title: The apoptosome activates caspase-9 by dimerization.
abstract: The apical protease of the human intrinsic apoptotic pathway, caspase-9, is activated in a polymeric activation platform known as the apoptosome. The mechanism has been debated, and two contrasting hypotheses have been suggested. One of these postulates an allosteric activation of monomeric caspase-9; the other postulates a dimer-driven assembly at the surface of the apoptosome--the "induced proximity" model. We show that both Hofmeister salts and a reconstituted mini-apoptosome activate caspase-9 by a second-order process, compatible with a conserved dimer-driven process. Significantly, replacement of the recruitment domain of the apical caspase of the extrinsic apoptotic pathway, caspase-8, by that of caspase-9 allows activation of this hybrid caspase by the apoptosome. Consequently, apical caspases can be activated simply by directing their zymogens to the apoptosome, ruling out the requirement for allosteric activation and supporting an induced proximity dimerization model for apical caspase activation in vivo.
authors.affiliation: Program in Apoptosis and Cell Death Research, The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Pop
authors.forename: John
authors.initials: J
authors.lastname: Timmer
authors.forename: Sabina
authors.initials: S
authors.lastname: Sperandio
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
mesh_terms: D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002384:Catalysis; D002460:Cell Line; D002951:Citrates / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D000077559:Sodium Citrate; D013379:Substrate Specificity
chemical_list: C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D002951:Citrates; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011994:Recombinant Proteins; D000077559:Sodium Citrate; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases