Atomic structure of the apoptosome: mechanism of cytochrome c- and dATP-mediated activation of Apaf-1

作者：Zhou, Mengying; Li, Yini; Hu, Qi; Bai, Xiao-chen; Huang, Weiyun; Yan, Chuangye; Scheres, Sjors H. W.; Shi, Yigong^*

来源：Genes & Development, 2015, 29(22): 2349-2361.

DOI：10.1101/gad.272278.115

• apoptosome
• cryo-EM structure
• apoptosis
• Apaf-1
• caspase activation
• caspase-9

The apoptotic protease-activating factor 1 (Apaf-1) controls the onset of many known forms of intrinsic apoptosis in mammals. Apaf-1 exists in normal cells as an autoinhibited monomer. Upon binding to cytochrome c and dATP, Apaf-1 oligomerizes into a heptameric complex known as the apoptosome, which recruits and activates cell-killing caspases. Here we present an atomic structure of an intact mammalian apoptosome at 3.8 angstrom resolution, determined by single-particle, cryo-electron microscopy (cryo-EM). Structural analysis, together with structure-guided biochemical characterization, uncovered how cytochrome c releases the autoinhibition of Apaf-1 through specific interactions with the WD40 repeats. Structural comparison with autoinhibited Apaf-1 revealed how dATP binding triggers a set of conformational changes that results in the formation of the apoptosome. Together, these results constitute the molecular mechanism of cytochrome c- and dATP-mediated activation of Apaf-1.

• 出版日期2015-11-15
• 单位清华大学