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A receptor for the immuno-suppressant FK506 is a cis–trans peptidyl-prolyl isomerase

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Abstract

THE structurally novel macrolide FK506 (refs 1,2) has recently been demonstrated to have potent immunosuppressive activity3–7 at concentrations several hundredfold lower than cyclosporin A (CsA). Cyclosporin A, a cyclic peptide, has found widespread clinical use in the prevention of graft rejection following bone marrow and organ transplantation8. The mechanisms of immunosuppression mediated by FK506 and CsA appear to be remarkably similar, suggesting that these unrelated structures act on a common receptor or on similar molecular targets, perhaps the CsA receptor, cyclophilin9–11, which has recently been shown by Fischer etal.12 and Takahashi etal.13 to have cis–trans peptidyl-prolyl isomerase activity. We have prepared an FK506 affinity matrix and purified a binding protein for FK506 from bovine thymus and from human spleen. This FK506-binding protein (FKBP) has a relative molecular mass (Mr) of ∼14,000(14K), a pi of 8.8–8.9, and does not cross-react with antisera against cyclophilin. The first 40 N-terminal residues of the bovine and 16 residues of the human FKBP were determined; the 16-residue fragments are identical to each other and unrelated to any known sequences. This protein catalyses the cis–trans isomerization of the proline amide in a tetrapeptide substrate and FK506 inhibits the action of this new isomerase. The FKBP and cyclophilin appear to be members of an emerging class of novel proteins that regulate T cell activation and other metabolic processes, perhaps by the recognition (and possibly the isomerization) of proline-containing epitopes in target proteins.

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References

  1. Tanaka, H. et al. J. Am. chem. Soc. 109, 5031–5033 (1987).

    Article  CAS  Google Scholar 

  2. Kino, T. et al. J. Antibiotics 40, 1249–1256 (1987).

    Article  CAS  Google Scholar 

  3. Thomson, A. W. Immunology Today 10, 6–9 (1989).

    Article  CAS  PubMed  Google Scholar 

  4. Sawada, S., Suzuki, G., Kawase, Y. & Takaku, F. J. Immun. 139, 1797–1803 (1987).

    CAS  PubMed  Google Scholar 

  5. Yoshimura, N., Matsui, S., Hamashima, T. & Oka, T. Transplantation 47, 351–356 (1989).

    Article  CAS  PubMed  Google Scholar 

  6. Yoshimura, N., Matsui, S., Hamashima, T. & Oka, T. Transplantation 47, 356–359 (1989).

    Article  CAS  PubMed  Google Scholar 

  7. Sanghvi, A. et al. Transplant. Proc. 19 (Suppl. 6) 45 (1987).

  8. Second International Congress on Cyclosporine. Transplant. Proc. 20, Suppl. 2 (1988).

  9. Handschumacher R. E., Harding M. W., Rice, J., Drugge, R. J. & Speicher, D. W. Science 226, 544–546 (1984).

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Harding, M. W., Handschumacher, R. E. & Speicher, D. W. J. biol. Chem. 261, 8547–8555 (1986).

    CAS  PubMed  Google Scholar 

  11. Warti, V. et al. Transplantation 46, 453–455 (1988).

    Article  Google Scholar 

  12. Fischer, G., Wittmann-Liebold, B., Lang, K., Kiefhaber, T. & Schmid, F. X. Nature 337, 476–478 (1989).

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Takahashi, N., Hayano, T. & Suzuki, M. Nature 337, 473–475 (1989).

    Article  ADS  CAS  PubMed  Google Scholar 

  14. Koletsky, A. J., Harding, M. W. & Handschumacher, R. E. J. Immun. 137, 1054–1059 (1986).

    CAS  PubMed  Google Scholar 

  15. Findlay, J. A. & Radics, L. Can. J. Chem. 58, 579–590 (1980).

    Article  CAS  Google Scholar 

  16. Martel, R. J., Klicius, J. & Galet, S. Can. J. Physiol. Pharmac. 55, 48 (1977).

    Article  CAS  Google Scholar 

  17. Shieh, B. H., Stamnes, M. A., Seavello, S., Harris, G. L. & Zuker, C. S. Nature 338, 67–70. (1989).

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Schneuwly, S. et al. Proc. natn. Acad. Sci. U.S.A. 86, 5390–5394 (1989).

    Article  ADS  CAS  Google Scholar 

  19. Tropschung, M. et al. J. biol. Chem. 263, 14433–14440 (1988).

    Google Scholar 

  20. Coleman, R. S. & Danishefsky, S. J. Heterocycles 28, 157–161 (1989).

    Article  CAS  Google Scholar 

  21. Bayley, H., Standring, D. & Knowles, J. R. Tetrahedron Lett. 39, 3633–3634 (1978).

    Article  Google Scholar 

  22. Gershoni, J. M., Davis, F. E. & Palade, G. E. Analyt. Biochem. 144, 32–40 (1085).

    Article  Google Scholar 

  23. Matsudaira, P. J. biol. Chem. 261, 10035–10038 (1987).

    Google Scholar 

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Harding, M., Galat, A., Uehling, D. et al. A receptor for the immuno-suppressant FK506 is a cis–trans peptidyl-prolyl isomerase. Nature 341, 758–760 (1989). https://doi.org/10.1038/341758a0

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  • DOI: https://doi.org/10.1038/341758a0

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