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(Received for publication, April 7, 1997, and in revised form, May 15, 1997)
From the In cytosols from animal and plant
cells, the abundant heat shock protein hsp90 is associated with several
proteins that act together to assemble steroid receptors into
receptor·hsp90 heterocomplexes. We have reconstituted a minimal
receptor·hsp90 assembly system containing four required components,
hsp90, hsp70, p60, and p23 (Dittmar, K. D., Hutchison, K. A.,
Owens-Grillo, J. K., and Pratt, W. B. (1996) J. Biol. Chem. 271, 12833-12839). We have shown that hsp90, p60,
and hsp70 are sufficient for carrying out the folding change that
converts the glucocorticoid receptor (GR) hormone binding domain (HBD)
from a non-steroid binding to a steroid binding conformation, but to
form stable GR·hsp90 heterocomplexes, p23 must also be present in the
incubation mix (Dittmar, K. D., and Pratt, W. B. (1997)
J. Biol. Chem. 272, 13047-13054). In this work, we
show that addition of p23 to native GR·hsp90 heterocomplexes immunoadsorbed from L cell cytosol or to GR·hsp90 heterocomplexes prepared with the minimal (hsp90·p60·hsp70) assembly system
inhibits both receptor heterocomplex disassembly and loss of steroid
binding activity. p23 stabilizes the GR·hsp90 heterocomplex in a
dynamic and ATP-independent manner. In contrast to hsp90 that is bound to the GR, free hsp90 binds p23 in an ATP-dependent manner,
and hsp90 in the hsp90·p60·hsp70 heterocomplex is in a conformation that does not bind p23 at all. The effect of p23 in the minimal GR
heterocomplex assembly system is to stabilize GR·hsp90
heterocomplexes once they are formed and it does not appear to affect
the rate of heterocomplex assembly. Molybdate has the same ability as
p23 to stabilize GR heterocomplexes with mammalian hsp90, but GR
heterocomplexes with plant hsp90 are stabilized by p23 and not by
molybdate. We propose that incubation of the GR with
hsp90·p60·hsp70 forms a GR·hsp90 heterocomplex in which hsp90 is
in an ATP-dependent conformation. The
ATP-dependent conformation of hsp90 is required for the
hormone binding domain to have a steroid binding site, and binding of p23 to that state of hsp90 stabilizes the GR·hsp90 heterocomplex to
inactivation and disassembly.
Volume 272, Number 34,
Issue of August 22, 1997
pp. 21213-21220
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
THE ROLE OF p23 IS TO STABILIZE RECEPTOR·hsp90 HETEROCOMPLEXES
FORMED BY hsp90·p60·hsp70
,
,
,
Department of Pharmacology, University of
Michigan Medical School, Ann Arbor, Michigan 48109 and the
¶ Department of Plant Sciences, University of Western
Ontario, London, Ontario N6A 5B7, Canada
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