P22449 (HNF4A_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	Hnf4a
Synonyms:	Hnf-4, Hnf4, Nr2a1, Tcf14

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	474 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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.
Subunit structure	Homodimerization is required for HNF4-alpha to bind to its recognition site.
Subcellular location	Nucleus.
Tissue specificity	Liver, kidney and intestine.
Post-translational modification	Phosphorylation at Ser-313 by AMPK reduces the ability to form homodimers and bind DNA By similarity. Phosphorylated in the recognition sequence R-R-S-S near the DNA-binding domain; phosphorylation results in decrease in DNA-binding activity. Phosphorylation of HNF4 depends on the diet and is decreased by a carbohydrate-rich diet and is increased by fasting. Ref.4 The N-terminus is blocked. Acetylation at Lys-458 lowers transcriptional activation by about two-fold By similarity.
Miscellaneous	DNA-binding activity of phosphorylated protein is reduced by fasting and by inducers of intracellular cyclic AMP. Binds fatty acids.
Sequence similarities	Belongs to the nuclear hormone receptor family. NR2 subfamily. Contains 1 nuclear receptor DNA-binding domain.
Sequence caution	The sequence BAA01411.1 differs from that shown. Reason: Erroneous initiation. The sequence CAA40412.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing
Domain	Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
Molecular function	Receptor
PTM	Acetylation Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	acyl-CoA metabolic process Inferred from direct assay PubMed 15870076. Source: RGD cell differentiation Inferred from mutant phenotype PubMed 16563856. Source: RGD cell-cell junction organization Inferred from direct assay PubMed 12749857. Source: RGD establishment of tissue polarity Inferred from direct assay PubMed 12749857. Source: RGD intracellular receptor mediated signaling pathway Inferred from electronic annotation. Source: GOC negative regulation of cell proliferation Inferred from direct assay PubMed 15541721. Source: RGD negative regulation of mitotic cell cycle Inferred from direct assay PubMed 15541721. Source: RGD negative regulation of protein import into nucleus, translocation Inferred from direct assay PubMed 16584384. Source: RGD negative regulation of sequence-specific DNA binding transcription factor activity Inferred from direct assay PubMed 16584384. Source: RGD negative regulation of tyrosine phosphorylation of Stat5 protein Inferred from direct assay PubMed 16584384. Source: RGD positive regulation of fatty acid biosynthetic process Inferred from mutant phenotype PubMed 16800817. Source: RGD positive regulation of gluconeogenesis Inferred from mutant phenotype PubMed 16893891. Source: RGD regulation of microvillus assembly Inferred from mutant phenotype PubMed 17178913. Source: RGD response to cAMP Inferred from expression pattern PubMed 16799975. Source: RGD response to drug Inferred from expression pattern PubMed 16799975. Source: RGD response to glucose stimulus Inferred from direct assay PubMed 16800817. Source: RGD
Cellular_component	cytoplasm Inferred from direct assay PubMed 16799975. Source: RGD transcription factor complex Inferred from direct assay PubMed 11741883. Source: RGD
Molecular_function	RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription Inferred from direct assay PubMed 20735474. Source: BHF-UCL fatty acid binding Inferred from physical interaction PubMed 15870076. Source: RGD fatty-acyl-CoA binding Inferred from physical interaction PubMed 15870076. Source: RGD ligand-activated sequence-specific DNA binding RNA polymerase II transcription factor activity Inferred from electronic annotation. Source: InterPro palmitoyl-CoA hydrolase activity Inferred from direct assay PubMed 15870076. Source: RGD protein homodimerization activity Inferred from mutant phenotype Ref.1. Source: RGD sequence-specific DNA binding Inferred from mutant phenotype PubMed 16893891. Source: RGD steroid hormone receptor activity Traceable author statement PubMed 11741883. Source: RGD zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform Long (identifier: P22449-1)

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.

Isoform Short (identifier: P22449-2)

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

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 474

474

Hepatocyte nuclear factor 4-alpha

PRO_0000053560

Regions

DNA binding

57 – 132

76

Nuclear receptor

Zinc finger

60 – 80

21

NR C4-type

Zinc finger

96 – 120

25

NR C4-type

Amino acid modifications

Modified residue

142

1

Phosphoserine; by PKA Probable

Modified residue

143

1

Phosphoserine; by PKA Probable

Modified residue

166

1

Phosphothreonine By similarity

Modified residue

167

1

Phosphoserine By similarity

Modified residue

313

1

Phosphoserine; by AMPK By similarity

Modified residue

429

1

Phosphothreonine By similarity

Modified residue

432

1

Phosphothreonine By similarity

Modified residue

436

1

Phosphoserine By similarity

Modified residue

458

1

N6-acetyllysine By similarity

Cross-link

234

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Cross-link

307

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Natural variations

Alternative sequence

418 – 428

11

CEWPRPRGQAA → S in isoform Short.

VSP_003677

Experimental info

Mutagenesis

142 – 143

2

SS → AG: Loss of phosphorylation, no effect on DNA-binding.

Mutagenesis

142 – 143

2

SS → LE: Loss of phosphorylation, no effect on DNA-binding.

Sequence conflict

180

1

K → R in CAA40412. Ref.1

Sequence conflict

183

1

N → S in CAA40412. Ref.1

Sequence conflict

378

1

S → L in ABM69090. Ref.3

Secondary structure

1

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474

Helix Strand Turn

Details...

Helix

152 – 164

13

Helix

184 – 203

20

Helix

206 – 209

4

Helix

213 – 222

10

Helix

224 – 234

11

Turn

235 – 238

4

Beta strand

239 – 244

6

Beta strand

250 – 254

5

Helix

256 – 258

3

Turn

259 – 261

3

Helix

262 – 271

10

Helix

273 – 279

7

Helix

283 – 294

12

Helix

305 – 324

20

Beta strand

326 – 328

3

Helix

333 – 338

6

Helix

341 – 360

20

Helix

368 – 373

6

Sequences

	Sequence		Length	Mass (Da)
	Isoform Long [UniParc]. Last modified May 29, 2007. Version 3. Checksum: E6DECA74FEA65E75	FASTA	474	52,712
	10 20 30 40 50 60 MRLSKTLADM DMADYSAALD PAYTTLEFEN VQVLTMGNDT SPSEGANLNS SNSLGVSALC 70 80 90 100 110 120 AICGDRATGK HYGASSCDGC KGFFRRSVRK NHMYSCRFSR QCVVDKDKRN QCRYCRLKKC 130 140 150 160 170 180 FRAGMKKEAV QNERDRISTR RSSYEDSSLP SINALLQAEV LSQQITSPIS GINGDIRAKK 190 200 210 220 230 240 IANITDVCES MKEQLLVLVE WAKYIPAFCE LLLDDQVALL RAHAGEHLLL GATKRSMVFK 250 260 270 280 290 300 DVLLLGNDYI VPRHCPELAE MSRVSIRILD ELVLPFQELQ IDDNEYACLK AIIFFDPDAK 310 320 330 340 350 360 GLSDPGKIKR LRSQVQVSLE DYINDRQYDS RGRFGELLLL LPTLQSITWQ MIEQIQFIKL 370 380 390 400 410 420 FGMAKIDNLL QEMLLGGSAS DAPHAHHPLH PHLMQEHMGT NVIVANTMPS HLSNGQMCEW 430 440 450 460 470 PRPRGQAATP ETPQPSPPSG SGSESYKLLP GAITTIVKPP SAIPQPTITK QEAI
	Isoform Short [UniParc]. Checksum: 6B0961382FB9A0F7	FASTA	464	51,546
	10 20 30 40 50 60 MRLSKTLADM DMADYSAALD PAYTTLEFEN VQVLTMGNDT SPSEGANLNS SNSLGVSALC 70 80 90 100 110 120 AICGDRATGK HYGASSCDGC KGFFRRSVRK NHMYSCRFSR QCVVDKDKRN QCRYCRLKKC 130 140 150 160 170 180 FRAGMKKEAV QNERDRISTR RSSYEDSSLP SINALLQAEV LSQQITSPIS GINGDIRAKK 190 200 210 220 230 240 IANITDVCES MKEQLLVLVE WAKYIPAFCE LLLDDQVALL RAHAGEHLLL GATKRSMVFK 250 260 270 280 290 300 DVLLLGNDYI VPRHCPELAE MSRVSIRILD ELVLPFQELQ IDDNEYACLK AIIFFDPDAK 310 320 330 340 350 360 GLSDPGKIKR LRSQVQVSLE DYINDRQYDS RGRFGELLLL LPTLQSITWQ MIEQIQFIKL 370 380 390 400 410 420 FGMAKIDNLL QEMLLGGSAS DAPHAHHPLH PHLMQEHMGT NVIVANTMPS HLSNGQMSTP 430 440 450 460 ETPQPSPPSG SGSESYKLLP GAITTIVKPP SAIPQPTITK QEAI

References

[1]	"Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily." Sladek F.M., Zhong W., Lai E., Darnell J.E. Jr. Genes Dev. 4:2353-2365(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE. Tissue: Liver.
[2]	"A novel isoform of rat hepatocyte nuclear factor 4 (HNF-4)." Hata S., Tsukamoto T., Osumi T. Biochim. Biophys. Acta 1131:211-213(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], ALTERNATIVE SPLICING. Strain: Wistar. Tissue: Liver.
[3]	"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: New England Deaconess Hospital. Tissue: Liver.
[4]	"Protein kinase A-dependent phosphorylation modulates DNA-binding activity of hepatocyte nuclear factor 4." Viollet B., Kahn A., Raymondjean M. Mol. Cell. Biol. 17:4208-4219(1997) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS, PHOSPHORYLATION AT SER-142 AND SER-143.
[5]	"Crystal structure of the HNF4 alpha ligand binding domain in complex with endogenous fatty acid ligand." Dhe-Paganon S., Duda K., Iwamoto M., Chi Y.I., Shoelson S.E. J. Biol. Chem. 277:37973-37976(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 142-391, FATTY ACID BINDING.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

D10554 mRNA. Translation: BAA01411.1. Different initiation.
X57133 mRNA. Translation: CAA40412.1. Different initiation.
EF193392 mRNA. Translation: ABM69090.1.

IPI

IPI00207142.
IPI00231412.

PIR

A36471.
S23502.

RefSeq

NP_071516.2. NM_022180.2.

UniGene

Rn.12238.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1M7W	X-ray	2.80	A/B/C/D	142-391	[»]

ProteinModelPortal

P22449.

SMR

P22449. Positions 59-134, 151-376.

ModBase

Search...

Protein-protein interaction databases

IntAct

P22449. 2 interactions.

PTM databases

PhosphoSite

P22449.

Proteomic databases

PRIDE

P22449.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

GeneID

25735.

KEGG

rno:25735.

Organism-specific databases

CTD

3172.

RGD

2810. Hnf4a.

Phylogenomic databases

eggNOG

NOG241134.

HOGENOM

HOG000260822.

HOVERGEN

HBG005606.

InParanoid

P22449.

KO

K07292.

Gene expression databases

ArrayExpress

P22449.

Genevestigator

P22449.

GermOnline

ENSRNOG00000008895. Rattus norvegicus.

Family and domain databases

Gene3D

1.10.565.10. 1 hit.
3.30.50.10. 1 hit.

InterPro

IPR003068. 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]

Pfam

PF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]

PRINTS

PR01282. COUPTNFACTOR.
PR00398. STRDHORMONER.
PR00047. STROIDFINGER.

SMART

SM00430. HOLI. 1 hit.
SM00399. ZnF_C4. 1 hit.
[Graphical view]

SUPFAM

SSF48508. Str_ncl_receptor. 1 hit.

PROSITE

PS00031. NUCLEAR_REC_DBD_1. 1 hit.
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P22449.

NextBio

607871.

Entry information

Entry name

HNF4A_RAT

Accession

Primary (citable) accession number: P22449
Secondary accession number(s): A2ICG9

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1991
Last sequence update:	May 29, 2007
Last modified:	May 1, 2013
This is version 134 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program