Cyclophilins (Cyp)

Cyclophilins are a highly conserved protein family with PPIase activity, crucial for the isomerization of peptide bonds at proline residues, thereby facilitating protein folding and function. Cyclophilin A (cytosolic), Cyclophilin B (endoplasmic reticulum), and Cyclophilin D (mitochondrial matrix) are the most extensively studied mammalian cyclophilins. These proteins are notable for their role as intracellular receptors for the immunosuppressive drug cyclosporine A, which blocks T-cell activation by interfering with cyclophilin-mediated calcineurin inhibition[7]. In addition to immune modulation, cyclophilins have important functions in chaperoning protein maturation, cell death regulation (notably, CypD’s involvement in mitochondrial permeability transition and necrosis)[3], and proteostasis, with substantial disease relevance in cancer, cardiovascular disease, neurodegeneration, and viral infections. Their central roles make them major targets for drug development aimed at modulating protein folding, cellular stress responses, and immune activity[6][9][3].\n- Cyclophilin A: cytosolic, major target for cyclosporine A, involved in immune modulation and inflammation[7][9].\n- Cyclophilin B: ER-localized, involved in protein folding, ER stress, extracellular matrix regulation, and cancer[5][6].\n- Cyclophilin D: mitochondrial, regulator of permeability transition pore opening, key role in cell death and neuro/cardiac injury[3].\nThese enzymes share a conserved β-barrel structure forming the PPIase domain and have distinct localization signals and functional properties[2][4][5].

Other names

CypACytosolic cyclophilinCypBEndoplasmic reticulum cyclophilinCypDMitochondrial cyclophilinPeptidyl-prolyl cis-trans isomerase APeptidyl-prolyl cis-trans isomerase BPeptidyl-prolyl cis-trans isomerase D

Inhibition of PPIase activity, blocking prolyl isomerization and interfering with protein folding\nImmunosuppression via blocking cyclophilin-calcineurin interaction (for cyclosporine A)\nModulation of mitochondrial permeability transition pore (CypD inhibitors)