C1GALT1 (core 1 beta-1,3-galactosyltransferase, T-synthase; EC 2.4.1.122) is a Golgi-resident, single-pass type II membrane glycosyltransferase that catalyses the committed step of mucin-type O-glycan elongation. It transfers galactose from UDP-galactose in a beta-1,3 linkage onto the alpha-linked N-acetylgalactosamine that polypeptide GalNAc-transferases have already attached to serine or threonine, converting the truncated Tn antigen (GalNAc-alpha1-O-Ser/Thr) into the core 1 disaccharide Gal-beta1-3-GalNAc-alpha1-O-Ser/Thr, known as the T antigen. Core 1 is the precursor from which most extended mucin-type O-glycans are built, including the core 2 branch and the sialylated and fucosylated structures that serve as selectin ligands, so this single enzyme controls the fate of the great majority of O-glycans on cell-surface and secreted glycoproteins. Unusually among glycosyltransferases, its folding depends absolutely on one dedicated endoplasmic reticulum chaperone, Cosmc (C1GALT1C1); without Cosmc the enzyme misfolds and no activity is produced. The enzyme is widely expressed, most strongly in kidney, heart, placenta and liver, and orthologues are present across metazoans including Drosophila and C. elegans. Loss of core 1 O-glycans exposes the Tn antigen and is associated with ulcerative colitis, Tn syndrome, and the galactose-deficient IgA1 that initiates IgA nephropathy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1964505 | ACCEPT | Summary: The Golgi membrane is where the T-synthase acts. Reactome's reaction "C1GALT1 transfers Galactose to the Tn antigen forming Core 1 glycoproteins" places the enzyme correctly, and the independent literature refers to it plainly as the Golgi enzyme of this pathway. Reason: Correct compartment at an appropriate level of specificity for a type II Golgi membrane glycosyltransferase. This is the location that should carry the gene's core cellular-component annotation. Supporting Evidence: PMID:37216524 requires the action of a single Golgi enzyme T-synthase (encoded by C1GALT1) |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-6785524 | ACCEPT | Summary: Duplicate Golgi membrane assignment from a second Reactome reaction. Exact duplicates from different source reactions are expected and unproblematic. Reason: Same correct compartment as the other Reactome-derived row. Supporting Evidence: PMID:37216524 requires the action of a single Golgi enzyme T-synthase (encoded by C1GALT1) |
| GO:0001525 angiogenesis | IMP PMID:17228361 Variants of C1GALT1 gene are associated with the genetic sus... | KEEP AS NON CORE | Summary: The cited reference is a case-control study of 670 IgA nephropathy patients and 494 controls that genotyped five SNPs in C1GALT1 and reported haplotype frequency differences. It contains no angiogenesis experiment. The term is nonetheless well-founded biologically: mice lacking T-synthase form a chaotic brain microvascular network with distorted capillary lumens and defective endothelial association with pericytes and extracellular matrix, and die of brain haemorrhage by embryonic day 14. Reason: The underlying biology is solid and is now cited directly rather than alluded to: the T-synthase knockout has a defined angiogenic phenotype. What that phenotype shows, however, is that losing core 1 O-glycans disorganises the vasculature, which is a consequence of altered glycan structures on other proteins rather than something this enzyme does in the course of angiogenesis. C1GALT1's molecular role is a single galactosyl transfer in the Golgi. Kept as genuine but downstream, pleiotropic biology. This is why it is treated differently from the sibling kidney development row: that row has no supporting phenotype at all, only a susceptibility association with an acquired adult glomerular disease, whereas this one has a direct developmental vascular phenotype in a knockout. The originally cited reference still supports neither term, which is recorded in its reference_review. Supporting Evidence: PMID:14745002 T-synthase-deficient brains formed a chaotic microvascular network with distorted capillary lumens and defective association of endothelial cells with pericytes and extracellular matrix. PMID:14745002 Gene-targeted mice lacking T-synthase instead expressed the nonsialylated Tn antigen in these cells and developed brain hemorrhage that was uniformly fatal by embryonic day 14. |
| GO:0001822 kidney development | IMP PMID:17228361 Variants of C1GALT1 gene are associated with the genetic sus... | MARK AS OVER ANNOTATED | Summary: Drawn from the same IgA nephropathy association study. IgA nephropathy is an acquired adult glomerular disease driven by deposition of galactose-deficient IgA1 immune complexes; susceptibility to it is not evidence of participation in kidney development. Reason: This term overreaches in a way the angiogenesis row does not. There is no developmental phenotype at issue: the association is with a disease of the mature kidney, and the mechanism runs through under-galactosylated IgA1 produced by plasma cells, not through renal morphogenesis. Reading a developmental process term out of a susceptibility association conflates the organ affected by a disease with the organ's formation. Supporting Evidence: PMID:17228361 A case-control association study was performed |
| GO:0005515 protein binding | IPI PMID:21496458 Co-translational function of Cosmc, core 1 synthase specific... | MODIFY | Summary: The partner is Q96EU7, Cosmc, the dedicated folding chaperone for this enzyme. The cited paper shows in a cell-free translation system that Cosmc must be present during C1GalT translation for active enzyme to be produced. From C1GALT1's side, this is the interaction of a client with its chaperone, which GO can express specifically. Reason: Generic protein binding conveys no functional information, but here the cited publication supports a specific molecular function term for the client side of the interaction. GO:0051087 protein-folding chaperone binding is defined as binding to a chaperone protein, which is exactly what is demonstrated. The reciprocal annotation on Cosmc should carry the chaperone activity itself. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:21496458 Core 1 synthase specific molecular chaperone (Cosmc), a molecular chaperone specific for C1GalT, is essential for the expression of functional C1GalT in mammalian cells. PMID:21496458 These results indicate that Cosmc mediates the co-translational activation of C1GalT |
| GO:0016020 membrane | IDA PMID:11677243 Cloning and expression of human core 1 beta1,3-galactosyltra... | MODIFY | Summary: From the cloning and expression paper, which established that the enzyme is a type II transmembrane protein. The membrane topology is correct, but GO:0016020 names no organelle, and the compartment is known independently. Reason: The bare membrane term is among the least informative cellular-component terms in the ontology. Since the enzyme's Golgi residence is established and already annotated from Reactome, this row should be collapsed to the specific compartment rather than left at a level that distinguishes nothing. Proposed replacements: Golgi membrane Supporting Evidence: PMID:11677243 The core 1 beta3-Gal-T predicts a 363-amino acid type II transmembrane protein PMID:37216524 requires the action of a single Golgi enzyme T-synthase (encoded by C1GALT1) |
| GO:0016020 membrane | IEA GO_REF:0000120 | MODIFY | Summary: Automated assignment from an InterPro signature and the UniProt "Membrane" subcellular-location keyword. Correct as far as it goes, and consistent with the type II topology, but not compartment-specific. Reason: Same collapse to the specific compartment as the IDA-supported membrane row. An electronic annotation is allowed to be broader than the experimental picture, but where the organelle is unambiguous and already annotated, the generic term adds nothing and dilutes the localisation. Proposed replacements: Golgi membrane Supporting Evidence: PMID:37216524 requires the action of a single Golgi enzyme T-synthase (encoded by C1GALT1) |
| GO:0016020 membrane | ISS GO_REF:0000024 | MODIFY | Summary: Curator-judged sequence-similarity transfer from mouse C1galt1 (Q9JJ05), whose own UniProt subcellular location is likewise the generic "Membrane". The donor annotation is sound but is itself non-specific, so the imprecision has been inherited rather than introduced. Reason: The orthology transfer is legitimate; the problem is the altitude of the term being transferred. Mouse and human C1GALT1 are both Golgi type II membrane enzymes, so the specific compartment term is transferable and preferable. Proposed replacements: Golgi membrane Supporting Evidence: PMID:37216524 requires the action of a single Golgi enzyme T-synthase (encoded by C1GALT1) |
| GO:0016263 N-acetylgalactosaminide beta-1,3-galactosyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic propagation from an ancestral node supported by Drosophila and C. elegans members alongside the human gene. The cloning paper independently reports that highly homologous cDNAs were recovered from rat, mouse, Drosophila and C. elegans, which is precisely the distribution the PAINT curator's node placement asserts. Reason: The node placement is well supported and the term is at the right level of specificity. The presence of the target's own accession (Q9NS00) in the WITH/FROM field is expected and correct: the gene's own experimental annotation is one of the descendant evidences used to place the ancestral node, and its reappearance here marks experimental grounding on the target rather than circular support. Supporting Evidence: PMID:11677243 Highly homologous cDNAs were identified and cloned from rat, mouse, Drosophila melanogaster, and Caenorhabditis elegans, suggesting that the enzyme is widely distributed in metazoans |
| GO:0016263 N-acetylgalactosaminide beta-1,3-galactosyltransferase activity | IDA PMID:11677243 Cloning and expression of human core 1 beta1,3-galactosyltra... | ACCEPT | Summary: The defining experiment for this gene. Full-length and soluble epitope-tagged forms expressed in human 293T cells generated core 1 beta3-Gal-T activity transferring galactose from UDP-Gal to GalNAc-alpha1-O-phenyl and to a synthetic glycopeptide bearing Thr-linked GalNAc, with the product confirmed to have the core 1 structure. Reason: Direct assay of the purified recombinant enzyme on both a simple acceptor and a physiologically relevant glycopeptide, with product structure verified. This is the gene's core molecular function and the term matches the assayed reaction exactly. Supporting Evidence: PMID:11677243 generated core 1 beta3-Gal-T activity that transferred galactose from UDP-Gal to GalNAcalpha1-O-phenyl |
| GO:0016263 N-acetylgalactosaminide beta-1,3-galactosyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated assignment via the EC number and three RHEA reactions. EC 2.4.1.122 is the core 1 beta-1,3-galactosyltransferase activity, matching the assayed reaction, and the RHEA entries give it at reaction-level precision. Reason: The reaction-based mapping agrees with the direct experimental evidence and is at the correct specificity. No correction needed. Supporting Evidence: PMID:11677243 generated core 1 beta3-Gal-T activity that transferred galactose from UDP-Gal to GalNAcalpha1-O-phenyl |
| GO:0016757 glycosyltransferase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping from the Fringe-like glycosyltransferase signature (IPR003378) to the broad glycosyltransferase activity parent. The domain assignment is right, but the term sits two levels above the specific activity this enzyme is known to have, which is already annotated three times over. Reason: A domain-level signature legitimately maps to a general activity class when nothing more is known, but that is not the situation here: the specific reaction is established by direct assay, by EC and RHEA mapping, and by phylogenetic inference. Collapsing the generic parent to the specific child is the dominant correction this project has found across glycosyltransferases, and it applies cleanly. Proposed replacements: N-acetylgalactosaminide beta-1,3-galactosyltransferase activity Supporting Evidence: PMID:11677243 generated core 1 beta3-Gal-T activity that transferred galactose from UDP-Gal to GalNAcalpha1-O-phenyl |
| GO:0016266 protein O-linked glycosylation via N-acetylgalactosamine | IDA PMID:11677243 Cloning and expression of human core 1 beta1,3-galactosyltra... | NEW | Summary: Proposed new annotation. C1GALT1 has no mucin-type O-glycosylation process annotation at all in GOA: its only two biological-process rows are angiogenesis and kidney development, both from a SNP association study. The enzyme that performs the committed galactosylation step of the pathway is therefore absent from the pathway's own process term. Reason: The participation test is met directly rather than by necessity: C1GALT1 itself catalyses a step of this process, transferring galactose onto the protein-linked alpha-GalNAc, and the term's definition explicitly covers the GalNAc-initiated glycan "further elongated with the sequential addition of" residues. The comparator check confirms this is a gap rather than a convention: the enzyme immediately upstream (GALNT1) carries GO:0016266, the enzyme immediately downstream (GCNT1) carries GO:0016266, and even this gene's own non-catalytic chaperone (C1GALT1C1) carries the parent term GO:0006493 three times. A pathway in which the initiating enzyme, the branching enzyme and a chaperone are annotated to the process but the committed enzyme is not reflects an omission, not a deliberate curatorial line. The direct assay in PMID:11677243 confirmed that the product formed on a Thr-linked GalNAc glycopeptide has the core 1 structure, which is this process. Supporting Evidence: PMID:11677243 generated core 1 beta3-Gal-T activity that transferred galactose from UDP-Gal to GalNAcalpha1-O-phenyl PMID:11677243 The common core 1 O-glycan structure Galbeta1--> 3GalNAc-R is the precursor for many extended mucin-type O-glycan structures in animal cell surface and secreted glycoproteins |
Loading supporting content…
Download this section (compressed HTML)Q: Why does C1GALT1 carry no mucin-type O-glycosylation biological-process annotation in GOA, when the enzyme upstream of it, the enzyme downstream of it and its own chaperone all do? If this is an intentional curatorial position rather than an omission, the reasoning would be worth recording, because the committed enzyme of a pathway being absent from that pathway's process term is a pattern that would mislead any pathway-completeness analysis.
Q: Are the angiogenesis and kidney development annotations on this gene intended to be supported by the cited association study, or were they meant to cite the mouse conditional-knockout literature on core 1 O-glycan loss? The evidence code (IMP) fits the latter but the reference is the former.
Experiment: Glycoproteomic comparison of C1GALT1-null and Cosmc-null cells to establish how much of the O-glycoproteome depends on the T-synthase specifically, which would quantify how much downstream physiology should be attributed to this single enzyme rather than to the pathway as a whole.
Experiment: Endothelium-restricted C1GALT1 deletion with direct vascular readouts, to test whether the angiogenesis annotation reflects a cell-autonomous requirement for core 1 O-glycans in endothelial cells rather than a systemic consequence.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)