id: P13807
gene_symbol: GYS1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
alternative_products:
- name: '1'
  id: P13807-1
- name: '2'
  id: P13807-2
  sequence_note: VSP_042745
existing_annotations:
- term:
    id: GO:0004373
    label: alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:35835870
      supporting_text: >-
        GYS, a retaining glycosyltransferase (GT) belonging to the GT3 superfamily,
        catalyzes successive addition of α-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.
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Directly supported by experimental and structural work on human GYS1; the enzyme
      catalyzes the rate-limiting elongation step of glycogen synthesis.
    supported_by:
    - reference_id: PMID:35835870
      supporting_text: >-
        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.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: MODIFY
    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.
    proposed_replacement_terms:
    - id: GO:0005829
      label: cytosol
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
    supported_by:
    - reference_id: PMID:35835870
      supporting_text: >-
        GYS1 is expressed in most tissues including the muscle and brain7, whereas GYS2 is
        expressed only in the liver.
- term:
    id: GO:0004373
    label: alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment of the canonical glycogen synthase activity, consistent with
      RHEA:18549 / EC 2.4.1.11 and with experimental evidence.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:35835870
      supporting_text: >-
        GYS, a retaining glycosyltransferase (GT) belonging to the GT3 superfamily,
        catalyzes successive addition of α-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.
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Consistent with UniPathway UPA00164 (glycogen biosynthesis) and with experimental
      evidence for the human enzyme.
    supported_by:
    - reference_id: PMID:35835870
      supporting_text: >-
        Mammalian GYS is the rate-limiting enzyme in glycogen biosynthesis, and its
        activity is regulated posttranslationally by two mechanisms
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10481074
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" IPI from an IntAct record; the recorded partner is GSK3B
      (UniProtKB:P49841), the kinase that phosphorylates and inhibits glycogen synthase.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:10481074
      supporting_text: >-
        FRATtide does not suppress GSK3 activity towards other
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" IPI derived from a genome-scale yeast two-hybrid interactome
      map (CCSB); partner UniProtKB:O15488 (GYG2).
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: >-
        proteome-scale map of the human protein-protein interaction network
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16282323
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" IPI; the IntAct partner is GSK3B (UniProtKB:P49841). The
      paper concerns Akt phosphorylation of BimEL, not GYS1 function directly.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" term; the source is not a study of GYS1 molecular
      function. Retain as over-annotation rather than a core function.
    supported_by:
    - reference_id: PMID:16282323
      supporting_text: Ser87 of BimEL is phosphorylated by Akt
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17055998
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:17055998
      supporting_text: >-
        Two glycogen synthase-interacting proteins were identified in human
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24165324
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative term and not a study of GYS1 molecular function; keep as
      over-annotation.
    supported_by:
    - reference_id: PMID:24165324
      supporting_text: directly associates with GSK-3β
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative term from a large-scale interactome dataset; not a core molecular
      function annotation.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28330616
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:28330616
      supporting_text: >-
        Yet, in contrast to kinases, much less is known about protein
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" IPI from the BioPlex human interactome (partner
      PPP1R3C/Q9UQK1).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative term from a proteome-scale affinity-purification interactome; not a
      core molecular function.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome defines protein communities
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" IPI from the HuRI reference binary interactome (many partners
      from a single high-throughput yeast two-hybrid screen).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative term; the numerous partners recorded from this one screen are
      largely incidental binary hits and do not define GYS1 molecular function.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" IPI from BioPlex 3.0 (partners GYG2/O15488 and
      PPP1R3C/Q9UQK1).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative term from a proteome-scale interactome dataset; keep as
      over-annotation.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: >-
        Dual proteome-scale networks reveal cell-specific remodeling of the human
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" IPI from the OpenCell endogenous-tagging interactome (partners
      include GYG1/GYG2).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative term from a systematic cell-organization mapping effort; not a core
      molecular function.
    supported_by:
    - reference_id: PMID:35271311
      supporting_text: >-
        OpenCell: Endogenous tagging for the cartography of human cellular organization
- term:
    id: GO:0005536
    label: D-glucose binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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).
    supported_by:
    - reference_id: PMID:35835870
      supporting_text: >-
        catalyzes successive addition of α-1,4-linked glucose residues to the nonreducing
        end of a growing polysaccharide chain, using UDP-glc as the sugar donor
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Electronic (Ensembl ortholog) localization to cytoplasm, consistent with GYS1 being
      a soluble cytosolic enzyme; cytosol (GO:0005829) is the more specific term.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0005829
      label: cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: >-
      GYS1 acts in the cytosol, where it associates with glycogen particles. This is the
      correct and informative cellular-component assignment.
    action: ACCEPT
    reason: >-
      GYS1 has no transmembrane region or signal peptide (UniProt) and is a soluble
      cytosolic glycogen-synthesizing enzyme; cytosol is the appropriate location.
    supported_by:
    - reference_id: PMID:35835870
      supporting_text: >-
        GYS1 is expressed in most tissues including the muscle and brain7, whereas GYS2 is
        expressed only in the liver.
- term:
    id: GO:0005977
    label: glycogen metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0005978
      label: glycogen biosynthetic process
    supported_by:
    - reference_id: PMID:35835870
      supporting_text: >-
        Mammalian GYS is the rate-limiting enzyme in glycogen biosynthesis, and its
        activity is regulated posttranslationally by two mechanisms
- term:
    id: GO:0016234
    label: inclusion body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:21356517
      supporting_text: >-
        deposits containing sparsely branched, insoluble glycogen-like polymers in many
        tissues, including neurons
- term:
    id: GO:0061547
    label: glycogen synthase activity, transferring glucose-1-phosphate
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:21356517
      supporting_text: >-
        the biosynthetic enzyme glycogen synthase, which normally adds glucose residues to
        glycogen, is capable of incorporating
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322077
  qualifier: involved_in
  review:
    summary: >-
      Reactome (Glycogen synthesis) traceable assignment of glycogen biosynthetic process;
      consistent with the core role of GYS1.
    action: ACCEPT
    reason: >-
      Matches the well-established biological process for GYS1 and duplicates the
      IBA/IEA/IDA annotations to the same term.
    supported_by:
    - reference_id: PMID:35835870
      supporting_text: >-
        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.
- term:
    id: GO:0004373
    label: alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity
  evidence_type: EXP
  original_reference_id: PMID:19699667
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Confirms the core catalytic function of GYS1 through a loss-of-function human
      phenotype (GSD 0b); supports GO:0004373 as the defining activity.
    supported_by:
    - reference_id: PMID:19699667
      supporting_text: >-
        A homozygous two base pair deletion was identified in
- term:
    id: GO:0004373
    label: alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity
  evidence_type: EXP
  original_reference_id: PMID:35835870
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Cryo-EM and enzymatic characterization of human GYS1 directly establish this as the
      core molecular function.
    supported_by:
    - reference_id: PMID:35835870
      supporting_text: >-
        resulting in a catalytically competent state for extending the associated glycogen
        chain
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3828061
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (from the "Defective GYS1" GSD 0 reaction
      context); consistent with GYS1 being a soluble cytosolic enzyme.
    action: ACCEPT
    reason: >-
      Cytosol is the correct and informative cellular component for this soluble,
      glycogen-associated enzyme.
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:35835870
  qualifier: involved_in
  review:
    summary: >-
      ComplexPortal IDA linking the GYS1-glycogenin complex to glycogen biosynthetic
      process, based on the cryo-EM characterization of the human complex.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for the involvement of GYS1 (in complex with GYG1) in
      glycogen biosynthesis; a core process annotation.
    supported_by:
    - reference_id: PMID:35835870
      supporting_text: >-
        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.
- term:
    id: GO:1902494
    label: catalytic complex
  evidence_type: IDA
  original_reference_id: PMID:35835870
  qualifier: part_of
  review:
    summary: >-
      ComplexPortal IDA: GYS1 is part of the catalytic glycogen synthase-glycogenin
      complex (a GYS1 tetramer with two GYG1 dimers), characterized by cryo-EM.
    action: ACCEPT
    reason: >-
      Direct experimental/structural evidence establishes GYS1 as a subunit of the
      GYS1-GYG1 catalytic complex; this is a core, biologically meaningful complex
      membership.
    supported_by:
    - reference_id: PMID:35835870
      supporting_text: >-
        Cryo-EM map and model of the tetrameric GYS1–GYG1ΔCD complex at 3.0 Å resolution.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322001
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (GYS1 polyglucosylation of oligoGlc-GYG1).
    action: ACCEPT
    reason: >-
      Correct informative cytosolic localization for this soluble enzyme; consistent with
      the other cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322005
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (branch-formation reaction context with
      GYS1-a).
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the other cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322025
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (autoglucosylation of GYG1 complexed with
      GYS1-a).
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the other cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3781001
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (EPM2A/laforin binding to
      PPP1R3C:phosphoglycogen-GYG1 complex context).
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the other cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3781009
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (NHLRC1-mediated ubiquitination context).
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the other cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3781018
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (EPM2A dephosphorylation of
      phosphoglycogen-GYG1 context).
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the other cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3781023
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (PPP1R3C binding to glycogen:GYG1:GYS1
      context).
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the other cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3781024
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (GYS1 incorporation of phosphoglucose into
      glycogen-GYG1 context; the phosphate-side-reaction).
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the other cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3791349
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (defective EPM2A / Lafora disease context).
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the other cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3797226
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (defective NHLRC1 / Lafora disease context).
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the other cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3814838
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (defective GYG1 autoglucosylation context).
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the other cytosol annotations.
- term:
    id: GO:0061547
    label: glycogen synthase activity, transferring glucose-1-phosphate
  evidence_type: EXP
  original_reference_id: PMID:21356517
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:21356517
      supporting_text: >-
        Glycogen synthase catalyzes the formation of the primary polymerizing
        α-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
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: >-
        could be predicted to be transiently associated with membranes
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322003
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (autoglucosylation of GYG1 complexed with
      GYS1-b).
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the other cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322041
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (phosphorylated GYS1 polyglucosylation of
      oligoGlc-GYG1).
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the other cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322057
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable localization to cytosol (branch formation in polyGlc-GYG1 complexed
      with GYS1-b).
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the other cytosol annotations.
core_functions:
- description: >-
    Elongation of glycogen chains by transfer of glucose from UDP-glucose to the alpha-1,4
    non-reducing end of the growing polymer (the committed, rate-limiting step of glycogen
    biosynthesis), acting on a glycogenin-primed chain and in concert with branching enzyme.
  molecular_function:
    id: GO:0004373
    label: alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity
  directly_involved_in:
  - id: GO:0005978
    label: glycogen biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  in_complex:
    id: GO:1902494
    label: catalytic complex
  supported_by:
  - reference_id: PMID:35835870
    supporting_text: >-
      GYS, a retaining glycosyltransferase (GT) belonging to the GT3 superfamily,
      catalyzes successive addition of α-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.
  - reference_id: PMID:35835870
    supporting_text: >-
      Cryo-EM map and model of the tetrameric GYS1–GYG1ΔCD complex at 3.0 Å resolution.
proposed_new_terms: []
suggested_questions:
- question: >-
    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?
- question: >-
    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?
suggested_experiments:
- description: >-
    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.
- description: >-
    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.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10481074
  title: A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed
    phosphorylation of axin and beta-catenin.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Study of FRAT1/GSK3 in beta-catenin signaling; only mentions glycogen synthase as a
      GSK3 substrate. IntAct records a GYS1-GSK3B binary interaction from it. Not a study of
      GYS1 molecular function; supports only a bare "protein binding" over-annotation.
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Genome-scale yeast two-hybrid interactome (CCSB). Source of a bare "protein binding"
      IPI (partner GYG2); high-throughput, uninformative for molecular function.
- id: PMID:16282323
  title: Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL
    apoptotic function.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Study of BimEL/Akt phosphorylation; the associated GYS1 IntAct entry (partner GSK3B) is
      incidental. Not a study of GYS1 function.
- id: PMID:17055998
  title: Interaction between glycogenin and glycogen synthase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes the physiologically core GYS1-glycogenin (GYG1) interaction by yeast
      two-hybrid in human skeletal muscle and maps the interacting regions. Cited by UniProt
      SUBUNIT. Supports complex membership rather than a bare "protein binding" term.
- id: PMID:19699667
  title: Identification of a novel mutation in GYS1 (muscle-specific glycogen synthase)
    resulting in sudden cardiac death, that is diagnosable from skin fibroblasts.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Human case of a homozygous GYS1 loss-of-function deletion causing muscle glycogen
      synthase deficiency and sudden cardiac death (GSD 0b), confirming the essential
      glucosyltransferase function of GYS1 through phenotype. Abstract-only in cache.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale NK-cell membrane proteomics; GYS1 detected in a membrane-enriched fraction.
      The study itself flags most non-integral hits as transiently membrane-associated. Basis
      of the GO:0016020 membrane over-annotation for a soluble cytosolic enzyme.
- id: PMID:21356517
  title: Phosphate incorporation during glycogen synthesis and Lafora disease.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Demonstrates GYS1 can transfer the beta-phosphate of UDP-glucose into glycogen (C2/C3
      phosphomonoesters) at ~1 per 10,000 glucoses, a rare catalytic side reaction relevant to
      Lafora disease. Basis of GO:0061547; supports treating that term as non-core.
- id: PMID:24165324
  title: Leucine-rich repeat kinase 2 regulates tau phosphorylation through direct
    activation of glycogen synthase kinase-3β.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Study of LRRK2/GSK-3beta in tau phosphorylation; the GYS1 IntAct entry (partner GSK3B) is
      incidental. Not a study of GYS1 function.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale human interactome map (HI-II-14). Source of bare "protein binding" IPIs;
      high-throughput, uninformative for molecular function.
- id: PMID:28330616
  title: Systematic Analysis of Human Protein Phosphatase Interactions and Dynamics.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Systematic phosphatase interactome; records GYS1-PPP1R3C (PTG) binding, a physiologically
      meaningful glycogen-targeting PP1 regulatory interaction, but annotated only as bare
      "protein binding".
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex proteome-scale interactome (partner PPP1R3C). Bare "protein binding" from a
      high-throughput affinity-purification network.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI binary interactome; many GYS1 partners recorded from a single yeast two-hybrid
      screen. Bare "protein binding", uninformative for molecular function.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex 3.0 dual proteome-scale interactome (partners GYG2, PPP1R3C). Bare "protein
      binding", high-throughput.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      OpenCell endogenous-tagging interactome (partners include GYG1/GYG2). Bare "protein
      binding" from a systematic cell-organization mapping effort.
- id: PMID:35835870
  title: Molecular basis for the regulation of human glycogen synthase by phosphorylation
    and glucose-6-phosphate.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Definitive cryo-EM and enzymatic characterization of human GYS1: catalytic activity
      (EC 2.4.1.11, RHEA:18549), UDP-glucose donor, alpha-1,4 elongation, allosteric Glc6P
      activation, phosphorylation-dependent inhibition, and the GYS1-GYG1 heterooctameric
      complex. Full text available; primary source for the core functions.
- id: Reactome:R-HSA-3322001
  title: GYS1 catalyzes the polyglucosylation of oligoGlc-GYG1
  findings: []
- id: Reactome:R-HSA-3322003
  title: Autoglucosylation of GYG1 complexed with GYS1-b
  findings: []
- id: Reactome:R-HSA-3322005
  title: GBE1 catalyzes branch formation in polyGlc-GYG1 complexed with GYS1-a
  findings: []
- id: Reactome:R-HSA-3322025
  title: Autoglucosylation of GYG1 complexed with GYS1-a
  findings: []
- id: Reactome:R-HSA-3322041
  title: Phosphorylated GYS1 catalyzes the polyglucosylation of oligoGlc-GYG1
  findings: []
- id: Reactome:R-HSA-3322057
  title: GBE1 catalyzes branch formation in polyGlc-GYG1 complexed with GYS1-b
  findings: []
- id: Reactome:R-HSA-3322077
  title: Glycogen synthesis
  findings: []
- id: Reactome:R-HSA-3781001
  title: EPM2A dimer binds PPP1R3C:phosphoglycogen-GYG1 complex
  findings: []
- id: Reactome:R-HSA-3781009
  title: NHLRC1 mediated ubiquitination of EPM2A and PPP1RC3 associated with glycogen-GYG1
  findings: []
- id: Reactome:R-HSA-3781018
  title: EPM2A dimer dephosphorylates phosphoglycogen-GYG1
  findings: []
- id: Reactome:R-HSA-3781023
  title: PPP1R3C binds to glycogen:GYG1:GYS1
  findings: []
- id: Reactome:R-HSA-3781024
  title: GYS1 catalyzes the incorporation of phosphoglucose into glycogen-GYG1
  findings: []
- id: Reactome:R-HSA-3791349
  title: Defective EPM2A does not dephosphorylate phosphoglycogen (type 2A disease)
  findings: []
- id: Reactome:R-HSA-3797226
  title: Defective NHLRC1 does not ubiquitinate EPM2A (laforin) and PPP1R3C (PTG)
    (type 2B disease)
  findings: []
- id: Reactome:R-HSA-3814838
  title: Defective GYG1 is not autoglucosyolated
  findings: []
- id: Reactome:R-HSA-3828061
  title: Defective GYS1 does not transfer glucose to growing glycogen chains
  findings: []