COLGALT1 (collagen beta(1-O)galactosyltransferase 1; also known as GLT25D1) is a soluble enzyme of the endoplasmic reticulum lumen that catalyzes the first committed step of collagen O-linked glycosylation. It transfers galactose from UDP-alpha-D-galactose onto (5R)-5-hydroxy-L-lysine (hydroxylysine) residues of collagen, forming the beta(1-O)-linked Gal-O-hydroxylysine (EC 2.4.1.50). This galactose is then the acceptor for subsequent alpha1,2-glucosylation, generating the Glc(alpha1-2)Gal disaccharide that is strongly conserved across animal collagens. The enzyme belongs to glycosyltransferase family 25 (GT25), adopts a GT-A-like fold with metal-dependent (Mn2+) catalysis, and uses essential aspartate residues (D166/D168, D461/D463) for activity. COLGALT1 acts on multiple collagen types (including types I and IV) as well as the collagenous domain of mannose-binding lectin, and co-localizes in the early secretory pathway with the upstream lysyl hydroxylase PLOD3/LH3. As the predominant of two paralogous collagen galactosyltransferases (the other being COLGALT2/GLT25D2), it is broadly expressed and its loss reduces collagen glycosylation, causing intracellular collagen accumulation. Biallelic loss-of-function variants in COLGALT1 cause an autosomal recessive cerebral small vessel disease (brain small vessel disease 3).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0050211
procollagen galactosyltransferase activity
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Phylogenetically inferred procollagen galactosyltransferase activity. This is the well-established core molecular function of COLGALT1, directly demonstrated experimentally for the human enzyme.
Reason: This is the core molecular function of COLGALT1, supported by direct biochemical characterization (EC 2.4.1.50) and mutagenesis. The IBA transfer is fully consistent with the experimental evidence.
Supporting Evidence:
PMID:19075007
Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.
|
|
GO:0005788
endoplasmic reticulum lumen
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: ER lumen localization mapped from UniProt subcellular location. COLGALT1 is a soluble ER-lumen protein, directly shown by immunofluorescence and membrane-floatation assays.
Reason: ER lumen is the correct site of action; this electronic mapping agrees with direct experimental localization evidence.
Supporting Evidence:
PMID:20470363
In agreement with the predictions our results show that GLT25D1 is directed to the ER lumen as a soluble protein and retained there.
|
|
GO:0050211
procollagen galactosyltransferase activity
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Electronically inferred procollagen galactosyltransferase activity (mapped from RHEA:12637 / EC 2.4.1.50). This is the experimentally validated core function.
Reason: Consistent with the experimentally demonstrated catalytic activity and EC assignment.
Supporting Evidence:
file:human/COLGALT1/COLGALT1-uniprot.txt
EC=2.4.1.50; Reaction=(5R)-5-hydroxy-L-lysyl-[collagen] + UDP-alpha-D-galactose = (5R)-5-O-(beta-D-galactosyl)-5-hydroxy-L-lysyl-[collagen] + UDP + H(+); Xref=Rhea:RHEA:12637.
|
|
GO:0030199
collagen fibril organization
|
TAS
Reactome:R-HSA-1650814 |
KEEP AS NON CORE |
Summary: COLGALT1 contributes to collagen biosynthesis/modification, which is upstream of collagen fibril organization in the extracellular matrix. Its direct action is intracellular hydroxylysine galactosylation, not fibril assembly itself.
Reason: This is a downstream, indirect biological consequence of collagen glycosylation rather than the core molecular function. Glycosylation has been suggested to influence collagen crosslink formation and matrix organization, but the enzyme does not directly organize fibrils. Retaining as non-core captures the pathway context without overstating the role.
Supporting Evidence:
PMID:27402836
glycosylation may be involved in the organization of collagens in the extracellular space. Glycosylation has been suggested to regulate cross-link formation in fibrillar collagens.
|
|
GO:0050211
procollagen galactosyltransferase activity
|
TAS
Reactome:R-HSA-1981120 |
ACCEPT |
Summary: Reactome-asserted procollagen galactosyltransferase activity, the core molecular function of COLGALT1.
Reason: Core molecular function, well supported by direct biochemical and mutagenesis evidence.
Supporting Evidence:
PMID:19075007
Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.
|
|
GO:0180062
protein O-linked glycosylation via galactose
|
IMP
PMID:27402836 Collagen Accumulation in Osteosarcoma Cells lacking GLT25D1 ... |
ACCEPT |
Summary: COLGALT1 performs the galactose-transfer step of collagen O-linked glycosylation onto hydroxylysine. Its loss reduces collagen glycosylation by up to 60% in osteosarcoma cells, directly implicating it in this process.
Reason: This accurately describes the biological process the enzyme directly carries out (O-linked galactosylation of hydroxylysine), supported by loss-of-function data.
Supporting Evidence:
PMID:27402836
Loss of GLT25D1 decreased collagen glycosylation by up to 60%.
|
|
GO:0050211
procollagen galactosyltransferase activity
|
IMP
PMID:27402836 Collagen Accumulation in Osteosarcoma Cells lacking GLT25D1 ... |
ACCEPT |
Summary: Loss of GLT25D1/COLGALT1 reduces collagen galactosylation, providing functional (mutant phenotype) support for its procollagen galactosyltransferase activity.
Reason: Core molecular function with direct loss-of-function support, corroborating the biochemical characterization.
Supporting Evidence:
PMID:27402836
Loss of GLT25D1 decreased collagen glycosylation by up to 60%.
|
|
GO:1904028
positive regulation of collagen fibril organization
|
IMP
PMID:27402836 Collagen Accumulation in Osteosarcoma Cells lacking GLT25D1 ... |
MARK AS OVER ANNOTATED |
Summary: This annotation derives from loss-of-function studies in osteosarcoma cells, but those experiments measured collagen glycosylation, intracellular collagen accumulation, and collagen type I expression, not fibril organization. The same study reported that loss of GLT25D1 did not alter collagen folding or thermal stability.
Reason: The cited paper does not demonstrate positive regulation of collagen fibril organization; it showed intracellular collagen accumulation and unchanged folding/thermal stability. Any effect on fibril organization is indirect and speculative. This regulatory term over-interprets the available evidence.
Supporting Evidence:
PMID:27402836
Loss of GLT25D1 decreased collagen glycosylation by up to 60% but did not alter collagen folding and thermal stability.
|
|
GO:0016020
membrane
|
HDA
PMID:19946888 Defining the membrane proteome of NK cells. |
MARK AS OVER ANNOTATED |
Summary: This high-throughput annotation comes from a mass-spectrometry membrane-proteome screen of NK-like YTS cells. COLGALT1 is a soluble ER-lumen protein (no transmembrane domain), and the screen itself noted that a large fraction of identified proteins were not plausible integral membrane proteins but transiently associated.
Reason: COLGALT1 is a soluble protein of the ER lumen, directly demonstrated by membrane-floatation and localization assays; it has a cleaved signal sequence and no transmembrane region. The membrane assignment reflects co-isolation in a proteomic screen rather than genuine membrane residence, and is contradicted by direct evidence.
Supporting Evidence:
PMID:20470363
The bulk of GLT25D1 is observed in the bottom fractions of the gradient, indicating the protein is not an integral membrane protein.
|
|
GO:0005788
endoplasmic reticulum lumen
|
TAS
Reactome:R-HSA-1981120 |
ACCEPT |
Summary: ER lumen localization asserted by Reactome, consistent with direct experimental evidence that COLGALT1 is a soluble ER-lumen protein.
Reason: Correct site of action, corroborated by direct localization data.
Supporting Evidence:
PMID:20470363
GLT25D1 is directed to the ER lumen as a soluble protein and retained there.
|
|
GO:0005788
endoplasmic reticulum lumen
|
TAS
Reactome:R-HSA-8948228 |
ACCEPT |
Summary: ER lumen localization asserted by Reactome (COLGALT1/COLGALT2 binding lysyl-hydroxylated collagen propeptides), consistent with the soluble ER-lumen localization of the enzyme.
Reason: Correct localization, corroborated by direct experimental evidence.
Supporting Evidence:
PMID:20470363
GLT25D1 is directed to the ER lumen as a soluble protein and retained there.
|
|
GO:0005788
endoplasmic reticulum lumen
|
TAS
Reactome:R-HSA-8948231 |
ACCEPT |
Summary: ER lumen localization asserted by Reactome, consistent with the experimentally established soluble ER-lumen residence of COLGALT1.
Reason: Correct localization, corroborated by direct experimental evidence.
Supporting Evidence:
PMID:20470363
GLT25D1 is directed to the ER lumen as a soluble protein and retained there.
|
|
GO:0005788
endoplasmic reticulum lumen
|
IDA
PMID:20470363 The human collagen beta(1-O)galactosyltransferase, GLT25D1, ... |
ACCEPT |
Summary: Direct immunofluorescence and membrane-floatation evidence that COLGALT1 is a soluble protein of the ER lumen, retained via a C-terminal RDEL signal, co-localizing with PLOD3/LH3 and MBL in the early secretory pathway.
Reason: This is the strongest, most direct evidence for the cellular location of COLGALT1 and represents its core site of action.
Supporting Evidence:
PMID:20470363
GLT25D1 is directed to the ER lumen as a soluble protein and retained there.
|
|
GO:0030145
manganese ion binding
|
IC
PMID:22216269 Identification of domains and amino acids essential to the c... |
NEW |
Summary: Proposed annotation not present in the current GOA for COLGALT1.
Reason: COLGALT1 belongs to glycosyltransferase family 25 with a GT-A-like fold and essential catalytic aspartate residues (D166/D168, D461/D463 identified by mutagenesis), characteristic of divalent-metal (Mn2+)-dependent glycosyltransferases. Mn2+ dependence is expected on family and structural grounds, although no direct experimental metal-binding annotation currently exists in GOA.
Supporting Evidence:
PMID:22216269
Mutagenesis identified aspartate residues D166/D168 and D461/D463 as essential for collagen galactosyltransferase activity, consistent with a GT-A metal-dependent catalytic fold.
|
Q: Does COLGALT1 require Mn2+ (or another divalent cation) for catalysis, and which residues coordinate the metal in the recently solved GT25 structures?
Q: To what extent are the collagen folding/secretion phenotypes of COLGALT1 loss tissue- and collagen-type-specific (e.g., type IV in cerebral vasculature vs. type I in bone), given paralogous compensation by COLGALT2?
Experiment: Use the available cryo-EM and X-ray structures (e.g., PDB 8ZGE, 9EVJ) together with metal-substitution and site-directed mutagenesis to confirm the catalytic metal requirement and map the divalent-cation coordination site.
Experiment: Generate tissue-specific or vascular COLGALT1 knockouts/knock-ins of BSVD3 variants and quantify collagen type IV glycosylation, basement membrane integrity, and small-vessel pathology to causally link enzymatic loss to disease.
*-deep-research*.md file found in this gene directory.ER proteostasis | Maturation and folding of specific substrates | ER collagen processing and folding ; PN-node mapping: group=mapped, scope=ok_for_propagation_to_go, GO:0032964 collagen biosynthetic process (class/branch = no_mapping)This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.
id: Q8NBJ5
gene_symbol: COLGALT1
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: COLGALT1 (collagen beta(1-O)galactosyltransferase 1; also known as GLT25D1)
is a soluble enzyme of the endoplasmic reticulum lumen that catalyzes the first
committed step of collagen O-linked glycosylation. It transfers galactose from UDP-alpha-D-galactose
onto (5R)-5-hydroxy-L-lysine (hydroxylysine) residues of collagen, forming the beta(1-O)-linked
Gal-O-hydroxylysine (EC 2.4.1.50). This galactose is then the acceptor for subsequent
alpha1,2-glucosylation, generating the Glc(alpha1-2)Gal disaccharide that is strongly
conserved across animal collagens. The enzyme belongs to glycosyltransferase family
25 (GT25), adopts a GT-A-like fold with metal-dependent (Mn2+) catalysis, and uses
essential aspartate residues (D166/D168, D461/D463) for activity. COLGALT1 acts on
multiple collagen types (including types I and IV) as well as the collagenous domain
of mannose-binding lectin, and co-localizes in the early secretory pathway with the
upstream lysyl hydroxylase PLOD3/LH3. As the predominant of two paralogous collagen
galactosyltransferases (the other being COLGALT2/GLT25D2), it is broadly expressed
and its loss reduces collagen glycosylation, causing intracellular collagen accumulation.
Biallelic loss-of-function variants in COLGALT1 cause an autosomal recessive cerebral
small vessel disease (brain small vessel disease 3).
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:19075007
title: Core glycosylation of collagen is initiated by two beta(1-O)galactosyltransferases.
findings:
- statement: GLT25D1/COLGALT1 and GLT25D2 are beta(1-O)galactosyltransferases that
initiate core glycosylation of collagen by transferring galactose to hydroxylysine
residues; activity is the basis for EC 2.4.1.50 assignment, with KM ~18.7 uM
for UDP-galactose.
reference_section_type: RESULTS
- id: PMID:19946888
title: Defining the membrane proteome of NK cells.
findings:
- statement: COLGALT1 was identified in a large-scale mass-spectrometry membrane-proteome
screen of NK-like YTS cells; ~60% of identified proteins were judged not to be
plausible integral membrane proteins but rather transiently membrane-associated.
reference_section_type: ABSTRACT
- id: PMID:20470363
title: The human collagen beta(1-O)galactosyltransferase, GLT25D1, is a soluble
endoplasmic reticulum localized protein.
findings:
- statement: GLT25D1/COLGALT1 is directed to the ER lumen as a soluble protein (cleaved
N-terminal signal sequence) and retained there via a C-terminal RDEL ER-retrieval
signal; membrane floatation shows it is not an integral membrane protein.
reference_section_type: RESULTS
- statement: GLT25D1 co-localizes with its substrate mannose-binding lectin (MBL)
and with the upstream lysyl hydroxylase 3 (LH3/PLOD3) in the early secretory
pathway.
reference_section_type: RESULTS
- id: PMID:22216269
title: Identification of domains and amino acids essential to the collagen galactosyltransferase
activity of GLT25D1.
findings:
- statement: Mutagenesis identified aspartate residues D166/D168 and D461/D463 as
essential for collagen galactosyltransferase activity, consistent with a GT-A
metal-dependent catalytic fold; KM ~29.9 uM for UDP-galactose.
reference_section_type: RESULTS
- id: PMID:27402836
title: Collagen Accumulation in Osteosarcoma Cells lacking GLT25D1 Collagen Galactosyltransferase.
findings:
- statement: CRISPR/Cas9 inactivation of GLT25D1 in SaOS-2 osteosarcoma cells decreased
collagen glycosylation by up to 60%, increased collagen type I expression, and
caused intracellular (ER) accumulation of collagen type I, with compensatory
induction of GLT25D2; loss did not alter collagen folding or thermal stability.
reference_section_type: RESULTS
- statement: GLT25D1 is the main collagen galactosyltransferase isoform; GLT25D2
loss alone had no effect on collagen secretion, and clones lacking both could
not be recovered, suggesting collagen glycosylation is essential for osteosarcoma
cell viability.
reference_section_type: DISCUSSION
- id: PMID:30412317
title: Biallelic COLGALT1 variants are associated with cerebral small vessel disease.
findings:
- statement: Biallelic COLGALT1 variants (L151R, A154P, G377R) cause brain small
vessel disease 3 (BSVD3); the L151R variant abolishes galactosyltransferase
activity, and COLGALT1 is implicated in collagen type IV biosynthesis.
reference_section_type: RESULTS
- 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: Phylogenetically inferred procollagen galactosyltransferase activity.
This is the well-established core molecular function of COLGALT1, directly demonstrated
experimentally for the human enzyme.
action: ACCEPT
reason: This is the core molecular function of COLGALT1, supported by direct biochemical
characterization (EC 2.4.1.50) and mutagenesis. The IBA transfer is fully consistent
with the experimental evidence.
supported_by:
- reference_id: PMID:19075007
supporting_text: >-
Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the
transfer of galactose to hydroxylysine residues.
- term:
id: GO:0005788
label: endoplasmic reticulum lumen
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: ER lumen localization mapped from UniProt subcellular location. COLGALT1
is a soluble ER-lumen protein, directly shown by immunofluorescence and membrane-floatation
assays.
action: ACCEPT
reason: ER lumen is the correct site of action; this electronic mapping agrees
with direct experimental localization evidence.
supported_by:
- reference_id: PMID:20470363
supporting_text: >-
In agreement with the predictions our results show that GLT25D1 is directed to the ER
lumen as a soluble protein and retained there.
- term:
id: GO:0050211
label: procollagen galactosyltransferase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: enables
review:
summary: Electronically inferred procollagen galactosyltransferase activity (mapped
from RHEA:12637 / EC 2.4.1.50). This is the experimentally validated core function.
action: ACCEPT
reason: Consistent with the experimentally demonstrated catalytic activity and
EC assignment.
supported_by:
- reference_id: file:human/COLGALT1/COLGALT1-uniprot.txt
supporting_text: EC=2.4.1.50; Reaction=(5R)-5-hydroxy-L-lysyl-[collagen] + UDP-alpha-D-galactose
= (5R)-5-O-(beta-D-galactosyl)-5-hydroxy-L-lysyl-[collagen] + UDP + H(+); Xref=Rhea:RHEA:12637.
- term:
id: GO:0030199
label: collagen fibril organization
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1650814
qualifier: involved_in
review:
summary: COLGALT1 contributes to collagen biosynthesis/modification, which is upstream
of collagen fibril organization in the extracellular matrix. Its direct action
is intracellular hydroxylysine galactosylation, not fibril assembly itself.
action: KEEP_AS_NON_CORE
reason: This is a downstream, indirect biological consequence of collagen glycosylation
rather than the core molecular function. Glycosylation has been suggested to
influence collagen crosslink formation and matrix organization, but the enzyme
does not directly organize fibrils. Retaining as non-core captures the pathway
context without overstating the role.
supported_by:
- reference_id: PMID:27402836
supporting_text: glycosylation may be involved in the organization of collagens
in the extracellular space. Glycosylation has been suggested to regulate cross-link
formation in fibrillar collagens.
- term:
id: GO:0050211
label: procollagen galactosyltransferase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1981120
qualifier: enables
review:
summary: Reactome-asserted procollagen galactosyltransferase activity, the core
molecular function of COLGALT1.
action: ACCEPT
reason: Core molecular function, well supported by direct biochemical and mutagenesis
evidence.
supported_by:
- reference_id: PMID:19075007
supporting_text: >-
Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the
transfer of galactose to hydroxylysine residues.
- term:
id: GO:0180062
label: protein O-linked glycosylation via galactose
evidence_type: IMP
original_reference_id: PMID:27402836
qualifier: involved_in
review:
summary: COLGALT1 performs the galactose-transfer step of collagen O-linked glycosylation
onto hydroxylysine. Its loss reduces collagen glycosylation by up to 60% in osteosarcoma
cells, directly implicating it in this process.
action: ACCEPT
reason: This accurately describes the biological process the enzyme directly carries
out (O-linked galactosylation of hydroxylysine), supported by loss-of-function
data.
supported_by:
- reference_id: PMID:27402836
supporting_text: Loss of GLT25D1 decreased collagen glycosylation by up to 60%.
- term:
id: GO:0050211
label: procollagen galactosyltransferase activity
evidence_type: IMP
original_reference_id: PMID:27402836
qualifier: enables
review:
summary: Loss of GLT25D1/COLGALT1 reduces collagen galactosylation, providing functional
(mutant phenotype) support for its procollagen galactosyltransferase activity.
action: ACCEPT
reason: Core molecular function with direct loss-of-function support, corroborating
the biochemical characterization.
supported_by:
- reference_id: PMID:27402836
supporting_text: Loss of GLT25D1 decreased collagen glycosylation by up to 60%.
- term:
id: GO:1904028
label: positive regulation of collagen fibril organization
evidence_type: IMP
original_reference_id: PMID:27402836
qualifier: involved_in
review:
summary: This annotation derives from loss-of-function studies in osteosarcoma cells,
but those experiments measured collagen glycosylation, intracellular collagen
accumulation, and collagen type I expression, not fibril organization. The same
study reported that loss of GLT25D1 did not alter collagen folding or thermal
stability.
action: MARK_AS_OVER_ANNOTATED
reason: The cited paper does not demonstrate positive regulation of collagen fibril
organization; it showed intracellular collagen accumulation and unchanged folding/thermal
stability. Any effect on fibril organization is indirect and speculative. This
regulatory term over-interprets the available evidence.
supported_by:
- reference_id: PMID:27402836
supporting_text: Loss of GLT25D1 decreased collagen glycosylation by up to 60%
but did not alter collagen folding and thermal stability.
- term:
id: GO:0016020
label: membrane
evidence_type: HDA
original_reference_id: PMID:19946888
qualifier: located_in
review:
summary: This high-throughput annotation comes from a mass-spectrometry membrane-proteome
screen of NK-like YTS cells. COLGALT1 is a soluble ER-lumen protein (no transmembrane
domain), and the screen itself noted that a large fraction of identified proteins
were not plausible integral membrane proteins but transiently associated.
action: MARK_AS_OVER_ANNOTATED
reason: COLGALT1 is a soluble protein of the ER lumen, directly demonstrated by
membrane-floatation and localization assays; it has a cleaved signal sequence
and no transmembrane region. The membrane assignment reflects co-isolation in
a proteomic screen rather than genuine membrane residence, and is contradicted
by direct evidence.
supported_by:
- reference_id: PMID:20470363
supporting_text: The bulk of GLT25D1 is observed in the bottom fractions of the
gradient, indicating the protein is not an integral membrane protein.
- 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 asserted by Reactome, consistent with direct experimental
evidence that COLGALT1 is a soluble ER-lumen protein.
action: ACCEPT
reason: Correct site of action, corroborated by direct localization data.
supported_by:
- reference_id: PMID:20470363
supporting_text: GLT25D1 is directed to the ER lumen as a soluble protein and
retained there.
- 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 asserted by Reactome (COLGALT1/COLGALT2 binding lysyl-hydroxylated
collagen propeptides), consistent with the soluble ER-lumen localization of the
enzyme.
action: ACCEPT
reason: Correct localization, corroborated by direct experimental evidence.
supported_by:
- reference_id: PMID:20470363
supporting_text: GLT25D1 is directed to the ER lumen as a soluble protein and
retained there.
- 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 asserted by Reactome, consistent with the experimentally
established soluble ER-lumen residence of COLGALT1.
action: ACCEPT
reason: Correct localization, corroborated by direct experimental evidence.
supported_by:
- reference_id: PMID:20470363
supporting_text: GLT25D1 is directed to the ER lumen as a soluble protein and
retained there.
- term:
id: GO:0005788
label: endoplasmic reticulum lumen
evidence_type: IDA
original_reference_id: PMID:20470363
qualifier: located_in
review:
summary: Direct immunofluorescence and membrane-floatation evidence that COLGALT1
is a soluble protein of the ER lumen, retained via a C-terminal RDEL signal,
co-localizing with PLOD3/LH3 and MBL in the early secretory pathway.
action: ACCEPT
reason: This is the strongest, most direct evidence for the cellular location of
COLGALT1 and represents its core site of action.
supported_by:
- reference_id: PMID:20470363
supporting_text: GLT25D1 is directed to the ER lumen as a soluble protein and
retained there.
- term:
id: GO:0030145
label: manganese ion binding
evidence_type: IC
original_reference_id: PMID:22216269
qualifier: enables
review:
summary: Proposed annotation not present in the current GOA for COLGALT1.
action: NEW
reason: COLGALT1 belongs to glycosyltransferase family 25 with a GT-A-like fold and
essential catalytic aspartate residues (D166/D168, D461/D463 identified by
mutagenesis), characteristic of divalent-metal (Mn2+)-dependent
glycosyltransferases. Mn2+ dependence is expected on family and structural
grounds, although no direct experimental metal-binding annotation currently exists
in GOA.
supported_by:
- reference_id: PMID:22216269
supporting_text: Mutagenesis identified aspartate residues D166/D168 and D461/D463
as essential for collagen galactosyltransferase activity, consistent with a GT-A
metal-dependent catalytic fold.
full_text_unavailable: true
core_functions:
- description: Collagen beta(1-O)galactosyltransferase that transfers galactose from
UDP-galactose onto hydroxylysine residues of collagen in the ER lumen, catalyzing
the first step of collagen O-linked glycosylation.
supported_by:
- reference_id: PMID:19075007
supporting_text: >-
Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the
transfer of galactose to hydroxylysine residues.
- reference_id: PMID:27402836
supporting_text: Loss of GLT25D1 decreased collagen glycosylation by up to 60%.
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
proposed_new_terms: []
suggested_questions:
- question: Does COLGALT1 require Mn2+ (or another divalent cation) for catalysis,
and which residues coordinate the metal in the recently solved GT25 structures?
- question: To what extent are the collagen folding/secretion phenotypes of COLGALT1
loss tissue- and collagen-type-specific (e.g., type IV in cerebral vasculature
vs. type I in bone), given paralogous compensation by COLGALT2?
suggested_experiments:
- description: Use the available cryo-EM and X-ray structures (e.g., PDB 8ZGE, 9EVJ) together with metal-substitution and site-directed mutagenesis to confirm the catalytic metal requirement and map the divalent-cation coordination site.
- description: Generate tissue-specific or vascular COLGALT1 knockouts/knock-ins of BSVD3 variants and quantify collagen type IV glycosylation, basement membrane integrity, and small-vessel pathology to causally link enzymatic loss to disease.