Caspase-9 and APAF-1 form an active holoenzyme

Autocatalytic activation of initiator caspases is the link between pro-apop totic signals and the destruction machinery of apoptosis. Activation of cas pase-9, which mediates oncogene and drug-induced apoptosis, requires bindin g to the protein APAF-1. We found that the proteolytic activity of caspase- 9 in a complex with APAF-1 is several orders of magnitude higher than that of the free enzyme. Thus, this complex functions as a holoenzyme in which c aspase-9 is the catalytic subunit and APAF-1 its allosteric regulator. We a rgue that caspase-9 is activated by allosteric regulation and suggest that this mechanism is common for other initiator caspases.