LMPD Database

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LMP003844

UniProt Annotations

Entry Information
Gene Nameegl-9 family hypoxia-inducible factor 3
Protein EntryEGLN3_MOUSE
UniProt IDQ91UZ4
SpeciesMouse
Comments
Comment typeDescription
Catalytic ActivityHypoxia-inducible factor-L-proline + 2- oxoglutarate + O(2) = hypoxia-inducible factor-trans-4-hydroxy-L- proline + succinate + CO(2).
CofactorName=Fe(2+); Xref=ChEBI:CHEBI:29033; Evidence={ECO:0000255|PROSITE-ProRule:PRU00805}; Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000255|PROSITE- ProRule:PRU00805};
CofactorName=L-ascorbate; Xref=ChEBI:CHEBI:38290; Evidence={ECO:0000250};
Developmental StageDetected at E8.5 in proliferating myoblasts of the dermomyotome and the developing heart tube. From dermomyotomal cells of the rostral somites expression progressed in a rostral to caudal pattern, with highest levels seen in the muscle primordia and mature muscles. {ECO:0000269|PubMed:10543731}.
Disruption PhenotypeNull mice exhibit reduced apoptosis of in sympathetic neurons. However, the sympathoadrenal system appears hypofunctional with reduced target tissue innervation, adrenal medullary secretory capacity, sympathoadrenal responses, and systemic blood pressure. There is an increase in ADRB2 abundance and decrease of ADRB1 abundance in heart. {ECO:0000269|PubMed:18332118, ECO:0000269|PubMed:19584355, ECO:0000269|PubMed:19720742}.
DomainThe Beta(2)beta(3) 'finger-like' loop domain is important for substrate (HIFs' CODD/NODD) selectivity. {ECO:0000250}.
FunctionPlays 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 (By similarity). 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. ELGN3 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. Target proteins are preferencially recognized via a LXXLAP motif. {ECO:0000250, ECO:0000269|PubMed:21317538}.
InductionInduced by hypoxia. Up-regulated in proliferating myoblasts induced to form differentiated myotubes. {ECO:0000269|PubMed:21317538}.
Sequence CautionSequence=AAH22961.1; Type=Erroneous initiation; Evidence={ECO:0000305};
SimilarityContains 1 Fe2OG dioxygenase domain. {ECO:0000255|PROSITE-ProRule:PRU00805}.
Subcellular LocationNucleus {ECO:0000250}. Cytoplasm {ECO:0000250}. Note=Colocalizes with WDR83 in the cytoplasm. {ECO:0000250}.
SubunitInteracts with ADRB2; the interaction hydroxylates ADRB2 facilitating its ubiquitination by the VHL-E3 ligase complex. Interacts with PKM; the interaction hydroxylates PKM in hypoxia. Interacts with WDR83; the interaction leads to almost complete elimination of HIF-mediated reporter activity (By similarity). Interacts with BCL2 (via its BH4 domain); the interaction disrupts the BAX-BCL4 complex inhibiting the anti-apoptotic activity of BCL2. Interacts with LIMD1, WTIP and AJUBA (By similarity). {ECO:0000250}.
Tissue SpecificityHighly expressed in cardiac and smooth muscle. Also high expression in brain, skeletal muscle and kidney. Low levels in lung. {ECO:0000269|PubMed:12234095}.