A receptor for the immuno-suppressant FK506 is a cis–trans peptidyl-prolyl isomerase (original) (raw)
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- Published: 26 October 1989
Nature volume 341, pages 758–760 (1989)Cite this article
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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 (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.
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Author notes
- Andrzej Galat, David E. Uehling and Stuart L. Schreiber: Department of Chemistry, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA
Authors and Affiliations
- Division of Organ Transplantation and Immunology, Department of Surgery, Yale University School of Medicine, 310 Cedar St, New Haven, Connecticut, 06510, USA
Matthew W. Harding, Andrzej Galat, David E. Uehling & Stuart L. Schreiber
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- Matthew W. Harding
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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
- Received: 06 July 1989
- Accepted: 11 September 1989
- Issue Date: 26 October 1989
- DOI: https://doi.org/10.1038/341758a0