GYG1

UniProt ID: P46976
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

Glycogenin-1 is the self-glucosylating protein primer that initiates glycogen biosynthesis. Using UDP-alpha-D-glucose as donor and a divalent metal cofactor (Mn2+ is most effective), it autoglucosylates a specific internal tyrosine (Tyr195), forming a covalent glucose-1-O-tyrosyl linkage and building a short alpha-1,4-glucan chain of roughly 8-12 glucose residues. This maltosaccharide primer serves as the substrate onto which glycogen synthase (GYS1 in muscle and most tissues, GYS2 in liver) elongates the glycogen molecule, with glycogen branching enzyme introducing alpha-1,6 branches; glycogenin remains covalently attached at the core of the mature glycogen granule. It is a glycosyltransferase family 8 (GT8) enzyme (EC 2.4.1.186), acts in the cytosol at glycogen granules, and forms a heterooctameric complex with glycogen synthase (a GYS1 tetramer with two GYG1 dimers). Loss-of-function variants cause glycogen storage disease type XV / polyglucosan body myopathy 2, characterized by glycogen depletion and accumulation of poorly branched polyglucosan bodies in skeletal and/or cardiac muscle.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0008466 glycogenin glucosyltransferase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic (IBA) assignment of the defining molecular function of glycogenin, glycogenin glucosyltransferase activity (EC 2.4.1.186). This is the core catalytic function of GYG1 and is strongly corroborated by direct experimental evidence in human and orthologs.
Reason: This is the well-established core molecular function, directly supported by crystallographic and enzymatic studies of human GYG1 and confirmed across orthologs.
Supporting Evidence:
PMID:22160680
Glycogenin initiates the synthesis of a maltosaccharide chain covalently attached to itself on Tyr195 via a stepwise glucosylation reaction, priming glycogen synthesis.
GO:0005978 glycogen biosynthetic process
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic (IBA) assignment placing glycogenin in the glycogen biosynthetic process. Glycogenin performs the obligatory priming step of glycogen synthesis.
Reason: Core biological process for GYG1; the priming reaction it catalyzes is required for glycogen synthesis.
Supporting Evidence:
PMID:20357282
The missense mutation resulted in inactivation of the autoglucosylation of glycogenin-1 that is necessary for the priming of glycogen synthesis in muscle.
GO:0005737 cytoplasm
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic (IBA) assignment that glycogenin is active in the cytoplasm. Glycogen synthesis and the self-glucosylation reaction occur in the cytosol at glycogen granules.
Reason: Consistent with the cytosolic/glycogen-granule localization of glycogen metabolism; is_active_in cytoplasm correctly captures where GYG1 acts. A more specific cytosol term (GO:0005829) is also annotated by Reactome.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005634 nucleus
IEA
GO_REF:0000044 		MARK AS OVER ANNOTATED
Summary: Electronic annotation to nucleus derived from UniProt Swiss-Prot subcellular location keyword mapping (SL-0191). The nuclear location in UniProt is itself an inference by similarity, with no direct experimental support for a nuclear function of GYG1.
Reason: The core biology of glycogenin is cytosolic (glycogen granules). The nucleus annotation is a keyword-mapping propagation of a by-similarity UniProt entry and does not reflect an established nuclear role; it risks over-annotating GYG1 as a nuclear protein.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic annotation to cytoplasm from UniProt subcellular location keyword mapping (SL-0086). Correct and consistent with the cytosolic/glycogen-granule localization of glycogenin.
Reason: Cytoplasmic localization is well established for glycogen metabolism enzymes and is consistent with the IBA and Reactome cytosol annotations.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0008466 glycogenin glucosyltransferase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Automated electronic annotation (multiple IEA methods, including ARBA and EC 2.4.1.186 mapping) of the defining glycogenin glucosyltransferase activity.
Reason: Correctly assigns the core catalytic function; redundant with the experimental IDA/EXP and IBA annotations of the same term.
Supporting Evidence:
PMID:30356213
GYG acts as a 'seed core' for the formation of the glycogen particle by catalysing its own stepwise autoglucosylation to form a covalently bound gluco-oligosaccharide chain at initiation site Tyr 195.
GO:0016757 glycosyltransferase activity
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro2GO electronic annotation from the glycosyltransferase family 8 signature (IPR002495) to the general parent term glycosyltransferase activity.
Reason: Correct but general; it is the direct parent of the specific glycogenin glucosyltransferase activity (GO:0008466) that is experimentally established. Retaining the general IEA is acceptable; the specific term should be the core function.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Belongs to the glycosyltransferase 8 family. Glycogenin
GO:0005515 protein binding
IPI
PMID:16189514
Towards a proteome-scale map of the human protein-protein in... 		MARK AS OVER ANNOTATED
Summary: IntAct-curated binary interaction (from a high-throughput yeast two-hybrid interactome map) recorded with the partner GYS1 (P13807). The GO term "protein binding" is uninformative on its own.
Reason: Bare "protein binding" adds no functional specificity. The biologically meaningful interaction (with glycogen synthase GYS1) is already captured by the protein homodimerization activity and catalytic-complex annotations. Per curation guidelines this uninformative term is marked as over-annotated rather than removed.
Supporting Evidence:
PMID:16189514
Here we describe an initial version of a proteome-scale map of human binary protein-protein interactions.
GO:0005515 protein binding
IPI
PMID:17055998
Interaction between glycogenin and glycogen synthase. 		MARK AS OVER ANNOTATED
Summary: IPI annotation to the biologically relevant GYS1 interaction (P13807), from a dedicated study mapping the glycogenin-glycogen synthase interaction to the GYG1 C-terminal 33 residues. The term "protein binding" itself is uninformative.
Reason: The interaction with glycogen synthase is real and important, but the bare "protein binding" term does not convey it. The functional content (GYS1-GYG1 complex, homodimerization) is captured by more specific terms. Marked over-annotated rather than removed.
Supporting Evidence:
PMID:17055998
The interaction with glycogenin was found to be mediated by the region of glycogenin which contains the 33 COOH-terminal amino acid residues.
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		MARK AS OVER ANNOTATED
Summary: IntAct-curated binary interaction with GYS1 (P13807) from a proteome-scale human interactome map. Uninformative "protein binding" term.
Reason: Bare "protein binding" is uninformative; the meaningful GYS1 interaction is already captured elsewhere. Marked over-annotated per guidelines rather than removed.
Supporting Evidence:
PMID:25416956
Combining high-quality binary pairs from the literature with systematic
GO:0005515 protein binding
IPI
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human ce... 		MARK AS OVER ANNOTATED
Summary: Interaction recorded with GYS1 (P13807) from the OpenCell endogenous-tagging IP-MS interactome resource. Uninformative "protein binding" term.
Reason: Bare "protein binding" is uninformative; the functionally meaningful GYS1 interaction is captured by homodimerization and complex annotations. Marked over-annotated rather than removed.
Supporting Evidence:
PMID:35271311
systematically map the localization and interactions of human proteins
GO:0005978 glycogen biosynthetic process
IEA
GO_REF:0000120 		ACCEPT
Summary: Automated electronic annotation (multiple IEA methods, including UniPathway UPA00164) placing GYG1 in glycogen biosynthesis.
Reason: Correct core biological process, redundant with the experimental and IBA annotations of 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:0005978 glycogen biosynthetic process
TAS
Reactome:R-HSA-3322077 		ACCEPT
Summary: Reactome traceable-author-statement annotation to glycogen biosynthetic process via the "Glycogen synthesis" pathway.
Reason: Correctly captures the core biological process; glycogenin performs the priming step of the Reactome glycogen synthesis pathway.
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:0008466 glycogenin glucosyltransferase activity
EXP
PMID:20357282
Glycogenin-1 deficiency and inactivated priming of glycogen ... 		ACCEPT
Summary: Experimental annotation of glycogenin glucosyltransferase (autoglucosylation) activity. The disease study showed unglucosylated glycogenin-1 in patient muscle and that the Thr83Met variant inactivates autoglucosylation.
Reason: Directly supports the core catalytic function; the loss of this activity in the Thr83Met patient causally links the enzyme activity to glycogen synthesis priming.
Supporting Evidence:
PMID:20357282
The missense mutation resulted in inactivation of the autoglucosylation of glycogenin-1 that is necessary for the priming of glycogen synthesis in muscle.
GO:0005978 glycogen biosynthetic process
IDA
PMID:35835870
Molecular basis for the regulation of human glycogen synthas... 		ACCEPT
Summary: ComplexPortal IDA annotation placing the GYS1-GYG1 complex in glycogen biosynthesis, based on the cryo-EM structural study of the glycogen synthase-glycogenin complex.
Reason: Core biological process, supported by structural characterization of the functional biosynthetic complex.
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 annotation that GYG1 is part of a catalytic complex, based on the cryo-EM structure of the tetrameric GYS1-GYG1 complex (the glycogen synthase-glycogenin complex, ComplexPortal CPX-26491).
Reason: Well supported; GYG1 is an integral subunit of the glycogen synthase-glycogenin biosynthetic complex, a catalytic complex.
Supporting Evidence:
PMID:35835870
Cryo-EM map and model of the tetrameric GYS1–GYG1ΔCD complex at 3.0 Å resolution.
GO:0005978 glycogen biosynthetic process
IMP
PMID:22160680
Conformational plasticity of glycogenin and its maltosacchar... 		ACCEPT
Summary: IMP annotation to glycogen biosynthetic process based on the structural and mutational study showing the GSD XV Thr83Met variant is conformationally locked and catalytically inactive, impairing glycogen synthesis priming.
Reason: The disease-causing loss-of-function mutation directly links GYG1 to the glycogen biosynthetic process (priming step).
Supporting Evidence:
PMID:22160680
The Thr83Met mutation, which causes glycogen storage disease XV, is conformationally locked in the ground state and catalytically inactive.
GO:0005634 nucleus
ISS
GO_REF:0000024 		MARK AS OVER ANNOTATED
Summary: Sequence-similarity (ISS) annotation to nucleus transferred from an ortholog (P13280). As with the SubCell IEA nucleus annotation, there is no direct experimental support for a nuclear function of GYG1.
Reason: The core localization and function of glycogenin are cytosolic (glycogen granules). The nucleus annotation is an inference by similarity without experimental support and risks over-annotating a nuclear role.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005737 cytoplasm
ISS
GO_REF:0000024 		ACCEPT
Summary: Sequence-similarity (ISS) annotation to cytoplasm transferred from an ortholog (P13280). Consistent with the established cytosolic localization of glycogenin.
Reason: Cytoplasmic localization is correct and well supported for glycogen metabolism.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005737 cytoplasm
ISS
GO_REF:0000024 		ACCEPT
Summary: Sequence-similarity (ISS) annotation that glycogenin is active in the cytoplasm, transferred from an ortholog (C4R941). Consistent with where the priming reaction occurs.
Reason: Correctly captures that GYG1 acts in the cytoplasm (at glycogen granules).
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Cytosolic localization
GO:0008466 glycogenin glucosyltransferase activity
IDA
PMID:22160680
Conformational plasticity of glycogenin and its maltosacchar... 		ACCEPT
Summary: Direct experimental (IDA) annotation of glycogenin glucosyltransferase activity from crystallographic snapshots of human glycogenin captured during its reaction cycle with UDP-glucose, Mn2+ and its maltosaccharide substrate.
Reason: Direct structural/enzymatic evidence for the core catalytic function in human GYG1.
Supporting Evidence:
PMID:22160680
Glycogenin initiates the synthesis of a maltosaccharide chain covalently attached to itself on Tyr195 via a stepwise glucosylation reaction, priming glycogen synthesis.
GO:0008466 glycogenin glucosyltransferase activity
IDA
PMID:30356213
Palladium-mediated enzyme activation suggests multiphase ini... 		ACCEPT
Summary: Direct experimental (IDA) annotation of glycogenin glucosyltransferase activity from a study that accessed homogeneous glucosylated states of GYG via palladium-mediated activation and characterized catalytic activity at distinct stages of autoglucosylation.
Reason: Direct enzymatic evidence for the core catalytic function.
Supporting Evidence:
PMID:30356213
GYG acts as a 'seed core' for the formation of the glycogen particle by catalysing its own stepwise autoglucosylation to form a covalently bound gluco-oligosaccharide chain at initiation site Tyr 195.
GO:0030145 manganese ion binding
IDA
PMID:22160680
Conformational plasticity of glycogenin and its maltosacchar... 		ACCEPT
Summary: Direct experimental (IDA) annotation of manganese ion binding, from crystal structures of human glycogenin in complex with manganese, UDP and UDP-alpha-D-glucose. Mn2+ is the catalytic cofactor coordinating the sugar donor.
Reason: Well supported; Mn2+ binding is a genuine, structurally defined cofactor requirement for the autoglucosylation reaction.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Required for self-glucosylation. Manganese is
GO:0030145 manganese ion binding
IDA
PMID:30356213
Palladium-mediated enzyme activation suggests multiphase ini... 		ACCEPT
Summary: Direct experimental (IDA) annotation of manganese ion binding from crystal structures of human glycogenin (residues 1-262) in complex with UDP and manganese.
Reason: Well supported cofactor requirement; redundant with the PMID:22160680 IDA annotation of the same term.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Required for self-glucosylation. Manganese is
GO:0042803 protein homodimerization activity
IDA
PMID:22160680
Conformational plasticity of glycogenin and its maltosacchar... 		ACCEPT
Summary: Direct experimental (IDA) annotation of protein homodimerization activity. Glycogenin functions as a dimer; the crystallographic study characterized inter- and intra-subunit modes of glucosylation dependent on the dimeric arrangement.
Reason: Well supported; GYG1 forms homodimers, and the dimer is functionally relevant to its intersubunit glucosylation mechanism and to the GYS1-GYG1 heterooctamer (two GYG1 dimers).
Supporting Evidence:
PMID:22160680
The rearranged lid guides the nascent maltosaccharide chain into the
GO:0042803 protein homodimerization activity
IDA
PMID:30356213
Palladium-mediated enzyme activation suggests multiphase ini... 		ACCEPT
Summary: Direct experimental (IDA) annotation of protein homodimerization activity from the structural study of homogeneously glucosylated GYG states.
Reason: Well supported homodimerization; redundant with the PMID:22160680 IDA annotation of the same term.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
2 dimers of GYG1
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-9036727 		MARK AS OVER ANNOTATED
Summary: Reactome TAS annotation placing GYG1 in the lysosomal lumen, arising from its appearance in the "GAA hydrolyzes lysosomal glycogen" reaction (Pompe disease / lysosomal glycogen degradation pathway) where glycogen (with its glycogenin core) is transported to the lysosome.
Reason: This is a pathway-context localization; glycogenin appears in the lysosome only as the buried core of glycogen delivered for lysosomal degradation, not as a lysosomal-lumen-resident protein with a lysosomal function. The core localization of GYG1 is cytosolic (glycogen granules).
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-9036729 		MARK AS OVER ANNOTATED
Summary: Reactome TAS annotation to lysosomal lumen from the "Defective GAA does not hydrolyze lysosomal glycogen" reaction (Pompe disease). Same pathway-context artifact as the R-HSA-9036727 annotation.
Reason: Pathway-context localization reflecting glycogen (with its glycogenin core) delivered to the lysosome; not a resident lysosomal-lumen protein. Core localization is cytosolic.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005576 extracellular region
TAS
Reactome:R-HSA-6798748 		MARK AS OVER ANNOTATED
Summary: Reactome TAS annotation to extracellular region from the "Exocytosis of secretory granule lumen proteins" reaction (neutrophil degranulation pathway), in which GYG1 was detected in neutrophil granule proteomes.
Reason: This localization derives from GYG1's incidental detection in neutrophil degranulation/secretory-granule proteomics and does not reflect an extracellular function. Glycogenin is a cytosolic glycogen-priming enzyme.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005576 extracellular region
TAS
Reactome:R-HSA-6800434 		MARK AS OVER ANNOTATED
Summary: Reactome TAS annotation to extracellular region from the "Exocytosis of ficolin-rich granule lumen proteins" reaction (neutrophil degranulation pathway).
Reason: Same neutrophil-degranulation pathway-context artifact; does not reflect an extracellular function of glycogenin. Core localization is cytosolic.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0034774 secretory granule lumen
TAS
Reactome:R-HSA-6798748 		MARK AS OVER ANNOTATED
Summary: Reactome TAS annotation to secretory granule lumen from the neutrophil degranulation pathway, based on detection of GYG1 in secretory granule proteomes.
Reason: Pathway-context localization from neutrophil granule proteomics; not the core cytosolic localization or function of glycogenin.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:1904813 ficolin-1-rich granule lumen
TAS
Reactome:R-HSA-6800434 		MARK AS OVER ANNOTATED
Summary: Reactome TAS annotation to ficolin-1-rich granule lumen from the neutrophil degranulation pathway.
Reason: Pathway-context localization from neutrophil granule proteomics; not the core cytosolic localization or function of glycogenin.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0016020 membrane
HDA
PMID:19946888
Defining the membrane proteome of NK cells. 		MARK AS OVER ANNOTATED
Summary: High-throughput direct assay (HDA) annotation to membrane, from a mass spectrometry study of the membrane proteome of an NK-like cell line in which GYG1 was among identified proteins.
Reason: The study itself notes that many identified species are proteins transiently associated with membranes rather than integral membrane proteins. Glycogenin has no transmembrane region and is a soluble cytosolic/glycogen-granule protein; the membrane co-fractionation is not evidence of a membrane localization function.
Supporting Evidence:
PMID:19946888
The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes.
GO:0005829 cytosol
TAS
Reactome:R-HSA-3322001 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "GYS1 catalyzes the polyglucosylation of oligoGlc-GYG1" reaction of glycogen synthesis. Correctly localizes GYG1 to the cytosol.
Reason: Cytosol is the correct core cellular location for glycogenin and glycogen synthesis.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-3322005 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "GBE1 catalyzes branch formation in polyGlc-GYG1 complexed with GYS1-a" reaction. Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for glycogen biosynthesis.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-3322041 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "Phosphorylated GYS1 catalyzes the polyglucosylation of oligoGlc-GYG1" reaction. Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for glycogen biosynthesis.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-3322057 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "GBE1 catalyzes branch formation in polyGlc-GYG1 complexed with GYS1-b" reaction. Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for glycogen biosynthesis.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-71552 		ACCEPT
Summary: Reactome TAS annotation to cytosol from a glycogenin/glycogen limit-dextrin reaction. Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for glycogen metabolism.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-71593 		ACCEPT
Summary: Reactome TAS annotation to cytosol from a glycogenin poly-glucosyl reaction. Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for glycogen metabolism.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-3322003 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "Autoglucosylation of GYG1 complexed with GYS1-b" reaction. Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for the autoglucosylation reaction.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-3322025 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "Autoglucosylation of GYG1 complexed with GYS1-a" reaction. Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for the autoglucosylation reaction.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-3781001 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "EPM2A dimer binds PPP1R3C:phosphoglycogen-GYG1 complex" reaction (Lafora disease pathway). Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for glycogen metabolism.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-3781009 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "NHLRC1 mediated ubiquitination of EPM2A and PPP1RC3 associated with glycogen-GYG1" reaction (Lafora disease pathway). Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for glycogen metabolism.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-3781018 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "EPM2A dimer dephosphorylates phosphoglycogen-GYG1" reaction (Lafora disease pathway). Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for glycogen metabolism.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-3781023 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "PPP1R3C binds to glycogen:GYG1:GYS1" reaction. Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for glycogen metabolism.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-3781024 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "GYS1 catalyzes the incorporation of phosphoglucose into glycogen-GYG1" reaction. Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for glycogen metabolism.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-3791349 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "Defective EPM2A does not dephosphorylate phosphoglycogen (type 2A disease)" reaction. Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for glycogen metabolism.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-3797226 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "Defective NHLRC1 does not ubiquitinate EPM2A (laforin) and PPP1R3C (PTG) (type 2B disease)" reaction. Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for glycogen metabolism.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-3814838 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "Defective GYG1 is not autoglucosyolated" reaction (glycogen storage disease type XV pathway). Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for the autoglucosylation reaction.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules
GO:0005829 cytosol
TAS
Reactome:R-HSA-3828061 		ACCEPT
Summary: Reactome TAS annotation to cytosol from the "Defective GYS1 does not transfer glucose to growing glycogen chains" reaction. Correct cytosolic localization.
Reason: Cytosol is the correct core cellular location for glycogen metabolism.
Supporting Evidence:
file:human/GYG1/GYG1-uniprot.txt
Localizes to glycogen granules

Core Functions

Self-glucosylating primer that initiates glycogen biosynthesis, transferring glucose from UDP-alpha-D-glucose onto its own Tyr195 (Mn2+-dependent) to build a short alpha-1,4-glucan primer for glycogen synthase.

Molecular Function:
glycogenin glucosyltransferase activity
Directly Involved In:
glycogen biosynthetic process
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:22160680
    Glycogenin initiates the synthesis of a maltosaccharide chain covalently attached to itself on Tyr195 via a stepwise glucosylation reaction, priming glycogen synthesis.
  • PMID:30356213
    GYG acts as a 'seed core' for the formation of the glycogen particle by catalysing its own stepwise autoglucosylation to form a covalently bound gluco-oligosaccharide chain at initiation site Tyr 195.

Requires a divalent metal cofactor for catalysis; binds manganese ion, which is coordinated in the active site and is the most effective cofactor for self-glucosylation.

Molecular Function:
manganese ion binding
Directly Involved In:
glycogen biosynthetic process
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/GYG1/GYG1-uniprot.txt
    Required for self-glucosylation. Manganese is

Forms homodimers and assembles with glycogen synthase into the glycogen synthase-glycogenin biosynthetic complex, presenting the glucan primer to glycogen synthase for elongation.

Molecular Function:
protein homodimerization activity
Directly Involved In:
glycogen biosynthetic process
Cellular Locations:
cytosol
In Complex:
catalytic complex
Supporting Evidence:
  • PMID:35835870
    Cryo-EM map and model of the tetrameric GYS1–GYG1ΔCD complex at 3.0 Å resolution.
  • PMID:17055998
    The interaction with glycogenin was found to be mediated by the region of glycogenin which contains the 33 COOH-terminal amino acid residues.

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:16189514
Towards a proteome-scale map of the human protein-protein interaction network.
PMID:17055998
Interaction between glycogenin and glycogen synthase.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:20357282
Glycogenin-1 deficiency and inactivated priming of glycogen synthesis.
PMID:22160680
Conformational plasticity of glycogenin and its maltosaccharide substrate during glycogen biogenesis.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:30356213
Palladium-mediated enzyme activation suggests multiphase initiation of glycogenesis.
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
PMID:35835870
Molecular basis for the regulation of human glycogen synthase by phosphorylation and glucose-6-phosphate.
file:human/GYG1/GYG1-uniprot.txt
UniProtKB entry P46976 (GLYG_HUMAN), Glycogenin-1
Reactome:R-HSA-3322001
GYS1 catalyzes the polyglucosylation of oligoGlc-GYG1
Reactome:R-HSA-3322003
Autoglucosylation of GYG1 complexed with GYS1-b
Reactome:R-HSA-3322005
GBE1 catalyzes branch formation in polyGlc-GYG1 complexed with GYS1-a
Reactome:R-HSA-3322025
Autoglucosylation of GYG1 complexed with GYS1-a
Reactome:R-HSA-3322041
Phosphorylated GYS1 catalyzes the polyglucosylation of oligoGlc-GYG1
Reactome:R-HSA-3322057
GBE1 catalyzes branch formation in polyGlc-GYG1 complexed with GYS1-b
Reactome:R-HSA-3322077
Glycogen synthesis
Reactome:R-HSA-3781001
EPM2A dimer binds PPP1R3C:phosphoglycogen-GYG1 complex
Reactome:R-HSA-3781009
NHLRC1 mediated ubiquitination of EPM2A and PPP1RC3 associated with glycogen-GYG1
Reactome:R-HSA-3781018
EPM2A dimer dephosphorylates phosphoglycogen-GYG1
Reactome:R-HSA-3781023
PPP1R3C binds to glycogen:GYG1:GYS1
Reactome:R-HSA-3781024
GYS1 catalyzes the incorporation of phosphoglucose into glycogen-GYG1
Reactome:R-HSA-3791349
Defective EPM2A does not dephosphorylate phosphoglycogen (type 2A disease)
Reactome:R-HSA-3797226
Defective NHLRC1 does not ubiquitinate EPM2A (laforin) and PPP1R3C (PTG) (type 2B disease)
Reactome:R-HSA-3814838
Defective GYG1 is not autoglucosyolated
Reactome:R-HSA-3828061
Defective GYS1 does not transfer glucose to growing glycogen chains
Reactome:R-HSA-6798748
Exocytosis of secretory granule lumen proteins
Reactome:R-HSA-6800434
Exocytosis of ficolin-rich granule lumen proteins
Reactome:R-HSA-71552
limit dextrin-glycogenin => ((1,6)-alpha-glucosyl)poly((1,4)-alpha-glucosyl) glycogenin
Reactome:R-HSA-71593
((1,6)-alpha-glucosyl)poly((1,4)-alpha-glucosyl)glycogenin => poly{(1,4)-alpha-glucosyl} glycogenin + alpha-D-glucose
Reactome:R-HSA-9036727
GAA hydrolyzes lysosomal glycogen
Reactome:R-HSA-9036729
Defective GAA does not hydrolyze lysosomal glycogen

Suggested Questions for Experts

Q: What determines the final length (~8-12 residues) of the self-glucosylated primer before handoff to glycogen synthase, and how is the transition between glycogenin priming and glycogen synthase elongation regulated?

Q: Does GYG1 have any physiologically relevant function outside the cytosolic glycogen granule (e.g. the reported nuclear localization by similarity)?

Suggested Experiments

Experiment: Quantitative reconstitution of primer chain-length distribution and GYG1-to-GYS1 handoff kinetics using the homogeneously glucosylated GYG1 intermediates.

Experiment: Structural and functional characterization of additional disease variants (beyond Thr83Met, Ala16Pro, Asp102His) to map genotype-phenotype relationships for GSD XV versus PGBM2.

📚 Additional Documentation

Notes

(GYG1-notes.md)

GYG1 (Glycogenin-1, UniProtKB:P46976) — review notes

Summary of verified biology

GYG1 encodes glycogenin-1, the self-glucosylating primer/initiator of glycogen
biosynthesis. It is a member of the glycosyltransferase 8 (GT8/CAZy GT8) family,
glycogenin subfamily. Using UDP-alpha-D-glucose as sugar donor and a divalent metal
cofactor (Mn2+ most effective), it autoglucosylates its own Tyr195, building a short
covalently attached alpha-1,4-glucan chain (~8–12 glucose residues) via a
glucose-1-O-tyrosyl linkage. This maltosaccharide primer is then elongated by glycogen
synthase (GYS1 in muscle/most tissues, GYS2 in liver), with glycogen branching enzyme
(GBE1) adding alpha-1,6 branch points. Glycogenin remains covalently buried at the core
of the mature glycogen granule.

  • EC 2.4.1.186; glycogenin glucosyltransferase activity (GO:0008466).
  • Reactions (from UniProt, RHEA:23360 initiation and RHEA:56560 elongation of the
    self-glucosyl chain).
  • Cofactor Mn2+ (CHEBI:29035), required for self-glucosylation
    [file:human/GYG1/GYG1-uniprot.txt "Required for self-glucosylation. Manganese is"].
  • Structure: many crystal structures of residues 1–262 with Mn/UDP/UDP-glucose
    (PMID:22160680, PDBs 3Q4S etc.); cryo-EM of the GYS1–GYG1 complex (PMID:35835870,
    PMID:35690592).

Complex / subunit

Part of the GYS1–GYG1 complex, a heterooctamer of a GYS1 tetramer + 2 GYG1 dimers, each
GYS1 protomer binding one GYG1 subunit via the GYG1 C-terminus
[file:human/GYG1/GYG1-uniprot.txt]. The GYG1 C-terminal ~33 residues mediate the
interaction with glycogen synthase [PMID:17055998, "The interaction with glycogenin was
found to be mediated by the region of glycogenin which contains the 33 COOH-terminal amino
acid residues."]. GYG1 forms homodimers (IDA, PMID:22160680, PMID:30356213). ComplexPortal
entries CPX-26491 (GYG1-GYS1) and CPX-26492 (GYG1-GYS2).

Disease

  • Glycogen storage disease 15 / GSD XV (MIM:613507): muscle weakness with skeletal
    muscle glycogen depletion + cardiac arrhythmia with abnormal cardiac storage material;
    Thr83Met abolishes autoglucosylation [PMID:20357282; PMID:22160680].
  • Polyglucosan body myopathy 2 (PGBM2) (MIM:616199): polyglucosan accumulation in
    muscle, skeletal myopathy without cardiac involvement (variants Ala16Pro, Asp102His;
    PMID:25272951).

Localization

Cytoplasmic; localizes to glycogen granules (glycosomes) in the cytoplasm; also reported
nucleus (by similarity). GOA carries many Reactome TAS "cytosol" annotations and a small
number of dubious localization terms (nucleus IEA/ISS via SubCell mapping; membrane HDA
from an NK-cell membrane proteome; and Reactome neutrophil-degranulation-pathway CC terms:
extracellular region, secretory/ficolin-1-rich granule lumen, lysosomal lumen). These
extracellular/granule/lysosomal-lumen terms come from GYG1's incidental appearance in
neutrophil-degranulation and Pompe-disease Reactome pathways and do not reflect the core
cytosolic/glycogen-granule biology; treated as over-annotations.

Annotation review disposition

  • Core MF: GO:0008466 glycogenin glucosyltransferase activity (EXP/IDA/IBA) — ACCEPT.
  • GO:0016757 glycosyltransferase activity (IEA InterPro) — parent of 0008466; ACCEPT as
    a correct-but-general IEA.
  • GO:0030145 manganese ion binding (IDA x2) — ACCEPT (structural + functional cofactor).
  • GO:0042803 protein homodimerization activity (IDA x2) — ACCEPT.
  • GO:0005515 protein binding IPI x5 — bare, uninformative; MARK_AS_OVER_ANNOTATED
    (real MF captured by homodimerization + the GYS1 complex). Do not REMOVE per policy.
  • GO:0005978 glycogen biosynthetic process (IBA/IEA/TAS/IDA/IMP) — ACCEPT (core BP).
    Note UniProt DR also has GO:0160249 "glycogen biosynthetic process via UDP-glucose"
    (IMP) which is not in GOA; more precise child; noted as a proposed refinement.
  • GO:1902494 catalytic complex (IDA, ComplexPortal PMID:35835870) — ACCEPT (GYS1-GYG1).
  • Cytoplasm/cytosol (IBA is_active_in cytoplasm; ISS; Reactome TAS cytosol x17) — ACCEPT
    the cytoplasm/cytosol location; is_active_in cytoplasm reflects where it acts.
  • Nucleus (IEA SubCell; ISS) — MARK_AS_OVER_ANNOTATED (SubCell keyword propagation; no
    direct experimental support for a nuclear function; core biology is cytosolic).
  • membrane (HDA, NK-cell membrane proteome PMID:19946888) — MARK_AS_OVER_ANNOTATED
    (mass-spec membrane co-fractionation; glycogenin is a peripheral/soluble protein).
  • extracellular region / secretory granule lumen / ficolin-1-rich granule lumen /
    lysosomal lumen (Reactome TAS from neutrophil-degranulation & Pompe pathways) —
    MARK_AS_OVER_ANNOTATED (pathway-context artifacts, not core localization).

📄 View Raw YAML

 
id: P46976
gene_symbol: GYG1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Glycogenin-1 is the self-glucosylating protein primer that initiates glycogen
  biosynthesis. Using UDP-alpha-D-glucose as donor and a divalent metal cofactor (Mn2+
  is most effective), it autoglucosylates a specific internal tyrosine (Tyr195), forming
  a covalent glucose-1-O-tyrosyl linkage and building a short alpha-1,4-glucan chain of
  roughly 8-12 glucose residues. This maltosaccharide primer serves as the substrate onto
  which glycogen synthase (GYS1 in muscle and most tissues, GYS2 in liver) elongates the
  glycogen molecule, with glycogen branching enzyme introducing alpha-1,6 branches;
  glycogenin remains covalently attached at the core of the mature glycogen granule. It
  is a glycosyltransferase family 8 (GT8) enzyme (EC 2.4.1.186), acts in the cytosol at
  glycogen granules, and forms a heterooctameric complex with glycogen synthase (a GYS1
  tetramer with two GYG1 dimers). Loss-of-function variants cause glycogen storage disease
  type XV / polyglucosan body myopathy 2, characterized by glycogen depletion and
  accumulation of poorly branched polyglucosan bodies in skeletal and/or cardiac muscle.
alternative_products:
- name: GN-1L
  id: P46976-1
- name: GN-1
  id: P46976-2
  sequence_note: VSP_001769
- name: GN-1S
  id: P46976-3
  sequence_note: VSP_001768
existing_annotations:
- term:
    id: GO:0008466
    label: glycogenin glucosyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) assignment of the defining molecular function of glycogenin,
      glycogenin glucosyltransferase activity (EC 2.4.1.186). This is the core catalytic
      function of GYG1 and is strongly corroborated by direct experimental evidence in
      human and orthologs.
    action: ACCEPT
    reason: This is the well-established core molecular function, directly supported by
      crystallographic and enzymatic studies of human GYG1 and confirmed across orthologs.
    supported_by:
    - reference_id: PMID:22160680
      supporting_text: |-
        Glycogenin initiates the synthesis of a maltosaccharide chain covalently
        attached to itself on Tyr195 via a stepwise glucosylation reaction, priming
        glycogen synthesis.
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) assignment placing glycogenin in the glycogen biosynthetic
      process. Glycogenin performs the obligatory priming step of glycogen synthesis.
    action: ACCEPT
    reason: Core biological process for GYG1; the priming reaction it catalyzes is required
      for glycogen synthesis.
    supported_by:
    - reference_id: PMID:20357282
      supporting_text: |-
        The missense mutation resulted in
        inactivation of the autoglucosylation of glycogenin-1 that is necessary for the
        priming of glycogen synthesis in muscle.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) assignment that glycogenin is active in the cytoplasm.
      Glycogen synthesis and the self-glucosylation reaction occur in the cytosol at
      glycogen granules.
    action: ACCEPT
    reason: Consistent with the cytosolic/glycogen-granule localization of glycogen
      metabolism; is_active_in cytoplasm correctly captures where GYG1 acts. A more
      specific cytosol term (GO:0005829) is also annotated by Reactome.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation to nucleus derived from UniProt Swiss-Prot subcellular
      location keyword mapping (SL-0191). The nuclear location in UniProt is itself an
      inference by similarity, with no direct experimental support for a nuclear function
      of GYG1.
    action: MARK_AS_OVER_ANNOTATED
    reason: The core biology of glycogenin is cytosolic (glycogen granules). The nucleus
      annotation is a keyword-mapping propagation of a by-similarity UniProt entry and does
      not reflect an established nuclear role; it risks over-annotating GYG1 as a nuclear
      protein.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation to cytoplasm from UniProt subcellular location keyword
      mapping (SL-0086). Correct and consistent with the cytosolic/glycogen-granule
      localization of glycogenin.
    action: ACCEPT
    reason: Cytoplasmic localization is well established for glycogen metabolism enzymes
      and is consistent with the IBA and Reactome cytosol annotations.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0008466
    label: glycogenin glucosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated electronic annotation (multiple IEA methods, including ARBA and EC
      2.4.1.186 mapping) of the defining glycogenin glucosyltransferase activity.
    action: ACCEPT
    reason: Correctly assigns the core catalytic function; redundant with the experimental
      IDA/EXP and IBA annotations of the same term.
    supported_by:
    - reference_id: PMID:30356213
      supporting_text: |-
        GYG acts as a 'seed core' for
        the formation of the glycogen particle by catalysing its own stepwise
        autoglucosylation to form a covalently bound gluco-oligosaccharide chain at
        initiation site Tyr 195.
- term:
    id: GO:0016757
    label: glycosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO electronic annotation from the glycosyltransferase family 8
      signature (IPR002495) to the general parent term glycosyltransferase activity.
    action: ACCEPT
    reason: Correct but general; it is the direct parent of the specific glycogenin
      glucosyltransferase activity (GO:0008466) that is experimentally established. Retaining
      the general IEA is acceptable; the specific term should be the core function.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Belongs to the glycosyltransferase 8 family. Glycogenin
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: IntAct-curated binary interaction (from a high-throughput yeast two-hybrid
      interactome map) recorded with the partner GYS1 (P13807). The GO term "protein
      binding" is uninformative on its own.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "protein binding" adds no functional specificity. The biologically
      meaningful interaction (with glycogen synthase GYS1) is already captured by the
      protein homodimerization activity and catalytic-complex annotations. Per curation
      guidelines this uninformative term is marked as over-annotated rather than removed.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: Here we describe an initial version of a proteome-scale map of
        human binary protein-protein interactions.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17055998
  qualifier: enables
  review:
    summary: IPI annotation to the biologically relevant GYS1 interaction (P13807), from a
      dedicated study mapping the glycogenin-glycogen synthase interaction to the GYG1
      C-terminal 33 residues. The term "protein binding" itself is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The interaction with glycogen synthase is real and important, but the bare
      "protein binding" term does not convey it. The functional content (GYS1-GYG1 complex,
      homodimerization) is captured by more specific terms. Marked over-annotated rather
      than removed.
    supported_by:
    - reference_id: PMID:17055998
      supporting_text: The interaction with glycogenin was found to be mediated by the
        region of glycogenin which contains the 33 COOH-terminal amino acid residues.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: IntAct-curated binary interaction with GYS1 (P13807) from a proteome-scale
      human interactome map. Uninformative "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "protein binding" is uninformative; the meaningful GYS1 interaction is
      already captured elsewhere. Marked over-annotated per guidelines rather than removed.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: Combining high-quality binary pairs from the literature with systematic
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: Interaction recorded with GYS1 (P13807) from the OpenCell endogenous-tagging
      IP-MS interactome resource. Uninformative "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "protein binding" is uninformative; the functionally meaningful GYS1
      interaction is captured by homodimerization and complex annotations. Marked
      over-annotated rather than removed.
    supported_by:
    - reference_id: PMID:35271311
      supporting_text: systematically map the localization and interactions of human proteins
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Automated electronic annotation (multiple IEA methods, including UniPathway
      UPA00164) placing GYG1 in glycogen biosynthesis.
    action: ACCEPT
    reason: Correct core biological process, redundant with the experimental and IBA
      annotations of 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:0005978
    label: glycogen biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322077
  qualifier: involved_in
  review:
    summary: Reactome traceable-author-statement annotation to glycogen biosynthetic
      process via the "Glycogen synthesis" pathway.
    action: ACCEPT
    reason: Correctly captures the core biological process; glycogenin performs the priming
      step of the Reactome glycogen synthesis pathway.
    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:0008466
    label: glycogenin glucosyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:20357282
  qualifier: enables
  review:
    summary: Experimental annotation of glycogenin glucosyltransferase (autoglucosylation)
      activity. The disease study showed unglucosylated glycogenin-1 in patient muscle and
      that the Thr83Met variant inactivates autoglucosylation.
    action: ACCEPT
    reason: Directly supports the core catalytic function; the loss of this activity in the
      Thr83Met patient causally links the enzyme activity to glycogen synthesis priming.
    supported_by:
    - reference_id: PMID:20357282
      supporting_text: |-
        The missense mutation resulted in
        inactivation of the autoglucosylation of glycogenin-1 that is necessary for the
        priming of glycogen synthesis in muscle.
- term:
    id: GO:0005978
    label: glycogen biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:35835870
  qualifier: involved_in
  review:
    summary: ComplexPortal IDA annotation placing the GYS1-GYG1 complex in glycogen
      biosynthesis, based on the cryo-EM structural study of the glycogen synthase-glycogenin
      complex.
    action: ACCEPT
    reason: Core biological process, supported by structural characterization of the
      functional biosynthetic complex.
    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 annotation that GYG1 is part of a catalytic complex, based
      on the cryo-EM structure of the tetrameric GYS1-GYG1 complex (the glycogen
      synthase-glycogenin complex, ComplexPortal CPX-26491).
    action: ACCEPT
    reason: Well supported; GYG1 is an integral subunit of the glycogen synthase-glycogenin
      biosynthetic complex, a catalytic complex.
    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:0005978
    label: glycogen biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:22160680
  qualifier: involved_in
  review:
    summary: IMP annotation to glycogen biosynthetic process based on the structural and
      mutational study showing the GSD XV Thr83Met variant is conformationally locked and
      catalytically inactive, impairing glycogen synthesis priming.
    action: ACCEPT
    reason: The disease-causing loss-of-function mutation directly links GYG1 to the glycogen
      biosynthetic process (priming step).
    supported_by:
    - reference_id: PMID:22160680
      supporting_text: |-
        The Thr83Met mutation, which causes glycogen storage disease XV, is
        conformationally locked in the ground state and catalytically inactive.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity (ISS) annotation to nucleus transferred from an ortholog
      (P13280). As with the SubCell IEA nucleus annotation, there is no direct experimental
      support for a nuclear function of GYG1.
    action: MARK_AS_OVER_ANNOTATED
    reason: The core localization and function of glycogenin are cytosolic (glycogen
      granules). The nucleus annotation is an inference by similarity without experimental
      support and risks over-annotating a nuclear role.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity (ISS) annotation to cytoplasm transferred from an ortholog
      (P13280). Consistent with the established cytosolic localization of glycogenin.
    action: ACCEPT
    reason: Cytoplasmic localization is correct and well supported for glycogen metabolism.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: is_active_in
  review:
    summary: Sequence-similarity (ISS) annotation that glycogenin is active in the
      cytoplasm, transferred from an ortholog (C4R941). Consistent with where the priming
      reaction occurs.
    action: ACCEPT
    reason: Correctly captures that GYG1 acts in the cytoplasm (at glycogen granules).
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Cytosolic localization
- term:
    id: GO:0008466
    label: glycogenin glucosyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:22160680
  qualifier: enables
  review:
    summary: Direct experimental (IDA) annotation of glycogenin glucosyltransferase activity
      from crystallographic snapshots of human glycogenin captured during its reaction cycle
      with UDP-glucose, Mn2+ and its maltosaccharide substrate.
    action: ACCEPT
    reason: Direct structural/enzymatic evidence for the core catalytic function in human
      GYG1.
    supported_by:
    - reference_id: PMID:22160680
      supporting_text: |-
        Glycogenin initiates the synthesis of a maltosaccharide chain covalently
        attached to itself on Tyr195 via a stepwise glucosylation reaction, priming
        glycogen synthesis.
- term:
    id: GO:0008466
    label: glycogenin glucosyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:30356213
  qualifier: enables
  review:
    summary: Direct experimental (IDA) annotation of glycogenin glucosyltransferase activity
      from a study that accessed homogeneous glucosylated states of GYG via palladium-mediated
      activation and characterized catalytic activity at distinct stages of autoglucosylation.
    action: ACCEPT
    reason: Direct enzymatic evidence for the core catalytic function.
    supported_by:
    - reference_id: PMID:30356213
      supporting_text: |-
        GYG acts as a 'seed core' for
        the formation of the glycogen particle by catalysing its own stepwise
        autoglucosylation to form a covalently bound gluco-oligosaccharide chain at
        initiation site Tyr 195.
- term:
    id: GO:0030145
    label: manganese ion binding
  evidence_type: IDA
  original_reference_id: PMID:22160680
  qualifier: enables
  review:
    summary: Direct experimental (IDA) annotation of manganese ion binding, from crystal
      structures of human glycogenin in complex with manganese, UDP and UDP-alpha-D-glucose.
      Mn2+ is the catalytic cofactor coordinating the sugar donor.
    action: ACCEPT
    reason: Well supported; Mn2+ binding is a genuine, structurally defined cofactor
      requirement for the autoglucosylation reaction.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Required for self-glucosylation. Manganese is
- term:
    id: GO:0030145
    label: manganese ion binding
  evidence_type: IDA
  original_reference_id: PMID:30356213
  qualifier: enables
  review:
    summary: Direct experimental (IDA) annotation of manganese ion binding from crystal
      structures of human glycogenin (residues 1-262) in complex with UDP and manganese.
    action: ACCEPT
    reason: Well supported cofactor requirement; redundant with the PMID:22160680 IDA
      annotation of the same term.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Required for self-glucosylation. Manganese is
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:22160680
  qualifier: enables
  review:
    summary: Direct experimental (IDA) annotation of protein homodimerization activity.
      Glycogenin functions as a dimer; the crystallographic study characterized inter- and
      intra-subunit modes of glucosylation dependent on the dimeric arrangement.
    action: ACCEPT
    reason: Well supported; GYG1 forms homodimers, and the dimer is functionally relevant
      to its intersubunit glucosylation mechanism and to the GYS1-GYG1 heterooctamer (two
      GYG1 dimers).
    supported_by:
    - reference_id: PMID:22160680
      supporting_text: The rearranged lid guides the nascent maltosaccharide chain into the
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:30356213
  qualifier: enables
  review:
    summary: Direct experimental (IDA) annotation of protein homodimerization activity from
      the structural study of homogeneously glucosylated GYG states.
    action: ACCEPT
    reason: Well supported homodimerization; redundant with the PMID:22160680 IDA annotation
      of the same term.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: 2 dimers of GYG1
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036727
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing GYG1 in the lysosomal lumen, arising from its
      appearance in the "GAA hydrolyzes lysosomal glycogen" reaction (Pompe disease /
      lysosomal glycogen degradation pathway) where glycogen (with its glycogenin core) is
      transported to the lysosome.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is a pathway-context localization; glycogenin appears in the lysosome only
      as the buried core of glycogen delivered for lysosomal degradation, not as a
      lysosomal-lumen-resident protein with a lysosomal function. The core localization of
      GYG1 is cytosolic (glycogen granules).
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036729
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to lysosomal lumen from the "Defective GAA does not
      hydrolyze lysosomal glycogen" reaction (Pompe disease). Same pathway-context artifact
      as the R-HSA-9036727 annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Pathway-context localization reflecting glycogen (with its glycogenin core)
      delivered to the lysosome; not a resident lysosomal-lumen protein. Core localization
      is cytosolic.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798748
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to extracellular region from the "Exocytosis of
      secretory granule lumen proteins" reaction (neutrophil degranulation pathway), in
      which GYG1 was detected in neutrophil granule proteomes.
    action: MARK_AS_OVER_ANNOTATED
    reason: This localization derives from GYG1's incidental detection in neutrophil
      degranulation/secretory-granule proteomics and does not reflect an extracellular
      function. Glycogenin is a cytosolic glycogen-priming enzyme.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to extracellular region from the "Exocytosis of
      ficolin-rich granule lumen proteins" reaction (neutrophil degranulation pathway).
    action: MARK_AS_OVER_ANNOTATED
    reason: Same neutrophil-degranulation pathway-context artifact; does not reflect an
      extracellular function of glycogenin. Core localization is cytosolic.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0034774
    label: secretory granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798748
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to secretory granule lumen from the neutrophil
      degranulation pathway, based on detection of GYG1 in secretory granule proteomes.
    action: MARK_AS_OVER_ANNOTATED
    reason: Pathway-context localization from neutrophil granule proteomics; not the core
      cytosolic localization or function of glycogenin.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:1904813
    label: ficolin-1-rich granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to ficolin-1-rich granule lumen from the neutrophil
      degranulation pathway.
    action: MARK_AS_OVER_ANNOTATED
    reason: Pathway-context localization from neutrophil granule proteomics; not the core
      cytosolic localization or function of glycogenin.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput direct assay (HDA) annotation to membrane, from a mass
      spectrometry study of the membrane proteome of an NK-like cell line in which GYG1 was
      among identified proteins.
    action: MARK_AS_OVER_ANNOTATED
    reason: The study itself notes that many identified species are proteins transiently
      associated with membranes rather than integral membrane proteins. Glycogenin has no
      transmembrane region and is a soluble cytosolic/glycogen-granule protein; the membrane
      co-fractionation is not evidence of a membrane localization function.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: The remaining species were largely involved in cellular processes and
        molecular functions that could be predicted to be transiently associated with membranes.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322001
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "GYS1 catalyzes the polyglucosylation
      of oligoGlc-GYG1" reaction of glycogen synthesis. Correctly localizes GYG1 to the
      cytosol.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for glycogenin and glycogen
      synthesis.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322005
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "GBE1 catalyzes branch formation
      in polyGlc-GYG1 complexed with GYS1-a" reaction. Correct cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for glycogen biosynthesis.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322041
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "Phosphorylated GYS1 catalyzes the
      polyglucosylation of oligoGlc-GYG1" reaction. Correct cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for glycogen biosynthesis.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322057
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "GBE1 catalyzes branch formation
      in polyGlc-GYG1 complexed with GYS1-b" reaction. Correct cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for glycogen biosynthesis.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71552
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from a glycogenin/glycogen limit-dextrin
      reaction. Correct cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for glycogen metabolism.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71593
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from a glycogenin poly-glucosyl reaction.
      Correct cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for glycogen metabolism.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322003
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "Autoglucosylation of GYG1 complexed
      with GYS1-b" reaction. Correct cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for the autoglucosylation reaction.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322025
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "Autoglucosylation of GYG1 complexed
      with GYS1-a" reaction. Correct cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for the autoglucosylation reaction.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3781001
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "EPM2A dimer binds
      PPP1R3C:phosphoglycogen-GYG1 complex" reaction (Lafora disease pathway). Correct
      cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for glycogen metabolism.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3781009
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "NHLRC1 mediated ubiquitination of
      EPM2A and PPP1RC3 associated with glycogen-GYG1" reaction (Lafora disease pathway).
      Correct cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for glycogen metabolism.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3781018
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "EPM2A dimer dephosphorylates
      phosphoglycogen-GYG1" reaction (Lafora disease pathway). Correct cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for glycogen metabolism.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3781023
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "PPP1R3C binds to glycogen:GYG1:GYS1"
      reaction. Correct cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for glycogen metabolism.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3781024
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "GYS1 catalyzes the incorporation
      of phosphoglucose into glycogen-GYG1" reaction. Correct cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for glycogen metabolism.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3791349
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "Defective EPM2A does not
      dephosphorylate phosphoglycogen (type 2A disease)" reaction. Correct cytosolic
      localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for glycogen metabolism.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3797226
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "Defective NHLRC1 does not
      ubiquitinate EPM2A (laforin) and PPP1R3C (PTG) (type 2B disease)" reaction. Correct
      cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for glycogen metabolism.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3814838
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "Defective GYG1 is not
      autoglucosyolated" reaction (glycogen storage disease type XV pathway). Correct
      cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for the autoglucosylation reaction.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3828061
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to cytosol from the "Defective GYS1 does not transfer
      glucose to growing glycogen chains" reaction. Correct cytosolic localization.
    action: ACCEPT
    reason: Cytosol is the correct core cellular location for glycogen metabolism.
    supported_by:
    - reference_id: file:human/GYG1/GYG1-uniprot.txt
      supporting_text: Localizes to glycogen granules
core_functions:
- description: Self-glucosylating primer that initiates glycogen biosynthesis, transferring
    glucose from UDP-alpha-D-glucose onto its own Tyr195 (Mn2+-dependent) to build a short
    alpha-1,4-glucan primer for glycogen synthase.
  molecular_function:
    id: GO:0008466
    label: glycogenin glucosyltransferase activity
  directly_involved_in:
  - id: GO:0005978
    label: glycogen biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:22160680
    supporting_text: |-
      Glycogenin initiates the synthesis of a maltosaccharide chain covalently
      attached to itself on Tyr195 via a stepwise glucosylation reaction, priming
      glycogen synthesis.
  - reference_id: PMID:30356213
    supporting_text: |-
      GYG acts as a 'seed core' for
      the formation of the glycogen particle by catalysing its own stepwise
      autoglucosylation to form a covalently bound gluco-oligosaccharide chain at
      initiation site Tyr 195.
- description: Requires a divalent metal cofactor for catalysis; binds manganese ion, which
    is coordinated in the active site and is the most effective cofactor for
    self-glucosylation.
  molecular_function:
    id: GO:0030145
    label: manganese ion binding
  directly_involved_in:
  - id: GO:0005978
    label: glycogen biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/GYG1/GYG1-uniprot.txt
    supporting_text: Required for self-glucosylation. Manganese is
- description: Forms homodimers and assembles with glycogen synthase into the glycogen
    synthase-glycogenin biosynthetic complex, presenting the glucan primer to glycogen
    synthase for elongation.
  molecular_function:
    id: GO:0042803
    label: protein homodimerization 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: Cryo-EM map and model of the tetrameric GYS1–GYG1ΔCD complex at 3.0
      Å resolution.
  - reference_id: PMID:17055998
    supporting_text: The interaction with glycogenin was found to be mediated by the
      region of glycogenin which contains the 33 COOH-terminal amino acid residues.
proposed_new_terms: []
suggested_questions:
- question: What determines the final length (~8-12 residues) of the self-glucosylated
    primer before handoff to glycogen synthase, and how is the transition between glycogenin
    priming and glycogen synthase elongation regulated?
- question: Does GYG1 have any physiologically relevant function outside the cytosolic
    glycogen granule (e.g. the reported nuclear localization by similarity)?
suggested_experiments:
- description: Quantitative reconstitution of primer chain-length distribution and
    GYG1-to-GYS1 handoff kinetics using the homogeneously glucosylated GYG1 intermediates.
- description: Structural and functional characterization of additional disease variants
    (beyond Thr83Met, Ala16Pro, Asp102His) to map genotype-phenotype relationships for
    GSD XV versus PGBM2.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- 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: High-throughput Y2H interactome map; source of a GYG1-GYS1 IntAct binary
      interaction recorded as uninformative "protein binding".
- id: PMID:17055998
  title: Interaction between glycogenin and glycogen synthase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Dedicated study mapping the GYG1-GYS1 interaction to the GYG1 C-terminal
      33 residues; supports the complex/subunit biology.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: NK-cell membrane proteome MS; source of the membrane HDA annotation.
      Authors note many hits are only transiently membrane-associated; not core GYG1 biology.
- id: PMID:20357282
  title: Glycogenin-1 deficiency and inactivated priming of glycogen synthesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: First description of human GYG1 deficiency (GSD XV); Thr83Met inactivates
      autoglucosylation and priming of glycogen synthesis.
- id: PMID:22160680
  title: Conformational plasticity of glycogenin and its maltosaccharide substrate
    during glycogen biogenesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Crystallographic snapshots of human glycogenin; establishes catalytic
      mechanism, Tyr195 autoglucosylation, Mn2+ cofactor, and GSD XV Thr83Met inactivation.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale binary interactome map; source of a GYG1-GYS1 IntAct
      interaction recorded as uninformative "protein binding".
- id: PMID:30356213
  title: Palladium-mediated enzyme activation suggests multiphase initiation of glycogenesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Accesses homogeneous glucosylated GYG states; confirms glycogenin as the
      autoglucosylating "seed core" primer initiating at Tyr195.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: OpenCell IP-MS/imaging resource; source of a GYG1-GYS1 interaction
      recorded as uninformative "protein binding".
- 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: Cryo-EM of the tetrameric GYS1-GYG1 complex; supports the catalytic
      complex and glycogen biosynthetic process annotations.
- id: file:human/GYG1/GYG1-uniprot.txt
  title: UniProtKB entry P46976 (GLYG_HUMAN), Glycogenin-1
  findings: []
- 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: []
- id: Reactome:R-HSA-6798748
  title: Exocytosis of secretory granule lumen proteins
  findings: []
- id: Reactome:R-HSA-6800434
  title: Exocytosis of ficolin-rich granule lumen proteins
  findings: []
- id: Reactome:R-HSA-71552
  title: limit dextrin-glycogenin => ((1,6)-alpha-glucosyl)poly((1,4)-alpha-glucosyl)
    glycogenin
  findings: []
- id: Reactome:R-HSA-71593
  title: ((1,6)-alpha-glucosyl)poly((1,4)-alpha-glucosyl)glycogenin => poly{(1,4)-alpha-glucosyl}
    glycogenin + alpha-D-glucose
  findings: []
- id: Reactome:R-HSA-9036727
  title: GAA hydrolyzes lysosomal glycogen
  findings: []
- id: Reactome:R-HSA-9036729
  title: Defective GAA does not hydrolyze lysosomal glycogen
  findings: []