FKBPs

FKBPs, or FK506-binding proteins, are a family of intracellular proteins that bind the macrolide immunosuppressants FK506 (tacrolimus) and rapamycin (sirolimus). They possess peptidyl-prolyl cis-trans isomerase (PPIase) activity, enabling them to catalyze the isomerization of proline-containing peptide bonds. As immunophilins, FKBPs participate in protein folding, assembly, trafficking, and the regulation of signaling pathways in a variety of cell types.

Many FKBPs act as molecular chaperones or co-chaperones. They commonly associate with the Hsp90 chaperone system and contribute to the maturation and stabilization of client proteins, including steroid receptors. Some family members, such as FKBP52 (FKBP4) and FKBP51 (FKBP5), contain tetratricopeptide repeat (TPR) domains and function as co-regulators of signaling complexes, influencing hormone receptor signaling and other pathways.

Pharmacologically, FKBPs are central to the actions of immunosuppressants. In T lymphocytes, the FKBP12–FK506 complex inhibits calcineurin, blocking NFAT activation and T cell responses. The FKBP12–rapamycin complex inhibits mTOR complex 1 (mTORC1), suppressing cell growth and proliferation. These mechanisms underlie the immunosuppressive effects of tacrolimus and sirolimus and explain their clinical use in transplantation and certain diseases.

The FKBP family in humans includes FKBP12 (FKBP1A), FKBP12.6 (FKBP1B), FKBP52 (FKBP4), FKBP51 (FKBP5), and additional members with varying sizes, domain organizations, and subcellular localizations (cytosol, nucleus, endoplasmic reticulum). Roles of FKBPs span development, neural signaling, stress response, and disease; for example, genetic variants in FKBP5 are linked to stress-related disorders and modulation of glucocorticoid signaling.