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Structure. 2010 May 12;18(5):571-83. doi: 10.1016/j.str.2010.04.001.

Structure of an apoptosome-procaspase-9 CARD complex.

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  • 1Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, MA 02118-2526, USA.

Abstract

Apaf-1 coassembles with cytochrome c to form the apoptosome, which then binds and activates procaspase-9 (pc-9). We removed pc-9 catalytic domains from the holoapoptosome by site-directed thrombinolysis. A structure of the resulting apoptosome-pc-9 CARD complex was then determined at approximately 9.5 A resolution. In our model, the central hub is constructed like other AAA+ protein rings but also contains novel features. At higher radius, the regulatory region of each Apaf-1 is comprised of tandem seven and eight blade beta-propellers with cytochrome c docked between them. Remarkably, Apaf-1 CARDs are disordered in the ground state. During activation, each Apaf-1 CARD interacts with a pc-9 CARD and these heterodimers form a flexibly tethered "disk" that sits above the central hub. When taken together, the data reveal conformational changes during Apaf-1 assembly that allow pc-9 activation. The model also provides a plausible explanation for the effects of NOD mutations that have been mapped onto the central hub.

Copyright 2010 Elsevier Ltd. All rights reserved.

PMID:
20462491
[PubMed - indexed for MEDLINE]
PMCID:
PMC2874686
Free PMC Article
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