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Protein

Bile acid receptor

Gene

NR1H4

Organism
Bos taurus (Bovine)
Status
Reviewed-Annotation score: Annotation score: 4 out of 5-Experimental evidence at transcript 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 similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei371 – 3711AgonistBy similarity
Binding sitei379 – 3791AgonistBy similarity
Binding sitei457 – 4571AgonistBy similarity
Binding sitei479 – 4791AgonistBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi134 – 20976Nuclear receptorPROSITE-ProRule annotationAdd
BLAST
Zinc fingeri137 – 15721NR C4-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri173 – 19725NR C4-typePROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

GO - Biological processi

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

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
Gene namesi
Name:NR1H4
OrganismiBos taurus (Bovine)
Taxonomic identifieri9913 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
Proteomesi
  • UP000009136 Componenti: Unplaced

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 482482Bile acid receptorPRO_0000283809Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Cross-linki132 – 132Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) ProbableBy similarity
Modified residuei145 – 1451Phosphoserine; by PKC/PRKCABy similarity
Modified residuei164 – 1641Phosphoserine; by PKC/PRKCABy similarity
Modified residuei167 – 1671N6-acetyllysine; by EP300By similarity
Modified residuei216 – 2161N6-methyllysine; by SETD7By similarity
Modified residuei223 – 2231N6-acetyllysine; by EP300By similarity
Cross-linki285 – 285Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) ProbableBy similarity
Modified residuei452 – 4521Phosphothreonine; by PKC/PRKCZ ProbableBy similarity

Post-translational modificationi

Acetylated by EP300. Lys-223 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, Isopeptide bond, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ3SZL0.
PRIDEiQ3SZL0.

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 similarity

Protein-protein interaction databases

STRINGi9913.ENSBTAP00000018079.

Structurei

3D structure databases

ProteinModelPortaliQ3SZL0.
SMRiQ3SZL0. Positions 135-220, 254-482.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni252 – 470219Ligand-bindingBy similarityAdd
BLAST
Regioni338 – 3469Agonist bindingBy similarity

Sequence similaritiesi

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

Zinc finger

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri137 – 15721NR C4-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri173 – 19725NR C4-typePROSITE-ProRule annotationAdd
BLAST

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG3575. Eukaryota.
ENOG410XRZC. LUCA.
HOGENOMiHOG000220843.
HOVERGENiHBG108655.
InParanoidiQ3SZL0.
KOiK08537.

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.

Q3SZL0-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MVMQFQELEN PVQISPCHSH TSSGFDMEVM SMKPAKGVLT EQVAGPLGQN
60 70 80 90 100
LEVEPYSQYN NVQFPQVQPQ ISSSSYYSNV GFYPQQPEEW YSPGIYELRR
110 120 130 140 150
MPAETLYQGE TEVVEIPITK KARLGASAGR IKGDELCVVC GDRASGYHYN
160 170 180 190 200
ALTCEGCKGF FRRSITKNAV YKCKNGGNCV MDMYMRRKCQ ECRLRKCKEM
210 220 230 240 250
GMLAECLLTE IQCKSKRLRK NVKQHADQAI HEDSEGRDLR QVTSTTKSCR
260 270 280 290 300
EKTELTPDQQ NLLHYIMDSY SKQRMPQEIT NKFLKEEFSA EENFIILTEM
310 320 330 340 350
ATSHVQVLVE FTKKLPGFQT LDHEDQIALL KGSAVEAMFL RSAEIFSKKL
360 370 380 390 400
PAGHTDLLEE RIRKSGISDE YITPMFSFYK SVAELKMTQE EYALLTAIVI
410 420 430 440 450
LSPDRQYIKD REAVEKLQEP LLDVLQKLCK IHQPENPQHF ACLLGRLTEL
460 470 480
RTFNHHHADM LMSWRVNDHK FTPLLCEIWD VQ
Length:482
Mass (Da):55,460
Last modified:October 11, 2005 - v1
Checksum:i3FB9E9F8C765A7DC
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC102805 mRNA. Translation: AAI02806.1.
RefSeqiNP_001029880.1. NM_001034708.2.
UniGeneiBt.48865.

Genome annotation databases

GeneIDi540528.
KEGGibta:540528.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC102805 mRNA. Translation: AAI02806.1.
RefSeqiNP_001029880.1. NM_001034708.2.
UniGeneiBt.48865.

3D structure databases

ProteinModelPortaliQ3SZL0.
SMRiQ3SZL0. Positions 135-220, 254-482.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9913.ENSBTAP00000018079.

Proteomic databases

PaxDbiQ3SZL0.
PRIDEiQ3SZL0.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi540528.
KEGGibta:540528.

Organism-specific databases

CTDi9971.

Phylogenomic databases

eggNOGiKOG3575. Eukaryota.
ENOG410XRZC. LUCA.
HOGENOMiHOG000220843.
HOVERGENiHBG108655.
InParanoidiQ3SZL0.
KOiK08537.

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. NIH - Mammalian Gene Collection (MGC) project
    Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: Crossbred X Angus.
    Tissue: Ileum.

Entry informationi

Entry nameiNR1H4_BOVIN
AccessioniPrimary (citable) accession number: Q3SZL0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 17, 2007
Last sequence update: October 11, 2005
Last modified: June 8, 2016
This is version 78 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

Complete proteome, Reference proteome

Documents

  1. 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.