Molecular mechanism of intramembrane proteolysis by γ-secretase.
Molecular mechanism of intramembrane proteolysis by γ-secretase.
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γ-分泌酶膜内蛋白水解的分子机制。
DOI：
10.1093/jb/mvu049
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发表时间：
2014
影响因子：
2.7
通讯作者：
T. Tomita
中科院分区：
文献类型：
--
作者：
T. Tomita
Presenilin 是一种膜嵌入的膜内切割蛋白酶，具有保守的催化 GxGD 基序。它是 γ-分泌酶的催化亚基，与三种膜蛋白辅因子尼卡斯特林、Aph-1 和 Pen-2 一起在发育生物学和阿尔茨海默病的分子病因学中发挥着关键作用。生化和酶分析表明，γ-分泌酶在单一底物上执行两种类型的蛋白水解活性；类似内肽酶的切割，随后是类似羧肽酶的持续切割。利用小分子抑制剂/调节剂以及取代的半胱氨酸可及性方法，我们鉴定了早老素的某些残基和区域，它们有助于在脂质双层内形成其膜内裂解活性所需的催化孔结构。最近，对古细菌早老素同系物的晶体结构的测定证实了两种保守且必需的天冬氨酸的膜内位置。在这篇综述中，我将介绍这种非典型蛋白酶分子作用机制的最新进展。
Presenilin is a membrane-embedded intramembrane-cleaving protease with a conserved catalytic G×GD motif. It is the catalytic subunit of γ-secretase, which plays critical roles in developmental biology and the molecular etiology of Alzheimer disease, together with three membrane protein cofactors, nicastrin, Aph-1 and Pen-2. Biochemical and enzymatic analyses have revealed that γ-secretase executes two types of proteolytic activities on a single substrate; an endopeptidase-like cleavage followed by carboxypeptidase-like processive cleavage. Utilizing small molecule inhibitors/modulators together with the substituted cysteine accessibility method, we identified certain residues and regions of presenilin that contribute to the formation of a catalytic pore structure within the lipid bilayer required for its intramembrane-cleaving activity. Recently, determination of the crystal structure of the archaeal presenilin homologue has confirmed the intramembranous location of the two conserved and essential aspartates. In this review, I will introduce the recent progresses in the understanding of the molecular mechanisms of action of this atypical protease.
影响因子：
2.9
作者：
Crump, Christina J.;Johnson, Douglas S.;Li, Yue-Ming
通讯作者：
Li, Yue-Ming
影响因子：
158.5
作者：
Doody, Rachelle S.;Raman, Rema;Mohs, Richard
通讯作者：
Mohs, Richard