GYS1 encodes glycogen synthase 1, the muscle (and general non-hepatic) isoform of glycogen synthase and the committed, rate-limiting elongation enzyme of glycogen biosynthesis. As a retaining glycosyltransferase of family GT3 (EC 2.4.1.11), it uses UDP-glucose as the glucosyl donor to add glucose units in alpha-1,4-glycosidic linkage to the non-reducing ends of a growing glycogen chain that has been primed by glycogenin (GYG1); glycogen branching enzyme (GBE1) subsequently introduces alpha-1,6 branch points. GYS1 forms a heterooctameric complex with glycogenin (a GYS1 tetramer bound to two GYG1 dimers). Its activity is tightly regulated: it is allosterically activated by glucose-6-phosphate and inhibited by hierarchical multi-site phosphorylation of its N- and C-terminal tails (by kinases including GSK3, AMPK, casein kinase 2, PASK and DYRK2), which is reversed by glycogen-associated protein phosphatase 1 (recruited by PPP1R3 targeting subunits such as PTG/PPP1R3C). GYS1 is cytosolic and associates with glycogen particles. In humans, loss-of-function variants cause muscle glycogen storage disease 0 (GSD 0b), characterized by cardiomyopathy, exercise intolerance and risk of sudden cardiac death.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004373 alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Canonical, phylogenetically inferred molecular function of glycogen synthase: it elongates glycogen chains by transferring glucose from UDP-glucose to the alpha-1,4 non-reducing end of the polymer. This is the core catalytic activity of GYS1. Reason: The IBA is well supported by direct experimental evidence for the human enzyme and by the biochemical literature. This is the defining activity of GYS1 (EC 2.4.1.11). Supporting Evidence: PMID:35835870 GYS, a retaining glycosyltransferase (GT) belonging to the GT3 superfamily, catalyzes successive addition of Ξ±-1,4-linked glucose residues to the nonreducing end of a growing polysaccharide chain, using UDP-glc as the sugar donor with the release of UDP5. |
| GO:0005978 glycogen biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: GYS1 is the elongation enzyme of glycogen biosynthesis, acting together with glycogenin (priming) and branching enzyme (branching). This is a core biological process for the gene. Reason: Directly supported by experimental and structural work on human GYS1; the enzyme catalyzes the rate-limiting elongation step of glycogen synthesis. Supporting Evidence: PMID:35835870 Glycogen synthesis is a multistep process consisting of a priming step by GYG followed by an elongation step carried out by GYS and then a branching step by GBE. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: GYS1 is a cytosolic enzyme that associates with glycogen particles. Cytoplasm is correct but non-specific; cytosol (GO:0005829) is the more informative term. Reason: Cytoplasm is correct but under-specific for this soluble, glycogen-associated enzyme. The GOA set already includes cytosol (GO:0005829) from Reactome/Ensembl, which is the more informative cellular-component assignment. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: cytosol Supporting Evidence: PMID:35835870 GYS1 is expressed in most tissues including the muscle and brain7, whereas GYS2 is expressed only in the liver. |
| GO:0004373 alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of the canonical glycogen synthase activity, consistent with RHEA:18549 / EC 2.4.1.11 and with experimental evidence. Reason: The IEA mapping (ARBA/RHEA/EC) matches the experimentally established catalytic activity of GYS1 and duplicates the IBA/EXP annotations to the same term. Supporting Evidence: PMID:35835870 GYS, a retaining glycosyltransferase (GT) belonging to the GT3 superfamily, catalyzes successive addition of Ξ±-1,4-linked glucose residues to the nonreducing end of a growing polysaccharide chain, using UDP-glc as the sugar donor with the release of UDP5. |
| GO:0005978 glycogen biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of glycogen biosynthetic process, matching the well-established role of GYS1 and duplicating the IBA/TAS/IDA annotations to the same term. Reason: Consistent with UniPathway UPA00164 (glycogen biosynthesis) and with experimental evidence for the human enzyme. Supporting Evidence: PMID:35835870 Mammalian GYS is the rate-limiting enzyme in glycogen biosynthesis, and its activity is regulated posttranslationally by two mechanisms |
| GO:0005515 protein binding | IPI PMID:10481074 A GSK3-binding peptide from FRAT1 selectively inhibits the G... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" IPI from an IntAct record; the recorded partner is GSK3B (UniProtKB:P49841), the kinase that phosphorylates and inhibits glycogen synthase. Reason: Per curation guidelines, the uninformative term "protein binding" does not convey a molecular function and should not be treated as a core annotation. The underlying GYS1-GSK3B relationship (a kinase-substrate interaction) is real, but this paper is about FRAT1/GSK3 and only mentions glycogen synthase as a GSK3 substrate; a specific MF term (e.g. protein kinase binding) would be more informative if experimentally warranted for GYS1 itself. Supporting Evidence: PMID:10481074 FRATtide does not suppress GSK3 activity towards other |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" IPI derived from a genome-scale yeast two-hybrid interactome map (CCSB); partner UniProtKB:O15488 (GYG2). Reason: "protein binding" is uninformative and this is a high-throughput proteome-scale screen. The GYG2 partner is biologically plausible (glycogenin-2), but a bare binding term adds no functional information beyond the specific GYG1/GYG2 complex annotations. Supporting Evidence: PMID:16189514 proteome-scale map of the human protein-protein interaction network |
| GO:0005515 protein binding | IPI PMID:16282323 Evidence that Ser87 of BimEL is phosphorylated by Akt and re... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" IPI; the IntAct partner is GSK3B (UniProtKB:P49841). The paper concerns Akt phosphorylation of BimEL, not GYS1 function directly. Reason: Uninformative "protein binding" term; the source is not a study of GYS1 molecular function. Retain as over-annotation rather than a core function. Supporting Evidence: PMID:16282323 Ser87 of BimEL is phosphorylated by Akt |
| GO:0005515 protein binding | IPI PMID:17055998 Interaction between glycogenin and glycogen synthase. | MARK AS OVER ANNOTATED | Summary: IPI recording the physiologically important GYS1-glycogenin (GYG1) interaction, established by yeast two-hybrid using human skeletal muscle. Although annotated as bare "protein binding", this partner (GYG1) is functionally central. Reason: The interaction itself is genuine and biologically core (GYS1 forms a complex with glycogenin), but the term "protein binding" is uninformative per curation guidelines. This is better captured by the GYS1-GYG1 complex annotation (GO:1902494, part_of catalytic complex) and could support a more specific term such as glucosyltransferase/enzyme complex membership. Supporting Evidence: PMID:17055998 Two glycogen synthase-interacting proteins were identified in human |
| GO:0005515 protein binding | IPI PMID:24165324 Leucine-rich repeat kinase 2 regulates tau phosphorylation t... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" IPI with partner GSK3B (UniProtKB:P49841); the paper is about LRRK2 activation of GSK-3beta and tau phosphorylation, not GYS1 function. Reason: Uninformative term and not a study of GYS1 molecular function; keep as over-annotation. Supporting Evidence: PMID:24165324 directly associates with GSK-3Ξ² |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" IPI from a proteome-scale human interactome map (HI-II-14); partners include GYG1 and other proteins from a high-throughput screen. Reason: Uninformative term from a large-scale interactome dataset; not a core molecular function annotation. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network |
| GO:0005515 protein binding | IPI PMID:28330616 Systematic Analysis of Human Protein Phosphatase Interaction... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" IPI from a systematic phosphatase interactome study; the recorded partner is PPP1R3C/PTG (UniProtKB:Q9UQK1), a glycogen-targeting PP1 regulatory subunit relevant to GYS1 dephosphorylation. Reason: The GYS1-PPP1R3C relationship is physiologically meaningful (PP1/PTG recruitment to glycogen dephosphorylates and thereby activates GYS1), but "protein binding" is uninformative and derives from a large affinity-proteomics survey. Keep as over-annotation; a more specific term could be warranted with dedicated evidence. Supporting Evidence: PMID:28330616 Yet, in contrast to kinases, much less is known about protein |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" IPI from the BioPlex human interactome (partner PPP1R3C/Q9UQK1). Reason: Uninformative term from a proteome-scale affinity-purification interactome; not a core molecular function. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" IPI from the HuRI reference binary interactome (many partners from a single high-throughput yeast two-hybrid screen). Reason: Uninformative term; the numerous partners recorded from this one screen are largely incidental binary hits and do not define GYS1 molecular function. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" IPI from BioPlex 3.0 (partners GYG2/O15488 and PPP1R3C/Q9UQK1). Reason: Uninformative term from a proteome-scale interactome dataset; keep as over-annotation. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" IPI from the OpenCell endogenous-tagging interactome (partners include GYG1/GYG2). Reason: Uninformative term from a systematic cell-organization mapping effort; not a core molecular function. Supporting Evidence: PMID:35271311 OpenCell: Endogenous tagging for the cartography of human cellular organization |
| GO:0005536 D-glucose binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation (from rat ortholog) of D-glucose binding, reflecting the substrate-binding aspect of the transferase; glucose is the moiety transferred from UDP-glucose to the growing chain. Reason: Plausible as an aspect of the catalytic mechanism (the glucosyl donor is UDP-glucose, and glucose-6-phosphate is an allosteric activator), but this generic sugar-binding term is not the core informative molecular function, which is the glucosyltransferase activity (GO:0004373). Supporting Evidence: PMID:35835870 catalyzes successive addition of Ξ±-1,4-linked glucose residues to the nonreducing end of a growing polysaccharide chain, using UDP-glc as the sugar donor |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | MODIFY | Summary: Electronic (Ensembl ortholog) localization to cytoplasm, consistent with GYS1 being a soluble cytosolic enzyme; cytosol (GO:0005829) is the more specific term. Reason: Cytoplasm is correct but under-specific; cytosol (GO:0005829), already present in the GOA set from Reactome/Ensembl, is the more informative assignment for this soluble glycogen-associated enzyme. Proposed replacements: cytosol |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: GYS1 acts in the cytosol, where it associates with glycogen particles. This is the correct and informative cellular-component assignment. Reason: GYS1 has no transmembrane region or signal peptide (UniProt) and is a soluble cytosolic glycogen-synthesizing enzyme; cytosol is the appropriate location. Supporting Evidence: PMID:35835870 GYS1 is expressed in most tissues including the muscle and brain7, whereas GYS2 is expressed only in the liver. |
| GO:0005977 glycogen metabolic process | IEA GO_REF:0000107 | MODIFY | Summary: Broad electronic annotation to glycogen metabolic process; correct but a parent of the more precise glycogen biosynthetic process (GO:0005978) that also annotates GYS1. Reason: GYS1 is specifically a biosynthetic (glycogen-synthesizing) enzyme, not a catabolic one; the more specific child term glycogen biosynthetic process (GO:0005978) is the informative annotation and is already present. Proposed replacements: glycogen biosynthetic process Supporting Evidence: PMID:35835870 Mammalian GYS is the rate-limiting enzyme in glycogen biosynthesis, and its activity is regulated posttranslationally by two mechanisms |
| GO:0016234 inclusion body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation (from mouse ortholog) placing GYS1 in inclusion bodies; likely reflects glycogen aggregates / polyglucosan (Lafora-body-type) inclusions with which the enzyme co-localizes when glycogen metabolism is perturbed, rather than a normal resident location. Reason: Not the physiological site of action of the enzyme; a peripheral/pathology-associated localization retained as non-core rather than as a core cellular component. Supporting Evidence: PMID:21356517 deposits containing sparsely branched, insoluble glycogen-like polymers in many tissues, including neurons |
| GO:0061547 glycogen synthase activity, transferring glucose-1-phosphate | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Electronic annotation of the glucose-1-phosphate-transferring (phosphate-incorporating) activity. Experimentally, GYS1 does introduce the beta-phosphate of UDP-glucose into glycogen, but only as a rare (~1 in 10,000 glucose) catalytic side reaction, not as a physiological function. Reason: The phosphate-transferring activity is a documented but low-frequency "catalytic error"; presenting it as an enabled molecular function on par with the canonical GO:0004373 activity over-states its biological significance. Supporting Evidence: PMID:21356517 the biosynthetic enzyme glycogen synthase, which normally adds glucose residues to glycogen, is capable of incorporating |
| GO:0005978 glycogen biosynthetic process | TAS Reactome:R-HSA-3322077 | ACCEPT | Summary: Reactome (Glycogen synthesis) traceable assignment of glycogen biosynthetic process; consistent with the core role of GYS1. Reason: Matches the well-established biological process for GYS1 and duplicates the IBA/IEA/IDA annotations to the same term. Supporting Evidence: PMID:35835870 Glycogen synthesis is a multistep process consisting of a priming step by GYG followed by an elongation step carried out by GYS and then a branching step by GBE. |
| GO:0004373 alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity | EXP PMID:19699667 Identification of a novel mutation in GYS1 (muscle-specific ... | ACCEPT | Summary: Experimental (Reactome-curated) evidence for the canonical glucosyltransferase activity; this clinical study identified a homozygous GYS1 loss-of-function deletion causing muscle glycogen synthase deficiency and sudden cardiac death. Reason: Confirms the core catalytic function of GYS1 through a loss-of-function human phenotype (GSD 0b); supports GO:0004373 as the defining activity. Supporting Evidence: PMID:19699667 A homozygous two base pair deletion was identified in |
| GO:0004373 alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity | EXP PMID:35835870 Molecular basis for the regulation of human glycogen synthas... | ACCEPT | Summary: Direct experimental/structural evidence for the canonical UDP-glucose-dependent alpha-1,4 glucosyltransferase activity of human GYS1, including catalytic activity (RHEA:18549), substrate binding and the catalytically competent state. Reason: Cryo-EM and enzymatic characterization of human GYS1 directly establish this as the core molecular function. Supporting Evidence: PMID:35835870 resulting in a catalytically competent state for extending the associated glycogen chain |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3828061 | ACCEPT | Summary: Reactome traceable localization to cytosol (from the "Defective GYS1" GSD 0 reaction context); consistent with GYS1 being a soluble cytosolic enzyme. Reason: Cytosol is the correct and informative cellular component for this soluble, glycogen-associated enzyme. |
| GO:0005978 glycogen biosynthetic process | IDA PMID:35835870 Molecular basis for the regulation of human glycogen synthas... | ACCEPT | Summary: ComplexPortal IDA linking the GYS1-glycogenin complex to glycogen biosynthetic process, based on the cryo-EM characterization of the human complex. Reason: Direct experimental evidence for the involvement of GYS1 (in complex with GYG1) in glycogen biosynthesis; a core process annotation. Supporting Evidence: PMID:35835870 Glycogen synthesis is a multistep process consisting of a priming step by GYG followed by an elongation step carried out by GYS and then a branching step by GBE. |
| GO:1902494 catalytic complex | IDA PMID:35835870 Molecular basis for the regulation of human glycogen synthas... | ACCEPT | Summary: ComplexPortal IDA: GYS1 is part of the catalytic glycogen synthase-glycogenin complex (a GYS1 tetramer with two GYG1 dimers), characterized by cryo-EM. Reason: Direct experimental/structural evidence establishes GYS1 as a subunit of the GYS1-GYG1 catalytic complex; this is a core, biologically meaningful complex membership. Supporting Evidence: PMID:35835870 Cryo-EM map and model of the tetrameric GYS1βGYG1ΞCD complex at 3.0 Γ
resolution. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3322001 | ACCEPT | Summary: Reactome traceable localization to cytosol (GYS1 polyglucosylation of oligoGlc-GYG1). Reason: Correct informative cytosolic localization for this soluble enzyme; consistent with the other cytosol annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3322005 | ACCEPT | Summary: Reactome traceable localization to cytosol (branch-formation reaction context with GYS1-a). Reason: Correct cytosolic localization, consistent with the other cytosol annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3322025 | ACCEPT | Summary: Reactome traceable localization to cytosol (autoglucosylation of GYG1 complexed with GYS1-a). Reason: Correct cytosolic localization, consistent with the other cytosol annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3781001 | ACCEPT | Summary: Reactome traceable localization to cytosol (EPM2A/laforin binding to PPP1R3C:phosphoglycogen-GYG1 complex context). Reason: Correct cytosolic localization, consistent with the other cytosol annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3781009 | ACCEPT | Summary: Reactome traceable localization to cytosol (NHLRC1-mediated ubiquitination context). Reason: Correct cytosolic localization, consistent with the other cytosol annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3781018 | ACCEPT | Summary: Reactome traceable localization to cytosol (EPM2A dephosphorylation of phosphoglycogen-GYG1 context). Reason: Correct cytosolic localization, consistent with the other cytosol annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3781023 | ACCEPT | Summary: Reactome traceable localization to cytosol (PPP1R3C binding to glycogen:GYG1:GYS1 context). Reason: Correct cytosolic localization, consistent with the other cytosol annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3781024 | ACCEPT | Summary: Reactome traceable localization to cytosol (GYS1 incorporation of phosphoglucose into glycogen-GYG1 context; the phosphate-side-reaction). Reason: Correct cytosolic localization, consistent with the other cytosol annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3791349 | ACCEPT | Summary: Reactome traceable localization to cytosol (defective EPM2A / Lafora disease context). Reason: Correct cytosolic localization, consistent with the other cytosol annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3797226 | ACCEPT | Summary: Reactome traceable localization to cytosol (defective NHLRC1 / Lafora disease context). Reason: Correct cytosolic localization, consistent with the other cytosol annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3814838 | ACCEPT | Summary: Reactome traceable localization to cytosol (defective GYG1 autoglucosylation context). Reason: Correct cytosolic localization, consistent with the other cytosol annotations. |
| GO:0061547 glycogen synthase activity, transferring glucose-1-phosphate | EXP PMID:21356517 Phosphate incorporation during glycogen synthesis and Lafora... | MARK AS OVER ANNOTATED | Summary: Experimental evidence that glycogen synthase (including recombinant human GYS1) can transfer the beta-phosphate of UDP-glucose into glycogen, forming glucose C2/C3 phosphomonoesters, at ~1 per 10,000 glucoses. This is the basis of the glucose-1-phosphate-transferring activity term. Reason: The activity is experimentally real but is explicitly described as a rare deviation from the normal reaction (a "catalytic error"), not a physiological function; it should not be presented as a core enabled molecular function alongside the canonical GO:0004373 activity. Retained as an over-annotation with its supporting EXP evidence. Supporting Evidence: PMID:21356517 Glycogen synthase catalyzes the formation of the primary polymerizing Ξ±-1,4-glycosidic linkages by transferring a glucosyl moiety from UDP-glucose to a non-reducing end of a glycogen molecule with the release of UDP |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput mass-spectrometry detection of GYS1 in a membrane-enriched fraction of an NK-cell line. GYS1 is a soluble cytosolic enzyme with no transmembrane region; the study itself notes that most non-integral hits are only transiently membrane-associated. Reason: GYS1 has no TM domain or signal peptide (UniProt) and is established as cytosolic. Detection in a membrane proteomics fraction most likely reflects transient/peripheral association (e.g. via glycogen particles) rather than true membrane residency; this is an over-annotation from a large-scale localization screen. Supporting Evidence: PMID:19946888 could be predicted to be transiently associated with membranes |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3322003 | ACCEPT | Summary: Reactome traceable localization to cytosol (autoglucosylation of GYG1 complexed with GYS1-b). Reason: Correct cytosolic localization, consistent with the other cytosol annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3322041 | ACCEPT | Summary: Reactome traceable localization to cytosol (phosphorylated GYS1 polyglucosylation of oligoGlc-GYG1). Reason: Correct cytosolic localization, consistent with the other cytosol annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3322057 | ACCEPT | Summary: Reactome traceable localization to cytosol (branch formation in polyGlc-GYG1 complexed with GYS1-b). Reason: Correct cytosolic localization, consistent with the other cytosol annotations. |
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Download this section (compressed HTML)Q: Is the glucose-1-phosphate-transferring (phosphate-incorporating) side reaction of GYS1 physiologically regulated, or is it purely a stochastic catalytic error whose rate is fixed by the enzyme mechanism?
Q: Beyond glycogenin (GYG1) and the PP1 targeting subunits (PPP1R3 family), which of the many high-throughput interactome partners of GYS1 represent bona fide regulatory or scaffolding interactions relevant to glycogen metabolism?
Experiment: Structure-guided mutagenesis of the Glc6P allosteric arginine cluster and the N-/C-terminal phosphorylation sites in human GYS1, coupled with kinetic assays, to quantify the independent contributions of allosteric activation and dephosphorylation to activation of the human enzyme.
Experiment: Cell-based tagging/fractionation of endogenous GYS1 to test whether the reported membrane association is genuine peripheral binding (e.g. via glycogen particles) or a proteomics artifact, and to map its localization relative to glycogen synthesis sites.
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