Cyclophilin A–Calcineurin complex (CypA–CaN complex)

The Cyclophilin A–Calcineurin complex is a critical ternary molecular assembly involved in the regulation of the adaptive immune response. Cyclophilin A (also known as Cyclophilin-1 or PPIA) is an intracellular immunophilin with peptidyl-prolyl cis-trans isomerase activity that serves as the primary receptor for the immunosuppressant drug Cyclosporine A [UniProt: P62937]. Upon binding the drug, Cyclophilin A undergoes a gain-of-function transformation, allowing it to bind and inhibit Calcineurin, a calcium-dependent serine/threonine protein phosphatase [PMID: 7504238]. This inhibition prevents the dephosphorylation of the Nuclear Factor of Activated T-cells (NFAT), blocking its translocation to the nucleus and the subsequent transcription of essential T-cell growth factors such as Interleukin-2 [StatPearls: NBK482450]. This pathway is the primary target for pharmacological immunosuppression used to prevent organ transplant rejection and treat various autoimmune conditions. However, because Calcineurin is expressed in many tissues, its systemic inhibition by this complex is associated with significant side effects, including dose-dependent nephrotoxicity and hypertension [PMID: 25831444].

Other names

Cyclophilin-1–Calcineurin complexPPIA–Calcineurin complexCyclosporine–Cyclophilin A–Calcineurin complexCypA–PPP3CA complex

The complex acts as a molecular wedge where the drug (e.g., Cyclosporine) binds to Cyclophilin A, and the resulting binary complex then binds to Calcineurin, sterically hindering the access of substrates like NFAT to the phosphatase active site, thereby inhibiting its activity [PMID: 7504238, StatPearls: NBK482450].