FK506-binding proteins

Fe-TPAA Fe(III)-tris[N-(2-pyridylmethyl)-2-aminoethyl] amine Fe-TPEN Fe(II)-tetrakis-N,N,N, N -(2-pyridyl methyl-2-aminoethyl)amine FFA Free fatty acids FGF Fibroblast growth factor FID Flame ionization detector FITC Fluorescein isothiocyanate FKBP FK506-binding protein FLAP 5-lipoxygenase-activating protein... 

Davis, E.C., Broekelmann, T.J., Ozawa, Y. and Mecham, R.P. (1998) Identification of tropoelastin as a ligand for the 65-kD FK506-binding protein, FKBP65, in the secretory pathway. Journal of Cell Biology 140, 295-303. 

Zeng, B.F., MacDonald, J.R., Bann, J.G., Reck, K., Gambee, J.E., Boswell, B.A. and Bachinger, H.P. (1998) Chicken FK506-binding protein, FKBP65, a member of the FKBP family of peptidylprolyl cis-lrans isomerases, is only partially inhibited by FK506. BiochemicalJournal 330, 109-114. 

Wulfing, C., Lombardero, J. and Pluckthun, A. (1994) An Escherichia coli protein consisting of a domain homologous to FK506-binding proteins (FKBP) and a new metal binding motif. Journal of Biological Chemistry 269, 2895-2901. 

Inhibitor 1, inhibitor 2 DARPP-32, NIPP1 Inhibitor 12A, inhibitor 22A Immunophilins Cyclosporin A-cyclophilin, FK06-FK506-binding protein... 

FE FKBP female equivalent FK506-binding protein... 

F.A. Etzkorn, L.A. Stolz, Z.Y. Chang, C.T. Walsh, Role of the cyclosporin-A-cyclophilin complex, FK506-FK506-binding protein complex and calcineurin in the inhibition of T-cell signal transduction, Curr. Opin. Struct. Biol. 3 (1993) 929-933. 

The protein phosphatase calcineurin was of particular interest since it mediates the immunosuppressive effect of the pharmaceuticals cyclosporin and FK506, often used in organ and tissue transplantations. The biochemical point of application of both pharmaceuticals was unclear for a long time. In initial experiments, it was found that cyclosporin and FK506 bind specifically to two proteins known as cyclophilin and FK506 binding protein, respectively. Both proteins function as peptidyl prolyl cis/trans isome-rases (review Fischer, 1994). 

The immimosuppressive effect of cyclosporin and FK506 could not initially be explained by these observations. Only with the discovery that cyclosporin and FK506 achieve their immunosuppressive effect via inhibition of calcineurin did it become clear that the immimosuppression is mediated by a complex reaction chain involving calcineurin. It was shown that the complexes of cyclosporin/cyclophilin and FK506/ FK506 binding protein bind to calcineurin and inhibit the phosphatase activity of the latter. 

A new class of immunosuppressive agents called proliferation-signal inhibitors (PSIs) includes sirolimus (rapamycin) and its derivative everolimus. The mechanism of action of PSIs differs from that of the calcineurin inhibitors. PSIs bind the circulating immunophilin FK506-binding protein 12, resulting in an active complex that blocks the molecular target of rapamycin (mTOR). 

L., Zhong, W., Xiao, J., Hu, Y., Li, S. (2006) FK506-binding protein ligands structure-based design, synthesis, and neurotrophic/neuroprotective properties of substituted 5,5-dimethyl-2-(4-thiazolidine)carboxylates. / Med Chem 49, 4059 071. 

Generates structures similar to known inhibitors of HIV protease, FK506 binding protein and carbonic anhydrase... 

It was a surprise to discover that all of the cyclo-philins and FK506-binding proteins are peptidyl prolyl cis—traits isomerases or rotamases. They all catalyze the following simple and reversible reaction of a prolyl peptide linkage ... 

Cyclophilins and FKBPs are large families of proteins. In E. coli there are two cyclophilin genes, three encoding FK506-binding proteins, and one of... 

K. F. Fulton, E. R. G. Main, and S. E. Jackson, personal communication (1998). FKBP12 = FK506 binding protein. 

Tacrolimus suppresses peptidyl-prolyl isomerase activity by binding to the immuno-philin FK506-binding protein-12 (FKBP-12), and the tacrolimus-FKBP-12 complex binds to calcineurin and inhibits calcineurin phosphatase activity. As a result, calcineurin is unable to dephosphorylate NFATc and thus its migration to nucleus is blocked where its association with NFATn is necessary for the activation of key cytokine genes. Therefore, its mechanism of action is similar to cyclosporine although tacrolimus binds to a separate set of immunophilins in the cytoplasm. Tacrolimus, like cyclosporine, inhibits the secretion of key cytokines and inhibits T-cell activation (Fig. 4.2). 

Patterson, C. E., Gao, J., Rooney, A. P., and Davis, E. C. (2002). Genomic organization of mouse and human 65 kDa FK506-binding protein genes and evolution of the FKBP multigene family. Genomics 79, 881-889. 

Prestle, J., Janssen, P. M., Janssen, A. P., Zeitz, O., Lehnart, S. E., Bruce, L., Smith, G. L., and Hasenfuss, G. (2001). Overexpression of FK506-Binding Protein FKBP12.6 in Cardiomyocytes Reduces Ryanodine Receptor-Mediated Ca(2+) Leak from the Sarcoplasmic Reticulum and Increases Contractility. Circ Res 88(2) 188-94. 

Xiao, B., Sutherland, C., Walsh, M.P., et al. 2004, Protein kinase A phosphorylation at serine-2808 of the cardiac Ca -release channel (ryanodine receptor) does not dissociate 12.6-kDa FK506-binding protein (FKBP12.6). Circ Res, 94(4), pp 487-95. 

---