Molecular determinants of caspase-9 activation by the Apaf-1 apoptosome.
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.
['Hu|Qi|Q|', 'Wu|Di|D|', 'Chen|Wen|W|', 'Yan|Zhen|Z|', 'Yan|Chuangye|C|', 'He|Tianxi|T|', 'Liang|Qionglin|Q|', 'Shi|Yigong|Y|']
D051017:Apoptosis Regulatory Proteins D053478:Apoptosomes D053453:Caspase 9 D002384:Catalysis D004789:Enzyme Activation D006801:Humans D006860:Hydrogen Bonding D066298:In Vitro Techniques D008239:Lysine D008956:Models, Chemical D008958:Models, Molecular D016297:Mutagenesis, Site-Directed D011487:Protein Conformation D025941:Protein Interaction Mapping D017433:Protein Structure, Secondary D017434:Protein Structure, Tertiary D011993:Recombinant Fusion Proteins
apoptosis mechanism CARD caspase activation induced proximity