id: Q32P28
gene_symbol: P3H1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: P3H1 (prolyl 3-hydroxylase 1; gene LEPRE1, also known as leprecan-1 and growth
  suppressor 1) is an endoplasmic-reticulum-lumenal 2-oxoglutarate/Fe(II)-dependent dioxygenase
  (EC 1.14.11.7) of the leprecan family. It catalyzes the post-translational formation of
  3-hydroxyproline at specific -Xaa-Pro-Gly- prolines in procollagen chains, most notably the
  alpha1(I)Pro986 residue of type I and type II collagen, a modification required for proper
  collagen triple-helix folding, assembly and stability. P3H1 is the catalytic core of the ER
  collagen prolyl 3-hydroxylation complex (the "PCP complex"), a 1:1:1 ternary assembly with
  cartilage-associated protein (CRTAP) and peptidyl-prolyl cis-trans isomerase B (PPIB/cyclophilin
  B). Within this complex P3H1 contributes prolyl 3-hydroxylase activity while PPIB provides
  cis-trans isomerase activity and CRTAP stabilizes the assembly and helps recruit collagen
  substrate; the complex also functions as a collagen chaperone. P3H1 carries a C-terminal KDEL
  ER-retrieval signal that retains it (and, with it, CRTAP) in the ER lumen. Catalysis requires a
  non-heme Fe(II) center, the co-substrate 2-oxoglutarate, molecular oxygen, and L-ascorbate
  (vitamin C) as cofactor. Loss-of-function mutations in LEPRE1 abolish alpha1(I)Pro986
  3-hydroxylation, delay collagen folding and cause overmodification of the collagen helix,
  resulting in autosomal recessive osteogenesis imperfecta type 8 (OI8). A secreted chondroitin
  sulfate proteoglycan form of leprecan can also be deposited in the extracellular matrix.
alternative_products:
- name: 1 (GROS1-L, LEPREa, P3H1a)
  id: Q32P28-1
- name: 2 (GROS1-S)
  id: Q32P28-2
  sequence_note: VSP_019346, VSP_019347
- name: 3 (LEPREc)
  id: Q32P28-3
  sequence_note: VSP_019348
- name: 4 (LEPREb, P3H1b)
  id: Q32P28-4
  sequence_note: VSP_054864
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: P3H1 acts in the ER lumen, where it 3-hydroxylates procollagen as part of the
      CRTAP/PPIB complex. The phylogenetic ER localization agrees with direct experimental
      evidence and the KDEL ER-retention signal.
    action: ACCEPT
    reason: Correct site of action; corroborated by EXP/IDA ER annotations and the KDEL retention
      motif retaining isoform 1 in the ER.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum'
- term:
    id: GO:0019797
    label: procollagen-proline 3-dioxygenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Core molecular function of P3H1, conserved across the leprecan/P3H family; it
      hydroxylates the 3-position of specific procollagen prolines.
    action: ACCEPT
    reason: Defining core MF; directly demonstrated experimentally (IDA, PMID:39245686, EC
      1.14.11.7) and conserved phylogenetically.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: Has prolyl 3-hydroxylase activity and catalyzes the post-
- term:
    id: GO:0032963
    label: collagen metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: P3H1 participates in collagen post-translational modification/biosynthesis, a
      defining biological process for the gene.
    action: ACCEPT
    reason: Correct biological process; the enzyme is required for proper collagen biosynthesis,
      folding and assembly and is conserved across the family.
    supported_by:
    - reference_id: PMID:15044469
      supporting_text: The collagen prolyl hydroxylases are enzymes that are required for proper
- term:
    id: GO:0005506
    label: iron ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: P3H1 coordinates a catalytic non-heme Fe(II)/Fe(3+) ion in its Fe2OG dioxygenase
      domain (residues His587, Asp589, His659), a structural requirement for hydroxylation.
    action: KEEP_AS_NON_CORE
    reason: Accurate cofactor-binding attribute that supports the catalytic MF; structurally
      demonstrated, but subsidiary to the informative procollagen-proline 3-dioxygenase activity.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: Name=Fe cation; Xref=ChEBI:CHEBI:24875;
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of ER localization from the UniProt subcellular location,
      consistent with stronger experimental evidence.
    action: ACCEPT
    reason: Correct compartment; redundant with EXP/IDA ER annotations.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum'
- term:
    id: GO:0016705
    label: oxidoreductase activity, acting on paired donors, with incorporation or
      reduction of molecular oxygen
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Parent molecular function describing the 2-oxoglutarate/Fe(II) dioxygenase chemistry
      that incorporates molecular oxygen during proline 3-hydroxylation.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific GO:0019797 procollagen-proline 3-dioxygenase
      activity better captures the core function.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'Reaction=L-prolyl-[collagen] + 2-oxoglutarate + O2 = trans-3-hydroxy-L-'
- term:
    id: GO:0019797
    label: procollagen-proline 3-dioxygenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic assignment of the core dioxygenase activity from the EC/Rhea mapping (EC
      1.14.11.7; RHEA:22872), consistent with experimental evidence.
    action: ACCEPT
    reason: Correct core molecular function; redundant with IDA/IBA/ISS evidence.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'Reaction=L-prolyl-[collagen] + 2-oxoglutarate + O2 = trans-3-hydroxy-L-'
- term:
    id: GO:0031418
    label: L-ascorbic acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: P3H1, like other collagen hydroxylases, uses L-ascorbate (vitamin C) as a cofactor
      to maintain the catalytic iron in its reduced state.
    action: KEEP_AS_NON_CORE
    reason: Accurate cofactor-binding attribute supporting the catalytic MF; subsidiary to the
      core dioxygenase activity.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: Name=L-ascorbate; Xref=ChEBI:CHEBI:38290;
- term:
    id: GO:0032963
    label: collagen metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic assignment of the collagen metabolic process, consistent
      with the experimental and phylogenetic evidence.
    action: ACCEPT
    reason: Correct biological process; redundant with IBA/ISS.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: in pro-collagen chains, a critical step for the formation of mature
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30021884
  qualifier: enables
  review:
    summary: High-throughput crosslinking mass-spectrometry interactome capturing P3H1 with CRTAP
      (O75718). CRTAP is a genuine PCP complex partner, but the bare protein binding term is
      uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction with the complex partner CRTAP, but bare protein binding is
      uninformative; complex membership is better captured by GO:0032991 and the core catalytic MF.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'Q32P28; O75718: CRTAP;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Proteome-scale (BioPlex) affinity-purification interactome capturing the P3H1-CRTAP
      (O75718) interaction. The partner is biologically real; the bare term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction with the complex partner CRTAP, but bare protein binding is
      uninformative and not elevated to core.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'Q32P28; O75718: CRTAP;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:39245686
  qualifier: enables
  review:
    summary: Structural study establishing P3H1's direct interactions with CRTAP (O75718) and
      PPIB (P23284) within the PCP ternary complex. These are the genuine, biologically central
      complex partners, but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Partners CRTAP and PPIB are the real PCP complex components (demonstrated
      structurally), but bare protein binding does not convey the core function; captured better
      by GO:0032991 and GO:0019797.
    supported_by:
    - reference_id: PMID:39245686
      supporting_text: P3H1 and PPIB were identified as components of an ER-associated ternary
        complex consisting of P3H1/CRTAP/PPIB
- term:
    id: GO:0019797
    label: procollagen-proline 3-dioxygenase activity
  evidence_type: IDA
  original_reference_id: PMID:39245686
  qualifier: enables
  review:
    summary: Direct biochemical/structural demonstration that P3H1 is the core prolyl
      3-hydroxylase of the PCP complex, hydroxylating Pro986 of collagen alpha1(I); active-site
      mutants (H587A, D589A, H659A, R669) lose catalytic activity.
    action: ACCEPT
    reason: Core molecular function with direct experimental (IDA) support, EC 1.14.11.7 assigned,
      and mutagenesis confirming the catalytic residues.
    supported_by:
    - reference_id: PMID:39245686
      supporting_text: P3H1 is the core prolyl 3-hydroxylase, specially hydroxylating Pro986
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: EXP
  original_reference_id: PMID:19088120
  qualifier: located_in
  review:
    summary: Experimental localization of the KDEL-bearing splice form (isoform 1) of P3H1 to the
      ER, the catalytically relevant compartment.
    action: ACCEPT
    reason: Experimentally supported ER localization consistent with the site of action.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum'
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IMP
  original_reference_id: PMID:19846465
  qualifier: involved_in
  review:
    summary: P3H1 and CRTAP are mutually stabilizing within the ER prolyl 3-hydroxylation complex;
      loss of either leads to proteasomal degradation of the other. P3H1 thus stabilizes its
      partner CRTAP (and the complex stabilizes/chaperones collagen).
    action: ACCEPT
    reason: Directly supported by mutational analysis (null cells deplete both proteins; proteasome
      inhibitors partially rescue); reflects a genuine stabilization function of the complex.
    supported_by:
    - reference_id: PMID:19846465
      supporting_text: CRTAP and P3H1 are mutually stabilized in the collagen prolyl 3-hydroxylation
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IMP
  original_reference_id: PMID:22615817
  qualifier: involved_in
  review:
    summary: A KDEL-only mutation that prevents ER retention of P3H1 impairs its function,
      consistent with P3H1's role in maintaining the ER collagen-modifying complex and stabilizing
      its components/substrate.
    action: ACCEPT
    reason: Supported by patient mutation analysis; consistent with the genuine stabilization role
      of P3H1 within the ER collagen prolyl 3-hydroxylation complex.
    supported_by:
    - reference_id: PMID:22615817
      supporting_text: the KDEL ER- retrieval sequence is essential for P3H1 functionality
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:28327460
  qualifier: colocalizes_with
  review:
    summary: High-throughput proteomic detection of P3H1 in stem-cell-derived extracellular
      matrix. Consistent with the secreted chondroitin-sulfate proteoglycan (leprecan) form, but
      not the catalytic ER site of action.
    action: KEEP_AS_NON_CORE
    reason: Plausible given the documented secreted ECM proteoglycan form, but a weak
      colocalizes_with proteomics annotation peripheral to the core ER enzymatic role.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'Secreted, extracellular space, extracellular'
- term:
    id: GO:0005518
    label: collagen binding
  evidence_type: ISS
  original_reference_id: PMID:15044469
  qualifier: contributes_to
  review:
    summary: P3H1 specifically interacts with denatured/unfolded collagen, contributing to the
      PCP complex's substrate-binding (collagen recruitment) function.
    action: ACCEPT
    reason: Supported by enzyme characterization (specific interaction with denatured collagen)
      and the structurally demonstrated collagen-binding of the complex; an informative MF.
    supported_by:
    - reference_id: PMID:15044469
      supporting_text: specifically interact with denatured collagen
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: ISS
  original_reference_id: PMID:15044469
  qualifier: involved_in
  review:
    summary: P3H1 (within the PCP complex) is required for proper collagen folding and assembly,
      and the complex has molecular chaperone activity.
    action: ACCEPT
    reason: Supported by enzyme characterization and the complex's documented chaperone role;
      loss of P3H1 delays collagen helix folding.
    supported_by:
    - reference_id: PMID:15044469
      supporting_text: required for proper
- term:
    id: GO:0010976
    label: positive regulation of neuron projection development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Electronic ISS transfer of a neuronal role from the rat leprecan ortholog (Q9R1J8).
      No human/primary evidence supports a neuron-projection function for P3H1, and it is tangential
      to its established collagen-modifying role.
    action: KEEP_AS_NON_CORE
    reason: Ortholog-based ISS with no supporting primary evidence in the P3H1 literature reviewed;
      peripheral and not corroborated, so retained only as non-core.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: Leucine- and proline-enriched proteoglycan 1
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput NK-cell membrane proteome detection. P3H1 is an ER-lumenal/secreted
      protein; the generic "membrane" assignment most likely reflects co-fractionation rather than
      a genuine integral-membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic, low-resolution proteomics localization inconsistent with the soluble
      ER-lumenal/secreted nature of P3H1; likely a contaminant/co-fractionation capture.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:20089953
  qualifier: located_in
  review:
    summary: Direct experimental ER localization of P3H1 from the cyclophilin B osteogenesis
      imperfecta study, consistent with the catalytic site of action.
    action: ACCEPT
    reason: IDA-supported ER localization agrees with the site of collagen hydroxylation.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum'
- term:
    id: GO:0019797
    label: procollagen-proline 3-dioxygenase activity
  evidence_type: ISS
  original_reference_id: PMID:15044469
  qualifier: enables
  review:
    summary: Sequence-similarity assignment of the core prolyl 3-hydroxylase activity, transferred
      from the chick P3H1 ortholog and consistent with the direct human evidence.
    action: ACCEPT
    reason: Correct core molecular function; redundant with IDA/IBA/IEA support.
    supported_by:
    - reference_id: PMID:15044469
      supporting_text: required for proper
- term:
    id: GO:0032963
    label: collagen metabolic process
  evidence_type: ISS
  original_reference_id: PMID:15044469
  qualifier: involved_in
  review:
    summary: Sequence-similarity assignment of the collagen metabolic process, consistent with the
      enzyme's documented role in collagen biosynthesis and modification.
    action: ACCEPT
    reason: Correct biological process; redundant with IBA/IEA support.
    supported_by:
    - reference_id: PMID:15044469
      supporting_text: required for proper
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: ISS
  original_reference_id: PMID:15044469
  qualifier: part_of
  review:
    summary: P3H1 exists in a tight ER-resident complex (the PCP complex with CRTAP and PPIB).
      This captures complex membership, now established structurally.
    action: ACCEPT
    reason: Genuine and central complex membership; the generic parent term is the available CC
      capturing the PCP ternary complex.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: Forms a ternary complex with PPIB (CYPB) and CRTAP, known as
- term:
    id: GO:0060348
    label: bone development
  evidence_type: IMP
  original_reference_id: PMID:22615817
  qualifier: involved_in
  review:
    summary: Loss-of-function LEPRE1 mutations cause recessive osteogenesis imperfecta, reflecting
      P3H1's requirement for normal skeletal collagen and bone development.
    action: KEEP_AS_NON_CORE
    reason: Bone development is a downstream physiological consequence of the core collagen
      3-hydroxylation function; experimentally grounded in OI phenotype but not the core MF/BP.
    supported_by:
    - reference_id: PMID:17277775
      supporting_text: crucial for bone development and collagen helix formation
- term:
    id: GO:1901874
    label: negative regulation of post-translational protein modification
  evidence_type: IMP
  original_reference_id: PMID:22615817
  qualifier: involved_in
  review:
    summary: Loss of P3H1 delays collagen folding, leading to overmodification (excess lysyl
      hydroxylation/glycosylation) of the helix; functional P3H1 thereby limits this
      overmodification.
    action: KEEP_AS_NON_CORE
    reason: An indirect, downstream description (overmodification follows delayed folding); a
      defensible IMP but secondary to the core hydroxylation function.
    supported_by:
    - reference_id: PMID:17277775
      supporting_text: excess lysyl hydroxylation and
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:19846465
  qualifier: located_in
  review:
    summary: Direct immunofluorescence/biochemical ER localization of P3H1 from the mutual
      stabilization study, consistent with its catalytic site.
    action: ACCEPT
    reason: IDA-supported ER localization agrees with the documented compartment.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum'
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IMP
  original_reference_id: PMID:17277775
  qualifier: involved_in
  review:
    summary: P3H1 deficiency delays collagen helix folding; P3H1 (within the PCP complex) is
      required for proper, timely collagen folding.
    action: ACCEPT
    reason: Supported by patient/mutation analysis showing delayed collagen folding in P3H1-null
      cells; reflects the complex's chaperone/folding role.
    supported_by:
    - reference_id: PMID:17277775
      supporting_text: crucial for bone development and collagen helix formation
- term:
    id: GO:0050708
    label: regulation of protein secretion
  evidence_type: IMP
  original_reference_id: PMID:17277775
  qualifier: involved_in
  review:
    summary: P3H1-null proband cells show altered collagen secretion (moderately delayed secretion
      but increased total collagen secretion), indicating an influence on collagen secretion.
    action: KEEP_AS_NON_CORE
    reason: A downstream/indirect effect on collagen secretion observed in null cells; secondary
      to the core hydroxylation/folding function.
    supported_by:
    - reference_id: PMID:17277775
      supporting_text: moderately delayed, but total collagen secretion was increased
- term:
    id: GO:0060348
    label: bone development
  evidence_type: IMP
  original_reference_id: PMID:17277775
  qualifier: involved_in
  review:
    summary: LEPRE1 null alleles cause a recessive metabolic bone disorder resembling
      severe/lethal osteogenesis imperfecta, establishing P3H1 as crucial for bone development.
    action: KEEP_AS_NON_CORE
    reason: Downstream physiological role; experimentally grounded in the OI phenotype but not the
      core molecular function.
    supported_by:
    - reference_id: PMID:17277775
      supporting_text: crucial for bone development and collagen helix formation
- term:
    id: GO:1901874
    label: negative regulation of post-translational protein modification
  evidence_type: IMP
  original_reference_id: PMID:17277775
  qualifier: involved_in
  review:
    summary: P3H1 deficiency leads to excess lysyl hydroxylation and glycosylation of the collagen
      helix; functional P3H1 limits this overmodification by enabling normal-rate folding.
    action: KEEP_AS_NON_CORE
    reason: Indirect downstream consequence of delayed folding; a defensible IMP but secondary to
      the core function.
    supported_by:
    - reference_id: PMID:17277775
      supporting_text: excess lysyl hydroxylation and
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: High-throughput detection of P3H1 in urinary exosomes. Consistent with the secreted
      proteoglycan form, but not the functional ER compartment.
    action: KEEP_AS_NON_CORE
    reason: Proteomics localization peripheral to the core ER catalytic role; plausible given the
      documented secreted form but non-core.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'Secreted, extracellular space, extracellular'
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1980233
  qualifier: located_in
  review:
    summary: Reactome curation of P3H1 in the ER lumen, the soluble compartment where it catalyzes
      collagen prolyl 3-hydroxylation.
    action: ACCEPT
    reason: Correct, specific compartment for this soluble KDEL-bearing enzyme; consistent with
      experimental ER evidence.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum'
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2022073
  qualifier: located_in
  review:
    summary: Reactome curation of P3H1 in the ER lumen during procollagen triple-helix formation.
    action: ACCEPT
    reason: Correct, specific compartment; redundant with experimental ER evidence.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum'
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8948226
  qualifier: located_in
  review:
    summary: Reactome curation of P3H1 in the ER lumen (prolyl 3-hydroxylase complex reaction).
    action: ACCEPT
    reason: Correct, specific compartment; redundant with experimental ER evidence.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum'
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8948230
  qualifier: located_in
  review:
    summary: Reactome curation of P3H1 in the ER lumen (binding of 4-Hyp collagen propeptides).
    action: ACCEPT
    reason: Correct, specific compartment; redundant with experimental ER evidence.
    supported_by:
    - reference_id: file:human/P3H1/P3H1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum'
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: NAS
  original_reference_id: PMID:10951563
  qualifier: involved_in
  review:
    summary: Historical "growth suppressor 1" (Gros1) annotation from the original cloning paper,
      based on slowed growth of NIH3T3 cells overexpressing the cDNA. This predates and is not part
      of the established collagen prolyl 3-hydroxylase function.
    action: MARK_AS_OVER_ANNOTATED
    reason: NAS, historical assertion superseded by enzymatic characterization; no mechanistic link
      to P3H1's established function and not corroborated by later work.
    supported_by:
    - reference_id: PMID:10951563
      supporting_text: 85-kDa protein into NIH3T3 cells resulted in their slow growth and reduced
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- 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: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:10951563
  title: 'Gros1, a potential growth suppressor on chromosome 1: its identity to basement
    membrane-associated proteoglycan, leprecan.'
  findings:
  - statement: Original cloning of leprecan/Gros1 as a putative growth suppressor; NIH3T3 cells
      overexpressing the cDNA showed slowed growth and reduced colony-forming efficiency.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Historical cloning/growth-suppressor paper predating the enzymatic
      characterization; source of the GO:0008285 NAS annotation and the "growth suppressor 1"
      synonym. Not relevant to the established collagen prolyl 3-hydroxylase function.
- id: PMID:15044469
  title: Prolyl 3-hydroxylase 1, enzyme characterization and identification of a novel
    family of enzymes.
  findings:
  - statement: P3H1 is an ER-resident 2-oxoglutarate/iron-dependent dioxygenase with prolyl
      3-hydroxylase activity on full-length procollagen, specifically interacts with denatured
      collagen, and exists in a tight complex with other ER-resident proteins.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Founding enzyme characterization of P3H1; supports the dioxygenase MF, collagen
      binding, protein folding and complex-membership annotations (abstract-only in cache).
- id: PMID:17277775
  title: Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder
    resembling lethal/severe osteogenesis imperfecta.
  findings:
  - statement: Null LEPRE1 alleles abolish alpha1(I)Pro986 3-hydroxylation, cause overmodification
      and delayed/altered collagen secretion, and produce recessive OI; P3H1 is crucial for bone
      development and collagen helix formation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the OI8 disease link and supports the bone development, protein
      folding, secretion regulation and negative regulation of PTM annotations.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput urinary exosome proteomics; source of the extracellular exosome
      HDA localization, peripheral to the core ER function.
- id: PMID:19088120
  title: 'Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation
    and identification of the splice form responsible for prolyl 3-hydroxylation.'
  findings:
  - statement: Identifies the 736-aa KDEL-bearing splice form (isoform 1) as the ER-resident form
      responsible for prolyl 3-hydroxylation; its loss severely reduces alpha1(I)Pro986
      3-hydroxylation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Supports the EXP ER localization and the functional relevance of the KDEL
      ER-retained isoform 1.
- 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 and P3H1 are mutually stabilized in the ER collagen prolyl 3-hydroxylation
      complex; loss of one leads to proteasomal degradation of the other, and the complex has
      chaperone activity.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Supports the protein stabilization annotation and the ER complex/chaperone role;
      full text available in cache.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput NK-cell membrane proteome; source of the generic "membrane" HDA
      localization, likely a co-fractionation capture for this soluble ER-lumenal protein.
- id: PMID:20089953
  title: Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding.
  findings:
  - statement: CRTAP and P3H1 are the catalytically essential components of the collagen prolyl
      3-hydroxylation complex; provides ER localization (IDA) for P3H1.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cyclophilin B OI paper; cited for P3H1 ER localization and complex context.
- id: PMID:22615817
  title: A novel mutation in LEPRE1 that eliminates only the KDEL ER- retrieval sequence
    causes non-lethal osteogenesis imperfecta.
  findings:
  - statement: The C-terminal KDEL ER-retrieval sequence is essential for P3H1 functionality in
      vivo; the complex has prolyl 3-hydroxylase, PPIase and molecular chaperone activities.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Supports the ER-retention requirement and the protein stabilization, bone
      development and negative-regulation-of-PTM annotations; full text available.
- id: PMID:31171565
  title: Cellular stress due to impairment of collagen prolyl hydroxylation complex
    is rescued by the chaperone 4-phenylbutyrate.
  findings:
  - statement: Primary fibroblasts from recessive OI patients (including P3H1/LEPRE1
      deficiency) retain overmodified type I collagen, causing ER enlargement, protein
      aggregates, PERK-branch unfolded protein response activation and apoptosis;
      4-phenylbutyrate (4-PBA) restores ER proteostasis and cell survival.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (DOI 10.1242/dmm.038521). Recessive-OI cohort spanning
      CRTAP/P3H1/PPIB complex defects; documents the downstream ER-stress/UPR/apoptosis
      pathophysiology and 4-PBA rescue. Supports the cellular consequences of P3H1
      loss-of-function (collagen overmodification, ER proteostasis) but is a
      complex-level/disease-mechanism study, not a P3H1-specific catalytic study.
      Not cached; no verbatim supporting_text added.
- id: PMID:38926541
  title: 'Clinical spectrum of rare bone fragility disorders and response to bisphosphonate
    treatment: a retrospective study.'
  findings:
  - statement: Retrospective cohort of bone-fragility patients with non-COL1A1/COL1A2
      variants (including pathogenic P3H1 variants) treated with bisphosphonates;
      lumbar-spine BMD increased dose-dependently and fracture rate decreased on treatment.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified (DOI 10.1038/s41431-024-01645-4). Clinical/therapeutic
      cohort that includes P3H1-variant patients among several rare-OI genotypes;
      relevant to the OI8 disease association and management, not to the molecular
      function. Not cached; no verbatim supporting_text added.
- id: PMID:28327460
  title: Comprehensive proteomic characterization of stem cell-derived extracellular
    matrices.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput ECM proteomics; source of the extracellular matrix
      colocalizes_with HDA annotation, consistent with the secreted proteoglycan form.
- id: PMID:30021884
  title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry
    in Intact Cell Nuclei.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput crosslinking MS; source of a P3H1-CRTAP (O75718) IPI protein
      binding annotation. Partner is a real complex member; bare protein binding uninformative.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex proteome-scale interactome; source of a P3H1-CRTAP (O75718) IPI protein
      binding annotation. Partner real; bare term uninformative.
- 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 P3H1/CRTAP/PPIB (PCP) ternary and dual-ternary complexes,
      with 2-oxoglutarate and Fe, and with a collagen peptide; P3H1 is the core prolyl
      3-hydroxylase hydroxylating Pro986 of collagen alpha1(I).
    reference_section_type: ABSTRACT
  - statement: P3H1 and PPIB active sites form a face-to-face bifunctional reaction center;
      active-site mutations (H587A, D589A, H659A, R669) abolish/severely reduce 2OG-dependent
      oxygenase activity, confirming the catalytic residues.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive structural/biochemical study; establishes the PCP complex
      architecture, the catalytic activity (EC 1.14.11.7 assigned), and the CRTAP/PPIB interactions.
- 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: []
- id: file:human/P3H1/P3H1-uniprot.txt
  title: UniProt entry Q32P28 (P3H1_HUMAN), prolyl 3-hydroxylase 1
  findings:
  - statement: ER-lumenal 2-oxoglutarate/Fe(II)-dependent dioxygenase (EC 1.14.11.7) that
      3-hydroxylates -Xaa-Pro-Gly- prolines in procollagen; forms a 1:1:1 PCP ternary complex with
      CRTAP and PPIB; uses Fe and L-ascorbate cofactors; KDEL-retained isoform 1 in the ER;
      loss-of-function causes OI8.
    reference_section_type: OTHER
core_functions:
- description: ER-lumenal procollagen-proline 3-dioxygenase that catalyzes 3-hydroxylation of
    specific procollagen prolines (notably alpha1(I)Pro986) using a non-heme Fe(II) center,
    2-oxoglutarate, O2 and L-ascorbate, a modification required for proper collagen folding.
  molecular_function:
    id: GO:0019797
    label: procollagen-proline 3-dioxygenase activity
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: PMID:39245686
    supporting_text: P3H1 is the core prolyl 3-hydroxylase, specially hydroxylating Pro986
  - reference_id: file:human/P3H1/P3H1-uniprot.txt
    supporting_text: Has prolyl 3-hydroxylase activity and catalyzes the post-
- description: Catalytic core of the ER collagen prolyl 3-hydroxylation (PCP) complex with CRTAP
    and PPIB/cyclophilin B, which binds, modifies and chaperones unfolded collagen and mutually
    stabilizes its components in the ER lumen.
  molecular_function:
    id: GO:0019797
    label: procollagen-proline 3-dioxygenase activity
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: file:human/P3H1/P3H1-uniprot.txt
    supporting_text: Forms a ternary complex with PPIB (CYPB) and CRTAP, known as
  - reference_id: PMID:19846465
    supporting_text: CRTAP and P3H1 are mutually stabilized in the collagen prolyl 3-hydroxylation
  directly_involved_in:
  - id: GO:0032963
    label: collagen metabolic process
proposed_new_terms: []
suggested_questions:
- question: Does P3H1 have any biologically meaningful function (e.g., growth suppression) outside
    the PCP collagen-modifying complex, or are the historical "growth suppressor 1" and secreted
    proteoglycan observations independent of its enzymatic role?
- question: What determines the strict substrate specificity of P3H1 for alpha1(I)Pro986 among the
    many Pro-containing triplets in collagen, and how is this encoded by the collagen-binding sites
    of the PCP complex?
suggested_experiments:
- description: Reconstitute the purified P3H1/CRTAP/PPIB complex with a full-length procollagen
    substrate and use mass spectrometry to map the complete set of 3-hydroxyproline sites and the
    kinetics conferred by each complex component.
- description: Generate catalytically dead (e.g., H587A/H659A) versus complex-assembly-deficient
    P3H1 knock-in cells and compare collagen 3-hydroxylation, folding kinetics, overmodification
    and secretion to separate the enzymatic from the chaperone/stabilization contributions.