HIF1N_HUMAN
ID HIF1N_HUMAN Reviewed; 349 AA.
AC Q9NWT6; D3DR69; Q5W147; Q969Q7; Q9NPV5;
DT 16-JUN-2003, integrated into UniProtKB/Swiss-Prot.
DT 16-JUN-2003, sequence version 2.
DT 03-AUG-2022, entry version 191.
DE RecName: Full=Hypoxia-inducible factor 1-alpha inhibitor;
DE EC=1.14.11.30;
DE EC=1.14.11.n4;
DE AltName: Full=Factor inhibiting HIF-1;
DE Short=FIH-1;
DE AltName: Full=Hypoxia-inducible factor asparagine hydroxylase;
GN Name=HIF1AN; Synonyms=FIH1;
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], AND INTERACTION WITH HIF1A; VHL AND HISTONE
RP DEACETYLASES.
RC TISSUE=Brain;
RX PubMed=11641274; DOI=10.1101/gad.924501;
RA Mahon P.C., Hirota K., Semenza G.L.;
RT "FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate
RT repression of HIF-1 transcriptional activity.";
RL Genes Dev. 15:2675-2686(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Signet-ring cell carcinoma;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT ALA-41.
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Muscle;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 89-349.
RC TISSUE=Melanoma;
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 [7]
RP CATALYTIC ACTIVITY, FUNCTION, AND MUTAGENESIS OF HIS-199 AND ASP-201.
RX PubMed=12080085; DOI=10.1101/gad.991402;
RA Lando D., Peet D.J., Gorman J.J., Whelan D.A., Whitelaw M.L., Bruick R.K.;
RT "FIH-1 is an asparaginyl hydroxylase enzyme that regulates the
RT transcriptional activity of hypoxia-inducible factor.";
RL Genes Dev. 16:1466-1471(2002).
RN [8]
RP CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=12042299; DOI=10.1074/jbc.c200273200;
RA Hewitson K.S., McNeill L.A., Riordan M.V., Tian Y.-M., Bullock A.N.,
RA Welford R.W., Elkins J.M., Oldham N.J., Bhattacharya S., Gleadle J.M.,
RA Ratcliffe P.J., Pugh C.W., Schofield C.J.;
RT "Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to
RT factor inhibiting HIF (FIH) and is related to the cupin structural
RT family.";
RL J. Biol. Chem. 277:26351-26355(2002).
RN [9]
RP DIMERIZATION, MASS SPECTROMETRY, AND MUTAGENESIS OF LEU-340 AND ILE-344.
RX PubMed=15239670; DOI=10.1042/bj20040735;
RA Lancaster D.E., McNeill L.A., McDonough M.A., Aplin R.T., Hewitson K.S.,
RA Pugh C.W., Ratcliffe P.J., Schofield C.J.;
RT "Disruption of dimerization and substrate phosphorylation inhibit factor
RT inhibiting hypoxia-inducible factor (FIH) activity.";
RL Biochem. J. 383:429-437(2004).
RN [10]
RP CATALYTIC ACTIVITY, SUBUNIT, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=14701857; DOI=10.1074/jbc.m312254200;
RA Koivunen P., Hirsila M., Gunzler V., Kivirikko K.I., Myllyharju J.;
RT "Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen
RT sensing pathway are distinct from those of its prolyl 4-hydroxylases.";
RL J. Biol. Chem. 279:9899-9904(2004).
RN [11]
RP SUBCELLULAR LOCATION.
RX PubMed=14734545; DOI=10.1074/jbc.m313614200;
RA Linke S., Stojkoski C., Kewley R.J., Booker G.W., Whitelaw M.L., Peet D.J.;
RT "Substrate requirements of the oxygen-sensing asparaginyl hydroxylase
RT factor-inhibiting hypoxia-inducible factor.";
RL J. Biol. Chem. 279:14391-14397(2004).
RN [12]
RP FUNCTION, INTERACTION WITH NFKB1 AND NFKBIA, AND CATALYTIC ACTIVITY.
RX PubMed=17003112; DOI=10.1073/pnas.0606877103;
RA Cockman M.E., Lancaster D.E., Stolze I.P., Hewitson K.S., McDonough M.A.,
RA Coleman M.L., Coles C.H., Yu X., Hay R.T., Ley S.C., Pugh C.W.,
RA Oldham N.J., Masson N., Schofield C.J., Ratcliffe P.J.;
RT "Posttranslational hydroxylation of ankyrin repeats in IkappaB proteins by
RT the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor
RT inhibiting HIF (FIH).";
RL Proc. Natl. Acad. Sci. U.S.A. 103:14767-14772(2006).
RN [13]
RP FUNCTION, SUBCELLULAR LOCATION, AND CATALYTIC ACTIVITY.
RX PubMed=18299578; DOI=10.1073/pnas.0711591105;
RA Zheng X., Linke S., Dias J.M., Zheng X., Gradin K., Wallis T.P.,
RA Hamilton B.R., Gustafsson M., Ruas J.L., Wilkins S., Bilton R.L.,
RA Brismar K., Whitelaw M.L., Pereira T., Gorman J.J., Ericson J., Peet D.J.,
RA Lendahl U., Poellinger L.;
RT "Interaction with factor inhibiting HIF-1 defines an additional mode of
RT cross-coupling between the Notch and hypoxia signaling pathways.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:3368-3373(2008).
RN [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [15]
RP FUNCTION, INTERACTION WITH PPP1R12A, AND CATALYTIC ACTIVITY.
RX PubMed=19245366; DOI=10.1042/bj20081905;
RA Webb J.D., Muranyi A., Pugh C.W., Ratcliffe P.J., Coleman M.L.;
RT "MYPT1, the targeting subunit of smooth-muscle myosin phosphatase, is a
RT substrate for the asparaginyl hydroxylase factor inhibiting hypoxia-
RT inducible factor (FIH).";
RL Biochem. J. 420:327-333(2009).
RN [16]
RP INTERACTION WITH APBA3, AND SUBCELLULAR LOCATION.
RX PubMed=19726677; DOI=10.1074/jbc.m109.019216;
RA Sakamoto T., Seiki M.;
RT "Mint3 enhances the activity of hypoxia-inducible factor-1 (HIF-1) in
RT macrophages by suppressing the activity of factor inhibiting HIF-1.";
RL J. Biol. Chem. 284:30350-30359(2009).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP INTERACTION WITH UBE3A.
RX PubMed=22645313; DOI=10.1128/mcb.00201-12;
RA Martinez-Noel G., Galligan J.T., Sowa M.E., Arndt V., Overton T.M.,
RA Harper J.W., Howley P.M.;
RT "Identification and proteomic analysis of distinct UBE3A/E6AP protein
RT complexes.";
RL Mol. Cell. Biol. 32:3095-3106(2012).
RN [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA Giglione C.;
RT "Comparative large-scale characterisation of plant vs. mammal proteins
RT reveals similar and idiosyncratic N-alpha acetylation features.";
RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN [20]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [21]
RP INTERACTION WITH NECAB3.
RX PubMed=26948053; DOI=10.1038/srep22784;
RA Nakaoka H.J., Hara T., Yoshino S., Kanamori A., Matsui Y., Shimamura T.,
RA Sato H., Murakami Y., Seiki M., Sakamoto T.;
RT "NECAB3 promotes activation of hypoxia-inducible factor-1 during normoxia
RT and enhances tumourigenicity of cancer cells.";
RL Sci. Rep. 6:22784-22784(2016).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) IN COMPLEX WITH IRON AND
RP 2-OXOGLUTARATE, AND SUBUNIT.
RX PubMed=12432100; DOI=10.1073/pnas.202614999;
RA Dann C.E. III, Bruick R.K., Deisenhofer J.;
RT "Structure of factor-inhibiting hypoxia-inducible factor 1: an asparaginyl
RT hydroxylase involved in the hypoxic response pathway.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:15351-15356(2002).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) IN COMPLEX WITH 786-826 OF HIF1A;
RP IRON; ZINC AND 2-OXOGLUTARATE.
RX PubMed=12446723; DOI=10.1074/jbc.c200644200;
RA Elkins J.M., Hewitson K.S., McNeill L.A., Seibel J.F., Schlemminger I.,
RA Pugh C.W., Ratcliffe P.J., Schofield C.J.;
RT "Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals
RT mechanism of oxidative modification of HIF-1 alpha.";
RL J. Biol. Chem. 278:1802-1806(2003).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS), AND SUBUNIT.
RX PubMed=12482756; DOI=10.1074/jbc.m210385200;
RA Lee C., Kim S.J., Jeong D.G., Lee S.M., Ryu S.E.;
RT "Structure of human FIH-1 reveals a unique active site pocket and
RT interaction sites for HIF-1 and von Hippel-Lindau.";
RL J. Biol. Chem. 278:7558-7563(2003).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) IN COMPLEX WITH IRON AND INHIBITOR.
RX PubMed=15913349; DOI=10.1021/ja050841b;
RA McDonough M.A., McNeill L.A., Tilliet M., Papamicael C.A., Chen Q.Y.,
RA Banerji B., Hewitson K.S., Schofield C.J.;
RT "Selective inhibition of factor inhibiting hypoxia-inducible factor.";
RL J. Am. Chem. Soc. 127:7680-7681(2005).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) IN COMPLEX WITH IRON; SUCCINATE AND
RP FUMARATE.
RX PubMed=17135241; DOI=10.1074/jbc.m608337200;
RA Hewitson K.S., Lienard B.M., McDonough M.A., Clifton I.J., Butler D.,
RA Soares A.S., Oldham N.J., McNeill L.A., Schofield C.J.;
RT "Structural and mechanistic studies on the inhibition of the hypoxia-
RT inducible transcription factor hydroxylases by tricarboxylic acid cycle
RT intermediates.";
RL J. Biol. Chem. 282:3293-3301(2007).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) IN COMPLEXES WITH 1930-1949 OR
RP 1997-2016 OF MOUSE NOTCH1; IRON AND 2-OXOGLUTARATE, FUNCTION, SUBUNIT, AND
RP CATALYTIC ACTIVITY.
RX PubMed=17573339; DOI=10.1074/jbc.m704102200;
RA Coleman M.L., McDonough M.A., Hewitson K.S., Coles C., Mecinovic J.,
RA Edelmann M., Cook K.M., Cockman M.E., Lancaster D.E., Kessler B.M.,
RA Oldham N.J., Ratcliffe P.J., Schofield C.J.;
RT "Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor
RT inhibiting hypoxia-inducible factor.";
RL J. Biol. Chem. 282:24027-24038(2007).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 11-349 OF MUTANTS ALA-201 AND
RP GLY-201 IN COMPLEXES WITH 786-826 OR 788-806 OF HIF1A; IRON OR ZINC AND
RP 2-OXOGLUTARATE, AND MUTAGENESIS OF ASP-201; TRP-296 AND LEU-340.
RX PubMed=18611856; DOI=10.1074/jbc.m804999200;
RA Hewitson K.S., Holmes S.L., Ehrismann D., Hardy A.P., Chowdhury R.,
RA Schofield C.J., McDonough M.A.;
RT "Evidence that two enzyme-derived histidine ligands are sufficient for iron
RT binding and catalysis by factor inhibiting HIF (FIH).";
RL J. Biol. Chem. 283:25971-25978(2008).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.12 ANGSTROMS) IN COMPLEX WITH IRON AND
RP 2-OXOGLUTARATE ANALOGS.
RX PubMed=20822901; DOI=10.1016/j.bmcl.2010.08.032;
RA Conejo-Garcia A., McDonough M.A., Loenarz C., McNeill L.A., Hewitson K.S.,
RA Ge W., Lienard B.M., Schofield C.J., Clifton I.J.;
RT "Structural basis for binding of cyclic 2-oxoglutarate analogues to factor-
RT inhibiting hypoxia-inducible factor.";
RL Bioorg. Med. Chem. Lett. 20:6125-6128(2010).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.59 ANGSTROMS) OF 15-349 IN COMPLEX WITH IRON AND
RP QUINOL FAMILY INHIBITORS.
RX PubMed=20396966; DOI=10.1007/s10059-010-0058-3;
RA Moon H., Han S., Park H., Choe J.;
RT "Crystal structures of human FIH-1 in complex with quinol family
RT inhibitors.";
RL Mol. Cells 29:471-474(2010).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) IN COMPLEX WITH IRON AND INHIBITORS.
RX PubMed=21460794; DOI=10.1038/embor.2011.43;
RA Chowdhury R., Yeoh K.K., Tian Y.M., Hillringhaus L., Bagg E.A., Rose N.R.,
RA Leung I.K., Li X.S., Woon E.C., Yang M., McDonough M.A., King O.N.,
RA Clifton I.J., Klose R.J., Claridge T.D., Ratcliffe P.J., Schofield C.J.,
RA Kawamura A.;
RT "The oncometabolite 2-hydroxyglutarate inhibits histone lysine
RT demethylases.";
RL EMBO Rep. 12:463-469(2011).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.28 ANGSTROMS) IN COMPLEX WITH IRON; 2-OXOGLUTARATE
RP AND 538-558 OF TNKS2, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=21251231; DOI=10.1111/j.1742-4658.2011.08022.x;
RA Yang M., Chowdhury R., Ge W., Hamed R.B., McDonough M.A., Claridge T.D.,
RA Kessler B.M., Cockman M.E., Ratcliffe P.J., Schofield C.J.;
RT "Factor-inhibiting hypoxia-inducible factor (FIH) catalyses the post-
RT translational hydroxylation of histidinyl residues within ankyrin repeat
RT domains.";
RL FEBS J. 278:1086-1097(2011).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF MUTANT HIS-239 IN COMPLEX WITH
RP ZINC; N-OXALYLGLYCINE AND PEPTIDE SUBSTRATE, FUNCTION, INTERACTION WITH
RP ANK1, MUTAGENESIS OF ASP-201 AND GLN-239, AND CATALYTIC ACTIVITY.
RX PubMed=21177872; DOI=10.1074/jbc.m110.193540;
RA Yang M., Ge W., Chowdhury R., Claridge T.D., Kramer H.B., Schmierer B.,
RA McDonough M.A., Gong L., Kessler B.M., Ratcliffe P.J., Coleman M.L.,
RA Schofield C.J.;
RT "Asparagine and aspartate hydroxylation of the cytoskeletal ankyrin family
RT is catalyzed by factor-inhibiting hypoxia-inducible factor.";
RL J. Biol. Chem. 286:7648-7660(2011).
CC -!- FUNCTION: Hydroxylates HIF-1 alpha at 'Asn-803' in the C-terminal
CC transactivation domain (CAD). Functions as an oxygen sensor and, under
CC normoxic conditions, the hydroxylation prevents interaction of HIF-1
CC with transcriptional coactivators including Cbp/p300-interacting
CC transactivator. Involved in transcriptional repression through
CC interaction with HIF1A, VHL and histone deacetylases. Hydroxylates
CC specific Asn residues within ankyrin repeat domains (ARD) of NFKB1,
CC NFKBIA, NOTCH1, ASB4, PPP1R12A and several other ARD-containing
CC proteins. Also hydroxylates Asp and His residues within ARDs of ANK1
CC and TNKS2, respectively. Negatively regulates NOTCH1 activity,
CC accelerating myogenic differentiation. Positively regulates ASB4
CC activity, promoting vascular differentiation.
CC {ECO:0000269|PubMed:12042299, ECO:0000269|PubMed:12080085,
CC ECO:0000269|PubMed:17003112, ECO:0000269|PubMed:17573339,
CC ECO:0000269|PubMed:18299578, ECO:0000269|PubMed:19245366,
CC ECO:0000269|PubMed:21177872, ECO:0000269|PubMed:21251231}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + L-asparaginyl-[hypoxia-inducible factor alpha
CC subunit] + O2 = (3S)-3-hydroxy-L-asparaginyl-[hypoxia-inducible
CC factor alpha subunit] + CO2 + succinate; Xref=Rhea:RHEA:54268,
CC Rhea:RHEA-COMP:13833, Rhea:RHEA-COMP:13834, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:30031,
CC ChEBI:CHEBI:50347, ChEBI:CHEBI:138107; EC=1.14.11.30;
CC Evidence={ECO:0000269|PubMed:12042299, ECO:0000269|PubMed:12080085,
CC ECO:0000269|PubMed:14701857, ECO:0000269|PubMed:17573339};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + L-histidyl-[ankyrin-repeat domain protein] +
CC O2 = (3S)-3-hydroxy-L-histidyl-[ankyrin-repeat domain protein] + CO2
CC + succinate; Xref=Rhea:RHEA:54264, Rhea:RHEA-COMP:13836, Rhea:RHEA-
CC COMP:13837, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810,
CC ChEBI:CHEBI:29979, ChEBI:CHEBI:30031, ChEBI:CHEBI:138021;
CC EC=1.14.11.n4; Evidence={ECO:0000269|PubMed:21251231};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + L-asparaginyl-[ankyrin-repeat domain protein]
CC + O2 = (3S)-3-hydroxy-L-asparaginyl-[ankyrin-repeat domain protein] +
CC CO2 + succinate; Xref=Rhea:RHEA:54272, Rhea:RHEA-COMP:13838,
CC Rhea:RHEA-COMP:13839, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:16810, ChEBI:CHEBI:30031, ChEBI:CHEBI:50347,
CC ChEBI:CHEBI:138107; EC=1.14.11.n4;
CC Evidence={ECO:0000269|PubMed:17003112, ECO:0000269|PubMed:17573339,
CC ECO:0000269|PubMed:18299578, ECO:0000269|PubMed:19245366,
CC ECO:0000269|PubMed:21177872};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + L-aspartyl-[ankyrin-repeat domain protein] +
CC O2 = (3S)-3-hydroxy-L-aspartyl-[ankyrin-repeat domain protein] + CO2
CC + succinate; Xref=Rhea:RHEA:54280, Rhea:RHEA-COMP:13843, Rhea:RHEA-
CC COMP:13844, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810,
CC ChEBI:CHEBI:29961, ChEBI:CHEBI:30031, ChEBI:CHEBI:138111;
CC EC=1.14.11.n4; Evidence={ECO:0000269|PubMed:21177872};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000269|PubMed:12432100, ECO:0000269|PubMed:12446723,
CC ECO:0000269|PubMed:15913349, ECO:0000269|PubMed:17135241,
CC ECO:0000269|PubMed:20396966, ECO:0000269|PubMed:20822901,
CC ECO:0000269|PubMed:21251231, ECO:0000269|PubMed:21460794};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=100 uM for HIF1A (788-822) peptide {ECO:0000269|PubMed:14701857};
CC KM=160 uM for HIF2A (832-866) peptide {ECO:0000269|PubMed:14701857};
CC KM=0.5 uM for Fe(2+) {ECO:0000269|PubMed:14701857};
CC KM=25 uM for 2-oxoglutarate {ECO:0000269|PubMed:14701857};
CC KM=260 uM for ascorbate {ECO:0000269|PubMed:14701857};
CC KM=90 uM for O(2) {ECO:0000269|PubMed:14701857};
CC Note=The kinetic constants are determined for the recombinant FLAG-
CC His-tagged protein.;
CC -!- SUBUNIT: Homodimer; homodimerization is essential for catalytic
CC activity. Interacts with VHL and HIF1A. Part of a complex with VHL,
CC HIF1A and HDAC1 or HDAC2 or HDAC3. Interacts with NFKB1 and NFKBIA.
CC Interacts with NOTCH1, NOTCH2 and NOTCH3 but not with NOTCH4. Interacts
CC with APBA3; binding inhibits HIF1AN binding to HIF1A. Interacts with
CC TNKS2. Interacts with PPP1R12A. Interacts with ASB4 (By similarity).
CC Interacts with UBE3A. Interacts with ANKS3 (By similarity). Interacts
CC with NECAB3; the interaction is indirect and seems to be mediated by
CC APBA3. {ECO:0000250|UniProtKB:Q8BLR9, ECO:0000269|PubMed:11641274,
CC ECO:0000269|PubMed:12432100, ECO:0000269|PubMed:12446723,
CC ECO:0000269|PubMed:12482756, ECO:0000269|PubMed:14701857,
CC ECO:0000269|PubMed:15913349, ECO:0000269|PubMed:17003112,
CC ECO:0000269|PubMed:17135241, ECO:0000269|PubMed:17573339,
CC ECO:0000269|PubMed:19245366, ECO:0000269|PubMed:19726677,
CC ECO:0000269|PubMed:20396966, ECO:0000269|PubMed:20822901,
CC ECO:0000269|PubMed:21177872, ECO:0000269|PubMed:21251231,
CC ECO:0000269|PubMed:21460794, ECO:0000269|PubMed:22645313,
CC ECO:0000269|PubMed:26948053}.
CC -!- INTERACTION:
CC Q9NWT6; Q8NFD2: ANKK1; NbExp=4; IntAct=EBI-745632, EBI-13280688;
CC Q9NWT6; Q6PG48: ANKRD12; NbExp=3; IntAct=EBI-745632, EBI-12304341;
CC Q9NWT6; Q7Z713: ANKRD37; NbExp=7; IntAct=EBI-745632, EBI-12373689;
CC Q9NWT6; Q8WVL7: ANKRD49; NbExp=4; IntAct=EBI-745632, EBI-9381820;
CC Q9NWT6; Q9ULJ7-2: ANKRD50; NbExp=3; IntAct=EBI-745632, EBI-12239063;
CC Q9NWT6; O96018: APBA3; NbExp=6; IntAct=EBI-745632, EBI-6115839;
CC Q9NWT6; Q9H672-2: ASB7; NbExp=3; IntAct=EBI-745632, EBI-12104328;
CC Q9NWT6; Q96DX5: ASB9; NbExp=5; IntAct=EBI-745632, EBI-745641;
CC Q9NWT6; Q9UK73: FEM1B; NbExp=3; IntAct=EBI-745632, EBI-310482;
CC Q9NWT6; Q16665: HIF1A; NbExp=12; IntAct=EBI-745632, EBI-447269;
CC Q9NWT6; Q13418: ILK; NbExp=2; IntAct=EBI-745632, EBI-747644;
CC Q9NWT6; P19838: NFKB1; NbExp=7; IntAct=EBI-745632, EBI-300010;
CC Q9NWT6; P25963: NFKBIA; NbExp=6; IntAct=EBI-745632, EBI-307386;
CC Q9NWT6; Q96FW1: OTUB1; NbExp=5; IntAct=EBI-745632, EBI-1058491;
CC Q9NWT6; O75832: PSMD10; NbExp=2; IntAct=EBI-745632, EBI-752185;
CC Q9NWT6; P57078: RIPK4; NbExp=4; IntAct=EBI-745632, EBI-4422308;
CC Q9NWT6; O95271: TNKS; NbExp=5; IntAct=EBI-745632, EBI-1105254;
CC Q9NWT6; Q9H2K2: TNKS2; NbExp=5; IntAct=EBI-745632, EBI-4398527;
CC Q9NWT6; Q9BZF9: UACA; NbExp=2; IntAct=EBI-745632, EBI-350510;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Cytoplasm, perinuclear
CC region. Note=Mainly cytoplasmic localization, but interaction with
CC NOTCH1 results in nuclear localization and interaction with ABPA3
CC results in perinuclear localization in macrophages.
CC -!- MASS SPECTROMETRY: Mass=40566; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:15239670};
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DR EMBL; AF395830; AAL27308.1; -; mRNA.
DR EMBL; AK000622; BAA91291.1; -; mRNA.
DR EMBL; AL133352; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471066; EAW49817.1; -; Genomic_DNA.
DR EMBL; CH471066; EAW49818.1; -; Genomic_DNA.
DR EMBL; BC007719; AAH07719.1; -; mRNA.
DR EMBL; AL359615; CAB94885.1; -; mRNA.
DR CCDS; CCDS7498.1; -.
DR PIR; T50633; T50633.
DR RefSeq; NP_060372.2; NM_017902.2.
DR PDB; 1H2K; X-ray; 2.15 A; A=1-349.
DR PDB; 1H2L; X-ray; 2.25 A; A=1-349.
DR PDB; 1H2M; X-ray; 2.50 A; A=1-349.
DR PDB; 1H2N; X-ray; 2.84 A; A=1-349.
DR PDB; 1IZ3; X-ray; 2.80 A; A=1-349.
DR PDB; 1MZE; X-ray; 2.20 A; A=1-349.
DR PDB; 1MZF; X-ray; 2.40 A; A=1-349.
DR PDB; 1YCI; X-ray; 2.70 A; A=1-349.
DR PDB; 2CGN; X-ray; 2.40 A; A=1-349.
DR PDB; 2CGO; X-ray; 2.30 A; A=1-349.
DR PDB; 2ILM; X-ray; 2.30 A; A=1-349.
DR PDB; 2W0X; X-ray; 2.12 A; A=1-349.
DR PDB; 2WA3; X-ray; 2.50 A; A=1-349.
DR PDB; 2WA4; X-ray; 2.50 A; A=1-349.
DR PDB; 2XUM; X-ray; 2.20 A; A=1-349.
DR PDB; 2Y0I; X-ray; 2.28 A; A=1-349.
DR PDB; 2YC0; X-ray; 2.15 A; A=1-349.
DR PDB; 2YDE; X-ray; 2.28 A; A=1-349.
DR PDB; 3D8C; X-ray; 2.10 A; A=11-349.
DR PDB; 3KCX; X-ray; 2.60 A; A=15-349.
DR PDB; 3KCY; X-ray; 2.59 A; A=15-349.
DR PDB; 3OD4; X-ray; 2.20 A; A=1-349.
DR PDB; 3P3N; X-ray; 2.40 A; A=1-349.
DR PDB; 3P3P; X-ray; 2.60 A; A=1-349.
DR PDB; 4AI8; X-ray; 2.40 A; A=1-349.
DR PDB; 4B7E; X-ray; 2.50 A; A=1-349.
DR PDB; 4B7K; X-ray; 2.39 A; A=1-349.
DR PDB; 4BIO; X-ray; 2.45 A; A=1-349.
DR PDB; 4JAA; X-ray; 2.39 A; A=1-349.
DR PDB; 4NR1; X-ray; 2.68 A; A=1-349.
DR PDB; 4Z1V; X-ray; 2.10 A; A=1-349.
DR PDB; 4Z2W; X-ray; 2.50 A; A=1-349.
DR PDB; 5JWK; X-ray; 2.30 A; A=1-349.
DR PDB; 5JWL; X-ray; 2.40 A; A=1-349.
DR PDB; 5JWP; X-ray; 2.10 A; A=1-349.
DR PDB; 5OP6; X-ray; 2.45 A; A=1-349.
DR PDB; 5OP8; X-ray; 2.30 A; A=1-349.
DR PDB; 5OPC; X-ray; 2.30 A; A=1-349.
DR PDB; 6H9J; X-ray; 1.83 A; A=12-349.
DR PDB; 6HA6; X-ray; 1.98 A; A=1-349.
DR PDB; 6HC8; X-ray; 1.90 A; A=1-349.
DR PDB; 6HKP; X-ray; 1.90 A; A=1-349.
DR PDB; 6HL5; X-ray; 1.98 A; A=1-349.
DR PDB; 6HL6; X-ray; 1.97 A; A=1-349.
DR PDB; 6RUJ; X-ray; 2.42 A; A=1-349.
DR PDB; 7A1J; X-ray; 1.90 A; A=1-349.
DR PDB; 7A1K; X-ray; 1.99 A; A=1-349.
DR PDB; 7A1L; X-ray; 2.29 A; A=1-349.
DR PDB; 7A1M; X-ray; 2.18 A; A=1-349.
DR PDB; 7A1N; X-ray; 2.01 A; A=1-349.
DR PDB; 7A1O; X-ray; 2.21 A; A=1-349.
DR PDB; 7A1P; X-ray; 1.76 A; A=1-349.
DR PDB; 7A1Q; X-ray; 1.75 A; A=1-349.
DR PDB; 7A1S; X-ray; 2.01 A; A=1-349.
DR PDBsum; 1H2K; -.
DR PDBsum; 1H2L; -.
DR PDBsum; 1H2M; -.
DR PDBsum; 1H2N; -.
DR PDBsum; 1IZ3; -.
DR PDBsum; 1MZE; -.
DR PDBsum; 1MZF; -.
DR PDBsum; 1YCI; -.
DR PDBsum; 2CGN; -.
DR PDBsum; 2CGO; -.
DR PDBsum; 2ILM; -.
DR PDBsum; 2W0X; -.
DR PDBsum; 2WA3; -.
DR PDBsum; 2WA4; -.
DR PDBsum; 2XUM; -.
DR PDBsum; 2Y0I; -.
DR PDBsum; 2YC0; -.
DR PDBsum; 2YDE; -.
DR PDBsum; 3D8C; -.
DR PDBsum; 3KCX; -.
DR PDBsum; 3KCY; -.
DR PDBsum; 3OD4; -.
DR PDBsum; 3P3N; -.
DR PDBsum; 3P3P; -.
DR PDBsum; 4AI8; -.
DR PDBsum; 4B7E; -.
DR PDBsum; 4B7K; -.
DR PDBsum; 4BIO; -.
DR PDBsum; 4JAA; -.
DR PDBsum; 4NR1; -.
DR PDBsum; 4Z1V; -.
DR PDBsum; 4Z2W; -.
DR PDBsum; 5JWK; -.
DR PDBsum; 5JWL; -.
DR PDBsum; 5JWP; -.
DR PDBsum; 5OP6; -.
DR PDBsum; 5OP8; -.
DR PDBsum; 5OPC; -.
DR PDBsum; 6H9J; -.
DR PDBsum; 6HA6; -.
DR PDBsum; 6HC8; -.
DR PDBsum; 6HKP; -.
DR PDBsum; 6HL5; -.
DR PDBsum; 6HL6; -.
DR PDBsum; 6RUJ; -.
DR PDBsum; 7A1J; -.
DR PDBsum; 7A1K; -.
DR PDBsum; 7A1L; -.
DR PDBsum; 7A1M; -.
DR PDBsum; 7A1N; -.
DR PDBsum; 7A1O; -.
DR PDBsum; 7A1P; -.
DR PDBsum; 7A1Q; -.
DR PDBsum; 7A1S; -.
DR AlphaFoldDB; Q9NWT6; -.
DR SMR; Q9NWT6; -.
DR BioGRID; 120794; 313.
DR DIP; DIP-35527N; -.
DR IntAct; Q9NWT6; 213.
DR MINT; Q9NWT6; -.
DR STRING; 9606.ENSP00000299163; -.
DR BindingDB; Q9NWT6; -.
DR ChEMBL; CHEMBL5909; -.
DR DrugBank; DB01694; D-tartaric acid.
DR DrugBank; DB08263; N-(carboxycarbonyl)-D-phenylalanine.
DR DrugCentral; Q9NWT6; -.
DR iPTMnet; Q9NWT6; -.
DR PhosphoSitePlus; Q9NWT6; -.
DR BioMuta; HIF1AN; -.
DR DMDM; 32129605; -.
DR EPD; Q9NWT6; -.
DR jPOST; Q9NWT6; -.
DR MassIVE; Q9NWT6; -.
DR MaxQB; Q9NWT6; -.
DR PaxDb; Q9NWT6; -.
DR PeptideAtlas; Q9NWT6; -.
DR PRIDE; Q9NWT6; -.
DR ProteomicsDB; 82978; -.
DR Antibodypedia; 17685; 660 antibodies from 36 providers.
DR DNASU; 55662; -.
DR Ensembl; ENST00000299163.7; ENSP00000299163.4; ENSG00000166135.14.
DR GeneID; 55662; -.
DR KEGG; hsa:55662; -.
DR MANE-Select; ENST00000299163.7; ENSP00000299163.4; NM_017902.3; NP_060372.2.
DR UCSC; uc001krj.5; human.
DR CTD; 55662; -.
DR DisGeNET; 55662; -.
DR GeneCards; HIF1AN; -.
DR HGNC; HGNC:17113; HIF1AN.
DR HPA; ENSG00000166135; Tissue enhanced (skeletal muscle, tongue).
DR MIM; 606615; gene.
DR neXtProt; NX_Q9NWT6; -.
DR OpenTargets; ENSG00000166135; -.
DR PharmGKB; PA29284; -.
DR VEuPathDB; HostDB:ENSG00000166135; -.
DR eggNOG; KOG2132; Eukaryota.
DR GeneTree; ENSGT00940000157409; -.
DR HOGENOM; CLU_016785_3_0_1; -.
DR InParanoid; Q9NWT6; -.
DR OMA; CLYPHPV; -.
DR OrthoDB; 1385616at2759; -.
DR PhylomeDB; Q9NWT6; -.
DR TreeFam; TF329609; -.
DR BioCyc; MetaCyc:HS15407-MON; -.
DR BRENDA; 1.14.11.16; 2681.
DR BRENDA; 1.14.11.30; 2681.
DR PathwayCommons; Q9NWT6; -.
DR Reactome; R-HSA-1234174; Cellular response to hypoxia.
DR SignaLink; Q9NWT6; -.
DR SIGNOR; Q9NWT6; -.
DR BioGRID-ORCS; 55662; 32 hits in 1091 CRISPR screens.
DR ChiTaRS; HIF1AN; human.
DR EvolutionaryTrace; Q9NWT6; -.
DR GeneWiki; HIF1AN; -.
DR GenomeRNAi; 55662; -.
DR Pharos; Q9NWT6; Tbio.
DR PRO; PR:Q9NWT6; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; Q9NWT6; protein.
DR Bgee; ENSG00000166135; Expressed in gastrocnemius and 202 other tissues.
DR ExpressionAtlas; Q9NWT6; baseline and differential.
DR Genevisible; Q9NWT6; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0016706; F:2-oxoglutarate-dependent dioxygenase activity; IBA:GO_Central.
DR GO; GO:0071532; F:ankyrin repeat binding; IPI:UniProtKB.
DR GO; GO:0031406; F:carboxylic acid binding; IDA:UniProtKB.
DR GO; GO:0008198; F:ferrous iron binding; IDA:UniProtKB.
DR GO; GO:0102113; F:hypoxia-inducible factor-asparagine oxygenase activity; IEA:UniProtKB-EC.
DR GO; GO:0051059; F:NF-kappaB binding; IPI:UniProtKB.
DR GO; GO:0005112; F:Notch binding; IPI:UniProtKB.
DR GO; GO:0019826; F:oxygen sensor activity; NAS:UniProtKB.
DR GO; GO:0036140; F:peptidyl-asparagine 3-dioxygenase activity; IDA:UniProtKB.
DR GO; GO:0036139; F:peptidyl-histidine dioxygenase activity; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; IDA:UniProtKB.
DR GO; GO:0061428; P:negative regulation of transcription from RNA polymerase II promoter in response to hypoxia; IDA:UniProtKB.
DR GO; GO:0042265; P:peptidyl-asparagine hydroxylation; IDA:UniProtKB.
DR GO; GO:0042264; P:peptidyl-aspartic acid hydroxylation; IDA:UniProtKB.
DR GO; GO:0036138; P:peptidyl-histidine hydroxylation; IDA:UniProtKB.
DR GO; GO:0045663; P:positive regulation of myoblast differentiation; IDA:UniProtKB.
DR GO; GO:2001214; P:positive regulation of vasculogenesis; NAS:UniProtKB.
DR Gene3D; 1.10.287.1010; -; 1.
DR Gene3D; 2.60.120.10; -; 1.
DR IDEAL; IID00396; -.
DR InterPro; IPR041667; Cupin_8.
DR InterPro; IPR027445; FIH-1.
DR InterPro; IPR027452; FIH-1_dom_II.
DR InterPro; IPR003347; JmjC_dom.
DR InterPro; IPR014710; RmlC-like_jellyroll.
DR PANTHER; PTHR12461:SF80; PTHR12461:SF80; 1.
DR Pfam; PF13621; Cupin_8; 1.
DR SMART; SM00558; JmjC; 1.
DR PROSITE; PS51184; JMJC; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cytoplasm; Dioxygenase; Iron; Metal-binding;
KW Nucleus; Oxidoreductase; Reference proteome; Transcription;
KW Transcription regulation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:22814378"
FT CHAIN 2..349
FT /note="Hypoxia-inducible factor 1-alpha inhibitor"
FT /id="PRO_0000083974"
FT DOMAIN 142..312
FT /note="JmjC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00538"
FT REGION 1..51
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2..125
FT /note="Interaction with VHL"
FT /evidence="ECO:0000269|PubMed:11641274"
FT BINDING 145
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000269|PubMed:12432100,
FT ECO:0000269|PubMed:12446723, ECO:0000269|PubMed:21251231"
FT BINDING 152
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:21177872"
FT BINDING 181..183
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:21177872"
FT BINDING 196
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000269|PubMed:12432100,
FT ECO:0000269|PubMed:12446723, ECO:0000269|PubMed:21251231"
FT BINDING 199
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:12432100,
FT ECO:0000269|PubMed:12446723, ECO:0000269|PubMed:15913349,
FT ECO:0000269|PubMed:17135241, ECO:0000269|PubMed:20396966,
FT ECO:0000269|PubMed:20822901, ECO:0000269|PubMed:21251231,
FT ECO:0000269|PubMed:21460794"
FT BINDING 201..203
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:21177872"
FT BINDING 201
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:12432100,
FT ECO:0000269|PubMed:12446723, ECO:0000269|PubMed:15913349,
FT ECO:0000269|PubMed:17135241, ECO:0000269|PubMed:20396966,
FT ECO:0000269|PubMed:20822901, ECO:0000269|PubMed:21251231,
FT ECO:0000269|PubMed:21460794"
FT BINDING 205
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000269|PubMed:12432100,
FT ECO:0000269|PubMed:12446723, ECO:0000269|PubMed:21251231"
FT BINDING 214
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000269|PubMed:12432100,
FT ECO:0000269|PubMed:12446723, ECO:0000269|PubMed:21251231"
FT BINDING 238..239
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:21177872"
FT BINDING 279
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:12432100,
FT ECO:0000269|PubMed:12446723, ECO:0000269|PubMed:15913349,
FT ECO:0000269|PubMed:17135241, ECO:0000269|PubMed:20396966,
FT ECO:0000269|PubMed:20822901, ECO:0000269|PubMed:21251231,
FT ECO:0000269|PubMed:21460794"
FT BINDING 294
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000269|PubMed:12432100,
FT ECO:0000269|PubMed:12446723, ECO:0000269|PubMed:21251231"
FT BINDING 300
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:21177872"
FT BINDING 321
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:21177872"
FT SITE 340
FT /note="Important for dimer formation"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:22814378"
FT VARIANT 41
FT /note="P -> A (in dbSNP:rs2295778)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_051028"
FT MUTAGEN 199
FT /note="H->A: Prevents suppression of HIF CAD activity.
FT Strongly stimulates 2-oxoglutarate turnover. No stimulation
FT of 2-oxoglutarate turnover; when associated with R-340."
FT /evidence="ECO:0000269|PubMed:12080085"
FT MUTAGEN 201
FT /note="D->A: Prevents suppression of HIF CAD activity."
FT /evidence="ECO:0000269|PubMed:12080085,
FT ECO:0000269|PubMed:18611856, ECO:0000269|PubMed:21177872"
FT MUTAGEN 201
FT /note="D->E: Loss of HIF1A Asn hydroxylation activity.
FT Slightly stimulates 2-oxoglutarate turnover."
FT /evidence="ECO:0000269|PubMed:12080085,
FT ECO:0000269|PubMed:18611856, ECO:0000269|PubMed:21177872"
FT MUTAGEN 201
FT /note="D->G: No impact on HIF1A Asn hydroxylation activity.
FT Loss of Asp hydroxylation ability. Strongly stimulates 2-
FT oxoglutarate turnover. Loss of HIF1A Asn hydroxylation
FT activity and slight stimulation of 2-oxoglutarate turnover;
FT when associated with R-296."
FT /evidence="ECO:0000269|PubMed:12080085,
FT ECO:0000269|PubMed:18611856, ECO:0000269|PubMed:21177872"
FT MUTAGEN 239
FT /note="Q->H: No effect on Asp hydroxylation ability."
FT /evidence="ECO:0000269|PubMed:21177872"
FT MUTAGEN 296
FT /note="W->R: Loss of HIF1A Asn hydroxylation activity and
FT slight stimulation of 2-oxoglutarate turnover; when
FT associated with G-201."
FT /evidence="ECO:0000269|PubMed:18611856"
FT MUTAGEN 340
FT /note="L->R: Impairs dimer formation, leading to loss of
FT HIF1A Asn hydroxylation activity. No stimulation of 2-
FT oxoglutarate turnover; when associated with A-201."
FT /evidence="ECO:0000269|PubMed:15239670,
FT ECO:0000269|PubMed:18611856"
FT MUTAGEN 344
FT /note="I->R: No effect on dimer formation and HIF1A Asn
FT hydroxylation activity."
FT /evidence="ECO:0000269|PubMed:15239670"
FT CONFLICT 10
FT /note="A -> T (in Ref. 2; BAA91291)"
FT /evidence="ECO:0000305"
FT CONFLICT 28
FT /note="D -> H (in Ref. 2; BAA91291)"
FT /evidence="ECO:0000305"
FT CONFLICT 156
FT /note="R -> G (in Ref. 2; BAA91291)"
FT /evidence="ECO:0000305"
FT HELIX 2..9
FT /evidence="ECO:0007829|PDB:2YC0"
FT HELIX 20..22
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 24..26
FT /evidence="ECO:0007829|PDB:7A1P"
FT HELIX 29..31
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 39..41
FT /evidence="ECO:0007829|PDB:7A1Q"
FT HELIX 50..57
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 62..65
FT /evidence="ECO:0007829|PDB:7A1Q"
FT HELIX 71..75
FT /evidence="ECO:0007829|PDB:7A1Q"
FT HELIX 78..84
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 85..88
FT /evidence="ECO:0007829|PDB:3P3P"
FT STRAND 90..99
FT /evidence="ECO:0007829|PDB:7A1Q"
FT HELIX 105..110
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 111..113
FT /evidence="ECO:0007829|PDB:3KCY"
FT STRAND 117..123
FT /evidence="ECO:0007829|PDB:7A1Q"
FT HELIX 125..138
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 143..149
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 151..154
FT /evidence="ECO:0007829|PDB:1MZE"
FT HELIX 156..163
FT /evidence="ECO:0007829|PDB:7A1Q"
FT HELIX 167..177
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 182..184
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 186..190
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 195..199
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 202..212
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 214..219
FT /evidence="ECO:0007829|PDB:7A1Q"
FT HELIX 221..223
FT /evidence="ECO:0007829|PDB:7A1Q"
FT HELIX 224..227
FT /evidence="ECO:0007829|PDB:7A1Q"
FT TURN 235..238
FT /evidence="ECO:0007829|PDB:7A1P"
FT STRAND 239..242
FT /evidence="ECO:0007829|PDB:4Z1V"
FT STRAND 244..246
FT /evidence="ECO:0007829|PDB:6HL5"
FT TURN 249..251
FT /evidence="ECO:0007829|PDB:7A1Q"
FT HELIX 253..257
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 260..265
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 270..273
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 278..283
FT /evidence="ECO:0007829|PDB:7A1Q"
FT STRAND 290..297
FT /evidence="ECO:0007829|PDB:7A1Q"
FT HELIX 312..330
FT /evidence="ECO:0007829|PDB:7A1Q"
FT HELIX 333..335
FT /evidence="ECO:0007829|PDB:7A1Q"
FT HELIX 336..344
FT /evidence="ECO:0007829|PDB:7A1Q"
FT TURN 345..347
FT /evidence="ECO:0007829|PDB:7A1Q"
SQ SEQUENCE 349 AA; 40285 MW; 96A033BA7B3BD8C7 CRC64;
MAATAAEAVA SGSGEPREEA GALGPAWDES QLRSYSFPTR PIPRLSQSDP RAEELIENEE
PVVLTDTNLV YPALKWDLEY LQENIGNGDF SVYSASTHKF LYYDEKKMAN FQNFKPRSNR
EEMKFHEFVE KLQDIQQRGG EERLYLQQTL NDTVGRKIVM DFLGFNWNWI NKQQGKRGWG
QLTSNLLLIG MEGNVTPAHY DEQQNFFAQI KGYKRCILFP PDQFECLYPY PVHHPCDRQS
QVDFDNPDYE RFPNFQNVVG YETVVGPGDV LYIPMYWWHH IESLLNGGIT ITVNFWYKGA
PTPKRIEYPL KAHQKVAIMR NIEKMLGEAL GNPQEVGPLL NTMIKGRYN
