Abstract
Some members of the inhibitor of apoptosis (IAP) family suppress apoptosis by neutralizing caspases. The current model suggests that all caspase-regulatory IAPs function as direct enzyme inhibitors, blocking effector caspases by binding to their catalytically active pockets. Here we show that IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms. Whereas XIAP binds directly to the active-site pockets of effector caspases, we find that regulation of effector caspases by Drosophila IAP1 (DIAP1) requires an evolutionarily conserved IAP-binding motif (IBM) at the neo-amino terminus of the large caspase subunit. Remarkably, unlike XIAP, DIAP1-sequestered effector caspases remain catalytically active, suggesting that DIAP1 does not function as a bona fide enzyme inhibitor. Moreover, we demonstrate that the mammalian IAP c-IAP1 interacts with caspase-7 in an exclusively IBM-dependent, but active site pocket-independent, manner that is mechanistically similar to DIAP1. The importance of IBM-mediated regulation of effector-caspases in vivo is substantiated by the enhanced apoptotic potency of IBM-mutant versions of drICE, DCP-1 and caspase-7.
Original language | English |
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Pages (from-to) | 70-7 |
Number of pages | 8 |
Journal | Nature Cell Biology |
Volume | 7 |
Issue number | 1 |
DOIs | |
Publication status | Published - Jan 2005 |
Keywords / Materials (for Non-textual outputs)
- Amino Acid Motifs
- Animals
- Apoptosis
- Binding Sites
- Caspase 7
- Caspases
- Drosophila Proteins
- Drosophila melanogaster
- Humans
- Inhibitor of Apoptosis Proteins
- Mice
- Mutation
- NIH 3T3 Cells
- Protein Binding
- Protein Subunits
- Proteins
- Signal Transduction
- X-Linked Inhibitor of Apoptosis Protein