys Gln Pro Cys Pro Gly 35 40 45 Asn Ala Gln Asn Val Cys Phe Gly Asn Gly Ile Cys Leu Asp Gly Val 50 55 60 Asn Gly Thr Gly Val Cys Glu Cys Gly Glu Gly Phe Ser Gly Thr Ala 65 70 75 80 Cys Glu Thr Cys Thr Glu Gly Lys Tyr Gly Ile His Cys Asp Gln Ala 85 90 95 Cys Ser Cys Val His Gly Arg Cys Asn Gln Gly Pro Leu Gly Asp Gly 100 105 110 Ser Cys Asp Cys Asp Val Gly Trp Arg Gly Val His Cys Asp Asn Ala 115 120 125 Thr Thr Glu Asp Asn Cys Asn Gly Thr Cys His Thr Ser Ala Asn Cys 130 135 140 Leu Thr Asn Ser Asp Gly Thr Ala Ser Cys Lys Cys Ala Ala Gly Phe 145 150 155 160 Gln Gly Asn Gly Thr Ile Cys Thr Ala Ile Asn Ala Cys Glu Ile Ser 165 170 175 Asn Gly Gly Cys Ser Ala Lys Ala Asp Cys Lys Arg Thr Thr Pro Gly 180 185 190 Arg Arg Val Cys Thr Cys Lys Ala Gly Tyr Thr Gly Asp Gly Ile Val 195 200 205 Cys Leu Glu Ile Asn Pro Cys Leu Glu Asn His Gly Gly Cys Asp Lys 210 215 220 Asn Ala Glu Cys Thr Gln Thr Gly Pro Asn Gln Ala Ala Cys Asn Cys 225 230 235 240 Leu Pro Ala Tyr Thr Gly Asp Gly Lys Val Cys Thr Leu Ile Asn Val 245 250 255 Cys Leu Thr Lys Asn Gly Gly Cys Ser Glu Phe Ala Ile Cys Asn His 260 265 270 Thr Gly Gln Val Glu Arg Thr Cys Thr Cys Lys Pro Asn Tyr Ile Gly 275 280 285 Asp Gly Phe Thr Cys Arg Gly Ser Ile Tyr Gln Glu Leu Pro Lys Asn 290 295 300 Pro Lys Thr Ser Gln Tyr Phe Phe Gln Leu Gln Glu His Phe Val Lys 305 310 315 320 Asp Leu Val Gly Pro Gly Pro Phe Thr Val Phe Ala Pro Leu Ser Ala 325 330 335 Ala Phe Asp Glu Glu Ala Arg Val Lys Asp Trp Asp Lys Tyr Gly Leu 340 345 350 Met Pro Gln Val Leu Arg Tyr His Val Val Ala Cys His Gln Leu Leu 355 360 365 Leu Glu Asn Leu Lys Leu Ile Ser Asn Ala Thr Ser Leu Gln Gly Glu 370 375 380 Pro Ile Val Ile Ser Val Ser Gln Ser Thr Val Tyr Ile Asn Asn Lys 385 390 395 400 Ala Lys Ile Ile Ser Ser Asp Ile Ile Ser Thr Asn Gly Ile Val His 405 410 415 Ile Ile Asp Lys Leu Leu Ser Pro Lys Asn Leu Leu Ile Thr Pro Lys 420 425 430 Asp Asn Ser Gly Arg Ile Leu Gln Asn Leu Thr Thr Leu Ala Thr Asn 435 440 445 Asn Gly Tyr Ile Lys Phe Ser Asn Leu Ile Gln Asp Ser Gly Leu Leu 450 455 460 Ser Val Ile Thr Asp Pro Ile His Thr Pro Val Thr Leu Phe Trp Pro 465 470 475 480 Thr Asp Gln Ala Leu His Ala Leu Pro Ala Glu Gln Gln Asp Phe Leu 485 490 495 Phe Asn Gln Asp Asn Lys Asp Lys Leu Lys Glu Tyr Leu Lys Phe His 500 505 510 Val Ile Arg Asp Ala Lys Val Leu Ala Val Asp Leu Pro Thr Ser Thr 515 520 525 Ala Trp Lys Thr Leu Gln Gly Ser Glu Leu Ser Val Lys Cys Gly Ala 530 535 540 Gly Arg Asp Ile Gly Asp Leu Phe Leu Asn Gly Gln Thr Cys Arg Ile 545 550 555 560 Val Gln Arg Glu Leu Leu Phe Asp Leu Gly Val Ala Tyr Gly Ile Asp 565 570 575 Cys Leu Leu Ile Asp 580 <210> 78 <211> 537 <212> PRT <213> Homo sapiens <400> 78 Arg Trp Ser Lys Pro Lys Gly Val Lys Gln Lys Cys Leu Tyr Asn Leu 1 5 10 15 Pro Phe Lys Arg Asn Leu Glu Gly Cys Arg Glu Arg Cys Ser Leu Val 20 25 30 Ile Gln Ile Pro Arg Cys Cys Lys Gly Tyr Phe Gly Arg Asp Cys Gln 35 40 45 Ala Cys Pro Gly Gly Pro Asp Ala Pro Cys Asn Asn Arg Gly Val Cys 50 55 60 Leu Asp Gln Tyr Ser Ala Thr Gly Glu Cys Lys Cys Asn Thr Gly Phe 65 70 75 80 Asn Gly Thr Ala Cys Glu Met Cys Trp Pro Gly Arg Phe Gly Pro Asp 85 90 95 Cys Leu Pro Cys Gly Cys Ser Asp His Gly Gln Cys Asp Asp Gly Ile 100 105 110 Thr Gly Ser Gly Gln Cys Leu Cys Glu Thr Gly Trp Thr Gly Pro Ser 115 120 125 Cys Asp Thr Gln Ala Val Leu Pro Ala Val Cys Thr Pro Pro Cys Ser 130 135 140 Ala His Ala Thr Cys Lys Glu Asn Asn Thr Cys Glu Cys Asn Leu Asp 145 150 155 160 Tyr Glu Gly Asp Gly Ile Thr Cys Thr Val Val Asp Phe Cys Lys Gln 165 170 175 Asp Asn Gly Gly Cys Ala Lys Val Ala Arg Cys Ser Gln Lys Gly Thr 180 185 190 Lys Val Ser Cys Ser Cys Gln Lys Gly Tyr Lys Gly Asp Gly His Ser 195 200 205 Cys Thr Glu Ile Asp Pro Cys Ala Asp Gly Leu Asn Gly Gly Cys His 210 215 220 Glu His Ala Thr Cys Lys Met Thr Gly Pro Gly Lys His Lys Cys Glu 225 230 235 240 Cys Lys Ser His Tyr Val Gly Asp Gly Leu Asn Cys Glu Pro Glu Gln 245 250 255 Leu Pro Ile Asp Arg Cys Leu Gln Asp Asn Gly Gln Cys His Ala Asp 260 265 270 Ala Lys Cys Val Asp Leu His Phe Gln Asp Thr Thr Val Gly Val Phe 275 280 285 His Leu Arg Ser Pro Leu Gly Gln Tyr Lys Leu Thr Phe Asp Lys Ala 290 295 300 Arg Glu Ala Cys Ala Asn Glu Ala Ala Thr Met Ala Thr Tyr Asn Gln 305 310 315 320 Leu Ser Tyr Ala Gln Lys Ala Lys Tyr His Leu Cys Ser Ala Gly Trp 325 330 335 Leu Glu Thr Gly Arg Val Ala Tyr Pro Thr Ala Phe Ala Ser Gln Asn 340 345 350 Cys Gly Ser Gly Val Val Gly Ile Val Asp Tyr Gly Pro Arg Pro Asn 355 360 365 Lys Ser Glu Met Trp Asp Val Phe Cys Tyr Arg Met Lys Asp Val Asn 370 375 380 Cys Thr Cys Lys Val Gly Tyr Val Gly Asp Gly Phe Ser Cys Ser Gly 385 390 395 400 Asn Leu Leu Gln Val Leu Met Ser Phe Pro Ser Leu Thr Asn Phe Leu 405 410 415 Thr Glu Val Leu Ala Tyr Ser Asn Ser Ser Ala Arg Gly Arg Ala Phe 420 425 430 Leu Glu His Leu Thr Asp Leu Ser Ile Arg Gly Thr Leu Phe Val Pro 435 440 445 Gln Asn Ser Gly Leu Gly Glu Asn Glu Thr Leu Ser Gly Arg Asp Ile 450 455 460 Glu His His Leu Ala Asn Val Ser Met Phe Phe Tyr Asn Asp Leu Val 465 470 475 480 Asn Gly Thr Thr Leu Gln Thr Arg Leu Gly Ser Lys Leu Leu Ile Thr 485 490 495 Ala Ser Gln Asp Pro Leu Gln Pro Thr Glu Thr Arg Phe Val Asp Gly 500 505 510 Arg Ala Ile Leu Gln Trp Asp Ile Phe Ala Ser Asn Gly Ile Ile His 515 520 525 Val Ile Ser Arg Pro Leu Lys Ala Pro 530 535 <210> 79 <211> 266 <212> PRT <213> Homo sapiens <400> 79 Gln Pro Arg Cys Cys Pro Gly Arg Trp Gly Pro Asp Cys Ile Glu Cys 1 5 10 15 Pro Gly Gly Ala Gly Ser Pro Cys Asn Gly Arg Gly Ser Cys Ala Glu 20 25 30 Gly Met Glu Gly Asn Gly Thr Cys Ser Cys Gln Glu Gly Phe Gly Gly 35 40 45 Thr Ala Cys Glu Thr Cys Ala Asp Asp Asn Leu Phe Gly Pro Ser Cys 50 55 60 Ser Ser Val Cys Asn Cys Val His Gly Val Cys Asn Ser Gly Leu Asp 65 70 75 80 Gly Asp Gly Thr Cys Glu Cys Tyr Ser Ala Tyr Thr Gly Pro Lys Cys 85 90 95 Asp Lys Pro Ile Pro Glu Cys Ala Ala Leu Leu Cys Pro Glu Asn Ser 100 105 110 Arg Cys Ser Pro Ser Thr Glu Asp Glu Asn Lys Leu Glu Cys Lys Cys 115 120 125 Leu Pro Asn Tyr Arg Gly Asp Gly Lys Tyr Cys Asp Pro Ile Asn Pro 130 135 140 Cys Leu Arg Lys Ile Cys His Pro His Ala His Cys Thr Tyr Leu Gly 145 150 155 160 Pro Asn Arg His Ser Cys Thr Cys Gln Glu Gly Tyr Arg Gly Asp Gly 165 170 175 Gln Val Cys Leu Pro Val Asp Pro Cys Gln Ile Asn Phe Gly Asn Cys 180 185 190 Pro Thr Lys Ser Thr Val Cys Lys Tyr Asp Gly Pro Gly Gln Ser His 195 200 205 Cys Glu Cys Lys Glu His Tyr Gln Asn Phe Val Pro Gly Val Gly Cys 210 215 220 Ser Met Thr Asp Ile Cys Lys Ser Asp Asn Pro Cys His Arg Asn Ala 225 230 235 240 Asn Cys Thr Thr Val Ala Pro Gly Arg Thr Glu Cys Ile Cys Gln Lys 245 250 255 Gly Tyr Val Gly Asp Gly Leu Thr Cys Tyr 260 265 <210> 80 <211> 270 <212> PRT <213> Homo sapiens <400> 80 Ile Pro Lys Cys Cys Lys Gly Phe Tyr Gly Pro Asp Cys Asn Gln Cys 1 5 10 15 Pro Gly Gly Phe Ser Asn Pro Cys Ser Gly Asn Gly Gln Cys Ala Asp 20 25 30 Ser Leu Gly Gly Asn Gly Thr Cys Ile Cys Glu Glu Gly Phe Gln Gly 35 40 45 Ser Gln Cys Gln Phe Cys Ser Asp Pro Asn Lys Tyr Gly Pro Arg Cys 50 55 60 Asn Lys Lys Cys Leu Cys Val His Gly Thr Cys Asn Asn Arg Ile Asp 65 70 75 80 Ser Asp Gly Ala Cys Leu Thr Gly Thr Cys Arg Asp Gly Ser Ala Gly 85 90 95 Arg Leu Cys Asp Lys Gln Thr Ser Ala Cys Gly Pro Tyr Val Gln Phe 100 105 110 Cys His Ile His Ala Thr Cys Glu Tyr Ser Asn Gly Thr Ala Ser Cys 115 120 125 Ile Cys Lys Ala Gly Tyr Glu Gly Asp Gly Thr Leu Cys Ser Glu Met 130 135 140 Asp Pro Cys Thr Gly Leu Thr Pro Gly Gly Cys Ser Arg Asn Ala Glu 145 150 155 160 Cys Ile Lys Thr Gly Thr Gly Thr His Thr Cys Val Cys Gln Gln Gly 165 170 175 Trp Thr Gly Asn Gly Arg Asp Cys Ser Glu Ile Asn Asn Cys Leu Leu 180 185 190 Pro Ser Ala Gly Gly Cys His Asp Asn Ala Ser Cys Leu Tyr Val Gly 195 200 205 Pro Gly Gln Asn Glu Cys Glu Cys Lys Lys Gly Phe Arg Gly Asn Gly 210 215 220 Ile Asp Cys Glu Pro Ile Thr Ser Cys Leu Glu Gln Thr Gly Lys Cys 225 230 235 240 His Pro Leu Ala Ser Cys Gln Ser Thr Ser Ser Gly Val Trp Ser Cys 245 250 255 Val Cys Gln Glu Gly Tyr Glu Gly Asp Gly Phe Leu Cys Tyr 260 265 270 <210> 81 <211> 264 <212> PRT <213> Homo sapiens <400> 81 Thr Arg Glu Cys Cys Ala Gly Phe Phe Gly Pro Gln Cys Gln Pro Cys 1 5 10 15 Pro Gly Asn Ala Gln Asn Val Cys Phe Gly Asn Gly Ile Cys Leu Asp 20 25 30 Gly Val Asn Gly Thr Gly Val Cys Glu Cys Gly Glu Gly Phe Ser Gly 35 40 45 Thr Ala Cys Glu Thr Cys Thr Glu Gly Lys Tyr Gly Ile His Cys Asp 50 55 60 Gln Ala Cys Ser Cys Val His Gly Arg Cys Asn Gln Gly Pro Leu Gly 65 70 75 80 Asp Gly Ser Cys Asp Cys Asp Val Gly Trp Arg Gly Val His Cys Asp 85 90 95 Asn Ala Thr Thr Glu Asp Asn Cys Asn Gly Thr Cys His Thr Ser Ala 100 105 110 Asn Cys Leu Thr Asn Ser Asp Gly Thr Ala Ser Cys Lys Cys Ala Ala 115 120 125 Gly Phe Gln Gly Asn Gly Thr Ile Cys Thr Ala Ile Asn Ala Cys Glu 130 135 140 Ile Ser Asn Gly Gly Cys Ser Ala Lys Ala Asp Cys Lys Arg Thr Thr 145 150 155 160 Pro Gly Arg Arg Val Cys Thr Cys Lys Ala Gly Tyr Thr Gly Asp Gly 165 170 175 Ile Val Cys Leu Glu Ile Asn Pro Cys Leu Glu Asn His Gly Gly Cys 180 185 190 Asp Lys Asn Ala Glu Cys Thr Gln Thr Gly Pro Asn Gln Ala Ala Cys 195 200 205 Asn Cys Leu Pro Ala Tyr Thr Gly Asp Gly Lys Val Cys Thr Leu Ile 210 215 220 Asn Val Cys Leu Thr Lys Asn Gly Gly Cys Ser Glu Phe Ala Ile Cys 225 230 235 240 Asn His Thr Gly Gln Val Glu Arg Thr Cys Thr Cys Lys Pro Asn Tyr 245 250 255 Ile Gly Asp Gly Phe Thr Cys Arg 260 <210> 82 <211> 219 <212> PRT <213> Homo sapiens <400> 82 Ile Pro Arg Cys Cys Lys Gly Tyr Phe Gly Arg Asp Cys Gln Ala Cys 1 5 10 15 Pro Gly Gly Pro Asp Ala Pro Cys Asn Asn Arg Gly Val Cys Leu Asp 20 25 30 Gln Tyr Ser Ala Thr Gly Glu Cys Lys Cys Asn Thr Gly Phe Asn Gly 35 40 45 Thr Ala Cys Glu Met Cys Trp Pro Gly Arg Phe Gly Pro Asp Cys Leu 50 55 60 Pro Cys Gly Cys Ser Asp His Gly Gln Cys Asp Asp Gly Ile Thr Gly 65 70 75 80 Ser Gly Gln Cys Leu Cys Glu Thr Gly Trp Thr Gly Pro Ser Cys Asp 85 90 95 Thr Gln Ala Val Leu Pro Ala Val Cys Thr Pro Pro Cys Ser Ala His 100 105 110 Ala Thr Cys Lys Glu Asn Asn Thr Cys Glu Cys Asn Leu Asp Tyr Glu 115 120 125 Gly Asp Gly Ile Thr Cys Thr Val Val Asp Phe Cys Lys Gln Asp Asn 130 135 140 Gly Gly Cys Ala Lys Val Ala Arg Cys Ser Gln Lys Gly Thr Lys Val 145 150 155 160 Ser Cys Ser Cys Gln Lys Gly Tyr Lys Gly Asp Gly His Ser Cys Thr 165 170 175 Glu Ile Asp Pro Cys Ala Asp Gly Leu Asn Gly Gly Cys His Glu His 180 185 190 Ala Thr Cys Lys Met Thr Gly Pro Gly Lys His Lys Cys Glu Cys Lys 195 200 205 Ser His Tyr Val Gly Asp Gly Leu Asn Cys Glu 210 215 <210> 83 <211> 51 <212> PRT <213> Homo sapiens <400> 83 Gln Pro Arg Cys Cys Pro Gly Arg Trp Gly Pro Asp Cys Ile Glu Cys 1 5 10 15 Pro Gly Gly Ala Gly Ser Pro Cys Asn Gly Arg Gly Ser Cys Ala Glu 20 25 30 Gly Met Glu Gly Asn Gly Thr Cys Ser Cys Gln Glu Gly Phe Gly Gly 35 40 45 Thr ala cys 50 <210> 84 <211> 47 <212> PRT <213> Homo sapiens <400> 84 Glu Thr Cys Ala Asp Asp Asn Leu Phe Gly Pro Ser Cys Ser Ser Val 1 5 10 15 Cys Asn Cys Val His Gly Val Cys Asn Ser Gly Leu Asp Gly Asp Gly 20 25 30 Thr Cys Glu Cys Tyr Ser Ala Tyr Thr Gly Pro Lys Cys Asp Lys 35 40 45 <210> 85 <211> 42 <212> PRT <213> Homo sapiens <400> 85 Pro Ile Pro Glu Cys Ala Ala Leu Leu Cys Pro Glu Asn Ser Arg Cys 1 5 10 15 Ser Pro Ser Thr Glu Asp Glu Asn Lys Leu Glu Cys Lys Cys Leu Pro 20 25 30 Asn Tyr Arg Gly Asp Gly Lys Tyr Cys Asp 35 40 <210> 86 <211> 40 <212> PRT <213> Homo sapiens <400> 86 Pro Ile Asn Pro Cys Leu Arg Lys Ile Cys His Pro His Ala His Cys 1 5 10 15 Thr Tyr Leu Gly Pro Asn Arg His Ser Cys Thr Cys Gln Glu Gly Tyr 20 25 30 Arg Gly Asp Gly Gln Val Cys Leu 35 40 <210> 87 <211> 45 <212> PRT <213> Homo sapiens <400> 87 Pro Val Asp Pro Cys Gln Ile Asn Phe Gly Asn Cys Pro Thr Lys Ser 1 5 10 15 Thr Val Cys Lys Tyr Asp Gly Pro Gly Gln Ser His Cys Glu Cys Lys 20 25 30 Glu His Tyr Gln Asn Phe Val Pro Gly Val Gly Cys Ser 35 40 45 <210> 88 <211> 41 <212> PRT <213> Homo sapiens <400> 88 Met Thr Asp Ile Cys Lys Ser Asp Asn Pro Cys His Arg Asn Ala Asn 1 5 10 15 Cys Thr Thr Val Ala Pro Gly Arg Thr Glu Cys Ile Cys Gln Lys Gly 20 25 30 Tyr Val Gly Asp Gly Leu Thr Cys Tyr 35 40 <210> 89 <211> 51 <212> PRT <213> Homo sapiens <400> 89 Ile Pro Lys Cys Cys Lys Gly Phe Tyr Gly Pro Asp Cys Asn Gln Cys 1 5 10 15 Pro Gly Gly Phe Ser Asn Pro Cys Ser Gly Asn Gly Gln Cys Ala Asp 20 25 30 Ser Leu Gly Gly Asn Gly Thr Cys Ile Cys Glu Glu Gly Phe Gln Gly 35 40 45 Ser Gln Cys 50 <210> 90 <211> 50 <212> PRT <213> Homo sapiens <400> 90 Gln Phe Cys Ser Asp Pro Asn Lys Tyr Gly Pro Arg Cys Asn Lys Lys 1 5 10 15 Cys Leu Cys Val His Gly Thr Cys Asn Asn Arg Ile Asp Ser Asp Gly 20 25 30 Ala Cys Leu Thr Gly Thr Cys Arg Asp Gly Ser Ala Gly Arg Leu Cys 35 40 45 Asp lys 50 <210> 91 <211> 41 <212> PRT <213> Homo sapiens <400> 91 Gln Thr Ser Ala Cys Gly Pro Tyr Val Gln Phe Cys His Ile His Ala 1 5 10 15 Thr Cys Glu Tyr Ser Asn Gly Thr Ala Ser Cys Ile Cys Lys Ala Gly 20 25 30 Tyr Glu Gly Asp Gly Thr Leu Cys Ser 35 40 <210> 92 <211> 43 <212> PRT <213> Homo sapiens <400> 92 Glu Met Asp Pro Cys Thr Gly Leu Thr Pro Gly Gly Cys Ser Arg Asn 1 5 10 15 Ala Glu Cys Ile Lys Thr Gly Thr Gly Thr His Thr Cys Val Cys Gln 20 25 30 Gln Gly Trp Thr Gly Asn Gly Arg Asp Cys Ser 35 40 <210> 93 <211> 43 <212> PRT <213> Homo sapiens <400> 93 Glu Ile Asn Asn Cys Leu Leu Pro Ser Ala Gly Gly Cys His Asp Asn 1 5 10 15 Ala Ser Cys Leu Tyr Val Gly Pro Gly Gln Asn Glu Cys Glu Cys Lys 20 25 30 Lys Gly Phe Arg Gly Asn Gly Ile Asp Cys Glu 35 40 <210> 94 <211> 42 <212> PRT <213> Homo sapiens <400> 94 Pro Ile Thr Ser Cys Leu Glu Gln Thr Gly Lys Cys His Pro Leu Ala 1 5 10 15 Ser Cys Gln Ser Thr Ser Ser Gly Val Trp Ser Cys Val Cys Gln Glu 20 25 30 Gly Tyr Glu Gly Asp Gly Phe Leu Cys Tyr 35 40 <210> 95 <211> 51 <212> PRT <213> Homo sapiens <400> 95 Thr Arg Glu Cys Cys Ala Gly Phe Phe Gly Pro Gln Cys Gln Pro Cys 1 5 10 15 Pro Gly Asn Ala Gln Asn Val Cys Phe Gly Asn Gly Ile Cys Leu Asp 20 25 30 Gly Val Asn Gly Thr Gly Val Cys Glu Cys Gly Glu Gly Phe Ser Gly 35 40 45 Thr ala cys 50 <210> 96 <211> 48 <212> PRT <213> Homo sapiens <400> 96 Glu Thr Cys Thr Glu Gly Lys Tyr Gly Ile His Cys Asp Gln Ala Cys 1 5 10 15 Ser Cys Val His Gly Arg Cys Asn Gln Gly Pro Leu Gly Asp Gly Ser 20 25 30 Cys Asp Cys Asp Val Gly Trp Arg Gly Val His Cys Asp Asn Ala Thr 35 40 45 <210> 97 <211> 39 <212> PRT <213> Homo sapiens <400> 97 Thr Glu Asp Asn Cys Asn Gly Thr Cys His Thr Ser Ala Asn Cys Leu 1 5 10 15 Thr Asn Ser Asp Gly Thr Ala Ser Cys Lys Cys Ala Ala Gly Phe Gln 20 25 30 Gly Asn Gly Thr Ile Cys Thr 35 <210> 98 <211> 42 <212> PRT <213> Homo sapiens <400> 98 Ala Ile Asn Ala Cys Glu Ile Ser Asn Gly Gly Cys Ser Ala Lys Ala 1 5 10 15 Asp Cys Lys Arg Thr Thr Pro Gly Arg Arg Val Cys Thr Cys Lys Ala 20 25 30 Gly Tyr Thr Gly Asp Gly Ile Val Cys Leu 35 40 <210> 99 <211> 42 <212> PRT <213> Homo sapiens <400> 99 Glu Ile Asn Pro Cys Leu Glu Asn His Gly Gly Cys Asp Lys Asn Ala 1 5 10 15 Glu Cys Thr Gln Thr Gly Pro Asn Gln Ala Ala Cys Asn Cys Leu Pro 20 25 30 Ala Tyr Thr Gly Asp Gly Lys Val Cys Thr 35 40 <210> 100 <211> 42 <212> PRT <213> Homo sapiens <400> 100 Leu Ile Asn Val Cys Leu Thr Lys Asn Gly Gly Cys Ser Glu Phe Ala 1 5 10 15 Ile Cys Asn His Thr Gly Gln Val Glu Arg Thr Cys Thr Cys Lys Pro 20 25 30 Asn Tyr Ile Gly Asp Gly Phe Thr Cys Arg 35 40 <210> 101 <211> 51 <212> PRT <213> Homo sapiens <400> 101 Ile Pro Arg Cys Cys Lys Gly Tyr Phe Gly Arg Asp Cys Gln Ala Cys 1 5 10 15 Pro Gly Gly Pro Asp Ala Pro Cys Asn Asn Arg Gly Val Cys Leu Asp 20 25 30 Gln Tyr Ser Ala Thr Gly Glu Cys Lys Cys Asn Thr Gly Phe Asn Gly 35 40 45 Thr ala cys 50 <210> 102 <211> 49 <212> PRT <213> Homo sapiens <400> 102 Glu Met Cys Trp Pro Gly Arg Phe Gly Pro Asp Cys Leu Pro Cys Gly 1 5 10 15 Cys Ser Asp His Gly Gln Cys Asp Asp Gly Ile Thr Gly Ser Gly Gln 20 25 30 Cys Leu Cys Glu Thr Gly Trp Thr Gly Pro Ser Cys Asp Thr Gln Ala 35 40 45 Val <210> 103 <211> 35 <212> PRT <213> Homo sapiens <400> 103 Leu Pro Ala Val Cys Thr Pro Pro Cys Ser Ala His Ala Thr Cys Lys 1 5 10 15 Glu Asn Asn Thr Cys Glu Cys Asn Leu Asp Tyr Glu Gly Asp Gly Ile 20 25 30 Thr Cys Thr 35 <210> 104 <211> 41 <212> PRT <213> Homo sapiens <400> 104 Val Val Asp Phe Cys Lys Gln Asp Asn Gly Gly Cys Ala Lys Val Ala 1 5 10 15 Arg Cys Ser Gln Lys Gly Thr Lys Val Ser Cys Ser Cys Gln Lys Gly 20 25 30 Tyr Lys Gly Asp Gly His Ser Cys Thr 35 40 <210> 105 <211> 43 <212> PRT <213> Homo sapiens <400> 105 Glu Ile Asp Pro Cys Ala Asp Gly Leu Asn Gly Gly Cys His Glu His 1 5 10 15 Ala Thr Cys Lys Met Thr Gly Pro Gly Lys His Lys Cys Glu Cys Lys 20 25 30 Ser His Tyr Val Gly Asp Gly Leu Asn Cys Glu 35 40 <210> 106 <211> 180 <212> PRT <213> Homo sapiens <400> 106 Gln Pro Arg Cys Cys Pro Gly Arg Trp Gly Pro Asp Cys Ile Glu Cys 1 5 10 15 Pro Gly Gly Ala Gly Ser Pro Cys Asn Gly Arg Gly Ser Cys Ala Glu 20 25 30 Gly Met Glu Gly Asn Gly Thr Cys Ser Cys Gln Glu Gly Phe Gly Gly 35 40 45 Thr Ala Cys Glu Thr Cys Ala Asp Asp Asn Leu Phe Gly Pro Ser Cys 50 55 60 Ser Ser Val Cys Asn Cys Val His Gly Val Cys Asn Ser Gly Leu Asp 65 70 75 80 Gly Asp Gly Thr Cys Glu Cys Tyr Ser Ala Tyr Thr Gly Pro Lys Cys 85 90 95 Asp Lys Pro Ile Pro Glu Cys Ala Ala Leu Leu Cys Pro Glu Asn Ser 100 105 110 Arg Cys Ser Pro Ser Thr Glu Asp Glu Asn Lys Leu Glu Cys Lys Cys 115 120 125 Leu Pro Asn Tyr Arg Gly Asp Gly Lys Tyr Cys Asp Pro Ile Asn Pro 130 135 140 Cys Leu Arg Lys Ile Cys His Pro His Ala His Cys Thr Tyr Leu Gly 145 150 155 160 Pro Asn Arg His Ser Cys Thr Cys Gln Glu Gly Tyr Arg Gly Asp Gly 165 170 175 Gln val cys leu 180 <210> 107 <211> 225 <212> PRT <213> Homo sapiens <400> 107 Gln Pro Arg Cys Cys Pro Gly Arg Trp Gly Pro Asp Cys Ile Glu Cys 1 5 10 15 Pro Gly Gly Ala Gly Ser Pro Cys Asn Gly Arg Gly Ser Cys Ala Glu 20 25 30 Gly Met Glu Gly Asn Gly Thr Cys Ser Cys Gln Glu Gly Phe Gly Gly 35 40 45 Thr Ala Cys Glu Thr Cys Ala Asp Asp Asn Leu Phe Gly Pro Ser Cys 50 55 60 Ser Ser Val Cys Asn Cys Val His Gly Val Cys Asn Ser Gly Leu Asp 65 70 75 80 Gly Asp Gly Thr Cys Glu Cys Tyr Ser Ala Tyr Thr Gly Pro Lys Cys 85 90 95 Asp Lys Pro Ile Pro Glu Cys Ala Ala Leu Leu Cys Pro Glu Asn Ser 100 105 110 Arg Cys Ser Pro Ser Thr Glu Asp Glu Asn Lys Leu Glu Cys Lys Cys 115 120 125 Leu Pro Asn Tyr Arg Gly Asp Gly Lys Tyr Cys Asp Pro Ile Asn Pro 130 135 140 Cys Leu Arg Lys Ile Cys His Pro His Ala His Cys Thr Tyr Leu Gly 145 150 155 160 Pro Asn Arg His Ser Cys Thr Cys Gln Glu Gly Tyr Arg Gly Asp Gly 165 170 175 Gln Val Cys Leu Pro Val Asp Pro Cys Gln Ile Asn Phe Gly Asn Cys 180 185 190 Pro Thr Lys Ser Thr Val Cys Lys Tyr Asp Gly Pro Gly Gln Ser His 195 200 205 Cys Glu Cys Lys Glu His Tyr Gln Asn Phe Val Pro Gly Val Gly Cys 210 215 220 Ser 225 <210> 108 <211> 174 <212> PRT <213> Homo sapiens <400> 108 Glu Thr Cys Ala Asp Asp Asn Leu Phe Gly Pro Ser Cys Ser Ser Val 1 5 10 15 Cys Asn Cys Val His Gly Val Cys Asn Ser Gly Leu Asp Gly Asp Gly 20 25 30 Thr Cys Glu Cys Tyr Ser Ala Tyr Thr Gly Pro Lys Cys Asp Lys Pro 35 40 45 Ile Pro Glu Cys Ala Ala Leu Leu Cys Pro Glu Asn Ser Arg Cys Ser 50 55 60 Pro Ser Thr Glu Asp Glu Asn Lys Leu Glu Cys Lys Cys Leu Pro Asn 65 70 75 80 Tyr Arg Gly Asp Gly Lys Tyr Cys Asp Pro Ile Asn Pro Cys Leu Arg 85 90 95 Lys Ile Cys His Pro His Ala His Cys Thr Tyr Leu Gly Pro Asn Arg 100 105 110 His Ser Cys Thr Cys Gln Glu Gly Tyr Arg Gly Asp Gly Gln Val Cys 115 120 125 Leu Pro Val Asp Pro Cys Gln Ile Asn Phe Gly Asn Cys Pro Thr Lys 130 135 140 Ser Thr Val Cys Lys Tyr Asp Gly Pro Gly Gln Ser His Cys Glu Cys 145 150 155 160 Lys Glu His Tyr Gln Asn Phe Val Pro Gly Val Gly Cys Ser 165 170 <210> 109 <211> 185 <212> PRT <213> Homo sapiens <400> 109 Ile Pro Lys Cys Cys Lys Gly Phe Tyr Gly Pro Asp Cys Asn Gln Cys 1 5 10 15 Pro Gly Gly Phe Ser Asn Pro Cys Ser Gly Asn Gly Gln Cys Ala Asp 20 25 30 Ser Leu Gly Gly Asn Gly Thr Cys Ile Cys Glu Glu Gly Phe Gln Gly 35 40 45 Ser Gln Cys Gln Phe Cys Ser Asp Pro Asn Lys Tyr Gly Pro Arg Cys 50 55 60 Asn Lys Lys Cys Leu Cys Val His Gly Thr Cys Asn Asn Arg Ile Asp 65 70 75 80 Ser Asp Gly Ala Cys Leu Thr Gly Thr Cys Arg Asp Gly Ser Ala Gly 85 90 95 Arg Leu Cys Asp Lys Gln Thr Ser Ala Cys Gly Pro Tyr Val Gln Phe 100 105 110 Cys His Ile His Ala Thr Cys Glu Tyr Ser Asn Gly Thr Ala Ser Cys 115 120 125 Ile Cys Lys Ala Gly Tyr Glu Gly Asp Gly Thr Leu Cys Ser Glu Met 130 135 140 Asp Pro Cys Thr Gly Leu Thr Pro Gly Gly Cys Ser Arg Asn Ala Glu 145 150 155 160 Cys Ile Lys Thr Gly Thr Gly Thr His Thr Cys Val Cys Gln Gln Gly 165 170 175 Trp Thr Gly Asn Gly Arg Asp Cys Ser 180 185 <210> 110 <211> 228 <212> PRT <213> Homo sapiens <400> 110 Ile Pro Lys Cys Cys Lys Gly Phe Tyr Gly Pro Asp Cys Asn Gln Cys 1 5 10 15 Pro Gly Gly Phe Ser Asn Pro Cys Ser Gly Asn Gly Gln Cys Ala Asp 20 25 30 Ser Leu Gly Gly Asn Gly Thr Cys Ile Cys Glu Glu Gly Phe Gln Gly 35 40 45 Ser Gln Cys Gln Phe Cys Ser Asp Pro Asn Lys Tyr Gly Pro Arg Cys 50 55 60 Asn Lys Lys Cys Leu Cys Val His Gly Thr Cys Asn Asn Arg Ile Asp 65 70 75 80 Ser Asp Gly Ala Cys Leu Thr Gly Thr Cys Arg Asp Gly Ser Ala Gly 85 90 95 Arg Leu Cys Asp Lys Gln Thr Ser Ala Cys Gly Pro Tyr Val Gln Phe 100 105 110 Cys His Ile His Ala Thr Cys Glu Tyr Ser Asn Gly Thr Ala Ser Cys 115 120 125 Ile Cys Lys Ala Gly Tyr Glu Gly Asp Gly Thr Leu Cys Ser Glu Met 130 135 140 Asp Pro Cys Thr Gly Leu Thr Pro Gly Gly Cys Ser Arg Asn Ala Glu 145 150 155 160 Cys Ile Lys Thr Gly Thr Gly Thr His Thr Cys Val Cys Gln Gln Gly 165 170 175 Trp Thr Gly Asn Gly Arg Asp Cys Ser Glu Ile Asn Asn Cys Leu Leu 180 185 190 Pro Ser Ala Gly Gly Cys His Asp Asn Ala Ser Cys Leu Tyr Val Gly 195 200 205 Pro Gly Gln Asn Glu Cys Glu Cys Lys Lys Gly Phe Arg Gly Asn Gly 210 215 220 Ile Asp Cys Glu 225 <210> 111 <211> 177 <212> PRT <213> Homo sapiens <400> 111 Gln Phe Cys Ser Asp Pro Asn Lys Tyr Gly Pro Arg Cys Asn Lys Lys 1 5 10 15 Cys Leu Cys Val His Gly Thr Cys Asn Asn Arg Ile Asp Ser Asp Gly 20 25 30 Ala Cys Leu Thr Gly Thr Cys Arg Asp Gly Ser Ala Gly Arg Leu Cys 35 40 45 Asp Lys Gln Thr Ser Ala Cys Gly Pro Tyr Val Gln Phe Cys His Ile 50 55 60 His Ala Thr Cys Glu Tyr Ser Asn Gly Thr Ala Ser Cys Ile Cys Lys 65 70 75 80 Ala Gly Tyr Glu Gly Asp Gly Thr Leu Cys Ser Glu Met Asp Pro Cys 85 90 95 Thr Gly Leu Thr Pro Gly Gly Cys Ser Arg Asn Ala Glu Cys Ile Lys 100 105 110 Thr Gly Thr Gly Thr His Thr Cys Val Cys Gln Gln Gly Trp Thr Gly 115 120 125 Asn Gly Arg Asp Cys Ser Glu Ile Asn Asn Cys Leu Leu Pro Ser Ala 130 135 140 Gly Gly Cys His Asp Asn Ala Ser Cys Leu Tyr Val Gly Pro Gly Gln 145 150 155 160 Asn Glu Cys Glu Cys Lys Lys Gly Phe Arg Gly Asn Gly Ile Asp Cys 165 170 175 Glu <210> 112 <211> 180 <212> PRT <213> Homo sapiens <400> 112 Thr Arg Glu Cys Cys Ala Gly Phe Phe Gly Pro Gln Cys Gln Pro Cys 1 5 10 15 Pro Gly Asn Ala Gln Asn Val Cys Phe Gly Asn Gly Ile Cys Leu Asp 20 25 30 Gly Val Asn Gly Thr Gly Val Cys Glu Cys Gly Glu Gly Phe Ser Gly 35 40 45 Thr Ala Cys Glu Thr Cys Thr Glu Gly Lys Tyr Gly Ile His Cys Asp 50 55 60 Gln Ala Cys Ser Cys Val His Gly Arg Cys Asn Gln Gly Pro Leu Gly 65 70 75 80 Asp Gly Ser Cys Asp Cys Asp Val Gly Trp Arg Gly Val His Cys Asp 85 90 95 Asn Ala Thr Thr Glu Asp Asn Cys Asn Gly Thr Cys His Thr Ser Ala 100 105 110 Asn Cys Leu Thr Asn Ser Asp Gly Thr Ala Ser Cys Lys Cys Ala Ala 115 120 125 Gly Phe Gln Gly Asn Gly Thr Ile Cys Thr Ala Ile Asn Ala Cys Glu 130 135 140 Ile Ser Asn Gly Gly Cys Ser Ala Lys Ala Asp Cys Lys Arg Thr Thr 145 150 155 160 Pro Gly Arg Arg Val Cys Thr Cys Lys Ala Gly Tyr Thr Gly Asp Gly 165 170 175 Ile val cys leu 180 <210> 113 <211> 222 <212> PRT <213> Homo sapiens <400> 113 Thr Arg Glu Cys Cys Ala Gly Phe Phe Gly Pro Gln Cys Gln Pro Cys 1 5 10 15 Pro Gly Asn Ala Gln Asn Val Cys Phe Gly Asn Gly Ile Cys Leu Asp 20 25 30 Gly Val Asn Gly Thr Gly Val Cys Glu Cys Gly Glu Gly Phe Ser Gly 35 40 45 Thr Ala Cys Glu Thr Cys Thr Glu Gly Lys Tyr Gly Ile His Cys Asp 50 55 60 Gln Ala Cys Ser Cys Val His Gly Arg Cys Asn Gln Gly Pro Leu Gly 65 70 75 80 Asp Gly Ser Cys Asp Cys Asp Val Gly Trp Arg Gly Val His Cys Asp 85 90 95 Asn Ala Thr Thr Glu Asp Asn Cys Asn Gly Thr Cys His Thr Ser Ala 100 105 110 Asn Cys Leu Thr Asn Ser Asp Gly Thr Ala Ser Cys Lys Cys Ala Ala 115 120 125 Gly Phe Gln Gly Asn Gly Thr Ile Cys Thr Ala Ile Asn Ala Cys Glu 130 135 140 Ile Ser Asn Gly Gly Cys Ser Ala Lys Ala Asp Cys Lys Arg Thr Thr 145 150 155 160 Pro Gly Arg Arg Val Cys Thr Cys Lys Ala Gly Tyr Thr Gly Asp Gly 165 170 175 Ile Val Cys Leu Glu Ile Asn Pro Cys Leu Glu Asn His Gly Gly Cys 180 185 190 Asp Lys Asn Ala Glu Cys Thr Gln Thr Gly Pro Asn Gln Ala Ala Cys 195 200 205 Asn Cys Leu Pro Ala Tyr Thr Gly Asp Gly Lys Val Cys Thr 210 215 220 <210> 114 <211> 171 <212> PRT <213> Homo sapiens <400> 114 Glu Thr Cys Thr Glu Gly Lys Tyr Gly Ile His Cys Asp Gln Ala Cys 1 5 10 15 Ser Cys Val His Gly Arg Cys Asn Gln Gly Pro Leu Gly Asp Gly Ser 20 25 30 Cys Asp Cys Asp Val Gly Trp Arg Gly Val His Cys Asp Asn Ala Thr 35 40 45 Thr Glu Asp Asn Cys Asn Gly Thr Cys His Thr Ser Ala Asn Cys Leu 50 55 60 Thr Asn Ser Asp Gly Thr Ala Ser Cys Lys Cys Ala Ala Gly Phe Gln 65 70 75 80 Gly Asn Gly Thr Ile Cys Thr Ala Ile Asn Ala Cys Glu Ile Ser Asn 85 90 95 Gly Gly Cys Ser Ala Lys Ala Asp Cys Lys Arg Thr Thr Pro Gly Arg 100 105 110 Arg Val Cys Thr Cys Lys Ala Gly Tyr Thr Gly Asp Gly Ile Val Cys 115 120 125 Leu Glu Ile Asn Pro Cys Leu Glu Asn His Gly Gly Cys Asp Lys Asn 130 135 140 Ala Glu Cys Thr Gln Thr Gly Pro Asn Gln Ala Ala Cys Asn Cys Leu 145 150 155 160 Pro Ala Tyr Thr Gly Asp Gly Lys Val Cys Thr 165 170 <210> 115 <211> 176 <212> PRT <213> Homo sapiens <400> 115 Ile Pro Arg Cys Cys Lys Gly Tyr Phe Gly Arg Asp Cys Gln Ala Cys 1 5 10 15 Pro Gly Gly Pro Asp Ala Pro Cys Asn Asn Arg Gly Val Cys Leu Asp 20 25 30 Gln Tyr Ser Ala Thr Gly Glu Cys Lys Cys Asn Thr Gly Phe Asn Gly 35 40 45 Thr Ala Cys Glu Met Cys Trp Pro Gly Arg Phe Gly Pro Asp Cys Leu 50 55 60 Pro Cys Gly Cys Ser Asp His Gly Gln Cys Asp Asp Gly Ile Thr Gly 65 70 75 80 Ser Gly Gln Cys Leu Cys Glu Thr Gly Trp Thr Gly Pro Ser Cys Asp 85 90 95 Thr Gln Ala Val Leu Pro Ala Val Cys Thr Pro Pro Cys Ser Ala His 100 105 110 Ala Thr Cys Lys Glu Asn Asn Thr Cys Glu Cys Asn Leu Asp Tyr Glu 115 120 125 Gly Asp Gly Ile Thr Cys Thr Val Val Asp Phe Cys Lys Gln Asp Asn 130 135 140 Gly Gly Cys Ala Lys Val Ala Arg Cys Ser Gln Lys Gly Thr Lys Val 145 150 155 160 Ser Cys Ser Cys Gln Lys Gly Tyr Lys Gly Asp Gly His Ser Cys Thr 165 170 175 <210> 116 <211> 168 <212> PRT <213> Homo sapiens <400> 116 Glu Met Cys Trp Pro Gly Arg Phe Gly Pro Asp Cys Leu Pro Cys Gly 1 5 10 15 Cys Ser Asp His Gly Gln Cys Asp Asp Gly Ile Thr Gly Ser Gly Gln 20 25 30 Cys Leu Cys Glu Thr Gly Trp Thr Gly Pro Ser Cys Asp Thr Gln Ala 35 40 45 Val Leu Pro Ala Val Cys Thr Pro Pro Cys Ser Ala His Ala Thr Cys 50 55 60 Lys Glu Asn Asn Thr Cys Glu Cys Asn Leu Asp Tyr Glu Gly Asp Gly 65 70 75 80 Ile Thr Cys Thr Val Val Asp Phe Cys Lys Gln Asp Asn Gly Cys 85 90 95 Ala Lys Val Ala Arg Cys Ser Gln Lys Gly Thr Lys Val Ser Cys Ser 100 105 110 Cys Gln Lys Gly Tyr Lys Gly Asp Gly His Ser Cys Thr Glu Ile Asp 115 120 125 Pro Cys Ala Asp Gly Leu Asn Gly Gly Cys His Glu His Ala Thr Cys 130 135 140 Lys Met Thr Gly Pro Gly Lys His Lys Cys Glu Cys Lys Ser His Tyr 145 150 155 160 Val Gly Asp Gly Leu Asn Cys Glu 165
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Non-Patent Citations (2)
Title |
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Cell Death Differ. 제15권, 제1호, 제192-201면, 2008년 1월. |
J. Biol. Chem. 제283권, 제16호, 제10593-10600면, 2008년 1월 온라인 공개. |
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