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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.
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