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A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis.

X-linked inhibitor-of-apoptosis protein (XIAP) interacts with caspase-9 and inhibits its activity, whereas Smac (also known as DIABLO) relieves this inhibition through interaction with XIAP. Here we show that XIAP associates with the active caspase-9-Apaf-1 holoenzyme complex through binding to the amino terminus of the linker peptide on the small subunit of caspase-9, which becomes exposed after proteolytic processing of procaspase-9 at Asp315. Supporting this observation, point mutations that abrogate the proteolytic processing but not the catalytic activity of caspase-9, or deletion of the linker peptide, prevented caspase-9 association with XIAP and its concomitant inhibition. We note that the N-terminal four residues of caspase-9 linker peptide share significant homology with the N-terminal tetra-peptide in mature Smac and in the Drosophila proteins Hid/Grim/Reaper, defining a conserved class of IAP-binding motifs. Consistent with this finding, binding of the caspase-9 linker peptide and Smac to the BIR3 domain of XIAP is mutually exclusive, suggesting that Smac potentiates caspase-9 activity by disrupting the interaction of the linker peptide of caspase-9 with BIR3. Our studies reveal a mechanism in which binding to the BIR3 domain by two conserved peptides, one from Smac and the other one from caspase-9, has opposing effects on caspase activity and apoptosis.

Pubmed ID: 11242052


  • Srinivasula SM
  • Hegde R
  • Saleh A
  • Datta P
  • Shiozaki E
  • Chai J
  • Lee RA
  • Robbins PD
  • Fernandes-Alnemri T
  • Shi Y
  • Alnemri ES



Publication Data

March 1, 2001

Associated Grants


Mesh Terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Apoptotic Protease-Activating Factor 1
  • Carrier Proteins
  • Caspase 9
  • Caspase Inhibitors
  • Caspases
  • Catalysis
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Drosophila
  • Enzyme Activation
  • Enzyme Inhibitors
  • Escherichia coli
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • Protein Processing, Post-Translational
  • Proteins
  • Recombinant Proteins
  • X-Linked Inhibitor of Apoptosis Protein