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

• Published in: The Journal of biological chemistry 1994-08, Vol.269 (33), p.21094-21102
• Main Authors: SEWELL, T. J, LAM, E, SIGAL, N. H, WIEDERRECHT, G. J, MARTIN, M. M, LESZYK, J, WEIDNER, J, CALAYCAY, J, GRIFFIN, P, WILLIAMS, H, HUNG, S, CRYAN, J
• Format: Article
• Language: English
• Subjects: Amino Acid Isomerases - antagonists & inhibitors; Amino Acid Sequence; Analytical, structural and metabolic biochemistry; Animals; Binding and carrier proteins; Biological and medical sciences; Blotting, Western; Brain - metabolism; Calcineurin; Calmodulin-Binding Proteins - antagonists & inhibitors; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - isolation & purification; Carrier Proteins - physiology; Cattle; Cross Reactions; Electrophoresis, Polyacrylamide Gel; Fundamental and applied biological sciences. Psychology; Heat-Shock Proteins - isolation & purification; Heat-Shock Proteins - physiology; Immunomodulators; Medical sciences; Molecular Sequence Data; Peptidylprolyl Isomerase; Pharmacology. Drug treatments; Phosphoprotein Phosphatases - antagonists & inhibitors; Polyenes - pharmacology; Proteins; Sequence Homology, Amino Acid; Sirolimus; Tacrolimus - pharmacology; Tacrolimus Binding Proteins
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/s0021-9258(17)31934-8

FK-506, a potent immunosuppressive drug, acts during the commitment phase of T-lymphocyte activation to block a subset of calcium-associated 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 calcium-dependent phosphatase that is a component of the signal 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 FK-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 FKBP12.6 to the immunosuppressive or toxic side effects of FK-506.