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Bile acid receptor (Farnesoid X-activated receptor) (Farnesol receptor HRR-1) (Nuclear receptor subfamily 1 group H member 4)

 NR1H4_BOVIN             Reviewed;         482 AA.
Q3SZL0;
17-APR-2007, integrated into UniProtKB/Swiss-Prot.
11-OCT-2005, sequence version 1.
28-FEB-2018, entry version 91.
RecName: Full=Bile acid receptor;
AltName: Full=Farnesoid X-activated receptor;
AltName: Full=Farnesol receptor HRR-1;
AltName: Full=Nuclear receptor subfamily 1 group H member 4;
Name=NR1H4;
Bos taurus (Bovine).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Laurasiatheria; Cetartiodactyla; Ruminantia;
Pecora; Bovidae; Bovinae; Bos.
NCBI_TaxID=9913;
[1]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
STRAIN=Crossbred X Angus; TISSUE=Ileum;
NIH - Mammalian Gene Collection (MGC) project;
Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
-!- FUNCTION: 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 homeostasis 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 an anti-
inflammatory role in liver inflammation; proposed to inhibit
proinflammatory (but not antiapoptotic) NF-kappa-B signaling.
{ECO:0000250|UniProtKB:Q60641, ECO:0000250|UniProtKB:Q96RI1}.
-!- SUBUNIT: 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).
{ECO:0000250|UniProtKB:Q60641, ECO:0000250|UniProtKB:Q96RI1}.
-!- SUBCELLULAR LOCATION: Nucleus {ECO:0000305}.
-!- PTM: 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. {ECO:0000250|UniProtKB:Q96RI1}.
-!- PTM: Methylation may increase transactivation of target genes.
{ECO:0000250|UniProtKB:Q96RI1}.
-!- PTM: Phosphorylation by PKC/PRKCA increases transactivation
activity by promoting association with PPARGC1A.
{ECO:0000250|UniProtKB:Q96RI1}.
-!- PTM: Sumoylated upon ligand binding.
{ECO:0000250|UniProtKB:Q96RI1}.
-!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR1
subfamily. {ECO:0000305}.
-----------------------------------------------------------------------
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EMBL; BC102805; AAI02806.1; -; mRNA.
RefSeq; NP_001029880.1; NM_001034708.2.
UniGene; Bt.48865; -.
ProteinModelPortal; Q3SZL0; -.
SMR; Q3SZL0; -.
STRING; 9913.ENSBTAP00000018079; -.
PaxDb; Q3SZL0; -.
PRIDE; Q3SZL0; -.
GeneID; 540528; -.
KEGG; bta:540528; -.
CTD; 9971; -.
eggNOG; KOG3575; Eukaryota.
eggNOG; ENOG410XRZC; LUCA.
HOGENOM; HOG000220843; -.
HOVERGEN; HBG108655; -.
InParanoid; Q3SZL0; -.
KO; K08537; -.
Proteomes; UP000009136; Unplaced.
GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
GO; GO:0043565; F:sequence-specific DNA binding; IEA:InterPro.
GO; GO:0003707; F:steroid hormone receptor activity; IEA:InterPro.
GO; GO:0004887; F:thyroid hormone receptor activity; IEA:InterPro.
GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
GO; GO:0006351; P:transcription, DNA-templated; IEA:UniProtKB-KW.
Gene3D; 3.30.50.10; -; 1.
InterPro; IPR035500; NHR_like_dom_sf.
InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd.
InterPro; IPR001723; Nuclear_hrmn_rcpt.
InterPro; IPR001728; ThyrH_rcpt.
InterPro; IPR001628; Znf_hrmn_rcpt.
InterPro; IPR013088; Znf_NHR/GATA.
Pfam; PF00104; Hormone_recep; 1.
Pfam; PF00105; zf-C4; 1.
PRINTS; PR00398; STRDHORMONER.
PRINTS; PR00047; STROIDFINGER.
PRINTS; PR00546; THYROIDHORMR.
SMART; SM00430; HOLI; 1.
SMART; SM00399; ZnF_C4; 1.
SUPFAM; SSF48508; SSF48508; 1.
PROSITE; PS51843; NR_LBD; 1.
PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1.
PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1.
2: Evidence at transcript level;
Acetylation; Activator; Complete proteome; DNA-binding; Immunity;
Inflammatory response; Innate immunity; Isopeptide bond;
Metal-binding; Methylation; Nucleus; Phosphoprotein; Receptor;
Reference proteome; Repressor; Transcription;
Transcription regulation; Ubl conjugation; Zinc; Zinc-finger.
CHAIN 1 482 Bile acid receptor.
/FTId=PRO_0000283809.
DOMAIN 258 482 NR LBD. {ECO:0000255|PROSITE-
ProRule:PRU01189}.
DNA_BIND 134 209 Nuclear receptor. {ECO:0000255|PROSITE-
ProRule:PRU00407}.
ZN_FING 137 157 NR C4-type. {ECO:0000255|PROSITE-
ProRule:PRU00407}.
ZN_FING 173 197 NR C4-type. {ECO:0000255|PROSITE-
ProRule:PRU00407}.
REGION 338 346 Agonist binding.
{ECO:0000250|UniProtKB:Q62735}.
BINDING 371 371 Agonist. {ECO:0000250|UniProtKB:Q62735}.
BINDING 379 379 Agonist. {ECO:0000250|UniProtKB:Q62735}.
BINDING 457 457 Agonist. {ECO:0000250|UniProtKB:Q62735}.
BINDING 479 479 Agonist. {ECO:0000250|UniProtKB:Q62735}.
MOD_RES 145 145 Phosphoserine; by PKC/PRKCA.
{ECO:0000250|UniProtKB:Q96RI1}.
MOD_RES 164 164 Phosphoserine; by PKC/PRKCA.
{ECO:0000250|UniProtKB:Q96RI1}.
MOD_RES 167 167 N6-acetyllysine; by EP300.
{ECO:0000250|UniProtKB:Q96RI1}.
MOD_RES 216 216 N6-methyllysine; by SETD7.
{ECO:0000250|UniProtKB:Q96RI1}.
MOD_RES 223 223 N6-acetyllysine; by EP300.
{ECO:0000250|UniProtKB:Q96RI1}.
MOD_RES 452 452 Phosphothreonine; by PKC/PRKCZ.
{ECO:0000250|UniProtKB:Q96RI1}.
CROSSLNK 132 132 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in SUMO1).
{ECO:0000250|UniProtKB:Q96RI1}.
CROSSLNK 285 285 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in SUMO1).
{ECO:0000250|UniProtKB:Q96RI1}.
SEQUENCE 482 AA; 55460 MW; 3FB9E9F8C765A7DC CRC64;
MVMQFQELEN PVQISPCHSH TSSGFDMEVM SMKPAKGVLT EQVAGPLGQN LEVEPYSQYN
NVQFPQVQPQ ISSSSYYSNV GFYPQQPEEW YSPGIYELRR MPAETLYQGE TEVVEIPITK
KARLGASAGR IKGDELCVVC GDRASGYHYN ALTCEGCKGF FRRSITKNAV YKCKNGGNCV
MDMYMRRKCQ ECRLRKCKEM GMLAECLLTE IQCKSKRLRK NVKQHADQAI HEDSEGRDLR
QVTSTTKSCR EKTELTPDQQ NLLHYIMDSY SKQRMPQEIT NKFLKEEFSA EENFIILTEM
ATSHVQVLVE FTKKLPGFQT LDHEDQIALL KGSAVEAMFL RSAEIFSKKL PAGHTDLLEE
RIRKSGISDE YITPMFSFYK SVAELKMTQE EYALLTAIVI LSPDRQYIKD REAVEKLQEP
LLDVLQKLCK IHQPENPQHF ACLLGRLTEL RTFNHHHADM LMSWRVNDHK FTPLLCEIWD
VQ


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