Cyclophilin, a primary molecular target for cyclosporine. Structural and functional implications.

An understanding of the mechanism of action of cyclosporine requires the identification and functional characterization of its molecular target or targets in the cell. Our laboratory has presented evidence that cyclophilin (CYP), a low-molecular-weight (Mr 17,737) basic protein, is the primary cytosolic receptor for CsA. The high affinity of CYP for CsA (Kd 30 nM) and specificity for immunosuppressive cyclosporine analogs implicate CYP as a pivotal regulator of T cell and B cell activation. CYP exists in at least two isoforms, is abundant (0.05% to 0.4% of total protein) in the cytosol, and is ubiquitous in cells and tissues of eukaryotic organisms. Its amino acid sequence is highly conserved and there is strong evidence that CYP is a member of a new multigene family. These features suggest that one or more CYP isoforms must play a crucial role in lymphocyte activation and perhaps a multifunctional role in cellular physiology. The ability of CsA to suppress expression of several lymphokine and proto-oncogene products via a transcriptional control mechanism suggests that CYP may function at some level in a signaling pathway linking membrane receptor stimulation to gene regulatory elements in lymphocytes, and possibly nonlymphoid cell types as well.