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J Biol Chem, Vol. 273, Issue 32, 20473-20480, August 7, 1998
From the Studies of hsp90 in yeast have supported the
notion that this chaperone plays a critical role in signaling by
steroid receptors. One limitation to these studies is that yeast
expressing hsp90 mutants may also be deficient in fundamental cellular
functions of the chaperone required for steroid-dependent
induction of transcription. In this work, we have prepared mutants of
the glucocorticoid receptor (GR) that permit analysis of hsp90 binding
and transcriptional activity in cells with normal chaperone function.
Our previous data supported a model in which hsp90 binds to the
receptor steroid binding domain according to a two-site model. By amino
acid mutagenesis of these two sites, we have now generated three
receptor mutants and analyzed their function. Upon their translation
in vitro, all three mutants interacted with hsp90 similarly
to the wild-type receptor. However, one mutant, P643A (GRo), was of
particular interest because, although it showed normal steroid binding
and transformation to a glucocorticoid response element-specific DNA binding form, it was remarkably deficient in nuclear translocation and
transcriptional function at 37 °C. Furthermore, GRo·hsp90 heterocomplexes formed in vivo or assembled under cell-free
conditions were much less stable than wild-type GR·hsp90
heterocomplexes. Our results demonstrate that Pro-643 plays a critical
role in both stabilizing the receptor·hsp90 complex and in permitting an efficient nuclear translocation and, thus, support the concept that
the chaperone is an integral component of the steroid-receptor signaling pathway.
A Conserved Proline in the hsp90 Binding Region of the
Glucocorticoid Receptor Is Required for hsp90 Heterocomplex
Stabilization and Receptor Signaling
,,
Mental Health Research Institute and the
¶ Department of Pharmacology, The University of Michigan Medical
School, Ann Arbor, Michigan 48109
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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