Cyclophilin

Cyclophilins are a family of highly conserved proteins that function as peptidyl-prolyl cis-trans isomerases (PPIases) and are classified as immunophilins. They catalyze the isomerization of peptide bonds preceding proline residues, a key step in protein folding and conformational maturation. In humans, the best characterized members include cyclophilin A (PPIA) in the cytosol, cyclophilin B (PPIB) in the endoplasmic reticulum, and cyclophilin D (PPIF) in mitochondria, along with additional isoforms that localize to other cellular compartments.

Cyclophilins share a conserved catalytic domain that forms a beta-barrel structure with a hydrophobic pocket that binds proline-containing substrates. They are notable for their high-affinity binding to the immunosuppressant cyclosporin A; this complex inhibits calcineurin and suppresses T-cell activation. Some cyclophilins also participate in chaperone-like activities independent of their PPIase function and assist in protein assembly, trafficking, and signaling processes.

Biological roles for cyclophilins are diverse. They contribute to proper protein folding in the cytosol, endoplasmic reticulum, and mitochondria, influence signaling pathways, and participate in stress responses. Cyclophilin D, in particular, regulates the mitochondrial permeability transition pore and can modulate cell death processes. The family is present across bacteria, archaea, and eukaryotes, with multiple human isoforms exhibiting distinct subcellular localizations and functions.

Medical relevance and research implications are notable. The cyclosporin A–cyclophilin complex is central to immunosuppression in transplant medicine. Cyclophilins also interact with various viral and cellular proteins, affecting viral replication and host responses in some contexts. Inhibitors and modulators of cyclophilins are investigated as potential therapeutic tools for immune, infectious, and neurodegenerative diseases.