CRTAP (cartilage-associated protein) is an endoplasmic reticulum (ER) lumen glycoprotein that is an essential, non-catalytic subunit of the collagen prolyl 3-hydroxylation complex, together with prolyl 3-hydroxylase 1 (P3H1/LEPRE1) and cyclophilin B (PPIB/CyPB). Within this ternary complex, P3H1 provides the catalytic prolyl 3-hydroxylase activity and PPIB the peptidyl-prolyl cis-trans isomerase activity, while CRTAP acts as a scaffolding/helper subunit required for complex assembly and stability. The complex 3-hydroxylates a single specific proline residue (Pro986) of the alpha1(I) and alpha1(II) fibrillar procollagen chains in the ER and also functions as a collagen-specific molecular chaperone/foldase that controls the rate of collagen triple-helix folding; delayed folding in its absence leads to overmodification of the collagen helix. CRTAP and P3H1 are mutually stabilizing: loss of either protein destabilizes the other. A minor fraction of CRTAP is secreted into the extracellular space/matrix. Biallelic loss-of-function variants cause autosomal recessive osteogenesis imperfecta type VII, underscoring an essential role in collagen biosynthesis and skeletal development.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005518
collagen binding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: The collagen prolyl 3-hydroxylation complex binds fibrillar (pro)collagen as substrate, and cryo-EM shows CRTAP contributes to a multi-site collagen substrate-interacting zone within the P3H1/CRTAP/PPIB complex. The contributes_to qualifier is appropriate because substrate binding is a property of the assembled complex rather than CRTAP alone.
Reason: Supported by structural evidence that CRTAP forms part of the collagen substrate-interacting surface of the complex; contributes_to qualifier is biologically accurate for an accessory subunit.
Supporting Evidence:
PMID:39245686
The structure of the P3H1/CRTAP/PPIB/collagen peptide complex reveals multiple binding sites, suggesting a substrate interacting zone.
|
|
GO:0005783
endoplasmic reticulum
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: CRTAP is active in the ER, where the prolyl 3-hydroxylation complex modifies and chaperones procollagen. This IBA agrees with direct experimental localization, though the more precise term is ER lumen.
Reason: ER is the validated functional compartment; consistent with IDA evidence and the ER-lumen Reactome annotations.
Supporting Evidence:
PMID:19846465
CRTAP and P3H1 form a complex with cyclophilin B (CyPB) in the endoplasmic reticulum (ER) which 3-hydroxylates the Pro986 residue of alpha1(I) and alpha1(II) collagen chains.
|
|
GO:0030199
collagen fibril organization
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: Loss of the complex delays collagen folding and causes overmodified collagen with disorganized matrix; the complex also modulates type I collagen fibril formation in vitro. CRTAP is therefore reasonably annotated to collagen fibril organization, though this is a downstream/structural consequence rather than CRTAP's direct molecular activity.
Reason: Supported but indirect; the core function is ER collagen 3-hydroxylation and chaperoning, with fibril organization being a downstream effect.
Supporting Evidence:
PMID:19846465
function as a chaperone in both classical chaperone assays inhibiting citrate synthase aggregation and rhodanese refolding and aggregation, as well as in a fibril formation assay of type I collagen
|
|
GO:0005515
protein binding
|
IPI
PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... |
MARK AS OVER ANNOTATED |
Summary: Bare protein binding from a high-throughput crosslinking-MS study. The WITH/FROM is P3H1 (UniProtKB:Q32P28), so the meaningful content is the CRTAP-P3H1 interaction, captured more specifically by complex membership.
Reason: Uninformative bare protein binding term; the specific, biologically relevant interaction (CRTAP-P3H1 within the prolyl 3-hydroxylation complex) is better represented by complex-membership annotations.
Supporting Evidence:
PMID:30021884
Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
|
|
GO:0005515
protein binding
|
IPI
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... |
MARK AS OVER ANNOTATED |
Summary: Bare protein binding from the BioPlex affinity-purification MS interactome. The WITH/FROM is P3H1 (UniProtKB:Q32P28), reflecting the CRTAP-P3H1 interaction, which is better captured by complex membership.
Reason: Uninformative bare protein binding term from a high-throughput dataset; the specific interaction with P3H1 is represented by complex-membership and core function annotations.
Supporting Evidence:
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
|
|
GO:0005783
endoplasmic reticulum
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Automated electronic annotation of ER localization, redundant with but consistent with the experimental IDA and IBA ER annotations for this gene.
Reason: Correct ER location, the validated functional compartment; consistent with the experimental IDA evidence for this gene.
Supporting Evidence:
PMID:19846465
CRTAP and P3H1 form a complex with cyclophilin B (CyPB) in the endoplasmic reticulum (ER)
|
|
GO:0007283
spermatogenesis
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: Electronic transfer from a mouse ortholog (UniProtKB:Q9CYD3) via Ensembl Compara. There is no human experimental evidence linking CRTAP to spermatogenesis, and the established core biology is ER collagen modification and skeletal connective tissue.
Reason: Broad ortholog-transfer annotation lacking human evidence and unrelated to the validated collagen-modification/chaperone function of CRTAP.
Supporting Evidence:
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
|
|
GO:0005515
protein binding
|
IPI
PMID:39245686 The structural basis for the collagen processing by human P3... |
MARK AS OVER ANNOTATED |
Summary: Bare protein binding term, but here supported by direct cryo-EM structural evidence of the P3H1/CRTAP/PPIB ternary complex (WITH/FROM P3H1, UniProtKB:Q32P28). The specific, informative content is complex membership / the CRTAP-P3H1 interaction rather than generic protein binding.
Reason: Bare protein binding is uninformative; the underlying structural finding is best represented by the prolyl 3-hydroxylation complex membership and the collagen-substrate-binding core function.
Supporting Evidence:
PMID:39245686
We determine cryo-EM structures of the P3H1/CRTAP/PPIB complex.
|
|
GO:0050821
protein stabilization
|
IMP
PMID:19846465 Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in... |
ACCEPT |
Summary: CRTAP stabilizes P3H1 in the ER: null mutation in either gene causes loss or substantial reduction of both proteins despite normal partner transcript levels, and proteasome inhibition partially rescues P3H1 in CRTAP-null cells. This is a genuine, experimentally demonstrated function (mutual stabilization of complex subunits).
Reason: Directly demonstrated by IMP in patient fibroblasts; CRTAP stabilizes its complex partner P3H1, a core aspect of complex assembly and integrity.
Supporting Evidence:
PMID:19846465
These data indicate that CRTAP and P3H1 are mutually stabilized in the collagen prolyl 3-hydroxylation complex.
|
|
GO:0006457
protein folding
|
ISS
GO_REF:0000024 |
MODIFY |
Summary: The prolyl 3-hydroxylation complex acts as a collagen-specific molecular chaperone/foldase; absence of CRTAP delays collagen helix folding. Protein folding is supported but generic; a more specific term such as protein folding in endoplasmic reticulum better captures the biology.
Reason: Supported chaperone/foldase activity, but the generic protein folding term can be made more precise to reflect the ER collagen-folding role.
Proposed replacements:
protein folding in endoplasmic reticulum
Supporting Evidence:
PMID:20089953
In the absence of P3H1 or CRTAP, alpha1(I)Pro986 3-hydroxylation is decreased and collagen folding is delayed, resulting in overmodification of the helical lysine and proline residues.
|
|
GO:0032991
protein-containing complex
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: CRTAP is part of the heterotrimeric P3H1/CRTAP/PPIB collagen prolyl 3-hydroxylation complex, now confirmed by cryo-EM. The generic protein-containing complex term is correct but uninformative about which complex; it is retained as the most specific validated CC complex term available in the existing annotation set.
Reason: Correct but generic; complex membership in the specific prolyl 3-hydroxylation complex is captured in core_functions (in_complex).
Supporting Evidence:
PMID:39245686
We determine cryo-EM structures of the P3H1/CRTAP/PPIB complex.
|
|
GO:0005783
endoplasmic reticulum
|
IDA
PMID:20089953 Lack of cyclophilin B in osteogenesis imperfecta with normal... |
ACCEPT |
Summary: Direct immunofluorescence localization of endogenous CRTAP to the ER in human fibroblasts. This is strong, primary evidence for the core ER location.
Reason: Direct experimental localization to the ER, the validated functional compartment for CRTAP.
Supporting Evidence:
PMID:20089953
Cells from the proband and a 5-year-old control subject were stained with antibodies to CyPB, P3H1, CRTAP ... to examine protein colocalization by means of confocal microscopy.
|
|
GO:0005576
extracellular region
|
IDA
PMID:19846465 Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in... |
KEEP AS NON CORE |
Summary: A minor fraction of CRTAP is secreted (~10-12% in normal cells, rising to 15-20% when its ER-retention partner P3H1 is absent). Secretion is real but represents a small, secondary pool; the dominant biology is ER-luminal.
Reason: Experimentally observed secreted pool, but a minor fraction relative to the ER-resident function; not a core localization.
Supporting Evidence:
PMID:19846465
in conditioned media from control cells ... about 10-12% of total CRTAP is secreted
|
|
GO:0005783
endoplasmic reticulum
|
IDA
PMID:19846465 Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in... |
ACCEPT |
Summary: Direct localization of CRTAP to the ER by immunofluorescence in patient and control fibroblasts, consistent with its role in the ER prolyl 3-hydroxylation complex.
Reason: Direct experimental evidence for the core ER location of CRTAP.
Supporting Evidence:
PMID:19846465
CRTAP and P3H1 form a complex with cyclophilin B (CyPB) in the endoplasmic reticulum (ER)
|
|
GO:1901874
negative regulation of post-translational protein modification
|
IMP
PMID:19846465 Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in... |
KEEP AS NON CORE |
Summary: This annotation reflects that loss of the complex causes overmodification (excess 4-hydroxylation and lysyl hydroxylation) of the collagen helix; i.e., the complex normally limits overmodification by controlling folding rate. This is an indirect consequence of the chaperone/foldase activity rather than a direct regulatory function of CRTAP on a modifying enzyme.
Reason: Supported as an indirect/consequential phenotype of delayed-folding prevention; not a direct molecular regulatory function of CRTAP.
Supporting Evidence:
PMID:19846465
Excess modification, or 'overmodification' of the collagen helix can be detected as delayed electrophoretic migration of collagen alpha chains
|
|
GO:0005788
endoplasmic reticulum lumen
|
TAS
Reactome:R-HSA-1980233 |
ACCEPT |
Summary: Reactome localizes CRTAP to the ER lumen, the precise compartment where the prolyl 3-hydroxylation complex acts on procollagen. This is more specific than the generic ER term and is well supported.
Reason: Accurate and more precise than endoplasmic reticulum; the ER lumen is the validated site of complex activity.
Supporting Evidence:
PMID:19846465
CRTAP and P3H1 form a complex with cyclophilin B (CyPB) in the endoplasmic reticulum (ER) which 3-hydroxylates the Pro986 residue
|
|
GO:0005788
endoplasmic reticulum lumen
|
TAS
Reactome:R-HSA-2022073 |
ACCEPT |
Summary: Redundant Reactome ER-lumen localization (procollagen triple helix formation reaction). Correct and consistent with the validated ER-luminal location.
Reason: Correct, precise ER-lumen location consistent with the accepted ER-lumen annotation; retained as a redundant but valid localization.
Supporting Evidence:
PMID:39245686
the modifications of proline residues play critical roles in the formation of triple helix and the maintenance of stability
|
|
GO:0005788
endoplasmic reticulum lumen
|
TAS
Reactome:R-HSA-8948226 |
ACCEPT |
Summary: Redundant Reactome ER-lumen localization (prolyl 3-hydroxylase complex dissociation reaction). Correct location, consistent with the accepted ER-lumen annotation.
Reason: Correct, precise ER-lumen location consistent with the accepted ER-lumen annotation; retained as a redundant but valid localization.
Supporting Evidence:
PMID:19846465
the collagen prolyl 3-hydroxylation complex in the endoplasmic reticulum (ER)
|
|
GO:0005788
endoplasmic reticulum lumen
|
TAS
Reactome:R-HSA-8948230 |
ACCEPT |
Summary: Redundant Reactome ER-lumen localization (P3HB binds 4-Hyp-collagen propeptides reaction). Correct location, consistent with the accepted ER-lumen annotation.
Reason: Correct, precise ER-lumen location consistent with the accepted ER-lumen annotation; retained as a redundant but valid localization.
Supporting Evidence:
PMID:19846465
the collagen prolyl 3-hydroxylation complex in the endoplasmic reticulum (ER)
|
Q: Is there a GO cellular component term specifically for the collagen prolyl 3-hydroxylation (P3H1/CRTAP/PPIB) complex, and if not should one be created so CRTAP can be annotated more specifically than protein-containing complex?
Q: Does CRTAP have any chaperone or substrate-binding function independent of P3H1 and PPIB, given that the proteins are mutually stabilizing and largely co-dependent?
Experiment: Reconstitute the P3H1/CRTAP/PPIB complex and assay prolyl 3-hydroxylase activity and collagen-folding (chaperone/foldase) activity with and without CRTAP to quantify CRTAP's specific contribution to catalysis versus substrate binding and folding.
Experiment: Map the CRTAP residues that form the collagen substrate-interacting zone (from the cryo-EM model) by structure-guided mutagenesis, and test effects on Pro986 3-hydroxylation efficiency and collagen folding rate in cells.
Experiment: Use proximity labeling (BioID/APEX) of CRTAP in osteoblasts/chondrocytes to define its ER interactome and any partners beyond P3H1/PPIB that participate in collagen maturation.
UniProt: O75718 (CRTAP_HUMAN), 401 aa precursor; gene CRTAP (synonym CASP); chr 3.
HGNC:2379. Member of the leprecan family (SIM, UniProt). Signal peptide 1-26;
secreted/ER-resident glycoprotein (N-glyc at 87, 363).
CRTAP is a non-catalytic, essential component of the endoplasmic reticulum
collagen prolyl 3-hydroxylation complex, together with prolyl 3-hydroxylase 1
(P3H1/LEPRE1, UniProt Q32P28) and cyclophilin B / peptidyl-prolyl isomerase B
(PPIB/CyPB). This ternary complex 3-hydroxylates a single specific proline,
Pro986, of the Ξ±1(I) and Ξ±1(II) fibrillar (pro)collagen chains in the ER lumen.
- PMID:19846465
- PMID:20089953
P3H1 carries the catalytic prolyl 3-hydroxylase activity and is the only complex
member with a KDEL ER-retrieval signal; CRTAP acts as the "helper protein" /
non-catalytic subunit, NOT the catalytic hydroxylase.
- PMID:19846465
CRTAP and P3H1 mutually stabilize each other in the ER: a null mutation in one
gene causes loss/reduction of BOTH proteins despite normal transcript levels of
the non-mutated gene. Proteasome inhibition partially rescues P3H1 in CRTAP-null
cells, indicating destabilized partner is degraded.
- PMID:19846465
- PMID:19846465
The complex also functions as a collagen chaperone/foldase: loss of P3H1 or CRTAP
delays collagen helix folding, causing overmodification (excess 4-hydroxylation /
lysyl hydroxylation) of the helical region. The complex has classical chaperone
activity in vitro (inhibits citrate synthase aggregation, rhodanese refolding) and
modulates collagen fibril formation.
- PMID:19846465
- PMID:20089953
Note (negative regulation of PTM): the IMP annotation GO:1901874 "negative
regulation of post-translational protein modification" reflects that the complex
LIMITS overmodification by P4H/LH β i.e., its absence causes overmodification.
This is an indirect/consequential phenotype of the chaperone/foldase role, not a
direct enzymatic activity of CRTAP. Best regarded as non-core.
Primary functional location is the ER lumen. Endogenous CRTAP detected in ER by
IDA (PMID:19846465, PMID:20089953). A minor fraction is secreted to the
extracellular space/matrix: in normal cells ~10-12% of CRTAP is secreted, rising
to 15-20% in LEPRE1-null cells (because P3H1's KDEL normally retains CRTAP).
- PMID:19846465
The UniProt SUBCELLULAR LOCATION line lists "Secreted, extracellular space,
extracellular matrix" (by similarity, ECO:0000250); the dominant biology is ER.
Cryo-EM structures of the human P3H1/CRTAP/PPIB ternary complex (PDB 8K0E, 8K0F,
8K0I, 8K0M, 8K17, 8KC9). The active sites of P3H1 and PPIB form a face-to-face
bifunctional reaction center; the complex binds collagen peptide across multiple
sites forming a "substrate interacting zone"; a dual-ternary state is observed.
CRTAP is a TPR-like Ξ±-helical (leprecan-domain) scaffold subunit.
- PMID:39245686
Biallelic loss-of-function CRTAP variants cause autosomal recessive osteogenesis
imperfecta type VII (OI7, MIM:610682), a severe-to-lethal bone dysplasia with
rhizomelia, overmodified type I collagen, reduced bone mass, fractures.
- [PMID:17055431 "CRTAP is required for prolyl 3-hydroxylation and mutations cause
recessive osteogenesis imperfecta." (title; UniProt FUNCTION + DISEASE)]
- UniProt DISEASE: OI7 autosomal recessive (ECO:0000269|PubMed:17055431,
18566967, 19550437, 21955071).
Crtap-knockout mice have recessive osteochondrodystrophy with loss of prolyl
3-hydroxylation in cartilage and bone.
- PMID:19846465
All three IPI GO:0005515 annotations (PMID:30021884, PMID:33961781, PMID:39245686)
use WITH/FROM UniProtKB:Q32P28 = P3H1, i.e. they capture the CRTAPβP3H1
interaction. PMID:39245686 (cryo-EM ternary complex) is direct, specific
structural evidence; PMID:33961781 (BioPlex affinity-MS interactome) and
PMID:30021884 (XL-MS) are high-throughput. Bare "protein binding" is
uninformative; the meaningful, specific statement is membership in the
P3H1/CRTAP/PPIB complex.
*-deep-research*.md file found in this gene directory.core_functions.directly_involved_in, and the GOA carries collagen-fibril-organization / protein-folding-in-ER terms. GO:0032964 verified real via OLS. No NEW-term pressure beyond what the review already proposes (MODIFY protein folding β GO:0034975; collagen complex CC term flagged as a suggested question). Conclusion: already captured.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 ancestors = no_mapping)core_functions.directly_involved_in, and the GOA carries collagen-fibril-organization / protein-folding-in-ER terms. GO:0032964 verified real via OLS. No NEW-term pressure beyond what the review already proposes (MODIFY protein folding β GO:0034975; collagen complex CC term flagged as a suggested question). Conclusion: already captured.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: O75718
gene_symbol: CRTAP
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
CRTAP (cartilage-associated protein) is an endoplasmic reticulum (ER) lumen
glycoprotein that is an essential, non-catalytic subunit of the collagen prolyl
3-hydroxylation complex, together with prolyl 3-hydroxylase 1 (P3H1/LEPRE1) and
cyclophilin B (PPIB/CyPB). Within this ternary complex, P3H1 provides the
catalytic prolyl 3-hydroxylase activity and PPIB the peptidyl-prolyl
cis-trans isomerase activity, while CRTAP acts as a scaffolding/helper subunit
required for complex assembly and stability. The complex 3-hydroxylates a single
specific proline residue (Pro986) of the alpha1(I) and alpha1(II) fibrillar
procollagen chains in the ER and also functions as a collagen-specific molecular
chaperone/foldase that controls the rate of collagen triple-helix folding;
delayed folding in its absence leads to overmodification of the collagen helix.
CRTAP and P3H1 are mutually stabilizing: loss of either protein destabilizes the
other. A minor fraction of CRTAP is secreted into the extracellular space/matrix.
Biallelic loss-of-function variants cause autosomal recessive osteogenesis
imperfecta type VII, underscoring an essential role in collagen biosynthesis and
skeletal development.
existing_annotations:
- term:
id: GO:0005518
label: collagen binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: contributes_to
review:
summary: >-
The collagen prolyl 3-hydroxylation complex binds fibrillar (pro)collagen as
substrate, and cryo-EM shows CRTAP contributes to a multi-site collagen
substrate-interacting zone within the P3H1/CRTAP/PPIB complex. The
contributes_to qualifier is appropriate because substrate binding is a
property of the assembled complex rather than CRTAP alone.
action: ACCEPT
reason: >-
Supported by structural evidence that CRTAP forms part of the collagen
substrate-interacting surface of the complex; contributes_to qualifier is
biologically accurate for an accessory subunit.
supported_by:
- reference_id: PMID:39245686
supporting_text: >-
The structure of the P3H1/CRTAP/PPIB/collagen peptide complex reveals
multiple binding sites, suggesting a substrate interacting zone.
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: >-
CRTAP is active in the ER, where the prolyl 3-hydroxylation complex modifies
and chaperones procollagen. This IBA agrees with direct experimental
localization, though the more precise term is ER lumen.
action: ACCEPT
reason: >-
ER is the validated functional compartment; consistent with IDA evidence and
the ER-lumen Reactome annotations.
supported_by:
- reference_id: PMID:19846465
supporting_text: >-
CRTAP and P3H1 form a complex with cyclophilin B (CyPB) in the endoplasmic
reticulum (ER) which 3-hydroxylates the Pro986 residue of alpha1(I) and
alpha1(II) collagen chains.
- term:
id: GO:0030199
label: collagen fibril organization
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: >-
Loss of the complex delays collagen folding and causes overmodified collagen
with disorganized matrix; the complex also modulates type I collagen fibril
formation in vitro. CRTAP is therefore reasonably annotated to collagen
fibril organization, though this is a downstream/structural consequence
rather than CRTAP's direct molecular activity.
action: KEEP_AS_NON_CORE
reason: >-
Supported but indirect; the core function is ER collagen 3-hydroxylation and
chaperoning, with fibril organization being a downstream effect.
supported_by:
- reference_id: PMID:19846465
supporting_text: >-
function as a chaperone in both classical chaperone assays inhibiting
citrate synthase aggregation and rhodanese refolding and aggregation, as
well as in a fibril formation assay of type I collagen
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:30021884
qualifier: enables
review:
summary: >-
Bare protein binding from a high-throughput crosslinking-MS study. The
WITH/FROM is P3H1 (UniProtKB:Q32P28), so the meaningful content is the
CRTAP-P3H1 interaction, captured more specifically by complex membership.
action: MARK_AS_OVER_ANNOTATED
reason: >-
Uninformative bare protein binding term; the specific, biologically relevant
interaction (CRTAP-P3H1 within the prolyl 3-hydroxylation complex) is better
represented by complex-membership annotations.
supported_by:
- reference_id: PMID:30021884
supporting_text: >-
Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry
in Intact Cell Nuclei.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
qualifier: enables
review:
summary: >-
Bare protein binding from the BioPlex affinity-purification MS interactome.
The WITH/FROM is P3H1 (UniProtKB:Q32P28), reflecting the CRTAP-P3H1
interaction, which is better captured by complex membership.
action: MARK_AS_OVER_ANNOTATED
reason: >-
Uninformative bare protein binding term from a high-throughput dataset; the
specific interaction with P3H1 is represented by complex-membership and core
function annotations.
supported_by:
- reference_id: PMID:33961781
supporting_text: >-
Dual proteome-scale networks reveal cell-specific remodeling of the human
interactome.
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: >-
Automated electronic annotation of ER localization, redundant with but
consistent with the experimental IDA and IBA ER annotations for this gene.
action: ACCEPT
reason: >-
Correct ER location, the validated functional compartment; consistent with the
experimental IDA evidence for this gene.
supported_by:
- reference_id: PMID:19846465
supporting_text: >-
CRTAP and P3H1 form a complex with cyclophilin B (CyPB) in the endoplasmic
reticulum (ER)
- term:
id: GO:0007283
label: spermatogenesis
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: >-
Electronic transfer from a mouse ortholog (UniProtKB:Q9CYD3) via Ensembl
Compara. There is no human experimental evidence linking CRTAP to
spermatogenesis, and the established core biology is ER collagen modification
and skeletal connective tissue.
action: MARK_AS_OVER_ANNOTATED
reason: >-
Broad ortholog-transfer annotation lacking human evidence and unrelated to
the validated collagen-modification/chaperone function of CRTAP.
supported_by:
- reference_id: GO_REF:0000107
supporting_text: >-
Automatic transfer of experimentally verified manual GO annotation data to
orthologs using Ensembl Compara
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:39245686
qualifier: enables
review:
summary: >-
Bare protein binding term, but here supported by direct cryo-EM structural
evidence of the P3H1/CRTAP/PPIB ternary complex (WITH/FROM P3H1,
UniProtKB:Q32P28). The specific, informative content is complex membership /
the CRTAP-P3H1 interaction rather than generic protein binding.
action: MARK_AS_OVER_ANNOTATED
reason: >-
Bare protein binding is uninformative; the underlying structural finding is
best represented by the prolyl 3-hydroxylation complex membership and the
collagen-substrate-binding core function.
supported_by:
- reference_id: PMID:39245686
supporting_text: >-
We determine cryo-EM structures of the P3H1/CRTAP/PPIB complex.
- term:
id: GO:0050821
label: protein stabilization
evidence_type: IMP
original_reference_id: PMID:19846465
qualifier: involved_in
review:
summary: >-
CRTAP stabilizes P3H1 in the ER: null mutation in either gene causes loss or
substantial reduction of both proteins despite normal partner transcript
levels, and proteasome inhibition partially rescues P3H1 in CRTAP-null cells.
This is a genuine, experimentally demonstrated function (mutual stabilization
of complex subunits).
action: ACCEPT
reason: >-
Directly demonstrated by IMP in patient fibroblasts; CRTAP stabilizes its
complex partner P3H1, a core aspect of complex assembly and integrity.
supported_by:
- reference_id: PMID:19846465
supporting_text: >-
These data indicate that CRTAP and P3H1 are mutually stabilized in the
collagen prolyl 3-hydroxylation complex.
- term:
id: GO:0006457
label: protein folding
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: involved_in
review:
summary: >-
The prolyl 3-hydroxylation complex acts as a collagen-specific molecular
chaperone/foldase; absence of CRTAP delays collagen helix folding. Protein
folding is supported but generic; a more specific term such as protein
folding in endoplasmic reticulum better captures the biology.
action: MODIFY
reason: >-
Supported chaperone/foldase activity, but the generic protein folding term
can be made more precise to reflect the ER collagen-folding role.
proposed_replacement_terms:
- id: GO:0034975
label: protein folding in endoplasmic reticulum
supported_by:
- reference_id: PMID:20089953
supporting_text: >-
In the absence of P3H1 or CRTAP, alpha1(I)Pro986 3-hydroxylation is
decreased and collagen folding is delayed, resulting in overmodification of
the helical lysine and proline residues.
- term:
id: GO:0032991
label: protein-containing complex
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: part_of
review:
summary: >-
CRTAP is part of the heterotrimeric P3H1/CRTAP/PPIB collagen prolyl
3-hydroxylation complex, now confirmed by cryo-EM. The generic
protein-containing complex term is correct but uninformative about which
complex; it is retained as the most specific validated CC complex term
available in the existing annotation set.
action: KEEP_AS_NON_CORE
reason: >-
Correct but generic; complex membership in the specific prolyl
3-hydroxylation complex is captured in core_functions (in_complex).
supported_by:
- reference_id: PMID:39245686
supporting_text: >-
We determine cryo-EM structures of the P3H1/CRTAP/PPIB complex.
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IDA
original_reference_id: PMID:20089953
qualifier: located_in
review:
summary: >-
Direct immunofluorescence localization of endogenous CRTAP to the ER in human
fibroblasts. This is strong, primary evidence for the core ER location.
action: ACCEPT
reason: >-
Direct experimental localization to the ER, the validated functional
compartment for CRTAP.
supported_by:
- reference_id: PMID:20089953
supporting_text: >-
Cells from the proband and a 5-year-old control subject were stained with
antibodies to CyPB, P3H1, CRTAP ... to examine protein colocalization by
means of confocal microscopy.
- term:
id: GO:0005576
label: extracellular region
evidence_type: IDA
original_reference_id: PMID:19846465
qualifier: located_in
review:
summary: >-
A minor fraction of CRTAP is secreted (~10-12% in normal cells, rising to
15-20% when its ER-retention partner P3H1 is absent). Secretion is real but
represents a small, secondary pool; the dominant biology is ER-luminal.
action: KEEP_AS_NON_CORE
reason: >-
Experimentally observed secreted pool, but a minor fraction relative to the
ER-resident function; not a core localization.
supported_by:
- reference_id: PMID:19846465
supporting_text: >-
in conditioned media from control cells ... about 10-12% of total CRTAP is
secreted
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IDA
original_reference_id: PMID:19846465
qualifier: located_in
review:
summary: >-
Direct localization of CRTAP to the ER by immunofluorescence in patient and
control fibroblasts, consistent with its role in the ER prolyl 3-hydroxylation
complex.
action: ACCEPT
reason: >-
Direct experimental evidence for the core ER location of CRTAP.
supported_by:
- reference_id: PMID:19846465
supporting_text: >-
CRTAP and P3H1 form a complex with cyclophilin B (CyPB) in the endoplasmic
reticulum (ER)
- term:
id: GO:1901874
label: negative regulation of post-translational protein modification
evidence_type: IMP
original_reference_id: PMID:19846465
qualifier: involved_in
review:
summary: >-
This annotation reflects that loss of the complex causes overmodification
(excess 4-hydroxylation and lysyl hydroxylation) of the collagen helix; i.e.,
the complex normally limits overmodification by controlling folding rate.
This is an indirect consequence of the chaperone/foldase activity rather than
a direct regulatory function of CRTAP on a modifying enzyme.
action: KEEP_AS_NON_CORE
reason: >-
Supported as an indirect/consequential phenotype of delayed-folding
prevention; not a direct molecular regulatory function of CRTAP.
supported_by:
- reference_id: PMID:19846465
supporting_text: >-
Excess modification, or 'overmodification' of the collagen helix can be
detected as delayed electrophoretic migration of collagen alpha chains
- term:
id: GO:0005788
label: endoplasmic reticulum lumen
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1980233
qualifier: located_in
review:
summary: >-
Reactome localizes CRTAP to the ER lumen, the precise compartment where the
prolyl 3-hydroxylation complex acts on procollagen. This is more specific than
the generic ER term and is well supported.
action: ACCEPT
reason: >-
Accurate and more precise than endoplasmic reticulum; the ER lumen is the
validated site of complex activity.
supported_by:
- reference_id: PMID:19846465
supporting_text: >-
CRTAP and P3H1 form a complex with cyclophilin B (CyPB) in the endoplasmic
reticulum (ER) which 3-hydroxylates the Pro986 residue
- term:
id: GO:0005788
label: endoplasmic reticulum lumen
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2022073
qualifier: located_in
review:
summary: >-
Redundant Reactome ER-lumen localization (procollagen triple helix formation
reaction). Correct and consistent with the validated ER-luminal location.
action: ACCEPT
reason: >-
Correct, precise ER-lumen location consistent with the accepted ER-lumen
annotation; retained as a redundant but valid localization.
supported_by:
- reference_id: PMID:39245686
supporting_text: >-
the modifications of proline residues play critical roles in the formation
of triple helix and the maintenance of stability
- term:
id: GO:0005788
label: endoplasmic reticulum lumen
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8948226
qualifier: located_in
review:
summary: >-
Redundant Reactome ER-lumen localization (prolyl 3-hydroxylase complex
dissociation reaction). Correct location, consistent with the accepted
ER-lumen annotation.
action: ACCEPT
reason: >-
Correct, precise ER-lumen location consistent with the accepted ER-lumen
annotation; retained as a redundant but valid localization.
supported_by:
- reference_id: PMID:19846465
supporting_text: >-
the collagen prolyl 3-hydroxylation complex in the endoplasmic reticulum
(ER)
- term:
id: GO:0005788
label: endoplasmic reticulum lumen
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8948230
qualifier: located_in
review:
summary: >-
Redundant Reactome ER-lumen localization (P3HB binds 4-Hyp-collagen
propeptides reaction). Correct location, consistent with the accepted
ER-lumen annotation.
action: ACCEPT
reason: >-
Correct, precise ER-lumen location consistent with the accepted ER-lumen
annotation; retained as a redundant but valid localization.
supported_by:
- reference_id: PMID:19846465
supporting_text: >-
the collagen prolyl 3-hydroxylation complex in the endoplasmic reticulum
(ER)
references:
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
by curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to
orthologs using Ensembl Compara
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:17055431
title: CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive
osteogenesis imperfecta.
findings:
- statement: >-
CRTAP is required for efficient 3-hydroxylation of fibrillar collagen prolyl
residues; loss-of-function mutations cause recessive osteogenesis imperfecta.
reference_section_type: ABSTRACT
- id: PMID:19846465
title: Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in the endoplasmic
reticulum collagen prolyl 3-hydroxylation complex.
findings:
- statement: >-
CRTAP, P3H1 and cyclophilin B form the ER collagen prolyl 3-hydroxylation
complex that 3-hydroxylates Pro986 of alpha1(I)/alpha1(II) chains; CRTAP and
P3H1 are mutually stabilized, and the complex also acts as a chaperone.
reference_section_type: ABSTRACT
- id: PMID:20089953
title: Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding.
findings:
- statement: >-
Confirms CRTAP as a component of the P3H1/CRTAP/CyPB complex; absence of P3H1
or CRTAP decreases Pro986 3-hydroxylation and delays collagen folding.
reference_section_type: ABSTRACT
- id: PMID:30021884
title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry
in Intact Cell Nuclei.
findings: []
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the human
interactome.
findings: []
- id: PMID:39245686
title: The structural basis for the collagen processing by human P3H1/CRTAP/PPIB
ternary complex.
findings:
- statement: >-
Cryo-EM structures of the human P3H1/CRTAP/PPIB ternary complex; P3H1 and
PPIB active sites form a bifunctional reaction center and CRTAP contributes to
a multi-site collagen substrate-interacting zone.
reference_section_type: ABSTRACT
- id: Reactome:R-HSA-1980233
title: Collagen prolyl 3-hydroxylase converts 4-Hyp collagen to 3,4-Hyp collagen
findings: []
- id: Reactome:R-HSA-2022073
title: Procollagen triple helix formation
findings: []
- id: Reactome:R-HSA-8948226
title: Prolyl 3-hydroxylases:Fe2+:3,4-Hyp collagen propeptides dissociates
findings: []
- id: Reactome:R-HSA-8948230
title: P3HB binds 4-Hyp-collagen propeptides
findings: []
core_functions:
- description: >-
Non-catalytic scaffolding/helper subunit of the ER collagen prolyl
3-hydroxylation complex (with P3H1 and PPIB). CRTAP is required for assembly,
stability and activity of the complex that 3-hydroxylates Pro986 of alpha1(I)
and alpha1(II) fibrillar procollagen chains; CRTAP contributes to collagen
substrate binding but does not itself catalyze hydroxylation.
supported_by:
- reference_id: PMID:19846465
supporting_text: >-
CRTAP and P3H1 form a complex with cyclophilin B (CyPB) in the endoplasmic
reticulum (ER) which 3-hydroxylates the Pro986 residue of alpha1(I) and
alpha1(II) collagen chains.
- reference_id: PMID:39245686
supporting_text: >-
The structure of the P3H1/CRTAP/PPIB/collagen peptide complex reveals
multiple binding sites, suggesting a substrate interacting zone.
molecular_function:
id: GO:0005198
label: structural molecule activity
contributes_to_molecular_function:
id: GO:0005518
label: collagen binding
directly_involved_in:
- id: GO:0032964
label: collagen biosynthetic process
locations:
- id: GO:0005788
label: endoplasmic reticulum lumen
substrates:
- id: GO:0005518
label: collagen binding
in_complex:
id: GO:0032991
label: protein-containing complex
- description: >-
Collagen-specific molecular chaperone/foldase activity of the complex: CRTAP is
required for normal collagen triple-helix folding rate, and its loss causes
delayed folding and overmodification of the collagen helix. CRTAP also mutually
stabilizes its complex partner P3H1 in the ER.
supported_by:
- reference_id: PMID:20089953
supporting_text: >-
In the absence of P3H1 or CRTAP, alpha1(I)Pro986 3-hydroxylation is decreased
and collagen folding is delayed, resulting in overmodification of the helical
lysine and proline residues.
- reference_id: PMID:19846465
supporting_text: >-
These data indicate that CRTAP and P3H1 are mutually stabilized in the
collagen prolyl 3-hydroxylation complex.
molecular_function:
id: GO:0044183
label: protein folding chaperone
directly_involved_in:
- id: GO:0034975
label: protein folding in endoplasmic reticulum
- id: GO:0050821
label: protein stabilization
locations:
- id: GO:0005788
label: endoplasmic reticulum lumen
proposed_new_terms: []
suggested_questions:
- question: >-
Is there a GO cellular component term specifically for the collagen prolyl
3-hydroxylation (P3H1/CRTAP/PPIB) complex, and if not should one be created so
CRTAP can be annotated more specifically than protein-containing complex?
- question: >-
Does CRTAP have any chaperone or substrate-binding function independent of P3H1
and PPIB, given that the proteins are mutually stabilizing and largely
co-dependent?
suggested_experiments:
- description: >-
Reconstitute the P3H1/CRTAP/PPIB complex and assay prolyl 3-hydroxylase
activity and collagen-folding (chaperone/foldase) activity with and without
CRTAP to quantify CRTAP's specific contribution to catalysis versus substrate
binding and folding.
- description: >-
Map the CRTAP residues that form the collagen substrate-interacting zone (from
the cryo-EM model) by structure-guided mutagenesis, and test effects on Pro986
3-hydroxylation efficiency and collagen folding rate in cells.
- description: >-
Use proximity labeling (BioID/APEX) of CRTAP in osteoblasts/chondrocytes to
define its ER interactome and any partners beyond P3H1/PPIB that participate in
collagen maturation.