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This version published online on March 31, 2005
Endocrinology, doi:10.1210/en.2005-0027
A more recent version of this article appeared on July 1, 2005
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Submitted on January 10, 2005
Accepted on March 23, 2005

Structure-function analysis of squirrel monkey FKBP51, a potent inhibitor of glucocorticoid receptor activity

Wesley B. Denny, Viravan Prapapanich, David F. Smith, and Jonathan G. Scammell*

Departments of Pharmacology (W.B.D., J.G.S.) and Comparative Medicine (J.G.S.), University of South Alabama, College of Medicine, Mobile, Alabama 36688; and Department of Biochemistry and Molecular Biology (V.P., D.F.S.), Mayo Clinic Scottsdale, Scottsdale, Arizona 85259

* To whom correspondence should be addressed. E-mail: jscammel{at}jaguar1.usouthal.edu.

FKBP51 and FKBP52 are large molecular weight immunophilins that are part of the mature glucocorticoid receptor (GR) heterocomplex. These proteins possess peptidyl-prolyl isomerase (PPIase) and tetratricopeptide repeats (TPR) domains that are important for modulation of GR activity. A naturally occurring animal model of glucocorticoid resistance, the squirrel monkey, results from the relative overexpression of FKBP51 that renders the GR in a low affinity state. In vitro studies demonstrated that the squirrel monkey form of FKBP51 is greater than 6-fold more potent than human FKBP51 in this respect. The goals of these studies were to determine the roles of the TPR and PPIase domains in the inhibitory activity of squirrel monkey FKBP51 and to gain insight into structural features of squirrel monkey FKBP51 responsible for potent inhibition of dexamethasone-stimulated GR activity. Mutations in the TPR of squirrel monkey FKBP51 that inhibit association with Hsp90 blocked GR inhibitory activity. Mutations that abrogate the PPIase activity of squirrel monkey FKBP51 had no effect on GR inhibitory activity. Chimeras of squirrel monkey and human FKBP51 were tested to identify domains responsible for their different inhibitory potencies. Amino acid differences in domains FK1 and FK2 between squirrel monkey and human FKBP51 contribute equally to the enhanced inhibitory activity of squirrel monkey FKBP51. Furthermore, squirrel monkey FKBP51 in which either FK1 or FK2 was deleted lacked GR inhibitory activity. Thus, the potent inhibitory activity of squirrel monkey FKBP51 involves both FK domains and the Hsp90-binding TPR domain.
Key words: immunophilin • tetratricopeptide repeat • isomerase • chimera




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