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TitleSugar phosphate activation of the stress sensor eIF2B.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 3440, Year 2021
Publish dateJun 8, 2021
AuthorsQi Hao / Jin-Mi Heo / Boguslaw P Nocek / Kevin G Hicks / Vincent S Stoll / Clint Remarcik / Sean Hackett / Lauren LeBon / Rinku Jain / Dan Eaton / Jared Rutter / Yao Liang Wong / Carmela Sidrauski /
PubMed AbstractThe multi-subunit translation initiation factor eIF2B is a control node for protein synthesis. eIF2B activity is canonically modulated through stress-responsive phosphorylation of its substrate eIF2. ...The multi-subunit translation initiation factor eIF2B is a control node for protein synthesis. eIF2B activity is canonically modulated through stress-responsive phosphorylation of its substrate eIF2. The eIF2B regulatory subcomplex is evolutionarily related to sugar-metabolizing enzymes, but the biological relevance of this relationship was unknown. To identify natural ligands that might regulate eIF2B, we conduct unbiased binding- and activity-based screens followed by structural studies. We find that sugar phosphates occupy the ancestral catalytic site in the eIF2Bα subunit, promote eIF2B holoenzyme formation and enhance enzymatic activity towards eIF2. A mutant in the eIF2Bα ligand pocket that causes Vanishing White Matter disease fails to engage and is not stimulated by sugar phosphates. These data underscore the importance of allosteric metabolite modulation for proper eIF2B function. We propose that eIF2B evolved to couple nutrient status via sugar phosphate sensing with the rate of protein synthesis, one of the most energetically costly cellular processes.
External linksNat Commun / PubMed:34103529 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.7 - 2.91 Å
Structure data

22924

7kmf

EMDB-22924, PDB-7kmf:
Sugar phosphate activation of the stress sensor eIF2B
Method: EM (single particle) / Resolution: 2.91 Å

PDB-7kma:
Crystal structure of eif2Balpha with a ligand.
Method: X-RAY DIFFRACTION / Resolution: 2.7 Å

Chemicals

ChemComp-M6P:
6-O-phosphono-alpha-D-mannopyranose

ChemComp-ACT:
ACETATE ION

ChemComp-HOH:
WATER

ChemComp-F6P:
6-O-phosphono-beta-D-fructofuranose

Source
  • homo sapiens (human)
KeywordsSUGAR BINDING PROTEIN / Translation initiation factor eif-2b / translation factor activity / RNA binding / translation regulator activity / nucleic acid binding / TRANSLATION

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