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

Nat Cell Biol. 2005 Jan;7(1):70-7. doi: 10.1038/ncb1204. Epub 2004 Dec 5.

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.

MeSH terms

  • Amino Acid Motifs / physiology
  • Animals
  • Apoptosis / physiology*
  • Binding Sites / physiology
  • Caspase 7
  • Caspases / genetics
  • Caspases / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Mice
  • Mutation / genetics
  • NIH 3T3 Cells
  • Protein Binding / physiology
  • Protein Subunits / metabolism
  • Proteins / metabolism*
  • Signal Transduction / physiology*
  • Ubiquitin-Protein Ligases
  • X-Linked Inhibitor of Apoptosis Protein

Substances

  • DIAP1 protein, Drosophila
  • Drosophila Proteins
  • Inhibitor of Apoptosis Proteins
  • Protein Subunits
  • Proteins
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • BIRC2 protein, human
  • Birc2 protein, mouse
  • Ubiquitin-Protein Ligases
  • CASP7 protein, human
  • Casp7 protein, mouse
  • Caspase 7
  • Caspases
  • Dcp-1 protein, Drosophila
  • drICE protein, Drosophila