Affinage

GYG1

Glycogenin-1 · UniProt P46976

Round 2 corrected
Length
350 aa
Mass
39.4 kDa
Annotated
2026-04-28
41 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GYG1 encodes glycogenin-1, a self-glucosylating UDP-glucose:protein glucosyltransferase that initiates glycogen biosynthesis by catalyzing the attachment and extension of a short maltosaccharide chain on its own Tyr194/195 residue in a Mn²⁺- and DxD-motif-dependent mechanism, after which its C-terminal domain recruits glycogen synthase for further chain elongation (PMID:1281472, PMID:8325847, PMID:12051921). Structural studies reveal a conformational 'lid' switch triggered by UDP-glucose binding that controls intra- versus intersubunit glucosylation modes, and the activator GNIP/TRIM7 stimulates autoglucosylation 3–4-fold (PMID:22160680, PMID:11916970). Loss-of-function mutations in GYG1 cause polyglucosan body myopathy (GSD XV), with phenotype severity—ranging from skeletal muscle glycogen depletion to cardiomyopathy—determined by whether residual protein retains partial priming or glycogen synthase-binding activity (PMID:20357282, PMID:25272951, PMID:31791869). GYG1-dependent glycogen synthesis also fuels inflammatory activation in myeloid cells, as in vivo Gyg1 knockdown in a sepsis model attenuates cytokine production and improves survival (PMID:41333476).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1992 High

    Establishing that glycogenin alone is sufficient to self-glucosylate and prime glycogen synthase-mediated elongation resolved whether additional mammalian cofactors are needed for glycogen initiation.

    Evidence Recombinant rabbit glycogenin expressed in E. coli performed Mn²⁺-dependent self-glucosylation and served as a glycogen synthase substrate in vitro

    PMID:1281472

    Open questions at the time
    • Glucosylation site not yet mapped
    • No structural information on active site
  2. 1993 High

    Identification of Tyr-194 as the sole and essential self-glucosylation site defined the initiation chemistry and established that the reaction is intramolecular.

    Evidence Y194F mutagenesis abolished self-glucosylation while retaining UDP-glucose binding; first-order kinetics confirmed intramolecular transfer

    PMID:8325847

    Open questions at the time
    • Active-site catalytic residues not yet identified
    • No structural basis for intramolecular reach
  3. 1997 High

    Discovery of the paralog GYG2 and demonstration that GYG1 and GYG2 prime distinct glycogen pools in liver cells established tissue-specific glycogen initiation pathways.

    Evidence cDNA cloning, recombinant activity assay, and α-amylase fractionation of hepatoma cell glycogen

    PMID:9346895

    Open questions at the time
    • Relative contribution of each paralog to total glycogen in each tissue unclear
    • No in vivo loss-of-function comparison
  4. 2002 High

    Crystal structure determination and identification of GNIP/TRIM7 as a stimulatory partner jointly defined the catalytic mechanism—Rossmann fold, DxD-motif Mn²⁺ coordination, and a possible Asp162 relay—and revealed external regulation of autoglucosylation.

    Evidence 1.9 Å crystal structure with UDP-glucose/Mn²⁺; yeast two-hybrid and co-IP identification of GNIP with 3–4-fold stimulation of self-glucosylation in vitro

    PMID:11916970 PMID:12051921

    Open questions at the time
    • Proposed Asp162 relay mechanism not validated by mutagenesis
    • GNIP stimulation mechanism structurally undefined
    • Intersubunit vs intrasubunit transfer not resolved
  5. 2010 Medium

    The first human GYG1 loss-of-function mutation (Thr83Met) linked glycogenin-1 inactivation to skeletal muscle glycogen depletion and cardiac storage disease, establishing GYG1 as a disease gene.

    Evidence Patient sequencing plus Western blot showing unglucosylated glycogenin-1 protein

    PMID:20357282

    Open questions at the time
    • Single patient; genotype-phenotype spectrum unknown
    • No in vitro rescue experiment
    • Structural basis of Thr83Met inactivation unresolved at this time
  6. 2011 High

    Reaction-cycle crystal structures revealed a conformational lid switch that governs intra- versus intersubunit glucosylation and explained how the Thr83Met mutation locks the enzyme in an inactive ground state, providing the structural basis for GSD XV.

    Evidence Multiple crystal structures of human glycogenin (apo, substrate-bound, growing chain, Thr83Met mutant)

    PMID:22160680

    Open questions at the time
    • Dynamic lid movement not confirmed in solution (e.g., NMR or FRET)
    • Chain-length dependence of the intra-to-inter switch not quantified
  7. 2014 Medium

    Multi-patient genetic study defined GSD XV as a spectrum disorder and showed that loss of the C-terminal glycogen synthase-binding domain causes polyglucosan accumulation, establishing a second disease mechanism distinct from catalytic inactivation.

    Evidence Exome sequencing, muscle histology, and Western blotting for glycogenin-1 C-terminal domain across multiple patients

    PMID:25272951

    Open questions at the time
    • C-terminal domain–glycogen synthase interaction not reconstituted structurally
    • Mechanism linking impaired GS recruitment to polyglucosan formation not directly tested
  8. 2017 Medium

    Functional validation of the Gly135Arg variant confirmed that the substrate-binding pocket is essential for autoglucosylation, extending the map of critical catalytic residues.

    Evidence In vitro autoglucosylation assay on recombinant Gly135Arg protein showed abolished activity

    PMID:29143313

    Open questions at the time
    • Single study; no structural explanation for Gly135Arg inactivation
    • Limited genotype-phenotype data for this variant
  9. 2019 Medium

    Dose-dependent genotype-phenotype correlation for the Asp102His variant revealed that residual glycogenin-1 protein level modulates cardiac involvement, refining the disease model toward a quantitative threshold.

    Evidence Multi-patient comparison of heterozygous vs. homozygous Asp102His carriers with cardiac phenotyping and Western blotting

    PMID:31791869

    Open questions at the time
    • No in vitro activity assay for Asp102His
    • Threshold protein level for cardiac protection not defined
  10. 2025 Medium

    In vivo knockdown of Gyg1 in a sepsis model demonstrated that GYG1-dependent glycogen synthesis fuels myeloid inflammatory activation, extending GYG1 function beyond muscle to innate immunity.

    Evidence LNP-mediated siRNA knockdown in LPS-challenged mice; reduced glycogen, IL-6, TNF-α, neutrophil activation, and improved survival

    PMID:41333476

    Open questions at the time
    • Myeloid-specific conditional knockout not performed
    • Whether GYG2 compensates in myeloid cells is untested
    • Downstream metabolic pathway linking glycogen to cytokine production not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the GNIP/TRIM7 stimulatory mechanism, the precise chain-length determinant for the intra-to-intersubunit glucosylation switch in solution, and the metabolic pathway by which GYG1-primed glycogen fuels inflammatory cytokine production in myeloid cells.
  • No co-crystal structure of glycogenin with GNIP/TRIM7
  • No solution-state dynamics data for lid conformational switch
  • Metabolic coupling between glycogenin-primed glycogen and immune signaling undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 1
Partners
GYG2GYS1TRIM7

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 Rabbit skeletal muscle glycogenin (GYG1 ortholog) was cloned and expressed in E. coli as a fully functional self-glucosylating protein. Recombinant glycogenin incorporated glucose from UDP-[14C]glucose in a Mn2+-dependent manner and, after self-glucosylation, could serve as a substrate for glycogen synthase to produce high-molecular-weight polysaccharide, demonstrating that no other mammalian protein is required for these initiation reactions. Molecular cloning, recombinant protein expression in E. coli, in vitro self-glucosylation assay with UDP-[14C]glucose, glycogen synthase elongation assay The Journal of biological chemistry High 1281472
1993 Tyr-194 of rabbit skeletal muscle glycogenin is the essential and sole site of self-glucosylation. Recombinant glycogenin purified via UDP-agarose affinity chromatography was already glucosylated at Tyr-194 (1–8 glucose residues) and could incorporate ~5 additional glucose mol/mol. A Tyr194Phe mutant retained UDP-agarose binding (indicating structural integrity) but was completely unable to self-glucosylate. The reaction was first-order with respect to glycogenin, indicating intramolecular transfer. Self-glucosylation significantly enhanced subsequent glycogen synthase-mediated elongation. Recombinant protein expression in E. coli, UDP-agarose affinity purification, site-directed mutagenesis (Y194F), in vitro glucosylation assay, mass spectrometry peptide analysis The Journal of biological chemistry High 8325847
1997 A second glycogenin gene, GYG2 (glycogenin-2), expressed preferentially in liver, heart, and pancreas was characterized. GYG2 protein is active in self-glucosylation and self-glucosylated GYG2 can be elongated by skeletal muscle glycogen synthase. In H4IIEC3 hepatoma cells, glycogenin-1 (GYG1) was covalently associated with a distinct glycogen fraction (separable from the GYG2-associated fraction), released only by α-amylase treatment, establishing that GYG1 and GYG2 prime separate glycogen pools in liver cells. cDNA cloning, recombinant expression in E. coli and COS cells, self-glucosylation assay, α-amylase treatment, immunoblotting with paralog-specific antibodies The Journal of biological chemistry High 9346895
2002 GNIP (glycogenin-interacting protein, also known as TRIM7) was identified as a direct binding partner and activator of glycogenin-1. Using rabbit skeletal muscle glycogenin as bait in a yeast two-hybrid screen of a human skeletal muscle cDNA library, GNIP cDNAs were isolated alongside glycogenin and glycogen synthase. Co-immunoprecipitation confirmed physical interaction between GNIP2 isoform and glycogenin. GNIP2 stimulated glycogenin self-glucosylation 3–4-fold in vitro. Yeast two-hybrid screen, co-immunoprecipitation, in vitro self-glucosylation stimulation assay The Journal of biological chemistry High 11916970
2002 The crystal structure of glycogenin was solved at 1.9 Å (with UDP-glucose/Mn2+ complex) and 3.4 Å. The structure revealed an N-terminal Rossmann-like fold, a conserved DxD motif that coordinates Mn2+ (the catalytic divalent cation), and positioned UDP-glucose far from Tyr194, suggesting a two-step mechanism: glucose is first transiently transferred to Asp162, then delivered to Tyr194 (or to growing chain). The DxD motif is essential for Lewis-acid stabilization of the UDP leaving group. X-ray crystallography (MAD phasing, molecular replacement), 1.9 Å resolution with UDP-glucose/Mn2+ ligand Journal of molecular biology High 12051921
2010 GYG1 missense mutation Thr83Met was identified in a patient with glycogen depletion in skeletal muscle and abnormal storage material in the heart. Western blotting showed unglucosylated glycogenin-1, and the Thr83Met substitution was shown to inactivate autoglucosylation of glycogenin-1, demonstrating that autoglucosylation is necessary for priming of glycogen synthesis in muscle in vivo. Patient genetic sequencing, Western blotting for glycogenin-1 glucosylation status, functional inference from loss of autoglucosylation The New England journal of medicine Medium 20357282
2011 Crystallographic snapshots of human glycogenin during its reaction cycle revealed a conformational switch between ground and active states driven by UDP-glucose binding. This involves ordering of a polypeptide stretch containing Tyr195 and a ~30-residue 'lid' movement that guides the nascent maltosaccharide into the active site. The lid supports both intra- and intersubunit glucosylation modes depending on chain length. The disease-causing Thr83Met mutation is conformationally locked in the ground state and is catalytically inactive, providing the structural basis for glycogen storage disease XV. X-ray crystallography of human glycogenin in multiple states (apo, with UDP-glucose, with growing chain), structural comparison of wild-type and Thr83Met mutant Proceedings of the National Academy of Sciences of the United States of America High 22160680
2014 A new glycogen storage disease (later designated GSD XV / polyglucosan body myopathy 2) was defined by homozygous or compound heterozygous deleterious variants in GYG1. Most patients showed depletion of glycogenin-1 in skeletal muscle; one patient retained a truncated glycogenin-1 lacking the C-terminal domain that normally binds glycogen synthase. This established that impaired interaction between glycogenin-1 and glycogen synthase (in addition to enzyme depletion) causes polyglucosan accumulation. Whole-exome/Sanger sequencing, muscle biopsy histology (PAS staining), Western blotting for glycogenin-1 protein and C-terminal domain Annals of neurology Medium 25272951
2017 A novel GYG1 missense mutation p.Gly135Arg located in the substrate-binding domain abolished enzymatic autoglucosylation activity as measured by an in vitro autoglucosylation assay, demonstrating functional importance of Gly135. Combined with a truncating c.484delG mutation on the other allele, both variants caused reduced glycogenin-1 protein expression and polyglucosan accumulation in muscle. Whole-exome sequencing, in vitro autoglucosylation assay, Western blotting for protein expression Acta neurologica Scandinavica Medium 29143313
2019 Compound heterozygous GYG1 variants including the p.Asp102His missense resulted in reduced but non-functional glycogenin-1 protein. The level of p.Asp102His mutated glycogenin-1 expression (partial vs. homozygous) was proposed to determine whether cardiomyopathy develops: a patient with only one p.Asp102His allele (and one null allele) had normal cardiac function at age 77, contrasting with homozygous p.Asp102His patients who develop severe cardiomyopathy between ages 30–50, suggesting a dose-dependent genotype-phenotype relationship for cardiac involvement. Protein analysis (Western blotting for glycogenin-1 expression), cardiac evaluation, genotype-phenotype correlation across multiple patients Neuromuscular disorders : NMD Medium 31791869
2025 In vivo siRNA knockdown of Gyg1 via LNP delivery in an LPS-induced sepsis mouse model significantly reduced glycogen content in myeloid cells, attenuated IL-6 and TNF-α production, alleviated LPS-induced neutrophil activation, and improved survival, demonstrating that GYG1-mediated glycogen synthesis fuels inflammatory activation of innate immune cells (monocytes, neutrophils). In vivo LNP-mediated siRNA knockdown in mouse sepsis model, cytokine measurement (IL-6, TNF-α), glycogen content assay, survival analysis Frontiers in immunology Medium 41333476

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Network organization of the human autophagy system. Nature 1286 20562859
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2015 A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 198 26673895
2013 Proteomic analysis of podocyte exosome-enriched fraction from normal human urine. Journal of proteomics 126 23376485
1989 Human muscle glycogen synthase cDNA sequence: a negatively charged protein with an asymmetric charge distribution. Proceedings of the National Academy of Sciences of the United States of America 118 2493642
2017 Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair. Nature communications 89 29229926
2002 Crystal structure of the autocatalytic initiator of glycogen biosynthesis, glycogenin. Journal of molecular biology 89 12051921
2020 Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. Molecular cell 88 32707033
2010 Glycogenin-1 deficiency and inactivated priming of glycogen synthesis. The New England journal of medicine 82 20357282
2014 A new muscle glycogen storage disease associated with glycogenin-1 deficiency. Annals of neurology 70 25272951
2020 Proteome-wide identification of HSP70/HSC70 chaperone clients in human cells. PLoS biology 65 32687490
2017 Systematic Analysis of Human Protein Phosphatase Interactions and Dynamics. Cell systems 65 28330616
1993 Characterization of rabbit skeletal muscle glycogenin. Tyrosine 194 is essential for function. The Journal of biological chemistry 58 8325847
2000 Identification of two essential glutamic acid residues in glycogen synthase. The Journal of biological chemistry 54 10924520
1997 Glycogenin-2, a novel self-glucosylating protein involved in liver glycogen biosynthesis. The Journal of biological chemistry 50 9346895
2002 GNIP, a novel protein that binds and activates glycogenin, the self-glucosylating initiator of glycogen biosynthesis. The Journal of biological chemistry 46 11916970
2011 Conformational plasticity of glycogenin and its maltosaccharide substrate during glycogen biogenesis. Proceedings of the National Academy of Sciences of the United States of America 44 22160680
1992 Rabbit skeletal muscle glycogenin. Molecular cloning and production of fully functional protein in Escherichia coli. The Journal of biological chemistry 44 1281472
2015 Late-onset polyglucosan body myopathy in five patients with a homozygous mutation in GYG1. Neuromuscular disorders : NMD 24 26652229
2015 GYG1 gene mutations in a family with polyglucosan body myopathy. Neurology. Genetics 17 27066558
2017 Polyglucosan myopathy and functional characterization of a novel GYG1 mutation. Acta neurologica Scandinavica 14 29143313
2019 Functional characterization of GYG1 variants in two patients with myopathy and glycogenin-1 deficiency. Neuromuscular disorders : NMD 11 31791869
2017 Clinical heterogeneity and phenotype/genotype findings in 5 families with GYG1 deficiency. Neurology. Genetics 11 29264399
2013 Structure of the red fluorescent protein from a lancelet (Branchiostoma lanceolatum): a novel GYG chromophore covalently bound to a nearby tyrosine. Acta crystallographica. Section D, Biological crystallography 9 23999308
2018 GYG1 causing progressive limb girdle myopathy with onset during teenage years (polyglucosan body myopathy 2). Neuromuscular disorders : NMD 6 29422440
2020 Sequential spontaneous compartment syndrome in multiple limbs in a young adult with GYG1 gene mutation. BMJ case reports 3 33257366
2025 Comprehensive analysis of metabolism-related genes in sepsis reveals metabolic-immune heterogeneity and highlights GYG1 as a potential therapeutic target. Frontiers in immunology 1 41333476
2026 GYG1 as a Dual Biomarker of Glucagon-Like Peptide-1 Receptor Agonist Weight-Loss Response: Findings from an Integrative Multi-Omics Substudy of a Phase II Trial. Endocrinology and metabolism (Seoul, Korea) 0 41634531
2026 Unmasking Compound Heterozygosity in GYG1 Myopathy: Diagnostic Insights From RNA-Seq and Long-Read Genomics. Clinical genetics 0 42023422