title: Activation and specificity of human caspase-10.
abstract: Two apical caspases, caspase-8 and -10, are involved in the extrinsic death receptor pathway in humans, but it is mainly caspase-8 in its apoptotic and nonapoptotic functions that has been an intense research focus. In this study we concentrate on caspase-10, its mechanism of activation, and the role of the intersubunit cleavage. Our data obtained through in vitro dimerization assays strongly suggest that caspase-10 follows the proximity-induced dimerization model for apical caspases. Furthermore, we compare the specificity and activity of the wild-type protease with a mutant incapable of autoprocessing by using positional scanning substrate analysis and cleavage of natural protein substrates. These experiments reveal a striking difference between the wild type and the mutant, leading us to hypothesize that the single chain enzyme has restricted activity on most proteins but high activity on the proapoptotic protein Bid, potentially supporting a prodeath role for both cleaved and uncleaved caspase-10.
authors.affiliation: Program in Apoptosis and Cell Death Research, Sanford-BurnhamMedical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Wachmann
authors.forename: Cristina
authors.initials: C
authors.lastname: Pop
authors.forename: Bram J
authors.initials: BJ
authors.lastname: van Raam
authors.forename: Marcin
authors.initials: M
authors.lastname: Drag
authors.forename: Peter D
authors.initials: PD
authors.lastname: Mace
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Snipas
authors.forename: Christian
authors.initials: C
authors.lastname: Zmasek
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarzenbacher
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Riedl
mesh_terms: D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053455:Caspase 10 / Q000096:biosynthesis*; D019281:Dimerization; D010450:Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D013379:Substrate Specificity
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D010450:Endopeptidases; D053455:Caspase 10; C506438:CASP10 protein, human
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