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Evolution of an allosteric "off switch" in apoptotic caspases
1From the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267 and andrew.herr@cchmc.org.
The Journal of Biological Chemistry
|April 15, 2018
Summary
Low levels of caspase-3 activity are crucial for development. A new study reveals how phosphorylation of specific sites on caspase-3 reduces its catalytic activity, balancing cell death and development.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Caspase-3 is recognized as the primary executioner caspase, initiating apoptosis.
- However, low levels of caspase-3 activity are essential for normal cellular development.
Purpose of the Study:
- To elucidate the mechanism by which cells regulate caspase-3 activity.
- To understand how caspase-3 balances its roles in apoptosis and development.
Main Methods:
- Biophysical techniques
- Structural biology approaches
- Computational modeling
Main Results:
- Phosphorylation of conserved sites on a distal surface loop of caspase-3.
- This phosphorylation significantly reduces or abolishes the enzyme's catalytic activity.
- Demonstration of an allosteric regulation mechanism.
Conclusions:
- Phosphorylation provides a mechanism for fine-tuning caspase-3 activity.
- This regulation is critical for balancing apoptosis and developmental roles.
- Findings offer opportunities for developing novel caspase-3 modulators.