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Protein

Bile acid receptor

Gene

Nr1h4

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Ligand-activated transcription factor. Receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential role in BA homeostasis through the regulation of genes involved in BA synthesis, conjugation and enterohepatic circulation. Also regulates lipid and glucose homeostasis and is involved innate immune response. The FXR-RXR heterodimer binds predominantly to farnesoid X receptor response elements (FXREs) containing two inverted repeats of the consensus sequence 5'-AGGTCA-3' in which the monomers are spaced by 1 nucleotide (IR-1) but also to tandem repeat DR1 sites with lower affinity, and can be activated by either FXR or RXR-specific ligands. It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1 bound to coregulatory nuclear responsive element (NRE) halfsites located in close proximity to FXREs modulate transcriptional activity. In the liver activates transcription of the corepressor NR0B2 thereby indirectly inhibiting CYP7A1 and CYP8B1 (involved in BA synthesis) implicating at least in part histone demethylase KDM1A resulting in epigenomic repression, and SLC10A1/NTCP (involved in hepatic uptake of conjugated BAs). Activates transcription of the repressor MAFG (involved in regulation of BA synthesis). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression. The function also involves the coordinated induction of hepatic KLB/beta-klotho expression. Regulates transcription of liver UGT2B4 and SULT2A1 involved in BA detoxification; binding to the UGT2B4 promoter seems to imply a monomeric transactivation independent of RXRA. Modulates lipid homoestasis by activating liver NR0B2/SHP-mediated repression of SREBF1 (involved in de novo lipogenesis), expression of PLTP (involved in HDL formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1, APOC4, PPARA (involved in beta-oxidation of fatty acids), VLDLR and SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and inhibiting expression of MTTP (involved in VLDL assembly). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element. Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase). Involved in glucose homeostasis by modulating hepatic gluconeogenesis through activation of NR0B2/SHP-mediated repression of respective genes. Modulates glycogen synthesis (inducing phosphorylation of glycogen synthase kinase-3). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance. Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier. Down-regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells. Mediates trans-repression of TLR4-induced cytokine expression; the function seems to require its sumoylation and prevents N-CoR nuclear receptor corepressor clearance from target genes such as IL1B and NOS2. Involved in the TLR9-mediated protective mechanism in intestinal inflammation. Plays a anti-inflammatory role in liver inflammation; proposed to inhibit proinflammatory (but not antiapoptotic) NF-kappa-B signaling.By similarity2 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei358 – 3581Agonist1 Publication
Binding sitei366 – 3661Agonist1 Publication
Binding sitei444 – 4441Agonist1 Publication
Binding sitei466 – 4661Agonist1 Publication

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi121 – 19676Nuclear receptorPROSITE-ProRule annotationAdd
BLAST
Zinc fingeri124 – 14421NR C4-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri160 – 18425NR C4-typePROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

  • bile acid binding Source: UniProtKB
  • bile acid receptor activity Source: UniProtKB
  • DNA binding Source: RGD
  • peptide binding Source: RGD
  • receptor activity Source: RGD
  • RNA polymerase II core promoter proximal region sequence-specific DNA binding Source: NTNU_SB
  • steroid hormone receptor activity Source: RGD
  • thyroid hormone receptor activity Source: InterPro
  • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding Source: NTNU_SB
  • zinc ion binding Source: InterPro

GO - Biological processi

  • bile acid metabolic process Source: RGD
  • digestive tract development Source: RGD
  • inflammatory response Source: UniProtKB-KW
  • innate immune response Source: UniProtKB-KW
  • negative regulation of transcription from RNA polymerase II promoter Source: RGD
  • positive regulation of transcription from RNA polymerase II promoter Source: NTNU_SB
  • regulation of carbohydrate metabolic process Source: RGD
  • response to glucose Source: RGD
  • response to lipopolysaccharide Source: RGD
Complete GO annotation...

Keywords - Molecular functioni

Activator, Receptor, Repressor

Keywords - Biological processi

Immunity, Inflammatory response, Innate immunity, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding, Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-RNO-159418. Recycling of bile acids and salts.
R-RNO-192105. Synthesis of bile acids and bile salts.
R-RNO-193368. Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol.
R-RNO-193807. Synthesis of bile acids and bile salts via 27-hydroxycholesterol.
R-RNO-211976. Endogenous sterols.
R-RNO-383280. Nuclear Receptor transcription pathway.

Names & Taxonomyi

Protein namesi
Recommended name:
Bile acid receptor
Alternative name(s):
Farnesoid X-activated receptor
Farnesol receptor HRR-1
Nuclear receptor subfamily 1 group H member 4
Retinoid X receptor-interacting protein 14
Short name:
RXR-interacting protein 14
Gene namesi
Name:Nr1h4
Synonyms:Bar, Fxr, Rip14
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 7

Organism-specific databases

RGDi628831. Nr1h4.

Subcellular locationi

GO - Cellular componenti

  • nucleus Source: RGD
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 469469Bile acid receptorPRO_0000053540Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei132 – 1321Phosphoserine; by PKC/PRKCABy similarity
Modified residuei151 – 1511Phosphoserine; by PKC/PRKCABy similarity
Modified residuei154 – 1541N6-acetyllysine; by EP300By similarity
Modified residuei203 – 2031N6-methyllysine; by SETD7By similarity
Modified residuei210 – 2101N6-acetyllysine; by EP300By similarity
Modified residuei439 – 4391Phosphothreonine; by PKC/PRKCZ ProbableBy similarity

Post-translational modificationi

Acetylated by EP300. Lys-210 as is the major acetylation site for EP300; the dynamicly regulated acetylation inhibits heterodimerization with RXRA and transactivation activity. Deacetylated by SIRT1.By similarity
Methylation may increase transactivation of target genes.By similarity
Phosphorylation by PKC/PRKCA increases transactivation activity by promoting association with PPARGC1A.By similarity
Sumoylated upon ligand binding.By similarity

Keywords - PTMi

Acetylation, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ62735.
PRIDEiQ62735.

PTM databases

PhosphoSiteiQ62735.

Expressioni

Inductioni

Heterodimer of NR1H4 and RXR activated by farnesol.1 Publication

Gene expression databases

ExpressionAtlasiQ62735. baseline and differential.
GenevisibleiQ62735. RN.

Interactioni

Subunit structurei

Binds DNA predominantly as a heterodimer with RXRA. After activation by agonist binding interacts with coactivators. Interacts with NCOA1, NCOA2, PPARGC1A, CARM1, SETD7, PRMT1, GPS2, SMARCA4 and MED1, EP300 and SMARCD1. Interacts with XRCC5 and XRCC6; decreasing NR1H4/FXR transactivation activity towards ABCB11/BSEP. Interacts with PAGR1 AND NCOA6; indicative for an association with an MLL2/MLL3 complex (ASCOM).By similarity2 Publications

Protein-protein interaction databases

IntActiQ62735. 1 interaction.
STRINGi10116.ENSRNOP00000009910.

Structurei

Secondary structure

1
469
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi244 – 25714Combined sources
Helixi264 – 2685Combined sources
Turni269 – 2713Combined sources
Helixi277 – 30024Combined sources
Helixi305 – 3073Combined sources
Helixi310 – 33324Combined sources
Helixi343 – 3497Combined sources
Beta strandi350 – 3534Combined sources
Helixi356 – 37116Combined sources
Helixi376 – 38712Combined sources
Helixi398 – 41922Combined sources
Helixi426 – 44823Combined sources
Helixi460 – 4656Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1OSVX-ray2.50A/B241-469[»]
1OT7X-ray2.90A/B240-468[»]
ProteinModelPortaliQ62735.
SMRiQ62735. Positions 122-207, 240-468.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ62735.

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni239 – 457219Ligand-bindingAdd
BLAST
Regioni325 – 3339Agonist binding1 Publication

Sequence similaritiesi

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

Zinc finger

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri124 – 14421NR C4-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri160 – 18425NR C4-typePROSITE-ProRule annotationAdd
BLAST

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG3575. Eukaryota.
ENOG410XRZC. LUCA.
GeneTreeiENSGT00840000129681.
HOGENOMiHOG000220843.
HOVERGENiHBG108655.
InParanoidiQ62735.
KOiK08537.
OMAiMKPAKGV.
OrthoDBiEOG7DC25S.

Family and domain databases

Gene3Di1.10.565.10. 2 hits.
3.30.50.10. 1 hit.
InterProiIPR000536. Nucl_hrmn_rcpt_lig-bd.
IPR001723. Nuclear_hrmn_rcpt.
IPR001728. ThyrH_rcpt.
IPR001628. Znf_hrmn_rcpt.
IPR013088. Znf_NHR/GATA.
[Graphical view]
PfamiPF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]
PRINTSiPR00398. STRDHORMONER.
PR00047. STROIDFINGER.
PR00546. THYROIDHORMR.
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]

Sequencei

Sequence statusi: Complete.

Q62735-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MNLIGPSHLQ ATDEFALSEN LFGVLTEHAA GPLGQNLDLE SYSPYNNVQF
60 70 80 90 100
PQVQPQISSS SYYSNLGFYP QQPEDWYSPG LYELRRMPTE SVYQGETEVS
110 120 130 140 150
EMPVTKKPRM AASSAGRIKG DELCVVCGDR ASGYHYNALT CEGCKGFFRR
160 170 180 190 200
SITKNAVYKC KNGGNCVMDM YMRRKCQDCR LRKCREMGML AECLLTEIQC
210 220 230 240 250
KSKRLRKNVK QHADQTVNED SEGRDLRQVT STTKLCREKT ELTVDQQTLL
260 270 280 290 300
DYIMDSYSKQ RMPQEITNKI LKEEFSAEEN FLILTEMATS HVQILVEFTK
310 320 330 340 350
RLPGFQTLDH EDQIALLKGS AVEAMFLRSA EIFNKKLPAG HADLLEERIR
360 370 380 390 400
KSGISDEYIT PMFSFYKSVG ELKMTQEEYA LLTAIVILSP DRQYIKDREA
410 420 430 440 450
VEKLQEPLLD VLQKLCKIYQ PENPQHFACL LGRLTELRTF NHHHAEMLMS
460
WRVNDHKFTP LLCEIWDVQ
Length:469
Mass (Da):53,935
Last modified:November 1, 1996 - v1
Checksum:i2BEAF5847D9E403C
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U18374 mRNA. Translation: AAC52205.1.
PIRiA56918.
RefSeqiNP_068513.1. NM_021745.1.
UniGeneiRn.42943.

Genome annotation databases

EnsembliENSRNOT00000009910; ENSRNOP00000009910; ENSRNOG00000007197.
GeneIDi60351.
KEGGirno:60351.
UCSCiRGD:628831. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U18374 mRNA. Translation: AAC52205.1.
PIRiA56918.
RefSeqiNP_068513.1. NM_021745.1.
UniGeneiRn.42943.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1OSVX-ray2.50A/B241-469[»]
1OT7X-ray2.90A/B240-468[»]
ProteinModelPortaliQ62735.
SMRiQ62735. Positions 122-207, 240-468.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ62735. 1 interaction.
STRINGi10116.ENSRNOP00000009910.

PTM databases

PhosphoSiteiQ62735.

Proteomic databases

PaxDbiQ62735.
PRIDEiQ62735.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000009910; ENSRNOP00000009910; ENSRNOG00000007197.
GeneIDi60351.
KEGGirno:60351.
UCSCiRGD:628831. rat.

Organism-specific databases

CTDi9971.
RGDi628831. Nr1h4.

Phylogenomic databases

eggNOGiKOG3575. Eukaryota.
ENOG410XRZC. LUCA.
GeneTreeiENSGT00840000129681.
HOGENOMiHOG000220843.
HOVERGENiHBG108655.
InParanoidiQ62735.
KOiK08537.
OMAiMKPAKGV.
OrthoDBiEOG7DC25S.

Enzyme and pathway databases

ReactomeiR-RNO-159418. Recycling of bile acids and salts.
R-RNO-192105. Synthesis of bile acids and bile salts.
R-RNO-193368. Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol.
R-RNO-193807. Synthesis of bile acids and bile salts via 27-hydroxycholesterol.
R-RNO-211976. Endogenous sterols.
R-RNO-383280. Nuclear Receptor transcription pathway.

Miscellaneous databases

EvolutionaryTraceiQ62735.
PROiQ62735.

Gene expression databases

ExpressionAtlasiQ62735. baseline and differential.
GenevisibleiQ62735. RN.

Family and domain databases

Gene3Di1.10.565.10. 2 hits.
3.30.50.10. 1 hit.
InterProiIPR000536. Nucl_hrmn_rcpt_lig-bd.
IPR001723. Nuclear_hrmn_rcpt.
IPR001728. ThyrH_rcpt.
IPR001628. Znf_hrmn_rcpt.
IPR013088. Znf_NHR/GATA.
[Graphical view]
PfamiPF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]
PRINTSiPR00398. STRDHORMONER.
PR00047. STROIDFINGER.
PR00546. THYROIDHORMR.
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

  1. "Identification of a nuclear receptor that is activated by farnesol metabolites."
    Forman B.M., Goode E., Chen J., Oro A.E., Bradley D.J., Perlmann T., Noonan D.J., Burka L.T., McMorris T., Lamph W.W., Evans R.M., Weinberger C.
    Cell 81:687-693(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH RXRA, INDUCTION.
    Strain: Lewis.
    Tissue: Liver.
  2. "Identification of the DNA binding specificity and potential target genes for the farnesoid X-activated receptor."
    Laffitte B.A., Kast H.R., Nguyen C.M., Zavacki A.M., Moore D.D., Edwards P.A.
    J. Biol. Chem. 275:10638-10647(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: DNA-BINDING.
  3. "BAF60a mediates critical interactions between nuclear receptors and the BRG1 chromatin-remodeling complex for transactivation."
    Hsiao P.W., Fryer C.J., Trotter K.W., Wang W., Archer T.K.
    Mol. Cell. Biol. 23:6210-6220(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH SMARCD1.
  4. "Bile acids regulate hepatic gluconeogenic genes and farnesoid X receptor via G(alpha)i-protein-coupled receptors and the AKT pathway."
    Cao R., Cronk Z.X., Zha W., Sun L., Wang X., Fang Y., Studer E., Zhou H., Pandak W.M., Dent P., Gil G., Hylemon P.B.
    J. Lipid Res. 51:2234-2244(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN GLUCOSE HOMEOSTASIS.
  5. "Structural basis for bile acid binding and activation of the nuclear receptor FXR."
    Mi L.Z., Devarakonda S., Harp J.M., Han Q., Pellicciari R., Willson T.M., Khorasanizadeh S., Rastinejad F.
    Mol. Cell 11:1093-1100(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 241-469 IN COMPLEXES WITH CHENODEOXYCHOLIC ACID ANALOGS AND NCOA2 COACTIVATOR PEPTIDE.

Entry informationi

Entry nameiNR1H4_RAT
AccessioniPrimary (citable) accession number: Q62735
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 27, 2002
Last sequence update: November 1, 1996
Last modified: July 6, 2016
This is version 132 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. SIMILARITY comments
    Index of protein domains and families

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 one 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.