DP00030: Glucocorticoid receptorFASTA viewXML view

General information
DisProt:DP00030
Name:Glucocorticoid receptor
Synonym(s):GCR_HUMAN
GR
Nuclear receptor subfamily 3 group C member 1
First appeared in release:Release 2.0 (02/14/2005)
UniProt:P04150
UniGene:Hs.122926
SwissProt: GCR_HUMAN
TrEMBL:  
NCBI (GI): 121069
Source organism:Homo sapiens (Human)
Sequence length:777
Percent disordered:64%
Homologues: 


Native sequence

        10         20         30         40         50         60
         |          |          |          |          |          |
MDSKESLTPG REENPSSVLA QERGDVMDFY KTLRGGATVK VSASSPSLAV ASQSDSKQRR - 60
LLVDFPKGSV SNAQQPDLSK AVSLSMGLYM GETETKVMGN DLGFPQQGQI SLSSGETDLK - 120
LLEESIANLN RSTSVPENPK SSASTAVSAA PTEKEFPKTH SDVSSEQQHL KGQTGTNGGN - 180
VKLYTTDQST FDILQDLEFS SGSPGKETNE SPWRSDLLID ENCLLSPLAG EDDSFLLEGN - 240
SNEDCKPLIL PDTKPKIKDN GDLVLSSPSN VTLPQVKTEK EDFIELCTPG VIKQEKLGTV - 300
YCQASFPGAN IIGNKMSAIS VHGVSTSGGQ MYHYDMNTAS LSQQQDQKPI FNVIPPIPVG - 360
SENWNRCQGS GDDNLTSLGT LNFPGRTVFS NGYSSPSMRP DVSSPPSSSS TATTGPPPKL - 420
CLVCSDEASG CHYGVLTCGS CKVFFKRAVE GQHNYLCAGR NDCIIDKIRR KNCPACRYRK - 480
CLQAGMNLEA RKTKKKIKGI QQATTGVSQE TSENPGNKTI VPATLPQLTP TLVSLLEVIE - 540
PEVLYAGYDS SVPDSTWRIM TTLNMLGGRQ VIAAVKWAKA IPGFRNLHLD DQMTLLQYSW - 600
MFLMAFALGW RSYRQSSANL LCFAPDLIIN EQRMTLPCMY DQCKHMLYVS SELHRLQVSY - 660
EEYLCMKTLL LLSSVPKDGL KSQELFDEIR MTYIKELGKA IVKREGNSSQ NWQRFYQLTK - 720
LLDSMHEVVE NLLNYCFQTF LDKTMSIEFP EMLAEIITNQ IPKYSNGNIK KLLFHQK



Functional narrative    

The glucocorticoid receptor (GR) protein is a member of the nuclear receptor family that mediates the biological effects of glucocorticoids. GR is widely expressed and affects inflammatory responses, cellular proliferation, and differentiation in target tissues. Glucocorticoid receptor is found in the cytoplasm in the absence of a ligand and in the nucleus once a ligand is bound. Glucocorticoid hormone binding transforms the GR into its active state enabling it to interact with glucocorticoid response elements (specific DNA sequences) on target genes. Regulatory activity results upon binding of the active form. GR modulates gene expression via two modes: 1) GR binds as a homodimer to glucocorticoid response elements (GRE), 2) GRE-independent action when the GR interacts as a monomer with other transcription factors bound to DNA. The protein is composed of four domains; residues 77-262 comprise the ligand-independent activation domain, residues 418-488 comprise the DNA-binding domain which contain two zinc fingers, the hinge region residues 490-515, and the ligand/steroid binding domain residues 526-777. The ligand-binding domain contains two subdomains; Tau2 (residues 526-556) and AF2/Tau c (727-763).

Region 1: 77-262 Region 2: 1-500

Map of ordered and disordered regions







Note: 'Mouse' over a region to see the start and stop residues. Click on a region to see detailed information.


Region 1
Type:Disordered - Extended
Name: 
Location:77 - 262
Length:186
Region sequence:

DLSKAVSLSMGLYMGETETKVMGNDLGFPQQGQISLSSGETDLKLLEESIANLNRSTSVP
ENPKSSASTAVSAAPTEKEFPKTHSDVSSEQQHLKGQTGTNGGNVKLYTTDQSTFDILQD
LEFSSGSPGKETNESPWRSDLLIDENCLLSPLAGEDDSFLLEGNSNEDCKPLILPDTKPK
IKDNGD

Modification type: Engineered
Fragment
PDB:  
Structural/functional type: Function arises via a disorder to order transition
Functional classes: Molecular recognition effectors
Functional subclasses: Metal binding
Phosphorylation
Protein-DNA binding
Protein-protein binding
Detection methods:
  1. Circular dichroism (CD) spectroscopy, far-UV (295 K; pH: 7; dithiothreitol 1 mM; phosphate 3 mM; TFE)

  2. Nuclear magnetic resonance (NMR) (289 K; pH: 5.9; dithiothreitiol 1 mM; phosphates 20 mM)
References:
  1. Baskakov IV, Kumar R, Srinivasan G, Ji YS, Bolen DW, Thompson EB. "Trimethylamine N-oxide-induced cooperative folding of an intrinsically unfolded transcription-activating fragment of human glucocorticoid receptor." J Biol Chem. 1999; 274(16): 10693-6. PubMed: 10196139

  2. Dahlman-Wright K, Baumann H, McEwan IJ, Almlöf T, Wright AP, Gustafsson JA, Härd T. "Structural characterization of a minimal functional transactivation domain from the human glucocorticoid receptor." Proc Natl Acad Sci U S A. 1995; 92(5): 1699-1703. PubMed: 7878043

  3. Li G, Wang S, Gelehrter TD. "Identification of glucocorticoid receptor domains involved in transrepression of transforming growth factor-beta action." J Biol Chem. 2003; 278(43): 41779-41788. PubMed: 12902338
Comments:
The 58 residue Tau1 core region of the disordered polypeptide from 187-244 retains 60-70% of the activity of the domain. The disordered region is devoid of structure at neutral pH in aqueous solution. The ligand-binding domain becomes notably more structured in the presence of triflouroethanol (TFE). TFE creates a more non-polar environment and favors secondary structure formation. The propensity towards alpha-helicial structure may be an important step in Tau1-mediated gene activation


Region 2
Type:Disordered
Name: 
Location:1 - 500
Length:500
Region sequence:

MDSKESLTPGREENPSSVLAQERGDVMDFYKTLRGGATVKVSASSPSLAVASQSDSKQRR
LLVDFPKGSVSNAQQPDLSKAVSLSMGLYMGETETKVMGNDLGFPQQGQISLSSGETDLK
LLEESIANLNRSTSVPENPKSSASTAVSAAPTEKEFPKTHSDVSSEQQHLKGQTGTNGGN
VKLYTTDQSTFDILQDLEFSSGSPGKETNESPWRSDLLIDENCLLSPLAGEDDSFLLEGN
SNEDCKPLILPDTKPKIKDNGDLVLSSPSNVTLPQVKTEKEDFIELCTPGVIKQEKLGTV
YCQASFPGANIIGNKMSAISVHGVSTSGGQMYHYDMNTASLSQQQDQKPIFNVIPPIPVG
SENWNRCQGSGDDNLTSLGTLNFPGRTVFSNGYSSPSMRPDVSSPPSSSSTATTGPPPKL
CLVCSDEASGCHYGVLTCGSCKVFFKRAVEGQHNYLCAGRNDCIIDKIRRKNCPACRYRK
CLQAGMNLEARKTKKKIKGI

Modification type: Engineered
Fragment
PDB:  
Structural/functional type: Function arises via a disorder to order transition
Functional classes: Molecular recognition effectors
Functional subclasses: Metal binding
Phosphorylation
Protein-DNA binding
Protein-protein binding
Detection methods:
  1. Circular dichroism (CD) spectroscopy, far-UV (295 K; NaCl (buffer pH 7.9) 10 mM; Tris 10 mM)
References:
  1. Baskakov IV, Kumar R, Srinivasan G, Ji YS, Bolen DW, Thompson EB. "Trimethylamine N-oxide-induced cooperative folding of an intrinsically unfolded transcription-activating fragment of human glucocorticoid receptor." J Biol Chem. 1999; 274(16): 10693-6. PubMed: 10196139
Comments:
 



References

  1. Garza AM, Khan SH, Kumar R. "Site-Specific Phosphorylation Induces Functionally Active Conformation in the Intrinsically Disordered N-Terminal Activation Function (AF1) Domain of the Glucocorticoid Receptor." Mol Cell Biol. 2010; 30(1): 220-30. PubMed: 19841061

  2. Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, Lebo R, Thompson EB, Rosenfeld MG, Evans RM. "Primary structure and expression of a functional human glucocorticoid receptor cDNA." Nature. 1985; 318(6047): 635-41. PubMed: 2867473



Comments


The sequence given in Hollenberg (1985) appears to be in error. Blasting against the Swiss-Prot sequence reveals only a 94% similarity with all the discrepancies being tyrosines replacing lysines.


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