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

• DOI: 10.1073/pnas.1418000111
• Publication Date: 2014-10-14T04:00:15Z
• Authors: Qi Hu; Di Wu; Wen Chen; Zhen Yan; Chuangye Yan; Tianxi He; Qionglin Liang; Yigong Shi
• Keywords: Models, Molecular; 0301 basic medicine; Protein Conformation; Lysine; Recombinant Fusion Proteins; Hydrogen Bonding; In Vitro Techniques; Caspase 9; Catalysis; Protein Structure, Secondary; Protein Structure, Tertiary; Enzyme Activation; 03 medical and health sciences; Models, Chemical; Apoptosomes; Protein Interaction Mapping; Mutagenesis, Site-Directed; Humans; Apoptosis Regulatory Proteins

Significance Upstream cell death stimuli culminate in the activation of an initiator caspase, marking the onset of apoptosis. Activation of the initiator caspase, caspase-9, is mediated by the heptameric Apaf-1 apoptosome. How Apaf-1 apoptosome facilitates the autocatalytic activation of caspase-9 has remained controversial and largely enigmatic. Two contrasting but not mutually exclusive hypotheses, proximity-induced dimerization vs. induced conformation, emphasize different aspects of initiator caspase activation. This study provides compelling evidence to support the induced conformation model for caspase-9 activation. A previously unknown interface between Apaf-1 and caspase-9 was identified to play an essential role in caspase-9 activation, and formation of a multimeric complex between Apaf-1 caspase recruitment domain (CARD) and caspase-9 was shown to be indispensable for caspase-9 activation.