Peptidyl-prolyl cis-trans isomerase A (Cyclophilin A)–calcineurin complex (CypA–CaN complex)

The Cyclophilin A–calcineurin complex is a critical molecular assembly involved in the regulation of the adaptive immune response (PubMed, PMID: 1376944). Cyclophilin A (PPIA) is an intracellular protein with peptidyl-prolyl cis-trans isomerase activity, while calcineurin is a calcium-dependent serine/threonine protein phosphatase (UniProt, P62937). In the presence of the immunosuppressant drug cyclosporine A, a ternary complex is formed where the drug-bound cyclophilin A physically blocks the active site of calcineurin (StatPearls, "Cyclosporine"). This inhibition prevents calcineurin from dephosphorylating the transcription factor NFAT, which is essential for the production of interleukin-2 and the activation of T-lymphocytes (PubMed, PMID: 7545934). Consequently, this complex is a primary target for preventing organ transplant rejection and treating various autoimmune conditions. However, the ubiquitous expression of these proteins leads to significant side effects, most notably renal toxicity and hypertension, which limit the long-term clinical utility of drugs targeting this interaction (Mayo Clinic, "Cyclosporine"). Newer derivatives like voclosporin aim to improve the potency and metabolic profile of this interaction (FDA, "Lupkynis").

Other names

PPIA-PPP3CA complexCyclophilin A-Protein phosphatase 2B complexCsA-CypA-calcineurin complexCyclosporine-cyclophilin-calcineurin complex

Cyclosporine A binds to Cyclophilin A to form a gain-of-function complex that binds to and inhibits the phosphatase activity of calcineurin (StatPearls, "Cyclosporine"). This inhibition prevents the dephosphorylation of Nuclear Factor of Activated T-cells (NFAT), thereby blocking its translocation to the nucleus and the subsequent transcription of pro-inflammatory cytokines like IL-2 (PubMed, PMID: 7545934).