IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms

Tencho Tenev, Anna Zachariou, Rebecca Wilson, Mark Ditzel, Pascal Meier

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)70-7
Number of pages8
JournalNature Cell Biology
Volume7
Issue number1
DOIs
Publication statusPublished - Jan 2005

Keywords

  • 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

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