to enhance allosterically caspase-9 activity, rather than mediate its cleavage. The
recombinant procaspase-9, containing mutations that abolish processing sites of the
zymogen, can activate downstream caspases, but only in the presence of cytosolic
factors, presumably cytochrome c and Apaf-1 (Stennicke et al., 1999).
The three-dimensional structure of the apoptosome has been determined recently.
It shows that the apoptosome is a wheel-like heptameric particle with the Apaf-1
CARDs located at the central ‘hub’ and the WD40 repeats at the extended arms
(Acehan et al., 2002). In this structure procaspase-9 is localized to the central region
of the apoptosome, whereas cytochrome c associates with the extended WD40 arms
(Figure 2). This model defines a role for cytochrome c in apoptosome assembly.
Figure 2. The assembly of Apaf-1 apoptosome. Please see text for details.
As in the case of caspase-9, the activation of CED-3 is mediated by its adaptor
CED-4 (Chinnaiyan et al., 1997); however, there is no evidence for the requirement
THE ROLE OF CASPASES IN APOPTOSIS 39