HIF1N_MOUSE
ID HIF1N_MOUSE Reviewed; 349 AA.
AC Q8BLR9; A1L3B7; Q3U3G4;
DT 16-JUN-2003, integrated into UniProtKB/Swiss-Prot.
DT 07-MAR-2006, sequence version 2.
DT 03-AUG-2022, entry version 146.
DE RecName: Full=Hypoxia-inducible factor 1-alpha inhibitor;
DE EC=1.14.11.30;
DE EC=1.14.11.n4;
DE AltName: Full=Hypoxia-inducible factor asparagine hydroxylase;
GN Name=Hif1an;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=C57BL/6J, and NOD; TISSUE=Brain cortex;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP FUNCTION, AND INTERACTION WITH ASB4.
RX PubMed=17636018; DOI=10.1128/mcb.00511-07;
RA Ferguson J.E. III, Wu Y., Smith K., Charles P., Powers K., Wang H.,
RA Patterson C.;
RT "ASB4 is a hydroxylation substrate of FIH and promotes vascular
RT differentiation via an oxygen-dependent mechanism.";
RL Mol. Cell. Biol. 27:6407-6419(2007).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP INTERACTION WITH ANKS3.
RX PubMed=25671767; DOI=10.1038/ki.2015.17;
RA Yakulov T.A., Yasunaga T., Ramachandran H., Engel C., Mueller B., Hoff S.,
RA Dengjel J., Lienkamp S.S., Walz G.;
RT "Anks3 interacts with nephronophthisis proteins and is required for normal
RT renal development.";
RL Kidney Int. 87:1191-1200(2015).
CC -!- FUNCTION: Hydroxylates HIF-1 alpha at 'Asn-799' 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 (By similarity). Positively
CC regulates ASB4 activity, promoting vascular differentiation.
CC {ECO:0000250|UniProtKB:Q9NWT6, ECO:0000269|PubMed:17636018}.
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 -!- 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;
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 -!- 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;
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000250|UniProtKB:Q9NWT6};
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 ABPA3. Interacts with TNKS2. Interacts with PPP1R12A (By
CC similarity). Interacts with UBE3A (By similarity). Interacts with ASB4.
CC Interacts with ANKS3 (PubMed:25671767). Interacts with NECAB3; the
CC interaction is indirect and seems to be mediated by APBA3 (By
CC similarity). {ECO:0000250, ECO:0000250|UniProtKB:Q9NWT6,
CC ECO:0000269|PubMed:17636018, ECO:0000269|PubMed:25671767}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q9NWT6}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q9NWT6}. Cytoplasm, perinuclear region
CC {ECO:0000250|UniProtKB:Q9NWT6}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8BLR9-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8BLR9-2; Sequence=VSP_017537, VSP_017538;
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DR EMBL; AK043636; BAC31602.1; -; mRNA.
DR EMBL; AK154774; BAE32822.1; -; mRNA.
DR EMBL; BC130013; AAI30014.1; -; mRNA.
DR CCDS; CCDS29852.1; -. [Q8BLR9-1]
DR RefSeq; NP_795932.2; NM_176958.3. [Q8BLR9-1]
DR AlphaFoldDB; Q8BLR9; -.
DR SMR; Q8BLR9; -.
DR BioGRID; 235386; 2.
DR CORUM; Q8BLR9; -.
DR IntAct; Q8BLR9; 2.
DR STRING; 10090.ENSMUSP00000035326; -.
DR PhosphoSitePlus; Q8BLR9; -.
DR EPD; Q8BLR9; -.
DR MaxQB; Q8BLR9; -.
DR PaxDb; Q8BLR9; -.
DR PeptideAtlas; Q8BLR9; -.
DR PRIDE; Q8BLR9; -.
DR ProteomicsDB; 273340; -. [Q8BLR9-1]
DR ProteomicsDB; 273341; -. [Q8BLR9-2]
DR Antibodypedia; 17685; 660 antibodies from 36 providers.
DR DNASU; 319594; -.
DR Ensembl; ENSMUST00000040455; ENSMUSP00000035326; ENSMUSG00000036450. [Q8BLR9-1]
DR GeneID; 319594; -.
DR KEGG; mmu:319594; -.
DR UCSC; uc008hpx.1; mouse. [Q8BLR9-2]
DR UCSC; uc008hpy.1; mouse. [Q8BLR9-1]
DR CTD; 55662; -.
DR MGI; MGI:2442345; Hif1an.
DR VEuPathDB; HostDB:ENSMUSG00000036450; -.
DR eggNOG; KOG2132; Eukaryota.
DR GeneTree; ENSGT00940000157409; -.
DR HOGENOM; CLU_016785_3_0_1; -.
DR InParanoid; Q8BLR9; -.
DR OMA; CLYPHPV; -.
DR OrthoDB; 1385616at2759; -.
DR PhylomeDB; Q8BLR9; -.
DR TreeFam; TF329609; -.
DR Reactome; R-MMU-1234174; Cellular response to hypoxia.
DR BioGRID-ORCS; 319594; 10 hits in 76 CRISPR screens.
DR ChiTaRS; Hif1an; mouse.
DR PRO; PR:Q8BLR9; -.
DR Proteomes; UP000000589; Chromosome 19.
DR RNAct; Q8BLR9; protein.
DR Bgee; ENSMUSG00000036450; Expressed in hindlimb stylopod muscle and 217 other tissues.
DR Genevisible; Q8BLR9; MM.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:UniProtKB.
DR GO; GO:0016706; F:2-oxoglutarate-dependent dioxygenase activity; IBA:GO_Central.
DR GO; GO:0071532; F:ankyrin repeat binding; ISS:UniProtKB.
DR GO; GO:0031406; F:carboxylic acid binding; ISS:UniProtKB.
DR GO; GO:0008198; F:ferrous iron binding; ISS:UniProtKB.
DR GO; GO:0102113; F:hypoxia-inducible factor-asparagine oxygenase activity; IEA:UniProtKB-EC.
DR GO; GO:0051059; F:NF-kappaB binding; ISS:UniProtKB.
DR GO; GO:0005112; F:Notch binding; ISS:UniProtKB.
DR GO; GO:0036140; F:peptidyl-asparagine 3-dioxygenase activity; ISS:UniProtKB.
DR GO; GO:0036139; F:peptidyl-histidine dioxygenase activity; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; ISS:UniProtKB.
DR GO; GO:0061428; P:negative regulation of transcription from RNA polymerase II promoter in response to hypoxia; ISS:UniProtKB.
DR GO; GO:0042265; P:peptidyl-asparagine hydroxylation; ISS:UniProtKB.
DR GO; GO:0042264; P:peptidyl-aspartic acid hydroxylation; ISS:UniProtKB.
DR GO; GO:0036138; P:peptidyl-histidine hydroxylation; ISS:UniProtKB.
DR GO; GO:0045663; P:positive regulation of myoblast differentiation; ISS:UniProtKB.
DR Gene3D; 1.10.287.1010; -; 1.
DR Gene3D; 2.60.120.10; -; 1.
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 Acetylation; Alternative splicing; Cytoplasm; Dioxygenase; Iron;
KW Metal-binding; Nucleus; Oxidoreductase; Reference proteome; Transcription;
KW Transcription regulation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q9NWT6"
FT CHAIN 2..349
FT /note="Hypoxia-inducible factor 1-alpha inhibitor"
FT /id="PRO_0000083975"
FT DOMAIN 142..307
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:0000250"
FT BINDING 145
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000250|UniProtKB:Q9NWT6"
FT BINDING 152
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9NWT6"
FT BINDING 181..183
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 196
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000250|UniProtKB:Q9NWT6"
FT BINDING 199
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9NWT6"
FT BINDING 201..203
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 201
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9NWT6"
FT BINDING 205
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000250|UniProtKB:Q9NWT6"
FT BINDING 214
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000250|UniProtKB:Q9NWT6"
FT BINDING 238..239
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 279
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q9NWT6"
FT BINDING 294
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000250|UniProtKB:Q9NWT6"
FT BINDING 300
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9NWT6"
FT BINDING 321
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9NWT6"
FT SITE 340
FT /note="Important for dimer formation"
FT /evidence="ECO:0000250|UniProtKB:Q9NWT6"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:Q9NWT6"
FT VAR_SEQ 241..263
FT /note="QVDFDNPDYERFPNFRNVVGYET -> GVKRRDQAKRETIAKEKYTKQNK
FT (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_017537"
FT VAR_SEQ 264..349
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_017538"
FT CONFLICT 177
FT /note="R -> L (in Ref. 2; AAI30014)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 349 AA; 40241 MW; ED5C2B875EBCE76E CRC64;
MAATAAEVAA SGSGEAREEA EAPGPAWDES QLRSYSFPTR PIPRLSQSDP RAEELIENEE
PVVLTDTNLV YPALKWDLEY LQENIGNGDF SVYSASTHKF LYYDEKKMGN FQNFKPRSNR
EEIKFHEFVE KLQAIQQRGG EERLYLQQTL NDTVGRKIVM DFLGFNWNWI NKQQGKRGWG
QLTSNLLLIG MEGNVTPAHY DEQQNFFAQI KGHKRCILFP PDQFECLYPY PVHHPCDRQS
QVDFDNPDYE RFPNFRNVVG YETVVGPGDV LYIPMYWWHH IESLLNGGIT ITVNFWYKGA
PTPKRIEYPL KAHQKVAIMR NIEKMLGEAL GNPQEVGPLL NTMIKGRYN
