EGLN3_HUMAN
ID EGLN3_HUMAN Reviewed; 239 AA.
AC Q9H6Z9; Q2TA79; Q3B8N4; Q6P1R2;
DT 16-JUN-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2001, sequence version 1.
DT 03-AUG-2022, entry version 180.
DE RecName: Full=Prolyl hydroxylase EGLN3 {ECO:0000305};
DE EC=1.14.11.- {ECO:0000269|PubMed:11598268, ECO:0000269|PubMed:21483450, ECO:0000269|PubMed:21620138, ECO:0000269|PubMed:22797300};
DE AltName: Full=Egl nine homolog 3;
DE EC=1.14.11.29 {ECO:0000269|PubMed:11598268};
DE AltName: Full=HPH-1;
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 {ECO:0000303|PubMed:12181324};
DE Short=PHD3 {ECO:0000303|PubMed:12181324};
GN Name=EGLN3 {ECO:0000303|PubMed:16098468, ECO:0000312|HGNC:HGNC:14661};
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].
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], AND SUBSTRATE SPECIFICITY.
RC TISSUE=Aorta, Colon, and Lung;
RX PubMed=12788921; DOI=10.1074/jbc.m304982200;
RA Hirsila M., Koivunen P., Gunzler V., Kivirikko K.I., Myllyharju J.;
RT "Characterization of the human prolyl 4-hydroxylases that modify the
RT hypoxia-inducible factor.";
RL J. Biol. Chem. 278:30772-30780(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon;
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].
RC TISSUE=Ovary, and Retinoblastoma;
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 [5]
RP FUNCTION, AND ACTIVITY REGULATION.
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 [6]
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 [7]
RP CATALYTIC ACTIVITY, AND MUTAGENESIS OF HIS-135; ASP-137 AND HIS-196.
RX PubMed=11598268; DOI=10.1126/science.1066373;
RA Bruick R.K., McKnight S.L.;
RT "A conserved family of prolyl-4-hydroxylases that modify HIF.";
RL Science 294:1337-1340(2001).
RN [8]
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 [9]
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 [10]
RP TISSUE SPECIFICITY, AND ACTIVITY REGULATION.
RX PubMed=12670503; DOI=10.1016/s0006-291x(03)00453-4;
RA Cioffi C.L., Qin Liu X., Kosinski P.A., Garay M., Bowen B.R.;
RT "Differential regulation of HIF-1alpha prolyl-4-hydroxylase genes by
RT hypoxia in human cardiovascular cells.";
RL Biochem. Biophys. Res. Commun. 303:947-953(2003).
RN [11]
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 [12]
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 [13]
RP FUNCTION.
RX PubMed=16098468; DOI=10.1016/j.ccr.2005.06.015;
RA Lee S., Nakamura E., Yang H., Wei W., Linggi M.S., Sajan M.P., Farese R.V.,
RA Freeman R.S., Carter B.D., Kaelin W.G. Jr., Schlisio S.;
RT "Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial
RT pheochromocytoma genes: developmental culling and cancer.";
RL Cancer Cell 8:155-167(2005).
RN [14]
RP FUNCTION.
RX PubMed=17684156; DOI=10.1182/blood-2007-06-094441;
RA Koeditz J., Nesper J., Wottawa M., Stiehl D.P., Camenisch G., Franke C.,
RA Myllyharju J., Wenger R.H., Katschinski D.M.;
RT "Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor.";
RL Blood 110:3610-3617(2007).
RN [15]
RP INTERACTION WITH ADRB2, FUNCTION, AND MUTAGENESIS OF 91-ILE--VAL-102.
RX PubMed=19584355; DOI=10.1126/scisignal.2000444;
RA Xie L., Xiao K., Whalen E.J., Forrester M.T., Freeman R.S., Fong G.,
RA Gygi S.P., Lefkowitz R.J., Stamler J.S.;
RT "Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and
RT ubiquitylation by pVHL.";
RL Sci. Signal. 2:RA33-RA33(2009).
RN [16]
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).
RN [17]
RP FUNCTION, AND INDUCTION.
RX PubMed=20978507; DOI=10.1038/sj.bjc.6605936;
RA Su Y., Loos M., Giese N., Hines O.J., Diebold I., Gorlach A., Metzen E.,
RA Pastorekova S., Friess H., Buchler P.;
RT "PHD3 regulates differentiation, tumour growth and angiogenesis in
RT pancreatic cancer.";
RL Br. J. Cancer 103:1571-1579(2010).
RN [18]
RP INTERACTION WITH PAX2, TISSUE SPECIFICITY, AND FUNCTION.
RX PubMed=21575608; DOI=10.1016/j.bbrc.2011.05.012;
RA Yan B., Jiao S., Zhang H.S., Lv D.D., Xue J., Fan L., Wu G.H., Fang J.;
RT "Prolyl hydroxylase domain protein 3 targets Pax2 for destruction.";
RL Biochem. Biophys. Res. Commun. 409:315-320(2011).
RN [19]
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 [20]
RP INTERACTION WITH PKM, CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=21620138; DOI=10.1016/j.cell.2011.03.054;
RA Luo W., Hu H., Chang R., Zhong J., Knabel M., O'Meally R., Cole R.N.,
RA Pandey A., Semenza G.L.;
RT "Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible
RT factor 1.";
RL Cell 145:732-744(2011).
RN [21]
RP INTERACTION WITH PKM, CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=21483450; DOI=10.1038/cr.2011.66;
RA Chen N., Rinner O., Czernik D., Nytko K.J., Zheng D., Stiehl D.P.,
RA Zamboni N., Gstaiger M., Frei C.;
RT "The oxygen sensor PHD3 limits glycolysis under hypoxia via direct binding
RT to pyruvate kinase.";
RL Cell Res. 21:983-986(2011).
RN [22]
RP FUNCTION, AND INDUCTION.
RX PubMed=21317538; DOI=10.1172/jci43273;
RA Walmsley S.R., Chilvers E.R., Thompson A.A., Vaughan K., Marriott H.M.,
RA Parker L.C., Shaw G., Parmar S., Schneider M., Sabroe I., Dockrell D.H.,
RA Milo M., Taylor C.T., Johnson R.S., Pugh C.W., Ratcliffe P.J.,
RA Maxwell P.H., Carmeliet P., Whyte M.K.;
RT "Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of
RT neutrophilic inflammation in humans and mice.";
RL J. Clin. Invest. 121:1053-1063(2011).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY, AND ACTIVITY REGULATION.
RX PubMed=21421125; DOI=10.1016/j.jinorgbio.2010.12.001;
RA Geng Z., Zhu J., Cao J., Geng J., Song X., Zhang Z., Bian N., Wang Z.;
RT "Effects of polynitrogen compounds on the activity of recombinant human
RT HIF-1alpha prolyl hydroxylase 3 in E. coli.";
RL J. Inorg. Biochem. 105:391-399(2011).
RN [24]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=22797300; DOI=10.1172/jci62374;
RA Xie L., Pi X., Mishra A., Fong G., Peng J., Patterson C.;
RT "PHD3-dependent hydroxylation of HCLK2 promotes the DNA damage response.";
RL J. Clin. Invest. 122:2827-2836(2012).
RN [25]
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).
CC -!- FUNCTION: Prolyl hydroxylase that mediates hydroxylation of proline
CC residues in target proteins, such as PKM, TELO2, ATF4 and HIF1A
CC (PubMed:19584355, PubMed:21620138, PubMed:21483450, PubMed:22797300,
CC PubMed:20978507, PubMed:21575608). Target proteins are preferentially
CC recognized via a LXXLAP motif. Cellular oxygen sensor that catalyzes,
CC under normoxic conditions, the post-translational formation of 4-
CC hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins
CC (PubMed:11595184, PubMed:12181324). Hydroxylates a specific proline
CC found in each of the oxygen-dependent degradation (ODD) domains (N-
CC terminal, NODD, and C-terminal, CODD) of HIF1A (PubMed:11595184,
CC PubMed:12181324). Also hydroxylates HIF2A (PubMed:11595184,
CC PubMed:12181324). Has a preference for the CODD site for both HIF1A and
CC HIF2A (PubMed:11595184, PubMed:12181324). Hydroxylation on the NODD
CC site by EGLN3 appears to require prior hydroxylation on the CODD site
CC (PubMed:11595184, PubMed:12181324). Hydroxylated HIFs are then targeted
CC for proteasomal degradation via the von Hippel-Lindau ubiquitination
CC complex (PubMed:11595184, PubMed:12181324). Under hypoxic conditions,
CC the 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 (PubMed:11595184, PubMed:12181324). ELGN3 is the most
CC important isozyme in limiting physiological activation of HIFs
CC (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia,
CC limiting glycolysis (PubMed:21620138, PubMed:21483450). Under normoxia,
CC hydroxylates and regulates the stability of ADRB2 (PubMed:19584355).
CC Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes,
CC inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2
CC complex (PubMed:20849813). In neurons, has a NGF-induced proapoptotic
CC effect, probably through regulating CASP3 activity (PubMed:16098468).
CC Also essential for hypoxic regulation of neutrophilic inflammation
CC (PubMed:21317538). Plays a crucial role in DNA damage response (DDR) by
CC hydroxylating TELO2, promoting its interaction with ATR which is
CC required for activation of the ATR/CHK1/p53 pathway (PubMed:22797300).
CC Also mediates hydroxylation of ATF4, leading to decreased protein
CC stability of ATF4 (Probable). {ECO:0000269|PubMed:11595184,
CC ECO:0000269|PubMed:12181324, ECO:0000269|PubMed:16098468,
CC ECO:0000269|PubMed:19584355, ECO:0000269|PubMed:20849813,
CC ECO:0000269|PubMed:20978507, ECO:0000269|PubMed:21317538,
CC ECO:0000269|PubMed:21483450, ECO:0000269|PubMed:21575608,
CC ECO:0000269|PubMed:21620138, ECO:0000269|PubMed:22797300,
CC ECO:0000305|PubMed:17684156}.
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:11598268, ECO:0000269|PubMed:21483450,
CC ECO:0000269|PubMed:21620138, ECO:0000269|PubMed:22797300};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63485;
CC Evidence={ECO:0000269|PubMed:11598268, ECO:0000269|PubMed:21483450,
CC ECO:0000269|PubMed:21620138, ECO:0000269|PubMed:22797300};
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:11598268};
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 -!- ACTIVITY REGULATION: Activated in cardiovascular cells and Hela cells
CC following exposure to hypoxia. Inhibited by polynitrogen compounds
CC probably by chelation to Fe(2+) ions. {ECO:0000269|PubMed:11595184,
CC ECO:0000269|PubMed:12670503, ECO:0000269|PubMed:21421125}.
CC -!- SUBUNIT: Interacts with BCL2 (via its BH4 domain); the interaction
CC disrupts the BAX-BCL4 complex inhibiting the anti-apoptotic activity of
CC BCL2 (PubMed:20849813). Interacts with WDR83; the interaction leads to
CC almost complete elimination of HIF-mediated reporter activity (By
CC similarity). Interacts with ADRB2; the interaction hydroxylates ADRB2
CC facilitating its ubiquitination by the VHL-E3 ligase complex
CC (PubMed:19584355). Interacts with PAX2; the interaction targets PAX2
CC for destruction (PubMed:21575608). Interacts with PKM; the interaction
CC hydroxylates PKM in hypoxia (PubMed:21620138, PubMed:21483450).
CC Interacts with LIMD1, WTIP and AJUBA (PubMed:22286099).
CC {ECO:0000250|UniProtKB:Q62630, ECO:0000269|PubMed:19584355,
CC ECO:0000269|PubMed:20849813, ECO:0000269|PubMed:21483450,
CC ECO:0000269|PubMed:21575608, ECO:0000269|PubMed:21620138,
CC ECO:0000269|PubMed:22286099}.
CC -!- INTERACTION:
CC Q9H6Z9; Q9NYB9: ABI2; NbExp=3; IntAct=EBI-1175354, EBI-743598;
CC Q9H6Z9; P56545-3: CTBP2; NbExp=3; IntAct=EBI-1175354, EBI-10171902;
CC Q9H6Z9; Q16829: DUSP7; NbExp=3; IntAct=EBI-1175354, EBI-1265847;
CC Q9H6Z9; Q5JST6: EFHC2; NbExp=3; IntAct=EBI-1175354, EBI-2349927;
CC Q9H6Z9; A1KXE4-2: FAM168B; NbExp=3; IntAct=EBI-1175354, EBI-12193763;
CC Q9H6Z9; Q9P0K8: FOXJ2; NbExp=6; IntAct=EBI-1175354, EBI-2869608;
CC Q9H6Z9; O15499: GSC2; NbExp=3; IntAct=EBI-1175354, EBI-19954058;
CC Q9H6Z9; D0VY79: HIF1A; NbExp=3; IntAct=EBI-1175354, EBI-10179332;
CC Q9H6Z9; Q16665: HIF1A; NbExp=6; IntAct=EBI-1175354, EBI-447269;
CC Q9H6Z9; Q13123: IK; NbExp=3; IntAct=EBI-1175354, EBI-713456;
CC Q9H6Z9; Q9UKT9: IKZF3; NbExp=3; IntAct=EBI-1175354, EBI-747204;
CC Q9H6Z9; O43679: LDB2; NbExp=3; IntAct=EBI-1175354, EBI-2865580;
CC Q9H6Z9; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-1175354, EBI-739832;
CC Q9H6Z9; Q16659: MAPK6; NbExp=6; IntAct=EBI-1175354, EBI-1384105;
CC Q9H6Z9; Q6IBW4-4: NCAPH2; NbExp=3; IntAct=EBI-1175354, EBI-10247000;
CC Q9H6Z9; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-1175354, EBI-741158;
CC Q9H6Z9; Q13438: OS9; NbExp=2; IntAct=EBI-1175354, EBI-725454;
CC Q9H6Z9; P14618-1: PKM; NbExp=2; IntAct=EBI-1175354, EBI-4304679;
CC Q9H6Z9; Q9HB19: PLEKHA2; NbExp=3; IntAct=EBI-1175354, EBI-4401947;
CC Q9H6Z9; Q8NC74: RBBP8NL; NbExp=3; IntAct=EBI-1175354, EBI-11322432;
CC Q9H6Z9; Q04864: REL; NbExp=4; IntAct=EBI-1175354, EBI-307352;
CC Q9H6Z9; Q53GC0: SERTAD1; NbExp=3; IntAct=EBI-1175354, EBI-2826300;
CC Q9H6Z9; Q6PF05-3: TTC23L; NbExp=3; IntAct=EBI-1175354, EBI-10182647;
CC Q9H6Z9; Q96GY0: ZC2HC1A; NbExp=3; IntAct=EBI-1175354, EBI-5458880;
CC Q9H6Z9; Q8N720: ZNF655; NbExp=3; IntAct=EBI-1175354, EBI-625509;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:12163023,
CC ECO:0000269|PubMed:12615973}. Cytoplasm {ECO:0000269|PubMed:12615973}.
CC Note=Colocalizes with WDR83 in the cytoplasm.
CC {ECO:0000250|UniProtKB:Q62630}.
CC -!- TISSUE SPECIFICITY: Widely expressed at low levels. Expressed at higher
CC levels in adult heart (cardiac myocytes, aortic endothelial cells and
CC coronary artery smooth muscle), lung and placenta, and in fetal spleen,
CC heart and skeletal muscle. Also expressed in pancreas. Localized to
CC pancreatic acini and islet cells. {ECO:0000269|PubMed:12163023,
CC ECO:0000269|PubMed:12670503, ECO:0000269|PubMed:21575608}.
CC -!- INDUCTION: Induced by hypoxia in a number of cells including
CC neutrophils and certain cancer cell lines. Up-regulated 10-fold in
CC pancreatic cancers. {ECO:0000269|PubMed:12615973,
CC ECO:0000269|PubMed:15247232, ECO:0000269|PubMed:20978507,
CC ECO:0000269|PubMed:21317538}.
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}.
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DR EMBL; AJ310545; CAC42511.1; -; mRNA.
DR EMBL; AK025273; BAB15101.1; -; mRNA.
DR EMBL; BC010992; AAH10992.3; -; mRNA.
DR EMBL; BC064924; AAH64924.2; -; mRNA.
DR EMBL; BC105939; AAI05940.1; -; mRNA.
DR EMBL; BC111057; AAI11058.2; -; mRNA.
DR CCDS; CCDS9646.1; -.
DR RefSeq; NP_001295032.1; NM_001308103.1.
DR RefSeq; NP_071356.1; NM_022073.3.
DR AlphaFoldDB; Q9H6Z9; -.
DR SMR; Q9H6Z9; -.
DR BioGRID; 125185; 1293.
DR CORUM; Q9H6Z9; -.
DR IntAct; Q9H6Z9; 231.
DR MINT; Q9H6Z9; -.
DR STRING; 9606.ENSP00000250457; -.
DR BindingDB; Q9H6Z9; -.
DR ChEMBL; CHEMBL5705; -.
DR DrugBank; DB00126; Ascorbic acid.
DR DrugBank; DB04847; Roxadustat.
DR DrugCentral; Q9H6Z9; -.
DR GuidetoPHARMACOLOGY; 2834; -.
DR iPTMnet; Q9H6Z9; -.
DR PhosphoSitePlus; Q9H6Z9; -.
DR BioMuta; EGLN3; -.
DR DMDM; 32129515; -.
DR EPD; Q9H6Z9; -.
DR MassIVE; Q9H6Z9; -.
DR MaxQB; Q9H6Z9; -.
DR PaxDb; Q9H6Z9; -.
DR PeptideAtlas; Q9H6Z9; -.
DR PRIDE; Q9H6Z9; -.
DR ProteomicsDB; 81067; -.
DR Antibodypedia; 23133; 479 antibodies from 35 providers.
DR DNASU; 112399; -.
DR Ensembl; ENST00000250457.9; ENSP00000250457.4; ENSG00000129521.15.
DR GeneID; 112399; -.
DR KEGG; hsa:112399; -.
DR MANE-Select; ENST00000250457.9; ENSP00000250457.4; NM_022073.4; NP_071356.1.
DR UCSC; uc001wsa.5; human.
DR CTD; 112399; -.
DR DisGeNET; 112399; -.
DR GeneCards; EGLN3; -.
DR HGNC; HGNC:14661; EGLN3.
DR HPA; ENSG00000129521; Tissue enhanced (heart muscle, skin).
DR MIM; 606426; gene.
DR neXtProt; NX_Q9H6Z9; -.
DR OpenTargets; ENSG00000129521; -.
DR PharmGKB; PA27672; -.
DR VEuPathDB; HostDB:ENSG00000129521; -.
DR eggNOG; KOG3710; Eukaryota.
DR GeneTree; ENSGT00940000158745; -.
DR HOGENOM; CLU_022206_0_1_1; -.
DR InParanoid; Q9H6Z9; -.
DR OMA; ITWIGHE; -.
DR OrthoDB; 1604981at2759; -.
DR PhylomeDB; Q9H6Z9; -.
DR TreeFam; TF314595; -.
DR BRENDA; 1.14.11.2; 2681.
DR BRENDA; 1.14.11.29; 2681.
DR PathwayCommons; Q9H6Z9; -.
DR Reactome; R-HSA-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
DR SignaLink; Q9H6Z9; -.
DR SIGNOR; Q9H6Z9; -.
DR BioGRID-ORCS; 112399; 14 hits in 1086 CRISPR screens.
DR ChiTaRS; EGLN3; human.
DR GeneWiki; EGLN3; -.
DR GenomeRNAi; 112399; -.
DR Pharos; Q9H6Z9; Tclin.
DR PRO; PR:Q9H6Z9; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; Q9H6Z9; protein.
DR Bgee; ENSG00000129521; Expressed in skin of leg and 167 other tissues.
DR ExpressionAtlas; Q9H6Z9; baseline and differential.
DR Genevisible; Q9H6Z9; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0016706; F:2-oxoglutarate-dependent dioxygenase activity; IDA:MGI.
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; IDA:FlyBase.
DR GO; GO:0031543; F:peptidyl-proline dioxygenase activity; IBA:GO_Central.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IEP:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEP: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:0018401; P:peptidyl-proline hydroxylation to 4-hydroxy-L-proline; IDA:FlyBase.
DR GO; GO:0018126; P:protein hydroxylation; IDA:UniProtKB.
DR GO; GO:0042127; P:regulation of cell population proliferation; IEP:UniProtKB.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:0001666; P:response to hypoxia; IEP: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 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_0000206666"
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:0000269|PubMed:19584355"
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"
FT VARIANT 136
FT /note="V -> L (in dbSNP:rs17102002)"
FT /id="VAR_050449"
FT VARIANT 234
FT /note="S -> T (in dbSNP:rs17101995)"
FT /id="VAR_050450"
FT MUTAGEN 91..102
FT /note="ISFLLSLIDRLV->RSFLRSLIRRLR: Abolishes interaction
FT with ADRB2 and no increase in cellular abundance of ADRB2."
FT /evidence="ECO:0000269|PubMed:19584355"
FT MUTAGEN 135
FT /note="H->A: Eliminates hydroxylase activity."
FT /evidence="ECO:0000269|PubMed:11598268"
FT MUTAGEN 137
FT /note="D->A: Eliminates hydroxylase activity."
FT /evidence="ECO:0000269|PubMed:11598268"
FT MUTAGEN 196
FT /note="H->A: Eliminates hydroxylase activity."
FT /evidence="ECO:0000269|PubMed:11598268"
SQ SEQUENCE 239 AA; 27261 MW; 9DA3A0F80168557B CRC64;
MPLGHIMRLD LEKIALEYIV PCLHEVGFCY LDNFLGEVVG DCVLERVKQL HCTGALRDGQ
LAGPRAGVSK RHLRGDQITW IGGNEEGCEA ISFLLSLIDR LVLYCGSRLG KYYVKERSKA
MVACYPGNGT GYVRHVDNPN GDGRCITCIY YLNKNWDAKL HGGILRIFPE GKSFIADVEP
IFDRLLFFWS DRRNPHEVQP SYATRYAMTV WYFDAEERAE AKKKFRNLTR KTESALTED
