Peptidyl-prolyl cis-trans isomerase FKBP5 (FKBP5) (FKBP5)

Peptidyl-prolyl cis-trans isomerase FKBP5, commonly known as FKBP51, is a member of the immunophilin protein family that functions as a co-chaperone for the glucocorticoid receptor (GR) (UniProt: Q13451). It plays a critical role in the negative feedback loop of the hypothalamic-pituitary-adrenal (HPA) axis by reducing the affinity of the GR for cortisol and hindering its translocation to the nucleus (PubMed: 26853340). This protein is part of a multi-protein complex including Hsp90, and its expression is induced by glucocorticoids, creating an ultra-short feedback loop. Overexpression or genetic variants of FKBP5 are strongly associated with an increased risk for stress-related psychiatric conditions, including post-traumatic stress disorder (PTSD) and major depressive disorder. Beyond its role in stress, FKBP5 is involved in regulating the NF-kappa-B and Akt signaling pathways, contributing to inflammation, metabolic disorders, and certain cancers (PubMed: 30635430). It also influences the activity of other steroid receptors, such as the androgen and progesterone receptors, making it a target of interest in oncology. Pharmacological targeting of FKBP5 focuses on developing selective inhibitors, such as the SAFit compounds, that can restore GR sensitivity and normalize the stress response without affecting the closely related FKBP4 protein (PubMed: 25533254). These selective inhibitors aim to provide a more targeted approach to treating mood disorders and chronic pain while minimizing side effects associated with broader immunophilin inhibition. Current research continues to explore the potential of FKBP5 as a biomarker for treatment response in psychiatric patients.

Other names

FK506-binding protein 5FKBP5151 kDa FK506-binding proteinFKBP54P54PPIase FKBP5

Inhibition of peptidyl-prolyl isomerase activity and modulation of glucocorticoid receptor sensitivity by disrupting the FKBP5-Hsp90-GR complex (PubMed: 25533254).