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Molecular mechanisms of caspase regulation during apoptosis

Molecular mechanisms of caspase regulation during apoptosis The molecular mechanism of activation for a representative effector caspase, caspase-7, is revealed by the conformational changes of the active site that take place after the activation cleavage. The essence of this mechanism is the provision of the L2′ loop, which is released by the activation cleavage and provides crucial support for the conformation of the active site. The molecular mechanism of inhibitor of apoptosis (IAP)-mediated inhibition of an effector caspase primarily involves the occupation of the caspase active site by an extended peptide fragment that immediately precedes the second baculoviral IAP repeat (BIR) domain, BIR2, of XIAP, c-IAP1 or c-IAP2. The BIR3 domain of XIAP inhibits caspase-9, an initiator caspase, by sequestering caspase-9 in a monomeric state, so that the L2′ loop cannot be provided by the adjacent monomer and the active site cannot be productively formed. This inhibition is dependent on, and initiated by, the binding between a conserved surface groove of the BIR3 domain of XIAP and the N-terminal tetrapeptide (Ala-Thr-Pro-Phe) of the small subunit of caspase-9. The viral protein p35 inhibits a caspase through the formation of a covalent thioester bond between the catalytic residue Cys360 of caspase-8 and Asp87 of p35, which follows caspase-mediated cleavage of the reactive-site loop of p35 after Asp87. The XIAP-mediated inhibition of caspase-9 can be countered effectively by SMAC/DIABLO, which uses its N-terminal tetrapeptide (Ala-Val-Pro-Ile) to compete with caspase-9 for binding to the same conserved surface groove of the BIR3 domain of XIAP. In Drosophila melanogaster, the caspase-9 orthologue Dronc is suppressed by Diap1 through an interaction that involves an internal peptide fragment of Dronc and the conserved surface groove of the BIR2 domain of Diap1. The pro-apoptotic proteins Reaper, Hid, Grim and Sickle use their N-terminal peptide fragments (which are similar to the SMAC/DIABLO tetrapeptide) to compete with Dronc for binding to the same conserved surface groove, thereby removing the Diap1-mediated negative regulation of Dronc. The exact mechanisms for the removal of effector-caspase inhibition remain to be defined. The prevailing model, which is supported by biochemical data, is that the binding of effector caspases by SMAC/DIABLO creates steric hindrance that dissociates the interaction between IAPs and the effector caspases. To gain a comprehensive picture of the molecular mechanisms of caspase regulation, future efforts should be directed at understanding the activation of initiator caspases and caspase pathways in Drosophila melanogaster and Caenorhabditis elegans. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Molecular Cell Biology Springer Journals

Molecular mechanisms of caspase regulation during apoptosis

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References (142)

Publisher
Springer Journals
Copyright
Copyright © 2004 by Nature Publishing Group
Subject
Life Sciences; Life Sciences, general; Cell Biology; Cancer Research; Developmental Biology; Stem Cells; Biochemistry, general
ISSN
1471-0072
eISSN
1471-0080
DOI
10.1038/nrm1496
Publisher site
See Article on Publisher Site

Abstract

The molecular mechanism of activation for a representative effector caspase, caspase-7, is revealed by the conformational changes of the active site that take place after the activation cleavage. The essence of this mechanism is the provision of the L2′ loop, which is released by the activation cleavage and provides crucial support for the conformation of the active site. The molecular mechanism of inhibitor of apoptosis (IAP)-mediated inhibition of an effector caspase primarily involves the occupation of the caspase active site by an extended peptide fragment that immediately precedes the second baculoviral IAP repeat (BIR) domain, BIR2, of XIAP, c-IAP1 or c-IAP2. The BIR3 domain of XIAP inhibits caspase-9, an initiator caspase, by sequestering caspase-9 in a monomeric state, so that the L2′ loop cannot be provided by the adjacent monomer and the active site cannot be productively formed. This inhibition is dependent on, and initiated by, the binding between a conserved surface groove of the BIR3 domain of XIAP and the N-terminal tetrapeptide (Ala-Thr-Pro-Phe) of the small subunit of caspase-9. The viral protein p35 inhibits a caspase through the formation of a covalent thioester bond between the catalytic residue Cys360 of caspase-8 and Asp87 of p35, which follows caspase-mediated cleavage of the reactive-site loop of p35 after Asp87. The XIAP-mediated inhibition of caspase-9 can be countered effectively by SMAC/DIABLO, which uses its N-terminal tetrapeptide (Ala-Val-Pro-Ile) to compete with caspase-9 for binding to the same conserved surface groove of the BIR3 domain of XIAP. In Drosophila melanogaster, the caspase-9 orthologue Dronc is suppressed by Diap1 through an interaction that involves an internal peptide fragment of Dronc and the conserved surface groove of the BIR2 domain of Diap1. The pro-apoptotic proteins Reaper, Hid, Grim and Sickle use their N-terminal peptide fragments (which are similar to the SMAC/DIABLO tetrapeptide) to compete with Dronc for binding to the same conserved surface groove, thereby removing the Diap1-mediated negative regulation of Dronc. The exact mechanisms for the removal of effector-caspase inhibition remain to be defined. The prevailing model, which is supported by biochemical data, is that the binding of effector caspases by SMAC/DIABLO creates steric hindrance that dissociates the interaction between IAPs and the effector caspases. To gain a comprehensive picture of the molecular mechanisms of caspase regulation, future efforts should be directed at understanding the activation of initiator caspases and caspase pathways in Drosophila melanogaster and Caenorhabditis elegans.

Journal

Nature Reviews Molecular Cell BiologySpringer Journals

Published: Nov 1, 2004

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