P41235 (HNF4A_HUMAN) 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:	HNF4, NR2A1, TCF14

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

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.
Post-translational modification	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. Ref.10 Ref.11 Ref.12 Acetylation at Lys-458 lowers transcriptional activation by about two-fold.
Involvement in disease	Maturity-onset diabetes of the young 1 (MODY1) [MIM:125850]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.14 Ref.15 Ref.17
Miscellaneous	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 CAA54248.1 differs from that shown. Reason: Erroneous initiation. The sequence CAA61133.1 differs from that shown. Reason: Frameshift at positions 2 and 7. The sequence CAA61134.1 differs from that shown. Reason: Frameshift at positions 2 and 7. The sequence CAA61135.1 differs from that shown. Reason: Frameshift at positions 2 and 7.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Alternative promoter usage Alternative splicing Polymorphism
Disease	Diabetes mellitus Disease mutation
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 Reference proteome
Gene Ontology (GO)
Biological_process	SMAD protein signal transduction Inferred from electronic annotation. Source: Compara blood coagulation Inferred from direct assay PubMed 12911579. Source: BHF-UCL endocrine pancreas development Traceable author statement. Source: Reactome glucose homeostasis Inferred from sequence or structural similarity. Source: BHF-UCL intracellular receptor mediated signaling pathway Inferred from electronic annotation. Source: GOC lipid metabolic process Inferred from electronic annotation. Source: Compara negative regulation of cell growth Inferred from mutant phenotype PubMed 18163890. Source: BHF-UCL negative regulation of cell proliferation Inferred from mutant phenotype PubMed 18163890. Source: BHF-UCL ornithine metabolic process Inferred from mutant phenotype PubMed 17827783. Source: BHF-UCL phospholipid homeostasis Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of cholesterol homeostasis Inferred from sequence or structural similarity. Source: BHF-UCL regulation of gastrulation Inferred from electronic annotation. Source: Compara regulation of growth hormone receptor signaling pathway Non-traceable author statement PubMed 17991764PubMed 17991764. Source: BHF-UCL regulation of insulin secretion Inferred from sequence or structural similarity. Source: BHF-UCL regulation of lipid metabolic process Inferred from direct assay PubMed 10551874. Source: BHF-UCL response to glucose stimulus Inferred from sequence or structural similarity. Source: BHF-UCL sex differentiation Inferred from electronic annotation. Source: Compara signal transduction involved in regulation of gene expression Inferred from electronic annotation. Source: Compara transcription initiation from RNA polymerase II promoter Traceable author statement. Source: Reactome triglyceride homeostasis Inferred from sequence or structural similarity. Source: BHF-UCL xenobiotic metabolic process Inferred from mutant phenotype PubMed 17827783. Source: BHF-UCL
Cellular_component	cytoplasm Inferred from direct assay PubMed 14563941. Source: BHF-UCL nucleoplasm Traceable author statement. Source: Reactome
Molecular_function	RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription Inferred from sequence or structural similarity. Source: BHF-UCL RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity Inferred from electronic annotation. Source: Compara activating transcription factor binding Inferred from sequence or structural similarity. Source: BHF-UCL fatty acid binding Inferred from direct assay PubMed 12220494. Source: BHF-UCL ligand-activated sequence-specific DNA binding RNA polymerase II transcription factor activity Inferred from electronic annotation. Source: InterPro protein homodimerization activity Inferred from direct assay PubMed 12220494. Source: BHF-UCL receptor binding Inferred from direct assay PubMed 12220494. Source: BHF-UCL sequence-specific DNA binding Inferred from electronic annotation. Source: Compara steroid hormone receptor activity Inferred from electronic annotation. Source: InterPro transcription regulatory region DNA binding Inferred from direct assay PubMed 16488887. Source: BHF-UCL zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

This entry describes 7 isoforms produced by alternative promoter usage and alternative splicing. [Align] [Select]

Note: Additional isoforms seem to exist.

Isoform HNF4-Alpha-1 (identifier: P41235-1)

Also known as: HNF-4B;

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.

Note: Produced by alternative promoter usage.

Isoform HNF4-Alpha-2 (identifier: P41235-2)

Also known as: HNF4-A;

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

Note: Produced by alternative splicing of isoform HNF4-Alpha-1.

Isoform HNF4-Alpha-3 (identifier: P41235-3)

Also known as: HNF4-C;

The sequence of this isoform differs from the canonical sequence as follows:
     378-474: SPSDAPHAHH...QPTITKQEVI → PCQAQEGRGW...SPLCRFGQVA

Note: Produced by alternative splicing of isoform HNF4-Alpha-1.

Isoform HNF4-Alpha-4 (identifier: P41235-4)

The sequence of this isoform differs from the canonical sequence as follows:
     38-38: N → NDLLPLRLARLRHPLRHHWSISGGVDSSPQG

Note: Produced by alternative splicing of isoform HNF4-Alpha-1.

Isoform HNF4-Alpha-7 (identifier: P41235-5)

The sequence of this isoform differs from the canonical sequence as follows:
     1-38: MRLSKTLVDMDMADYSAALDPAYTTLEFENVQVLTMGN → MVSVNAPLGAPVESSY

Note: Produced by alternative promoter usage.

Isoform HNF4-Alpha-8 (identifier: P41235-6)

The sequence of this isoform differs from the canonical sequence as follows:
     1-38: MRLSKTLVDMDMADYSAALDPAYTTLEFENVQVLTMGN → MVSVNAPLGAPVESSY
     418-428: CEWPRPRGQAA → S

Note: Produced by alternative splicing of isoform HNF4-Alpha-7.

Isoform HNF4-Alpha-9 (identifier: P41235-7)

The sequence of this isoform differs from the canonical sequence as follows:
     1-38: MRLSKTLVDMDMADYSAALDPAYTTLEFENVQVLTMGN → MVSVNAPLGAPVESSY
     378-474: SPSDAPHAHH...QPTITKQEVI → PCQAQEGRGW...SPLCRFGQVA

Note: Produced by alternative splicing of isoform HNF4-Alpha-7.

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_0000053558

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 Ref.12

Modified residue

166

1

Phosphothreonine Ref.12

Modified residue

167

1

Phosphoserine Ref.12

Modified residue

313

1

Phosphoserine; by AMPK Ref.11

Modified residue

429

1

Phosphothreonine By similarity

Modified residue

432

1

Phosphothreonine Ref.12

Modified residue

436

1

Phosphoserine Ref.12

Modified residue

458

1

N6-acetyllysine Ref.12

Cross-link

234

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.12

Cross-link

307

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.12

Natural variations

Alternative sequence

1 – 38

38

MRLSK…LTMGN → MVSVNAPLGAPVESSY in isoform HNF4-Alpha-7, isoform HNF4-Alpha-8 and isoform HNF4-Alpha-9.

VSP_026030

Alternative sequence

38

1

N → NDLLPLRLARLRHPLRHHWS ISGGVDSSPQG in isoform HNF4-Alpha-4.

VSP_003673

Alternative sequence

378 – 474

97

SPSDA…KQEVI → PCQAQEGRGWSGDSPGDRPH TVSSPLSSLASPLCRFGQVA in isoform HNF4-Alpha-3 and isoform HNF4-Alpha-9.

VSP_003675

Alternative sequence

418 – 428

11

CEWPRPRGQAA → S in isoform HNF4-Alpha-2 and isoform HNF4-Alpha-8.

VSP_003674

Natural variant

136

1

R → W in MODY1. Ref.14

VAR_004668

Natural variant

139

1

T → I. Ref.5 Ref.16
Corresponds to variant rs1800961 [ dbSNP | Ensembl ].

VAR_004669

Natural variant

264

1

V → M in late-onset NIDDM. Ref.16

VAR_010600

Natural variant

285

1

E → Q in MODY1. Ref.15

VAR_010601

Natural variant

402

1

V → I in MODY1; reduced transactivation activity. Ref.17

VAR_004670

Natural variant

445

1

P → S. Ref.1
Corresponds to variant rs1063239 [ dbSNP | Ensembl ].

VAR_011785

Natural variant

453

1

V → I. Ref.5

VAR_062267

Experimental info

Mutagenesis

313

1

S → A: Abolishes AMPK-mediated phosphorylation. Ref.11

Mutagenesis

313

1

S → D: Phosphomimetic mutant that leads to reduced ability to bind DNA. Ref.11

Sequence conflict

440

1

G → A in CAA54248. Ref.9

Secondary structure

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474

Helix Strand Turn

Details...

Turn

61 – 63

3

Beta strand

64 – 66

3

Beta strand

69 – 71

3

Helix

78 – 89

12

Turn

106 – 111

6

Helix

113 – 123

11

Helix

127 – 129

3

Helix

149 – 153

5

Helix

155 – 163

9

Turn

176 – 178

3

Helix

184 – 202

19

Helix

206 – 209

4

Helix

213 – 222

10

Helix

224 – 236

13

Beta strand

239 – 244

6

Beta strand

250 – 254

5

Helix

256 – 261

6

Helix

262 – 271

10

Helix

273 – 279

7

Helix

283 – 294

12

Helix

305 – 324

20

Beta strand

325 – 328

4

Helix

333 – 338

6

Helix

340 – 360

21

Helix

368 – 374

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform HNF4-Alpha-1 (HNF-4B) [UniParc]. Last modified May 29, 2007. Version 3. Checksum: 5F1309B89D95DCAF	FASTA	474	52,785
	10 20 30 40 50 60 MRLSKTLVDM DMADYSAALD PAYTTLEFEN VQVLTMGNDT SPSEGTNLNA PNSLGVSALC 70 80 90 100 110 120 AICGDRATGK HYGASSCDGC KGFFRRSVRK NHMYSCRFSR QCVVDKDKRN QCRYCRLKKC 130 140 150 160 170 180 FRAGMKKEAV QNERDRISTR RSSYEDSSLP SINALLQAEV LSRQITSPVS GINGDIRAKK 190 200 210 220 230 240 IASIADVCES MKEQLLVLVE WAKYIPAFCE LPLDDQVALL RAHAGEHLLL GATKRSMVFK 250 260 270 280 290 300 DVLLLGNDYI VPRHCPELAE MSRVSIRILD ELVLPFQELQ IDDNEYAYLK AIIFFDPDAK 310 320 330 340 350 360 GLSDPGKIKR LRSQVQVSLE DYINDRQYDS RGRFGELLLL LPTLQSITWQ MIEQIQFIKL 370 380 390 400 410 420 FGMAKIDNLL QEMLLGGSPS DAPHAHHPLH PHLMQEHMGT NVIVANTMPT HLSNGQMCEW 430 440 450 460 470 PRPRGQAATP ETPQPSPPGG SGSEPYKLLP GAVATIVKPL SAIPQPTITK QEVI
	Isoform HNF4-Alpha-2 (HNF4-A) [UniParc]. Checksum: FF0A4FB233ADCC56	FASTA	464	51,619
	10 20 30 40 50 60 MRLSKTLVDM DMADYSAALD PAYTTLEFEN VQVLTMGNDT SPSEGTNLNA PNSLGVSALC 70 80 90 100 110 120 AICGDRATGK HYGASSCDGC KGFFRRSVRK NHMYSCRFSR QCVVDKDKRN QCRYCRLKKC 130 140 150 160 170 180 FRAGMKKEAV QNERDRISTR RSSYEDSSLP SINALLQAEV LSRQITSPVS GINGDIRAKK 190 200 210 220 230 240 IASIADVCES MKEQLLVLVE WAKYIPAFCE LPLDDQVALL RAHAGEHLLL GATKRSMVFK 250 260 270 280 290 300 DVLLLGNDYI VPRHCPELAE MSRVSIRILD ELVLPFQELQ IDDNEYAYLK AIIFFDPDAK 310 320 330 340 350 360 GLSDPGKIKR LRSQVQVSLE DYINDRQYDS RGRFGELLLL LPTLQSITWQ MIEQIQFIKL 370 380 390 400 410 420 FGMAKIDNLL QEMLLGGSPS DAPHAHHPLH PHLMQEHMGT NVIVANTMPT HLSNGQMSTP 430 440 450 460 ETPQPSPPGG SGSEPYKLLP GAVATIVKPL SAIPQPTITK QEVI
	Isoform HNF4-Alpha-3 (HNF4-C) [UniParc]. Checksum: DE7D9F4F6436EFE2	FASTA	417	46,623
	10 20 30 40 50 60 MRLSKTLVDM DMADYSAALD PAYTTLEFEN VQVLTMGNDT SPSEGTNLNA PNSLGVSALC 70 80 90 100 110 120 AICGDRATGK HYGASSCDGC KGFFRRSVRK NHMYSCRFSR QCVVDKDKRN QCRYCRLKKC 130 140 150 160 170 180 FRAGMKKEAV QNERDRISTR RSSYEDSSLP SINALLQAEV LSRQITSPVS GINGDIRAKK 190 200 210 220 230 240 IASIADVCES MKEQLLVLVE WAKYIPAFCE LPLDDQVALL RAHAGEHLLL GATKRSMVFK 250 260 270 280 290 300 DVLLLGNDYI VPRHCPELAE MSRVSIRILD ELVLPFQELQ IDDNEYAYLK AIIFFDPDAK 310 320 330 340 350 360 GLSDPGKIKR LRSQVQVSLE DYINDRQYDS RGRFGELLLL LPTLQSITWQ MIEQIQFIKL 370 380 390 400 410 FGMAKIDNLL QEMLLGGPCQ AQEGRGWSGD SPGDRPHTVS SPLSSLASPL CRFGQVA
	Isoform HNF4-Alpha-4 [UniParc]. Checksum: F291EFDE331E9338	FASTA	504	56,139
	10 20 30 40 50 60 MRLSKTLVDM DMADYSAALD PAYTTLEFEN VQVLTMGNDL LPLRLARLRH PLRHHWSISG 70 80 90 100 110 120 GVDSSPQGDT SPSEGTNLNA PNSLGVSALC AICGDRATGK HYGASSCDGC KGFFRRSVRK 130 140 150 160 170 180 NHMYSCRFSR QCVVDKDKRN QCRYCRLKKC FRAGMKKEAV QNERDRISTR RSSYEDSSLP 190 200 210 220 230 240 SINALLQAEV LSRQITSPVS GINGDIRAKK IASIADVCES MKEQLLVLVE WAKYIPAFCE 250 260 270 280 290 300 LPLDDQVALL RAHAGEHLLL GATKRSMVFK DVLLLGNDYI VPRHCPELAE MSRVSIRILD 310 320 330 340 350 360 ELVLPFQELQ IDDNEYAYLK AIIFFDPDAK GLSDPGKIKR LRSQVQVSLE DYINDRQYDS 370 380 390 400 410 420 RGRFGELLLL LPTLQSITWQ MIEQIQFIKL FGMAKIDNLL QEMLLGGSPS DAPHAHHPLH 430 440 450 460 470 480 PHLMQEHMGT NVIVANTMPT HLSNGQMCEW PRPRGQAATP ETPQPSPPGG SGSEPYKLLP 490 500 GAVATIVKPL SAIPQPTITK QEVI
	Isoform HNF4-Alpha-7 [UniParc]. Checksum: 96854D18F389B0F9	FASTA	452	50,150
	10 20 30 40 50 60 MVSVNAPLGA PVESSYDTSP SEGTNLNAPN SLGVSALCAI CGDRATGKHY GASSCDGCKG 70 80 90 100 110 120 FFRRSVRKNH MYSCRFSRQC VVDKDKRNQC RYCRLKKCFR AGMKKEAVQN ERDRISTRRS 130 140 150 160 170 180 SYEDSSLPSI NALLQAEVLS RQITSPVSGI NGDIRAKKIA SIADVCESMK EQLLVLVEWA 190 200 210 220 230 240 KYIPAFCELP LDDQVALLRA HAGEHLLLGA TKRSMVFKDV LLLGNDYIVP RHCPELAEMS 250 260 270 280 290 300 RVSIRILDEL VLPFQELQID DNEYAYLKAI IFFDPDAKGL SDPGKIKRLR SQVQVSLEDY 310 320 330 340 350 360 INDRQYDSRG RFGELLLLLP TLQSITWQMI EQIQFIKLFG MAKIDNLLQE MLLGGSPSDA 370 380 390 400 410 420 PHAHHPLHPH LMQEHMGTNV IVANTMPTHL SNGQMCEWPR PRGQAATPET PQPSPPGGSG 430 440 450 SEPYKLLPGA VATIVKPLSA IPQPTITKQE VI
	Isoform HNF4-Alpha-8 [UniParc]. Checksum: 8FD1619FC51F7217	FASTA	442	48,984
	10 20 30 40 50 60 MVSVNAPLGA PVESSYDTSP SEGTNLNAPN SLGVSALCAI CGDRATGKHY GASSCDGCKG 70 80 90 100 110 120 FFRRSVRKNH MYSCRFSRQC VVDKDKRNQC RYCRLKKCFR AGMKKEAVQN ERDRISTRRS 130 140 150 160 170 180 SYEDSSLPSI NALLQAEVLS RQITSPVSGI NGDIRAKKIA SIADVCESMK EQLLVLVEWA 190 200 210 220 230 240 KYIPAFCELP LDDQVALLRA HAGEHLLLGA TKRSMVFKDV LLLGNDYIVP RHCPELAEMS 250 260 270 280 290 300 RVSIRILDEL VLPFQELQID DNEYAYLKAI IFFDPDAKGL SDPGKIKRLR SQVQVSLEDY 310 320 330 340 350 360 INDRQYDSRG RFGELLLLLP TLQSITWQMI EQIQFIKLFG MAKIDNLLQE MLLGGSPSDA 370 380 390 400 410 420 PHAHHPLHPH LMQEHMGTNV IVANTMPTHL SNGQMSTPET PQPSPPGGSG SEPYKLLPGA 430 440 VATIVKPLSA IPQPTITKQE VI
	Isoform HNF4-Alpha-9 [UniParc]. Checksum: DC25511938ED9EF0	FASTA	395	43,988
	10 20 30 40 50 60 MVSVNAPLGA PVESSYDTSP SEGTNLNAPN SLGVSALCAI CGDRATGKHY GASSCDGCKG 70 80 90 100 110 120 FFRRSVRKNH MYSCRFSRQC VVDKDKRNQC RYCRLKKCFR AGMKKEAVQN ERDRISTRRS 130 140 150 160 170 180 SYEDSSLPSI NALLQAEVLS RQITSPVSGI NGDIRAKKIA SIADVCESMK EQLLVLVEWA 190 200 210 220 230 240 KYIPAFCELP LDDQVALLRA HAGEHLLLGA TKRSMVFKDV LLLGNDYIVP RHCPELAEMS 250 260 270 280 290 300 RVSIRILDEL VLPFQELQID DNEYAYLKAI IFFDPDAKGL SDPGKIKRLR SQVQVSLEDY 310 320 330 340 350 360 INDRQYDSRG RFGELLLLLP TLQSITWQMI EQIQFIKLFG MAKIDNLLQE MLLGGPCQAQ 370 380 390 EGRGWSGDSP GDRPHTVSSP LSSLASPLCR FGQVA

References

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[1]	"Isolation and characterization of a third isoform of human hepatocyte nuclear factor 4." Kritis A.A., Argyrokastritis A., Moschonas N.K., Power S., Katrakili N., Zannis V.I., Cereghini S., Talianidis I. Gene 173:275-280(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS HNF4-ALPHA-1; HNF4-ALPHA-2 AND HNF4-ALPHA-3), VARIANT SER-445. Tissue: Liver.
[2]	"Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes." Drewes T., Senkel S., Holewa B., Ryffel G.U. Mol. Cell. Biol. 16:925-931(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], ALTERNATIVE SPLICING. Tissue: Kidney.
[3]	"Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1)." Yamagata K., Furuta H., Oda N., Kaisaki P.J., Menzel S., Cox N.J., Fajans S.S., Signorini S., Stoffel M., Bell G.I. Nature 384:458-460(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Variation in P1 and P2 promoter-driven hepatocyte nuclear factor-4a (HNF4a) expression in human tissues: implications for carcinogenesis." Tanaka T., Jiang S., Hotta H., Takano K., Iwanari H., Hirayama Y., Midorikawa Y., Hippo Y., Watanabe A., Yamashita H., Kumakura J., Uchiyama Y., Hasegawa G., Aburatani H., Hamakubo T., Naito M., Sakai J., Kodama T. Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA], ALTERNATIVE PROMOTER USAGE (ISOFORMS HNF4-ALPHA-7; HNF4-ALPHA-8 AND HNF4-ALPHA-9).
[5]	SeattleSNPs variation discovery resource Submitted (MAY-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ILE-139 AND ILE-453.
[6]	"The DNA sequence and comparative analysis of human chromosome 20." Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J. Nature 414:865-871(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	"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] (ISOFORM HNF4-ALPHA-3).
[9]	"Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear factor 4 indicate the presence of two isoforms in human liver." Chartier F.L., Bossu J.-P., Laudet V., Fruchart J.-C., Laine B. Gene 147:269-272(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 4-474, ALTERNATIVE SPLICING. Tissue: Liver.
[10]	"Recruitment of hepatocyte nuclear factor 4 into specific intranuclear compartments depends on tyrosine phosphorylation that affects its DNA-binding and transactivation potential." Ktistaki E., Ktistakis N.T., Papadogeorgaki E., Talianidis I. Proc. Natl. Acad. Sci. U.S.A. 92:9876-9880(1995) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION.
[11]	"AMP-activated protein kinase regulates HNF4alpha transcriptional activity by inhibiting dimer formation and decreasing protein stability." Hong Y.H., Varanasi U.S., Yang W., Leff T. J. Biol. Chem. 278:27495-27501(2003) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-313, MUTAGENESIS OF SER-313.
[12]	"Multiple post-translational modifications in hepatocyte nuclear factor 4alpha." Yokoyama A., Katsura S., Ito R., Hashiba W., Sekine H., Fujiki R., Kato S. Biochem. Biophys. Res. Commun. 410:749-753(2011) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-142; THR-166; SER-167; THR-432 AND SER-436, UBIQUITINATION AT LYS-234 AND LYS-307, ACETYLATION AT LYS-458.
[13]	"Structural basis for HNF-4alpha activation by ligand and coactivator binding." Duda K., Chi Y.-I., Shoelson S.E. J. Biol. Chem. 279:23311-23316(2004) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 142-378, FATTY ACID BINDING.
[14]	"Organization and partial sequence of the hepatocyte nuclear factor-4-alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY." Furuta H., Iwasaki N., Oda N., Hinokio Y., Horikawa Y., Yamagata K., Yano N., Sugahiro J., Ogata M., Ohgawara H., Omori Y., Iwamoto Y., Bell G.I. Diabetes 46:1652-1657(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MODY1 TRP-136.
[15]	"A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young." Bulman M.P., Dronsfield M.J., Frayling T.M., Appleton M., Bain S.C., Ellard S., Hattersley A.T. Diabetologia 40:859-862(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MODY1 GLN-285.
[16]	"Studies of the genetic variability of the coding region of the hepatocyte nuclear factor-4alpha in Caucasians with maturity onset NIDDM." Moeller A.M., Urhammer S.A., Dalgaard L.T., Reneland R., Berglund L., Hansen T., Clausen J.O., Lithell H., Pedersen O. Diabetologia 40:980-983(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT NIDDM MET-264, VARIANT ILE-139.
[17]	"A missense mutation in hepatocyte nuclear factor-4-alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus." Hani E.H., Suaud L., Boutin P., Chevre J.-C., Durand E., Philippi A., Demenais F., Vionnet N., Furuta H., Velho G., Bell G.I., Laine B., Froguel P. J. Clin. Invest. 101:521-526(1998) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MODY1 ILE-402.
+	Additional computationally mapped references.

Web resources

GeneReviews

Wikipedia

Hepatocyte nuclear factors entry

SeattleSNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X87870 mRNA. Translation: CAA61133.1. Frameshift.
X87871 mRNA. Translation: CAA61134.1. Frameshift.
X87872 mRNA. Translation: CAA61135.1. Frameshift.
Z49825 mRNA. Translation: CAA89989.1.
AY680696 mRNA. Translation: AAT91237.1.
AY680697 mRNA. Translation: AAT91238.1.
AY680698 mRNA. Translation: AAT91239.1.
U72969 , U72959, U72961, U72962, U72963, U72964, U72965, U72966, U72967, U72968 Genomic DNA. Translation: AAB48082.1. Sequence problems.
U72967 , U72959, U72961, U72962, U72963, U72964, U72965, U72966 Genomic DNA. Translation: AAB48083.1.
EF591040 Genomic DNA. Translation: ABQ52204.1.
AL132772 Genomic DNA. Translation: CAC01303.1.
AL132772 Genomic DNA. Translation: CAI18856.1.
CH471077 Genomic DNA. Translation: EAW75924.1.
CH471077 Genomic DNA. Translation: EAW75925.1.
BC137539 mRNA. Translation: AAI37540.1.
BC137540 mRNA. Translation: AAI37541.1.
X76930 mRNA. Translation: CAA54248.1. Different initiation.

IPI

IPI00013196.
IPI00216080.
IPI00300558.
IPI00412368.
IPI00641248.
IPI00645235.
IPI00847265.

PIR

JC4937.
JC4938.
JC6096.

RefSeq

NP_000448.3. NM_000457.4.
NP_001025174.1. NM_001030003.2.
NP_001025175.1. NM_001030004.2.
NP_001245284.1. NM_001258355.1.
NP_787110.2. NM_175914.4.
NP_849181.1. NM_178850.2.

UniGene

Hs.116462.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1PZL	X-ray	2.10	A	142-378	[»]
3CBB	X-ray	2.00	A/B	58-135	[»]
3FS1	X-ray	2.20	A	148-377	[»]

ProteinModelPortal

P41235.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-499N.

IntAct

P41235. 1 interaction.

MINT

MINT-269829.

PTM databases

PhosphoSite

P41235.

Polymorphism databases

DMDM

148886624.

Proteomic databases

PaxDb

P41235.

PRIDE

P41235.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000316099; ENSP00000312987; ENSG00000101076.
ENST00000316673; ENSP00000315180; ENSG00000101076.
ENST00000415691; ENSP00000412111; ENSG00000101076.
ENST00000443598; ENSP00000410911; ENSG00000101076.
ENST00000457232; ENSP00000396216; ENSG00000101076.

GeneID

3172.

KEGG

hsa:3172.

UCSC

uc002xlt.3. human.
uc002xlu.3. human.
uc002xly.3. human.
uc002xma.3. human.

Organism-specific databases

CTD

3172.

GeneCards

GC20P042984.

HGNC

HGNC:5024. HNF4A.

HPA

CAB019417.
HPA004712.

MIM

125850. phenotype.
600281. gene.
606391. phenotype.

neXtProt

NX_P41235.

Orphanet

263455. Hyperinsulinism due to HNF4A deficiency.
552. MODY syndrome.

PharmGKB

PA29349.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG241134.

HOVERGEN

HBG005606.

KO

K07292.

Enzyme and pathway databases

Pathway_Interaction_DB

hnf3bpathway. FOXA2 and FOXA3 transcription factor networks.
hif1_tfpathway. HIF-1-alpha transcription factor network.
smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling.

Reactome

REACT_111045. Developmental Biology.
REACT_71. Gene Expression.

Gene expression databases

ArrayExpress

P41235.

Bgee

P41235.

Genevestigator

P41235.

GermOnline

ENSG00000101076. Homo sapiens.

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

BindingDB

P41235.

ChEMBL

CHEMBL5398.

EvolutionaryTrace

P41235.

GenomeRNAi

3172.

NextBio

12578.

SOURCE

Search...

Entry information

Entry name

HNF4A_HUMAN

Accession

Primary (citable) accession number: P41235
Secondary accession number(s): A5JW41 , B2RPP8, O00659, O00723, Q14540, Q5QPB8, Q6B4V5, Q6B4V6, Q6B4V7, Q92653, Q92654, Q92655, Q99864, Q9NQH0

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	May 29, 2007
Last modified:	May 1, 2013
This is version 158 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.