GCR_SAGOE
ID GCR_SAGOE Reviewed; 777 AA.
AC P79269;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1997, sequence version 1.
DT 03-AUG-2022, entry version 138.
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 Saguinus oedipus (Cotton-top tamarin).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Platyrrhini; Cebidae;
OC Callitrichinae; Saguinus.
OX NCBI_TaxID=9490;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9024238; DOI=10.1210/jcem.82.2.3755;
RA Reynolds P.D., Pittler S.J., Scammell J.G.;
RT "Cloning and expression of the glucocorticoid receptor from the squirrel
RT monkey (Saimiri boliviensis boliviensis), a glucocorticoid-resistant
RT primate.";
RL J. Clin. Endocrinol. Metab. 82:465-472(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. 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: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-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-703 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-703 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; U87953; AAC51133.1; -; mRNA.
DR PDB; 6BSE; X-ray; 2.35 A; A/B=420-505.
DR PDB; 6BSF; X-ray; 2.40 A; A/B=419-505.
DR PDBsum; 6BSE; -.
DR PDBsum; 6BSF; -.
DR AlphaFoldDB; P79269; -.
DR SMR; P79269; -.
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 3D-structure; Acetylation; Chromatin regulator; Cytoplasm; Cytoskeleton;
KW DNA-binding; Isopeptide bond; Lipid-binding; Metal-binding; Methylation;
KW Mitochondrion; Nucleus; Phosphoprotein; Receptor; Steroid-binding;
KW Transcription; Transcription regulation; Ubl conjugation; Zinc;
KW Zinc-finger.
FT CHAIN 1..777
FT /note="Glucocorticoid receptor"
FT /id="PRO_0000053674"
FT DOMAIN 524..758
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..183
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..777
FT /note="Interaction with CLOCK"
FT /evidence="ECO:0000250"
FT REGION 487..523
FT /note="Hinge"
FT REGION 532..697
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..183
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 703
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250|UniProtKB:P04150"
FT TURN 422..424
FT /evidence="ECO:0007829|PDB:6BSE"
FT STRAND 430..432
FT /evidence="ECO:0007829|PDB:6BSE"
FT STRAND 435..437
FT /evidence="ECO:0007829|PDB:6BSE"
FT HELIX 439..450
FT /evidence="ECO:0007829|PDB:6BSE"
FT STRAND 458..461
FT /evidence="ECO:0007829|PDB:6BSE"
FT TURN 467..472
FT /evidence="ECO:0007829|PDB:6BSE"
FT HELIX 474..483
FT /evidence="ECO:0007829|PDB:6BSE"
SQ SEQUENCE 777 AA; 85593 MW; E4F9D24AEC5F9D58 CRC64;
MDSKESLTPG KEENPSSVLT QERGNVMDFC KILRGGATLK VSVSSTSLAA ASQSDSKQQR
LLVDFPKGSV SNAQQPDLSK AVSLSMGLYM GETETKVMGN DLGFPQQGQI SLSSGETDLQ
LLEESIANLN RSTSVPENPK SSASSSVSAA PKEKEFPKTH SDVSSEQQNL KGQTGTNGGN
AKLCTADQST FDILQDLEFS SGSPGKETNQ SPWRSDLLID 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 RKTKKKIKGI QQATTGVSQE TSENPANKTI VPATLPQLTP TLVSLLEVIE
PEVLYAGYDS TVPDSTWRIM TTLNMLGGRQ VIAAVKWAKA IPGFRNLHLD DQMTLLQYSW
MFLMAFALGW RSYRQASSNL LCFAPDLIIN EQRMTLPCMY DQCKHMLYVS SELHRLQVSY
EEYLCMKTLL LLSSVPKDGL KSQELFDEIR MTYIKELGKA IVKREGNSSQ NWQRFYQLTK
LLDSMHEVVE NLLNYCFQTF LDKTMSIEFP EMLAEIITNQ LPKYSNGNIR KLLFHQK
