NR1H4_BOVIN
ID NR1H4_BOVIN Reviewed; 482 AA.
AC Q3SZL0;
DT 17-APR-2007, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2005, sequence version 1.
DT 03-AUG-2022, entry version 107.
DE RecName: Full=Bile acid receptor;
DE AltName: Full=Farnesoid X-activated receptor;
DE AltName: Full=Farnesol receptor HRR-1;
DE AltName: Full=Nuclear receptor subfamily 1 group H member 4;
GN Name=NR1H4;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Crossbred X Angus; TISSUE=Ileum;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Ligand-activated transcription factor. Receptor for bile
CC acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid,
CC deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential
CC role in BA homeostasis through the regulation of genes involved in BA
CC synthesis, conjugation and enterohepatic circulation. Also regulates
CC lipid and glucose homeostasis and is involved innate immune response.
CC The FXR-RXR heterodimer binds predominantly to farnesoid X receptor
CC response elements (FXREs) containing two inverted repeats of the
CC consensus sequence 5'-AGGTCA-3' in which the monomers are spaced by 1
CC nucleotide (IR-1) but also to tandem repeat DR1 sites with lower
CC affinity, and can be activated by either FXR or RXR-specific ligands.
CC It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1
CC bound to coregulatory nuclear responsive element (NRE) halfsites
CC located in close proximity to FXREs modulate transcriptional activity.
CC In the liver activates transcription of the corepressor NR0B2 thereby
CC indirectly inhibiting CYP7A1 and CYP8B1 (involved in BA synthesis)
CC implicating at least in part histone demethylase KDM1A resulting in
CC epigenomic repression, and SLC10A1/NTCP (involved in hepatic uptake of
CC conjugated BAs). Activates transcription of the repressor MAFG
CC (involved in regulation of BA synthesis). Activates transcription of
CC SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP
CC (involved in bile salt export) by directly recruiting histone
CC methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of
CC conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine
CC in the small intestine). Activates transcription of SLC27A5/BACS and
CC BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt
CC export) by directly recruiting histone methyltransferase CARM1, and
CC ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4
CC (involved in secretion of phosphatidylcholine in the small intestine).
CC In the intestine activates FGF19 expression and secretion leading to
CC hepatic CYP7A1 repression. The function also involves the coordinated
CC induction of hepatic KLB/beta-klotho expression. Regulates
CC transcription of liver UGT2B4 and SULT2A1 involved in BA
CC detoxification; binding to the UGT2B4 promoter seems to imply a
CC monomeric transactivation independent of RXRA. Modulates lipid
CC homeostasis by activating liver NR0B2/SHP-mediated repression of SREBF1
CC (involved in de novo lipogenesis), expression of PLTP (involved in HDL
CC formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1,
CC APOC4, PPARA (involved in beta-oxidation of fatty acids), VLDLR and
CC SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and
CC inhibiting expression of MTTP (involved in VLDL assembly). Increases
CC expression of APOC2 (promoting lipoprotein lipase activity implicated
CC in triglyceride clearance). Transrepresses APOA1 involving a monomeric
CC competition with NR2A1 for binding to a DR1 element. Also reduces
CC triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3
CC (both involved in inhibition of lipoprotein lipase). Involved in
CC glucose homeostasis by modulating hepatic gluconeogenesis through
CC activation of NR0B2/SHP-mediated repression of respective genes.
CC Modulates glycogen synthesis (inducing phosphorylation of glycogen
CC synthase kinase-3). Modulates glucose-stimulated insulin secretion and
CC is involved in insulin resistance. Involved in intestinal innate
CC immunity. Plays a role in protecting the distal small intestine against
CC bacterial overgrowth and preservation of the epithelial barrier. Down-
CC regulates inflammatory cytokine expression in several types of immune
CC cells including macrophages and mononuclear cells. Mediates trans-
CC repression of TLR4-induced cytokine expression; the function seems to
CC require its sumoylation and prevents N-CoR nuclear receptor corepressor
CC clearance from target genes such as IL1B and NOS2. Involved in the
CC TLR9-mediated protective mechanism in intestinal inflammation. Plays an
CC anti-inflammatory role in liver inflammation; proposed to inhibit pro-
CC inflammatory (but not antiapoptotic) NF-kappa-B signaling.
CC {ECO:0000250|UniProtKB:Q60641, ECO:0000250|UniProtKB:Q96RI1}.
CC -!- SUBUNIT: Heterodimer with RXRA; the heterodimerization enhances the
CC binding affinity for LXXLL motifs from coactivators (By similarity).
CC Binds DNA predominantly as a heterodimer with RXRA. After activation by
CC agonist binding interacts with coactivators. Interacts with NCOA1,
CC NCOA2, PPARGC1A, CARM1, SETD7, PRMT1, GPS2, SMARCA4 and MED1, EP300 and
CC SMARCD1. Interacts with XRCC5 and XRCC6; decreasing NR1H4/FXR
CC transactivation activity towards ABCB11/BSEP. Interacts with PAGR1 AND
CC NCOA6; indicative for an association with an MLL2/MLL3 complex (ASCOM).
CC {ECO:0000250|UniProtKB:Q60641, ECO:0000250|UniProtKB:Q96RI1}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000305}.
CC -!- PTM: Acetylated by EP300. Lys-223 as is the major acetylation site for
CC EP300; the dynamicly regulated acetylation inhibits heterodimerization
CC with RXRA and transactivation activity. Deacetylated by SIRT1.
CC {ECO:0000250|UniProtKB:Q96RI1}.
CC -!- PTM: Methylation may increase transactivation of target genes.
CC {ECO:0000250|UniProtKB:Q96RI1}.
CC -!- PTM: Phosphorylation by PKC/PRKCA increases transactivation activity by
CC promoting association with PPARGC1A. {ECO:0000250|UniProtKB:Q96RI1}.
CC -!- PTM: Sumoylated upon ligand binding. {ECO:0000250|UniProtKB:Q96RI1}.
CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR1
CC subfamily. {ECO:0000305}.
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DR EMBL; BC102805; AAI02806.1; -; mRNA.
DR RefSeq; NP_001029880.1; NM_001034708.2.
DR AlphaFoldDB; Q3SZL0; -.
DR SMR; Q3SZL0; -.
DR STRING; 9913.ENSBTAP00000018079; -.
DR PaxDb; Q3SZL0; -.
DR PRIDE; Q3SZL0; -.
DR GeneID; 540528; -.
DR KEGG; bta:540528; -.
DR CTD; 9971; -.
DR eggNOG; KOG3575; Eukaryota.
DR InParanoid; Q3SZL0; -.
DR OrthoDB; 1137281at2759; -.
DR Proteomes; UP000009136; Unplaced.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0032052; F:bile acid binding; IEA:InterPro.
DR GO; GO:0004879; F:nuclear receptor activity; IEA:InterPro.
DR GO; GO:0043565; F:sequence-specific DNA binding; IEA:InterPro.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0038183; P:bile acid signaling pathway; IEA:InterPro.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR CDD; cd06936; NR_LBD_Fxr; 1.
DR Gene3D; 1.10.565.10; -; 1.
DR Gene3D; 3.30.50.10; -; 1.
DR InterPro; IPR035500; NHR-like_dom_sf.
DR InterPro; IPR044114; NR_LBD_NR1H4.
DR InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd.
DR InterPro; IPR001723; Nuclear_hrmn_rcpt.
DR InterPro; IPR001728; ThyrH_rcpt.
DR InterPro; IPR001628; Znf_hrmn_rcpt.
DR InterPro; IPR013088; Znf_NHR/GATA.
DR Pfam; PF00104; Hormone_recep; 1.
DR Pfam; PF00105; zf-C4; 1.
DR PRINTS; PR00398; STRDHORMONER.
DR PRINTS; PR00047; STROIDFINGER.
DR PRINTS; PR00546; THYROIDHORMR.
DR SMART; SM00430; HOLI; 1.
DR SMART; SM00399; ZnF_C4; 1.
DR SUPFAM; SSF48508; SSF48508; 1.
DR PROSITE; PS51843; NR_LBD; 1.
DR PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1.
DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1.
PE 2: Evidence at transcript level;
KW Acetylation; Activator; DNA-binding; Immunity; Inflammatory response;
KW Innate immunity; Isopeptide bond; Metal-binding; Methylation; Nucleus;
KW Phosphoprotein; Receptor; Reference proteome; Repressor; Transcription;
KW Transcription regulation; Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1..482
FT /note="Bile acid receptor"
FT /id="PRO_0000283809"
FT DOMAIN 258..482
FT /note="NR LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189"
FT DNA_BIND 134..209
FT /note="Nuclear receptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 137..157
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 173..197
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT REGION 229..253
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 341
FT /ligand="chenodeoxycholate"
FT /ligand_id="ChEBI:CHEBI:36234"
FT /ligand_note="agonist"
FT /evidence="ECO:0000250|UniProtKB:Q96RI1"
FT BINDING 371
FT /ligand="chenodeoxycholate"
FT /ligand_id="ChEBI:CHEBI:36234"
FT /ligand_note="agonist"
FT /evidence="ECO:0000250|UniProtKB:Q96RI1"
FT BINDING 379
FT /ligand="chenodeoxycholate"
FT /ligand_id="ChEBI:CHEBI:36234"
FT /ligand_note="agonist"
FT /evidence="ECO:0000250|UniProtKB:Q96RI1"
FT BINDING 457
FT /ligand="chenodeoxycholate"
FT /ligand_id="ChEBI:CHEBI:36234"
FT /ligand_note="agonist"
FT /evidence="ECO:0000250|UniProtKB:Q96RI1"
FT MOD_RES 145
FT /note="Phosphoserine; by PKC/PRKCA"
FT /evidence="ECO:0000250|UniProtKB:Q96RI1"
FT MOD_RES 164
FT /note="Phosphoserine; by PKC/PRKCA"
FT /evidence="ECO:0000250|UniProtKB:Q96RI1"
FT MOD_RES 167
FT /note="N6-acetyllysine; by EP300"
FT /evidence="ECO:0000250|UniProtKB:Q96RI1"
FT MOD_RES 216
FT /note="N6-methyllysine; by SETD7"
FT /evidence="ECO:0000250|UniProtKB:Q96RI1"
FT MOD_RES 223
FT /note="N6-acetyllysine; by EP300"
FT /evidence="ECO:0000250|UniProtKB:Q96RI1"
FT MOD_RES 452
FT /note="Phosphothreonine; by PKC/PRKCZ"
FT /evidence="ECO:0000250|UniProtKB:Q96RI1"
FT CROSSLNK 132
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000250|UniProtKB:Q96RI1"
FT CROSSLNK 285
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000250|UniProtKB:Q96RI1"
SQ 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
