Structure of an apoptosome-procaspase-9 CARD complex.

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.

Citation

Shujun Yuan, Xinchao Yu, Maya Topf, Steven J Ludtke, Xiaodong Wang, Christopher W Akey. Structure of an apoptosome-procaspase-9 CARD complex. Structure (London, England : 1993). 2010 May 12;18(5):571-83

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PMID: 20462491

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