Transmembrane prolyl 4-hydroxylase

Function

Catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates HIF1A at 'Pro-402' and 'Pro-564'. May function as a cellular oxygen sensor and, under normoxic conditions, may target HIF through the hydroxylation for proteasomal degradation via the von Hippel-Lindau ubiquitination complex.

Classification

Family (Pfam)

PF13640 2OG-FeII_Oxy_3, PF13499 EF-hand_7

InterPro

EF-hand-dom_pair, EF_Hand_1_Ca_BS, EF_hand_dom, Oxoglu/Fe-dep_dioxygenase_dom, P4HA-like, Pro_4_hyd_alph, Pro_4_hyd_alph_FE2OG_OXY

Functional cluster

Secreted Growth Factors & Cytokines

Experimental structures · PDB · 1

• 6TP5 X-ray 2.25A

A predicted model is available from AlphaFold.

Gene Ontology · 9

• GO:0005783 endoplasmic reticulum
• GO:0005789 endoplasmic reticulum membrane
• GO:0016706 2-oxoglutarate-dependent dioxygenase activity
• GO:0005509 calcium ion binding
• GO:0160082 hypoxia-inducible factor-proline dioxygenase activity
• GO:0005506 iron ion binding
• GO:0031418 L-ascorbic acid binding
• GO:0004656 procollagen-proline 4-dioxygenase activity
• GO:0045646 regulation of erythrocyte differentiation

Disease associations

• hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities MONDO:0032780

Drugs targeting this protein · 2

• ROXADUSTAT inhibitor
• DAPRODUSTAT inhibitor

Related proteins · sequence + function similarity

• Transmembrane prolyl 4-hydroxylase 0.98
• Prolyl 4-hydroxylase subunit alpha-3 0.72
• Prolyl 4-hydroxylase subunit alpha-3 0.70
• Prolyl 4-hydroxylase subunit alpha-3 0.70
• Prolyl 4-hydroxylase subunit alpha-3 0.69
• Prolyl 3-hydroxylase 3 0.68
• Prolyl 3-hydroxylase 3 0.67
• Prolyl 3-hydroxylase 1 0.67
• Prolyl 3-hydroxylase 1 0.66
• Prolyl 3-hydroxylase 2 0.65
• Prolyl 3-hydroxylase 2 0.65
• Prolyl 3-hydroxylase 2 0.64

Co-cited proteins · studied together in the literature

• Prolyl hydroxylase EGLN2 1 shared papers
• Prolyl hydroxylase EGLN3 1 shared papers
• Egl nine homolog 1 1 shared papers

Literature · 6 cited papers

• Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome). Genet. Med. · 2019
• The full-ORF clone resource of the German cDNA consortium. BMC Genomics · 2007
• An endoplasmic reticulum transmembrane prolyl 4-hydroxylase is induced by hypoxia and acts on hypoxia-inducible factor alpha. J. Biol. Chem. · 2007
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat. Genet. · 2004
• Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. Biochem. Biophys. Res. Commun. · 2002