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 language | English (US) |
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Pages (from-to) | 2349-2361 |
Number of pages | 13 |
Journal | Genes and Development |
Volume | 29 |
Issue number | 22 |
DOIs | |
State | Published - Nov 15 2015 |
Keywords
- Apaf-1
- Apoptosis
- Apoptosome
- Caspase activation
- Caspase-9
- Cryo-EM structure
ASJC Scopus subject areas
- Genetics
- Developmental Biology