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Maintenance of caspase-3 proenzyme dormancy by an intrinsic “safety catch” regulatory tripeptide
Open accessAbstract
Caspase-3 is synthesized as a dormant proenzyme and is maintained in an inactive conformation by an Asp-Asp-Asp “safety-catch” regulatory tripeptide contained within a flexible loop near the large-subunit/small-subunit junction. Removal of this “safety catch” results in substantially enhanced autocatalytic maturation as well as increased vulnerability to proteolytic activation by upstream proteases in the apoptotic pathway such as caspase-9 and granzyme B. The safety catch functions through multiple ionic interactions that are disrupted by acidification, which occurs in the cytosol of cells during the early stages of apoptosis. We propose that the caspase-3 safety catch is a key regulatory checkpoint in the apoptotic cascade that regulates terminal events in the caspase cascade by modulating the triggering of caspase-3 activation.
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Cited by
Alterations of intracellular pH homeostasis in apoptosis: origins and roles
Lagadic-Gossmann, D., Huc, L., & Lecureur, V (2004) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401466 · Cited by 522
The Long Form of FLIP Is an Activator of Caspase-8 at the Fas Death-inducing Signaling Complex
Micheau, O., Thome, M., Schneider, P., Holler, N., Tschopp, J., Nicholson, D. W., Briand, C., & Grütter, M. G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206882200 · Cited by 482
Self-citationNew Approaches and Therapeutics Targeting Apoptosis in Disease
Fischer, U., & Schulze-Osthoff, K. (2005) · Pharmacological Reviews · doi:10.1124/pr.57.2.6 · Cited by 257
Lengthening the Intersubunit Linker of Procaspase 3 Leads to Constitutive Activation
MacKenzie, S. H., Schipper, J. L., England, E. J., Thomas, M. E., Blackburn, K., Swartz, P., & Clark, A. C. (2013) · Biochemistry · doi:10.1021/bi400793s · Cited by 15
Metadata
- Authors
- Roy, S., Bayly, C. I., Gareau, Y., Houtzager, V. M., Kargman, S., Keen, S. L. C., Rowland, K., Seiden, I. M., Thornberry, N. A., & Nicholson, D. W.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2001-05-15
- Volume
- 98
- Issue
- 11
- Pages
- 6132-6137
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2114344465
- Cited by
- 183
- References
- 0
- FWCI
- 4.56
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: Maintenance of caspase-3 proenzyme dormancy by an intrinsic “safety catch” regulatory tripeptide. https://app.cochat.ai/papers/10.1073/pnas.111085198
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- Roy, S., Bayly, C. I., Gareau, Y., Houtzager, V. M., Kargman, S., Keen, S. L. C., Rowland, K., Seiden, I. M., Thornberry, N. A., & Nicholson, D. W. (2001). Maintenance of caspase-3 proenzyme dormancy by an intrinsic “safety catch” regulatory tripeptide. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.111085198
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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