夏普
半胱氨酸蛋白酶
凋亡抑制因子
生物
细胞生物学
细胞凋亡
半胱氨酸蛋白酶-9
半胱氨酸蛋白酶3
凋亡结构域抑制剂
酶激活剂
生物物理学
生物化学
信号转导
程序性细胞死亡
作者
Eric N. Shiozaki,Jijie Chai,Daniel J. Rigotti,Stefan J. Riedl,Pingwei Li,Srinivasa M. Srinivasula,Emad S. Alnemri,Robert Fairman,Yigong Shi
出处
期刊:Molecular Cell
[Elsevier]
日期:2003-02-01
卷期号:11 (2): 519-527
被引量:647
标识
DOI:10.1016/s1097-2765(03)00054-6
摘要
The inhibitor of apoptosis (IAP) proteins potently inhibit the catalytic activity of caspases. While profound insight into the inhibition of the effector caspases has been gained in recent years, the mechanism of how the initiator caspase-9 is regulated by IAPs remains enigmatic. This paper reports the crystal structure of caspase-9 in an inhibitory complex with the third baculoviral IAP repeat (BIR3) of XIAP at 2.4 A resolution. The structure reveals that the BIR3 domain forms a heterodimer with a caspase-9 monomer. Strikingly, the surface of caspase-9 that interacts with BIR3 also mediates its homodimerization. We demonstrate that monomeric caspase-9 is catalytically inactive due to the absence of a supporting sequence element that could be provided by homodimerization. Thus, XIAP sequesters caspase-9 in a monomeric state, which serves to prevent catalytic activity. These studies, in conjunction with other observations, define a unified mechanism for the activation of all caspases.
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