Structural and biochemical basis of apoptotic activation by Smac/DIABLO

Nature. 2000 Aug 24;406(6798):855-62. doi: 10.1038/35022514.


Apoptosis (programmed cell death), an essential process in the development and homeostasis of metazoans, is carried out by caspases. The mitochondrial protein Smac/DIABLO performs a critical function in apoptosis by eliminating the inhibitory effect of IAPs (inhibitor of apoptosis proteins) on caspases. Here we show that Smac/DIABLO promotes not only the proteolytic activation of procaspase-3 but also the enzymatic activity of mature caspase-3, both of which depend upon its ability to interact physically with IAPs. The crystal structure of Smac/DIABLO at 2.2 A resolution reveals that it homodimerizes through an extensive hydrophobic interface. Missense mutations inactivating this dimeric interface significantly compromise the function of Smac/DIABLO. As in the Drosophila proteins Reaper, Grim and Hid, the amino-terminal amino acids of Smac/DIABLO are indispensable for its function, and a seven-residue peptide derived from the amino terminus promotes procaspase-3 activation in vitro. These results establish an evolutionarily conserved structural and biochemical basis for the activation of apoptosis by Smac/DIABLO.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Carrier Proteins / chemistry*
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology
  • Caspase 3
  • Caspases / metabolism*
  • Crystallography, X-Ray
  • Dimerization
  • Enzyme Activation
  • Enzyme Precursors / metabolism
  • Escherichia coli
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins*
  • Models, Chemical
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Protein Conformation


  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • DIABLO protein, human
  • Enzyme Precursors
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • CASP3 protein, human
  • Caspase 3
  • Caspases

Associated data

  • PDB/1FEW