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Genes Dev. 2015 Nov 15;29(22):2349-61. doi: 10.1101/gad.272278.115. Epub 2015 Nov 5.

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

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Ministry of Education Protein Science Laboratory, Center for Structural Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China;
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom.


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 Å 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.


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

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