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Mechanism of Selective Degradation of Proteins

蛋白质选择性降解机制

基本信息

批准号：
08278102
负责人：
SUZUKI Koichi
金额：
$ 214.14万
依托单位：
Tokyo Metropolitan Institute of Gerontology (2000)The University of Tokyo (1996-1999)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1999
项目状态：
已结题

项目摘要

To analyze mechanisms for selective intracellular protein degradation, two major protease systems in cells, proteasome and calpain, were mainly studied. Suzuki succeeded to analyze the crystal structure of calpain at 2.3Å and found that calpain exists as an inactive proenzyme which requires Ca-induced large conformational changes to become active. Domain III of unknown function is responsible for the Ca-induced conformational changes and translocation to biological membrane. Maki identified 4 novel calpastatin species produced by alternative splicing. Tanaka identified 5 alternative splicing variants of poly-ubiquitin receptor of 26S proteasome differently expressed in various tissues and thus showed distinct functions. A novel proteasome species responsible for endogenous antigen processing containing catalytic and regulatory subunits distinct from 26S proteasome was discovered and named immune proteasome. Further, the gene product for Parkinsonism was identified to be ubiquitin ligase suggesting that the deposition of its target protein of the ligase would be the cause of the disease. Yamao identified a novel proteolytic system of fission yeast for degradation of M phase cyclin containing novel E2. Murakami clarified the molecular mechanism for binding and degradation of ornithine decarboxylase by proteasome and the function of antizyme and ATP in the process. Kido analyzed molecular basis for influenza virus infection to host cells that requires specific degradation of virus membrane proteins by host cell tryptase clara. A specific inhibitor protein for clara tryptase was also fund.

为了分析细胞内蛋白质选择性降解的机制，主要研究了细胞中两个主要的蛋白水解酶系统：蛋白酶体和钙蛋白酶。铃木成功地在2.3Å分析了钙蛋白酶的晶体结构，发现它是以失活的酶原形式存在的，需要钙诱导的大的构象变化才能变得活跃。功能未知的结构域III负责钙诱导的构象变化和向生物膜的移位。Maki鉴定了通过选择性剪接产生的4种新的钙调蛋白。田中鉴定了26S蛋白酶体多聚泛素受体的5个选择性剪接变异体，它们在不同组织中表达不同，因此显示出不同的功能。发现了一种新的蛋白酶体，该蛋白酶体负责内源性抗原的加工，含有不同于26S蛋白酶体的催化和调节亚基，命名为免疫蛋白酶体。此外，帕金森病的基因产物被鉴定为泛素连接酶，这表明连接酶的目标蛋白的沉积可能是帕金森病的原因。Yamao鉴定了一种新的裂解酵母蛋白分解系统，用于降解含有新的E2的M期细胞周期蛋白。村上阐明了蛋白酶体结合和降解鸟氨酸脱羧酶的分子机制，以及抗酶和ATP在这一过程中的作用。Kido分析了流感病毒感染宿主细胞的分子基础，这需要宿主细胞类胰蛋白酶Clara特异性地降解病毒膜蛋白。此外，还发现了Clara类胰蛋白酶的特异性抑制蛋白。