Molecular mechanism of action of X-linked inhibitor of apoptosis protein

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X-linked inhibitor of apoptosis protein (XIAP), a member of IAP fatmly, is an endogenous caspase inhibitor and has three tandem repeats of BIR sequences at its NH2-terminus and a RlNG finger motif at its COOH terminus. BIR2 domain is responsible for XIAP mediated caspase-3/-7.We found that caspase-3 is inhibited in a competitive manner while caspase-7 inhibition occurs through a mixed competitive and noncompetitive mechanism. Further analyses revealed that the linker region between BIRI and BIR2 domains is responsible for active site-directed, competitive inhibition of both caspase-3 and -7, whereas the BIR2_ itself is involved in noncompetitive inhibition of caspase-7 (J Biol Chem, 2001). Next, we found that XIAP acts as a ubiquitin-protein ligase for caspase-3.We demonstrated that the ubiquitin-protein ligase activity of XIAP promotes the degradation of caspase-3, which enhances its anti-apoptotic effect (Proc Natl Acad Sci, 2001). Finally, we found that a serine protease termed HtrA2/0mi is released from the mitochondria upon apoptotic stimuli, and binds to and inhibits XIAP (Mol. Cell, 2OOl).