Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Hypoxia-inducible factor 1-alpha inhibitor

Gene

HIF1AN

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Hydroxylates HIF-1 alpha at 'Asn-803' in the C-terminal transactivation domain (CAD). Functions as an oxygen sensor and, under normoxic conditions, the hydroxylation prevents interaction of HIF-1 with transcriptional coactivators including Cbp/p300-interacting transactivator. Involved in transcriptional repression through interaction with HIF1A, VHL and histone deacetylases. Hydroxylates specific Asn residues within ankyrin repeat domains (ARD) of NFKB1, NFKBIA, NOTCH1, ASB4, PPP1R12A and several other ARD-containing proteins. Also hydroxylates Asp and His residues within ARDs of ANK1 and TNKS2, respectively. Negatively regulates NOTCH1 activity, accelerating myogenic differentiation. Positively regulates ASB4 activity, promoting vascular differentiation.8 Publications

Catalytic activityi

Hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2 = hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2.4 Publications
[Ankyrin-repeat domain protein]-L-histidine + 2-oxoglutarate + O2 = [ankyrin-repeat domain protein]-(3S)-3-hydroxy-L-histidine + succinate + CO2.1 Publication
[Ankyrin-repeat domain protein]-L-asparagine + 2-oxoglutarate + O2 = [ankyrin-repeat domain protein]-(3S)-3-hydroxy-L-asparagine + succinate + CO2.5 Publications
[Ankyrin-repeat domain protein]-L-aspartate + 2-oxoglutarate + O2 = [ankyrin-repeat domain protein]-(3S)-3-hydroxy-L-aspartate + succinate + CO2.1 Publication

Cofactori

Fe2+8 Publications

Kineticsi

The kinetic constants are determined for the recombinant FLAG-His-tagged protein.
  1. KM=100 µM for HIF1A (788-822) peptide1 Publication
  2. KM=160 µM for HIF2A (832-866) peptide1 Publication
  3. KM=0.5 µM for Fe2+1 Publication
  4. KM=25 µM for 2-oxoglutarate1 Publication
  5. KM=260 µM for ascorbate1 Publication
  6. KM=90 µM for O21 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei1452-oxoglutarate3 Publications1
    Binding sitei152Substrate1 Publication1
    Binding sitei1962-oxoglutarate3 Publications1
    Metal bindingi199Iron; via tele nitrogen; catalytic8 Publications1
    Metal bindingi201Iron; catalytic8 Publications1
    Binding sitei2052-oxoglutarate3 Publications1
    Binding sitei2142-oxoglutarate3 Publications1
    Metal bindingi279Iron; via tele nitrogen; catalytic8 Publications1
    Binding sitei2942-oxoglutarate3 Publications1
    Binding sitei300Substrate; via amide nitrogen1 Publication1
    Binding sitei321Substrate1 Publication1
    Sitei340Important for dimer formation1

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionDioxygenase, Oxidoreductase
    Biological processTranscription, Transcription regulation
    LigandIron, Metal-binding

    Enzyme and pathway databases

    BioCyciMetaCyc:HS15407-MONOMER
    BRENDAi1.14.11.16 2681
    ReactomeiR-HSA-1234162 Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha
    SIGNORiQ9NWT6

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Hypoxia-inducible factor 1-alpha inhibitor (EC:1.14.11.30, EC:1.14.11.n4)
    Alternative name(s):
    Factor inhibiting HIF-1
    Short name:
    FIH-1
    Hypoxia-inducible factor asparagine hydroxylase
    Gene namesi
    Name:HIF1AN
    Synonyms:FIH1
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 10

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000166135.13
    HGNCiHGNC:17113 HIF1AN
    MIMi606615 gene
    neXtProtiNX_Q9NWT6

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi199H → A: Prevents suppression of HIF CAD activity. Strongly stimulates 2-oxoglutarate turnover. No stimulation of 2-oxoglutarate turnover; when associated with R-340. 1 Publication1
    Mutagenesisi201D → A: Prevents suppression of HIF CAD activity. 3 Publications1
    Mutagenesisi201D → E: Loss of HIF1A Asn hydroxylation activity. Slightly stimulates 2-oxoglutarate turnover. 3 Publications1
    Mutagenesisi201D → G: No impact on HIF1A Asn hydroxylation activity. Loss of Asp hydroxylation ability. Strongly stimulates 2-oxoglutarate turnover. Loss of HIF1A Asn hydroxylation activity and slight stimulation of 2-oxoglutarate turnover; when associated with R-296. 3 Publications1
    Mutagenesisi239Q → H: No effect on Asp hydroxylation ability. 1 Publication1
    Mutagenesisi296W → R: Loss of HIF1A Asn hydroxylation activity and slight stimulation of 2-oxoglutarate turnover; when associated with G-201. 1 Publication1
    Mutagenesisi340L → R: Impairs dimer formation, leading to loss of HIF1A Asn hydroxylation activity. No stimulation of 2-oxoglutarate turnover; when associated with A-201. 2 Publications1
    Mutagenesisi344I → R: No effect on dimer formation and HIF1A Asn hydroxylation activity. 1 Publication1

    Organism-specific databases

    DisGeNETi55662
    OpenTargetsiENSG00000166135
    PharmGKBiPA29284

    Chemistry databases

    ChEMBLiCHEMBL5909
    DrugBankiDB01694 D-tartaric acid
    DB08263 N-(carboxycarbonyl)-D-phenylalanine
    DB09459 Tartaric acid

    Polymorphism and mutation databases

    BioMutaiHIF1AN
    DMDMi32129605

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Initiator methionineiRemovedCombined sources
    ChainiPRO_00000839742 – 349Hypoxia-inducible factor 1-alpha inhibitorAdd BLAST348

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei2N-acetylalanineCombined sources1

    Keywords - PTMi

    Acetylation

    Proteomic databases

    EPDiQ9NWT6
    MaxQBiQ9NWT6
    PaxDbiQ9NWT6
    PeptideAtlasiQ9NWT6
    PRIDEiQ9NWT6
    ProteomicsDBi82978

    PTM databases

    iPTMnetiQ9NWT6
    PhosphoSitePlusiQ9NWT6

    Expressioni

    Gene expression databases

    BgeeiENSG00000166135 Expressed in 219 organ(s), highest expression level in muscle of leg
    CleanExiHS_HIF1AN
    ExpressionAtlasiQ9NWT6 baseline and differential
    GenevisibleiQ9NWT6 HS

    Organism-specific databases

    HPAiCAB069903
    HPA048742
    HPA065302

    Interactioni

    Subunit structurei

    Homodimer; homodimerization is essential for catalytic activity. Interacts with VHL and HIF1A. Part of a complex with VHL, HIF1A and HDAC1 or HDAC2 or HDAC3. Interacts with NFKB1 and NFKBIA. Interacts with NOTCH1, NOTCH2 and NOTCH3 but not with NOTCH4. Interacts with APBA3; binding inhibits HIF1AN binding to HIF1A. Interacts with TNKS2. Interacts with PPP1R12A. Interacts with ASB4 (By similarity). Interacts with UBE3A. Interacts with ANKS3 (By similarity). Interacts with NECAB3; the interaction is indirect and seems to be mediated by APBA3.By similarity18 Publications

    Binary interactionsi

    GO - Molecular functioni

    Protein-protein interaction databases

    BioGridi120794, 80 interactors
    DIPiDIP-35527N
    IntActiQ9NWT6, 187 interactors
    MINTiQ9NWT6
    STRINGi9606.ENSP00000299163

    Chemistry databases

    BindingDBiQ9NWT6

    Structurei

    Secondary structure

    1349
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    ProteinModelPortaliQ9NWT6
    SMRiQ9NWT6
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ9NWT6

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini142 – 312JmjCPROSITE-ProRule annotationAdd BLAST171

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni2 – 125Interaction with VHL1 PublicationAdd BLAST124
    Regioni181 – 183Substrate binding1 Publication3
    Regioni201 – 203Substrate binding1 Publication3
    Regioni238 – 239Substrate binding1 Publication2

    Phylogenomic databases

    eggNOGiKOG2132 Eukaryota
    ENOG410XQDR LUCA
    GeneTreeiENSGT00530000062914
    HOGENOMiHOG000008146
    HOVERGENiHBG051903
    InParanoidiQ9NWT6
    KOiK18055
    OMAiMMIKGRY
    OrthoDBiEOG091G0C8E
    PhylomeDBiQ9NWT6
    TreeFamiTF329609

    Family and domain databases

    Gene3Di1.10.287.1010, 1 hit
    InterProiView protein in InterPro
    IPR027445 FIH-1
    IPR027452 FIH-1_dom_II
    IPR003347 JmjC_dom
    PANTHERiPTHR12461:SF51 PTHR12461:SF51, 1 hit
    SMARTiView protein in SMART
    SM00558 JmjC, 1 hit
    PROSITEiView protein in PROSITE
    PS51184 JMJC, 1 hit

    Sequence (1+)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.Show allAlign All

    Q9NWT6-1 [UniParc]FASTAAdd to basket
    « Hide
            10         20         30         40         50
    MAATAAEAVA SGSGEPREEA GALGPAWDES QLRSYSFPTR PIPRLSQSDP
    60 70 80 90 100
    RAEELIENEE PVVLTDTNLV YPALKWDLEY LQENIGNGDF SVYSASTHKF
    110 120 130 140 150
    LYYDEKKMAN FQNFKPRSNR EEMKFHEFVE KLQDIQQRGG EERLYLQQTL
    160 170 180 190 200
    NDTVGRKIVM DFLGFNWNWI NKQQGKRGWG QLTSNLLLIG MEGNVTPAHY
    210 220 230 240 250
    DEQQNFFAQI KGYKRCILFP PDQFECLYPY PVHHPCDRQS QVDFDNPDYE
    260 270 280 290 300
    RFPNFQNVVG YETVVGPGDV LYIPMYWWHH IESLLNGGIT ITVNFWYKGA
    310 320 330 340
    PTPKRIEYPL KAHQKVAIMR NIEKMLGEAL GNPQEVGPLL NTMIKGRYN
    Length:349
    Mass (Da):40,285
    Last modified:June 16, 2003 - v2
    Checksum:i96A033BA7B3BD8C7
    GO

    Computationally mapped potential isoform sequencesi

    There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    E9PL41E9PL41_HUMAN
    Hypoxia-inducible factor 1-alpha in...
    HIF1AN
    191Annotation score:
    E9PNR8E9PNR8_HUMAN
    Hypoxia-inducible factor 1-alpha in...
    HIF1AN
    35Annotation score:

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti10A → T in BAA91291 (PubMed:14702039).Curated1
    Sequence conflicti28D → H in BAA91291 (PubMed:14702039).Curated1
    Sequence conflicti156R → G in BAA91291 (PubMed:14702039).Curated1

    Mass spectrometryi

    Molecular mass is 40566 Da from positions 1 - 349. Determined by ESI. 1 Publication

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_05102841P → A1 PublicationCorresponds to variant dbSNP:rs2295778Ensembl.1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF395830 mRNA Translation: AAL27308.1
    AK000622 mRNA Translation: BAA91291.1
    AL133352 Genomic DNA No translation available.
    CH471066 Genomic DNA Translation: EAW49817.1
    CH471066 Genomic DNA Translation: EAW49818.1
    BC007719 mRNA Translation: AAH07719.1
    AL359615 mRNA Translation: CAB94885.1
    CCDSiCCDS7498.1
    PIRiT50633
    RefSeqiNP_060372.2, NM_017902.2
    UniGeneiHs.500788

    Genome annotation databases

    EnsembliENST00000299163; ENSP00000299163; ENSG00000166135
    GeneIDi55662
    KEGGihsa:55662
    UCSCiuc001krj.5 human

    Keywords - Coding sequence diversityi

    Polymorphism

    Similar proteinsi

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF395830 mRNA Translation: AAL27308.1
    AK000622 mRNA Translation: BAA91291.1
    AL133352 Genomic DNA No translation available.
    CH471066 Genomic DNA Translation: EAW49817.1
    CH471066 Genomic DNA Translation: EAW49818.1
    BC007719 mRNA Translation: AAH07719.1
    AL359615 mRNA Translation: CAB94885.1
    CCDSiCCDS7498.1
    PIRiT50633
    RefSeqiNP_060372.2, NM_017902.2
    UniGeneiHs.500788

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1H2KX-ray2.15A1-349[»]
    1H2LX-ray2.25A1-349[»]
    1H2MX-ray2.50A1-349[»]
    1H2NX-ray2.84A1-349[»]
    1IZ3X-ray2.80A1-349[»]
    1MZEX-ray2.20A1-349[»]
    1MZFX-ray2.40A1-349[»]
    1YCIX-ray2.70A1-349[»]
    2CGNX-ray2.40A1-349[»]
    2CGOX-ray2.30A1-349[»]
    2ILMX-ray2.30A1-349[»]
    2W0XX-ray2.12A1-349[»]
    2WA3X-ray2.50A1-349[»]
    2WA4X-ray2.50A1-349[»]
    2XUMX-ray2.20A1-349[»]
    2Y0IX-ray2.28A1-349[»]
    2YC0X-ray2.15A1-349[»]
    2YDEX-ray2.28A1-349[»]
    3D8CX-ray2.10A11-349[»]
    3KCXX-ray2.60A15-349[»]
    3KCYX-ray2.59A15-349[»]
    3OD4X-ray2.20A1-349[»]
    3P3NX-ray2.40A1-349[»]
    3P3PX-ray2.60A1-349[»]
    4AI8X-ray2.40A1-349[»]
    4B7EX-ray2.50A1-349[»]
    4B7KX-ray2.39A1-349[»]
    4BIOX-ray2.45A1-349[»]
    4JAAX-ray2.39A1-349[»]
    4NR1X-ray2.68A1-349[»]
    4Z1VX-ray2.10A1-349[»]
    4Z2WX-ray2.50A1-349[»]
    5JWKX-ray2.30A1-349[»]
    5JWLX-ray2.40A1-349[»]
    5JWPX-ray2.10A1-349[»]
    5OP6X-ray2.45A1-349[»]
    5OP8X-ray2.30A1-349[»]
    5OPCX-ray2.30A1-349[»]
    ProteinModelPortaliQ9NWT6
    SMRiQ9NWT6
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi120794, 80 interactors
    DIPiDIP-35527N
    IntActiQ9NWT6, 187 interactors
    MINTiQ9NWT6
    STRINGi9606.ENSP00000299163

    Chemistry databases

    BindingDBiQ9NWT6
    ChEMBLiCHEMBL5909
    DrugBankiDB01694 D-tartaric acid
    DB08263 N-(carboxycarbonyl)-D-phenylalanine
    DB09459 Tartaric acid

    PTM databases

    iPTMnetiQ9NWT6
    PhosphoSitePlusiQ9NWT6

    Polymorphism and mutation databases

    BioMutaiHIF1AN
    DMDMi32129605

    Proteomic databases

    EPDiQ9NWT6
    MaxQBiQ9NWT6
    PaxDbiQ9NWT6
    PeptideAtlasiQ9NWT6
    PRIDEiQ9NWT6
    ProteomicsDBi82978

    Protocols and materials databases

    DNASUi55662
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000299163; ENSP00000299163; ENSG00000166135
    GeneIDi55662
    KEGGihsa:55662
    UCSCiuc001krj.5 human

    Organism-specific databases

    CTDi55662
    DisGeNETi55662
    EuPathDBiHostDB:ENSG00000166135.13
    GeneCardsiHIF1AN
    HGNCiHGNC:17113 HIF1AN
    HPAiCAB069903
    HPA048742
    HPA065302
    MIMi606615 gene
    neXtProtiNX_Q9NWT6
    OpenTargetsiENSG00000166135
    PharmGKBiPA29284
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG2132 Eukaryota
    ENOG410XQDR LUCA
    GeneTreeiENSGT00530000062914
    HOGENOMiHOG000008146
    HOVERGENiHBG051903
    InParanoidiQ9NWT6
    KOiK18055
    OMAiMMIKGRY
    OrthoDBiEOG091G0C8E
    PhylomeDBiQ9NWT6
    TreeFamiTF329609

    Enzyme and pathway databases

    BioCyciMetaCyc:HS15407-MONOMER
    BRENDAi1.14.11.16 2681
    ReactomeiR-HSA-1234162 Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha
    SIGNORiQ9NWT6

    Miscellaneous databases

    ChiTaRSiHIF1AN human
    EvolutionaryTraceiQ9NWT6
    GeneWikiiHIF1AN
    GenomeRNAii55662
    PROiPR:Q9NWT6
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000166135 Expressed in 219 organ(s), highest expression level in muscle of leg
    CleanExiHS_HIF1AN
    ExpressionAtlasiQ9NWT6 baseline and differential
    GenevisibleiQ9NWT6 HS

    Family and domain databases

    Gene3Di1.10.287.1010, 1 hit
    InterProiView protein in InterPro
    IPR027445 FIH-1
    IPR027452 FIH-1_dom_II
    IPR003347 JmjC_dom
    PANTHERiPTHR12461:SF51 PTHR12461:SF51, 1 hit
    SMARTiView protein in SMART
    SM00558 JmjC, 1 hit
    PROSITEiView protein in PROSITE
    PS51184 JMJC, 1 hit
    ProtoNetiSearch...

    Entry informationi

    Entry nameiHIF1N_HUMAN
    AccessioniPrimary (citable) accession number: Q9NWT6
    Secondary accession number(s): D3DR69
    , Q5W147, Q969Q7, Q9NPV5
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 16, 2003
    Last sequence update: June 16, 2003
    Last modified: November 7, 2018
    This is version 170 of the entry and version 2 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    2. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    3. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    4. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    5. Human chromosome 10
      Human chromosome 10: entries, gene names and cross-references to MIM
    UniProt is an ELIXIR core data resource
    Main funding by: National Institutes of Health

    We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.

    Do not show this banner again