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   27-MAR-2024, entry version 155.
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; 3.
DR   CORUM; Q8BLR9; -.
DR   IntAct; Q8BLR9; 2.
DR   STRING; 10090.ENSMUSP00000035326; -.
DR   PhosphoSitePlus; Q8BLR9; -.
DR   EPD; Q8BLR9; -.
DR   MaxQB; Q8BLR9; -.
DR   PaxDb; 10090-ENSMUSP00000035326; -.
DR   PeptideAtlas; Q8BLR9; -.
DR   ProteomicsDB; 273340; -. [Q8BLR9-1]
DR   ProteomicsDB; 273341; -. [Q8BLR9-2]
DR   Pumba; Q8BLR9; -.
DR   Antibodypedia; 17685; 718 antibodies from 36 providers.
DR   DNASU; 319594; -.
DR   Ensembl; ENSMUST00000040455.5; ENSMUSP00000035326.5; ENSMUSG00000036450.5. [Q8BLR9-1]
DR   GeneID; 319594; -.
DR   KEGG; mmu:319594; -.
DR   UCSC; uc008hpx.1; mouse. [Q8BLR9-2]
DR   UCSC; uc008hpy.1; mouse. [Q8BLR9-1]
DR   AGR; MGI:2442345; -.
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; TVSVNFW; -.
DR   OrthoDB; 2945786at2759; -.
DR   PhylomeDB; Q8BLR9; -.
DR   TreeFam; TF329609; -.
DR   Reactome; R-MMU-1234174; Cellular response to hypoxia.
DR   BioGRID-ORCS; 319594; 11 hits in 82 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 220 other cell types or tissues.
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; IBA:GO_Central.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:UniProtKB.
DR   GO; GO:0036140; F:[protein]-asparagine 3-dioxygenase activity; ISS:UniProtKB.
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:0051059; F:NF-kappaB binding; ISS:UniProtKB.
DR   GO; GO:0005112; F:Notch binding; ISS:UniProtKB.
DR   GO; GO:0062101; F:peptidyl-aspartic acid 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:0003714; F:transcription corepressor 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:0045663; P:positive regulation of myoblast differentiation; ISO:MGI.
DR   Gene3D; 1.10.287.1010; Clavaminate synthase-like; 1.
DR   Gene3D; 2.60.120.10; Jelly Rolls; 1.
DR   InterPro; IPR041667; Cupin_8.
DR   InterPro; IPR027452; FIH-1_dom_II.
DR   InterPro; IPR003347; JmjC_dom.
DR   InterPro; IPR014710; RmlC-like_jellyroll.
DR   PANTHER; PTHR12461; HYPOXIA-INDUCIBLE FACTOR 1 ALPHA INHIBITOR-RELATED; 1.
DR   PANTHER; PTHR12461:SF93; HYPOXIA-INDUCIBLE FACTOR 1-ALPHA INHIBITOR; 1.
DR   Pfam; PF13621; Cupin_8; 1.
DR   SMART; SM00558; JmjC; 1.
DR   SUPFAM; SSF51197; Clavaminate synthase-like; 1.
DR   PROSITE; PS51184; JMJC; 1.
DR   Genevisible; Q8BLR9; MM.
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
//