14
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

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

      Nature
      Amino Acid Motifs, Amino Acid Sequence, Animals, Apoptosis, Apoptotic Protease-Activating Factor 1, Carrier Proteins, metabolism, 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, chemistry, Recombinant Proteins, X-Linked Inhibitor of Apoptosis Protein

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          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.

          Related collections

          Author and article information

          Comments

          Comment on this article