Structural highlights
Function
APAF_HUMAN Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis. This activation requires ATP. Isoform 6 is less effective in inducing apoptosis.[1] [2]
Publication Abstract from PubMed
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 A 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.
Atomic structure of the apoptosome: mechanism of cytochrome c- and dATP-mediated activation of Apaf-1.,Zhou M, Li Y, Hu Q, Bai XC, Huang W, Yan C, Scheres SH, Shi Y Genes Dev. 2015 Nov 15;29(22):2349-61. doi: 10.1101/gad.272278.115. Epub 2015 Nov, 5. PMID:26543158[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hu Y, Benedict MA, Ding L, Nunez G. Role of cytochrome c and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. EMBO J. 1999 Jul 1;18(13):3586-95. PMID:10393175 doi:10.1093/emboj/18.13.3586
- ↑ Ogawa T, Shiga K, Hashimoto S, Kobayashi T, Horii A, Furukawa T. APAF-1-ALT, a novel alternative splicing form of APAF-1, potentially causes impeded ability of undergoing DNA damage-induced apoptosis in the LNCaP human prostate cancer cell line. Biochem Biophys Res Commun. 2003 Jun 27;306(2):537-43. PMID:12804598
- ↑ Zhou M, Li Y, Hu Q, Bai XC, Huang W, Yan C, Scheres SH, Shi Y. Atomic structure of the apoptosome: mechanism of cytochrome c- and dATP-mediated activation of Apaf-1. Genes Dev. 2015 Nov 15;29(22):2349-61. doi: 10.1101/gad.272278.115. Epub 2015 Nov, 5. PMID:26543158 doi:http://dx.doi.org/10.1101/gad.272278.115
