EGLN2_HUMAN
ID EGLN2_HUMAN Reviewed; 407 AA.
AC Q96KS0; A8K5S0; Q8WWY4; Q9BV14;
DT 16-JUN-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 182.
DE RecName: Full=Prolyl hydroxylase EGLN2 {ECO:0000305};
DE EC=1.14.11.- {ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12039559, ECO:0000269|PubMed:15925519, ECO:0000269|PubMed:17114296, ECO:0000269|PubMed:23932902};
DE AltName: Full=Egl nine homolog 2 {ECO:0000305};
DE EC=1.14.11.29 {ECO:0000255|PROSITE-ProRule:PRU00805, ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12039559, ECO:0000269|PubMed:15925519};
DE AltName: Full=Estrogen-induced tag 6 {ECO:0000303|PubMed:11850811};
DE Short=EIT-6 {ECO:0000303|PubMed:11850811};
DE AltName: Full=HPH-3;
DE AltName: Full=Hypoxia-inducible factor prolyl hydroxylase 1;
DE Short=HIF-PH1;
DE Short=HIF-prolyl hydroxylase 1;
DE Short=HPH-1;
DE AltName: Full=Prolyl hydroxylase domain-containing protein 1 {ECO:0000303|PubMed:11595184};
DE Short=PHD1 {ECO:0000303|PubMed:11595184};
GN Name=EGLN2 {ECO:0000312|HGNC:HGNC:14660};
GN Synonyms=EIT6 {ECO:0000303|PubMed:11850811};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM P43).
RX PubMed=11574160; DOI=10.1016/s0378-1119(01)00633-3;
RA Taylor M.S.;
RT "Characterization and comparative analysis of the EGLN gene family.";
RL Gene 275:125-132(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM P43), AND INDUCTION.
RC TISSUE=Mammary cancer;
RX PubMed=11850811; DOI=10.1038/sj.onc.1205113;
RA Seth P., Krop I., Porter D., Polyak K.;
RT "Novel estrogen and tamoxifen induced genes identified by SAGE (Serial
RT Analysis of Gene Expression).";
RL Oncogene 21:836-843(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM P43).
RC TISSUE=Fetal brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM P43).
RC TISSUE=Endometrium;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM P43).
RC TISSUE=Lung, and Testis;
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 [8]
RP REVIEW.
RX PubMed=11595178; DOI=10.1016/s0092-8674(01)00518-9;
RA Semenza G.L.;
RT "HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the
RT nucleus.";
RL Cell 107:1-3(2001).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF HIS-358.
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 [10]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=12163023; DOI=10.1016/s0006-291x(02)00862-8;
RA Oehme F., Ellinghaus P., Kolkhof P., Smith T.J., Ramakrishnan S.,
RA Huetter J., Schramm M., Flamme I.;
RT "Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates
RT activity of hypoxia-inducible transcription factors.";
RL Biochem. Biophys. Res. Commun. 296:343-349(2002).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF HIS-297; ASP-299; HIS-358
RP AND ARG-367.
RX PubMed=12039559; DOI=10.1016/s0960-894x(02)00219-6;
RA McNeill L.A., Hewitson K.S., Gleadle J.M., Horsfall L.E., Oldham N.J.,
RA Maxwell P.H., Pugh C.W., Ratcliffe P.J., Schofield C.J.;
RT "The use of dioxygen by HIF prolyl hydroxylase (PHD1).";
RL Bioorg. Med. Chem. Lett. 12:1547-1550(2002).
RN [12]
RP FUNCTION, AND SUBSTRATE RECOGNITION MOTIF.
RX PubMed=12181324; DOI=10.1074/jbc.m206955200;
RA Huang J., Zhao Q., Mooney S.M., Lee F.S.;
RT "Sequence determinants in hypoxia-inducible factor-1alpha for hydroxylation
RT by the prolyl hydroxylases PHD1, PHD2, and PHD3.";
RL J. Biol. Chem. 277:39792-39800(2002).
RN [13]
RP SUBCELLULAR LOCATION, AND INDUCTION.
RX PubMed=12615973; DOI=10.1242/jcs.00318;
RA Metzen E., Berchner-Pfannschmidt U., Stengel P., Marxsen J.H., Stolze I.,
RA Klinger M., Huang W.Q., Wotzlaw C., Hellwig-Burgel T., Jelkmann W.,
RA Acker H., Fandrey J.;
RT "Intracellular localisation of human HIF-1 alpha hydroxylases: implications
RT for oxygen sensing.";
RL J. Cell Sci. 116:1319-1326(2003).
RN [14]
RP INDUCTION, AND SUBSTRATE SPECIFICITY.
RX PubMed=15247232; DOI=10.1074/jbc.m406026200;
RA Appelhoff R.J., Tian Y.M., Raval R.R., Turley H., Harris A.L., Pugh C.W.,
RA Ratcliffe P.J., Gleadle J.M.;
RT "Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in
RT the regulation of hypoxia-inducible factor.";
RL J. Biol. Chem. 279:38458-38465(2004).
RN [15]
RP CATALYTIC ACTIVITY, COFACTOR, AND BIOPHYSICOCHEMICAL PROPERTIES.
RC TISSUE=Liver;
RX PubMed=15925519; DOI=10.1016/j.pep.2005.03.036;
RA Cobb R.R., McClary J., Manzana W., Finster S., Larsen B., Blasko E.,
RA Pearson J., Biancalana S., Kauser K., Bringmann P., Light D.R., Schirm S.;
RT "Cloning and characterization of the rat HIF-1 alpha prolyl-4-hydroxylase-1
RT gene.";
RL Protein Expr. Purif. 42:295-304(2005).
RN [16]
RP FUNCTION, INTERACTION WITH SIAH2, ALTERNATIVE INITIATION, INDUCTION, AND
RP MUTAGENESIS OF MET-1 AND MET-34.
RX PubMed=16509823; DOI=10.1042/bj20051996;
RA Tian Y.M., Mole D.R., Ratcliffe P.J., Gleadle J.M.;
RT "Characterization of different isoforms of the HIF prolyl hydroxylase PHD1
RT generated by alternative initiation.";
RL Biochem. J. 397:179-186(2006).
RN [17]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=17114296; DOI=10.1073/pnas.0602235103;
RA Cummins E.P., Berra E., Comerford K.M., Ginouves A., Fitzgerald K.T.,
RA Seeballuck F., Godson C., Nielsen J.E., Moynagh P., Pouyssegur J.,
RA Taylor C.T.;
RT "Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving
RT insight into hypoxia-induced NFkappaB activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:18154-18159(2006).
RN [18]
RP SUBCELLULAR LOCATION.
RX PubMed=19631610; DOI=10.1016/j.bbrc.2009.07.090;
RA Steinhoff A., Pientka F.K., Mockel S., Kettelhake A., Hartmann E.,
RA Kohler M., Depping R.;
RT "Cellular oxygen sensing: Importins and exportins are mediators of
RT intracellular localisation of prolyl-4-hydroxylases PHD1 and PHD2.";
RL Biochem. Biophys. Res. Commun. 387:705-711(2009).
RN [19]
RP SUBCELLULAR LOCATION, FUNCTION, MOTIF, AND MUTAGENESIS OF LYS-102; ARG-106;
RP ARG-113; ARG-119 AND ARG-134.
RX PubMed=19339211; DOI=10.1016/j.bbamcr.2009.01.014;
RA Yasumoto K., Kowata Y., Yoshida A., Torii S., Sogawa K.;
RT "Role of the intracellular localization of HIF-prolyl hydroxylases.";
RL Biochim. Biophys. Acta 1793:792-797(2009).
RN [20]
RP SUBSTRATE SPECIFICITY, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=21410436; DOI=10.1042/bj20101201;
RA Pappalardi M.B., McNulty D.E., Martin J.D., Fisher K.E., Jiang Y.,
RA Burns M.C., Zhao H., Ho T., Sweitzer S., Schwartz B., Annan R.S.,
RA Copeland R.A., Tummino P.J., Luo L.;
RT "Biochemical characterization of human HIF hydroxylases using HIF protein
RT substrates that contain all three hydroxylation sites.";
RL Biochem. J. 436:363-369(2011).
RN [21]
RP INTERACTION WITH LIMD1; WTIP AND AJUBA.
RX PubMed=22286099; DOI=10.1038/ncb2424;
RA Foxler D.E., Bridge K.S., James V., Webb T.M., Mee M., Wong S.C., Feng Y.,
RA Constantin-Teodosiu D., Petursdottir T.E., Bjornsson J., Ingvarsson S.,
RA Ratcliffe P.J., Longmore G.D., Sharp T.V.;
RT "The LIMD1 protein bridges an association between the prolyl hydroxylases
RT and VHL to repress HIF-1 activity.";
RL Nat. Cell Biol. 14:201-208(2012).
RN [22]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=23932902; DOI=10.1016/j.devcel.2013.06.014;
RA Moser S.C., Bensaddek D., Ortmann B., Maure J.F., Mudie S., Blow J.J.,
RA Lamond A.I., Swedlow J.R., Rocha S.;
RT "PHD1 links cell-cycle progression to oxygen sensing through hydroxylation
RT of the centrosomal protein Cep192.";
RL Dev. Cell 26:381-392(2013).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-130, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [24] {ECO:0007744|PDB:5V1B}
RP X-RAY CRYSTALLOGRAPHY (2.49 ANGSTROMS) OF 167-403 IN COMPLEX WITH INHIBITOR
RP AND IRON, AND COFACTOR.
RX PubMed=28594552; DOI=10.1021/acs.jmedchem.7b00352;
RA Ahmed S., Ayscough A., Barker G.R., Canning H.E., Davenport R., Downham R.,
RA Harrison D., Jenkins K., Kinsella N., Livermore D.G., Wright S.,
RA Ivetac A.D., Skene R., Wilkens S.J., Webster N.A., Hendrick A.G.;
RT "1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1)
RT Inhibitors With a Novel Monodentate Binding Interaction.";
RL J. Med. Chem. 60:5663-5672(2017).
CC -!- FUNCTION: Prolyl hydroxylase that mediates hydroxylation of proline
CC residues in target proteins, such as ATF4, IKBKB, CEP192 and HIF1A
CC (PubMed:11595184, PubMed:12039559, PubMed:15925519, PubMed:16509823,
CC PubMed:17114296, PubMed:23932902). Target proteins are preferentially
CC recognized via a LXXLAP motif (PubMed:11595184, PubMed:12039559,
CC PubMed:15925519). Cellular oxygen sensor that catalyzes, under normoxic
CC conditions, the post-translational formation of 4-hydroxyproline in
CC hypoxia-inducible factor (HIF) alpha proteins (PubMed:11595184,
CC PubMed:12039559, PubMed:12181324, PubMed:15925519, PubMed:19339211).
CC Hydroxylates a specific proline found in each of the oxygen-dependent
CC degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of
CC HIF1A (PubMed:11595184, PubMed:12039559, PubMed:12181324,
CC PubMed:15925519). Also hydroxylates HIF2A (PubMed:11595184,
CC PubMed:12039559, PubMed:15925519). Has a preference for the CODD site
CC for both HIF1A and HIF2A (PubMed:11595184, PubMed:12039559,
CC PubMed:15925519). Hydroxylated HIFs are then targeted for proteasomal
CC degradation via the von Hippel-Lindau ubiquitination complex
CC (PubMed:11595184, PubMed:12039559, PubMed:15925519). 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 (PubMed:11595184, PubMed:12039559, PubMed:15925519).
CC EGLN2 is involved in regulating hypoxia tolerance and apoptosis in
CC cardiac and skeletal muscle (PubMed:11595184, PubMed:12039559,
CC PubMed:15925519). Also regulates susceptibility to normoxic oxidative
CC neuronal death (PubMed:11595184, PubMed:12039559, PubMed:15925519).
CC Links oxygen sensing to cell cycle and primary cilia formation by
CC hydroxylating the critical centrosome component CEP192 which promotes
CC its ubiquitination and subsequent proteasomal degradation
CC (PubMed:23932902). Hydroxylates IKBKB, mediating NF-kappa-B activation
CC in hypoxic conditions (PubMed:17114296). Also mediates hydroxylation of
CC ATF4, leading to decreased protein stability of ATF4 (By similarity).
CC {ECO:0000250|UniProtKB:Q91YE2, ECO:0000269|PubMed:11595184,
CC ECO:0000269|PubMed:12039559, ECO:0000269|PubMed:12181324,
CC ECO:0000269|PubMed:15925519, ECO:0000269|PubMed:16509823,
CC ECO:0000269|PubMed:17114296, ECO:0000269|PubMed:19339211,
CC ECO:0000269|PubMed:23932902}.
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:0000269|PubMed:11595184, ECO:0000269|PubMed:12039559,
CC ECO:0000269|PubMed:15925519, ECO:0000269|PubMed:17114296,
CC ECO:0000269|PubMed:23932902};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63485;
CC Evidence={ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12039559,
CC ECO:0000269|PubMed:15925519, ECO:0000269|PubMed:17114296,
CC ECO:0000269|PubMed:23932902};
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:0000269|PubMed:11595184, ECO:0000269|PubMed:12039559,
CC ECO:0000269|PubMed:15925519};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU00805,
CC ECO:0000269|PubMed:15925519, ECO:0000269|PubMed:28594552,
CC ECO:0007744|PDB:5V1B};
CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000255|PROSITE-
CC ProRule:PRU00805, ECO:0000269|PubMed:15925519,
CC ECO:0000269|PubMed:28594552, ECO:0007744|PDB:5V1B};
CC -!- COFACTOR:
CC Name=L-ascorbate; Xref=ChEBI:CHEBI:38290;
CC Evidence={ECO:0000269|PubMed:15925519};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=20 uM for HIF1A DLDLEMLAPYIPMDDDFQL peptide (at pH 7.5 and 37
CC degrees Celsius) {ECO:0000269|PubMed:15925519};
CC KM=50 uM for L-ascorbate (at pH 7.5 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:15925519};
CC KM=1.0 uM for Fe(2+) (at pH 7.5 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:15925519};
CC -!- SUBUNIT: Interacts (preferably isoform p40) with SIAH2; the interaction
CC targets both SIAH2 isoforms for proteasomal degradation in vitro
CC (PubMed:16509823). Interacts with LIMD1, WTIP and AJUBA
CC (PubMed:22286099). {ECO:0000269|PubMed:16509823,
CC ECO:0000269|PubMed:22286099}.
CC -!- INTERACTION:
CC Q96KS0; Q16665: HIF1A; NbExp=2; IntAct=EBI-726614, EBI-447269;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:12163023,
CC ECO:0000269|PubMed:12615973, ECO:0000269|PubMed:19339211,
CC ECO:0000269|PubMed:19631610}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=p43; Synonyms=PHD1p43;
CC IsoId=Q96KS0-1; Sequence=Displayed;
CC Name=p40; Synonyms=PHD1p40;
CC IsoId=Q96KS0-2; Sequence=VSP_038836;
CC -!- TISSUE SPECIFICITY: Expressed in adult and fetal heart, brain, liver,
CC lung, skeletal muscle, and kidney. Also expressed in testis and
CC placenta. Highest levels in adult brain, placenta, lung, kidney, and
CC testis. Expressed in hormone responsive tissues, including normal and
CC cancerous mammary, ovarian and prostate epithelium.
CC {ECO:0000269|PubMed:12163023}.
CC -!- INDUCTION: By estrogen (PubMed:11850811). Induced by proteasomal
CC inhibitor MG132 (at protein level) (PubMed:16509823).
CC {ECO:0000269|PubMed:11850811, ECO:0000269|PubMed:16509823}.
CC -!- INDUCTION: [Isoform p43]: Induced by hypoxia leading to protein
CC stability. {ECO:0000269|PubMed:15247232}.
CC -!- INDUCTION: [Isoform p40]: Repressed by hypoxia.
CC {ECO:0000269|PubMed:15247232}.
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:Q91YE2}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH01723.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AJ310544; CAC42510.1; -; mRNA.
DR EMBL; AY040565; AAK82943.1; -; mRNA.
DR EMBL; AK291385; BAF84074.1; -; mRNA.
DR EMBL; AL832506; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC008537; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471126; EAW57008.1; -; Genomic_DNA.
DR EMBL; BC001723; AAH01723.1; ALT_INIT; mRNA.
DR EMBL; BC036051; AAH36051.1; -; mRNA.
DR CCDS; CCDS12567.1; -. [Q96KS0-1]
DR RefSeq; NP_444274.1; NM_053046.3. [Q96KS0-1]
DR RefSeq; NP_542770.2; NM_080732.3. [Q96KS0-1]
DR PDB; 5V1B; X-ray; 2.49 A; A=167-403.
DR PDBsum; 5V1B; -.
DR AlphaFoldDB; Q96KS0; -.
DR SMR; Q96KS0; -.
DR BioGRID; 125184; 37.
DR CORUM; Q96KS0; -.
DR IntAct; Q96KS0; 8.
DR MINT; Q96KS0; -.
DR STRING; 9606.ENSP00000469686; -.
DR BindingDB; Q96KS0; -.
DR ChEMBL; CHEMBL3028; -.
DR DrugBank; DB00126; Ascorbic acid.
DR DrugBank; DB04847; Roxadustat.
DR DrugCentral; Q96KS0; -.
DR GuidetoPHARMACOLOGY; 2832; -.
DR GlyGen; Q96KS0; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q96KS0; -.
DR PhosphoSitePlus; Q96KS0; -.
DR BioMuta; EGLN2; -.
DR DMDM; 32129513; -.
DR MassIVE; Q96KS0; -.
DR MaxQB; Q96KS0; -.
DR PaxDb; Q96KS0; -.
DR PeptideAtlas; Q96KS0; -.
DR PRIDE; Q96KS0; -.
DR ProteomicsDB; 77112; -. [Q96KS0-1]
DR ProteomicsDB; 77113; -. [Q96KS0-2]
DR Antibodypedia; 66726; 445 antibodies from 32 providers.
DR DNASU; 112398; -.
DR Ensembl; ENST00000303961.9; ENSP00000307080.3; ENSG00000269858.6. [Q96KS0-1]
DR Ensembl; ENST00000406058.6; ENSP00000385253.1; ENSG00000269858.6. [Q96KS0-1]
DR Ensembl; ENST00000593726.5; ENSP00000469686.1; ENSG00000269858.6. [Q96KS0-1]
DR GeneID; 112398; -.
DR KEGG; hsa:112398; -.
DR MANE-Select; ENST00000303961.9; ENSP00000307080.3; NM_080732.4; NP_542770.2.
DR UCSC; uc002opg.5; human. [Q96KS0-1]
DR CTD; 112398; -.
DR DisGeNET; 112398; -.
DR GeneCards; EGLN2; -.
DR HGNC; HGNC:14660; EGLN2.
DR HPA; ENSG00000269858; Low tissue specificity.
DR MIM; 606424; gene.
DR neXtProt; NX_Q96KS0; -.
DR OpenTargets; ENSG00000269858; -.
DR PharmGKB; PA27671; -.
DR VEuPathDB; HostDB:ENSG00000269858; -.
DR eggNOG; KOG3710; Eukaryota.
DR GeneTree; ENSGT00940000160655; -.
DR HOGENOM; CLU_063064_0_0_1; -.
DR InParanoid; Q96KS0; -.
DR OMA; WSIGALM; -.
DR PhylomeDB; Q96KS0; -.
DR TreeFam; TF314595; -.
DR BioCyc; MetaCyc:ENSG00000171570-MON; -.
DR BRENDA; 1.14.11.2; 2681.
DR BRENDA; 1.14.11.29; 2681.
DR PathwayCommons; Q96KS0; -.
DR Reactome; R-HSA-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
DR SignaLink; Q96KS0; -.
DR SIGNOR; Q96KS0; -.
DR BioGRID-ORCS; 112398; 148 hits in 1082 CRISPR screens.
DR GeneWiki; EGLN2; -.
DR GenomeRNAi; 112398; -.
DR Pharos; Q96KS0; Tclin.
DR PRO; PR:Q96KS0; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q96KS0; protein.
DR Bgee; ENSG00000269858; Expressed in left testis and 96 other tissues.
DR ExpressionAtlas; Q96KS0; baseline and differential.
DR Genevisible; Q96KS0; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0016706; F:2-oxoglutarate-dependent dioxygenase activity; IDA:UniProtKB.
DR GO; GO:0008198; F:ferrous iron binding; IDA:UniProtKB.
DR GO; GO:0031418; F:L-ascorbic acid binding; IEA:UniProtKB-KW.
DR GO; GO:0019826; F:oxygen sensor activity; IDA:UniProtKB.
DR GO; GO:0031545; F:peptidyl-proline 4-dioxygenase activity; IDA:UniProtKB.
DR GO; GO:0031543; F:peptidyl-proline dioxygenase activity; IBA:GO_Central.
DR GO; GO:0045454; P:cell redox homeostasis; IDA:UniProtKB.
DR GO; GO:0071456; P:cellular response to hypoxia; IBA:GO_Central.
DR GO; GO:0030520; P:intracellular estrogen receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0018401; P:peptidyl-proline hydroxylation to 4-hydroxy-L-proline; IDA:UniProtKB.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:UniProtKB.
DR GO; GO:0001558; P:regulation of cell growth; NAS:UniProtKB.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; IMP:UniProtKB.
DR GO; GO:0001666; P:response to hypoxia; IDA:UniProtKB.
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 3D-structure; Alternative initiation; Dioxygenase; Iron; Metal-binding;
KW Nucleus; Oxidoreductase; Phosphoprotein; Reference proteome;
KW Ubl conjugation; Vitamin C.
FT CHAIN 1..407
FT /note="Prolyl hydroxylase EGLN2"
FT /id="PRO_0000206664"
FT DOMAIN 278..376
FT /note="Fe2OG dioxygenase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT REGION 1..34
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 50..89
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 108..157
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 225..235
FT /note="Beta(2)beta(3) 'finger-like' loop"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT MOTIF 89..134
FT /note="Bipartite nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:19339211"
FT COMPBIAS 1..19
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 60..77
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 297
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805,
FT ECO:0000269|PubMed:28594552, ECO:0000312|PDB:5V1B"
FT BINDING 299
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805,
FT ECO:0000269|PubMed:28594552, ECO:0000312|PDB:5V1B"
FT BINDING 358
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805,
FT ECO:0000269|PubMed:28594552, ECO:0000312|PDB:5V1B"
FT BINDING 367
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT MOD_RES 130
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1..33
FT /note="Missing (in isoform p40)"
FT /evidence="ECO:0000305"
FT /id="VSP_038836"
FT MUTAGEN 1
FT /note="M->A: Leads to expression of isoform p40 only."
FT /evidence="ECO:0000269|PubMed:16509823"
FT MUTAGEN 34
FT /note="M->A: Leads to expression of isoform p43 only."
FT /evidence="ECO:0000269|PubMed:16509823"
FT MUTAGEN 102
FT /note="K->A: Retained in the nucleus."
FT /evidence="ECO:0000269|PubMed:19339211"
FT MUTAGEN 106
FT /note="R->A: Retained in the nucleus."
FT /evidence="ECO:0000269|PubMed:19339211"
FT MUTAGEN 113
FT /note="R->A: Retained in the nucleus."
FT /evidence="ECO:0000269|PubMed:19339211"
FT MUTAGEN 119
FT /note="R->A: Cytoplasmic and nuclear localization. Reduced
FT transcriptional activity of HIF1A as for wild type."
FT /evidence="ECO:0000269|PubMed:19339211"
FT MUTAGEN 134
FT /note="R->A: Retained in the nucleus."
FT /evidence="ECO:0000269|PubMed:19339211"
FT MUTAGEN 297
FT /note="H->A: Eliminates hydroxylase activity."
FT /evidence="ECO:0000269|PubMed:12039559"
FT MUTAGEN 299
FT /note="D->A: Eliminates hydroxylase activity."
FT /evidence="ECO:0000269|PubMed:12039559"
FT MUTAGEN 358
FT /note="H->A: Eliminates hydroxylase activity."
FT /evidence="ECO:0000269|PubMed:11595184,
FT ECO:0000269|PubMed:12039559"
FT MUTAGEN 367
FT /note="R->A: Eliminates hydroxylase activity."
FT /evidence="ECO:0000269|PubMed:12039559"
FT MUTAGEN 367
FT /note="R->K: Eliminates hydroxylase activity on a HIF1A
FT peptide."
FT /evidence="ECO:0000269|PubMed:12039559"
FT CONFLICT 176
FT /note="R -> P (in Ref. 2; AAK82943)"
FT /evidence="ECO:0000305"
FT HELIX 173..180
FT /evidence="ECO:0007829|PDB:5V1B"
FT HELIX 182..188
FT /evidence="ECO:0007829|PDB:5V1B"
FT STRAND 190..195
FT /evidence="ECO:0007829|PDB:5V1B"
FT HELIX 199..215
FT /evidence="ECO:0007829|PDB:5V1B"
FT STRAND 239..243
FT /evidence="ECO:0007829|PDB:5V1B"
FT HELIX 251..265
FT /evidence="ECO:0007829|PDB:5V1B"
FT TURN 266..269
FT /evidence="ECO:0007829|PDB:5V1B"
FT STRAND 270..273
FT /evidence="ECO:0007829|PDB:5V1B"
FT STRAND 282..287
FT /evidence="ECO:0007829|PDB:5V1B"
FT STRAND 294..297
FT /evidence="ECO:0007829|PDB:5V1B"
FT STRAND 305..313
FT /evidence="ECO:0007829|PDB:5V1B"
FT HELIX 320..323
FT /evidence="ECO:0007829|PDB:5V1B"
FT STRAND 327..329
FT /evidence="ECO:0007829|PDB:5V1B"
FT STRAND 332..335
FT /evidence="ECO:0007829|PDB:5V1B"
FT STRAND 338..340
FT /evidence="ECO:0007829|PDB:5V1B"
FT STRAND 346..351
FT /evidence="ECO:0007829|PDB:5V1B"
FT STRAND 358..360
FT /evidence="ECO:0007829|PDB:5V1B"
FT STRAND 363..365
FT /evidence="ECO:0007829|PDB:5V1B"
FT STRAND 367..375
FT /evidence="ECO:0007829|PDB:5V1B"
FT HELIX 377..385
FT /evidence="ECO:0007829|PDB:5V1B"
FT HELIX 392..395
FT /evidence="ECO:0007829|PDB:5V1B"
SQ SEQUENCE 407 AA; 43650 MW; F172E9B0482C9CF3 CRC64;
MDSPCQPQPL SQALPQLPGS SSEPLEPEPG RARMGVESYL PCPLLPSYHC PGVPSEASAG
SGTPRATATS TTASPLRDGF GGQDGGELRP LQSEGAAALV TKGCQRLAAQ GARPEAPKRK
WAEDGGDAPS PSKRPWARQE NQEAEREGGM SCSCSSGSGE ASAGLMEEAL PSAPERLALD
YIVPCMRYYG ICVKDSFLGA ALGGRVLAEV EALKRGGRLR DGQLVSQRAI PPRSIRGDQI
AWVEGHEPGC RSIGALMAHV DAVIRHCAGR LGSYVINGRT KAMVACYPGN GLGYVRHVDN
PHGDGRCITC IYYLNQNWDV KVHGGLLQIF PEGRPVVANI EPLFDRLLIF WSDRRNPHEV
KPAYATRYAI TVWYFDAKER AAAKDKYQLA SGQKGVQVPV SQPPTPT
