FKBP51

FKBP51, also known as FKBP5, is a member of the immunophilin family of proteins that function as peptidyl-prolyl cis-trans isomerases. It binds the immunosuppressants FK506 and rapamycin and contributes to protein folding and trafficking. The human FKBP5 gene encodes a ~51-kilodalton cytosolic protein with two FKBP-like domains (FK1 with isomerase activity and FK2) in tandem, followed by a tetratricopeptide repeat (TPR) region that mediates interaction with the HSP90 chaperone complex. Its localization is primarily cytosolic, with potential nuclear presence under certain conditions.

FKBP51 is best known for its role in modulating glucocorticoid receptor signaling. By associating with the GR-HSP90 complex, it influences receptor sensitivity, hormone binding, and nuclear translocation, thereby affecting the strength and duration of glucocorticoid signaling and HPA axis feedback. Through its scaffolding capabilities, FKBP51 also participates in other signaling cascades and has been linked to NF-kB and AKT pathways in various cellular contexts.

Clinically, FKBP5 gene variation and its epigenetic regulation are associated with stress-related psychiatric conditions, including post-traumatic stress disorder, major depressive disorder, and anxiety disorders, particularly in interaction with early-life stress. FKBP5 variants can influence treatment response to antidepressants and stress hormone reactivity, making FKBP51 a focus of research on stress biology and potential therapeutic targets. FKBP51 is distinct from the related FKBP52 (FKBP4), though both regulate steroid receptor complexes and chaperone networks.