Structural basis of IAP recognition by Smac/DIABLO

Nature. 2000 Dec 21-28;408(6815):1008-12. doi: 10.1038/35050012.

Abstract

Apoptosis is an essential process in the development and homeostasis of all metazoans. The inhibitor-of-apoptosis (IAP) proteins suppress cell death by inhibiting the activity of caspases; this inhibition is performed by the zinc-binding BIR domains of the IAP proteins. The mitochondrial protein Smac/DIABLO promotes apoptosis by eliminating the inhibitory effect of IAPs through physical interactions. Amino-terminal sequences in Smac/DIABLO are required for this function, as mutation of the very first amino acid leads to loss of interaction with IAPs and concomitant loss of Smac/DIABLO function. Here we report the high-resolution crystal structure of Smac/DIABLO complexed with the third BIR domain (BIR3) of XIAP. Our results show that the N-terminal four residues (Ala-Val-Pro-Ile) in Smac/DIABLO recognize a surface groove on BIR3, with the first residue Ala binding a hydrophobic pocket and making five hydrogen bonds to neighbouring residues on BIR3. These observations provide a structural explanation for the roles of the Smac N terminus as well as the conserved N-terminal sequences in the Drosophila proteins Hid/Grim/Reaper. In conjunction with other observations, our results reveal how Smac may relieve IAP inhibition of caspase-9 activity. In addition to explaining a number of biological observations, our structural analysis identifies potential targets for drug screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • Binding Sites
  • Carrier Proteins / chemistry*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Caspase 9
  • Caspase Inhibitors
  • Crystallography, X-Ray
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / metabolism
  • Drosophila
  • Drosophila Proteins*
  • Escherichia coli
  • Hydrogen Bonding
  • Insect Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins*
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Neuropeptides / metabolism
  • Peptides / metabolism
  • Protein Conformation
  • Protein Structure, Tertiary
  • Proteins / chemistry*
  • Proteins / genetics
  • Proteins / metabolism
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Structure-Activity Relationship
  • X-Linked Inhibitor of Apoptosis Protein

Substances

  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • DIABLO protein, human
  • Drosophila Proteins
  • Insect Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Neuropeptides
  • Peptides
  • Proteins
  • Recombinant Fusion Proteins
  • X-Linked Inhibitor of Apoptosis Protein
  • grim protein, Drosophila
  • rpr protein, Drosophila
  • CASP9 protein, human
  • Caspase 9

Associated data

  • PDB/1G73