ID NR4A1_RAT Reviewed; 597 AA. AC P22829; Q4V8M4; DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 2. DT 24-JAN-2024, entry version 197. DE RecName: Full=Nuclear receptor subfamily 4 group A member 1; DE AltName: Full=NUR77; DE AltName: Full=Nerve growth factor-induced protein I-B; DE Short=NGFI-B; DE AltName: Full=Orphan nuclear receptor HMR; GN Name=Nr4a1; Synonyms=Hmr, Ngfib; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=3272167; DOI=10.1016/0896-6273(88)90138-9; RA Milbrandt J.; RT "Nerve growth factor induces a gene homologous to the glucocorticoid RT receptor gene."; RL Neuron 1:183-188(1988). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Placenta; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [3] RP CHARACTERIZATION. RX PubMed=8395013; DOI=10.1128/mcb.13.9.5794-5804.1993; RA Wilson T.E., Fahrner T.J., Milbrandt J.; RT "The orphan receptors NGFI-B and steroidogenic factor 1 establish monomer RT binding as a third paradigm of nuclear receptor-DNA interaction."; RL Mol. Cell. Biol. 13:5794-5804(1993). RN [4] RP DNA-BINDING REGION. RX PubMed=1314418; DOI=10.1126/science.1314418; RA Wilson T.E., Paulsen R.E., Padgett K.A., Milbrandt J.; RT "Participation of non-zinc finger residues in DNA binding by two nuclear RT orphan receptors."; RL Science 256:107-110(1992). RN [5] RP FUNCTION. RX PubMed=8473329; DOI=10.1016/s0021-9258(18)52952-5; RA Scearce L.M., Laz T.M., Hazel T.G., Lau L.F., Taub R.; RT "RNR-1, a nuclear receptor in the NGFI-B/Nur77 family that is rapidly RT induced in regenerating liver."; RL J. Biol. Chem. 268:8855-8861(1993). RN [6] RP PHOSPHORYLATION AT SER-340 AND SER-350, SUBCELLULAR LOCATION, AND RP MUTAGENESIS. RX PubMed=8227042; DOI=10.1016/s0021-9258(19)74536-0; RA Hirata Y., Kiuchi K., Chen H.-C., Milbrandt J., Guroff G.; RT "The phosphorylation and DNA binding of the DNA-binding domain of the RT orphan nuclear receptor NGFI-B."; RL J. Biol. Chem. 268:24808-24812(1993). RN [7] {ECO:0007744|PDB:1CIT} RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 264-351 IN COMPLEX WITH NBRE, AND RP COFACTOR. RX PubMed=10331876; DOI=10.1038/8276; RA Meinke G., Sigler P.B.; RT "DNA-binding mechanism of the monomeric orphan nuclear receptor NGFI-B."; RL Nat. Struct. Biol. 6:471-477(1999). RN [8] {ECO:0007744|PDB:1YJE} RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 354-597. RX PubMed=15716272; DOI=10.1074/jbc.m413175200; RA Flaig R., Greschik H., Peluso-Iltis C., Moras D.; RT "Structural basis for the cell-specific activities of the NGFI-B and the RT Nurr1 ligand-binding domain."; RL J. Biol. Chem. 280:19250-19258(2005). CC -!- FUNCTION: Orphan nuclear receptor. Binds the NGFI-B response element CC (NBRE) 5'-AAAGGTCA-3' (PubMed:10331876). Binds 9-cis-retinoic acid CC outside of its ligand-binding (NR LBD) domain (By similarity). CC Participates in energy homeostasis by sequestrating the kinase STK11 in CC the nucleus, thereby attenuating cytoplasmic AMPK activation (By CC similarity). Regulates the inflammatory response in macrophages by CC regulating metabolic adaptations during inflammation, including CC repressing the transcription of genes involved in the citric acid cycle CC (TCA) (By similarity). Inhibits NF-kappa-B signaling by binding to low- CC affinity NF-kappa-B binding sites, such as at the IL2 promoter (By CC similarity). May act concomitantly with NR4A2 in regulating the CC expression of delayed-early genes during liver regeneration CC (PubMed:8473329). Plays a role in the vascular response to injury (By CC similarity). {ECO:0000250|UniProtKB:P12813, CC ECO:0000250|UniProtKB:P22736, ECO:0000269|PubMed:10331876, CC ECO:0000269|PubMed:8473329}. CC -!- FUNCTION: In the cytosol, upon its detection of both bacterial CC lipopolysaccharide (LPS) and NBRE-containing mitochondrial DNA released CC by GSDMD pores during pyroptosis, it promotes non-canonical NLRP3 CC inflammasome activation by stimulating association of NLRP3 and NEK7. CC {ECO:0000250|UniProtKB:P12813}. CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000269|PubMed:10331876}; CC Note=Binds 2 zinc ions. {ECO:0000269|PubMed:10331876}; CC -!- SUBUNIT: Binds the NGFI-B response element (NBRE) as a monomer CC (PubMed:10331876). Binds the Nur response element (NurRE), consisting CC of two inverse NBRE-related octanucleotide repeats separated by 6 base- CC pairs, as a dimer (By similarity). Interacts (via N-terminus) with CC NLRP3 (via LRR repeat domain); the interaction is direct, requires CC binding of NR4A1/Nur77 to NBRE-containing dsDNA and lipopolysaccharide, CC and leads to non-canonical NLRP3 inflammasome activation (By CC similarity). Interacts with GADD45GIP1. Interacts with STK11 (By CC similarity). Interacts with IFI27 (By similarity). Heterodimer (via CC DNA-binding domain) with RXRA (via C-terminus); DNA-binding of the CC heterodimer is enhanced by 9-cis retinoic acid (By similarity). CC Competes for the RXRA interaction with EP300 and thereby attenuates CC EP300 mediated acetylation of RXRA (By similarity). Interacts with CC NCOA1 (By similarity). Interacts with NCOA2 (By similarity). Interacts CC with NCOA3 (By similarity). {ECO:0000250|UniProtKB:P12813, CC ECO:0000250|UniProtKB:P22736, ECO:0000269|PubMed:10331876}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000305|PubMed:8227042}. Cytoplasm, CC cytosol {ECO:0000250|UniProtKB:P22736}. Mitochondrion CC {ECO:0000250|UniProtKB:P22736}. Note=Nuclear export to the cytosol is CC XPO1-mediated and positively regulated by IFI27. Translocation to the CC mitochondrion upon interaction with RXRA and upon the presence of 9-cis CC retinoic acid (By similarity). {ECO:0000250|UniProtKB:P22736}. CC -!- TISSUE SPECIFICITY: Expressed in lung, brain and superior cervical CC ganglia. High levels are seen in the adrenal tissue. CC -!- INDUCTION: By nerve growth factor and during liver regeneration. CC -!- DOMAIN: The NR LBD domain binds the lipid A moiety of CC lipopolysaccharide (LPS) in the cytosol. CC {ECO:0000250|UniProtKB:P12813}. CC -!- PTM: Phosphorylated at Ser-350 by RPS6KA1 and RPS6KA3 in response to CC mitogenic or stress stimuli (By similarity). Phosphorylation of Ser-350 CC results in decrease in NBRE binding while phosphorylation of Ser-340 CC has little effect on it. {ECO:0000250, ECO:0000269|PubMed:8227042}. CC -!- PTM: Acetylated by p300/CBP, acetylation increases stability. CC Deacetylated by HDAC1 (By similarity). {ECO:0000250}. CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR4 CC subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA56770.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC Sequence=AAH97313.2; Type=Erroneous initiation; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U17254; AAA56770.1; ALT_INIT; mRNA. DR EMBL; BC097313; AAH97313.2; ALT_INIT; mRNA. DR PIR; JQ0623; JQ0623. DR RefSeq; NP_077364.2; NM_024388.2. DR RefSeq; XP_006242418.1; XM_006242356.2. DR RefSeq; XP_006242420.1; XM_006242358.2. DR RefSeq; XP_017450619.1; XM_017595130.1. DR PDB; 1CIT; X-ray; 2.70 A; A=264-352. DR PDB; 1YJE; X-ray; 2.40 A; A=354-597. DR PDBsum; 1CIT; -. DR PDBsum; 1YJE; -. DR AlphaFoldDB; P22829; -. DR SMR; P22829; -. DR IntAct; P22829; 2. DR MINT; P22829; -. DR STRING; 10116.ENSRNOP00000010171; -. DR iPTMnet; P22829; -. DR PhosphoSitePlus; P22829; -. DR PaxDb; 10116-ENSRNOP00000010171; -. DR Ensembl; ENSRNOT00000010171.5; ENSRNOP00000010171.2; ENSRNOG00000007607.5. DR Ensembl; ENSRNOT00055050397; ENSRNOP00055041483; ENSRNOG00055029103. DR Ensembl; ENSRNOT00060026731; ENSRNOP00060021406; ENSRNOG00060015611. DR GeneID; 79240; -. DR KEGG; rno:79240; -. DR AGR; RGD:620029; -. DR CTD; 3164; -. DR RGD; 620029; Nr4a1. DR eggNOG; KOG4217; Eukaryota. DR GeneTree; ENSGT00950000183038; -. DR HOGENOM; CLU_007368_14_2_1; -. DR InParanoid; P22829; -. DR OMA; MEVIRKW; -. DR OrthoDB; 5395768at2759; -. DR PhylomeDB; P22829; -. DR TreeFam; TF315430; -. DR Reactome; R-RNO-198693; AKT phosphorylates targets in the nucleus. DR Reactome; R-RNO-383280; Nuclear Receptor transcription pathway. DR EvolutionaryTrace; P22829; -. DR PRO; PR:P22829; -. DR Proteomes; UP000002494; Chromosome 7. DR Bgee; ENSRNOG00000007607; Expressed in skeletal muscle tissue and 19 other cell types or tissues. DR ExpressionAtlas; P22829; baseline and differential. DR GO; GO:0000785; C:chromatin; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; ISS:UniProtKB. DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB. DR GO; GO:0031965; C:nuclear membrane; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0098793; C:presynapse; IEA:GOC. DR GO; GO:0005667; C:transcription regulator complex; ISO:RGD. DR GO; GO:0003677; F:DNA binding; ISO:RGD. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:UniProtKB. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISO:RGD. DR GO; GO:0003690; F:double-stranded DNA binding; ISS:UniProtKB. DR GO; GO:0042802; F:identical protein binding; ISO:RGD. DR GO; GO:0001530; F:lipopolysaccharide binding; ISS:UniProtKB. DR GO; GO:0035259; F:nuclear glucocorticoid receptor binding; IPI:UniProtKB. DR GO; GO:0004879; F:nuclear receptor activity; IEA:InterPro. DR GO; GO:0046982; F:protein heterodimerization activity; IDA:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central. DR GO; GO:0043565; F:sequence-specific DNA binding; ISO:RGD. DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:RGD. DR GO; GO:0008134; F:transcription factor binding; IPI:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:0006915; P:apoptotic process; ISO:RGD. DR GO; GO:0002042; P:cell migration involved in sprouting angiogenesis; ISO:RGD. DR GO; GO:0071376; P:cellular response to corticotropin-releasing hormone stimulus; ISS:UniProtKB. DR GO; GO:0044344; P:cellular response to fibroblast growth factor stimulus; ISO:RGD. DR GO; GO:0071310; P:cellular response to organic substance; ISO:RGD. DR GO; GO:0035924; P:cellular response to vascular endothelial growth factor stimulus; ISO:RGD. DR GO; GO:0032497; P:detection of lipopolysaccharide; ISS:UniProtKB. DR GO; GO:0035767; P:endothelial cell chemotaxis; ISO:RGD. DR GO; GO:0045444; P:fat cell differentiation; ISS:UniProtKB. DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW. DR GO; GO:0045786; P:negative regulation of cell cycle; ISS:UniProtKB. DR GO; GO:0014860; P:neurotransmitter secretion involved in regulation of skeletal muscle contraction; IMP:RGD. DR GO; GO:0160075; P:non-canonical inflammasome complex assembly; ISS:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:RGD. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; ISO:RGD. DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; ISO:RGD. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0061469; P:regulation of type B pancreatic cell proliferation; IMP:UniProtKB. DR GO; GO:0001975; P:response to amphetamine; IMP:RGD. DR GO; GO:0051602; P:response to electrical stimulus; IEP:RGD. DR GO; GO:0032496; P:response to lipopolysaccharide; IEP:RGD. DR GO; GO:0035914; P:skeletal muscle cell differentiation; ISO:RGD. DR GO; GO:0006366; P:transcription by RNA polymerase II; ISO:RGD. DR CDD; cd06969; NR_DBD_NGFI-B; 1. DR CDD; cd07348; NR_LBD_NGFI-B; 1. DR Gene3D; 3.30.50.10; Erythroid Transcription Factor GATA-1, subunit A; 1. DR Gene3D; 1.10.565.10; Retinoid X Receptor; 1. DR InterPro; IPR035500; NHR-like_dom_sf. DR InterPro; IPR003071; NR4A1. DR InterPro; IPR003070; NR4A1-3. DR InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd. DR InterPro; IPR001723; Nuclear_hrmn_rcpt. DR InterPro; IPR001628; Znf_hrmn_rcpt. DR InterPro; IPR013088; Znf_NHR/GATA. DR PANTHER; PTHR24085; NUCLEAR HORMONE RECEPTOR; 1. DR PANTHER; PTHR24085:SF1; NUCLEAR RECEPTOR SUBFAMILY 4 GROUP A MEMBER 1; 1. DR Pfam; PF00104; Hormone_recep; 1. DR Pfam; PF00105; zf-C4; 1. DR PRINTS; PR01285; HMRNUCRECPTR. DR PRINTS; PR01284; NUCLEARECPTR. DR PRINTS; PR00398; STRDHORMONER. DR PRINTS; PR00047; STROIDFINGER. DR SMART; SM00430; HOLI; 1. DR SMART; SM00399; ZnF_C4; 1. DR SUPFAM; SSF57716; Glucocorticoid receptor-like (DNA-binding domain); 1. DR SUPFAM; SSF48508; Nuclear receptor ligand-binding domain; 1. DR PROSITE; PS51843; NR_LBD; 1. DR PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1. DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1. DR Genevisible; P22829; RN. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Cytoplasm; DNA-binding; Inflammatory response; KW Metal-binding; Mitochondrion; Nucleus; Phosphoprotein; Receptor; KW Reference proteome; Transcription; Transcription regulation; Zinc; KW Zinc-finger. FT CHAIN 1..597 FT /note="Nuclear receptor subfamily 4 group A member 1" FT /id="PRO_0000053717" FT DOMAIN 359..594 FT /note="NR LBD" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189" FT DNA_BIND 263..338 FT /note="Nuclear receptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407" FT ZN_FING 266..286 FT /note="NR C4-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407" FT ZN_FING 302..326 FT /note="NR C4-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407" FT REGION 1..22 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 170..465 FT /note="Required for nuclear import" FT /evidence="ECO:0000250|UniProtKB:P22736" FT REGION 267..353 FT /note="Required for binding NBRE-containing DNA" FT /evidence="ECO:0000250|UniProtKB:P12813" FT REGION 298..360 FT /note="Required for the interaction with RXRA" FT /evidence="ECO:0000250|UniProtKB:P22736" FT REGION 341..360 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 520..543 FT /note="Binds lipopolysaccharide" FT /evidence="ECO:0000250|UniProtKB:P12813" FT REGION 583..594 FT /note="AF-2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189" FT MOD_RES 340 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:8227042" FT MOD_RES 350 FT /note="Phosphoserine; by PKA, RPS6KA1 and RPS6KA3" FT /evidence="ECO:0000269|PubMed:8227042" FT MUTAGEN 340 FT /note="S->A: Loss of phosphorylation." FT /evidence="ECO:0000269|PubMed:8227042" FT MUTAGEN 345 FT /note="R->K: Decreased NBRE binding." FT /evidence="ECO:0000269|PubMed:8227042" FT MUTAGEN 348 FT /note="L->V: Almost complete loss of NBRE binding." FT /evidence="ECO:0000269|PubMed:8227042" FT MUTAGEN 350 FT /note="S->A: Loss of phosphorylation." FT /evidence="ECO:0000269|PubMed:8227042" FT STRAND 267..269 FT /evidence="ECO:0007829|PDB:1CIT" FT STRAND 275..277 FT /evidence="ECO:0007829|PDB:1CIT" FT STRAND 280..282 FT /evidence="ECO:0007829|PDB:1CIT" FT HELIX 284..296 FT /evidence="ECO:0007829|PDB:1CIT" FT STRAND 303..306 FT /evidence="ECO:0007829|PDB:1CIT" FT TURN 312..317 FT /evidence="ECO:0007829|PDB:1CIT" FT HELIX 319..328 FT /evidence="ECO:0007829|PDB:1CIT" FT HELIX 333..335 FT /evidence="ECO:0007829|PDB:1CIT" FT HELIX 339..341 FT /evidence="ECO:0007829|PDB:1CIT" FT HELIX 363..374 FT /evidence="ECO:0007829|PDB:1YJE" FT HELIX 378..380 FT /evidence="ECO:0007829|PDB:1YJE" FT HELIX 399..421 FT /evidence="ECO:0007829|PDB:1YJE" FT TURN 424..428 FT /evidence="ECO:0007829|PDB:1YJE" FT HELIX 431..453 FT /evidence="ECO:0007829|PDB:1YJE" FT TURN 456..459 FT /evidence="ECO:0007829|PDB:1YJE" FT STRAND 460..462 FT /evidence="ECO:0007829|PDB:1YJE" FT STRAND 466..470 FT /evidence="ECO:0007829|PDB:1YJE" FT HELIX 471..478 FT /evidence="ECO:0007829|PDB:1YJE" FT HELIX 481..495 FT /evidence="ECO:0007829|PDB:1YJE" FT HELIX 499..510 FT /evidence="ECO:0007829|PDB:1YJE" FT HELIX 520..540 FT /evidence="ECO:0007829|PDB:1YJE" FT HELIX 550..555 FT /evidence="ECO:0007829|PDB:1YJE" FT HELIX 558..578 FT /evidence="ECO:0007829|PDB:1YJE" FT HELIX 585..592 FT /evidence="ECO:0007829|PDB:1YJE" SQ SEQUENCE 597 AA; 64282 MW; 9CFA987112337E53 CRC64; MPCIQAQYGT PATSPGPRDH LTGDPLALEF SKPTMDLASP ETAPTAPATL PSFSTFMDGG YTGEFDTFLY QLPGTAQPCS SASSTSSSSS SATSPASASF KFEDFQVYGC YPGTLSGPLD ETLSSSGSDY YGSPCSAPSP PTPNFQPSQL SPWDGSFGHF SPSQTYEGLR VWTEQLPKAS GPPPPPTFFS FSPPTGPSPS LAQSSLKLFP APATHQLGEG ESYSVPAAFP GLAPTSPNCD TSGILDAPVT STKARSGSSG GSEGRCAVCG DNASCQHYGV RTCEGCKGFF KRTVQKSAKY ICLANKDCPV DKRRRNRCQF CRFQKCLAVG MVKEVVRTDS LKGRRGRLPS KPKQPPDASP TNLLTSLIRA HLDSGPNTAK LDYSKFQELV LPRFGKEDAG DVQQFYDLLS GSLDVIRKWA EKIPGFIELS PGDQDLLLES AFLELFILRL AYRSKPGEGK LIFCSGLVLH RLQCARGFGD WIDNILAFSR SLHSLGVDVP AFACLSALVL ITDRHGLQDP RRVEELQNRI ASCLKEHMAA VAGDPQPASC LSRLLGKLPE LRTLCTQGLQ RIFCLKLEDL VPPPPIVDKI FMDTLSF //