Names & Taxonomy
- Uniprot ID:
- Q9H6Z9
- Entry Name:
- EGLN3_HUMAN
- Status:
- reviewed
- Protein Names:
- Egl nine homolog 3 (EC 1.14.11.29) (HPH-1) (Hypoxia-inducible factor prolyl hydroxylase 3) (HIF-PH3) (HIF-prolyl hydroxylase 3) (HPH-3) (Prolyl hydroxylase domain-containing protein 3) (PHD3)
- Gene Names:
- EGLN3
- Gene Names Primary:
- EGLN3
- Organism:
- Homo sapiens (Human)
Structure
- Length:
- 239
- Sequence:
- MPLGHIMRLDLEKIALEYIVPCLHEVGFCYLDNFLGEVVGDCVLERVKQLHCTGALRDGQLAGPRAGVSKRHLRGDQITWIGGNEEGCEAISFLLSLIDRLVLYCGSRLGKYYVKERSKAMVACYPGNGTGYVRHVDNPNGDGRCITCIYYLNKNWDAKLHGGILRIFPEGKSFIADVEPIFDRLLFFWSDRRNPHEVQPSYATRYAMTVWYFDAEERAEAKKKFRNLTRKTESALTED
- Proteomes:
- UP000005640
Subcellular location
- Subcellular Location:
- Nucleus. Cytoplasm. Note=Colocalizes with WDR83 in the cytoplasm.
Function
- Function:
- 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.
- Catalytic Activity:
- Hypoxia-inducible factor-L-proline + 2-oxoglutarate + O(2) = hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO(2).
- Cofactor:
- COFACTOR: Name=Fe(2+); Xref=ChEBI:CHEBI:29033; ; Note=Binds 1 Fe(2+) ion per subunit.;; COFACTOR: Name=L-ascorbate; Xref=ChEBI:CHEBI:38290;
- Enzyme Regulation:
- ENZYME REGULATION: Activated in cardiovascular cells and Hela cells following exposure to hypoxia. Inhibited by polynitrogen compounds probably by chelation to Fe(2+) ions.
- Cross Reference Drug Bank:
- DB00126
- Gene Ontology Go:
- cytoplasm
cytosol
nucleoplasm
nucleus
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
activation of cysteine-type endopeptidase activity involved in apoptotic process
apoptotic process
cellular response to DNA damage stimulus
cellular response to hypoxia
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 - Gene Ontology Biological Process:
- activation of cysteine-type endopeptidase activity involved in apoptotic process
apoptotic process
cellular response to DNA damage stimulus
cellular response to hypoxia
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 - Gene Ontology 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 - Gene Ontology Cellular Component:
- cytoplasm
cytosol
nucleoplasm
nucleus - Keywords:
- Apoptosis
Complete proteome
Cytoplasm
DNA damage
Dioxygenase
Iron
Metal-binding
Nucleus
Oxidoreductase
Polymorphism
Reference proteome
Vitamin C - Interacts With:
- Q9NYB9; Q5JST6; Q9P0K8; D0VY79; Q16665; Q6IBW4-4; P14618-1; Q04864; Q53GC0; Q6PF05-3