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Molecular and Cellular Biology, December 2007, p. 8658-8669, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.00985-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Daniel L. Riggs,1 Marc B. Cox,1,{dagger} Heather L. Tardif,1 Martin Hessling,2 Johannes Buchner,2 and David F. Smith1*

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.

* Corresponding author. Mailing address: S. C. Johnson Research Building, Mayo Clinic Arizona, 13400 E. Shea Blvd., Scottsdale, AZ 85259. Phone: (480) 301-6595. Fax: (480) 301-9162. E-mail: smith.david26{at}mayo.edu

{triangledown} Published ahead of print on 15 October 2007.

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

Molecular and Cellular Biology, December 2007, p. 8658-8669, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.00985-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Smith, D. F., Toft, D. O. (2008). Minireview: The Intersection of Steroid Receptors with Molecular Chaperones: Observations and Questions. Mol. Endocrinol. 22: 2229-2240 [Abstract] [Full Text]  


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