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FKBP51 and FKBP52 differentially regulate corticosteroid receptors at distinct levels: Importance of the peptidylprolyl isomerase domain
The activity of corticosteroid receptors (CR) is regulated by numerous cofactors that are also frequently involved in the regulation of other signaling proteins. We found that the immunophilin FKBP51 specifically reduced the transcriptional activity of CR. Nuclear translocation of CR at sub-saturating hormone concentrations was diminished by FKBP51, consistent with the reduced interaction of FKBP51 with the motor protein dynein, in contrast to the close homologue FKBP52. FKBP52 alone did not affect CR, but mitigated the inhibitory effect of FKBP51. Point mutations revealed that the effect of FKBP51 depends on its interaction with hsp90, but not on its peptidylprolyl isomerase (PPIase) activity. However, abolition of the PPIase activity turned FKBP52 into a potent inhibitor of CR. Domain swapping substantiated differential interaction of the PPIase domains of FKBP51 and FKBP52 with dynein as explanation for their discriminative actions. Thus, FKBP51 inhibits CR by reducing nuclear translocation, in addition to its reported reduction of hormone binding. We propose that three features of the immunophilins are required for efficient CR signaling, hsp90 interaction, dynein association, and PPIase enzyme activity.