Caspase-7 uses an exosite to promote poly(ADP ribose) polymerase 1 proteolysis

Dave Boucher, Véronique Blais, Jean-Bernard Denault

Research output: Contribution to journalArticlepeer-review


During apoptosis, hundreds of proteins are cleaved by caspases, most of them by the executioner caspase-3. However, caspase-7, which shares the same substrate primary sequence preference as caspase-3, is better at cleaving poly(ADP ribose) polymerase 1 (PARP) and Hsp90 cochaperone p23, despite a lower intrinsic activity. Here, we identified key lysine residues (K(38)KKK) within the N-terminal domain of caspase-7 as critical elements for the efficient proteolysis of these two substrates. Caspase-7's N-terminal domain binds PARP and improves its cleavage by a chimeric caspase-3 by ∼30-fold. Cellular expression of caspase-7 lacking the critical lysine residues resulted in less-efficient PARP and p23 cleavage compared with cells expressing the wild-type peptidase. We further showed, using a series of caspase chimeras, the positioning of p23 on the enzyme providing us with a mechanistic insight into the binding of the exosite. In summary, we have uncovered a role for the N-terminal domain (NTD) and the N-terminal peptide of caspase-7 in promoting key substrate proteolysis.

Original languageEnglish
Pages (from-to)5669-74
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number15
Publication statusPublished - 10 Apr 2012


  • Amino Acid Motifs
  • Amino Acid Sequence
  • Apoptosis
  • Caspase 3/metabolism
  • Caspase 7/chemistry
  • Cell Line
  • Humans
  • Intramolecular Oxidoreductases/metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Poly(ADP-ribose) Polymerases/metabolism
  • Prostaglandin-E Synthases
  • Protein Structure, Tertiary
  • Proteolysis
  • Structure-Activity Relationship
  • Substrate Specificity

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