施一公2014-04-14 4:25 PM

与ADP结合的Apaf-1(凋亡蛋白酶活化因子1)结构  Structure of the apoptotic protease activating factor 1 (Apaf-1) bound to ADP. 

论文摘要

半胱天冬酶能通过蛋白水解激活响应于细胞死亡刺激物从而使细胞凋亡。细胞凋亡蛋白酶活化因子1APAF- 1)能控制线粒体的半胱天冬酶活化下端。在细胞凋亡过程中,APAF- 1与细胞色素c的结合以及ATP /dATP出现构成了凋亡,这导致了半胱天冬酶启动子以及caspase-9的聚集和激活。我们对Apaf – 1的潜在功能机制仍所知甚少。在此我们展示了2.2 –A分辨率下ADP结合物和剔除Apaf – 1WD40的晶体结构,这揭示了它的分子机制,在该机制下Apaf – 1 ATP结合前以惰性状态存在。氨基末端半胱天冬酶聚集域对着三层α/β层,即短螺旋图案和翅螺旋结构域进行折叠,这导致了caspase-9结合界面的堆埋。被深埋的ADP分子作为组织中心加强了四个相邻域之间的互动,从而在非活性构象中锁定APAF- 1Apaf -1ATP /dATP和他们的类似物结合并将其水解。核苷酸的结合与水解似乎驱使了构象变化,这对胱天蛋白酶-9凋亡和活化的形成至关重要。

Abstract

Apoptosis is executed by caspases, which undergo proteolytic activation in response to cell death stimuli. The apoptotic protease-activating factor 1 (Apaf-1) controls caspase activation downstream of mitochondria. During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 (ref. 2). The mechanisms underlying Apaf-1 function are largely unknown. Here we report the 2.2-A crystal structure of an ADP-bound, WD40-deleted Apaf-1, which reveals the molecular mechanism by which Apaf-1 exists in an inactive state before ATP binding. The amino-terminal caspase recruitment domain packs against a three-layered alpha/beta fold, a short helical motif and a winged-helix domain, resulting in the burial of the caspase-9-binding interface. The deeply buried ADP molecule serves as an organizing centre to strengthen interactions between these four adjoining domains, thus locking Apaf-1 in an inactive conformation. Apaf-1 binds to and hydrolyses ATP/dATP and their analogues. The binding and hydrolysis of nucleotides seem to drive conformational changes that are essential for the formation of the apoptosome and the activation of caspase-9.


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