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

Boucher, Dave, Blais, Véronique and Denault, Jean-Bernard (2012) Caspase-7 uses an exosite to promote poly(ADP ribose) polymerase 1 proteolysis. Proceedings of the National Academy of Sciences of the United States of America, 109 15: 5669-5674. doi:10.1073/pnas.1200934109


Author Boucher, Dave
Blais, Véronique
Denault, Jean-Bernard
Title Caspase-7 uses an exosite to promote poly(ADP ribose) polymerase 1 proteolysis
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2012-04-10
Sub-type Article (original research)
DOI 10.1073/pnas.1200934109
Open Access Status
Volume 109
Issue 15
Start page 5669
End page 5674
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Abstract 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 38KKK) 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.
Keyword Caspase substrate
Enzymology
Molecular recognition
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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