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Noncatalytic Role of the FKBP52 Peptidyl-Prolyl Isomerase Domain in the Regulation of Steroid Hormone Signaling

Daniel L. Riggs,¹ Marc B. Cox,^1, Heather L. Tardif,¹ Martin Hessling,² Johannes Buchner,² and David F. Smith^1*

Mayo Clinic Arizona, Scottsdale, Arizona 85259,¹ Institut fur Organische Chemie und Biochemie, Technische Universitat Munchen, 85747 Garching, Germany²

Received 4 June 2007/ Returned for modification 9 July 2007/ Accepted 1 October 2007

Hormone-dependent transactivation by several of the steroid hormone receptors is potentiated by the Hsp90-associated cochaperone FKBP52, although not by the closely related FKBP51. Here we analyze the mechanisms of potentiation and the functional differences between FKBP51 and FKBP52. While both have peptidyl-prolyl isomerase activity, this is not required for potentiation, as mutations abolishing isomerase activity did not affect potentiation. Genetic selection in Saccharomyces cerevisiae for gain of potentiation activity in a library of randomly mutated FKBP51 genes identified a single residue at position 119 in the N-terminal FK1 domain as being a critical difference between these two proteins. In both the yeast model and mammalian cells, the FKBP51 mutation L119P, which is located in a hairpin loop overhanging the catalytic pocket and introduces the proline found in FKBP52, conferred significant potentiation activity, whereas the converse P119L mutation in FKBP52 decreased potentiation. A second residue in this loop, A116, also influences potentiation levels; in fact, the FKBP51-A116V L119P double mutant potentiated hormone signaling as well as wild-type FKBP52 did. These results suggest that the FK1 domain, and in particular the loop overhanging the catalytic pocket, is critically involved in receptor interactions and receptor activity.

Published ahead of print on 15 October 2007.

Present address: Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79902.