Sugar phosphate activation of the stress sensor eIF2B.

Autor: Hao Q; Calico Life Sciences LLC, South San Francisco, CA, USA., Heo JM; Calico Life Sciences LLC, South San Francisco, CA, USA.; Loxo Oncology at Lilly, South San Francisco, CA, USA., Nocek BP; Research & Development, AbbVie, North Chicago, IL, USA., Hicks KG; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA., Stoll VS; Research & Development, AbbVie, North Chicago, IL, USA., Remarcik C; Calico Life Sciences LLC, South San Francisco, CA, USA., Hackett S; Calico Life Sciences LLC, South San Francisco, CA, USA., LeBon L; Calico Life Sciences LLC, South San Francisco, CA, USA., Jain R; Research & Development, AbbVie, North Chicago, IL, USA., Eaton D; Calico Life Sciences LLC, South San Francisco, CA, USA., Rutter J; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA.; Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT, USA., Wong YL; Calico Life Sciences LLC, South San Francisco, CA, USA. yao@calicolabs.com., Sidrauski C; Calico Life Sciences LLC, South San Francisco, CA, USA. carmela@calicolabs.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Jun 08; Vol. 12 (1), pp. 3440. Date of Electronic Publication: 2021 Jun 08.
DOI: 10.1038/s41467-021-23836-z
Abstrakt: 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.
Databáze: MEDLINE
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