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(Received for publication, February 13, 1997)
From the Department of Physiology, McGill University,
Montréal, Québec H3G 1Y6, Canada
The 90-kDa heat shock protein (hsp90) has been
implicated in modulating steroid receptor function in vitro
and in vivo. Previous studies have suggested that hsp90
interacts with large portions of the estrogen receptor (ER)
ligand-binding domain and sequences of the receptor required for stable
DNA binding. To characterize the interaction of the ER ligand-binding
domain with hsp90, we have compared the properties of chimeras created
by coupling the ligand-binding domain to the constitutive
transactivator VP16-GAL. Two types of chimeras were created:
VP16-GAL-ERG, containing the wild-type ligand-binding
domain derived from the cDNA HEG0, and VP16-GAL-ERV,
containing the substitution G400V derived from the ligand-binding
domain of the original ER cDNA isolate, HE0. The G400V mutation
alters the physical properties of VP16-GAL-ERV by rendering
it hormone-dependent for DNA binding and more
strongly dependent on estradiol for transactivation compared with
VP16-GAL-ERG. Glycerol gradient analyses and chemical
cross-linking/coimmunoprecipitation showed that, unlike
VP16-GAL-ERG, VP16-GAL-ERV formed stable
complexes with hsp90 in vitro. These data show that hsp90
selectively recognizes the altered ER ligand-binding domain containing
the G400V substitution and indicate that the wild-type ER
ligand-binding domain of VP16-GAL-ERG does not interact
with hsp90 in vitro. Hormone binding studies showed that
the ligand-binding domain of VP16-GAL-ERV was destabilized by incubation in the presence of high concentrations of salt or in the
absence of sodium molybdate, conditions that disrupt its interaction
with hsp90. The ligand-binding domain of the Val-400 ER thus behaves
similarly to that of the wild-type glucocorticoid receptor, which has
previously been shown to interact with hsp90 in vitro.
These results provide evidence for the action of hsp90 as a molecular
chaperone by selectively recognizing destabilized proteins.
Volume 272, Number 18,
Issue of May 2, 1997
pp. 12229-12235
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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