title: Cyclolinopeptide A (CLA) mediates its immunosuppressive activity through cyclophilin-dependent calcineurin inactivation.
abstract: The immunosuppressive cyclic nonapeptide cyclolinopeptide A inhibits calcium-dependent, but not calcium-independent, activation of T lymphocytes comparably to the actions of cyclosporin A and FK506. The concentration required for complete inhibition, however, is 10 times higher than that of cyclosporin A. In addition, we demonstrate that calcineurin, a phosphatase which plays an important role in T lymphocyte signalling, is inhibited in vitro by cyclolinopeptide A by a mechanism dependent on the peptidyl-prolyl cis-trans isomerase (PPIase) cyclophilin A but not FKBP12. Direct binding of cyclolinopeptide A to cyclophilin A was confirmed using tryptophan fluorescence studies and PPIase assays. These results represent a third example of the production of a natural product that neutralises calcineurin by a mechanism dependent on the primary binding to a PPIase.
authors.affiliation: School of Biological Sciences, University of Sussex, Brighton, UK.
authors.forename: T J
authors.initials: TJ
authors.lastname: Gaymes
authors.forename: M
authors.initials: M
authors.lastname: Cebrat
authors.forename: I Z
authors.initials: IZ
authors.lastname: Siemion
authors.forename: J E
authors.initials: JE
authors.lastname: Kay
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation; D011090:Polyenes / Q000494:pharmacology; D020123:Sirolimus; D013552:Swine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D010455:Peptides; D010456:Peptides, Cyclic; D011090:Polyenes; C055018:cyclolinopeptide A; D016572:Cyclosporine; D019696:Peptidylprolyl Isomerase; D013755:Tetradecanoylphorbol Acetate; D020123:Sirolimus