title: Interdimer processing and linearity of procaspase-3 activation. A unifying mechanism for the activation of initiator and effector caspases.
abstract: Caspase activation during apoptosis occurs in a cascade from the initiator caspase(s) (e.g. caspase-8) to the effector caspases (e.g. caspase-3), which ensures the generation of large amounts of active caspases to dismantle cells. However, the mechanism that safeguards against inadvertent caspase activation is not well understood. Previous studies have suggested that the activation of procaspase-8 is mediated by cross-cleavage of precursor dimers, formed upon apoptosis induction, which are not only enzymatically competent but also highly susceptible to cleavage, and that procaspase-8 activation is a linear process without self-amplification. Effector procaspases constitutively exist as dimers and their activation is started by trans-cleavage by an initiator caspase followed by autocleavage of effector caspases. Here we show that the dimerization of caspase-3 molecules through their protease domains is required for their processing by initiator caspases. The subsequent autoprocessing takes place through cleavage between the dimeric intermediates. Moreover, mature caspase-3 fails to process its own precursor. Thus, despite a marked difference in the generation of active intermediates, the activation of initiator and effector caspases shares the features of interdimer cleavage and lack of self-amplification. These features may be important in preventing accidental cell death.
authors.affiliation: Abramson Family Cancer Research Institute and Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Hongtu
authors.initials: H
authors.lastname: Liu
authors.forename: David W
authors.initials: DW
authors.lastname: Chang
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Yang
mesh_terms: D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D004789:Enzyme Activation; D009154:Mutation
chemical_list: D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases