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eIF2B conformation and assembly state regulate the integrated stress response.

Michael Schoof1,2, Morgane Boone1,2, Lan Wang1,2

  • 1Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, United States.

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|March 10, 2021
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Summary
This summary is machine-generated.

The integrated stress response (ISR) is regulated by eIF2B assembly. A small molecule, ISRIB, promotes eIF2B assembly and inhibits the ISR, revealing new insights into stress pathway regulation.

Keywords:
ISRISRIBallosterybiochemistrycell biologychemical biologyeIF2eIF2Bhuman

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Area of Science:

  • Molecular Biology
  • Cellular Stress Response

Background:

  • The integrated stress response (ISR) is a critical cellular pathway activated by stress.
  • Phosphorylation of eIF2 (eIF2-P) inhibits its guanine nucleotide exchange factor, eIF2B, a heterodecameric complex.
  • eIF2B assembly is crucial for regulating the ISR.

Purpose of the Study:

  • To investigate the mechanisms of eIF2B assembly and its role in ISR regulation.
  • To explore how the small molecule ISRIB affects eIF2B assembly and ISR activity.
  • To elucidate the structural basis of eIF2B regulation by eIF2-P and ISRIB.

Main Methods:

  • In vitro and in vivo monitoring and manipulation of eIF2B assembly.
  • Cryo-electron microscopy (cryo-EM) to determine structural changes in eIF2B.
  • Biochemical assays to assess eIF2B enzymatic activity.

Main Results:

  • Absence of eIF2B's α-subunit leads to ISR induction due to accumulated unassembled eIF2B tetramers.
  • ISRIB promotes the assembly of eIF2B tetramers into active octamers.
  • ISRIB inhibits the ISR even in fully assembled eIF2B decamers, indicating allosteric regulation.
  • Cryo-EM structures reveal a rocking motion in eIF2B coupling binding sites.
  • eIF2-P binding induces a conformational change in eIF2B decamers to 'conjoined tetramers' with reduced activity.

Conclusions:

  • eIF2B assembly dynamics are central to ISR regulation.
  • ISRIB acts as an allosteric inhibitor of the ISR by modulating eIF2B conformation.
  • The study reveals a novel mechanism of ISR activation via eIF2-P-induced conformational changes in eIF2B.