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The apoptosome activates caspase-9 by dimerization.

Cristina Pop·John Timmer·Sabina Sperandio·Guy S Salvesen
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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.

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ApoptosisApoptotic Protease-Activating Factor 1Caspase 8Caspase 9CaspasesCatalysisCell LineCitratesDimerizationDose-Response Relationship, DrugEnzyme ActivationEnzyme PrecursorsHumansIntracellular Signaling Peptides and ProteinsKineticsModels, BiologicalProtein Structure, TertiaryProteinsRecombinant ProteinsSodium CitrateSubstrate SpecificityJournal ArticleResearch Support, N.I.H., Extramural

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Cristina Pop, John Timmer, Sabina Sperandio, Guy S Salvesen. 2006-04-21. The apoptosome activates caspase-9 by dimerization.. https://doi.org/10.1016/j.molcel.2006.03.009

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