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.
Highlights
Caspase activation during apoptosis occurs in a cascade from the initiator caspase(s) to the effector caspases, which ensures the generation of large amounts of active caspases to dismantle cells
Previous studies have suggested that the activation of procaspase-8 is mediated by cross-cleavage of precursor dimers, formed upon apoptosis induction, which are enzymatically competent and highly susceptible to cleavage, and that procaspase-8 activation is a linear process without self-amplification
Despite the difference in the generation of the dimeric intermediate, the activation of initiator caspases and effector caspases are similar with regards to autoproteolytic processing between these enzymatically active dimers and the lack of self-amplification
Summary
Different from initiator caspases, which exist as monomers prior to apoptosis induction, effector procaspases constitutively form dimers likely because of the strong hydrophobic nature of the dimer interface in these caspases [24] These precursor dimers, are inactive because of the structural constraints imposed by the covalent link between the large and small subunits. A cleavage of this link by an initiator caspase allows for re-ordering of catalytic and substrate-binding residues to form proper active sites, generating an enzymatically competent intermediate [25,26,27] This intermediate undergoes autoproteolytic processing to separate the large subunit from the prodomain. Despite the difference in the generation of the dimeric intermediate, the activation of initiator caspases and effector caspases are similar with regards to autoproteolytic processing between these enzymatically active dimers and the lack of self-amplification
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