EGLN1_RAT
ID EGLN1_RAT Reviewed; 338 AA.
AC P59722; Q642G6;
DT 16-JUN-2003, integrated into UniProtKB/Swiss-Prot.
DT 26-NOV-2014, sequence version 2.
DT 03-AUG-2022, entry version 131.
DE RecName: Full=Egl nine homolog 1;
DE EC=1.14.11.29 {ECO:0000250|UniProtKB:Q9GZT9};
DE AltName: Full=Hypoxia-inducible factor prolyl hydroxylase 2;
DE Short=HIF-PH2;
DE Short=HIF-prolyl hydroxylase 2;
DE Short=HPH-2;
DE AltName: Full=Prolyl hydroxylase domain-containing protein 2;
DE Short=PHD2;
DE Flags: Fragment;
GN Name=Egln1;
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 [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 36-338.
RC TISSUE=Heart {ECO:0000312|EMBL:AAH81694.1};
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 117-338.
RC STRAIN=Sprague-Dawley; TISSUE=Glial cell;
RA Duplan E.;
RT "Characterization of prolyl hydroxylase EGLN1 in rat C6 glioma cell line.";
RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=12586829; DOI=10.1074/jbc.m211293200;
RA D'Angelo G., Duplan E., Vigne P., Frelin C.;
RT "Cyclosporin A prevents the hypoxic adaptation by activating hypoxia-
RT inducible factor-1alpha Pro-564 hydroxylation.";
RL J. Biol. Chem. 278:15406-15411(2003).
RN [5]
RP ACTIVITY REGULATION, AND INDUCTION.
RX PubMed=12876291; DOI=10.1074/jbc.m302244200;
RA D'Angelo G., Duplan E., Boyer N., Vigne P., Frelin C.;
RT "Hypoxia up-regulates prolyl hydroxylase activity: a feedback mechanism
RT that limits HIF-1 responses during reoxygenation.";
RL J. Biol. Chem. 278:38183-38187(2003).
RN [6]
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).
CC -!- FUNCTION: Cellular oxygen sensor that catalyzes, under normoxic
CC conditions, the post-translational formation of 4-hydroxyproline in
CC hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific
CC proline found in each of the oxygen-dependent degradation (ODD) domains
CC (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates
CC HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B.
CC Hydroxylated HIFs are then targeted for proteasomal degradation via the
CC von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the
CC hydroxylation reaction is attenuated allowing HIFs to escape
CC degradation resulting in their translocation to the nucleus,
CC heterodimerization with HIF1B, and increased expression of hypoxy-
CC inducible genes. EGLN1 is the most important isozyme under normoxia
CC and, through regulating the stability of HIF1, involved in various
CC hypoxia-influenced processes such as angiogenesis in retinal and
CC cardiac functionality. Target proteins are preferentially recognized
CC via a LXXLAP motif. {ECO:0000250|UniProtKB:Q9GZT9,
CC ECO:0000269|PubMed:12586829}.
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:Q9GZT9};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000250|UniProtKB:Q9GZT9,
CC ECO:0000255|PROSITE-ProRule:PRU00805};
CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000250|UniProtKB:Q9GZT9,
CC ECO:0000255|PROSITE-ProRule:PRU00805};
CC -!- COFACTOR:
CC Name=L-ascorbate; Xref=ChEBI:CHEBI:38290;
CC Evidence={ECO:0000250|UniProtKB:Q9GZT9};
CC -!- ACTIVITY REGULATION: Increased activation in hypoxia. Hydroxylation of
CC the C-terminal ODD domain (CODD) proline of HIF1A is activated by
CC cyclosporin A (CsA). {ECO:0000269|PubMed:12586829,
CC ECO:0000269|PubMed:12876291}.
CC -!- SUBUNIT: Monomer. Interacts with ING4; the interaction inhibits the
CC hydroxylation of HIF alpha proteins. Interacts with PTGES3 (via PXLE
CC motif); thereby recruiting EGLN1 to the HSP90 pathway to facilitate HIF
CC alpha proteins hydroxylation. Interacts with LIMD1. Found in a complex
CC composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts with
CC EPAS1. Interacts with CBFA2T3 and HIF1A.
CC {ECO:0000250|UniProtKB:Q9GZT9}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16765982}. Nucleus
CC {ECO:0000269|PubMed:16765982}. Note=Mainly cytoplasmic. Shuttles
CC between the nucleus and cytoplasm. Nuclear export requires functional
CC XPO1. {ECO:0000250|UniProtKB:Q9GZT9}.
CC -!- TISSUE SPECIFICITY: Expressed in heart, liver, kidney, brain, liver and
CC testis. Highest levels in heart, lowest in liver.
CC {ECO:0000269|PubMed:16765982}.
CC -!- INDUCTION: Up-regulated by hypoxia especially in liver and testis.
CC Levels up-regulated also in myocardial infarction predominantly in
CC cardiomyocytes. {ECO:0000269|PubMed:12876291,
CC ECO:0000269|PubMed:16765982}.
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: S-nitrosylation inhibits the enzyme activity up to 60% under
CC aerobic conditions. Chelation of Fe(2+) has no effect on the S-
CC nitrosylation. It is uncertain whether nitrosylation occurs on Cys-238
CC or Cys-241. {ECO:0000250|UniProtKB:Q9GZT9}.
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DR EMBL; BC081694; AAH81694.1; -; mRNA.
DR EMBL; AY228140; AAO34711.1; -; mRNA.
DR RefSeq; XP_002725482.2; XM_002725436.3.
DR AlphaFoldDB; P59722; -.
DR SMR; P59722; -.
DR BioGRID; 259192; 1.
DR STRING; 10116.ENSRNOP00000026767; -.
DR BindingDB; P59722; -.
DR ChEMBL; CHEMBL3638322; -.
DR PhosphoSitePlus; P59722; -.
DR jPOST; P59722; -.
DR PaxDb; P59722; -.
DR PRIDE; P59722; -.
DR GeneID; 308913; -.
DR UCSC; RGD:631375; rat.
DR CTD; 54583; -.
DR RGD; 631375; Egln1.
DR eggNOG; KOG3710; Eukaryota.
DR InParanoid; P59722; -.
DR OrthoDB; 1604981at2759; -.
DR BRENDA; 1.14.11.29; 5301.
DR Reactome; R-RNO-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR GO; GO:0005829; C:cytosol; IDA:RGD.
DR GO; GO:0098978; C:glutamatergic synapse; ISO:RGD.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0014069; C:postsynaptic density; ISO:RGD.
DR GO; GO:0016706; F:2-oxoglutarate-dependent dioxygenase activity; ISO:RGD.
DR GO; GO:0019899; F:enzyme binding; IPI:BHF-UCL.
DR GO; GO:0008198; F:ferrous iron binding; ISS:UniProtKB.
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; IDA:RGD.
DR GO; GO:0055008; P:cardiac muscle tissue morphogenesis; ISO:RGD.
DR GO; GO:0006879; P:cellular iron ion homeostasis; ISO:RGD.
DR GO; GO:0071456; P:cellular response to hypoxia; IBA:GO_Central.
DR GO; GO:0060347; P:heart trabecula formation; ISO:RGD.
DR GO; GO:0060711; P:labyrinthine layer development; ISO:RGD.
DR GO; GO:1905290; P:negative regulation of CAMKK-AMPK signaling cascade; IMP:RGD.
DR GO; GO:0051344; P:negative regulation of cyclic-nucleotide phosphodiesterase activity; IDA:RGD.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; IDA:RGD.
DR GO; GO:0032364; P:oxygen homeostasis; ISO:RGD.
DR GO; GO:0018401; P:peptidyl-proline hydroxylation to 4-hydroxy-L-proline; ISO:RGD.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:RGD.
DR GO; GO:1901216; P:positive regulation of neuron death; IDA:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0045765; P:regulation of angiogenesis; ISS:UniProtKB.
DR GO; GO:1901214; P:regulation of neuron death; ISO:RGD.
DR GO; GO:0099175; P:regulation of postsynapse organization; ISO:RGD.
DR GO; GO:0099576; P:regulation of protein catabolic process at postsynapse, modulating synaptic transmission; ISO:RGD.
DR GO; GO:0001666; P:response to hypoxia; IDA:RGD.
DR GO; GO:0071731; P:response to nitric oxide; ISS:UniProtKB.
DR GO; GO:0060412; P:ventricular septum morphogenesis; 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 2: Evidence at transcript level;
KW Cytoplasm; Dioxygenase; Iron; Metal-binding; Nucleus; Oxidoreductase;
KW Phosphoprotein; Reference proteome; S-nitrosylation; Vitamin C.
FT CHAIN <1..338
FT /note="Egl nine homolog 1"
FT /id="PRO_0000206663"
FT DOMAIN 209..307
FT /note="Fe2OG dioxygenase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT REGION 1..99
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 156..166
FT /note="Beta(2)beta(3) 'finger-like' loop"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT COMPBIAS 1..17
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 58..72
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 228
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9,
FT ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 230
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9,
FT ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 289
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9,
FT ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 298
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT MOD_RES 52
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT MOD_RES 116
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT MOD_RES 123
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT MOD_RES 217
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT MOD_RES 238
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT MOD_RES 241
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT CONFLICT 36
FT /note="T -> R (in Ref. 2; AAH81694)"
FT /evidence="ECO:0000305"
FT NON_TER 1
FT /evidence="ECO:0000305"
SQ SEQUENCE 338 AA; 36093 MW; B82FF7AA0417198B CRC64;
PRAQPAPAQP RVAPPPGGAP GAARAGGAAR RGDSSTAASR VPGPEDATQA GSGPGPAEPS
SEDPPPSRSP GPERASLCPA GGGPGEALSP SGGLRPNGQT KPLPALKLAL EYIVPCMNKH
GICVVDDFLG RETGQQIGDE VRALHDTGKF TDGQLVSQKS DSSKDIRGDK ITWIEGKEPG
CETIGLLMSS MDDLIRHCSG KLGNYRINGR TKAMVACYPG NGTGYVRHVD NPNGDGRCVT
CIYYLNKDWD AKVSGGILRI FPEGKAQFAD IEPKFDRLLF FWSDRRNPHE VQPAYATRYA
ITVWYFDADE RARAKVKYLT GEKGVRVELK PNSVSKDV
