Reviewed, UniProtKB/Swiss-Prot P04150 (GCR_HUMAN)

Names and origin

Protein names

Recommended name:
    Glucocorticoid receptor
      Short name(s)=GR
Alternative name(s):
    Nuclear receptor subfamily 3 group C member 1

Gene names

Name:	NR3C1
Synonyms:	GRL

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	777 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE) and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation. Involved in nuclear translocation By similarity.
Subunit structure	Heteromultimeric cytoplasmic complex with HSP90, HSP70, and FKBP5 or another immunophilin, or the immunophilin homolog PPP5C. Directly interacts with UNC45A. Upon ligand binding FKBP5 dissociates from the complex and FKBP4 takes its place, thereby linking the complex to dynein and mediating transport to the nucleus, where the complex dissociates By similarity. Binds to DNA as a homodimer, and as a heterodimer with NR3C2 or the retinoid X receptor. Binds STAT5A and STAT5B homodimers and heterodimers. Interacts with NRIP1, POU2F1, POU2F2 and TRIM28. Interacts with NCOA1, NCOA3, SMARCA4, SMARCC1, SMARCD1, and SMARCE1 By similarity. Interacts with several coactivator complexes, including the SMARCA4 complex, CREBBP/EP300, TADA2L and p160 coactivators such as NCOA2 and NCOA6. Interaction with BAG1 inhibits transactivation. Interacts with HEXIM1, PELP1 and TGFB1I1.
Subcellular location	Cytoplasm. Nucleus. Note= Cytoplasmic in the absence of ligand, nuclear after ligand-binding.
Tissue specificity	Widely expressed. In the heart, detected in left and right atria, left and right ventricles, aorta, apex, intraventricular septum, and atrioventricular node as well as whole adult and fetal heart.
Domain	Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal steroid-binding domain.
Post-translational modification	Increased proteasome-mediated degradation in response to glucocorticoids. Phosphorylated in the absence of hormone; becomes hyperphosphorylated in the presence of glucocorticoid. The Ser-203-phosphorylated form is mainly cytoplasmic, and the Ser-211-phosphorylated form is nuclear. Transcriptional activity correlates with the amount of phosphorylation at Ser-211. Sumoylated; this reduces transcription transactivation. Ubiquitinated; restricts glucocorticoid-mediated transcriptional signaling By similarity.
Polymorphism	Carriers of the 22-Glu-Lys-23 allele are relatively more resistant to the effects of GCs with respect to the sensitivity of the adrenal feedback mechanism than non-carriers, resulting in a better metabolic health profile. Carriers have a better survival than non-carriers, as well as lower serum CRP levels. The 22-Glu-Lys-23 polymorphism is associated with a sex-specific, beneficial body composition at young-adult age, as well as greater muscle strength in males.
Involvement in disease	Defects in NR3C1 are a cause of glucocorticoid resistance [MIM:138040]; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.
Miscellaneous	High constitutive expression of isoform beta by neutrophils may provide a mechanism by which these cells escape glucocorticoid-induced cell death. Up-regulation by proinflammatory cytokines such as IL8 further enhances their survival in the presence of glucocorticoids during inflammation. Can up- or down-modulate aggregation and nuclear localization of expanded polyglutamine polypeptides derived from AR and HD through specific regulation of gene expression. Aggregation and nuclear localization of expanded polyglutamine proteins are regulated cellular processes that can be modulated by this receptor, a well-characterized transcriptional regulator.
Sequence similarities	Belongs to the nuclear hormone receptor family. NR3 subfamily. Contains 1 nuclear receptor DNA-binding domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative initiation Alternative splicing Polymorphism
Disease	Disease mutation Pseudohermaphroditism
Domain	Zinc-finger
Ligand	DNA-binding Lipid-binding Metal-binding Steroid-binding Zinc
Molecular function	Chromatin regulator Receptor
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure
Gene Ontology (GO)
Biological process	signal transduction Traceable author statement. Source: ProtInc transcription from RNA polymerase II promoter Traceable author statement. Source: ProtInc
Cellular component	mitochondrial matrix Traceable author statement. Source: ProtInc nucleus Traceable author statement. Source: ProtInc
Molecular function	glucocorticoid receptor activity Traceable author statement. Source: ProtInc protein binding Ref.14 Ref.28 Inferred from physical interaction. Source: UniProtKB transcription factor activity Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Mvp	Q62667	1	EBI-493507,EBI-918333	From a different organism.
SMARCA4	P51532	1	EBI-493507,EBI-302489
SMARCC1	Q92922	1	EBI-493507,EBI-355653

Alternative products

This entry describes 9 isoforms produced by alternative splicing and alternative initiation. [Align] [Select]

Notes: At least 4 isoforms, Alpha (shown here), Alpha-B, Beta and Beta-B, are produced by alternative initiation at Met-1 and Met-27. The existence of isoform Alpha and isoform Alpha-B has been proved by mutagenesis. As the sequence environment of the 2 potential ATG initiator codons is the same for the other altrnatively spliced isoforms, alternative initiation of translation could also occur on these transcripts. Additional isoforms seem to exist.

Isoform Alpha (identifier: P04150-1)

Also known as: Alpha-A;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Notes: Predominant physiological form. Isoform Alpha-B is produced by alternative initiation at Met-27 of isoform Alpha. Both isoforms exhibit similar subcellular location and nuclear translocation after ligand activation. Isoform Alpha-B appears to be more susceptible to degradation, at least when expressed in mammalian cells, but more effective in transcriptional activation and not in transrepression.

Isoform Beta (identifier: P04150-2)

Also known as: Beta-A;

The sequence of this isoform differs from the canonical sequence as follows:
     728-777: VVENLLNYCFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGNIKKLLFHQK → NVMWLKPESTSHTLI

Notes: No hormone-binding activity. Widely expressed at low level. Localized largely in the nucleus.

Isoform Alpha-2 (identifier: P04150-3)

Also known as: Gamma;

The sequence of this isoform differs from the canonical sequence as follows:
     451-451: G → GR

Notes: Due to a partial intron retention. Lower transcriptional activity. Expressed at low level.

Isoform Beta-2 (identifier: P04150-6)

The sequence of this isoform differs from the canonical sequence as follows:
     451-451: G → GR
     728-777: VVENLLNYCFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGNIKKLLFHQK → NVMWLKPESTSHTLI

Notes: Due to a partial intron retention.

Isoform GR-A alpha (identifier: P04150-5)

The sequence of this isoform differs from the canonical sequence as follows:
     491-674: Missing.

Notes: Lacks exons 5, 6 and 7. Found in glucocorticoid-resistant myeloma patients.

Isoform GR-A beta (identifier: P04150-7)

The sequence of this isoform differs from the canonical sequence as follows:
     491-674: Missing.
     728-777: VVENLLNYCFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGNIKKLLFHQK → NVMWLKPESTSHTLI

Notes: Lacks exons 5, 6 and 7.

Isoform GR-P (identifier: P04150-4)

The sequence of this isoform is not available.

Notes: Encoded by exons 2-7 plus several basepairs from the subsequent intron region. Lacks the ligand binding domain. Accounts for up to 10-20% of mRNAs.

Isoform Alpha-B (identifier: P04150-8)

Also known as: Beta-B;

The sequence of this isoform differs from the canonical sequence as follows:
     1-26: Missing.

Notes: Produced by alternative initiation at Met-27 of isoform Alpha. Both isoforms exhibit similar subcellular location and nuclear translocation after ligand activation. Isoform Alpha-B appears to be more susceptible to degradation, at least when expressed in mammalian cells, but more effective in transcriptional activation and not in transrepression.

Isoform Beta-B (identifier: P04150-9)

The sequence of this isoform differs from the canonical sequence as follows:
     1-26: Missing.
     728-777: VVENLLNYCFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGNIKKLLFHQK → NVMWLKPESTSHTLI

Notes: Produced by alternative initiation at Met-27 of isoform Beta.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Chain

1 – 777

777

Glucocorticoid receptor

Regions

DNA binding

421 – 486

66

Nuclear receptor

Zinc finger

421 – 441

21

NR C4-type

Zinc finger

457 – 481

25

NR C4-type

Region

1 – 420

420

Modulating

Region

487 – 527

41

Hinge

Region

528 – 777

250

Steroid-binding

Compositional bias

399 – 418

20

Glu/Pro/Ser/Thr-rich (PEST region)

Amino acid modifications

Modified residue

113

1

Phosphoserine By similarity

Modified residue

141

1

Phosphoserine By similarity

Modified residue

203

1

Phosphoserine

Modified residue

211

1

Phosphoserine

Modified residue

226

1

Phosphoserine By similarity

Cross-link

277

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)

Cross-link

293

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)

Cross-link

419

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Probable

Natural variations

Alternative sequence

1 – 26

26

Missing in isoform Alpha-B and isoform Beta-B.

Alternative sequence

451

1

G → GR in isoform Alpha-2 and isoform Beta-2.

Alternative sequence

491 – 674

184

Missing in isoform GR-A alpha and isoform GR-A beta.

Alternative sequence

728 – 777

50

VVENL…LFHQK → NVMWLKPESTSHTLI in isoform Beta, isoform Beta-B, isoform Beta-2 and isoform GR-A beta.

Natural variant

23

1

R → K: dbSNP rs6190.

Natural variant

29

1

F → L

Natural variant

65

1

F → V: dbSNP rs6192.

Natural variant

112

1

L → F

Natural variant

233

1

D → N

Natural variant

363

1

N → S May increase sensitivity to exogenously administered glucocorticoids; may contribute to central obesity in men and show lack of association with other risk factors for coronary heart disease and diabetes mellitus. dbSNP rs6195.

Natural variant

421

1

C → Y in a glucocorticoid resistant leukemia cell line.

Natural variant

477

1

R → H in glucocorticoid resistance.

Natural variant

559

1

I → N in glucocorticoid resistance; interferes with translocation to the nucleus and thereby strongly reduces transcription activation. Is equally impaired in nuclear export. Acts as dominant negative mutant.

Natural variant

571

1

V → A in pseudohermaphroditism; female with hypokalemia due to glucocorticoid resistance; 6-fold reduction in binding affinity compared with the wild-type receptor.

Natural variant

641

1

D → V in glucocorticoid resistance.

Natural variant

679

1

G → S in glucocorticoid resistance; has 50% binding affinity.

Natural variant

729

1

V → I in glucocorticoid resistance.

Natural variant

747

1

I → M in glucocorticoid resistance; alters interaction with NCOA2 and strongly reduces transcription activation; acts as dominant negative mutant.

Natural variant

753

1

L → F in two glucocorticoid resistant leukemia cell lines lacking the normal allele.

Experimental info

Mutagenesis

1

1

M → T: Abolishes expression of A-type isoforms

Mutagenesis

27

1

M → T: Abolishes expression of B-type isoforms

Mutagenesis

191

1

F → D: Reduces transactivation by the ADA complex

Mutagenesis

193

1

I → D: Reduces transactivation by the ADA complex

Mutagenesis

194

1

L → A: Strongly reduces transactivation by the ADA complex; when associated with V-224 and F-225

Mutagenesis

197

1

L → E: Reduces transactivation by the ADA complex

Mutagenesis

213

1

W → A: Strongly reduces transactivation by the ADA complex

Mutagenesis

224

1

L → V: Strongly reduces transactivation by the ADA complex; when associated with A-194 and F-225

Mutagenesis

225

1

L → F: Strongly reduces transactivation by the ADA complex; when associated with A-194 and V-224

Mutagenesis

235

1

F → L: Strongly reduces transactivation by the ADA complex; when associated with V-236

Mutagenesis

236

1

L → V: Strongly reduces transactivation by the ADA complex; when associated with L-235

Mutagenesis

277

1

K → R: Strongly reduces sumoylation. Almost complete loss of sumoylation; when associated with R-293

Mutagenesis

293

1

K → R: Strongly reduces sumoylation. Almost complete loss of sumoylation; when associated with R-277

Mutagenesis

585

1

R → A: Reduces activation mediated by ligand binding domain; when associated with A-590

Mutagenesis

590

1

D → A: Reduces activation mediated by ligand binding domain; when associated with A-585

Mutagenesis

602

1

F → S: Increases solubility. No effect on transactivation by dexamethasone

Mutagenesis

625

1

P → A: Decreases transactivation by dexamethasone by 95%

Mutagenesis

628

1

I → A: Decreases dimerization and transactivation by dexamethasone; when associated with S-602

Mutagenesis

703

1

K → R: Slightly reduces sumoylation

Sequence conflict

399

1

R → G in BAD97314. Ref.5

Sequence conflict

754

1

A → T in BAD97314. Ref.5

Secondary structure

1

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777

Helix Strand Turn

Details...

Helix

532 – 539

8

Helix

556 – 578

23

Helix

584 – 586

3

Helix

589 – 616

28

Beta strand

619 – 624

6

Beta strand

627 – 629

3

Helix

633 – 635

3

Helix

639 – 655

17

Helix

660 – 671

12

Beta strand

673 – 676

4

Helix

683 – 704

22

Helix

709 – 732

24

Beta strand

735 – 739

5

Helix

740 – 746

7

Helix

749 – 757

9

Beta strand

769 – 771

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform Alpha (Alpha-A) [UniParc]. Last modified November 1, 1986. Version 1. Checksum: C5C90C9A5DD16AAB	FASTA	777	85,659
	10 20 30 40 50 60 MDSKESLTPG REENPSSVLA QERGDVMDFY KTLRGGATVK VSASSPSLAV ASQSDSKQRR 70 80 90 100 110 120 LLVDFPKGSV SNAQQPDLSK AVSLSMGLYM GETETKVMGN DLGFPQQGQI SLSSGETDLK 130 140 150 160 170 180 LLEESIANLN RSTSVPENPK SSASTAVSAA PTEKEFPKTH SDVSSEQQHL KGQTGTNGGN 190 200 210 220 230 240 VKLYTTDQST FDILQDLEFS SGSPGKETNE SPWRSDLLID ENCLLSPLAG EDDSFLLEGN 250 260 270 280 290 300 SNEDCKPLIL PDTKPKIKDN GDLVLSSPSN VTLPQVKTEK EDFIELCTPG VIKQEKLGTV 310 320 330 340 350 360 YCQASFPGAN IIGNKMSAIS VHGVSTSGGQ MYHYDMNTAS LSQQQDQKPI FNVIPPIPVG 370 380 390 400 410 420 SENWNRCQGS GDDNLTSLGT LNFPGRTVFS NGYSSPSMRP DVSSPPSSSS TATTGPPPKL 430 440 450 460 470 480 CLVCSDEASG CHYGVLTCGS CKVFFKRAVE GQHNYLCAGR NDCIIDKIRR KNCPACRYRK 490 500 510 520 530 540 CLQAGMNLEA RKTKKKIKGI QQATTGVSQE TSENPGNKTI VPATLPQLTP TLVSLLEVIE 550 560 570 580 590 600 P