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| A unified model for apical caspase activation |
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| Author(s): Boatright KM, Renatus M, Scott FL, Sperandio S, Shin H, Pedersen IM, Ricci JE, Edris WA, Sutherlin DP, Green DR, Salvesen GS |
| Source: MOLECULAR CELL Volume: 11 Issue: 2 Pages: 529-541 Published: FEB 2003 |
| Times Cited: 340 References: 55 |
| 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Salvesen, GS (reprint author), Burnham Inst, Program Apoptosis & Cell Death Res, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA |
Addresses:
1. Burnham Inst, Program Apoptosis & Cell Death Res, La Jolla, CA 92037 USA
2. Univ Calif San Diego, Dept Mol Pathol, La Jolla, CA 92037 USA
3. La Jolla Inst Allergy & Immunol, San Diego, CA 92121 USA
4. Wyeth Neurosci, Princeton, NJ 08543 USA
5. Genentech Inc, Dept Bioorgan Chem, San Francisco, CA 94080 USA |
| Publisher: CELL PRESS, 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA |
| Subject Category: Biochemistry & Molecular Biology; Cell Biology |
| IDS Number: 651AG |
| ISSN: 1097-2765 |
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