Cyclophilin A-calcineurin signaling complex (CypA-CaN complex)

The Cyclophilin A-calcineurin signaling complex is a multi-protein assembly central to the activation of T lymphocytes and the subsequent adaptive immune response (PMID: 1711499). It consists of the peptidyl-prolyl cis-trans isomerase Cyclophilin A (CypA) and the calcium-dependent serine/threonine phosphatase calcineurin (CaN). In the presence of the immunosuppressant drug Cyclosporine A, a ternary complex is formed where the drug-CypA unit binds to calcineurin, sterically hindering its phosphatase activity (UniProt P62937, P16298). This inhibition prevents the dephosphorylation of the Nuclear Factor of Activated T-cells (NFAT), thereby blocking its translocation into the nucleus and the transcription of critical cytokines like Interleukin-2 (IL-2). This pathway is a primary therapeutic target for preventing organ transplant rejection and treating autoimmune disorders such as rheumatoid arthritis and psoriasis (StatPearls: Cyclosporine). However, because calcineurin is also expressed in non-immune tissues, targeting this complex can lead to significant adverse effects, most notably dose-dependent nephrotoxicity and hypertension.

Other names

PPIA-PPP3CA complexCyclosporine-Cyclophilin-Calcineurin complexPeptidyl-prolyl cis-trans isomerase A-calcineurin complexCypA-CaN-NFAT signaling axis

The drug (e.g., Cyclosporine) binds to the peptidyl-prolyl isomerase Cyclophilin A to form a gain-of-function complex that binds to and inhibits the phosphatase activity of calcineurin, thereby preventing the dephosphorylation and nuclear translocation of the transcription factor NFAT (PMID: 1711499).