UniProt: P13674 (P4HA1_HUMAN), 534 aa precursor (signal 1-17, chain 18-534). HGNC:8546. EC 1.14.11.2.
P4HA1 is the catalytic alpha-1 subunit of collagen prolyl 4-hydroxylase (C-P4H). The active
enzyme is an alpha2-beta2 heterotetramer in which the beta subunit is P4HB (the multifunctional
protein disulfide isomerase, PDI). The alpha subunits provide the catalytic and peptide-substrate-
binding activity; P4HB is a structural subunit that also retains the tetramer in the ER lumen via
its KDEL signal.
It is a Fe(II)- and 2-oxoglutarate-dependent dioxygenase. Catalysis requires molecular O2, with
2-oxoglutarate decarboxylated to succinate + CO2, and requires ascorbate (vitamin C) to keep the
iron reduced.
ER lumen. The alpha subunit lacks a KDEL/retention signal; ER retention of the tetramer is conferred
by P4HB.
- [file:human/P4HA1/P4HA1-uniprot.txt "SUBCELLULAR LOCATION: Endoplasmic reticulum lumen."]
- PMID:2543975
Two enzyme isotypes exist: type I (P4HA1/alphaI) and type II (P4HA2/alphaII). They do NOT form mixed
alphaI-alphaII-beta2 tetramers. P4HA1 also undergoes alternative splicing (3 isoforms; mutually
exclusive exons VSP_004504, plus VSP_044578 in isoform 3).
- PMID:9211872
- PMID:2543975
The defining process is peptidyl-proline hydroxylation to 4-hydroxy-L-proline, which is essential for
collagen triple-helix stability (4-Hyp stabilizes the helix; under-hydroxylated collagen is thermally
unstable). Downstream, this supports collagen biosynthesis and collagen fibril organization.
GO annotations include GO:0030199 collagen fibril organization (IBA), which is a reasonable
downstream/process role for the modifying enzyme; keep as non-core (the enzyme modifies procollagen
but the assembly of fibrils is performed by other machinery — accept as involved_in, non-core).
Core MF:
- GO:0004656 procollagen-proline 4-dioxygenase activity — IDA (PMID:9211872), TAS (PMID:2543975),
IBA, IEA. ACCEPT (core). Direct catalytic activity demonstrated.
Cofactor/mechanism MF (accept, non-core supporting features):
- GO:0005506 iron ion binding (IEA, InterPro) — ACCEPT, supported by Fe2OG domain + COFACTOR Fe(2+).
- GO:0031418 L-ascorbic acid binding (IEA, UniProtKB-KW Vitamin C) — ACCEPT.
- GO:0016705 oxidoreductase, paired donors with O2 (IEA, InterPro) — ACCEPT (parent of the precise
dioxygenase activity).
CC:
- GO:0005788 ER lumen (IEA SubCell, TAS Reactome x2) — ACCEPT (core location).
- GO:0005783 endoplasmic reticulum (IEA, IDA-HPA, TAS PMID:2543975) — ACCEPT (parent of ER lumen).
- GO:0016222 procollagen-proline 4-dioxygenase complex (IBA, IEA) — ACCEPT (the alpha2-beta2 C-P4H
complex). This is the relevant complex CC.
- GO:0016020 membrane (HDA, PMID:19946888 — NK cell membrane proteome MS) — over-annotation. P4HA1 is
a soluble ER-lumenal protein; a membrane HDA from a bulk membrane-fraction proteomics screen is a
likely co-fractionation artifact (or ER-membrane association of the secretory machinery). Do not
REMOVE an experimental annotation on weak grounds → MARK_AS_OVER_ANNOTATED (HDA, not core; not the
documented soluble ER-lumen localization).
MF protein binding (IPI):
- GO:0005515 protein binding, IPI vs HTT (PMID:17500595, Htt-fragment interactome) — KEEP_AS_NON_CORE;
bare protein binding; the HTT interaction is in UniProt INTERACTION but unrelated to catalytic core.
- GO:0005515 protein binding, IPI vs P4HA2/O15460 (PMID:30021884, histone XL-MS) — KEEP_AS_NON_CORE;
high-throughput, partner is paralog P4HA2; uninformative bare term.
- GO:0005515 protein binding, IPI vs P4HA2/O15460 (PMID:40205054, multimodal cell map) — KEEP_AS_NON_CORE.
- GO:0042802 identical protein binding, IPI vs P13674 (PMID:24207127) — KEEP_AS_NON_CORE; this is the
alpha-alpha homodimerization within the tetramer (structurally demonstrated), functionally real but
subsidiary to catalytic core.
P4HA1 is induced by hypoxia (HIF target) and is implicated in ECM remodeling / tumor progression in
several cancers. No such BP annotations are present in this GOA; if added they should be non-core.
(Not in the cached pubs; noted for completeness.)