7TRJ

The eukaryotic translation initiation factor 2B from Homo sapiens with a H160D mutation in the beta subunit

Summary for 7TRJ

• Entry DOI: 10.2210/pdb7trj/pdb
• EMDB information: 26098
• Descriptor: Translation initiation factor eIF-2B subunit epsilon, Translation initiation factor eIF-2B subunit beta, Translation initiation factor eIF-2B subunit delta, ... (5 entities in total)
• Functional Keywords: translation, integrated stress response
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 10
• Total formula weight: 522363.29

Authors

Wang, L.,Schoof, M.,Lawrence, R.,Boone, M.,Frost, A.,Walter, P. (deposition date: 2022-01-29, release date: 2022-04-27, Last modification date: 2024-02-21)

Primary citation

Boone, M.,Wang, L.,Lawrence, R.,Frost, A.,Walter, P.,Schoof, M.
A point mutation in the nucleotide exchange factor eIF2B constitutively activates the integrated stress response by allosteric modulation.
Elife, 11:-, 2022

PubMed Abstract: In eukaryotic cells, stressors reprogram the cellular proteome by activating the integrated stress response (ISR). In its canonical form, stress-sensing kinases phosphorylate the eukaryotic translation initiation factor eIF2 (eIF2-P), which ultimately leads to reduced levels of ternary complex required for initiation of mRNA translation. Previously we showed that translational control is primarily exerted through a conformational switch in eIF2's nucleotide exchange factor, eIF2B, which shifts from its active A-State conformation to its inhibited I-State conformation upon eIF2-P binding, resulting in reduced nucleotide exchange on eIF2 (Schoof et al. 2021). Here, we show functionally and structurally how a single histidine to aspartate point mutation in eIF2B's β subunit (H160D) mimics the effects of eIF2-P binding by promoting an I-State like conformation, resulting in eIF2-P independent activation of the ISR. These findings corroborate our previously proposed A/I-State model of allosteric ISR regulation.

PubMed: 35416150
DOI: 10.7554/eLife.76171

Experimental method

ELECTRON MICROSCOPY (2.8 Å)