Nature 341, 758 - 760 (26 October 1989); doi:10.1038/341758a0

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

Matthew W. Harding, Andrzej Galat^†, David E. Uehling^† & Stuart L. Schreiber^†

Division of Organ Transplantation and Immunology, Department of Surgery, Yale University School of Medicine, 310 Cedar St, New Haven, Connecticut 06510, USA
^† Department of Chemistry, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA

THE structurally novel macrolide FK506 (refs 1,2) has recently been demonstrated to have potent immunosuppressive activity^3–7 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, cyclophilin^9–11, 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 (M_r) 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.

References

1.	Tanaka, H. et al. J. Am. chem. Soc. 109, 5031−5033 (1987). | Article | ChemPort |
2.	Kino, T. et al. J. Antibiotics 40, 1249−1256 (1987). | ISI | ChemPort |
3.	Thomson, A. W. Immunology Today 10, 6−9 (1989). | Article | PubMed | ChemPort |
4.	Sawada, S., Suzuki, G., Kawase, Y. & Takaku, F. J. Immun. 139, 1797−1803 (1987). | PubMed | ChemPort |
5.	Yoshimura, N., Matsui, S., Hamashima, T. & Oka, T. Transplantation 47, 351−356 (1989). | PubMed | ChemPort |
6.	Yoshimura, N., Matsui, S., Hamashima, T. & Oka, T. Transplantation 47, 356−359 (1989). | PubMed | ChemPort |
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). | PubMed | ISI | ChemPort |
10.	Harding, M. W., Handschumacher, R. E. & Speicher, D. W. J. biol. Chem. 261, 8547−8555 (1986). | PubMed | ChemPort |
11.	Warti, V. et al. Transplantation 46, 453−455 (1988). | PubMed | ChemPort |
12.	Fischer, G., Wittmann-Liebold, B., Lang, K., Kiefhaber, T. & Schmid, F. X. Nature 337, 476−478 (1989). | Article | PubMed | ISI | ChemPort |
13.	Takahashi, N., Hayano, T. & Suzuki, M. Nature 337, 473−475 (1989). | Article | PubMed | ISI | ChemPort |
14.	Koletsky, A. J., Harding, M. W. & Handschumacher, R. E. J. Immun. 137, 1054−1059 (1986). | PubMed | ChemPort |
15.	Findlay, J. A. & Radics, L. Can. J. Chem. 58, 579−590 (1980). | ChemPort |
16.	Martel, R. J., Klicius, J. & Galet, S. Can. J. Physiol. Pharmac. 55, 48 (1977). | ChemPort |
17.	Shieh, B. H., Stamnes, M. A., Seavello, S., Harris, G. L. & Zuker, C. S. Nature 338, 67−70. (1989). | Article | PubMed | ISI | ChemPort |
18.	Schneuwly, S. et al. Proc. natn. Acad. Sci. U.S.A. 86, 5390−5394 (1989). | ChemPort |
19.	Tropschung, M. et al. J. biol. Chem. 263, 14433−14440 (1988). | PubMed | ISI | ChemPort |
20.	Coleman, R. S. & Danishefsky, S. J. Heterocycles 28, 157−161 (1989). | ChemPort |
21.	Bayley, H., Standring, D. & Knowles, J. R. Tetrahedron Lett. 39, 3633−3634 (1978).
22.	Gershoni, J. M., Davis, F. E. & Palade, G. E. Analyt. Biochem. 144, 32−40 (1085).
23.	Matsudaira, P. J. biol. Chem. 261, 10035−10038 (1987).