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

Mengying Zhou, Yini Li, Qi Hu, Xiao Chen Bai, Weiyun Huang, Chuangye Yan, Sjors H.W. Scheres, Yigong Shi

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2349-2361
Number of pages13
JournalGenes and Development
Volume29
Issue number22
DOIs
StatePublished - Nov 15 2015

Keywords

  • Apaf-1
  • Apoptosis
  • Apoptosome
  • Caspase activation
  • Caspase-9
  • Cryo-EM structure

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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