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

Abstract

The structurally novel macrolide FK506 (refs 1,2) has recently been demonstrated to have potent immunosuppressive activity 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 transplantation. 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, which has recently been shown by Fischer et al. and Takahashi et al. 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 approximately 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.

Active site mutants of human cyclophilin A separate peptidyl‐prolyl isomerase activity from cyclosporin A binding and calcineurin inhibition

“…Similar to CyP, the FK506 binding protein (FKBP) is an active PPIase (Harding et al, 1989;Siekierka et al, 1989). Both the FKBP-FKSO6 and the CyPCsA complexes have been shown to inhibit the in vitro activity of protein phosphatase 2B, calcineurin (Friedman & Weissman, 1991;Liu et al, 1991b).…”

A small molecule‐directed approach to control protein localization and function

“…As presented schematically in Figure 1B, rapamycin is a bifunctional molecule that binds with one face to FKBP (Harding et al, 1989;Siekierka et al, 1989), and this drug-protein complex then gains high affinity for the FRB domain (Bierer et al, 1990;Brown et al, 1994;Sabatini et al, 1994;Banaszynski et al, 2006b). Thus, the addition of rapamycin causes selective heterodimerization of the FKBP-and FRB-containing chimeras, reversibly reconstituting the target protein with a cellular address signal.…”

Clinical efficacy and cytokine network-modulating effects of tacrolimus in myasthenia gravis

“…Tacrolimus binds to FK506-binding protein 12 (FKBP12) which is the intracellular receptor of tacrolimus (Harding et al, 1989) and the FKBP12-tacrolimus complex inhibits dephosphorylation of nuclear factor (NF)-AT by calcineurin (Liu et al, 1991). As a result, inhibition of calcineurin prevents translocation of NF-AT to the nucleus, which is essential for transcription of IL-2 (Flanagan et al, 1991).…”