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Protein

Hepatocyte nuclear factor 4-alpha

Gene

Hnf4a

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transcriptionally controlled transcription factor. Binds to DNA sites required for the transcription of alpha 1-antitrypsin, apolipoprotein CIII, transthyretin genes and HNF1-alpha. May be essential for development of the liver, kidney and intestine.

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi57 – 13276Nuclear receptorPROSITE-ProRule annotationAdd
BLAST
Zinc fingeri60 – 8021NR C4-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri96 – 12025NR C4-typePROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

  1. DNA binding Source: MGI
  2. fatty acid binding Source: MGI
  3. ligand-activated sequence-specific DNA binding RNA polymerase II transcription factor activity Source: InterPro
  4. protein homodimerization activity Source: MGI
  5. receptor binding Source: MGI
  6. RNA polymerase II activating transcription factor binding Source: BHF-UCL
  7. RNA polymerase II core promoter sequence-specific DNA binding Source: MGI
  8. RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity Source: MGI
  9. RNA polymerase II transcription regulatory region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription Source: MGI
  10. sequence-specific DNA binding Source: MGI
  11. sequence-specific DNA binding transcription factor activity Source: BHF-UCL
  12. steroid hormone receptor activity Source: InterPro
  13. transcription regulatory region DNA binding Source: BHF-UCL
  14. zinc ion binding Source: InterPro

GO - Biological processi

  1. blood coagulation Source: MGI
  2. endocrine pancreas development Source: Reactome
  3. glucose homeostasis Source: BHF-UCL
  4. lipid homeostasis Source: MGI
  5. lipid metabolic process Source: MGI
  6. negative regulation of cell growth Source: MGI
  7. negative regulation of cell proliferation Source: MGI
  8. ornithine metabolic process Source: MGI
  9. phospholipid homeostasis Source: BHF-UCL
  10. positive regulation of cholesterol homeostasis Source: BHF-UCL
  11. positive regulation of transcription, DNA-templated Source: MGI
  12. positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  13. regulation of gastrulation Source: MGI
  14. regulation of insulin secretion Source: BHF-UCL
  15. regulation of lipid metabolic process Source: MGI
  16. regulation of transcription, DNA-templated Source: MGI
  17. regulation of transcription from RNA polymerase II promoter Source: MGI
  18. response to glucose Source: BHF-UCL
  19. sex differentiation Source: MGI
  20. signal transduction involved in regulation of gene expression Source: MGI
  21. SMAD protein signal transduction Source: MGI
  22. transcription from RNA polymerase II promoter Source: GOC
  23. triglyceride homeostasis Source: BHF-UCL
  24. xenobiotic metabolic process Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Receptor

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding, Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiREACT_214529. Regulation of gene expression in beta cells.
REACT_234105. Nuclear Receptor transcription pathway.

Names & Taxonomyi

Protein namesi
Recommended name:
Hepatocyte nuclear factor 4-alpha
Short name:
HNF-4-alpha
Alternative name(s):
Nuclear receptor subfamily 2 group A member 1
Transcription factor 14
Short name:
TCF-14
Transcription factor HNF-4
Gene namesi
Name:Hnf4a
Synonyms:Hnf-4, Hnf4, Nr2a1, Tcf14
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 2

Organism-specific databases

MGIiMGI:109128. Hnf4a.

Subcellular locationi

GO - Cellular componenti

  1. cytoplasm Source: MGI
  2. cytosol Source: Reactome
  3. nucleus Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Disruption phenotypei

Pancreatic beta-cells-specific knockout results in hyperinsulinemia and hypoglycemia.1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 474474Hepatocyte nuclear factor 4-alphaPRO_0000053559Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei142 – 1421PhosphoserineBy similarity
Modified residuei144 – 1441PhosphotyrosineBy similarity
Modified residuei166 – 1661PhosphothreonineBy similarity
Modified residuei167 – 1671PhosphoserineBy similarity
Cross-linki234 – 234Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki307 – 307Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei313 – 3131Phosphoserine; by AMPKBy similarity
Modified residuei429 – 4291Phosphothreonine1 Publication
Modified residuei432 – 4321Phosphothreonine1 Publication
Modified residuei436 – 4361PhosphoserineBy similarity
Modified residuei458 – 4581N6-acetyllysineBy similarity

Post-translational modificationi

Phosphorylated on tyrosine residue(s); phosphorylation is important for its DNA-binding activity. Phosphorylation may directly or indirectly play a regulatory role in the subnuclear distribution. Phosphorylation at Ser-313 by AMPK reduces the ability to form homodimers and bind DNA (By similarity).By similarity
Acetylation at Lys-458 lowers transcriptional activation by about two-fold.By similarity

Keywords - PTMi

Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiP49698.
PaxDbiP49698.
PRIDEiP49698.

PTM databases

PhosphoSiteiP49698.

Expressioni

Gene expression databases

BgeeiP49698.
CleanExiMM_HNF4A.
ExpressionAtlasiP49698. baseline and differential.
GenevestigatoriP49698.

Interactioni

Subunit structurei

Homodimerization is required for HNF4-alpha to bind to its recognition site. Interacts with PER2.1 Publication

Protein-protein interaction databases

BioGridi200354. 4 interactions.
IntActiP49698. 3 interactions.
MINTiMINT-5027670.

Structurei

3D structure databases

ProteinModelPortaliP49698.
SMRiP49698. Positions 58-377.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Contains 1 nuclear receptor DNA-binding domain.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri60 – 8021NR C4-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri96 – 12025NR C4-typePROSITE-ProRule annotationAdd
BLAST

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiNOG241134.
GeneTreeiENSGT00760000118948.
HOGENOMiHOG000260822.
HOVERGENiHBG005606.
InParanoidiP49698.
KOiK07292.
OMAiANTMPSH.
PhylomeDBiP49698.
TreeFamiTF352097.

Family and domain databases

Gene3Di1.10.565.10. 1 hit.
3.30.50.10. 1 hit.
InterProiIPR003068. COUP_TF.
IPR008946. Nucl_hormone_rcpt_ligand-bd.
IPR000536. Nucl_hrmn_rcpt_lig-bd_core.
IPR001723. Str_hrmn_rcpt.
IPR001628. Znf_hrmn_rcpt.
IPR013088. Znf_NHR/GATA.
[Graphical view]
PfamiPF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]
PRINTSiPR01282. COUPTNFACTOR.
PR00398. STRDHORMONER.
PR00047. STROIDFINGER.
SMARTiSM00430. HOLI. 1 hit.
SM00399. ZnF_C4. 1 hit.
[Graphical view]
SUPFAMiSSF48508. SSF48508. 1 hit.
PROSITEiPS00031. NUCLEAR_REC_DBD_1. 1 hit.
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform Long (identifier: P49698-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MRLSKTLAGM DMADYSAALD PAYTTLEFEN VQVLTMGNDT SPSEGANLNS
60 70 80 90 100
SNSLGVSALC AICGDRATGK HYGASSCDGC KGFFRRSVRK NHMYSCRFSR
110 120 130 140 150
QCVVDKDKRN QCRYCRLKKC FRAGMKKEAV QNERDRISTR RSSYEDSSLP
160 170 180 190 200
SINALLQAEV LSQQITSPIS GINGDIRAKK IANITDVCES MKEQLLVLVE
210 220 230 240 250
WAKYIPAFCE LLLDDQVALL RAHAGEHLLL GATKRSMVFK DVLLLGNDYI
260 270 280 290 300
VPRHCPELAE MSRVSIRILD ELVLPFQELQ IDDNEYACLK AIIFFDPDAK
310 320 330 340 350
GLSDPGKIKR LRSQVQVSLE DYINDRQYDS RGRFGELLLL LPTLQSITWQ
360 370 380 390 400
MIEQIQFIKL FGMAKIDNLL QEMLLGGSAS DAPHTHHPLH PHLMQEHMGT
410 420 430 440 450
NVIVANTMPS HLSNGQMCEW PRPRGQAATP ETPQPSPPSG SGSESYKLLP
460 470
GAITTIVKPP SAIPQPTITK QEAI
Length:474
Mass (Da):52,684
Last modified:May 29, 2007 - v2
Checksum:i10843D528EAE87EE
GO
Isoform Short (identifier: P49698-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     418-428: CEWPRPRGQAA → S

Show »
Length:464
Mass (Da):51,518
Checksum:i4C293463C33B2D76
GO

Sequence cautioni

The sequence BAA06101.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti55 – 551G → S in BAA06101 (PubMed:7999795).Curated
Sequence conflicti365 – 3651K → R in BAE25624 (PubMed:16141072).Curated
Sequence conflicti378 – 3781S → L in ABM69091 (Ref. 6) Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei418 – 42811CEWPRPRGQAA → S in isoform Short. 1 PublicationVSP_003676Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D29015 mRNA. Translation: BAA06101.1. Different initiation.
AY902317 Genomic DNA. Translation: AAX90602.1.
AK143948 mRNA. Translation: BAE25624.1.
AL591488 Genomic DNA. No translation available.
BC039220 mRNA. Translation: AAH39220.1.
EF193393 mRNA. Translation: ABM69091.1.
CCDSiCCDS17012.1. [P49698-1]
PIRiS52074.
RefSeqiNP_032287.2. NM_008261.2. [P49698-1]
XP_006498850.1. XM_006498787.1. [P49698-2]
UniGeneiMm.202383.

Genome annotation databases

EnsembliENSMUST00000018094; ENSMUSP00000018094; ENSMUSG00000017950. [P49698-1]
GeneIDi15378.
KEGGimmu:15378.
UCSCiuc008nta.2. mouse. [P49698-1]
uc012cit.1. mouse. [P49698-2]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D29015 mRNA. Translation: BAA06101.1. Different initiation.
AY902317 Genomic DNA. Translation: AAX90602.1.
AK143948 mRNA. Translation: BAE25624.1.
AL591488 Genomic DNA. No translation available.
BC039220 mRNA. Translation: AAH39220.1.
EF193393 mRNA. Translation: ABM69091.1.
CCDSiCCDS17012.1. [P49698-1]
PIRiS52074.
RefSeqiNP_032287.2. NM_008261.2. [P49698-1]
XP_006498850.1. XM_006498787.1. [P49698-2]
UniGeneiMm.202383.

3D structure databases

ProteinModelPortaliP49698.
SMRiP49698. Positions 58-377.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi200354. 4 interactions.
IntActiP49698. 3 interactions.
MINTiMINT-5027670.

PTM databases

PhosphoSiteiP49698.

Proteomic databases

MaxQBiP49698.
PaxDbiP49698.
PRIDEiP49698.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000018094; ENSMUSP00000018094; ENSMUSG00000017950. [P49698-1]
GeneIDi15378.
KEGGimmu:15378.
UCSCiuc008nta.2. mouse. [P49698-1]
uc012cit.1. mouse. [P49698-2]

Organism-specific databases

CTDi3172.
MGIiMGI:109128. Hnf4a.

Phylogenomic databases

eggNOGiNOG241134.
GeneTreeiENSGT00760000118948.
HOGENOMiHOG000260822.
HOVERGENiHBG005606.
InParanoidiP49698.
KOiK07292.
OMAiANTMPSH.
PhylomeDBiP49698.
TreeFamiTF352097.

Enzyme and pathway databases

ReactomeiREACT_214529. Regulation of gene expression in beta cells.
REACT_234105. Nuclear Receptor transcription pathway.

Miscellaneous databases

ChiTaRSiHnf4a. mouse.
NextBioi288038.
PROiP49698.
SOURCEiSearch...

Gene expression databases

BgeeiP49698.
CleanExiMM_HNF4A.
ExpressionAtlasiP49698. baseline and differential.
GenevestigatoriP49698.

Family and domain databases

Gene3Di1.10.565.10. 1 hit.
3.30.50.10. 1 hit.
InterProiIPR003068. COUP_TF.
IPR008946. Nucl_hormone_rcpt_ligand-bd.
IPR000536. Nucl_hrmn_rcpt_lig-bd_core.
IPR001723. Str_hrmn_rcpt.
IPR001628. Znf_hrmn_rcpt.
IPR013088. Znf_NHR/GATA.
[Graphical view]
PfamiPF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]
PRINTSiPR01282. COUPTNFACTOR.
PR00398. STRDHORMONER.
PR00047. STROIDFINGER.
SMARTiSM00430. HOLI. 1 hit.
SM00399. ZnF_C4. 1 hit.
[Graphical view]
SUPFAMiSSF48508. SSF48508. 1 hit.
PROSITEiPS00031. NUCLEAR_REC_DBD_1. 1 hit.
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Identification of two splice isoforms of mRNA for mouse hepatocyte nuclear factor 4 (HNF-4)."
    Hata S., Inoue T., Kosuga K., Nakashima T., Tsukamoto T., Osumi T.
    Biochim. Biophys. Acta 1260:55-61(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LONG AND SHORT).
    Strain: C57BL/6 X CBA.
    Tissue: Liver.
  2. "Genome-wide isolation of growth and obesity QTL using mouse speed congenic strains."
    Farber C.R., Corva P.M., Medrano J.F.
    BMC Genomics 7:102-102(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    Strain: CAST/Ei.
    Tissue: Liver.
  3. "The transcriptional landscape of the mammalian genome."
    Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
    , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
    Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: C57BL/6J.
    Tissue: Kidney.
  4. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: C57BL/6J.
  5. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: FVB/N.
    Tissue: Kidney.
  6. "Expression of HNF4 alpha 3 in pancreatic islets and Ins-1 beta cells."
    Huang J., Karakucuk V., Levitsky L.L., Rhoads D.B.
    Submitted (DEC-2006) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 21-378.
    Strain: C57BL/6.
    Tissue: Liver.
  7. "Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene."
    Pearson E.R., Boj S.F., Steele A.M., Barrett T., Stals K., Shield J.P., Ellard S., Ferrer J., Hattersley A.T.
    PLoS Med. 4:E118-E118(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE.
  8. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-429 AND THR-432, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.
  9. "The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors."
    Schmutz I., Ripperger J.A., Baeriswyl-Aebischer S., Albrecht U.
    Genes Dev. 24:345-357(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH PER2.

Entry informationi

Entry nameiHNF4A_MOUSE
AccessioniPrimary (citable) accession number: P49698
Secondary accession number(s): A2A5I5
, A2ICH0, Q3UNX3, Q8CFY1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: May 29, 2007
Last modified: March 4, 2015
This is version 146 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

Binds fatty acids.By similarity

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.