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Updated: Jul 1, 2026
10:36
Measurements of Physiological Stress Responses in C. Elegans
Published on: May 21, 2020
Allosteric disordering of eIF2B regulates the integrated stress response
Udit Dalwadi1, Advait Subramanian1, Aniliese Deal1
1Institute of Science, Altos Labs, Redwood City, CA, USA.
Nature Chemical Biology
|June 29, 2026
Summary
Researchers discovered how the eIF2B protein complex regulates the integrated stress response (ISR). They identified a key 'latch-helix' mechanism and developed compounds to control ISR activity for therapeutic potential.
Area of Science:
- Molecular Biology
- Biochemistry
- Cellular Stress Response
Background:
- The ternary complex (eIF2, GTP, methionyl-tRNA) initiates protein synthesis.
- Eukaryotic initiation factor 2B (eIF2B) regulates ternary complex levels by catalyzing GDP/GTP exchange on eIF2.
- Stress-induced phosphorylation of eIF2 converts it into an inhibitor of eIF2B, activating the integrated stress response (ISR).
Purpose of the Study:
- To elucidate the allosteric regulation of eIF2B activity.
- To understand the mechanism by which phosphorylated eIF2 (eIF2-P) inhibits eIF2B.
- To explore the potential for pharmacological manipulation of the ISR via eIF2B.
Main Methods:
- Structural and biochemical analysis of eIF2B allosteric regulation.
- Investigation of the role of the eIF2B β-subunit 'latch-helix'.
- Characterization of viral protein interactions with eIF2B.
- Development and testing of ISR-modulating compounds.
Main Results:
- An allosteric axis in eIF2B was identified, involving a 'latch-helix' in the β-subunit that is crucial for activity.
- eIF2-P binding causes the latch-helix to unhook, inhibiting eIF2B and activating the ISR.
- Viral proteins stabilize the active, latched state of eIF2B.
- Novel compounds were generated that stabilize the inhibited, unlatched state of eIF2B, activating the ISR.
Conclusions:
- Long-range allostery governs eIF2B function and ISR regulation.
- The latch-helix mechanism is a key target for modulating the ISR.
- Pharmacological agents stabilizing the inhibited eIF2B state can sustain or attenuate the ISR, offering therapeutic avenues.
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