COLGALT2 (collagen beta(1-O)galactosyltransferase 2; also known as GLT25D2, glycosyltransferase 25 family member 2) is an endoplasmic reticulum-luminal, manganese-dependent glycosyltransferase that catalyzes the transfer of beta-galactose from UDP-galactose to hydroxylysine residues of collagens, forming galactosyl-O-hydroxylysine (Gal-O-Hyl). This is the first step of collagen O-glycosylation, which precedes glucosylation to generate the glucosylgalactosyl-hydroxylysine (Glc-Gal-O-Hyl) disaccharide found on collagens and other proteins with collagenous domains. It is a member of the glycosyltransferase 25 (GT25) family and a paralog of COLGALT1, with which it shares procollagen galactosyltransferase activity (EC 2.4.1.50) but no glucosyltransferase activity. The mature protein is a soluble ER-luminal enzyme retained in the ER by a C-terminal SRDEL (KDEL-like) retention signal. Compared with the ubiquitously expressed COLGALT1, COLGALT2 has a more restricted tissue distribution, with expression enriched in brain and skeletal muscle.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0050211 procollagen galactosyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. COLGALT2 is a procollagen galactosyltransferase that transfers beta-galactose to collagen hydroxylysine residues. This phylogenetic (IBA) inference is concordant with direct biochemical characterization of the human enzyme. Reason: This is the well-established core activity of COLGALT2, directly demonstrated biochemically (EC 2.4.1.50) and consistent across IBA, IEA and TAS evidence. The IBA transfer within the GT25 procollagen galactosyltransferase family is appropriate. Supporting Evidence: file:human/COLGALT2/COLGALT2-uniprot.txt Beta-galactosyltransferase that transfers beta-galactose to hydroxylysine residues of collagen. |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000044 | ACCEPT | Summary: Core cellular component. COLGALT2 is a soluble ER-luminal enzyme bearing a C-terminal SRDEL ER-retention motif, consistent with action on collagens during their transit through the ER. Reason: ER lumen localization is supported by the UniProt subcellular location and the C-terminal KDEL-like (...SRDEL) retention signal that prevents secretion. This annotation correctly localizes the enzyme to its site of action. Supporting Evidence: file:human/COLGALT2/COLGALT2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0050211 procollagen galactosyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core molecular function inferred by automated mapping from the RHEA reaction and EC number (EC 2.4.1.50). Concordant with the direct biochemical characterization of COLGALT2. Reason: The EC 2.4.1.50 / RHEA:12637 mapping accurately reflects the experimentally demonstrated galactosyltransferase activity of COLGALT2 on collagen hydroxylysine. Supporting Evidence: file:human/COLGALT2/COLGALT2-uniprot.txt EC=2.4.1.50 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' from a high-throughput interactome screen. This term is uninformative and does not identify a specific, functionally meaningful partner relevant to COLGALT2's galactosyltransferase function. Reason: GO:0005515 protein binding conveys no specific functional information. The interaction (with UBQLN1) derives from a proteome-scale binary interactome map and has no validated functional relationship to collagen galactosylation. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' from a high-throughput affinity-purification interactome study. Uninformative about COLGALT2's actual function. Reason: GO:0005515 protein binding is non-informative and the interactors (e.g. SEMG1, C1QTNF3) come from a large-scale interactome screen with no demonstrated functional role in collagen glycosylation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' from the HuRI reference binary interactome map. Does not specify an informative function. Reason: GO:0005515 protein binding is uninformative; the reported interactors (HPCAL1, UBQLN2) are from a systematic interactome screen and are not validated functional partners relevant to COLGALT2's enzymatic role. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' from a proteome-scale interactome remodeling study. Uninformative regarding COLGALT2 function. Reason: GO:0005515 protein binding adds no specific functional information; the underlying interactions are high-throughput and lack a demonstrated link to collagen galactosylation. |
| GO:0030199 collagen fibril organization | TAS Reactome:R-HSA-1650814 | KEEP AS NON CORE | Summary: Pathway-level biological process annotation placing COLGALT2 within collagen biosynthesis and modification. COLGALT2 contributes to collagen post-translational modification, but its direct, evolved role is the galactosylation reaction rather than fibril organization per se, which is a downstream consequence of properly modified collagen. Reason: COLGALT2 acts upstream of fibril assembly by glycosylating collagen hydroxylysines; its effect on collagen fibril organization is indirect/downstream. Retain as a non-core contextual annotation rather than a core function. Supporting Evidence: file:human/COLGALT2/COLGALT2-uniprot.txt Beta-galactosyltransferase that transfers beta-galactose to hydroxylysine residues of collagen. |
| GO:0050211 procollagen galactosyltransferase activity | TAS Reactome:R-HSA-1981120 | ACCEPT | Summary: Core molecular function captured from Reactome (galactosylation of collagen propeptide hydroxylysines). Concordant with the direct biochemical evidence. Reason: This TAS annotation correctly reflects COLGALT2's experimentally established galactosyltransferase activity on collagen hydroxylysine residues. Supporting Evidence: file:human/COLGALT2/COLGALT2-uniprot.txt Beta-galactosyltransferase that transfers beta-galactose to hydroxylysine residues of collagen. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-1981120 | ACCEPT | Summary: ER lumen localization from Reactome, consistent with the UniProt subcellular location and the C-terminal ER-retention signal. Reason: Correct localization of COLGALT2 to the ER lumen, its site of action on collagen during biosynthesis. Supporting Evidence: file:human/COLGALT2/COLGALT2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8948228 | ACCEPT | Summary: ER lumen localization from a Reactome reaction (COLGALT1,COLGALT2 bind lysyl hydroxylated collagen propeptides). Redundant with the other ER lumen annotations but correct. Reason: Consistent with the established ER-luminal localization of COLGALT2; redundant with other ER lumen annotations but accurate. Supporting Evidence: file:human/COLGALT2/COLGALT2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8948231 | ACCEPT | Summary: ER lumen localization from a Reactome reaction (dissociation of COLGALT enzymes from galactosyl-hydroxylysyl collagen propeptides). Redundant but correct. Reason: Consistent with the established ER-luminal localization of COLGALT2; redundant with other ER lumen annotations but accurate. Supporting Evidence: file:human/COLGALT2/COLGALT2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0180062 protein O-linked glycosylation via galactose | IBA GO_REF:0000033 | NEW | Summary: Core biological process. COLGALT2 galactosylates collagen hydroxylysine residues (Gal-O-Hyl), which is the protein O-linked glycosylation via galactose step of collagen O-glycosylation. This BP is more directly representative of COLGALT2's evolved function than collagen fibril organization, and is the curated IMP-supported process for its paralog COLGALT1. Reason: This term precisely captures the biological process effected by COLGALT2's galactosyltransferase activity. It is proposed as a NEW annotation because the existing BP block only contains the more downstream collagen fibril organization term. Supporting Evidence: file:human/COLGALT2/COLGALT2-uniprot.txt Beta-galactosyltransferase that transfers beta-galactose to hydroxylysine residues of collagen. |
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Download this section (compressed HTML)Q: Why does COLGALT2 have a more restricted (brain/skeletal-muscle-enriched) tissue distribution than the ubiquitously expressed COLGALT1, and which collagen types are its preferred substrates in those tissues?
Q: Does COLGALT2 have non-redundant, tissue-specific functions in collagen glycosylation that cannot be compensated by COLGALT1, and is there an associated human phenotype?
Experiment: In vitro galactosyltransferase assays with purified recombinant COLGALT2 against a panel of hydroxylysine-containing collagen substrates, varying Mn2+ and UDP-galactose, to define substrate preference and metal dependence relative to COLGALT1.
Hypothesis: COLGALT2 galactosylates collagen hydroxylysine with Mn2+ dependence and has substrate preferences distinct from COLGALT1.
Type: enzymology/biochemistry
Experiment: CRISPR knockout of COLGALT2 (alone and combined with COLGALT1) in brain- and muscle-derived cell models, followed by mass-spectrometric quantification of Gal-O-Hyl and Glc-Gal-O-Hyl on collagens to assess its non-redundant contribution.
Hypothesis: Loss of COLGALT2 reduces collagen hydroxylysine galactosylation in a tissue-restricted manner not fully rescued by COLGALT1.
Type: genetic manipulation/glycoproteomics
Experiment: Tissue-resolved expression and localization profiling (RNA-seq plus immunohistochemistry/fractionation) to map where COLGALT2 versus COLGALT1 act and confirm ER-luminal residence in vivo.
Hypothesis: COLGALT2 is the predominant collagen galactosyltransferase in specific tissues such as brain and skeletal muscle.
Type: expression profiling/cell biology
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