Work

Inhibition of calcineurin by a novel FK-506-binding protein.

Year: 1994

Type: article

Abstract: FK-506, a potent immunosuppressive drug, acts during the commitment phase of T-lymphocyte activation to block a subset of c a l c i u m -~s ~i a t e d events necessary for transcription of certain early lymphokine genes.The drug binds to an abundant, cytosolic 11.8-kDa protein termed the FK-506-binding protein (FKBP12).The FKBP12-FK-506 complex inhibits calcineurin, a calciumdependent phosphatase that is a component of the sip nal transduction pathway leading to early lymphokine gene transcription.FKBP12 is one member of a growing gene family.Prior to this report, all other FKBP family members had been irrelevant to the mechanism of action of FK-506 because no other FKBP-FK-506 complexes were able to bind and inhibit calcineurin.Here, we report the purification and characterization of a novel m-506-binding protein, FKBP12.6.Having 85% amino acid sequence identity to FKBP12, FKBP12.6 is, among the FKBPs, most closely related to FKBP12.When complexed with FK-506, FKBP12.6 binds to and inhibits calcineurin, making it only the second FKBP discovered thus far to do so.The ability to inhibit calcineurin establishes the potential relevance of FKf3P12.6 to the im- munosuppressive or toxic side effects of FK-506.FK-506 (tacrolimus, Prograf) is a powerful immunosuppressive drug useful in the prophylaxis of allograft rejection following transplant surgery.Although having no structural resemblance to cyclosporin (CsA),' an immunosuppressant used in organ transplantation for more than a decade, both drugs derive their therapeutic benefit from inhibiting T-lymphocyte activation by a similar mechanism of action.In response to presentation with cognate antigen, signal transduction events occur during the commitment phase of T-lymphocyte activation that include the activation of protein kinase C and an increase in intracellular calcium (1).It is a calcium-associated pathway that is sensitive to both FK-506 and CsA (2).Both drugs block transcription of a set of early lymphokine genes, including IL-2, IL-3, IL-4, interferon-y, granulocyte/macrophage colony-stimulating factor, and tumor necrosis factor-a, that are required for generation of the immune response (31, * The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.

Source: Journal of Biological Chemistry

DOI: 10.1016/s0021-9258(17)31934-8