id: Q8IYK4
gene_symbol: COLGALT2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
references:
- 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:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:19075007
  title: Core glycosylation of collagen is initiated by two beta(1-O)galactosyltransferases.
  findings:
  - statement: COLGALT2 (GLT25D2) is a beta(1-O)galactosyltransferase that transfers
      galactose to hydroxylysine residues of collagen, initiating the core glycosylation
      of collagen; it has no glucosyltransferase activity and is expressed in brain
      and skeletal muscle.
    reference_section_type: ABSTRACT
- id: Reactome:R-HSA-1650814
  title: Collagen biosynthesis and modifying enzymes
  findings: []
- id: Reactome:R-HSA-1981120
  title: Galactosylation of collagen propeptide hydroxylysines by procollagen galactosyltransferases
    1, 2
  findings: []
- id: Reactome:R-HSA-8948228
  title: COLGALT1,COLGALT2 bind Lysyl hydroxylated collagen propeptides
  findings: []
- id: Reactome:R-HSA-8948231
  title: COLGALT1,COLGALT2:Galactosyl-hydroxylysyl collagen propeptides dissociates
  findings: []
existing_annotations:
- term:
    id: GO:0050211
    label: procollagen galactosyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/COLGALT2/COLGALT2-uniprot.txt
      supporting_text: Beta-galactosyltransferase that transfers beta-galactose to
        hydroxylysine residues of collagen.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/COLGALT2/COLGALT2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum lumen"
- term:
    id: GO:0050211
    label: procollagen galactosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: The EC 2.4.1.50 / RHEA:12637 mapping accurately reflects the experimentally
      demonstrated galactosyltransferase activity of COLGALT2 on collagen hydroxylysine.
    supported_by:
    - reference_id: file:human/COLGALT2/COLGALT2-uniprot.txt
      supporting_text: EC=2.4.1.50
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Bare 'protein binding' from a high-throughput affinity-purification interactome
      study. Uninformative about COLGALT2's actual function.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Bare 'protein binding' from the HuRI reference binary interactome map. Does
      not specify an informative function.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Bare 'protein binding' from a proteome-scale interactome remodeling study.
      Uninformative regarding COLGALT2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 protein binding adds no specific functional information; the underlying
      interactions are high-throughput and lack a demonstrated link to collagen galactosylation.
- term:
    id: GO:0030199
    label: collagen fibril organization
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1650814
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/COLGALT2/COLGALT2-uniprot.txt
      supporting_text: Beta-galactosyltransferase that transfers beta-galactose to
        hydroxylysine residues of collagen.
- term:
    id: GO:0050211
    label: procollagen galactosyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1981120
  qualifier: enables
  review:
    summary: Core molecular function captured from Reactome (galactosylation of collagen
      propeptide hydroxylysines). Concordant with the direct biochemical evidence.
    action: ACCEPT
    reason: This TAS annotation correctly reflects COLGALT2's experimentally established
      galactosyltransferase activity on collagen hydroxylysine residues.
    supported_by:
    - reference_id: file:human/COLGALT2/COLGALT2-uniprot.txt
      supporting_text: Beta-galactosyltransferase that transfers beta-galactose to
        hydroxylysine residues of collagen.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1981120
  qualifier: located_in
  review:
    summary: ER lumen localization from Reactome, consistent with the UniProt subcellular
      location and the C-terminal ER-retention signal.
    action: ACCEPT
    reason: Correct localization of COLGALT2 to the ER lumen, its site of action on collagen
      during biosynthesis.
    supported_by:
    - reference_id: file:human/COLGALT2/COLGALT2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum lumen"
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8948228
  qualifier: located_in
  review:
    summary: ER lumen localization from a Reactome reaction (COLGALT1,COLGALT2 bind lysyl
      hydroxylated collagen propeptides). Redundant with the other ER lumen annotations
      but correct.
    action: ACCEPT
    reason: Consistent with the established ER-luminal localization of COLGALT2; redundant
      with other ER lumen annotations but accurate.
    supported_by:
    - reference_id: file:human/COLGALT2/COLGALT2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum lumen"
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8948231
  qualifier: located_in
  review:
    summary: ER lumen localization from a Reactome reaction (dissociation of COLGALT
      enzymes from galactosyl-hydroxylysyl collagen propeptides). Redundant but correct.
    action: ACCEPT
    reason: Consistent with the established ER-luminal localization of COLGALT2; redundant
      with other ER lumen annotations but accurate.
    supported_by:
    - reference_id: file:human/COLGALT2/COLGALT2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum lumen"
- term:
    id: GO:0180062
    label: protein O-linked glycosylation via galactose
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: NEW
    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.
    supported_by:
    - reference_id: file:human/COLGALT2/COLGALT2-uniprot.txt
      supporting_text: Beta-galactosyltransferase that transfers beta-galactose to
        hydroxylysine residues of collagen.
core_functions:
- description: Manganese-dependent transfer of beta-galactose from UDP-galactose to
    collagen hydroxylysine residues in the ER lumen, forming galactosyl-O-hydroxylysine,
    the first committed step of collagen O-glycosylation.
  molecular_function:
    id: GO:0050211
    label: procollagen galactosyltransferase activity
  directly_involved_in:
  - id: GO:0180062
    label: protein O-linked glycosylation via galactose
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: file:human/COLGALT2/COLGALT2-uniprot.txt
    supporting_text: Beta-galactosyltransferase that transfers beta-galactose to
      hydroxylysine residues of collagen.
  - reference_id: file:human/COLGALT2/COLGALT2-uniprot.txt
    supporting_text: EC=2.4.1.50
  - reference_id: file:human/COLGALT2/COLGALT2-uniprot.txt
    supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum lumen"
proposed_new_terms: []
suggested_questions:
- question: 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?
- question: Does COLGALT2 have non-redundant, tissue-specific functions in collagen
    glycosylation that cannot be compensated by COLGALT1, and is there an associated
    human phenotype?
suggested_experiments:
- description: 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.
  experiment_type: enzymology/biochemistry
  hypothesis: COLGALT2 galactosylates collagen hydroxylysine with Mn2+ dependence and
    has substrate preferences distinct from COLGALT1.
- description: 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.
  experiment_type: genetic manipulation/glycoproteomics
  hypothesis: Loss of COLGALT2 reduces collagen hydroxylysine galactosylation in a tissue-restricted
    manner not fully rescued by COLGALT1.
- description: 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.
  experiment_type: expression profiling/cell biology
  hypothesis: COLGALT2 is the predominant collagen galactosyltransferase in specific tissues
    such as brain and skeletal muscle.