EGLN3 Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis. Under normoxia, hydroxylates and regulates the stability of ADRB2. Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex. In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity. Also essential for hypoxic regulation of neutrophilic inflammation. Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway. Target proteins are preferentially recognized via a LXXLAP motif. Widely expressed at low levels. Expressed at higher levels in adult heart (cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle), lung and placenta, and in fetal spleen, heart and skeletal muscle. Also expressed in pancreas. Localized to pancreatic acini and islet cells. Note: This description may include information from UniProtKB.
Protein type: EC; Oxidoreductase
Chromosomal Location of human Ortholog: 14q13.1
Cellular Component:  cytoplasm; cytosol; nucleoplasm; nucleus
Molecular Function:  iron ion binding; L-ascorbic acid binding; oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, 2-oxoglutarate as one donor, and incorporation of one atom each of oxygen into both donors; peptidyl-proline 4-dioxygenase activity; protein binding
Biological Process:  activation of cysteine-type endopeptidase activity involved in apoptotic process; apoptotic process; cellular response to DNA damage stimulus; oxidation-reduction process; peptidyl-proline hydroxylation to 4-hydroxy-L-proline; protein hydroxylation; regulation of cell proliferation; regulation of neuron apoptotic process; regulation of transcription from RNA polymerase II promoter in response to hypoxia; response to hypoxia
Reference #:  Q9H6Z9 (UniProtKB)
Alt. Names/Synonyms: Egl nine homolog 3; egl nine homolog 3 (C. elegans); egl nine-like protein 3 isoform; egl-9 family hypoxia inducible factor 3; EGLN3; FLJ21620; HIF prolyl hydroxylase 3; HIF-PH3; HIF-prolyl hydroxylase 3; HIFP4H3; HIFPH3; HPH-1; HPH-3; Hypoxia-inducible factor prolyl hydroxylase 3; MGC125998; MGC125999; PHD3; Prolyl hydroxylase domain-containing protein 3; Prolyl hydroxylase EGLN3
Gene Symbols: EGLN3
Molecular weight: 27,261 Da
Basal Isoelectric point: 7.56  Predict pI for various phosphorylation states
CST Pathways:  Angiogenesis
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Protein Structure Not Found.

Cross-references to other databases:  AlphaFold  |  STRING  |  cBioPortal  |  Wikipedia  |  Reactome  |  neXtProt  |  Protein Atlas  |  BioGPS  |  Pfam  |  ENZYME  |  Phospho.ELM  |  UniProtKB  |  Entrez-Gene  |  GenPept  |  Ensembl Gene  |  InnateDB