Immunophilins, FK506 binding protein (FKBP) and cyclophilin (CYP) have been identified as the major intracellular molecules that bind to their immunosuppressive drugs, FK506 and cyclosporin A, respectively. These immunophilin-immunosuppressant complexes prevent the dephosphorylation of calcineurin which subsequently inactivate the cascade events leading to the inhibition of T-cell activation. We found sequence homology between the amino acid sequences of the three microtubule binding domains (MBD) of the microtubule-associated protein and protein kinase C inhibitor-l (PKCI-l), FKBP and CYP. We proposed that PKCI-1 and immunophilins are topographically associated with microtubules (MT) through the MBD. We demonstrated that the cellular organization of PKCI-1, FKBP and CYP was topographic...[ Read more ]

Immunophilins, FK506 binding protein (FKBP) and cyclophilin (CYP) have been identified as the major intracellular molecules that bind to their immunosuppressive drugs, FK506 and cyclosporin A, respectively. These immunophilin-immunosuppressant complexes prevent the dephosphorylation of calcineurin which subsequently inactivate the cascade events leading to the inhibition of T-cell activation. We found sequence homology between the amino acid sequences of the three microtubule binding domains (MBD) of the microtubule-associated protein and protein kinase C inhibitor-l (PKCI-l), FKBP and CYP. We proposed that PKCI-1 and immunophilins are topographically associated with microtubules (MT) through the MBD. We demonstrated that the cellular organization of PKCI-1, FKBP and CYP was topographically associated with MT by double immunofluorescence staining analysis. In addition, it was found that PKCI-1 and CYP were both co-purified with tubulin using a GTP and temperature dependent in vitro microtubule polymerization technique. Moreover, cyclosporin A, the ligand of cyclophilin, increased the level of microtubule polymerization induced by taxol. Therefore, our results demonstrated that, similar to the microtubule-associated proteins (MAPS), PKCI-1 and immunophilins were associated with microtubules. Furthermore, the MBD-like peptides of PKCI-1 affected the dynamics of microtubule polymerization and inhibited DNA synthesis during T-cell activation. Thus, the immunosuppressive activity of these immunosupppressive drugs might be mediated by the alteration of the MT organization through the MBD. It may be possible to develop immunosuppressive agents that target the MBD of immunophilins.