Swiss-Prot entry
ID GCR_HUMAN STANDARD; PRT; 777 AA.
AC P04150; P04151;
DT 01-NOV-1986 (Rel. 03, Created)
DT 01-NOV-1986 (Rel. 03, Last sequence update)
DT 01-MAY-2005 (Rel. 47, Last annotation update)
DE Glucocorticoid receptor (GR).
GN Name=NR3C1; Synonyms=GRL;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ALPHA AND BETA).
RC TISSUE=Fibroblast;
RX MEDLINE=86092206; PubMed=2867473 [NCBI, ExPASy, EBI, Israel, Japan];
RA Hollenberg S.M., Weinberger C., Ong E.S., Cerelli G., Oro A., Lebo R.,
RA Thompson E.B., Rosenfeld M.G., Evans R.M.;
RT "Primary structure and expression of a functional human glucocorticoid
RT receptor cDNA.";
RL Nature 318:635-641(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS ALPHA AND BETA).
RX MEDLINE=91201378; PubMed=1707881 [NCBI, ExPASy, EBI, Israel, Japan];
RA Encio I.J., Detera-Wadleigh S.D.;
RT "The genomic structure of the human glucocorticoid receptor.";
RL J. Biol. Chem. 266:7182-7188(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM GAMMA).
RA Munroe D.G., Pang J., Taylor G.R., Lau C., Plante R.K., Zhou L.;
RT "Alternative splicing within the DNA binding domain creates a novel
RT isoform of the human glucocorticoid receptor.";
RL Submitted (SEP-1993) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM ALPHA), AND VARIANTS LYS-23
RP AND VAL-65.
RA Rieder M.J., Livingston R.J., Daniels M.R., Chung M.-W.,
RA Miyamoto K.E., Nguyen C.P., Nguyen D.A., Poel C.L., Robertson P.D.,
RA Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A.;
RT "NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department
RT of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu).";
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA).
RC TISSUE=Placenta;
RX MEDLINE=22388257; PubMed=12477932 [NCBI, ExPASy, EBI, Israel, Japan]; DOI=10.1073/pnas.242603899;
RA Strausberg R.L., Feingold E.A., Grouse L.H., Derge J.G.,
RA Klausner R.D., Collins F.S., Wagner L., Shenmen C.M., Schuler G.D.,
RA Altschul S.F., Zeeberg B., Buetow K.H., Schaefer C.F., Bhat N.K.,
RA Hopkins R.F., Jordan H., Moore T., Max S.I., Wang J., Hsieh F.,
RA Diatchenko L., Marusina K., Farmer A.A., Rubin G.M., Hong L.,
RA Stapleton M., Soares M.B., Bonaldo M.F., Casavant T.L., Scheetz T.E.,
RA Brownstein M.J., Usdin T.B., Toshiyuki S., Carninci P., Prange C.,
RA Raha S.S., Loquellano N.A., Peters G.J., Abramson R.D., Mullahy S.J.,
RA Bosak S.A., McEwan P.J., McKernan K.J., Malek J.A., Gunaratne P.H.,
RA Richards S., Worley K.C., Hale S., Garcia A.M., Gay L.J., Hulyk S.W.,
RA Villalon D.K., Muzny D.M., Sodergren E.J., Lu X., Gibbs R.A.,
RA Fahey J., Helton E., Ketteman M., Madan A., Rodrigues S., Sanchez A.,
RA Whiting M., Madan A., Young A.C., Shevchenko Y., Bouffard G.G.,
RA Blakesley R.W., Touchman J.W., Green E.D., Dickson M.C.,
RA Rodriguez A.C., Grimwood J., Schmutz J., Myers R.M.,
RA Butterfield Y.S.N., Krzywinski M.I., Skalska U., Smailus D.E.,
RA Schnerch A., Schein J.E., Jones S.J.M., Marra M.A.;
RT "Generation and initial analysis of more than 15,000 full-length human
RT and mouse cDNA sequences.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:16899-16903(2002).
RN [6]
RP NUCLEOTIDE SEQUENCE OF 1-394.
RX MEDLINE=91224961; PubMed=2026589 [NCBI, ExPASy, EBI, Israel, Japan];
RA Leclerc S., Xie B.X., Roy R., Govindan M.V.;
RT "Purification of a human glucocorticoid receptor gene promoter-binding
RT protein. Production of polyclonal antibodies against the purified
RT factor.";
RL J. Biol. Chem. 266:8711-8719(1991).
RN [7]
RP NUCLEOTIDE SEQUENCE OF 1-394.
RX PubMed=1958537 [NCBI, ExPASy, EBI, Israel, Japan];
RA Govindan M.V., Pothier F., Leclerc S., Palaniswami R., Xie B.;
RT "Human glucocorticoid receptor gene promotor-homologous down
RT regulation.";
RL J. Steroid Biochem. Mol. Biol. 40:317-323(1991).
RN [8]
RP NUCLEOTIDE SEQUENCE OF 396-630.
RA Kimmerly W., Bondoc M., Cheng J., Connolly K.S., Gunning K.M.,
RA Kadner K., Miguel T., Miller C., Pitluck S., Pollard M., Rojeski H.,
RA Subramanian S., Martin C.H.;
RL Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP ALTERNATIVE INITIATION, AND MUTAGENESIS OF MET-1 AND MET-27.
RX MEDLINE=21329577; PubMed=11435610 [NCBI, ExPASy, EBI, Israel, Japan]; DOI=10.1210/me.15.7.1093;
RA Yudt M.R., Cidlowski J.A.;
RT "Molecular identification and characterization of A and B forms of the
RT glucocorticoid receptor.";
RL Mol. Endocrinol. 15:1093-1103(2001).
RN [10]
RP DOMAINS.
RX MEDLINE=86092211; PubMed=3841189 [NCBI, ExPASy, EBI, Israel, Japan];
RA Weinberger C., Hollenberg S.M., Rosenfeld M.G., Evans R.M.;
RT "Domain structure of human glucocorticoid receptor and its
RT relationship to the v-erb-A oncogene product.";
RL Nature 318:670-672(1985).
RN [11]
RP INTERACTIONS WITH TADA2L AND THE ADA COMPLEX, AND MUTAGENESIS OF
RP PHE-191; ILE-193; LEU-194; LEU-197; TRP-213; LEU-224; LEU-225; PHE-235
RP AND LEU-236.
RX MEDLINE=97299656; PubMed=9154805 [NCBI, ExPASy, EBI, Israel, Japan];
RA Henriksson A., Almloef T., Ford J., McEwan I.J., Gustafsson J.-A.,
RA Wright A.P.H.;
RT "Role of the Ada adaptor complex in gene activation by the
RT glucocorticoid receptor.";
RL Mol. Cell. Biol. 17:3065-3073(1997).
RN [12]
RP INTERACTIONS WITH THE SMARCA4 COMPLEX; NCOA1; NCOA2 AND THE
RP CREBBP/EP300 COMPLEX.
RX MEDLINE=98250578; PubMed=9590696 [NCBI, ExPASy, EBI, Israel, Japan]; DOI=10.1038/30032;
RA Fryer C.J., Archer T.K.;
RT "Chromatin remodelling by the glucocorticoid receptor requires the
RT BRG1 complex.";
RL Nature 393:88-91(1998).
RN [13]
RP INTERACTION WITH BAG1.
RX MEDLINE=99408777; PubMed=10477749 [NCBI, ExPASy, EBI, Israel, Japan]; DOI=10.1083/jcb.146.5.929;
RA Schneikert J., Huebner S., Martin E., Cato A.B.C.;
RT "A nuclear action of the eukaryotic cochaperone RAP46 in
RT downregulation of glucocorticoid receptor activity.";
RL J. Cell Biol. 146:929-940(1999).
RN [14]
RP ALTERNATIVE SPLICING (ISOFORM GAMMA).
RX MEDLINE=20030962; PubMed=10566686 [NCBI, ExPASy, EBI, Israel, Japan]; DOI=10.1210/jc.84.11.4283;
RA Rivers C., Levy A., Hancock J., Lightman S., Norman M.;
RT "Insertion of an amino acid in the DNA-binding domain of the
RT glucocorticoid receptor as a result of alternative splicing.";
RL J. Clin. Endocrinol. Metab. 84:4283-4286(1999).
RN [15]
RP ALTERNATIVE SPLICING (ISOFORMS GP-P AND GP-A).
RX PubMed=8358712 [NCBI, ExPASy, EBI, Israel, Japan];
RA Moalli P.A., Pillay S., Krett N.L., Rosen S.T.;
RT "Alternatively spliced glucocorticoid receptor messenger RNAs in
RT glucocorticoid-resistant human multiple myeloma cells.";
RL Cancer Res. 53:3877-3879(1993).
RN [16]
RP REVIEW ON ALTERNATIVE SPLICING, ALTERNATIVE INITIATION, AND
RP POSTTRANSLATION MODIFICATIONS.
RX PubMed=15265776 [NCBI, ExPASy, EBI, Israel, Japan];
RA Lu N.Z., Cidlowski J.A.;
RT "The origin and functions of multiple human glucocorticoid receptor
RT isoforms.";
RL Ann. N. Y. Acad. Sci. 1024:102-123(2004).
RN [17]
RP INTERACTION WITH NCOA6.
RX MEDLINE=20325329; PubMed=10866662 [NCBI, ExPASy, EBI, Israel, Japan];
RX DOI=10.1128/MCB.20.14.5048-5063.2000;
RA Mahajan M.A., Samuels H.H.;
RT "A new family of nuclear receptor coregulators that integrates nuclear
RT receptor signaling through CBP.";
RL Mol. Cell. Biol. 20:5048-5063(2000).
RN [18]
RP GLUCOCORTICOID-MEDIATED DOWN-REGULATION.
RX MEDLINE=21560972; PubMed=11555652 [NCBI, ExPASy, EBI, Israel, Japan]; DOI=10.1074/jbc.M106033200;
RA Wallace A.D., Cidlowski J.A.;
RT "Proteasome-mediated glucocorticoid receptor degradation restricts
RT transcriptional signaling by glucocorticoids.";
RL J. Biol. Chem. 276:42714-42721(2001).
RN [19]
RP SUMOYLATION, AND MUTAGENESIS OF LYS-277; LYS-293 AND LYS-703.
RX MEDLINE=22280317; PubMed=12144530 [NCBI, ExPASy, EBI, Israel, Japan]; DOI=10.1042/BJ20021085;
RA Tian S., Poukka H., Palvimo J.J., Jaenne O.A.;
RT "Small ubiquitin-related modifier-1 (SUMO-1) modification of the
RT glucocorticoid receptor.";
RL Biochem. J. 367:907-911(2002).
RN [20]
RP PHOSPHORYLATION SITES SER-203 AND SER-211.
RX MEDLINE=22113030; PubMed=12000743 [NCBI, ExPASy, EBI, Israel, Japan]; DOI=10.1074/jbc.M110530200;
RA Wang Z., Frederick J., Garabedian M.J.;
RT "Deciphering the phosphorylation 'code' of the glucocorticoid receptor
RT in vivo.";
RL J. Biol. Chem. 277:26573-26580(2002).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 521-777 OF MUTANT SER-602 IN
RP COMPLEX WITH NCOA2; DEXAMETHASONE AND RU-486, AND MUTAGENESIS OF
RP ARG-585; ASP-590; PHE-602; PRO-625 AND ILE-628.
RX PubMed=12151000 [NCBI, ExPASy, EBI, Israel, Japan];
RA Bledsoe R.K., Montana V.G., Stanley T.B., Delves C.J., Apolito C.J.,
RA McKee D.D., Consler T.G., Parks D.J., Stewart E.L., Willson T.M.,
RA Lambert M.H., Moore J.T., Pearce K.H., Xu H.E.;
RT "Crystal structure of the glucocorticoid receptor ligand binding
RT domain reveals a novel mode of receptor dimerization and coactivator
RT recognition.";
RL Cell 110:93-105(2002).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 500-777 OF MUTANT SER-602 IN
RP COMPLEX WITH COACTIVATOR PEPTIDE; DEXAMETHASONE AND WITH RU-486.
RX PubMed=12686538 [NCBI, ExPASy, EBI, Israel, Japan]; DOI=10.1074/jbc.M212711200;
RA Kauppi B., Jakob C., Faernegaardh M., Yang J., Ahola H., Alarcon M.,
RA Calles K., Engstrom O., Harlan J., Muchmore S., Ramqvist A.-K.,
RA Thorell S., Oehman L., Greer J., Gustafsson J.-A., Carlstedt-Duke J.,
RA Carlquist M.;
RT "The three-dimensional structures of antagonistic and agonistic forms
RT of the glucocorticoid receptor ligand-binding domain: RU-486 induces a
RT transconformation that leads to active antagonism.";
RL J. Biol. Chem. 278:22748-22754(2003).
RN [23]
RP CHARACTERIZATION OF VARIANT GLUCOCORTICOID RESISTANCE VAL-641.
RX MEDLINE=91123468; PubMed=1704018 [NCBI, ExPASy, EBI, Israel, Japan];
RA Hurley D.M., Accili D., Stratakis C.A., Karl M., Vamvakopoulos N.,
RA Rorer E., Constantine K., Taylor S.I., Chrousos G.P.;
RT "Point mutation causing a single amino acid substitution in the
RT hormone binding domain of the glucocorticoid receptor in familial
RT glucocorticoid resistance.";
RL J. Clin. Invest. 87:680-686(1991).
RN [24]
RP VARIANTS TYR-421 AND PHE-753.
RX MEDLINE=93364907; PubMed=8358735 [NCBI, ExPASy, EBI, Israel, Japan];
RA Powers J.H., Hillmann A.G., Tang D.C., Harmon J.M.;
RT "Cloning and expression of mutant glucocorticoid receptors from
RT glucocorticoid-sensitive and -resistant human leukemic cells.";
RL Cancer Res. 53:4059-4065(1993).
RN [25]
RP VARIANT SER-363.
RX MEDLINE=93187003; PubMed=8445027 [NCBI, ExPASy, EBI, Israel, Japan]; DOI=10.1210/jc.76.3.683;
RA Karl M., Lamberts S.W.J., Detera-Wadleigh S.D., Encio I.J.,
RA Stratakis C.A., Hurley D.M., Accili D., Chrousos G.P.;
RT "Familial glucocorticoid resistance caused by a splice site deletion
RT in the human glucocorticoid receptor gene.";
RL J. Clin. Endocrinol. Metab. 76:683-689(1993).
RN [26]
RP VARIANT GLUCOCORTICOID RESISTANCE ILE-729.
RX MEDLINE=93253031; PubMed=7683692 [NCBI, ExPASy, EBI, Israel, Japan];
RA Malchoff D.M., Brufsky A., Reardon G., McDermott P., Javier E.C.,
RA Bergh C.H., Rowe D., Malchoff C.D.;
RT "A mutation of the glucocorticoid receptor in primary cortisol
RT resistance.";
RL J. Clin. Invest. 91:1918-1925(1993).
RN [27]
RP VARIANT PHE-753.
RX MEDLINE=93302771; PubMed=8316249 [NCBI, ExPASy, EBI, Israel, Japan]; DOI=10.1210/me.7.5.631;
RA Ashraf J., Thompson E.B.;
RT "Identification of the activation-labile gene: a single point mutation
RT in the human glucocorticoid receptor presents as two distinct receptor
RT phenotypes.";
RL Mol. Endocrinol. 7:631-642(1993).
RN [28]
RP VARIANTS LYS-23 AND SER-363.
RX MEDLINE=97295085; PubMed=9150737 [NCBI, ExPASy, EBI, Israel, Japan];
RA Koper J.W., Stolk R.P., de Lange P., Huizenga N.A.T.M., Molijn G.-J.,
RA Pols H.A.P., Grobbee D.E., Karl M., de Jong F.H., Brinkmann A.O.,
RA Lamberts S.W.J.;
RT "Lack of association between five polymorphisms in the human
RT glucocorticoid receptor gene and glucocorticoid resistance.";
RL Hum. Genet. 99:663-668(1997).
RN [29]
RP VARIANTS LYS-23; VAL-65 AND SER-363.
RX MEDLINE=99318093; PubMed=10391209 [NCBI, ExPASy, EBI, Israel, Japan]; DOI=10.1038/10290;
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RT "Characterization of single-nucleotide polymorphisms in coding regions
RT of human genes.";
RL Nat. Genet. 22:231-238(1999).
RN [30]
RP ERRATUM.
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RL Nat. Genet. 23:373-373(1999).
RN [31]
RP VARIANTS LYS-23; LEU-29; PHE-112; ASN-233 AND SER-363.
RX MEDLINE=20357652; PubMed=10898924 [NCBI, ExPASy, EBI, Israel, Japan];
RX DOI=10.1002/1096-8628(20000612)96:3<412::AID-AJMG33>3.0.CO;2-C;
RA Feng J., Zheng J., Bennett W.P., Heston L.L., Jones I.R., Craddock N.,
RA Sommer S.S.;
RT "Five missense variants in the amino-terminal domain of the
RT glucocorticoid receptor: no association with puerperal psychosis or
RT schizophrenia.";
RL Am. J. Med. Genet. 96:412-417(2000).
RN [32]
RP VARIANTS GLUCOCORTICOID RESISTANCE HIS-477 AND SER-679.
RX MEDLINE=21473978; PubMed=11589680 [NCBI, ExPASy, EBI, Israel, Japan];
RA Ruiz M., Lind U., Gaafvels M., Eggertsen G., Carlstedt-Duke J.,
RA Nilsson L., Holtmann M., Stierna P., Wikstroem A.-C., Werner S.;
RT "Characterization of two novel mutations in the glucocorticoid
RT receptor gene in patients with primary cortisol resistance.";
RL Clin. Endocrinol. (Oxf.) 55:363-371(2001).
RN [33]
RP CHARACTERIZATION OF VARIANT GLUCOCORTICOID RESISTANCE ASN-559.
RX MEDLINE=21558592; PubMed=11701741 [NCBI, ExPASy, EBI, Israel, Japan]; DOI=10.1210/jc.86.11.5600;
RA Kino T., Stauber R.H., Resau J.H., Pavlakis G.N., Chrousos G.P.;
RT "Pathologic human GR mutant has a transdominant negative effect on the
RT wild-type GR by inhibiting its translocation into the nucleus:
RT importance of the ligand-binding domain for intracellular GR
RT trafficking.";
RL J. Clin. Endocrinol. Metab. 86:5600-5608(2001).
RN [34]
RP VARIANT GLUCOCORTICOID RESISTANCE MET-747, AND ALTERED INTERACTION
RP WITH THE COACTIVATOR NCOA2.
RX MEDLINE=22045363; PubMed=12050230 [NCBI, ExPASy, EBI, Israel, Japan]; DOI=10.1210/jc.87.6.2658;
RA Vottero A., Kino T., Combe H., Lecomte P., Chrousos G.P.;
RT "A novel, C-terminal dominant negative mutation of the GR causes
RT familial glucocorticoid resistance through abnormal interactions with
RT p160 steroid receptor coactivators.";
RL J. Clin. Endocrinol. Metab. 87:2658-2667(2002).
CC -!- FUNCTION: Receptor for glucocorticoids (GC). Has a dual mode of
CC action: as a transcription factor that binds to glucocorticoid
CC response elements (GRE) and as a modulator of other transcription
CC factors. Affects inflammatory responses, cellular proliferation
CC and differentiation in target tissues.
CC -!- SUBUNIT: Heteromultimeric cytoplasmic complex with HSP90, HSP70,
CC and FKBP5 or another immunophilin, or the immunophilin homolog
CC PPP5C. Upon ligand binding FKBP5 dissociates from the complex and
CC FKBP4 takes its place, thereby linking the complex to dynein and
CC mediating transport to the nucleus, where the complex dissociates
CC (By similarity). Binds to DNA as a homodimer, and as a heterodimer
CC with NR3C2 or the retinoid X receptor. Binds STAT5A and STAT5B
CC homodimers and heterodimers. Interacts with NRIP1, POU2F1, POU2F2
CC and TRIM28 (By similarity). Interacts with several coactivator
CC complexes, including the SMARCA4 complex, CREBBP/EP300, TADA2L and
CC p160 coactivators such as NCOA2 and NCOA6. Interaction with BAG1
CC inhibits transactivation.
CC -!- SUBCELLULAR LOCATION: Cytoplasmic in the absence of ligand;
CC nuclear after ligand-binding.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Comment=Additional isoforms seem to exist;
CC Name=Alpha; Synonyms=Alpha-A;
CC IsoId=P04150-1; Sequence=Displayed;
CC Note=Predominant physiological form. Isoform Alpha-B is produced
CC by alternative initiation at Met-27 of isoform Alpha. Both
CC isoforms exhibit similar subcellular location and nuclear
CC translocation after ligand activation. Isoform Alpha-B appears
CC to be more susceptible to degradation, at least when expressed
CC in mammalian cells, but more effective in transcriptional
CC activation and not in transrepression;
CC Name=Beta; Synonyms=Beta-A;
CC IsoId=P04150-2; Sequence=VSP_003703;
CC Note=No hormone-binding activity. Widely expressed at low level.
CC Localized largely in the nucleus. Isoform Beta-B is produced by
CC alternative initiation at Met-27 of isoform Beta;
CC Name=Gamma; Synonyms=Alpha-2, Gamma-A, Alpha-2-A;
CC IsoId=P04150-3; Sequence=VSP_007363;
CC Note=Lower transcriptional activity. Expressed at low level;
CC Name=GR-P;
CC IsoId=P04150-4; Sequence=Not described;
CC Note=Encoded by exons 2-7 plus several basepairs from the
CC subsequent intron region. Lacks the ligand binding domain.
CC Accounts for up to 10-20% of mRNAs;
CC Name=GR-A;
CC IsoId=P04150-5; Sequence=VSP_013340;
CC Note=Lacks exons 5, 6 and 7. Found in glucocorticoid-resistant
CC myeloma patients;
CC Event=Alternative initiation;
CC Comment=At least 4 isoforms, Alpha (shown here), Alpha-B, Beta
CC and Beta-B, are produced by alternative initiation at Met-1 and
CC Met-27. The existence of isoform Alpha and isoform Alpha-B has
CC been proved by mutagenesis. As the sequence environment of the 2
CC potential ATG initiator codons is the same for the other
CC isoforms, alternative initiation of translation could also occur
CC on these transcripts;
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- DOMAIN: Composed of three domains: a modulating N-terminal domain,
CC a DNA-binding domain and a C-terminal steroid-binding domain.
CC -!- PTM: Increased proteasome-mediated degradation in response to
CC glucocorticoids.
CC -!- PTM: Phosphorylated in the absence of hormone; becomes
CC hyperphosphorylated in the presence of glucocorticoid. The Ser-
CC 203-phosphorylated form is mainly cytoplasmic, and the Ser-211-
CC phosphorylated form is nuclear. Transcriptional activity
CC correlates with the amount of phosphorylation at Ser-211.
CC -!- PTM: Sumoylated; this reduces transcription transactivation.
CC -!- DISEASE: Defects in NR3C1 are a cause of glucocorticoid resistance
CC [MIM:138040]; also known as cortisol resistance. It is a
CC hypertensive, hyperandrogenic disorder characterized by increased
CC serum cortisol concentrations. Inheritance is autosomal dominant.
CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR3
CC subfamily.
CC -!- SIMILARITY: Contains 1 nuclear receptor DNA-binding domain.
CC --------------------------------------------------------------------------
CC This Swiss-Prot entry is copyright. It is produced through a collaboration
CC between the Swiss Institute of Bioinformatics and the EMBL outstation -
CC the European Bioinformatics Institute. There are no restrictions on its
CC use as long as its content is in no way modified and this statement is not
CC removed.
CC --------------------------------------------------------------------------
DR EMBL; X03225; CAA26976.1; -. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; X03348; CAA27054.1; -. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U80946; AAB64353.1; -. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U78506; AAB64353.1; JOINED. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U78507; AAB64353.1; JOINED. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U78508; AAB64353.1; JOINED. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U78509; AAB64353.1; JOINED. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U78510; AAB64353.1; JOINED. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U78511; AAB64353.1; JOINED. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U78512; AAB64353.1; JOINED. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U80947; AAB64354.1; -. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U78506; AAB64354.1; JOINED. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U78507; AAB64354.1; JOINED. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U78508; AAB64354.1; JOINED. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U78509; AAB64354.1; JOINED. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U78510; AAB64354.1; JOINED. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U78511; AAB64354.1; JOINED. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U78512; AAB64354.1; JOINED. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; U01351; AAA16603.1; -. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; AY436590; AAQ97180.1; -. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; BC015610; AAH15610.1; -. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; M69104; AAA88049.1; -. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; M73816; AAA53151.1; -. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; S68378; AAB20466.1; -. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR EMBL; AC005601; AAC34207.1; -. [EMBL / GenBank / DDBJ] [CoDingSequence]
DR PIR; A93370; QRHUGA.
DR PIR; B93370; QRHUGB.
DR PDB; 1M2Z; X-ray; A/D=521-777. [ExPASy / RCSB]
DR PDB; 1NHZ; X-ray; A=500-777. [ExPASy / RCSB]
DR PDB; 1P93; X-ray; A/B/C/D=500-777. [ExPASy / RCSB]
DR SMR; P04150; 417-491.
DR IntAct; P04150; -.
DR TRANSFAC; T00337; -.
DR TRANSFAC; T01920; -.
DR Ensembl; ENSG00000113580; Homo_sapiens
DR Genew; HGNC:7978; NR3C1.
DR CleanEx; HGNC:7978; NR3C1.
DR H-InvDB; HIX0005273; -.
DR MIM; 138040; -. [NCBI / EBI]
DR GeneCards; NR3C1.
DR GeneLynx; NR3C1.
DR GenAtlas; NR3C1.
DR SOURCE; NR3C1.
DR GO; GO:0005737; C:cytoplasm; TAS.
DR GO; GO:0005759; C:mitochondrial matrix; TAS.
DR GO; GO:0005634; C:nucleus; TAS.
DR GO; GO:0004883; F:glucocorticoid receptor activity; TAS.
DR GO; GO:0003700; F:transcription factor activity; TAS.
DR GO; GO:0007165; P:signal transduction; TAS.
DR GO; GO:0006366; P:transcription from Pol II promoter; TAS.
DR InterPro; IPR001409; Glcrtcd_receptor.
DR InterPro; IPR000536; Hrmon_recept_lig.
DR InterPro; IPR001723; Stdhrmn_receptor.
DR InterPro; IPR008946; Str_ncl_receptor.
DR InterPro; IPR001628; Znf_C4steroid.
DR InterPro; Graphical view of domain structure.
DR Pfam; PF02155; GCR; 1.
DR Pfam; PF00104; Hormone_recep; 1.
DR Pfam; PF00105; zf-C4; 1.
DR Pfam; Graphical view of domain structure.
DR PRINTS; PR00528; GLCORTICOIDR.
DR PRINTS; PR00398; STRDHORMONER.
DR PRINTS; PR00047; STROIDFINGER.
DR ProDom; PD000035; Znf_C4steroid; 1.
DR ProDom [Domain structure / List of seq. sharing at least 1 domain ]
DR SMART; SM00430; HOLI; 1.
DR SMART; SM00399; ZnF_C4; 1.
DR PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1.
DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1.
DR CMR; P04150.
DR HOVERGEN [Family / Alignment / Tree]
DR BLOCKS; P04150.
DR ProtoNet; P04150.
DR ProtoMap; P04150.
DR PRESAGE; P04150.
DR DIP; P04150.
DR ModBase; P04150.
DR SWISS-2DPAGE; GET REGION ON 2D PAGE.
KW 3D-structure; Alternative initiation; Alternative splicing;
KW Disease mutation; DNA-binding; Nuclear protein; Phosphorylation;
KW Polymorphism; Receptor; Steroid-binding; Trans-acting factor;
KW Transcription; Transcription regulation; Ubl conjugation; Zinc-finger.
FT CHAIN 1 777 Glucocorticoid receptor, A-type isoforms.
FT CHAIN 27 777 Glucocorticoid receptor, B-type isoforms.
FT INIT_MET 27 27 For B-type isoforms.
FT DOMAIN 1 420 Modulating.
FT DOMAIN 399 418 Glu/Ser/Pro/Thr-rich (PEST region)
FT (Potential).
FT DNA_BIND 421 486 Nuclear receptor-type.
FT ZN_FING 421 441 C4-type.
FT ZN_FING 457 481 C4-type.
FT DOMAIN 487 527 Hinge.
FT DOMAIN 528 777 Steroid-binding.
FT MOD_RES 113 113 Phosphoserine (By similarity).
FT MOD_RES 141 141 Phosphoserine (By similarity).
FT MOD_RES 203 203 Phosphoserine.
FT MOD_RES 211 211 Phosphoserine.
FT MOD_RES 226 226 Phosphoserine (By similarity).
FT VARSPLIC 728 777 VVENLLNYCFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGN
FT IKKLLFHQK -> NVMWLKPESTSHTLI (in isoform
FT Beta).
FT /FTId=VSP_003703.
FT VARSPLIC 451 451 G -> GR (in isoform Gamma).
FT /FTId=VSP_007363.
FT VARSPLIC 491 674 Missing (in isoform GR-A).
FT /FTId=VSP_013340.
FT VARIANT 23 23 R -> K (in dbSNP:6190).
FT /FTId=VAR_014140.
FT VARIANT 29 29 F -> L.
FT /FTId=VAR_015628.
FT VARIANT 65 65 F -> V (in dbSNP:6192).
FT /FTId=VAR_014622.
FT VARIANT 112 112 L -> F.
FT /FTId=VAR_015629.
FT VARIANT 233 233 D -> N.
FT /FTId=VAR_015630.
FT VARIANT 363 363 N -> S (may increase sensitivity to
FT exogenously administered glucocorticoids;
FT dbSNP:6195).
FT /FTId=VAR_004675.
FT VARIANT 421 421 C -> Y (in a glucocorticoid resistant
FT leukemia cell line).
FT /FTId=VAR_015631.
FT VARIANT 477 477 R -> H (in glucocorticoid resistance).
FT /FTId=VAR_013472.
FT VARIANT 559 559 I -> N (in glucocorticoid resistance;
FT interferes with translocation to the
FT nucleus and thereby strongly reduces
FT transcription activation. Is equally
FT impaired in nuclear export. Acts as
FT dominant negative mutant).
FT /FTId=VAR_015632.
FT VARIANT 641 641 D -> V (in glucocorticoid resistance).
FT /FTId=VAR_004676.
FT VARIANT 679 679 G -> S (in glucocorticoid resistance; has
FT 50% binding affinity).
FT /FTId=VAR_013473.
FT VARIANT 729 729 V -> I (in glucocorticoid resistance).
FT /FTId=VAR_004677.
FT VARIANT 747 747 I -> M (in glucocorticoid resistance;
FT alters interaction with NCOA2 and
FT strongly reduces transcription
FT activation. Acts as dominant negative
FT mutant).
FT /FTId=VAR_015633.
FT VARIANT 753 753 L -> F (in two glucocorticoid resistant
FT leukemia cell lines lacking the normal
FT allele).
FT /FTId=VAR_004678.
FT MUTAGEN 1 1 M->T: Abolishes expression of A-type
FT isoforms.
FT MUTAGEN 27 27 M->T: Abolishes expression of B-type
FT isoforms.
FT MUTAGEN 191 191 F->D: Reduces transactivation by the ADA
FT complex.
FT MUTAGEN 193 193 I->D: Reduces transactivation by the ADA
FT complex.
FT MUTAGEN 194 194 L->A: Strongly reduces transactivation by
FT the ADA complex; when associated with V-
FT 224 and F-225.
FT MUTAGEN 197 197 L->E: Reduces transactivation by the ADA
FT complex.
FT MUTAGEN 213 213 W->A: Strongly reduces transactivation by
FT the ADA complex.
FT MUTAGEN 224 224 L->V: Strongly reduces transactivation by
FT the ADA complex; when associated with A-
FT 194 and F-225.
FT MUTAGEN 225 225 L->F: Strongly reduces transactivation by
FT the ADA complex; when associated with A-
FT 194 and V-224.
FT MUTAGEN 235 235 F->L: Strongly reduces transactivation by
FT the ADA complex; when associated with V-
FT 236.
FT MUTAGEN 236 236 L->V: Strongly reduces transactivation by
FT the ADA complex; when associated with L-
FT 235.
FT MUTAGEN 277 277 K->R: Strongly reduces sumoylation.
FT Almost complete loss of sumoylation; when
FT associated with R-293.
FT MUTAGEN 293 293 K->R: Strongly reduces sumoylation.
FT Almost complete loss of sumoylation; when
FT associated with R-277.
FT MUTAGEN 585 585 R->A: Reduces activation mediated by
FT ligand binding domain; when associated
FT with A-590.
FT MUTAGEN 590 590 D->A: Reduces activation mediated by
FT ligand binding domain; when associated
FT with A-585.
FT MUTAGEN 602 602 F->S: Increases solubility. No effect on
FT transactivation by dexamethasone.
FT MUTAGEN 625 625 P->A: Decreases transactivation by
FT dexamethasone by 95%.
FT MUTAGEN 628 628 I->A: Decreases dimerization and
FT transactivation by dexamethasone; when
FT associated with S-602.
FT MUTAGEN 703 703 K->R: Slightly reduces sumoylation.
SQ SEQUENCE 777 AA; 85659 MW; C5C90C9A5DD16AAB CRC64;
MDSKESLTPG REENPSSVLA QERGDVMDFY KTLRGGATVK VSASSPSLAV ASQSDSKQRR
LLVDFPKGSV SNAQQPDLSK AVSLSMGLYM GETETKVMGN DLGFPQQGQI SLSSGETDLK
LLEESIANLN RSTSVPENPK SSASTAVSAA PTEKEFPKTH SDVSSEQQHL KGQTGTNGGN
VKLYTTDQST FDILQDLEFS SGSPGKETNE SPWRSDLLID ENCLLSPLAG EDDSFLLEGN
SNEDCKPLIL PDTKPKIKDN GDLVLSSPSN VTLPQVKTEK EDFIELCTPG VIKQEKLGTV
YCQASFPGAN IIGNKMSAIS VHGVSTSGGQ MYHYDMNTAS LSQQQDQKPI FNVIPPIPVG
SENWNRCQGS GDDNLTSLGT LNFPGRTVFS NGYSSPSMRP DVSSPPSSSS TATTGPPPKL
CLVCSDEASG CHYGVLTCGS CKVFFKRAVE GQHNYLCAGR NDCIIDKIRR KNCPACRYRK
CLQAGMNLEA RKTKKKIKGI QQATTGVSQE TSENPGNKTI VPATLPQLTP TLVSLLEVIE
PEVLYAGYDS SVPDSTWRIM TTLNMLGGRQ VIAAVKWAKA IPGFRNLHLD DQMTLLQYSW
MFLMAFALGW RSYRQSSANL LCFAPDLIIN EQRMTLPCMY DQCKHMLYVS SELHRLQVSY
EEYLCMKTLL LLSSVPKDGL KSQELFDEIR MTYIKELGKA IVKREGNSSQ NWQRFYQLTK
LLDSMHEVVE NLLNYCFQTF LDKTMSIEFP EMLAEIITNQ IPKYSNGNIK KLLFHQK
//