Atomic structure of the apoptosome: mechanism of cytochrome c- and dATP-mediated activation of Apaf-1
- Mengying Zhou1,3,
- Yini Li1,3,
- Qi Hu1,
- Xiao-chen Bai2,
- Weiyun Huang1,
- Chuangye Yan1,
- Sjors H.W. Scheres2 and
- Yigong Shi1
- 1Ministry 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;
- 2MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom
- Corresponding authors: shi-lab{at}tsinghua.edu.cn, scheres{at}mrc-lmb.cam.ac.uk
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↵3 These authors contributed equally to this work.
Abstract
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.272278.115.
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Freely available online through the Genes & Development Open Access option.
- Received September 20, 2015.
- Accepted October 13, 2015.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.