Demonstration of ternary immunophilin-calcineurin complexes with the immunosuppressants cyclosporin and macrolide FK506

Biochemical Pharmacology
G WoerlyB Ryffel

Abstract

The specificity of cyclosporin A (CsA) binding to the major intracellular receptor proteins, cyclophilin A and B, as well as the interaction of CsA with the phosphatase calcineurin were investigated. Binding of photoaffinity-labeled CsA (PL-CS), a photoaffinity probe of CsA, to recombinant human cyclophilin A and B is saturable and specific. Non-specific PL-CS binding to calcineurin is observed in the absence of cyclophilin and calmodulin. In the presence of cyclophilin, cyclosporin-calcineurin binding becomes specific. Ternary complexes containing an equimolar ratio of cyclophilin A or B, PL-CS and calcineurin are resolved using the chemical-crosslinking technique. The formation of these complexes is specific, calcium- but not calmodulin-dependent, and is only inhibitable by cyclosporins, which bind cyclophilin. The drug-immunophilin complex binds to the calcineurin A subunit. The proteolytic 43 kDa product of calcineurin A retains binding properties, suggesting that the C-terminal domains are not necessary for complex formation. A trimeric complex of FKBP-calcineurin is also formed with FK506, but not with rapamycin. As expected, these complexes are only competed with by homologous derivatives. Chemical crosslinking of photol...Continue Reading

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Citations

Mar 28, 1998·Japanese Journal of Pharmacology·J UchidaT Kishimoto
Sep 19, 2003·Proceedings of the National Academy of Sciences of the United States of America·Perry L HowardTony Pawson
Nov 11, 2005·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Anna SaurinaFederico Oppenheimer
Apr 27, 2011·Journal of Neurochemistry·Wei-Li ZhuLin Lu
Feb 24, 2001·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·E MorelonH Kreis
Jun 29, 2001·Transplant Infectious Disease : an Official Journal of the Transplantation Society·R H RubinR E Morris
Mar 5, 2003·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·K E S PlathB F Gibbs

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