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Molecular determinants of caspase-9 activation by the Apaf-1 apoptosome.


ABSTRACT: Autocatalytic activation of an initiator caspase triggers the onset of apoptosis. In dying cells, caspase-9 activation is mediated by a multimeric adaptor complex known as the Apaf-1 apoptosome. The molecular mechanism by which caspase-9 is activated by the Apaf-1 apoptosome remains largely unknown. Here we demonstrate that the previously reported 1:1 interaction between Apaf-1 caspase recruitment domain (CARD) and caspase-9 CARD is insufficient for the activation of caspase-9. Rather, formation of a multimeric CARD:CARD assembly between Apaf-1 and caspase-9, which requires three types of distinct interfaces, underlies caspase-9 activation. Importantly, an additional surface area on the multimeric CARD assembly is essential for caspase-9 activation. Together, these findings reveal mechanistic insights into the activation of caspase-9 by the Apaf-1 apoptosome and support the induced conformation model for initiator caspase activation by adaptor complexes.

SUBMITTER: Hu Q 

PROVIDER: S-EPMC4246342 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Molecular determinants of caspase-9 activation by the Apaf-1 apoptosome.

Hu Qi Q   Wu Di D   Chen Wen W   Yan Zhen Z   Yan Chuangye C   He Tianxi T   Liang Qionglin Q   Shi Yigong Y  

Proceedings of the National Academy of Sciences of the United States of America 20141013 46


Autocatalytic activation of an initiator caspase triggers the onset of apoptosis. In dying cells, caspase-9 activation is mediated by a multimeric adaptor complex known as the Apaf-1 apoptosome. The molecular mechanism by which caspase-9 is activated by the Apaf-1 apoptosome remains largely unknown. Here we demonstrate that the previously reported 1:1 interaction between Apaf-1 caspase recruitment domain (CARD) and caspase-9 CARD is insufficient for the activation of caspase-9. Rather, formation  ...[more]

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