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Measurements of Physiological Stress Responses in C. Elegans
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Measurements of Physiological Stress Responses in C. Elegans

Published on: May 21, 2020

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A helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling

Rosalie E Lawrence1,2, Sophie R Shoemaker3, Aniliese Deal4,5,6

  • 1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. rosalie@walterlab.ucsf.edu.

Nature Chemical Biology
|November 9, 2023
PubMed

Insights

Scientists discovered a key mechanism in the integrated stress response (ISR) that regulates cellular stress. This finding reveals how the

Area of Science:

  • Cellular Biology
  • Molecular Mechanisms
  • Biochemistry

Background:

  • The integrated stress response (ISR) is crucial for cellular survival during acute stress but contributes to age-related diseases when chronically activated.
  • ISR signaling involves the inhibition of the guanine nucleotide exchange factor eIF2B, which regulates translation and stress responses.
  • The precise allosteric mechanisms governing eIF2B conformational changes and the therapeutic action of ISR inhibitors like ISRIB remain unclear.

Purpose of the Study:

  • To elucidate the allosteric mechanisms controlling eIF2B conformation and assembly.
  • To understand how these mechanisms mediate the therapeutic effects of ISR inhibitors.
  • To identify key regulatory elements within eIF2B involved in ISR signal transduction.

Main Methods:

  • Hydrogen-deuterium exchange-mass spectrometry (HDX-MS) to probe protein dynamics.
  • Cryo-electron microscopy (cryo-EM) for high-resolution structural analysis.
  • Biochemical assays and cellular signaling experiments to assess eIF2B activity and ISR pathway modulation.

Main Results:

  • Identification of a central 'switch-helix' whose orientation allosterically coordinates eIF2B conformation and assembly.
  • Demonstration that the switch-helix is a critical regulator of eIF2B activity and ISR signaling.
  • Evidence that this mechanism is conserved across species, highlighting its fundamental role.

Conclusions:

  • The switch-helix acts as a central regulatory pivot for eIF2B, controlling its conformational states and assembly.
  • This conserved allosteric mechanism is a key actuator of the integrated stress response.
  • Uncovering this mechanism opens new avenues for therapeutic interventions targeting ISR-related diseases.

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