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Molecular Endocrinology 12 (3): 342-354
Copyright © 1998 by The Endocrine Society

Analysis of FKBP51/FKBP52 Chimeras and Mutants for Hsp90 Binding and Association with Progesterone Receptor Complexes

Richard L. Barent, Satish C. Nair, Damon C. Carr, Ying Ruan, Ronald A. Rimerman, Jennifer Fulton, Yan Zhang and David F. Smith

Department of Pharmacology University of Nebraska Medical Center Omaha, Nebraska 68198-6260

FKBP51, FKBP52, and Cyp40 bind competitively to Hsp90 through their respective tetratricopeptide repeat (TPR) domains, and any one of the three immunophilins can be isolated in mature steroid receptor complexes. During cell-free assembly reactions, FKBP51 associates preferentially with progesterone and glucocorticoid receptors, but less preference is observed in FKBP51 association with estrogen receptor. A number of mutant FKBP forms were generated to map sequences responsible for FKBP51’s preferred association with progesterone receptor. A double-point mutation in the peptidyl prolyl isomerase domain of FKBP51 that reduces enzymatic activity by greater than 90% had no observed effect on FKBP51 interactions with progesterone receptor or Hsp90. Coprecipitation of FKBP51 and FKBP52 truncation mutants with Hsp90 indicated that sequences both upstream and downstream of the TPR domain are necessary for Hsp90 binding. FKBP chimeric constructs were also generated and tested for Hsp90 binding and receptor association. The TPR domain of FKBP51 required appropriate downstream sequences for Hsp90 binding, but FKBP52’s TPR domain did not. The C-terminal region of FKBP51 that functionally interacts with the TPR domain to permit Hsp90 binding also conferred preferential association with PR. In conclusion, despite the overall similarity of FKBP51 and FKBP52, these two immunophilins associate differentially with steroid receptors, and the difference relates to both the Hsp90-binding TPR domain and to poorly conserved C-terminal sequences.




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