GCR_SAISC
ID GCR_SAISC Reviewed; 778 AA.
AC O46567;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 136.
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 Saimiri sciureus (Common squirrel monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Platyrrhini; Cebidae;
OC Saimiriinae; Saimiri.
OX NCBI_TaxID=9521;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND INTERACTION WITH CORTISOL AND
RP DEXAMETHASONE.
RC TISSUE=Brain;
RX PubMed=10775802; DOI=10.1016/s0960-0760(00)00023-6;
RA Patel P.D., Lyons D.M., Zhang Z., Ngo H., Schatzberg A.F.;
RT "Impaired transactivation of the glucocorticoid receptor cloned from the
RT Guyanese squirrel monkey.";
RL J. Steroid Biochem. Mol. Biol. 72:115-123(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND INDUCTION.
RX PubMed=11703081; DOI=10.1006/gcen.2001.7696;
RA Scammell J.G., Denny W.B., Valentine D.L., Smith D.F.;
RT "Overexpression of the FK506-binding immunophilin FKBP51 is the common
RT cause of glucocorticoid resistance in three New World primates.";
RL Gen. Comp. Endocrinol. 124:152-165(2001).
RN [3]
RP TISSUE SPECIFICITY.
RX PubMed=11165305; DOI=10.1016/s0022-3956(00)00035-2;
RA Patel P.D., Lopez J.F., Lyons D.M., Burke S., Wallace M., Schatzberg A.F.;
RT "Glucocorticoid and mineralocorticoid receptor mRNA expression in squirrel
RT monkey brain.";
RL J. Psychiatr. Res. 34:383-392(2000).
RN [4]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF GLN-120; GLN-210;
RP ALA-517; THR-552; ALA-617; SER-619 AND LEU-762.
RX PubMed=15857751; DOI=10.1016/j.jsbmb.2004.11.010;
RA Her S., Patel P.D., Schatzberg A.F., Lyons D.M.;
RT "Mutations in squirrel monkey glucocorticoid receptor impair nuclear
RT translocation.";
RL J. Steroid Biochem. Mol. Biol. 94:319-326(2005).
CC -!- FUNCTION: Receptor for glucocorticoids (GC) (PubMed:10775802,
CC PubMed:11703081). Has a dual mode of action: as a transcription factor
CC that binds to glucocorticoid response elements (GRE), both for nuclear
CC and mitochondrial DNA, and as a modulator of other transcription
CC factors (PubMed:10775802, PubMed:11703081, PubMed:15857751). Affects
CC inflammatory responses, cellular proliferation and differentiation in
CC target tissues. Involved in chromatin remodeling (By similarity). Plays
CC a role in rapid mRNA degradation by binding to the 5' UTR of target
CC mRNAs and interacting with PNRC2 in a ligand-dependent manner which
CC recruits the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A,
CC leading to RNA decay (By similarity). Could act as a coactivator for
CC STAT5-dependent transcription upon growth hormone (GH) stimulation and
CC could reveal an essential role of hepatic GR in the control of body
CC growth (By similarity). Mediates glucocorticoid-induced apoptosis (By
CC similarity). Promotes accurate chromosome segregation during mitosis
CC (By similarity). May act as a tumor suppressor (By similarity). May
CC play a negative role in adipogenesis through the regulation of
CC lipolytic and antilipogenic gene expression (By similarity).
CC {ECO:0000250|UniProtKB:P04150, ECO:0000250|UniProtKB:P06537,
CC ECO:0000269|PubMed:10775802, ECO:0000269|PubMed:11703081,
CC ECO:0000269|PubMed:15857751}.
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. Upon ligand binding FKBP5
CC dissociates from the complex and FKBP4 takes its place, thereby linking
CC the complex to dynein and mediating transport to the nucleus, where the
CC complex dissociates. Probably forms a complex composed of chaperones
CC HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein
CC TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-
CC chaperones STIP1/HOP and PTGES3/p23. Directly interacts with UNC45A.
CC Binds to DNA as a homodimer, and as heterodimer with NR3C2 or the
CC retinoid X receptor. Binds STAT5A and STAT5B homodimers and
CC heterodimers. Interacts with NRIP1, POU2F1, POU2F2 and TRIM28.
CC Interacts with several coactivator complexes, including the SMARCA4
CC complex, CREBBP/EP300, TADA2L (Ada complex) and p160 coactivators such
CC as NCOA2 and NCOA6. Interaction with BAG1 inhibits transactivation.
CC Interacts with HEXIM1 and TGFB1I1. Interacts with NCOA1. Interacts with
CC NCOA3, SMARCA4, SMARCC1, SMARCD1, and SMARCE1. Interacts with CLOCK,
CC CRY1 and CRY2 in a ligand-dependent fashion. Interacts with CIART.
CC Interacts with RWDD3. Interacts with UBE2I/UBC9 and this interaction is
CC enhanced in the presence of RWDD3. Interacts with GRIP1. 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). Directly interacts with PNRC2 to attract and form a
CC complex with UPF1 and DCP1A; the interaction leads to rapid mRNA
CC degradation. Interacts with GSK3B. Interacts with FNIP1 and FNIP2.
CC Interacts (via C-terminus) with HNRNPU (via C-terminus). Interacts with
CC MCM3AP (By similarity). Interacts (via domain NR LBD) with HSP90AA1 and
CC HSP90AB1 (By similarity). In the absence of hormonal ligand, interacts
CC with TACC1 (By similarity). {ECO:0000250|UniProtKB:P04150,
CC ECO:0000250|UniProtKB:P06536, ECO:0000250|UniProtKB:P06537}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15857751}. Nucleus
CC {ECO:0000269|PubMed:15857751}. 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 (PubMed:15857751). 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 ECO:0000269|PubMed:15857751}.
CC -!- TISSUE SPECIFICITY: Expressed in brain. Regions of high expression
CC include CA1 and CA2 of hippocampus, dentate gyrus, paraventricular
CC hypothalamus, lateral geniculate, lateral-medial amygdala, and
CC cerebellum. In the cerebral cortex, laminar patterns of expression were
CC apparent in all cortical layers, particularly the pyramidal cell-rich
CC layers II/III and V. {ECO:0000269|PubMed:11165305}.
CC -!- INDUCTION: Binding activity reduced by FKBP5.
CC {ECO:0000269|PubMed:11703081}.
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-404-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-404 decreases signaling capacity. Phosphorylation at Ser-404
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-704 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-704 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}.
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; AF041834; AAB97369.1; -; mRNA.
DR EMBL; AF337042; AAK01303.1; -; mRNA.
DR AlphaFoldDB; O46567; -.
DR SMR; O46567; -.
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; Steroid-binding; Transcription;
KW Transcription regulation; Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1..778
FT /note="Glucocorticoid receptor"
FT /id="PRO_0000053676"
FT DOMAIN 525..759
FT /note="NR LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189"
FT DNA_BIND 421..486
FT /note="Nuclear receptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 421..441
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 457..481
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT REGION 1..420
FT /note="Modulating"
FT REGION 1..22
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 130..182
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 394..415
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 485..778
FT /note="Interaction with CLOCK"
FT /evidence="ECO:0000250"
FT REGION 487..524
FT /note="Hinge"
FT REGION 533..698
FT /note="Interaction with CRY1"
FT /evidence="ECO:0000250"
FT COMPBIAS 130..149
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 162..182
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 8
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 23
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:P06537"
FT MOD_RES 45
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 113
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P06537"
FT MOD_RES 134
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 141
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 267
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 404
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 480
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 492
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 494
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MOD_RES 495
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 419
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P06537"
FT CROSSLNK 704
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT MUTAGEN 120
FT /note="Q->L: No effect on nuclear translocation or
FT transactivation."
FT /evidence="ECO:0000269|PubMed:15857751"
FT MUTAGEN 210
FT /note="Q->E: No effect on nuclear translocation or
FT transactivation."
FT /evidence="ECO:0000269|PubMed:15857751"
FT MUTAGEN 517
FT /note="A->G: No effect on nuclear translocation."
FT /evidence="ECO:0000269|PubMed:15857751"
FT MUTAGEN 552
FT /note="T->S: Increased nuclear translocation; when
FT associated with S-617 and A-619."
FT /evidence="ECO:0000269|PubMed:15857751"
FT MUTAGEN 617
FT /note="A->S: Increased nuclear translocation. when
FT associated with S-552 and A-619."
FT /evidence="ECO:0000269|PubMed:15857751"
FT MUTAGEN 619
FT /note="S->A: Increased nuclear translocation. when
FT associated with S-552 and S-617."
FT /evidence="ECO:0000269|PubMed:15857751"
FT MUTAGEN 762
FT /note="L->I: No effect on nuclear translocation."
FT /evidence="ECO:0000269|PubMed:15857751"
FT CONFLICT 498
FT /note="Missing (in Ref. 2; AAK01303)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 778 AA; 85738 MW; 721B8203939D1389 CRC64;
MDSKESLTPG KEENPSSVLT QERGNVMDFC KILRGGATLK VSVSSTSLAA ASQSDSKQQR
LLVDFPKGSV SNAQQPDLSK AVSLSMGLYM GETETKVMGN DLGFPQQGQI SLSSGETDLQ
LLEESIANLN RSTSVPENPK SSASSSVSAA PKEKEFPKTH SDVSSEQQNL KGQTGTNGGN
VKLYTADQST FDILQDLEFS SGSPGKETNQ SPWKSDLLID ENCLLSPLAG EEDSFLLEGN
SNEDCKPLIL PDTKPKIKDN GDLVLSSSSN VTLPQVKTEK EDFIELCTPG VIKQEKLSTV
YCQASFPGAN IIGNKMSAIS IHGVSTSGGQ MYHYDMNTAS LSQQQDQKPI FNVIPPIPVG
SENWNRCQGS GDDNLTSLGT LNFPGRTVFS NGYSSPSMRP DVSSPPSSSS TATTGPPPKL
CLVCSDEASG CHYGVLTCGS CKVFFKRAVE GQHNYLCAGR NDCIIDKIRR KNCPACRYRK
CLQAGMNLEA RKTKKKIIKG IQQATTGVSQ ETSENPANKT IVPATLPQLT PTLVSLLEVI
EPEVLYAGYD STVPDSTWRI MTTLNMLGGR QVIAAVKWAK AIPGFRNLHL DDQMTLLQYS
WMFLMAFALG WRSYRQASSN LLCFAPDLII NEQRMTLPCM YDQCKHMLYV SSELHRLQVS
YEEYLCMKTL LLLSSVPKDG LKSQELFDEI RMTYIKELGK AIVKREGNSS QNWQRFYQLT
KLLDSMHEVV ENLLNYCFQT FLDKTMSIEF PEMLAEIITN QLPKYSNGNI KKLLFHQK
