Peptidyl-prolyl cis-trans isomerase A-Calcineurin complex (CypA-CaN complex)

The Peptidyl-prolyl cis-trans isomerase A-Calcineurin complex is a multi-protein assembly that serves as the primary pharmacological target for the immunosuppressant drug Cyclosporine A (Liu et al., 1991, Cell). Peptidyl-prolyl cis-trans isomerase A (also known as Cyclophilin A or PPIA) is an intracellular enzyme that facilitates protein folding, but in the presence of Cyclosporine, it forms a binary complex that gains the ability to bind and inhibit Calcineurin (a heterodimer of Protein phosphatase 3 catalytic subunit alpha and a regulatory subunit) (UniProt P62937). Calcineurin is a calcium-calmodulin-dependent serine/threonine phosphatase essential for the dephosphorylation of the Nuclear Factor of Activated T-cells (NFAT) (PubMed: 7529392). Once dephosphorylated, NFAT translocates to the nucleus to initiate the transcription of Interleukin-2 (IL-2) and other pro-inflammatory cytokines necessary for T-cell activation and proliferation (StatPearls, "Cyclosporine"). By blocking this pathway, the complex prevents the immune system from attacking transplanted organs or self-tissues in autoimmune diseases (NIH, "Cyclosporine"). However, because Calcineurin is expressed in various tissues, its inhibition leads to significant adverse effects such as nephrotoxicity, hypertension, and neurotoxicity (PubMed: 25637478).

Other names

Cyclophilin A-Calcineurin complexPPIA-PPP3CA complexCyclosporine-Cyclophilin-Calcineurin complexCsA-CypA-CaN complex

Cyclosporine binds to Peptidyl-prolyl cis-trans isomerase A (Cyclophilin A) to form a gain-of-function complex that binds to and inhibits the phosphatase activity of Calcineurin. This inhibition prevents the dephosphorylation of the Nuclear Factor of Activated T-cells (NFAT), thereby blocking its translocation to the nucleus and the subsequent transcription of pro-inflammatory cytokines like Interleukin-2 (IL-2).