FKBP51, A NOVEL T-CELL-SPECIFIC IMMUNOPHILIN CAPABLE OF CALCINEURIN INHIBITION

The immunosuppressive drugs FK506 and cyclosporin A block T-lymphocyte proliferation by inhibiting calcineurin, a critical signaling molecul e for activation. Multiple intracellular receptors (immunophilins) for these drugs that specifically bind either FK506 and rapamycin (FK506- binding proteins [FKBPs]) or cyclosporin A (cyclophilins) have been id entified. We report the cloning and characterization of a new 51-kDa m ember of the FKBP family from murine T cells. The novel immunophilin, FKBP51, is distinct from the previously isolated and sequenced 52-kDa murine FKBP, demonstrating 53% identity overall. Importantly, Western blot (immunoblot) analysis showed that unlike all other FKBPs characte rized to date, FKBP51 expression was largely restricted to T cells. Dr ug binding to recombinant FKBP51 was demonstrated by inhibition of pep tidyl prolyl isomerase activity. As judged from peptidyl prolyl isomer ase activity, FKBP51 had a slightly higher affinity for rapamycin than for FK520, an FK506 analog, FKBP51, when complexed with FK520, was ca pable of inhibiting calcineurin phosphatase activity in an in vitro as say system. Inhibition of calcineurin phosphatase activity has been im plicated both in the mechanism of immunosuppression and in the observe d toxic side effects of FK506 in nonlymphoid cells. Identification of a new FKBP that can mediate calcineurin inhibition and is restricted i n its expression to T cells suggests that new immunosuppressive drugs may be identified that, by virtue of their specific interaction with F KBP51, would be targeted in their site of action.