近日来自清华大学生命科学学院的研究人员报告了一个presenilin/SPP家族膜内天冬氨酸蛋白酶的晶体结构,推近了人们对阿兹海默症致病机理的认识和理解,也为之后基于晶体结构的药物设计和筛选打下了良好的基础。

-2013年1月3日《自然》


中文翻译


【题目】早老素家族成员膜内天冬氨酸蛋白酶的结构

【译文】早老素和信号肽肽酶(SPP)是膜内天冬氨酰蛋白酶,可以调控真核生物中的重要生物功能。对早老素和SPP的机制学理解受到相关结构信息缺乏的限制。本研究报道了古细菌甲烷囊菌属marisnigri JR1中早老素/SPP同源物(PSH)的晶体结构。该蛋白酶由9个跨膜片段(TM)组成,它采用了一种先前未有报道的蛋白折叠。氨基端结构域由TM1-6组成,形成了一种马蹄形结构,羧基端结构域由TM7-9围绕。两个催化的天冬氨酸残基位于TM6和TM7胞质内侧,空间上相互靠近,在类脂膜表面内约8 Å。水分子常常通过氨基端和羧基端结构域间大的空洞接近催化的天冬氨酸。结构分析阐明膜内蛋白酶早老素/SPP家族的结构。

英文原稿


[Title]: Structure of a presenilin family intramembrane aspartate protease

[Authors]:Xiaochun Li,1, 2, 4 Shangyu Dang,1, 2, 4 Chuangye Yan,1, 2 Xinqi Gong,1, 2 Jiawei Wang2, 3 & Yigong Shi1, 2

[Abstract]Presenilin and signal peptide peptidase (SPP) are intramembrane aspartyl proteases that regulate important biological functions in eukaryotes. Mechanistic understanding of presenilin and SPP has been hampered by lack of relevant structural information. Here we report the crystal structure of a presenilin/SPP homologue (PSH) from the archaeon Methanoculleus marisnigri JR1. The protease, comprising nine transmembrane segments (TMs), adopts a previously unreported protein fold. The amino-terminal domain, consisting of TM1–6, forms a horseshoe-shaped structure, surrounding TM7–9 of the carboxy-terminal domain. The two catalytic aspartate residues are located on the cytoplasmic side of TM6 and TM7, spatially close to each other and approximately 8 Å into the lipid membrane surface. Water molecules gain constant access to the catalytic aspartates through a large cavity between the amino- and carboxy-terminal domains. Structural analysis reveals insights into the presenilin/SPP family of intramembrane proteases.

原文地址

http://www.nature.com/nature/journal/v493/n7430/full/nature11801.html

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