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Molecular basis for the regulation of human glycogen synthase by phosphorylation and glucose-6-phosphate.

<div class='caption-title'>Structure of the phosphorylated inhibited (T state) GYS1–GYG1ΔCD complex.</div>
<div class='caption-title'>N and C termini of phosphorylated GYS1–GYG1ΔCD complex in the inhibited (T) state.</div>
<div class='caption-title'>Activated structures of the phosphorylated R-state GYS1–GYG1ΔCD complex with and without substrate.</div>
McCorvie TJ, Loria PM, Tu M, Han S, Shrestha L, Froese DS, Ferreira IM, Berg AP, Yue WW
OpenAccess logo Nat Struct Mol Biol 29 628-638 (2022)
Related entries: 7q0b, 7q0s, 7q12

Cited: 10 times
EuropePMC logo PMID: 35835870

Abstract

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.

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  2. Molecular basis for the regulation of human glycogen synthase by phosphorylation and glucose-6-phosphate. McCorvie TJ, Loria PM, Tu M, Han S, Shrestha L, Froese DS, Ferreira IM, Berg AP, Yue WW. Nat Struct Mol Biol 29 628-638 (2022)
  3. Transcriptional regulators and regulatory pathways involved in prostate gland adaptation to a hypoandrogen environment. Nishan U, da Rosa-Ribeiro R, Damas-Souza DM, Barbosa GO, Carvalho HF. Genet Mol Biol 42 e20180362 (2020)


Reviews citing this publication (2)

  1. Architecture, Function, Regulation, and Evolution of α-Glucans Metabolic Enzymes in Prokaryotes. Cifuente JO, Colleoni C, Kalscheuer R, Guerin ME. Chem Rev 124 4863-4934 (2024)
  2. Biosynthesis, structure and biological function of cholesterol glucoside in Helicobacter pylori: A review. Zhang L, Xie J. Medicine (Baltimore) 102 e34911 (2023)

Articles citing this publication (4)

  1. Glycogen synthase 1 targeting reveals a metabolic vulnerability in triple-negative breast cancer. de Heer EC, Zois CE, Bridges E, van der Vegt B, Sheldon H, Veldman WA, Zwager MC, van der Sluis T, Haider S, Morita T, Baba O, Schröder CP, de Jong S, Harris AL, Jalving M. J Exp Clin Cancer Res 42 143 (2023)
  2. Identification of disulfidptosis-related genes and subgroups in Alzheimer's disease. Ma S, Wang D, Xie D. Front Aging Neurosci 15 1236490 (2023)
  3. gys1 regulates maternal glycogen reserve essential for embryonic development in zebrafish. Chen J, Ji X, Gao J, Huang J, Ren J. Heliyon 10 e31149 (2024)
  4. Inhibition of mitochondrial fission activates glycogen synthesis to support cell survival in colon cancer. Hasani S, Young LEA, Van Nort W, Banerjee M, Rivas DR, Kim J, Xiong X, Sun RC, Gentry MS, Sesaki H, Gao T. Cell Death Dis 14 664 (2023)


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