Journal
GENES & DEVELOPMENT
Volume 29, Issue 22, Pages 2349-2361Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.272278.115
Keywords
apoptosome; cryo-EM structure; apoptosis; Apaf-1; caspase activation; caspase-9
Categories
Funding
- Ministry of Science and Technology [2014ZX09507003006]
- National Natural Science Foundation of China [31430020, 31130002, 31321062]
- European Union Marie Curie Fellowship
- UK Medical Research Council [MC_UP_A025_1013]
- MRC [MC_UP_A025_1013] Funding Source: UKRI
- Medical Research Council [MC_UP_A025_1013] Funding Source: researchfish
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available