Glycogen synthase

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Glycogen synthase kinase-3 GSK3 may be the busiest kinase in most cells, with over known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders.

Glycogen synthase

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. 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 glucosephosphate Glc6P. We present cryo-EM structures at 3. 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.

In this structure, each GYS1 active site, at the cleft between the two Rossmann domains, was in a closed conformation owing to additional intersubunit contacts at a minor glycogen synthase B—D or A—C 16 Human muscle glycogen synthase cDNA sequence: a negatively charged protein with an asymmetric charge distribution, glycogen synthase. However, it glycogen synthase proven to be challenging given the complexity of its regulation, implication in several diverse pathways and the proposed side effect of GSK3 inhibitors leading to cancer.

Federal government websites often end in. The site is secure. Glycogen synthase kinase 3 GSK3 , a constitutively acting multi-functional serine threonine kinase is involved in diverse physiological pathways ranging from metabolism, cell cycle, gene expression, development and oncogenesis to neuroprotection. GSK3 has been implicated in various diseases such as diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. GSK3 negatively regulates insulin-mediated glycogen synthesis and glucose homeostasis, and increased expression and activity of GSK3 has been reported in type II diabetics and obese animal models. Consequently, inhibitors of GSK3 have been demonstrated to have anti-diabetic effects in vitro and in animal models. However, inhibition of GSK3 poses a challenge as achieving selectivity of an over achieving kinase involved in various pathways with multiple substrates may lead to side effects and toxicity.

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Glycogen is the major glucose reserve in eukaryotes, and defects in glycogen metabolism and structure lead to disease. Glycogenesis involves interaction of glycogenin GN with glycogen synthase GS , where GS is activated by glucosephosphate G6P and inactivated by phosphorylation. We describe the 2.

Glycogen synthase

Although glucose is the primary fuel for cells, it is not an efficient molecule for long-term storage in complex i. Therefore, in both plants and animals, the glucose molecules are linked together to form polysaccharides known as glucans. The average size of a glycogen unit is a cytoplasmic granule containing over glucose molecules. The addition of a glucosephosphate to another or to a glycogen chain is energetically unfavorable, so it must be coupled with a sufficiently exergonic reaction to proceed. The phosphoanhydride exchange reaction catalyzed by UDP-glucose phosphorylase is minimally exergonic.

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This interaction therefore provides a crucial activity switch mechanism from a tense phosphorylated state to a relaxed G6P-bound state Dev Cell. Mahalingan, K. View author publications. The New England Journal of Medicine. Glycogen phosphorylase Debranching enzyme Phosphoglucomutase. Endocr Rev. Marr, L. Chikwana, V. NiceZyme view. The N- and C-terminal tails of each GS protomer lie almost parallel to each other, and travel side by side along the GS tetrameric core to reach the centre Fig. Crystal structure of glycogen synthase: homologous enzymes catalyze glycogen synthesis and degradation. Molecular basis for the regulation of human glycogen synthase by phosphorylation and glucosephosphate.

Glycogen synthase UDP-glucose-glycogen glucosyltransferase is a key enzyme in glycogenesis , the conversion of glucose into glycogen. It is a glycosyltransferase EC 2.

Neurosci Biobehav Rev. This intermediate state is more susceptible to the allosteric effects of Glc6P binding, shifting the dynamic equilibrium more toward the activated state. Crystal structures of the starch-binding domain from Rhizopus oryzae glucoamylase reveal a polysaccharide-binding path. For more detailed information on the processing workflow for all data sets, please see Extended Data Figs. This article is cited by Glycogen synthase 1 targeting reveals a metabolic vulnerability in triple-negative breast cancer E. BMC Dev Biol. Mutations of muscle glycogen synthase that disable activation by glucose 6-phosphate. Human GS phosphorylation sites lie at the N-terminus sites 2 and 2a and C-terminus sites 3a, 3b, 3c, 4, 5, 1a, 1b , and phosphorylation occurs in a hierarchical fashion, whereby the phosphorylation of a specific site is the recognition motif for subsequent phosphorylation 31 , 32 , 33 Fig. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Source data are provided with this paper. Ashcroft, F.