Sugar phosphate activation of the stress sensor eIF2B

被引:14
作者
Hao, Qi [1 ]
Heo, Jin-Mi [1 ,5 ]
Nocek, Boguslaw P. [2 ]
Hicks, Kevin G. [3 ]
Stoll, Vincent S. [2 ]
Remarcik, Clint [1 ]
Hackett, Sean [1 ]
LeBon, Lauren [1 ]
Jain, Rinku [2 ]
Eaton, Dan [1 ]
Rutter, Jared [3 ,4 ]
Wong, Yao Liang [1 ]
Sidrauski, Carmela [1 ]
机构
[1] Calico Life Sci LLC, South San Francisco, CA 94080 USA
[2] AbbVie, Res & Dev, N Chicago, IL USA
[3] Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
[4] Univ Utah, Sch Med, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA
[5] Loxo Oncol Lilly, South San Francisco, CA USA
关键词
GUANINE-NUCLEOTIDE EXCHANGE; CRYSTAL-STRUCTURE; REGULATORY SUBCOMPLEX; ALPHA-SUBUNIT; CRYO-EM; INHIBITION; MUTATIONS; COMPLEX; IDENTIFICATION; ARCHITECTURE;
D O I
10.1038/s41467-021-23836-z
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 eIF2B alpha subunit, promote eIF2B holoenzyme formation and enhance enzymatic activity towards eIF2. A mutant in the eIF2B alpha 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. The activity of translation initiation factor eIF2B is known to be modulated through stress-responsive phosphorylation of its substrate eIF2. Here, the authors uncover the regulation of eIF2B by the binding of sugar phosphates, suggesting a link between nutrient status and the rate of protein synthesis.
引用
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页数:12
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