Journal
PROTEIN SCIENCE
Volume 21, Issue 7, Pages 1056-1065Publisher
WILEY-BLACKWELL
DOI: 10.1002/pro.2090
Keywords
apoptosis; regulation; protease; initiator caspase; exosite binding; active-site inhibition
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Funding
- NIH [R01 GM080532]
- Research Corporation for the Advancement of Science
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Zinc-mediated inhibition is implicated in global caspase regulation, with relief of zinc-mediated inhibition central to both small-molecule and natively induced caspase activation. As an initiator, caspase-9 regulates the upstream stages of the apoptotic caspase cascade, making it a critical control point. Here we identify two distinct zinc-binding sites on caspase-9. The first site, composed of H237, C239, and C287, includes the active site dyad and is primarily responsible for zinc-mediated inhibition. The second binding site at C272 is distal from the active site. Given the amino-acid conservation in both regions, these sites appear to be present across the caspase family underscoring the importance of zinc-mediated regulation of this class of enzymes.
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