title: A unified model for apical caspase activation.
abstract: Apoptosis is orchestrated by the concerted action of caspases, activated in a minimal two-step proteolytic cascade. Existing data suggests that apical caspases are activated by adaptor-mediated clustering of inactive zymogens. However, the mechanism by which apical caspases achieve catalytic competence in their recruitment/activation complexes remains unresolved. We explain that proximity-induced activation of apical caspases is attributable to dimerization. Internal proteolysis does not activate these apical caspases but is a secondary event resulting in partial stabilization of activated dimers. Activation of caspases-8 and -9 occurs by dimerization that is fully recapitulated in vitro by kosmotropes, salts with the ability to stabilize the structure of proteins. Further, single amino acid substitutions at the dimer interface abrogate the activity of caspases-8 and -9 introduced into recipient mammalian cells. We propose a unified caspase activation hypothesis whereby apical caspases are activated by dimerization of monomeric zymogens.
authors.affiliation: The Program in Apoptosis and Cell Death Research, Burnham Institute, 10901 North Torrey Pines Road, University of California, San Diego, La Jolla, CA 92037, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Boatright
authors.forename: Martin
authors.initials: M
authors.lastname: Renatus
authors.forename: Fiona L
authors.initials: FL
authors.lastname: Scott
authors.forename: Sabina
authors.initials: S
authors.lastname: Sperandio
authors.forename: Hwain
authors.initials: H
authors.lastname: Shin
authors.forename: Irene M
authors.initials: IM
authors.lastname: Pedersen
authors.forename: Jean Ehrland
authors.initials: JE
authors.lastname: Ricci
authors.forename: Wade A
authors.initials: WA
authors.lastname: Edris
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sutherlin
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
mesh_terms: D019943:Amino Acid Substitution; D017209:Apoptosis / Q000502:physiology; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D019281:Dimerization; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D015853:Cysteine Proteinase Inhibitors; D011994:Recombinant Proteins; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases