The glucocorticoid receptor also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1) is the receptor to which cortisol and other glucocorticoids bind.
The GR is expressed in almost every cell in the body and regulates genes controlling the development, metabolism, and immune response. Because the receptor gene is expressed in several forms, it has many different (pleiotropic) effects in different parts of the body.
When the GR binds to glucocorticoids, its primary mechanism of action is the regulation of gene transcription.
FKBP4 = FKBP52
FKBP5 = FKBP51
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
Protein Aminoacids Percentage (Width 700 px)
GCR looks like a very old protein whilst its regulators HSP90 and FKBP looks very recent even more than aromatase, the latest of CytP450s involved in steroid hormones synthesis
A microarray study on the effect of four hormone therapy regimens on gene transcription in whole blood from healthy postmenopausal women. 2012
RESULTS The genes FKBP5, IL13RA1, TPST1, and TLR2 were up-regulated and among the most significantly changed genes in the groups treated with conventional-dose 17β-estradiol/NETA and tibolone.
Working hypothesis: Estrogens induce the synthesis of FKBP51 mRNA that is translated into the protein only in very well oxigenated tissues. FKBP51 inactivates GR- Upon replacement of FKBP51 with FKBP52 (that requires a lower oxygen tension for its synthesis) GR is released from the complex with HSP90 and drives specific genes transcription.
Dual targeting of the androgen receptor and hypoxia-inducible factor 1α pathways synergistically inhibits castration-resistant prostate cancer cells. 2015
In prostate cancer cells, the gene expression of AR targets (KLK3, FKBP5, TMPRSS2) was repressed by HIF-signaling;
Stress-response pathways are altered in the hippocampus of chronic alcoholics. 2014
Differentially expressed genes included the glucocorticoid receptor and the related gene FK506 binding protein 5 (FKBP5), UDP glycosyltransferase 8 (UGT8), urea transporter (SLC14A1), zinc transporter (SLC39A10), Interleukin 1 receptor type 1 (IL1R1), thioredoxin interacting protein (TXNIP), and many metallothioneins. Pathways related to inflammation, hypoxia, and stress showed activation, and pathways that play roles in neurogenesis and myelination showed decreases.
SYNTHESIS AND TURNOVER
FKBP5 and SUMO
Atlas of Genetics and Cytogenetics in Oncology and Haematology: FKBP5
FKBP51 is a member of immunophilin family, proteins characterized by their ability to bind immunosuppresive drugs. Additionally, immunophilins are peptidylprolyl isomerases (PPIase) that catalyze the cis-trans conversion of peptidylprolyl bonds, a reaction important for protein folding.
FKBP51 is an important protein involved in the regulation of many key signaling cascades in the cell, such as Akt (Pei et al., 2009), NFκB (Bouwmeester et al., 2004), and androgen receptor pathways (Ni et al., 2010).
Importance of FKBP5 in regulating activity of Akt pathway. FKBP5 acts as a scaffolding protein, enhancing the interaction of PHLPP and Akt,
- Cell signaling and Ligand transport
- Structural proteins