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Lookup NU author(s): Dr Thomas McCorvieORCiD, Professor Wyatt YueORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022, The Author(s). Glycogen synthase (GYS1) is the central enzyme in muscle glycogen biosynthesis. GYS1 activity is inhibited by phosphorylation of its amino (N) and carboxyl (C) termini, which is relieved by allosteric activation of glucose-6-phosphate (Glc6P). We present cryo-EM structures at 3.0–4.0 Å resolution of phosphorylated human GYS1, in complex with a minimal interacting region of glycogenin, in the inhibited, activated and catalytically competent states. Phosphorylations of specific terminal residues are sensed by different arginine clusters, locking the GYS1 tetramer in an inhibited state via intersubunit interactions. The Glc6P activator promotes conformational change by disrupting these interactions and increases the flexibility of GYS1, such that it is poised to adopt a catalytically competent state when the sugar donor UDP-glucose (UDP-glc) binds. We also identify an inhibited-like conformation that has not transitioned into the activated state, in which the locking interaction of phosphorylation with the arginine cluster impedes subsequent conformational changes due to Glc6P binding. Our results address longstanding questions regarding the mechanism of human GYS1 regulation.
Author(s): McCorvie TJ, Loria PM, Tu M, Han S, Shrestha L, Froese DS, Ferreira IM, Berg AP, Yue WW
Publication type: Article
Publication status: Published
Journal: Nature Structural and Molecular Biology
Year: 2022
Volume: 29
Issue: 7
Pages: 628-638
Online publication date: 14/07/2022
Acceptance date: 02/05/2022
Date deposited: 12/09/2024
ISSN (print): 1545-9993
ISSN (electronic): 1545-9985
Publisher: Nature Research
URL: https://doi.org/10.1038/s41594-022-00799-3
DOI: 10.1038/s41594-022-00799-3
Data Access Statement: Structures and EM maps of GYS1–GYG1?CD inhibited state (EMDB-13743, PDB 7Q0B), GYS1–GYG1?CD + Glc6P inhibited-like state (EMDB-13751, PDB 7Q0S), GYS1–GYG1?CD + Glc6P activated state (EMDB-13752, PDB 7Q12) and GYS1–GYG1?CD + Glc6P+UDP-Glc activated state (EMDB-13753, PDB 7Q13) have been deposited in the Electron Microscopy Data Bank and Protein Data Bank. All main data supporting the findings of this study are available within the article, Extended Data and Supplementary Information. Source data are provided with this paper.
PubMed id: 35835870
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