An atomic structure of human γ-secretase.
An atomic structure of human γ-secretase.
复制标题
DOI：
10.1038/nature14892
复制
发表时间：
2015-09-10
期刊：
影响因子：
64.8
通讯作者：
Shi Y
中科院分区：
文献类型：
--
作者：
Bai XC;Yan C;Yang G;Lu P;Ma D;Sun L;Zhou R;Scheres SHW;Shi Y
膜内蛋白酶γ-分泌酶的功能障碍被认为是导致阿尔茨海默病（AD）的原因，大多数AD衍生的突变定位于催化亚基早老素1 （PS1）。在这里，我们报告了3.4 Å分辨率的人γ-分泌酶的原子结构，用单粒子冷冻电镜测定。PS1中ad衍生的突变影响两个热点的残基，每个热点位于不同的四个跨膜节段（TM）束的中心。TM2和较小程度的TM6表现出相当大的灵活性，产生塑性活性位点和适应性强的周围元素。PS1的活性位点可以从TM马蹄形的凸侧进入，这表明nicastrin胞外结构域（ECD）在底物募集后发生了相当大的构象变化。Aph-1作为支架，锚定尼克斯特林的单独TM，并支持PS1的柔性构象。有序的磷脂稳定了膜内的复合物。我们的结构是了解γ-分泌酶功能机制的分子基础。
Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer’s disease (AD), with most AD-derived mutations mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. AD-derived mutations in PS1 affect residues at two hotspots, each located at the center of a distinct four transmembrane segment (TM) bundle. TM2, and to a lesser extent TM6, exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain (ECD) following substrate recruitment. Aph-1 serves as a scaffold, anchoring the lone TM from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function.