Sugar phosphate activation of the stress sensor eIF2B

Qi 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 () and Carmela Sidrauski ()
Additional contact information
Qi Hao: Calico Life Sciences LLC
Jin-Mi Heo: Calico Life Sciences LLC
Boguslaw P. Nocek: Research & Development, AbbVie
Kevin G. Hicks: University of Utah School of Medicine
Vincent S. Stoll: Research & Development, AbbVie
Clint Remarcik: Calico Life Sciences LLC
Sean Hackett: Calico Life Sciences LLC
Lauren LeBon: Calico Life Sciences LLC
Rinku Jain: Research & Development, AbbVie
Dan Eaton: Calico Life Sciences LLC
Jared Rutter: University of Utah School of Medicine
Yao Liang Wong: Calico Life Sciences LLC
Carmela Sidrauski: Calico Life Sciences LLC

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23836-z

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