Molecular determinants of caspase-9 activation by the Apaf-1 apoptosome
Molecular determinants of caspase-9 activation by the Apaf-1 apoptosome
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Apaf-1 凋亡体激活 caspase-9 的分子决定因素。
DOI：
10.1073/pnas.1418000111
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发表时间：
2014-11-18
影响因子：
11.1
通讯作者：
Shi, Yigong
中科院分区：
文献类型：
--
作者：
Hu, Qi;Wu, Di;Shi, Yigong
引发剂半胱天冬酶的自催化活化触发细胞凋亡的开始。在垂死的细胞中，半胱天冬酶-9的活化是由称为Apaf-1的多聚体接头复合物介导的。caspase-9被Apaf-1转录体激活的分子机制仍不清楚。在这里，我们证明了之前报道的Apaf-1 caspase募集结构域（CARD）和caspase-9 CARD之间的1：1相互作用不足以激活caspase-9。相反，在Apaf-1和半胱天冬酶-9之间形成多聚CARD：CARD组装，这需要三种类型的不同界面，是半胱天冬酶-9激活的基础。重要的是，多聚体CARD组件上的额外表面积对于胱天蛋白酶-9活化是必需的。总之，这些发现揭示了Apaf-1介体激活caspase-9的机制，并支持了衔接子复合物激活caspase启动子的诱导构象模型。
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.