Cyclophilin–Calcineurin complex (Cyp–CaN)

The Cyclophilin–Calcineurin complex is a multi-protein assembly that serves as a pivotal regulator of the adaptive immune response [1, 4]. It primarily consists of the cytosolic immunophilin Cyclophilin A (PPIA) and the heterodimeric phosphatase Calcineurin, which is composed of a catalytic subunit (CNA) and a regulatory subunit (CNB) [4, 9]. While these proteins exist independently, they form a stable ternary complex in the presence of the immunosuppressive drug Cyclosporine A [3, 11]. This drug-induced complex sterically blocks the active site of Calcineurin, preventing it from dephosphorylating the Nuclear Factor of Activated T-cells (NFAT) [1, 2]. Without dephosphorylation, NFAT cannot translocate to the nucleus to initiate the transcription of interleukin-2 (IL-2) and other pro-inflammatory cytokines [2, 3]. Consequently, the inhibition of this complex leads to potent suppression of T-cell activation and proliferation [1, 6]. This mechanism is therapeutically exploited to prevent organ transplant rejection and manage various autoimmune disorders such as psoriasis and rheumatoid arthritis [1, 12]. However, the ubiquitous expression of these proteins leads to significant off-target effects, including nephrotoxicity and hypertension, which limit the long-term clinical utility of drugs targeting this complex [13, 16].

Other names

Cyclophilin A–Calcineurin complex [4, 10]CypA–CaN [4, 5]CsA–CypA–CaN complex [11]Immunophilin–Calcineurin complex [4, 7]

Cyclosporine A binds to Cyclophilin A to form a complex that inhibits the phosphatase activity of Calcineurin, preventing NFAT dephosphorylation and subsequent T-cell activation [1, 2, 4].