Hsp90 mutants disrupt glucocorticoid receptor ligand binding and destabilize aporeceptor complexes.
In order to attain competence to respond to hormone, certain steroid hormone receptors must be assembled into hetero-oligomeric aporeceptor complexes, containing Hsp90 and other proteins. Members of the Hsp90 gene family are highly conserved, strongly expressed, and required for viability in eukaryotic organisms. To elucidate the role of Hsp90 in the activity of steroid hormone receptors in vivo, four Hsp90 mutatns, which cause defects in glucocorticoid receptor (GR) signaling, but support the viability of Saccharomyces cerevisiae, were previously isolated (Bohen, S. P., and Yamamoto, K. R. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 11424-11428). In this study, I characterize the effects of the Hsp90 mutants on GR ligand response, ligand binding activity, and aporeceptor complex stability. The mutants fall into two classes. Three of the Hsp90 mutants cause defects in GR ligand binding in vivo and form aporeceptor complexes that are unstable in vitro, relative to those containing wild-type Hsp90. The other mutant affects GR signaling, but aporeceptor complexes with this mutant are not defective for ligand binding or stability. These findings indicate that the binding of Hsp90 to GR in the aporeceptor complex is insufficient to induce a high ligand affinity conformation, rather the high ligand affinity to GR requires a specific interaction with Hsp90, which is altered by certain Hsp90 mutants.
D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000502:physiology; D008024:Ligands; D009154:Mutation; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction
C074510:HSP82 protein, S cerevisiae; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008024:Ligands; D011965:Receptors, Glucocorticoid; D029701:Saccharomyces cerevisiae Proteins