HNF4A_RAT
ID HNF4A_RAT Reviewed; 474 AA.
AC P22449; A2ICG9;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
DT 29-MAY-2007, sequence version 3.
DT 25-MAY-2022, entry version 199.
DE RecName: Full=Hepatocyte nuclear factor 4-alpha;
DE Short=HNF-4-alpha;
DE AltName: Full=Nuclear receptor subfamily 2 group A member 1;
DE AltName: Full=Transcription factor 14;
DE Short=TCF-14;
DE AltName: Full=Transcription factor HNF-4;
GN Name=Hnf4a; Synonyms=Hnf-4, Hnf4, Nr2a1, Tcf14;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Liver;
RX PubMed=2279702; DOI=10.1101/gad.4.12b.2353;
RA Sladek F.M., Zhong W., Lai E., Darnell J.E. Jr.;
RT "Liver-enriched transcription factor HNF-4 is a novel member of the steroid
RT hormone receptor superfamily.";
RL Genes Dev. 4:2353-2365(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT), AND ALTERNATIVE SPLICING.
RC STRAIN=Wistar; TISSUE=Liver;
RX PubMed=1610903; DOI=10.1016/0167-4781(92)90080-j;
RA Hata S., Tsukamoto T., Osumi T.;
RT "A novel isoform of rat hepatocyte nuclear factor 4 (HNF-4).";
RL Biochim. Biophys. Acta 1131:211-213(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 21-378 (ISOFORMS LONG AND SHORT).
RC STRAIN=New England Deaconess Hospital; TISSUE=Liver;
RA Huang J., Karakucuk V., Levitsky L.L., Rhoads D.B.;
RT "Expression of HNF4 alpha 3 in pancreatic islets and Ins-1 beta cells.";
RL Submitted (DEC-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP MUTAGENESIS, AND PHOSPHORYLATION AT SER-142 AND SER-143.
RX PubMed=9234678; DOI=10.1128/mcb.17.8.4208;
RA Viollet B., Kahn A., Raymondjean M.;
RT "Protein kinase A-dependent phosphorylation modulates DNA-binding activity
RT of hepatocyte nuclear factor 4.";
RL Mol. Cell. Biol. 17:4208-4219(1997).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-432 AND SER-436, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 142-391, FATTY ACID BINDING, AND
RP SUBUNIT.
RX PubMed=12193589; DOI=10.1074/jbc.c200420200;
RA Dhe-Paganon S., Duda K., Iwamoto M., Chi Y.I., Shoelson S.E.;
RT "Crystal structure of the HNF4 alpha ligand binding domain in complex with
RT endogenous fatty acid ligand.";
RL J. Biol. Chem. 277:37973-37976(2002).
CC -!- FUNCTION: Transcriptional regulator which controls the expression of
CC hepatic genes during the transition of endodermal cells to hepatic
CC progenitor cells, facilitating the recruitment of RNA pol II to the
CC promoters of target genes (By similarity). Activates the transcription
CC of CYP2C38 (By similarity). Represses the CLOCK-ARNTL/BMAL1
CC transcriptional activity and is essential for circadian rhythm
CC maintenance and period regulation in the liver and colon cells (By
CC similarity). {ECO:0000250|UniProtKB:P41235,
CC ECO:0000250|UniProtKB:P49698}.
CC -!- SUBUNIT: Homodimerization is required for HNF4-alpha to bind to its
CC recognition site (PubMed:12193589). Interacts with CLOCK, ARNTL, CRY1,
CC CRY2, PER1 and PER2 (By similarity). Interacts with NR0B2/SHP; the
CC resulting heterodimer is transcriptionnally inactive (By similarity).
CC Interacts with DDX3X; this interaction disrupts the interaction between
CC HNF4 and NR0B2 that forms inactive heterodimers and enhances the
CC formation of active HNF4 homodimers (By similarity).
CC {ECO:0000250|UniProtKB:P41235, ECO:0000269|PubMed:12193589}.
CC -!- INTERACTION:
CC P22449; P02692: Fabp1; NbExp=3; IntAct=EBI-5261592, EBI-1209448;
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Long;
CC IsoId=P22449-1; Sequence=Displayed;
CC Name=Short;
CC IsoId=P22449-2; Sequence=VSP_003677;
CC -!- TISSUE SPECIFICITY: Liver, kidney and intestine.
CC -!- DOMAIN: The 9aaTAD motif is a transactivation domain present in a large
CC number of yeast and animal transcription factors.
CC {ECO:0000250|UniProtKB:P41235}.
CC -!- PTM: Phosphorylation at Ser-313 by AMPK reduces the ability to form
CC homodimers and bind DNA (By similarity). Phosphorylated in the
CC recognition sequence R-R-S-S near the DNA-binding domain;
CC phosphorylation results in decrease in DNA-binding activity.
CC Phosphorylation of HNF4 depends on the diet and is decreased by a
CC carbohydrate-rich diet and is increased by fasting. {ECO:0000250,
CC ECO:0000269|PubMed:9234678}.
CC -!- PTM: The N-terminus is blocked.
CC -!- PTM: Acetylation at Lys-458 lowers transcriptional activation by about
CC two-fold. {ECO:0000250}.
CC -!- MISCELLANEOUS: DNA-binding activity of phosphorylated protein is
CC reduced by fasting and by inducers of intracellular cyclic AMP.
CC -!- MISCELLANEOUS: Binds fatty acids.
CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR2
CC subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA01411.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=CAA40412.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; D10554; BAA01411.1; ALT_INIT; mRNA.
DR EMBL; X57133; CAA40412.1; ALT_INIT; mRNA.
DR EMBL; EF193392; ABM69090.1; -; mRNA.
DR PIR; A36471; A36471.
DR PIR; S23502; S23502.
DR RefSeq; NP_071516.2; NM_022180.2.
DR PDB; 1M7W; X-ray; 2.80 A; A/B/C/D=142-391.
DR PDBsum; 1M7W; -.
DR AlphaFoldDB; P22449; -.
DR SMR; P22449; -.
DR BioGRID; 247763; 1.
DR IntAct; P22449; 2.
DR MINT; P22449; -.
DR STRING; 10116.ENSRNOP00000011978; -.
DR ChEMBL; CHEMBL3714705; -.
DR iPTMnet; P22449; -.
DR PhosphoSitePlus; P22449; -.
DR PaxDb; P22449; -.
DR PRIDE; P22449; -.
DR GeneID; 25735; -.
DR KEGG; rno:25735; -.
DR CTD; 3172; -.
DR RGD; 2810; Hnf4a.
DR eggNOG; KOG4215; Eukaryota.
DR InParanoid; P22449; -.
DR OrthoDB; 622732at2759; -.
DR PhylomeDB; P22449; -.
DR Reactome; R-RNO-383280; Nuclear Receptor transcription pathway.
DR EvolutionaryTrace; P22449; -.
DR PRO; PR:P22449; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0050544; F:arachidonic acid binding; IDA:RGD.
DR GO; GO:0003682; F:chromatin binding; ISO:RGD.
DR GO; GO:0000987; F:cis-regulatory region sequence-specific DNA binding; IDA:RGD.
DR GO; GO:0003677; F:DNA binding; ISO:RGD.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:BHF-UCL.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISO:RGD.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISO:RGD.
DR GO; GO:0005504; F:fatty acid binding; IPI:RGD.
DR GO; GO:0000062; F:fatty-acyl-CoA binding; IPI:RGD.
DR GO; GO:0036042; F:long-chain fatty acyl-CoA binding; IDA:RGD.
DR GO; GO:0004879; F:nuclear receptor activity; IBA:GO_Central.
DR GO; GO:0016290; F:palmitoyl-CoA hydrolase activity; IDA:RGD.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:RGD.
DR GO; GO:0044877; F:protein-containing complex binding; IMP:RGD.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISO:RGD.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:RGD.
DR GO; GO:0043565; F:sequence-specific DNA binding; IMP:RGD.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:RGD.
DR GO; GO:0005102; F:signaling receptor binding; ISO:RGD.
DR GO; GO:0070540; F:stearic acid binding; IDA:RGD.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISO:RGD.
DR GO; GO:0001221; F:transcription coregulator binding; IPI:BHF-UCL.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006637; P:acyl-CoA metabolic process; IDA:RGD.
DR GO; GO:0007568; P:aging; IEP:RGD.
DR GO; GO:0048856; P:anatomical structure development; IBA:GO_Central.
DR GO; GO:0007596; P:blood coagulation; ISO:RGD.
DR GO; GO:0030154; P:cell differentiation; IMP:RGD.
DR GO; GO:0045216; P:cell-cell junction organization; IDA:RGD.
DR GO; GO:0071456; P:cellular response to hypoxia; IEP:RGD.
DR GO; GO:0042632; P:cholesterol homeostasis; ISO:RGD.
DR GO; GO:0007164; P:establishment of tissue polarity; IDA:RGD.
DR GO; GO:0042593; P:glucose homeostasis; ISO:RGD.
DR GO; GO:0070365; P:hepatocyte differentiation; IEP:RGD.
DR GO; GO:0055088; P:lipid homeostasis; ISO:RGD.
DR GO; GO:0006629; P:lipid metabolic process; ISO:RGD.
DR GO; GO:1902569; P:negative regulation of activation of Janus kinase activity; IDA:RGD.
DR GO; GO:0030308; P:negative regulation of cell growth; ISO:RGD.
DR GO; GO:0030336; P:negative regulation of cell migration; IDA:RGD.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:RGD.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; IDA:RGD.
DR GO; GO:0045930; P:negative regulation of mitotic cell cycle; IDA:RGD.
DR GO; GO:0042308; P:negative regulation of protein import into nucleus; IDA:RGD.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0042532; P:negative regulation of tyrosine phosphorylation of STAT protein; IDA:RGD.
DR GO; GO:0006591; P:ornithine metabolic process; ISO:RGD.
DR GO; GO:0055091; P:phospholipid homeostasis; ISO:RGD.
DR GO; GO:0045723; P:positive regulation of fatty acid biosynthetic process; IMP:RGD.
DR GO; GO:0045722; P:positive regulation of gluconeogenesis; IMP:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:BHF-UCL.
DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:0010470; P:regulation of gastrulation; ISO:RGD.
DR GO; GO:0050796; P:regulation of insulin secretion; ISO:RGD.
DR GO; GO:0019216; P:regulation of lipid metabolic process; ISO:RGD.
DR GO; GO:0032534; P:regulation of microvillus assembly; IMP:RGD.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISO:RGD.
DR GO; GO:0051591; P:response to cAMP; IEP:RGD.
DR GO; GO:0071548; P:response to dexamethasone; IEP:RGD.
DR GO; GO:0009749; P:response to glucose; IDA:RGD.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEP:RGD.
DR GO; GO:0031667; P:response to nutrient levels; IEP:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR GO; GO:0007548; P:sex differentiation; ISO:RGD.
DR GO; GO:0023019; P:signal transduction involved in regulation of gene expression; ISO:RGD.
DR GO; GO:0060395; P:SMAD protein signal transduction; ISO:RGD.
DR GO; GO:0070328; P:triglyceride homeostasis; ISO:RGD.
DR GO; GO:0003323; P:type B pancreatic cell development; IEA:InterPro.
DR GO; GO:0006805; P:xenobiotic metabolic process; ISO:RGD.
DR DisProt; DP02610; -.
DR Gene3D; 1.10.565.10; -; 1.
DR Gene3D; 3.30.50.10; -; 1.
DR InterPro; IPR039067; HNF4A.
DR InterPro; IPR035500; NHR-like_dom_sf.
DR InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd.
DR InterPro; IPR001723; Nuclear_hrmn_rcpt.
DR InterPro; IPR001628; Znf_hrmn_rcpt.
DR InterPro; IPR013088; Znf_NHR/GATA.
DR PANTHER; PTHR24083:SF41; PTHR24083:SF41; 1.
DR Pfam; PF00104; Hormone_recep; 1.
DR Pfam; PF00105; zf-C4; 1.
DR PRINTS; PR00398; STRDHORMONER.
DR PRINTS; PR00047; STROIDFINGER.
DR SMART; SM00430; HOLI; 1.
DR SMART; SM00399; ZnF_C4; 1.
DR SUPFAM; SSF48508; SSF48508; 1.
DR PROSITE; PS51843; NR_LBD; 1.
DR PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1.
DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Activator; Alternative splicing;
KW Biological rhythms; Direct protein sequencing; DNA-binding;
KW Isopeptide bond; Metal-binding; Nucleus; Phosphoprotein; Receptor;
KW Reference proteome; Repressor; Transcription; Transcription regulation;
KW Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1..474
FT /note="Hepatocyte nuclear factor 4-alpha"
FT /id="PRO_0000053560"
FT DOMAIN 147..377
FT /note="NR LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189"
FT DNA_BIND 57..132
FT /note="Nuclear receptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 60..80
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 96..120
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT REGION 413..450
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 368..376
FT /note="9aaTAD"
FT /evidence="ECO:0000250|UniProtKB:P41235"
FT MOD_RES 142
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000305|PubMed:9234678"
FT MOD_RES 143
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000305|PubMed:9234678"
FT MOD_RES 144
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P41235"
FT MOD_RES 166
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P41235"
FT MOD_RES 167
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P41235"
FT MOD_RES 313
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000250|UniProtKB:P41235"
FT MOD_RES 429
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P41235"
FT MOD_RES 432
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 436
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 458
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P41235"
FT CROSSLNK 234
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P41235"
FT CROSSLNK 307
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P41235"
FT VAR_SEQ 418..428
FT /note="CEWPRPRGQAA -> S (in isoform Short)"
FT /evidence="ECO:0000303|PubMed:1610903, ECO:0000303|Ref.3"
FT /id="VSP_003677"
FT MUTAGEN 142..143
FT /note="SS->AG: Loss of phosphorylation, no effect on DNA-
FT binding."
FT /evidence="ECO:0000269|PubMed:9234678"
FT MUTAGEN 142..143
FT /note="SS->LE: Loss of phosphorylation, no effect on DNA-
FT binding."
FT /evidence="ECO:0000269|PubMed:9234678"
FT CONFLICT 180
FT /note="K -> R (in Ref. 1; CAA40412)"
FT /evidence="ECO:0000305"
FT CONFLICT 183
FT /note="N -> S (in Ref. 1; CAA40412)"
FT /evidence="ECO:0000305"
FT CONFLICT 378
FT /note="S -> L (in Ref. 3; ABM69090)"
FT /evidence="ECO:0000305"
FT HELIX 152..164
FT /evidence="ECO:0007829|PDB:1M7W"
FT HELIX 184..203
FT /evidence="ECO:0007829|PDB:1M7W"
FT HELIX 206..209
FT /evidence="ECO:0007829|PDB:1M7W"
FT HELIX 213..222
FT /evidence="ECO:0007829|PDB:1M7W"
FT HELIX 224..234
FT /evidence="ECO:0007829|PDB:1M7W"
FT TURN 235..238
FT /evidence="ECO:0007829|PDB:1M7W"
FT STRAND 239..244
FT /evidence="ECO:0007829|PDB:1M7W"
FT STRAND 250..254
FT /evidence="ECO:0007829|PDB:1M7W"
FT HELIX 256..258
FT /evidence="ECO:0007829|PDB:1M7W"
FT TURN 259..261
FT /evidence="ECO:0007829|PDB:1M7W"
FT HELIX 262..271
FT /evidence="ECO:0007829|PDB:1M7W"
FT HELIX 273..279
FT /evidence="ECO:0007829|PDB:1M7W"
FT HELIX 283..294
FT /evidence="ECO:0007829|PDB:1M7W"
FT HELIX 305..324
FT /evidence="ECO:0007829|PDB:1M7W"
FT STRAND 326..328
FT /evidence="ECO:0007829|PDB:1M7W"
FT HELIX 333..338
FT /evidence="ECO:0007829|PDB:1M7W"
FT HELIX 341..360
FT /evidence="ECO:0007829|PDB:1M7W"
FT HELIX 368..373
FT /evidence="ECO:0007829|PDB:1M7W"
SQ SEQUENCE 474 AA; 52712 MW; E6DECA74FEA65E75 CRC64;
MRLSKTLADM DMADYSAALD PAYTTLEFEN VQVLTMGNDT SPSEGANLNS SNSLGVSALC
AICGDRATGK HYGASSCDGC KGFFRRSVRK NHMYSCRFSR QCVVDKDKRN QCRYCRLKKC
FRAGMKKEAV QNERDRISTR RSSYEDSSLP SINALLQAEV LSQQITSPIS GINGDIRAKK
IANITDVCES MKEQLLVLVE WAKYIPAFCE LLLDDQVALL RAHAGEHLLL GATKRSMVFK
DVLLLGNDYI VPRHCPELAE MSRVSIRILD ELVLPFQELQ IDDNEYACLK AIIFFDPDAK
GLSDPGKIKR LRSQVQVSLE DYINDRQYDS RGRFGELLLL LPTLQSITWQ MIEQIQFIKL
FGMAKIDNLL QEMLLGGSAS DAPHAHHPLH PHLMQEHMGT NVIVANTMPS HLSNGQMCEW
PRPRGQAATP ETPQPSPPSG SGSESYKLLP GAITTIVKPP SAIPQPTITK QEAI
