RARA_CANLF
ID RARA_CANLF Reviewed; 462 AA.
AC Q5FBR4;
DT 26-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 15-MAR-2005, sequence version 1.
DT 25-MAY-2022, entry version 106.
DE RecName: Full=Retinoic acid receptor alpha;
DE Short=RAR-alpha;
DE AltName: Full=Nuclear receptor subfamily 1 group B member 1;
GN Name=RARA; Synonyms=NR1B1;
OS Canis lupus familiaris (Dog) (Canis familiaris).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis.
OX NCBI_TaxID=9615;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Spleen;
RA Miyajima N., Watanabe M., Sugano S., Sasaki N.;
RT "Molecular cloning of canine highly similar retinoic acid receptor alpha.";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Receptor for retinoic acid. Retinoic acid receptors bind as
CC heterodimers to their target response elements in response to their
CC ligands, all-trans or 9-cis retinoic acid, and regulate gene expression
CC in various biological processes. The RXR/RAR heterodimers bind to the
CC retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3'
CC sites known as DR1-DR5. In the absence of ligand, the RXR-RAR
CC heterodimers associate with a multiprotein complex containing
CC transcription corepressors that induce histone deacetylation, chromatin
CC condensation and transcriptional suppression. On ligand binding, the
CC corepressors dissociate from the receptors and associate with the
CC coactivators leading to transcriptional activation. Formation of
CC heterocomplex with histone deacetylases might lead to inhibition of
CC RARE DNA element binding and to transcriptional repression (By
CC similarity). Transcriptional activation and RARE DNA element binding
CC might be supported by the transcription factor KLF2 (By similarity).
CC RARA plays an essential role in the regulation of retinoic acid-induced
CC germ cell development during spermatogenesis. Has a role in the
CC survival of early spermatocytes at the beginning prophase of meiosis.
CC In Sertoli cells, may promote the survival and development of early
CC meiotic prophase spermatocytes. Together with RXRA, positively
CC regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1
CC signaling response to pulsatile shear stress in vascular endothelial
CC cells (By similarity). In association with HDAC3, HDAC5 and HDAC7
CC corepressors, plays a role in the repression of microRNA-10a and
CC thereby promotes the inflammatory response (By similarity).
CC {ECO:0000250|UniProtKB:P10276, ECO:0000250|UniProtKB:P11416}.
CC -!- SUBUNIT: Heterodimer; with RXRA (By similarity). Binds DNA
CC preferentially as a heterodimer (By similarity). RXRA serves as
CC enhancer to induce RARA binding to RARE (By similarity). Interacts with
CC NCOA3 and NCOA6 coactivators, leading to a strong increase of
CC transcription of target genes (By similarity). Interacts with NCOA7 in
CC a ligand-inducible manner (By similarity). Interacts (via the ligand-
CC binding domain) with PRAME; interaction is direct and ligand (retinoic
CC acid)-dependent (By similarity). Interacts with PRKAR1A; the
CC interaction negatively regulates RARA transcriptional activity (By
CC similarity). Interacts with NCOR1 and NCOR2; the interaction occurs in
CC the absence of ligand and represses transcriptional activity (By
CC similarity). Interacts with NCOA3 and NCOA6 coactivators, leading to a
CC strong increase of transcription of target genes (By similarity).
CC Interacts with CDK7; the interaction is enhanced by interaction with
CC GTF2H3 (By similarity). Interacts with GTF2H3; the interaction requires
CC prior phosphorylation on Ser-369 which then enhances interaction with
CC CDK7. Interacts with PRMT2 (By similarity). Interacts with LRIF1 (By
CC similarity). Interacts with ASXL1 and NCOA1 (By similarity). Interacts
CC with ACTN4 (By similarity). In a complex with HDAC3, HDAC5 and HDAC7;
CC the HDACs serve as corepressors of RARA, causing its deacetylation and
CC inhibition of RARE DNA element binding; association with HDAC3, HDAC5
CC and HDAC7 is increased upon oscillatory shear stress (By similarity).
CC In the absence of hormonal ligand, interacts with TACC1 (By
CC similarity). {ECO:0000250|UniProtKB:P10276,
CC ECO:0000250|UniProtKB:P11416}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00407}.
CC Cytoplasm {ECO:0000250|UniProtKB:P10276}. Note=Nuclear localization
CC depends on ligand binding, phosphorylation and sumoylation.
CC Translocation to the nucleus is dependent on activation of PKC and the
CC downstream MAPK phosphorylation (By similarity). Increased nuclear
CC localization upon pulsatile shear stress (By similarity).
CC {ECO:0000250|UniProtKB:P10276}.
CC -!- DOMAIN: Composed of three domains: a modulating N-terminal domain, a
CC DNA-binding domain and a C-terminal ligand-binding domain.
CC -!- DOMAIN: The 9aaTAD motif is a transactivation domain present in a large
CC number of yeast and animal transcription factors.
CC {ECO:0000250|UniProtKB:P10276}.
CC -!- PTM: Phosphorylated on serine and threonine residues. Phosphorylation
CC does not change during cell cycle. Phosphorylation on Ser-77 is crucial
CC for the N-terminal AF1 transcriptional activity. Under stress
CC conditions, MAPK8 enhances phosphorylation on Thr-181, Ser-445 and Ser-
CC 461 leading to RARA ubiquitination and degradation. Phosphorylation by
CC AKT1 inhibits the transactivation activity. On retinoic acid
CC stimulation, phosphorylation on Ser-369 by RPS6KA5 promotes interaction
CC with GTF2H3 and the CDK7-mediated phosphorylation of Ser-77 (By
CC similarity). {ECO:0000250}.
CC -!- PTM: Sumoylated with SUMO2, mainly on Lys-399 which is also required
CC for SENP6 binding. On all-trans retinoic acid (ATRA) binding, a
CC confromational change may occur that allows sumoylation on two
CC additional site, Lys-166 and Lys-171. Probably desumoylated by SENP6.
CC Sumoylation levels determine nuclear localization and regulate ATRA-
CC mediated transcriptional activity (By similarity). {ECO:0000250}.
CC -!- PTM: Acetylated; acetylation is increased upon pulsatile shear stress
CC and decreased upon oscillatory shear stress.
CC {ECO:0000250|UniProtKB:P10276}.
CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR1
CC subfamily. {ECO:0000305}.
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DR EMBL; AB179779; BAD89859.1; -; mRNA.
DR RefSeq; NP_001012663.1; NM_001012645.1.
DR AlphaFoldDB; Q5FBR4; -.
DR SMR; Q5FBR4; -.
DR STRING; 9615.ENSCAFP00000010481; -.
DR GeneID; 480526; -.
DR KEGG; cfa:480526; -.
DR CTD; 5914; -.
DR eggNOG; KOG3575; Eukaryota.
DR InParanoid; Q5FBR4; -.
DR Proteomes; UP000002254; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0004879; F:nuclear receptor activity; IBA:GO_Central.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0009755; P:hormone-mediated signaling pathway; IBA:GO_Central.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0048384; P:retinoic acid receptor signaling pathway; IBA:GO_Central.
DR Gene3D; 1.10.565.10; -; 1.
DR Gene3D; 3.30.50.10; -; 1.
DR InterPro; IPR035500; NHR-like_dom_sf.
DR InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd.
DR InterPro; IPR001723; Nuclear_hrmn_rcpt.
DR InterPro; IPR003078; Retinoic_acid_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; PR01292; RETNOICACIDR.
DR PRINTS; PR00398; STRDHORMONER.
DR PRINTS; PR00047; STROIDFINGER.
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 Cytoplasm; DNA-binding; Isopeptide bond; Metal-binding; Nucleus;
KW Phosphoprotein; Receptor; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1..462
FT /note="Retinoic acid receptor alpha"
FT /id="PRO_0000053460"
FT DOMAIN 183..417
FT /note="NR LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189"
FT DNA_BIND 88..153
FT /note="Nuclear receptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 88..108
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 124..148
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT REGION 1..87
FT /note="Modulating"
FT REGION 52..77
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 154..182
FT /note="Hinge"
FT REGION 419..462
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 408..416
FT /note="9aaTAD"
FT /evidence="ECO:0000250|UniProtKB:P10276"
FT COMPBIAS 52..71
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 447..462
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 77
FT /note="Phosphoserine; by CDK7"
FT /evidence="ECO:0000250|UniProtKB:P11416"
FT MOD_RES 96
FT /note="Phosphoserine; by PKB/AKT1"
FT /evidence="ECO:0000250|UniProtKB:P10276"
FT MOD_RES 219
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000250|UniProtKB:P10276"
FT MOD_RES 369
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000250|UniProtKB:P11416"
FT CROSSLNK 166
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
FT CROSSLNK 171
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
FT CROSSLNK 399
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
SQ SEQUENCE 462 AA; 50771 MW; 8E63EE98C4E0FB4A CRC64;
MASNSSSCPT PGGGHLNGYP VPPYAFFFPP MLGGLSPPGA LTTLQHQLPV SGYSTPSPAT
IETQSSSSEE IVPSPPSPPP LPRIYKPCFV CQDKSSGYHY GVSACEGCKG FFRRSIQKNM
VYTCHRDKNC IINKVTRNRC QYCRLQKCFE VGMSKESVRN DRNKKKKEAP KPECSESYTL
TPEVGELIEK VRKAHQETFP ALCQLGKYTT NNSSEQRVSL DIDLWDKFSE LSTKCIIKTV
EFAKQLPGFT TLTIADQITL LKAACLDILI LRICTRYTPE QDTMTFSEGL TLNRTQMHKA
GFGPLTDLVF AFANQLLPLE MDDAETGLLS AICLICGDRQ DLEQPDRVDM LQEPLLEALK
VYVRKRRPSR PHMFPKMLMK ITDLRSISAK GAERVITLKM EIPGSMPPLI QEMLENSEGL
DTLSGQPGGG GRDGGGLAPP PGSCSPSLSP SSNRSSPATH SP
