FKBP4

FKBP4, also known as FKBP52, is a member of the immunophilin family of peptidyl-prolyl cis-trans isomerases. In humans, it is encoded by the FKBP4 gene and is primarily localized in the cytoplasm, where it functions as a co-chaperone in protein folding and signaling pathways.

The protein architecture of FKBP4 includes two N-terminal FKBP domains (FK1 and FK2) and a C-terminal tetratricopeptide repeat (TPR) domain. The TPR portion mediates binding to the HSP90 chaperone complex, positioning FKBP52 as a regulatory component of the HSP90 machinery. While FKBP52 possesses measurable isomerase activity in vitro, the biological significance of this activity in vivo is considered to be variable and not always essential for its co-chaperone functions.

Functionally, FKBP4 serves as a co-chaperone that assists in the maturation, stabilization, and trafficking of client proteins within steroid receptor signaling pathways. It facilitates proper ligand binding and promotes the nuclear translocation of steroid receptors such as the androgen receptor, glucocorticoid receptor, and progesterone receptor, with potential effects on estrogen receptor signaling as well. FKBP4 also participates in broader client protein networks through its interactions with HSP90, HOP, p23, and components of the dynein motor system.

Expression of FKBP4 is tissue-dependent, with notable levels in reproductive tissues and the nervous system. Alterations in FKBP4 expression or function have been investigated for potential roles in cancer biology and fertility, particularly regarding hormone-responsive pathways and therapy responses. Ongoing research aims to clarify its full range of clients and the precise mechanisms by which FKBP4 modulates chaperone-assisted signaling.