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Evolution of an allosteric "off switch" in apoptotic caspases

Andrew B Herr1,2

  • 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
PubMed

Insights

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.
Keywords:
allosteric regulationapoptosiscaspasephosphorylationprotein evolution

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