Prolyl isomerases Immunophilins

FKBP12 is a member of immunophilin family that has prolyl isomerase activity and is related to the cyclophi-lins in function. FKBP12 binds immunosuppressant molecule FK506 (tacrolimus). The FBKP-FK506 complex inhibits calcineurin, a protein phosphatase, thus blocking signal transduction in the T-lymphocyte... 

Tacrolimus (FK 506) is an immunosuppressant macrolide antibiotic produced by Streptomyces tsukubaensis. It is not chemically related to cyclosporine, but their mechanisms of action are similar. Both drugs bind to cytoplasmic peptidyl-prolyl isomerases that are abundant in all tissues. While cyclosporine binds to cyclophilin, tacrolimus binds to the immunophilin FK-binding protein (FKBP). Both complexes inhibit calcineurin, which is necessary for the activation of the T-cell-specific transcription factor NF-AT. 

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). 

FKBP, for example, the FK506-binding protein is a member of the family of immuno-phUins. Immunophilins are receptor-like small binding proteins that participate in T cell activation. These small proteins have peptidyl-prolyl-isomerase activity. Binding of the complex of FK506 with its FKBP blocks the action of calcineurin, a phosphatase which is involved in T ceU activation. 

Cyclophilin A, a member of the immunophilin family, is secreted by vascular smooth muscle cells in response to oxidative stress and mediates extracellular signal-regulated kinase (ERKl/2) activation and vascular smooth muscle cell growth by reactive oxygen species (Jin et al. 2000). Human recombinant cyclophilin A can mimic the effects of secreted cyclophilin A to stimulate ERKl/2 and cell growth. The peptidyl-prolyl isomerase activity is required for ERKl/2 activation by cyclophilin A. In vivo, cyclophilin A expression and secretion are increased by oxidative stress and vascular injury. 

Initial Cellular Target for FK506 and Rapamycin Peptidyl Prolyl cis-trans Isomerases (Rotamases, Immunophilins). 586... 

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