7q13
From Proteopedia
Human GYS1-GYG1 complex activated state bound to glucose-6-phosphate, uridine diphosphate, and glucose
Structural highlights
DiseaseGYS1_HUMAN Glycogen storage disease due to muscle and heart glycogen synthase deficiency. The disease is caused by variants affecting the gene represented in this entry. FunctionGYS1_HUMAN Glycogen synthase participates in the glycogen biosynthetic process along with glycogenin and glycogen branching enzyme. Extends the primer composed of a few glucose units formed by glycogenin by adding new glucose units to it. In this context, glycogen synthase transfers the glycosyl residue from UDP-Glc to the non-reducing end of alpha-1,4-glucan.[1] Publication Abstract from PubMedGlycogen 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 A 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. 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. 2022 Jul;29(7):628-638. doi: 10.1038/s41594-022-00799-3. , Epub 2022 Jul 14. PMID:35835870[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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