A helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling

Rosalie E Lawrence; Sophie R Shoemaker; Aniliese Deal; Smriti Sangwan; Aditya A Anand; Lan Wang; Susan Marqusee; Peter Walter

doi:10.1038/s41589-023-01453-9

A helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling

Nat Chem Biol. 2024 Apr;20(4):422-431. doi: 10.1038/s41589-023-01453-9. Epub 2023 Nov 9.

Authors

Rosalie E Lawrence^{1

2}, Sophie R Shoemaker^#³, Aniliese Deal^#^{4

5

6}, Smriti Sangwan^{4

5}, Aditya A Anand^{4

5

7}, Lan Wang^{8

9

10}, Susan Marqusee^{11

12

13

14}, Peter Walter^{15

16

17}

Affiliations

¹ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. rosalie@walterlab.ucsf.edu.
² Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA. rosalie@walterlab.ucsf.edu.
³ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
⁴ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
⁵ Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA.
⁶ Altos Laboratories, Bay Area Institute of Science, Redwood City, CA, USA.
⁷ Genentech, Inc., South San Francisco, CA, USA.
⁸ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. lanwang@ust.hk.
⁹ Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA. lanwang@ust.hk.
¹⁰ The Hong Kong University of Science and Technology, Hong Kong, Hong Kong. lanwang@ust.hk.
¹¹ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. marqusee@berkeley.edu.
¹² Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA. marqusee@berkeley.edu.
¹³ Chan Zuckerberg Biohub, San Francisco, CA, USA. marqusee@berkeley.edu.
¹⁴ California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA. marqusee@berkeley.edu.
¹⁵ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. pwalter@altoslabs.com.
¹⁶ Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA. pwalter@altoslabs.com.
¹⁷ Altos Laboratories, Bay Area Institute of Science, Redwood City, CA, USA. pwalter@altoslabs.com.

^# Contributed equally.

Abstract

The integrated stress response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR underlies age-related diseases. ISR signaling downregulates translation and activates expression of stress-responsive factors that promote return to homeostasis and is initiated by inhibition of the decameric guanine nucleotide exchange factor eIF2B. Conformational and assembly transitions regulate eIF2B activity, but the allosteric mechanisms controlling these dynamic transitions and mediating the therapeutic effects of the small-molecule ISR inhibitor ISRIB are unknown. Using hydrogen-deuterium exchange-mass spectrometry and cryo-electron microscopy, we identified a central α-helix whose orientation allosterically coordinates eIF2B conformation and assembly. Biochemical and cellular signaling assays show that this 'switch-helix' controls eIF2B activity and signaling. In sum, the switch-helix acts as a fulcrum of eIF2B conformational regulation and is a highly conserved actuator of ISR signal transduction. This work uncovers a conserved allosteric mechanism and unlocks new therapeutic possibilities for ISR-linked diseases.

MeSH terms

Allosteric Regulation
Cryoelectron Microscopy
Eukaryotic Initiation Factor-2B* / chemistry
Eukaryotic Initiation Factor-2B* / metabolism
Guanine Nucleotide Exchange Factors* / metabolism
Phosphorylation
Signal Transduction

Substances

Eukaryotic Initiation Factor-2B
Guanine Nucleotide Exchange Factors

Abstract

MeSH terms

Substances

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