GCR_RABIT
ID GCR_RABIT Reviewed; 772 AA.
AC P59667;
DT 30-APR-2003, integrated into UniProtKB/Swiss-Prot.
DT 30-APR-2003, sequence version 1.
DT 03-AUG-2022, entry version 134.
DE RecName: Full=Glucocorticoid receptor;
DE Short=GR;
DE AltName: Full=Nuclear receptor subfamily 3 group C member 1;
GN Name=NR3C1; Synonyms=GRL;
OS Oryctolagus cuniculus (Rabbit).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX NCBI_TaxID=9986;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Lens epithelium;
RA James E.R., Robertson L.L.;
RT "Rabbit glucocorticoid receptor from lens epithelial cells.";
RL Submitted (OCT-2002) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP IDENTIFICATION IN A COMPLEX WITH NR3C1 AND FKBP4; PPID; PPP5C OR STIP1.
RX PubMed=9195923; DOI=10.1074/jbc.272.26.16224;
RA Silverstein A.M., Galigniana M.D., Chen M.S., Owens-Grillo J.K.,
RA Chinkers M., Pratt W.B.;
RT "Protein phosphatase 5 is a major component of glucocorticoid
RT receptor.hsp90 complexes with properties of an FK506-binding
RT immunophilin.";
RL J. Biol. Chem. 272:16224-16230(1997).
CC -!- FUNCTION: Receptor for glucocorticoids (GC). Has a dual mode of action:
CC as a transcription factor that binds to glucocorticoid response
CC elements (GRE), both for nuclear and mitochondrial DNA, and as a
CC modulator of other transcription factors. Affects inflammatory
CC responses, cellular proliferation and differentiation in target
CC tissues. Involved in chromatin remodeling. Plays a role in rapid mRNA
CC degradation by binding to the 5' UTR of target mRNAs and interacting
CC with PNRC2 in a ligand-dependent manner which recruits the RNA helicase
CC UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay. Could
CC act as a coactivator for STAT5-dependent transcription upon growth
CC hormone (GH) stimulation and could reveal an essential role of hepatic
CC GR in the control of body growth. Mediates glucocorticoid-induced
CC apoptosis. Promotes accurate chromosome segregation during mitosis. May
CC act as a tumor suppressor. May play a negative role in adipogenesis
CC through the regulation of lipolytic and antilipogenic gene expression.
CC {ECO:0000250|UniProtKB:P04150, ECO:0000250|UniProtKB:P06537}.
CC -!- SUBUNIT: Heteromultimeric cytoplasmic complex with HSP90AA1,
CC HSPA1A/HSPA1B, and FKBP5 or another immunophilin such as PPID, STIP1,
CC or the immunophilin homolog PPP5C (PubMed:9195923). Upon ligand binding
CC FKBP5 dissociates from the complex and FKBP4 takes its place, thereby
CC linking the complex to dynein and mediating transport to the nucleus,
CC where the complex dissociates (PubMed:9195923). Probably forms a
CC complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37,
CC PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this
CC complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (By
CC similarity). Directly interacts with UNC45A (By similarity). Binds to
CC DNA as a homodimer, and as heterodimer with NR3C2 or the retinoid X
CC receptor (By similarity). Binds STAT5A and STAT5B homodimers and
CC heterodimers (By similarity). Interacts with NRIP1, POU2F1, POU2F2 and
CC TRIM28 (By similarity). Interacts with several coactivator complexes,
CC including the SMARCA4 complex, CREBBP/EP300, TADA2L (Ada complex) and
CC p160 coactivators such as NCOA2 and NCOA6 (By similarity). Interaction
CC with BAG1 inhibits transactivation (By similarity). Interacts with
CC HEXIM1 and TGFB1I1 (By similarity). Interacts with NCOA1 (By
CC similarity). Interacts with NCOA3, SMARCA4, SMARCC1, SMARCD1, and
CC SMARCE1 (By similarity). Interacts with CLOCK, CRY1 and CRY2 in a
CC ligand-dependent fashion (By similarity). Interacts with CIART (By
CC similarity). Interacts with RWDD3 (By similarity). Interacts with
CC UBE2I/UBC9 and this interaction is enhanced in the presence of RWDD3
CC (By similarity). Interacts with GRIP1 (By similarity). Interacts with
CC NR4A3 (via nuclear receptor DNA-binding domain), represses
CC transcription activity of NR4A3 on the POMC promoter Nur response
CC element (NurRE) (By similarity). Directly interacts with PNRC2 to
CC attract and form a complex with UPF1 and DCP1A; the interaction leads
CC to rapid mRNA degradation (By similarity). Interacts with GSK3B (By
CC similarity). Interacts with FNIP1 and FNIP2 (By similarity). Interacts
CC (via C-terminus) with HNRNPU (via C-terminus) (By similarity).
CC Interacts with MCM3AP (By similarity). Interacts (via domain NR LBD)
CC with HSP90AA1 and HSP90AB1 (By similarity). In the absence of hormonal
CC ligand, interacts with TACC1 (By similarity).
CC {ECO:0000250|UniProtKB:P04150, ECO:0000250|UniProtKB:P06536,
CC ECO:0000250|UniProtKB:P06537, ECO:0000269|PubMed:9195923}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P04150}. Nucleus
CC {ECO:0000250|UniProtKB:P04150}. Mitochondrion
CC {ECO:0000250|UniProtKB:P04150}. Cytoplasm, cytoskeleton, spindle
CC {ECO:0000250|UniProtKB:P04150}. Cytoplasm, cytoskeleton, microtubule
CC organizing center, centrosome {ECO:0000250|UniProtKB:P04150}.
CC Note=After ligand activation, translocates from the cytoplasm to the
CC nucleus (By similarity). In the presence of NR1D1 shows a time-
CC dependent subcellular localization, localizing to the cytoplasm at ZT8
CC and to the nucleus at ZT20 (By similarity). Lacks this diurnal pattern
CC of localization in the absence of NR1D1, localizing to both nucleus and
CC the cytoplasm at ZT8 and ZT20 (By similarity).
CC {ECO:0000250|UniProtKB:P04150, ECO:0000250|UniProtKB:P06537}.
CC -!- DOMAIN: Composed of three domains: a modulating N-terminal domain, a
CC DNA-binding domain and a C-terminal ligand-binding domain. The ligand-
CC binding domain is required for correct chromosome segregation during
CC mitosis although ligand binding is not required.
CC {ECO:0000250|UniProtKB:P04150}.
CC -!- PTM: Acetylation by CLOCK reduces its binding to glucocorticoid
CC response elements and its transcriptional activity. {ECO:0000250}.
CC -!- PTM: Increased proteasome-mediated degradation in response to
CC glucocorticoids. {ECO:0000250|UniProtKB:P04150}.
CC -!- PTM: Phosphorylated in the absence of hormone; becomes
CC hyperphosphorylated in the presence of glucocorticoid. The Ser-203,
CC Ser-226 and Ser-399-phosphorylated forms are mainly cytoplasmic, and
CC the Ser-211-phosphorylated form is nuclear. Phosphorylation at Ser-211
CC increases transcriptional activity. Phosphorylation at Ser-203, Ser-226
CC and Ser-399 decreases signaling capacity. Phosphorylation at Ser-399
CC may protect from glucocorticoid-induced apoptosis. Phosphorylation at
CC Ser-203 and Ser-211 is not required in regulation of chromosome
CC segregation. May be dephosphorylated by PPP5C, attenuates NR3C1 action.
CC {ECO:0000250|UniProtKB:P04150, ECO:0000250|UniProtKB:P06537}.
CC -!- PTM: Ubiquitinated; restricts glucocorticoid-mediated transcriptional
CC signaling. {ECO:0000250|UniProtKB:P06537}.
CC -!- PTM: Sumoylation at Lys-277 and Lys-293 negatively regulates its
CC transcriptional activity. Sumoylation at Lys-698 positively regulates
CC its transcriptional activity in the presence of RWDD3. Sumoylation at
CC Lys-277 and Lys-293 is dispensable whereas sumoylation at Lys-698 is
CC critical for the stimulatory effect of RWDD3 on its transcriptional
CC activity. Heat shock increases sumoylation in a RWDD3-dependent manner.
CC {ECO:0000250|UniProtKB:P06536}.
CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR3
CC subfamily. {ECO:0000305}.
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DR EMBL; AY161275; AAN75442.1; -; mRNA.
DR RefSeq; NP_001075616.1; NM_001082147.1.
DR AlphaFoldDB; P59667; -.
DR SMR; P59667; -.
DR BioGRID; 1171913; 1.
DR STRING; 9986.ENSOCUP00000010039; -.
DR PRIDE; P59667; -.
DR GeneID; 100008890; -.
DR KEGG; ocu:100008890; -.
DR CTD; 2908; -.
DR eggNOG; KOG3575; Eukaryota.
DR InParanoid; P59667; -.
DR Proteomes; UP000001811; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005815; C:microtubule organizing center; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0016607; C:nuclear speck; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005819; C:spindle; IEA:UniProtKB-SubCell.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB.
DR GO; GO:0004883; F:nuclear glucocorticoid receptor activity; IEA:InterPro.
DR GO; GO:0004879; F:nuclear receptor activity; ISS:UniProtKB.
DR GO; GO:0043565; F:sequence-specific DNA binding; IEA:InterPro.
DR GO; GO:0005496; F:steroid binding; ISS:UniProtKB.
DR GO; GO:1990239; F:steroid hormone binding; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0071385; P:cellular response to glucocorticoid stimulus; ISS:UniProtKB.
DR GO; GO:0071383; P:cellular response to steroid hormone stimulus; ISS:UniProtKB.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR Gene3D; 1.10.565.10; -; 1.
DR Gene3D; 3.30.50.10; -; 1.
DR InterPro; IPR001409; Glcrtcd_rcpt.
DR InterPro; IPR035500; NHR-like_dom_sf.
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 Pfam; PF02155; GCR; 1.
DR Pfam; PF00104; Hormone_recep; 1.
DR Pfam; PF00105; zf-C4; 1.
DR PRINTS; PR00528; GLCORTICOIDR.
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 1: Evidence at protein level;
KW Acetylation; Chromatin regulator; Cytoplasm; Cytoskeleton; DNA-binding;
KW Isopeptide bond; Lipid-binding; Metal-binding; Methylation; Mitochondrion;
KW Nucleus; Phosphoprotein; Receptor; Reference proteome; Steroid-binding;
KW Transcription; Transcription regulation; Ubl conjugation; Zinc;
KW Zinc-finger.
FT CHAIN 1..772
FT /note="Glucocorticoid receptor"
FT /id="PRO_0000053673"
FT DOMAIN 519..753
FT /note="NR LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189"
FT DNA_BIND 416..481
FT /note="Nuclear receptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 416..436
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 452..476
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT REGION 1..415
FT /note="Modulating"
FT REGION 1..22
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 39..82
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 132..186
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 480..772
FT /note="Interaction with CLOCK"
FT /evidence="ECO:0000250"
FT REGION 482..518
FT /note="Hinge"
FT REGION 494..513
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 527..692
FT /note="Interaction with CRY1"
FT /evidence="ECO:0000250"
FT COMPBIAS 167..186
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 25
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:P06537"
FT MOD_RES 47
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 115
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P06537"
FT MOD_RES 136
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 143
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P06537"
FT MOD_RES 203
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 211
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 226
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 307
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P06537"
FT MOD_RES 400
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 475
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 487
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 489
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 490
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT CROSSLNK 258
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT CROSSLNK 277
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT CROSSLNK 277
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT CROSSLNK 293
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT CROSSLNK 293
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT CROSSLNK 414
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P06537"
FT CROSSLNK 698
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250|UniProtKB:P04150"
SQ SEQUENCE 772 AA; 84863 MW; C16D6CF799F83148 CRC64;
MDSKESLSPP GREEVPSSVL RPAERGNVMD LYKTLRGGAP VRVPASSPSL APAAQPDSKQ
QRLAVDFPKG SASNAQQPDL SRAVSLSMGL YMGETETKVM GSDLAFPQQG QTSLSSGETD
FRLLEESIAS LNRSASGADN PRSTAPAAGS AAPTEGFPKT HSDLASERQN PKGQTGGSAG
SAKLHPTDQS TFDILQDLEF SGSPSKDRSE SPWRSDLLMD ENCLLSPLAG EDDPFLLEGN
SSEDCKPLIL PDTKPKIKDN GDLILSNSNN VPLPQVKTEK EDFIELCTPG VIKQEKLGPV
YCQASFSGAN IIGNKISAIS VHGVSTSGGQ MYHYDMNAQQ QEQKPLFNVI PPIPVGSENW
NRCQGSGDDN LTSLGTMNFP GRSVFSNGYS SPGMRPDVSS PPSNSTTAAG PPPKLCLVCS
DEASGCHYGV LTCGSCKVFF KRAVKGQHNY LCAGRNDCII DKIRRKNCPA CRYRKCLQAG
MNLEARKTKK KIKGIQQTST GVSQETSENP SNRTVVPAAL PQLTPTLVSL LEVIEPEVLY
AGYDSSVPDS TWRIMTTLNM LGGRQVIAAV KWAKAIPGFR NLHLDDQMTL LQYSWMFLMA
FALGWRSYKQ SSGNMLCFAP DLVINEQRMT LPYMYDQCKH MLFVSSELKR LQVSYEEYLC
MKTLLLLSTV PKEGLKSQEL FDEIRMTYIK ELGKAIVKRE GNSSQNWQRF YQLTKLLDSM
HEVVENLLHY CFQTFLDKTM SIEFPEMLAE IITNQIPKYS NGNIKKLLFH QK
