title: IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms.
abstract: Some members of the inhibitor of apoptosis (IAP) family suppress apoptosis by neutralizing caspases. The current model suggests that all caspase-regulatory IAPs function as direct enzyme inhibitors, blocking effector caspases by binding to their catalytically active pockets. Here we show that IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms. Whereas XIAP binds directly to the active-site pockets of effector caspases, we find that regulation of effector caspases by Drosophila IAP1 (DIAP1) requires an evolutionarily conserved IAP-binding motif (IBM) at the neo-amino terminus of the large caspase subunit. Remarkably, unlike XIAP, DIAP1-sequestered effector caspases remain catalytically active, suggesting that DIAP1 does not function as a bona fide enzyme inhibitor. Moreover, we demonstrate that the mammalian IAP c-IAP1 interacts with caspase-7 in an exclusively IBM-dependent, but active site pocket-independent, manner that is mechanistically similar to DIAP1. The importance of IBM-mediated regulation of effector-caspases in vivo is substantiated by the enhanced apoptotic potency of IBM-mutant versions of drICE, DCP-1 and caspase-7.
authors.affiliation: The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, Fulham Road, London SW3 6JB, UK.
authors.forename: Tencho
authors.initials: T
authors.lastname: Tenev
authors.forename: Anna
authors.initials: A
authors.lastname: Zachariou
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wilson
authors.forename: Mark
authors.initials: M
authors.lastname: Ditzel
authors.forename: Pascal
authors.initials: P
authors.lastname: Meier
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites / Q000502:physiology; D053179:Caspase 7; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000502:physiology; D021122:Protein Subunits / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: C111891:DIAP1 protein, Drosophila; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D021122:Protein Subunits; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C494833:BIRC2 protein, human; C494834:Birc2 protein, mouse; D044767:Ubiquitin-Protein Ligases; C505520:CASP7 protein, human; C505524:Casp7 protein, mouse; D053179:Caspase 7; D020169:Caspases; C103568:Dcp-1 protein, Drosophila; C109171:drICE protein, Drosophila