UniProt: Q32P28 (P3H1_HUMAN), 736 aa precursor. HGNC:19316. Human.
EC 1.14.11.7 (procollagen-proline 3-dioxygenase / prolyl 3-hydroxylase).
P3H1 is an ER-lumenal 2-oxoglutarate / Fe(II)-dependent dioxygenase that catalyzes
3-hydroxylation of specific proline residues in procollagen.
The specific physiological substrate residue is alpha1(I)Pro986 (and alpha1(II)Pro986).
- PMID:17277775
- PMID:22615817
P3H1 is the catalytic core of the ER collagen prolyl 3-hydroxylation complex
("PCP complex") with CRTAP (O75718) and PPIB / cyclophilin B (P23284), in 1:1:1 stoichiometry.
- [file:human/P3H1/P3H1-uniprot.txt "Forms a ternary complex with PPIB (CYPB) and CRTAP, known as"] / "the PCP complex, in a 1:1:1 stoichiometric ratio; this complex binds unfolded collagen (PubMed:39245686)."
- Cryo-EM structures (8K0E/F/I/M/8K17/8KC9) of the ternary and dual-ternary complex with 2-OG and Fe(3+) and a collagen analog PMID:39245686.
- PMID:39245686
- The active sites of P3H1 and PPIB form a face-to-face bifunctional reaction center: "The active sites of P3H1 and PPIB form a face-to-face bifunctional reaction center, indicating a coupled modification mechanism." PMID:39245686
- P3H1 is the only complex component with a KDEL ER-retrieval signal (C-terminal "...KPKDEL", residues 733-736 "Prevents secretion from ER"). KDEL is essential for function in vivo PMID:22615817.
CRTAP and P3H1 mutually stabilize each other in the ER; loss of either depletes both (proteasomal degradation of the orphan).
- PMID:19846465
- PMID:19846465
- The complex also has chaperone activity (inhibits citrate synthase aggregation, assists rhodanese refolding, collagen fibrillogenesis): PMID:19846465; PMID:22615817. This underpins protein folding / protein stabilization GO terms.
PPIB/CyPB loss does NOT abolish Pro986 3-hydroxylation PMID:20089953, i.e. P3H1 is the catalytic core; CyPB is the PPIase partner.
Isoform 1 (736 aa, KDEL) is ER-resident; this is the catalytically relevant location.
- [file:human/P3H1/P3H1-uniprot.txt "SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum"]
- ER lumen (Reactome TAS), ER (IDA PMID:19846465, PMID:20089953; EXP PMID:19088120).
- [PMID:19088120 "The affected splice form encodes a 736 amino acid (AA) protein with a \"KDEL\" endoplasmic reticulum retention signal."] — establishes isoform 1 / ER as the functional form.
- Secondary/secreted: as a CSPG, P3H1 (leprecan) can be secreted into ECM. UniProt: "Secreted, extracellular space, extracellular matrix" (by similarity to rat). This and proteomics localizations (exosome, membrane, ECM colocalization) are non-core / context-specific captures.
Osteogenesis imperfecta type 8 (OI8; MIM 610915), autosomal recessive, severe/lethal. Null LEPRE1 -> loss of Pro986 3-hydroxylation, collagen overmodification, delayed folding.
- PMID:17277775
- W675L variant: loss of catalytic activity (UniProt VARIANT + PMID:39245686).
Original cloning as Gros1, a putative growth suppressor in fibroblasts (NIH3T3 overexpression slowed growth). This predates knowledge of its enzymatic role; NAS, weak/historical.
- PMID:10951563
- UniProt FUNCTION: "Has growth suppressive activity in fibroblasts." Keep as non-core (over-annotated relative to the well-established collagen-modifying enzyme role).
CORE:
- GO:0019797 procollagen-proline 3-dioxygenase activity (MF) — ACCEPT core (IDA PMID:39245686; IBA; ISS; IEA). EC 1.14.11.7.
- GO:0005788 ER lumen / GO:0005783 ER (CC) — ACCEPT (site of action).
- GO:0032963 collagen metabolic process (BP) — ACCEPT/core-ish (its biological role).
- GO:0032991 protein-containing complex part_of — ACCEPT (PCP complex membership).
Cofactor / catalytic-support MF (keep, but not bare core):
- GO:0005506 iron ion binding — ACCEPT (catalytic Fe(II) cofactor; structurally demonstrated).
- GO:0031418 L-ascorbic acid binding — KEEP_AS_NON_CORE / ACCEPT (vitamin C cofactor).
- GO:0016705 oxidoreductase activity (paired donors, O2) — parent of the specific dioxygenase MF; KEEP_AS_NON_CORE (generic; GO:0019797 is the informative term).
BP (complex chaperone / collagen biogenesis):
- GO:0006457 protein folding — ACCEPT/KEEP (complex chaperone function; IMP PMID:17277775, ISS PMID:15044469).
- GO:0050821 protein stabilization — ACCEPT (mutual stabilization, IMP PMID:19846465, PMID:22615817).
- GO:0060348 bone development — KEEP_AS_NON_CORE (downstream physiology; OI phenotype).
- GO:0050708 regulation of protein secretion — KEEP_AS_NON_CORE (collagen secretion delay in nulls).
- GO:1901874 negative regulation of post-translational protein modification — KEEP_AS_NON_CORE. This reflects that loss of P3H1 leads to OVER-modification (lysyl hydroxylation/glycosylation) of the helix; the wild-type complex limits over-modification by speeding folding. Slightly contorted but defensible from the IMP data (overmodification on P3H1 loss).
CC bare-binding / proteomics (non-core):
- GO:0005515 protein binding (IPI x3: PMID:30021884, PMID:33961781, PMID:39245686) — KEEP_AS_NON_CORE. Partners O75718=CRTAP and P23284=PPIB (in 39245686) are real complex partners; 30021884 (histone XL-MS) and 33961781 (BioPlex) capture CRTAP. Bare "protein binding" uninformative.
- GO:0005518 collagen binding contributes_to (ISS PMID:15044469) — ACCEPT/KEEP_AS_NON_CORE; the complex binds unfolded/denatured collagen substrate (consistent with structure & enzymology).
- GO:0070062 extracellular exosome (HDA PMID:19056867) — KEEP_AS_NON_CORE (urinary exosome proteomics; not the functional ER site).
- GO:0016020 membrane (HDA PMID:19946888) — KEEP_AS_NON_CORE (NK-cell membrane proteome; original immunoscreen was a "plasma membrane protein"; low-resolution).
- GO:0031012 extracellular matrix colocalizes_with (HDA PMID:28327460) — KEEP_AS_NON_CORE (consistent with secreted CSPG leprecan form; not the catalytic ER role).
- GO:0010976 positive regulation of neuron projection development (ISS GO_REF:0000024 from rat Q9R1J8) — MARK_AS_OVER_ANNOTATED (electronic ISS transfer from rat leprecan; no human evidence; tangential to collagen-modifying role).
- GO:0008285 negative regulation of cell population proliferation (NAS PMID:10951563) — KEEP_AS_NON_CORE (historical Gros1 growth-suppressor assertion; superseded by enzymatic characterization).
Falcon report largely corroborated the existing review; the PCP cryo-EM structural paper it foregrounds (Li et al. 2024, Nat Commun, DOI 10.1038/s41467-024-52321-6) is already in the review as PMID:39245686. Two additional verified references were added:
action: changes made; reviews were already COMPLETE and these papers are downstream disease/mechanism context. Edits are additive (new references only).