The death morphology commonly known as apoptosis results from a post-translational pathway driven largely by specific limited proteolysis. In the last decade the structural basis for apoptosis regulation has moved from nothing to ‘quite good’, and we now know the fundamental structures of examples from the initiator phase, the pre-mitochondrial regulator phase, the executioner phase, inhibitors and their antagonists, and even the structures of some substrates. The field is as well advanced as the best known of proteolytic pathways, the coagulation cascade. Fundamentally new mechanisms in protease regulation have been disclosed. Structural evidence suggests that caspases have an unusual catalytic mechanism, and that they are activated by apparently unrelated events, depending on which position in the apoptotic pathway they occupy. Some naturally occurring caspase inhibitors have adopted classic inhibition strategies, but other have revealed completely novel mechanisms. All of the structural and mechanistic information can, and is, being applied to drive therapeutic strategies to combat overactivation of apoptosis in degenerative disease, and underactivation in neoplasia. We present a comprehensive review of the caspases, their regulators and inhibitors from a structural and mechanistic point of view, and with an aim to consolidate the many threads that define the rapid growth of this field.
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December 2004
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Review Article|
November 23 2004
The protein structures that shape caspase activity, specificity, activation and inhibition
Pablo FUENTES-PRIOR;
Pablo FUENTES-PRIOR
1
*Abteilung Strukturforschung, Max-Planck-Institut für Biochemie, Am Klopferspitz 18a, D82152, Planegg-Martinsried, Germany and Cardiovascular Research Center, Sant Antoni Ma. Claret 167, 08025 Barcelona, Spain
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Guy S. SALVESEN
Guy S. SALVESEN
2
†The Program in Apoptosis and Cell Death Research, Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, U.S.A.
2email gsalvesen@burnham.org
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Publisher: Portland Press Ltd
Received:
July 05 2004
Revision Received:
August 31 2004
Accepted:
September 27 2004
Accepted Manuscript online:
September 27 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2004
Biochem J (2004) 384 (2): 201–232.
Article history
Received:
July 05 2004
Revision Received:
August 31 2004
Accepted:
September 27 2004
Accepted Manuscript online:
September 27 2004
Citation
Pablo FUENTES-PRIOR, Guy S. SALVESEN; The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem J 1 December 2004; 384 (2): 201–232. doi: https://doi.org/10.1042/BJ20041142
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