EGLN3_RAT
ID EGLN3_RAT Reviewed; 239 AA.
AC Q62630;
DT 16-JUN-2003, integrated into UniProtKB/Swiss-Prot.
DT 25-JAN-2012, sequence version 2.
DT 03-AUG-2022, entry version 134.
DE RecName: Full=Prolyl hydroxylase EGLN3 {ECO:0000305};
DE EC=1.14.11.- {ECO:0000250|UniProtKB:Q9H6Z9};
DE AltName: Full=Egl nine homolog 3;
DE EC=1.14.11.29 {ECO:0000250|UniProtKB:Q9H6Z9};
DE AltName: Full=Hypoxia-inducible factor prolyl hydroxylase 3;
DE Short=HIF-PH3;
DE Short=HIF-prolyl hydroxylase 3;
DE Short=HPH-3;
DE AltName: Full=Prolyl hydroxylase domain-containing protein 3;
DE Short=PHD3;
DE AltName: Full=SM-20 {ECO:0000303|PubMed:10386996, ECO:0000303|PubMed:11060309};
GN Name=Egln3;
GN Synonyms=Sm20 {ECO:0000303|PubMed:10386996, ECO:0000303|PubMed:11060309};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND INDUCTION.
RC STRAIN=Sprague-Dawley; TISSUE=Aortic smooth muscle;
RX PubMed=8175725; DOI=10.1016/s0021-9258(18)99981-3;
RA Wax S.D., Rosenfield C.L., Taubman M.B.;
RT "Identification of a novel growth factor-responsive gene in vascular smooth
RT muscle cells.";
RL J. Biol. Chem. 269:13041-13047(1994).
RN [2]
RP FUNCTION, AND INDUCTION.
RX PubMed=10386996; DOI=10.1046/j.1471-4159.1999.0730429.x;
RA Lipscomb E.A., Sarmiere P.D., Crowder R.J., Freeman R.S.;
RT "Expression of the SM-20 gene promotes death in nerve growth factor-
RT dependent sympathetic neurons.";
RL J. Neurochem. 73:429-432(1999).
RN [3]
RP FUNCTION.
RX PubMed=11595184; DOI=10.1016/s0092-8674(01)00507-4;
RA Epstein A.C.R., Gleadle J.M., McNeill L.A., Hewitson K.S., O'Rourke J.,
RA Mole D.R., Mukherji M., Metzen E., Wilson M.I., Dhanda A., Tian Y.M.,
RA Masson N., Hamilton D.L., Jaakkola P., Barstead R., Hodgkin J.,
RA Maxwell P.H., Pugh C.W., Schofield C.J., Ratcliffe P.J.;
RT "C. elegans EGL-9 and mammalian homologs define a family of dioxygenases
RT that regulate HIF by prolyl hydroxylation.";
RL Cell 107:43-54(2001).
RN [4]
RP FUNCTION.
RX PubMed=11060309; DOI=10.1074/jbc.m008407200;
RA Lipscomb E.A., Sarmiere P.D., Freeman R.S.;
RT "SM-20 is a novel mitochondrial protein that causes caspase-dependent cell
RT death in nerve growth factor-dependent neurons.";
RL J. Biol. Chem. 276:5085-5092(2001).
RN [5]
RP IDENTIFICATION OF INITIATION SITE, INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=15081411; DOI=10.1016/j.bbrc.2004.03.115;
RA Menzies K., Liu B., Kim W.J., Moschella M.C., Taubman M.B.;
RT "Regulation of the SM-20 prolyl hydroxylase gene in smooth muscle cells.";
RL Biochem. Biophys. Res. Commun. 317:801-810(2004).
RN [6]
RP INTERACTION WITH WDR83, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=16407229; DOI=10.1074/jbc.m513751200;
RA Hopfer U., Hopfer H., Jablonski K., Stahl R.A.K., Wolf G.;
RT "The novel WD-repeat protein Morg1 acts as a molecular scaffold for
RT hypoxia-inducible factor prolyl hydroxylase 3 (PHD3).";
RL J. Biol. Chem. 281:8645-8655(2006).
RN [7]
RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND INDUCTION.
RX PubMed=16765982; DOI=10.1016/j.yjmcc.2006.04.009;
RA Willam C., Maxwell P.H., Nichols L., Lygate C., Tian Y.M., Bernhardt W.,
RA Wiesener M., Ratcliffe P.J., Eckardt K.U., Pugh C.W.;
RT "HIF prolyl hydroxylases in the rat; organ distribution and changes in
RT expression following hypoxia and coronary artery ligation.";
RL J. Mol. Cell. Cardiol. 41:68-77(2006).
RN [8]
RP INTERACTION WITH BCL2, AND FUNCTION.
RX PubMed=20849813; DOI=10.1016/j.bbrc.2010.09.037;
RA Liu Y., Huo Z., Yan B., Lin X., Zhou Z.N., Liang X., Zhu W., Liang D.,
RA Li L., Liu Y., Zhao H., Sun Y., Chen Y.H.;
RT "Prolyl hydroxylase 3 interacts with Bcl-2 to regulate doxorubicin-induced
RT apoptosis in H9c2 cells.";
RL Biochem. Biophys. Res. Commun. 401:231-237(2010).
CC -!- FUNCTION: Prolyl hydroxylase that mediates hydroxylation of proline
CC residues in target proteins, such as PKM, TELO2, ATF4 and HIF1A (By
CC similarity). Target proteins are preferentially recognized via a LXXLAP
CC motif (By similarity). Cellular oxygen sensor that catalyzes, under
CC normoxic conditions, the post-translational formation of 4-
CC hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins
CC (PubMed:11595184). Hydroxylates a specific proline found in each of the
CC oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-
CC terminal, CODD) of HIF1A (By similarity). Also hydroxylates HIF2A (By
CC similarity). Has a preference for the CODD site for both HIF1A and
CC HIF2A (By similarity). Hydroxylation on the NODD site by EGLN3 appears
CC to require prior hydroxylation on the CODD site (By similarity).
CC Hydroxylated HIFs are then targeted for proteasomal degradation via the
CC von Hippel-Lindau ubiquitination complex (By similarity). Under hypoxic
CC conditions, the hydroxylation reaction is attenuated allowing HIFs to
CC escape degradation resulting in their translocation to the nucleus,
CC heterodimerization with HIF1B, and increased expression of hypoxy-
CC inducible genes (By similarity). ELGN3 is the most important isozyme in
CC limiting physiological activation of HIFs (particularly HIF2A) in
CC hypoxia (By similarity). Also hydroxylates PKM in hypoxia, limiting
CC glycolysis (By similarity). Under normoxia, hydroxylates and regulates
CC the stability of ADRB2 (By similarity). Regulator of cardiomyocyte and
CC neuronal apoptosis (By similarity). In cardiomyocytes, inhibits the
CC anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex
CC (PubMed:20849813). In neurons, has a NGF-induced proapoptotic effect,
CC probably through regulating CASP3 activity (PubMed:10386996,
CC PubMed:11060309). Also essential for hypoxic regulation of neutrophilic
CC inflammation (By similarity). Plays a crucial role in DNA damage
CC response (DDR) by hydroxylating TELO2, promoting its interaction with
CC ATR which is required for activation of the ATR/CHK1/p53 pathway (By
CC similarity). Also mediates hydroxylation of ATF4, leading to decreased
CC protein stability of ATF4 (By similarity).
CC {ECO:0000250|UniProtKB:Q91UZ4, ECO:0000250|UniProtKB:Q9H6Z9,
CC ECO:0000269|PubMed:10386996, ECO:0000269|PubMed:11060309,
CC ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:20849813}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + L-prolyl-[protein] + O2 = CO2 + succinate +
CC trans-4-hydroxy-L-prolyl-[protein]; Xref=Rhea:RHEA:63484, Rhea:RHEA-
CC COMP:12408, Rhea:RHEA-COMP:16354, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:30031,
CC ChEBI:CHEBI:50342, ChEBI:CHEBI:61965;
CC Evidence={ECO:0000250|UniProtKB:Q9H6Z9};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63485;
CC Evidence={ECO:0000250|UniProtKB:Q9H6Z9};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + L-prolyl-[hypoxia-inducible factor alpha
CC subunit] + O2 = CO2 + succinate + trans-4-hydroxy-L-prolyl-[hypoxia-
CC inducible factor alpha subunit]; Xref=Rhea:RHEA:48400, Rhea:RHEA-
CC COMP:12093, Rhea:RHEA-COMP:12094, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:30031,
CC ChEBI:CHEBI:50342, ChEBI:CHEBI:61965; EC=1.14.11.29;
CC Evidence={ECO:0000250|UniProtKB:Q9H6Z9};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU00805};
CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000255|PROSITE-
CC ProRule:PRU00805};
CC -!- COFACTOR:
CC Name=L-ascorbate; Xref=ChEBI:CHEBI:38290;
CC Evidence={ECO:0000250|UniProtKB:Q96KS0};
CC -!- SUBUNIT: Interacts with ADRB2; the interaction hydroxylates ADRB2
CC facilitating its ubiquitination by the VHL-E3 ligase complex (By
CC similarity). Interacts with PAX2; the interaction targets PAX2 for
CC destruction (By similarity). Interacts with PKM; the interaction
CC hydroxylates PKM in hypoxia (By similarity). Interacts with WDR83; the
CC interaction leads to almost complete elimination of HIF-mediated
CC reporter activity (PubMed:16407229). Interacts with BCL2 (via its BH4
CC domain); the interaction disrupts the BAX-BCL4 complex inhibiting the
CC anti-apoptotic activity of BCL2 (By similarity).
CC {ECO:0000250|UniProtKB:Q9H6Z9, ECO:0000269|PubMed:16407229}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q9H6Z9}. Cytoplasm
CC {ECO:0000269|PubMed:16407229}. Note=Colocalizes with WDR83 in the
CC cytoplasm. {ECO:0000269|PubMed:16407229}.
CC -!- TISSUE SPECIFICITY: Highly expressed in vascular smooth muscle.
CC Moderately expressed in esophagus, stomach, small bowel and aorta. Low
CC levels in tail and kidney. Expression also in pheochromocytoma cell
CC line PC-12. {ECO:0000269|PubMed:15081411, ECO:0000269|PubMed:16407229,
CC ECO:0000269|PubMed:16765982, ECO:0000269|PubMed:8175725}.
CC -!- INDUCTION: By PDGF and angiotensin II in aortic smooth muscle cells. By
CC deprivation of NGF in neuronal cell cultures. Induced during coronary
CC heart ligation. {ECO:0000269|PubMed:10386996,
CC ECO:0000269|PubMed:15081411, ECO:0000269|PubMed:16765982,
CC ECO:0000269|PubMed:8175725}.
CC -!- DOMAIN: The Beta(2)beta(3) 'finger-like' loop domain is important for
CC substrate (HIFs' CODD/NODD) selectivity.
CC {ECO:0000250|UniProtKB:Q9GZT9}.
CC -!- PTM: Ubiquitinated by SIAH1 and/or SIAH2 in response to the unfolded
CC protein response (UPR), leading to its degradation.
CC {ECO:0000250|UniProtKB:Q91UZ4}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA19321.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; U06713; AAA19321.1; ALT_INIT; mRNA.
DR PIR; A53770; A53770.
DR RefSeq; NP_062244.1; NM_019371.1.
DR AlphaFoldDB; Q62630; -.
DR SMR; Q62630; -.
DR BioGRID; 248549; 1.
DR STRING; 10116.ENSRNOP00000007219; -.
DR PhosphoSitePlus; Q62630; -.
DR PaxDb; Q62630; -.
DR GeneID; 54702; -.
DR KEGG; rno:54702; -.
DR UCSC; RGD:71019; rat.
DR CTD; 112399; -.
DR RGD; 71019; Egln3.
DR eggNOG; KOG3710; Eukaryota.
DR InParanoid; Q62630; -.
DR OrthoDB; 1604981at2759; -.
DR Reactome; R-RNO-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
DR PRO; PR:Q62630; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0016706; F:2-oxoglutarate-dependent dioxygenase activity; ISO:RGD.
DR GO; GO:0008198; F:ferrous iron binding; IBA:GO_Central.
DR GO; GO:0031418; F:L-ascorbic acid binding; IEA:UniProtKB-KW.
DR GO; GO:0031545; F:peptidyl-proline 4-dioxygenase activity; ISO:RGD.
DR GO; GO:0031543; F:peptidyl-proline dioxygenase activity; ISO:RGD.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; ISS:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:UniProtKB-KW.
DR GO; GO:0071456; P:cellular response to hypoxia; IBA:GO_Central.
DR GO; GO:1990830; P:cellular response to leukemia inhibitory factor; ISO:RGD.
DR GO; GO:0018401; P:peptidyl-proline hydroxylation to 4-hydroxy-L-proline; ISO:RGD.
DR GO; GO:0018126; P:protein hydroxylation; ISO:RGD.
DR GO; GO:0042127; P:regulation of cell population proliferation; IMP:RGD.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:0001666; P:response to hypoxia; ISO:RGD.
DR InterPro; IPR005123; Oxoglu/Fe-dep_dioxygenase.
DR InterPro; IPR006620; Pro_4_hyd_alph.
DR InterPro; IPR044862; Pro_4_hyd_alph_FE2OG_OXY.
DR Pfam; PF13640; 2OG-FeII_Oxy_3; 1.
DR SMART; SM00702; P4Hc; 1.
DR PROSITE; PS51471; FE2OG_OXY; 1.
PE 1: Evidence at protein level;
KW Apoptosis; Cytoplasm; Dioxygenase; DNA damage; Iron; Metal-binding;
KW Nucleus; Oxidoreductase; Reference proteome; Ubl conjugation; Vitamin C.
FT CHAIN 1..239
FT /note="Prolyl hydroxylase EGLN3"
FT /id="PRO_0000022730"
FT DOMAIN 116..214
FT /note="Fe2OG dioxygenase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT REGION 62..73
FT /note="Beta(2)beta(3) 'finger-like' loop"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT REGION 88..104
FT /note="Required for interaction with ADRB2"
FT /evidence="ECO:0000250|UniProtKB:Q9H6Z9"
FT BINDING 135
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 137
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 196
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 205
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
SQ SEQUENCE 239 AA; 27242 MW; F410274976499755 CRC64;
MPLGHIMRLD LEKIALEYIV PCLHEVGFCY LDNFLGEVVG DCVLERVKQL HYNGALRDGQ
LAGPRAGVSK RHLRGDQITW IGGNEEGCEA INFLLSLIDR LVLYCGSRLG KYYVKERSKA
MVACYPGNGT GYVRHVDNPN GDGRCITCIY YLNKNWDAKL HGGVLRIFPE GKSFVADVEP
IFDRLLFSWS DRRNPHEVQP SYATRYAMTV WYFDAEERAE AKKKFRNLTR KTESALAKD
