'Allosteric mechanisms of cellular stress response'
The integrated stress response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR drives disease via incompletely understood metabolic mechanisms. 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. I will present on the discovery of eIF2B’s allosteric mechanism: 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. To conclude the talk, I will discuss future directions leveraging our understanding of the eIF2B Switch-Helix to gain rational control over signaling in cultured cells, opening up the ability to define precise mechanisms of metabolic mechanisms of chronic stress-induced disease.
Date: 25 June 2024, 11:30 (Tuesday, 10th week, Trinity 2024)
Venue: Dorothy Crowfoot Hodgkin Building, off South Parks Road OX1 3QU
Venue Details: Seminar Room 1, Room 20-026
Speaker: Dr. Rosalie Lawrence (Jane Coffin Childs Postdoctoral Fellow, Peter Walter Lab, UCSF)
Organising department: Department of Biochemistry
Organiser: Sarah-jane Scard (Department of Biochemistry)
Organiser contact email address: sarah-jane.scard@bioch.ox.ac.uk
Host: Professor Simon Newstead (University of Oxford,)
Part of: Special Seminar
Booking required?: Not required
Audience: Members of the University only
Editor: Sarah-Jane Scard