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A helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling.
Lawrence, Rosalie E; Shoemaker, Sophie R; Deal, Aniliese; Sangwan, Smriti; Anand, Aditya A; Wang, Lan; Marqusee, Susan; Walter, Peter.
Afiliación
  • Lawrence RE; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. rosalie@walterlab.ucsf.edu.
  • Shoemaker SR; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA. rosalie@walterlab.ucsf.edu.
  • Deal A; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • Sangwan S; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • Anand AA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA.
  • Wang L; Altos Laboratories, Bay Area Institute of Science, Redwood City, CA, USA.
  • Marqusee S; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • Walter P; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA.
Nat Chem Biol ; 20(4): 422-431, 2024 Apr.
Article en En | MEDLINE | ID: mdl-37945896
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Intercambio de Guanina Nucleótido / Factor 2B Eucariótico de Iniciación Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Intercambio de Guanina Nucleótido / Factor 2B Eucariótico de Iniciación Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos