An atomic structure of human gamma-secretase

Bai Xiao-chen; Yan Chuangye; Yang Guanghui; Lu Peilong; Ma Dan; Sun Linfeng; Zhou Rui; Scheres Sjors H. W.; Shi Yigong

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An atomic structure of human gamma-secretase

机译：人γ分泌酶的原子结构

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Dysfunction of the intramembrane protease gamma-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human gamma-secretase at 3.4 angstrom resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre 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 after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix 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 c-secretase function.

机译：膜内蛋白酶γ-分泌酶的功能障碍被认为是引起阿尔茨海默氏病的原因，大多数源自阿尔茨海默氏病的突变都映射到催化亚基早老素1（PS1）。在这里，我们报告了由单粒子低温电子显微镜确定的3.4埃分辨率的人类γ-分泌酶的原子结构。源自阿尔茨海默氏病的突变影响PS1中两个热点处的残基，每个残基位于不同的四个跨膜片段（TM）束的中心。 TM2和较小程度的TM6表现出相当大的柔韧性，产生可塑性的活性位点和可适应的周围元素。 PS1的活性位点可从TM马掌的凸面访问，这表明底物募集后尼卡斯特林胞外域的构象发生了显着变化。成分蛋白APH-1充当支架，锚定来自尼卡斯汀的孤立的跨膜螺旋并支持PS1的柔性构象。有序的磷脂稳定了膜内部的复合物。我们的结构是对c-分泌酶功能的机械理解的分子基础。

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来源
《Nature》 |2015年第7568期|212-217|共6页
作者
Bai Xiao-chen; Yan Chuangye; Yang Guanghui; Lu Peilong; Ma Dan; Sun Linfeng; Zhou Rui; Scheres Sjors H. W.; Shi Yigong;
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作者单位

MRC Lab Mol Biol, Cambridge CB2 0QH, England;

Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Minist Educ Key Lab Prot Sci,Tsinghua Peking Join, Beijing 100084, Peoples R China;

Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Minist Educ Key Lab Prot Sci,Tsinghua Peking Join, Beijing 100084, Peoples R China;

Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Minist Educ Key Lab Prot Sci,Tsinghua Peking Join, Beijing 100084, Peoples R China;

Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Minist Educ Key Lab Prot Sci,Tsinghua Peking Join, Beijing 100084, Peoples R China;

Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Minist Educ Key Lab Prot Sci,Tsinghua Peking Join, Beijing 100084, Peoples R China;

Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Minist Educ Key Lab Prot Sci,Tsinghua Peking Join, Beijing 100084, Peoples R China;

MRC Lab Mol Biol, Cambridge CB2 0QH, England;

Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Minist Educ Key Lab Prot Sci,Tsinghua Peking Join, Beijing 100084, Peoples R China;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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机译：盘基网柄菌拥有高度分化的早老素/γ-分泌酶，可准确加工人淀粉样蛋白前体蛋白，是生长和正确确定细胞命运所必需的。
6. Atomic structures and deletion mutant reveal different capsid-binding patterns and functional significance of tegument protein pp150 in murine and human cytomegaloviruses with implications for therapeutic development [O] . Wei Liu, Xinghong Dai, Jonathan Jih, 2019

机译：原子结构和缺失突变体揭示了鼠和人巨细胞病毒中外皮蛋白pp150的不同衣壳结合模式和功能意义对治疗发展具有重要意义
7. Structure/function of human herpesvirus-8 MIP-II (1–71) and the antagonist N-terminal segment (1–10)11The atomic coordinates for the family of 55 peptide structures for vMIP-II(1–10) have been deposited in the Protein Data Bank, Brookhaven National Laboratory, Upton, NY, USA with access code 1hff. The atomic coordinates of the minimised average structure and restraint files of full length vMIP-II (1–71) have been deposited in the Protein Data Bank, Brookhaven National Laboratory, Upton, NY, USA with access code 1hfg and r1hfgmr and the family of 38 structures with code 1hfn. Chemical shifts have been deposited in the BioMagResBank with access code 4914. [O] . Crump Matthew P, Elisseeva Elena, Gong Jiang-Hong, 2001

机译：人类疱疹病毒8 MIP-II（1-71）和拮抗剂N末端片段（1-10）11的结构/功能vMIP-II（1-10）的55个肽结构家族的原子坐标已经保存位于美国纽约州阿普顿布鲁克海文国家实验室蛋白质数据库中，密码为1hff。全长vMIP-II（1-71）的最小化平均结构和约束文件的原子坐标已存放在美国纽约州阿普顿Brookhaven国家实验室的蛋白质数据库中，访问代码为1hfg和r1hfgmr，代码为1hfn的38个结构。化学位移已存储在BioMagResBank中，访问代码为4914。

An atomic structure of human gamma-secretase

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