Peptidyl-prolyl cis-trans isomerase (Immunophilin) (PPIase)

Cyclophilins and FK506-binding proteins (FKBPs) are collectively referred to as immunophilins, a family of proteins characterized by their peptidyl-prolyl cis-trans isomerase (PPIase) activity. These proteins facilitate the folding and assembly of other proteins by catalyzing the interconversion of cis and trans isomers of peptide bonds involving proline (UniProt P62937, P62942). In clinical medicine, they are the primary intracellular targets for potent immunosuppressive agents used to prevent organ transplant rejection and treat autoimmune diseases. Cyclophilin A serves as the receptor for Cyclosporine A, while FKBP12 binds to Tacrolimus (FK506) or Sirolimus (Rapamycin); these drug-immunophilin complexes then inhibit key signaling enzymes such as calcineurin or the mechanistic target of rapamycin (mTOR) (PubMed: 1703530). This inhibition prevents the activation and proliferation of T-lymphocytes, which is critical for managing the immune response. Beyond their role in immunosuppression, immunophilins are involved in various pathological processes, including viral replication (e.g., Hepatitis C and HIV) and neurodegeneration, making them significant targets for diverse therapeutic interventions (PubMed: 22430111).

Other names

CyclophilinFKBP12FK506-binding protein 12Cyclophilin APPIAFKBP1AImmunophilin

Immunosuppressive drugs bind to immunophilins to form a gain-of-function complex. The Cyclosporine-Cyclophilin and Tacrolimus-FKBP12 complexes inhibit calcineurin, a phosphatase required for NFAT activation and IL-2 production. The Sirolimus-FKBP12 complex inhibits the mechanistic target of rapamycin (mTOR), blocking growth factor-induced cell cycle progression.