Caspases, a unique family of cysteine proteases, execute programmed cell death (apoptosis). Caspases exist as inactive zymogens in cells and undergo a cascade of catalytic activation at the onset of apoptosis. The activated caspases are subject to inhibition by the inhibitor-of-apoptosis (IAP) family of proteins. This inhibition can be effectively removed by diverse proteins that share an IAP-binding tetrapeptide motif.

Caspases are a subfamily of cysteine proteases that specifically cleave after an aspartic acid residue. They are synthesized as inactive zymogens. They play essential roles inprogrammed cell death(includingapoptosis,pyroptosisandnecroptosis) andinflammation. They are named caspases due to their specificcysteine proteaseactivity-a cysteine in its active sitenucleophilicallyattacks and cleaves a target protein only after anaspartic acidresidue. Activation is mediated by a series of cleavages which result in the removal of the N-terminal prodomain and the generation of the large and small subunits. Once cleaved, caspases form inactive heterodimers and later active tretramers. Both subunits contribute residues that form the active site and there are two active sites per caspase.

Caspases have been placed in subgroups depending on substrate specificity, possible roles in vivo and domain composition. Regardless of the subgroup, caspases seem to fall into two general groups: initiator and effector. Initiator caspases are characterized by a long prodomain and are usually involved in the initial steps of apoptosis; their substrates include effector caspases. Effector caspases usually have a short prodomain and are involved in the later steps of apoptosis; their substrates include structural and functional proteins vital for the integrity of the cell.

Two major mechanisms of caspase regulation have been described

In mammals, two mechanisms of caspase regulation have been described using XIAP. The first mechanism describes the regulation of the initiator caspase-9. XIAP interactswith the active caspase-9 through the linker peptide of the small subunit in the caspase. This region in the small subunit becomes exposed after caspase self-processing. The peptide exposed has remarkable similarity with the RHG motif in the stimulators. Crystal structure studies show that the linker peptide in the small subunit of caspase 9 fits in the smac pocket of the BIR3 in XIAP. The residues in caspase-9 that bind to BIR3 are the same ones required for the formation of an active caspase tetramer. Binding of caspase-9 to the smac pocket of BIR3 sequesters the caspase in an inactive dimeric state. Caspase-9 binding to XIAP is challenged by the RHG motif in Smac. Both proteins compete for the same binding region in the BIR3 domain providing a mechanism for caspase-9 regulation.

A second mechanism has been described for the regulation of effector caspases -3 and -7. Unlike caspase-9, inhibition of these effector caspases does not directly involve a BIR domain. Known as the “hook, line, sinker” inhibition, this caspase regulation involves the linker region between BIR1 and BIR2 of XIAP. The “hook” (residues 138-145) interacts by sterically inhibiting substrate access. The “line” stretches across the caspase active site and connects with the “sinker” (residues 148-156). The “sinker” region forms hydrophobic and hydrogen-bonds with the caspase, completing the inhibition. The BIR2 domain stabilizes the interactions by the “hook, line, sinker”. In the case of caspase-3, XIAP BIR2 is not directly involved in the caspase inhibition; actually it can even be replaced by a non-related protein such as GST (Glutothione Transferase). However, XIAP BIR2 makes direct contacts with the Nterminus of the small subunit in caspase-7. In both cases however, binding of the stimulator Smac to the smac pocket of the BIR2 domain releases the inhibition on the caspase. The exact mechanism by which Smac removes the inhibition of effector caspases is yet to be resolved.


Luque, Laura E.Biochemical mechanisms of caspase regulation in apoptosis. 2005.

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