Structure and Function of the γ-Secretase Complex
Structure and Function of the γ-Secretase Complex
复制标题
DOI：
10.1021/acs.biochem.9b00401
复制
发表时间：
2019-07-09
期刊：
影响因子：
2.9
通讯作者：
Wolfe, Michael S.
中科院分区：
文献类型：
--
作者：
Wolfe, Michael S.
γ-分泌酶是一种膜包埋蛋白酶复合物，以早老素为催化组分，在活性部位含有两个跨膜磷酸盐。有超过90种已知的底物，γ-分泌酶复合物被认为是“膜的蛋白酶体”，在生物学和医学中发挥着重要作用。蛋白酶在脂质双层内进行水解，以在释放分泌产物之前多次切割底物的跨膜结构域。多年来，γ-分泌酶的结构和功能的阐明主要依赖于小分子探针和诱变。然而，最近，冷冻电子显微镜的进步导致了蛋白酶复合物的第一个详细结构。结合膜蛋白底物的γ-分泌酶的结构的两个新的报告提供了很大的洞察底物识别的性质，以及如何阿尔茨海默氏病引起的早老素突变可能会改变底物结合和加工。这些新结构为阐明酶机制、破译致病突变的影响和推进阿尔茨海默病药物发现提供了一个强大的平台。
gamma-Secretase is a membrane-embedded protease complex, with presenilin as the catalytic component containing two transmembrane aspartates in the active site. With more than 90 known substrates, the gamma-secretase complex is considered "the proteasome of the membrane", with central roles in biology and medicine. The protease carries out hydrolysis within the lipid bilayer to cleave the transmembrane domain of the substrate multiple times before releasing secreted products. For many years, elucidation of gamma-secretase structure and function largely relied on small-molecule probes and mutagenesis. Recently, however, advances in cryo-electron microscopy have led to the first detailed structures of the protease complex. Two new reports of structures of gamma-secretase bound to membrane protein substrates provide great insight into the nature of substrate recognition and how Alzheimer's disease-causing mutations in presenilin might alter substrate binding and processing. These new structures offer a powerful platform for elucidating enzyme mechanisms, deciphering effects of disease-causing mutations, and advancing Alzheimer's disease drug discovery.