Oligomerization is a general mechanism for the activation of apoptosis initiator and inflammatory procaspases.
Proteolytic activation of initiator procaspases is a crucial step in the cellular commitment to apoptosis. Alternative models have been postulated for the activation mechanism, namely the oligomerization or induced proximity model and the allosteric regulation model. While the former holds that procaspases become activated upon proper oligomerization by an adaptor protein, the latter states that the adaptor is an allosteric regulator for procaspases. The allosteric regulation model has been applied for the activation of procaspase-9 by apoptotic protease-activating factor (Apaf-1) in an oligomeric complex known as the apoptosome. Using approaches that allow for controlled oligomerization, we show here that aggregation of multiple procaspase-9 molecules can induce their activation independent of the apoptosome. Oligomerization-induced procaspase-9 activation, both within the apoptosome and in artificial systems, requires stable homophilic association of the protease domains, raising the possibility that the function of Apaf-1 is not only to oligomerize procaspase-9 but also to maintain the interaction of the caspase-9 protease domain after processing. In addition, we provide biochemical evidence that other apoptosis initiator caspases (caspase-2 and -10) as well as a procaspase involved in inflammation (murine caspase-11) are also activated by oligomerization. Thus, oligomerization of precursor molecules appears to be a general mechanism for the activation of both apoptosis initiator and inflammatory procaspases.
Chang
David W
DW
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Ditsworth
Dara
D
Liu
Hongtu
H
Srinivasula
Srinivasa M
SM
Alnemri
Emad S
ES
Yang
Xiaolu
X
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1; D053455:Caspase 10; D053143:Caspase 2; D053453:Caspase 9; D020169:Caspases / Q000737:chemistry* / Q000502:physiology; D019281:Dimerization; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000737:chemistry* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000201:enzymology*; D051379:Mice; D011506:Proteins / Q000737:chemistry* / Q000502:physiology
C506592:APAF1 protein, human; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D004792:Enzyme Precursors; D011506:Proteins; C506433:CASP9 protein, human; C506434:Casp9 protein, mouse; D053455:Caspase 10; D053143:Caspase 2; D053453:Caspase 9; D020169:Caspases; C506438:CASP10 protein, human