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TitleA helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling.
Journal, issue, pagesNat Chem Biol, Vol. 20, Issue 4, Page 422-431, Year 2024
Publish dateNov 9, 2023
AuthorsRosalie E Lawrence / Sophie R Shoemaker / Aniliese Deal / Smriti Sangwan / Aditya A Anand / Lan Wang / Susan Marqusee / Peter Walter /
PubMed AbstractThe 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 ...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.
External linksNat Chem Biol / PubMed:37945896 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 3.1 Å
Structure data

41510

8tqo

EMDB-41510, PDB-8tqo:
Eukaryotic translation initiation factor 2B tetramer
Method: EM (single particle) / Resolution: 3.1 Å

41566

8tqz

EMDB-41566, PDB-8tqz:
Eukaryotic translation initiation factor 2B with a mutation (L516A) in the delta subunit
Method: EM (single particle) / Resolution: 2.9 Å

Source
  • homo sapiens (human)
KeywordsTRANSLATION / Protein translation / eIF2B / integrated stress response

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