A model of glucocorticoid receptor unfolding and stabilization by a heat shock protein complex.
It has recently been reported that incubation of avian progesterone receptors, mouse glucocorticoid receptors, or the viral tyrosine kinase pp60src with rabbit reticulocyte lysate reconstitutes their association with the 90 kDa heat shock protein, hsp90. The reassociation is thought to require unfolding of the steroid receptor or pp60src before hsp90 can bind. The unfoldase activity may be provided by hsp70, which is also present in the reconstituted receptor heterocomplex. In this paper we review evidence that hsp70 and hsp90 are associated in cytosolic heterocomplexes that contain a limited number of other proteins. From an analysis of known receptor-hsp interactions and a predicted direct interaction between hsp90 and hsp70 we have developed an admittedly very speculative model of glucocorticoid receptor unfolding and stabilization. One important feature of the model is that the receptor becomes attached to a heat shock protein heterocomplex rather than undergoing independent unfolding and stabilization events. The model requires that hsp70 and hsp90 bind directly to the receptor at independent sites. Importantly, the model accommodates the stoichiometry of 2 hsp90 per 1 molecule of receptor that has been assayed in the untransformed GR heterocomplex in cytosols prepared from hormone-free cells.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109.
W B
WB
Pratt
L C
LC
Scherrer
K A
KA
Hutchison
F C
FC
Dalman
D000818:Animals; D003600:Cytosol / Q000378:metabolism; D004355:Drug Stability; D006360:Heat-Shock Proteins / Q000378:metabolism*; D046911:Macromolecular Substances; D051379:Mice; D008954:Models, Biological; D011487:Protein Conformation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011817:Rabbits; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012156:Reticulocytes / Q000378:metabolism
D006360:Heat-Shock Proteins; D046911:Macromolecular Substances; D011965:Receptors, Glucocorticoid; D016392:Proto-Oncogene Proteins pp60(c-src)