Allosteric Regulation of Glycogen Synthase Controls Glycogen Synthesis in Muscle

SummaryGlycogen synthase (GS), a key enzyme in glycogen synthesis, is activated by the allosteric stimulator glucose-6-phosphate (G6P) and by dephosphorylation through inactivation of GS kinase-3 with insulin. The relative importance of these two regulatory mechanisms in controlling GS is not established, mainly due to the complex interplay between multiple phosphorylation sites and allosteric effectors. Here we identify a residue that plays an important role in the allosteric activation of GS by G6P. We generated knockin mice in which wild-type muscle GS was replaced by a mutant that could not be activated by G6P but could still be activated normally by dephosphorylation. We demonstrate that knockin mice expressing the G6P-insensitive mutant display an ∼80% reduced muscle glycogen synthesis by insulin and markedly reduced glycogen levels. Our study provides genetic evidence that allosteric activation of GS is the primary mechanism by which insulin promotes muscle glycogen accumulation in vivo.

Graphical AbstractFigure optionsDownload high-quality image (153 K)Download as PowerPoint slideHighlights
► A critical glucose-6-phosphate (G6P) action site on glycogen synthase (GS) identified
► A knockin mouse expressing G6P-insensitive mutant GS generated
► GS knockin mice display dramatically reduced ability to accumulate muscle glycogen
► Insulin promotes glycogen synthesis mainly via allosteric activation of GS by G6P