A model of glucocorticoid receptor unfolding and stabilization by a heat shock protein complex

Pratt, William B.; Scherrer, Lawrence C.; Hutchison, Kevin A.; Dalman, Friedrich C.

doi:10.1016/0960-0760(92)90348-m

Cited by 59 publications

(25 citation statements)

References 40 publications

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“…Hsp90 acts with a number of associated proteins (42,57), including Hsp70, p60-Sti1, immunophilins, and p23-Sba1, to promote the maturation of substrate proteins. Several lines of evidence have converged on the hypothesis that p23 is required for Hsp90-dependent steroid receptor function.…”

Section: Discussionmentioning

confidence: 99%

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Genetic and Biochemical Analysis of p23 and Ansamycin Antibiotics in the Function of Hsp90-Dependent Signaling Proteins

Bohen

1998

Molecular and Cellular Biology

102

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The ubiquitous molecular chaperone Hsp90 acts in concert with a cohort of associated proteins to facilitate the functional maturation of a number of cellular signaling proteins, such as steroid hormone receptors and oncogene tyrosine kinases. The Hsp90-associated protein p23 is required for the assembly of functional steroid aporeceptor complexes in cell lysates, and Hsp90-binding ansamycin antibiotics disrupt the activity of Hsp90-dependent signaling proteins in cultured mammalian cells and prevent the association of p23 with Hsp90-receptor heterocomplexes; these observations have led to the hypotheses that p23 is required for the maturation of Hsp90 target proteins and that ansamycin antibiotics abrogate the activity of such proteins by disrupting the interaction of p23 with Hsp90. In this study, I demonstrate that ansamycin antibiotics disrupt the function of Hsp90 target proteins expressed in yeast cells; prevent the assembly of Sba1, a yeast p23-like protein, into steroid receptor-Hsp90 complexes; and result in the assembly of receptor-Hsp90 complexes that are defective for ligand binding. To assess the role of p23 in Hsp90 target protein function, I show that the activity of Hsp90 target proteins is unaffected by deletion of SBA1. Interestingly, steroid receptor activity in cells lacking Sba1 displays increased sensitivity to ansamycin antibiotics, and this phenotype is rescued by the expression of human p23 in yeast cells. These findings indicate that Hsp90-dependent signaling proteins can achieve a functional conformation in vivo in the absence of p23. Furthermore, while the presence of p23 decreases the sensitivity of Hsp90-dependent processes to ansamycin treatment, ansamycin antibiotics disrupt signaling through some mechanism other than altering the Hsp90-p23 interaction.

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Section: Discussionmentioning

confidence: 99%

“…A significant fraction of cellular Hsp90 exists in complex with other proteins, including Hsp70, p60 (a Sti1-like protein), immunophilins, and p23 (42,57). Steroid hormone receptors have served as a useful model for the functional characterization of the Hsp90 protein complex.…”

mentioning

confidence: 99%

Genetic and Biochemical Analysis of p23 and Ansamycin Antibiotics in the Function of Hsp90-Dependent Signaling Proteins

Bohen

1998

Molecular and Cellular Biology

102

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“…Because of this activity these proteins have been called chaperonins (Ellis and van der Vies, 1991). Chaperonins have a characteristic oligomeric structure usually consisting of 14 subunits of approximately 60 kDa each arranged in two heptameric rings stacked on top of each other (Hendrix, 1979;Hohn et al, 1979;Pushkin et al, 1982).…”

Section: Hsp60mentioning

confidence: 99%

Heat‐shock proteins as molecular chaperones

Becker

Craig

1994

European Journal of Biochemistry

488

221

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Functional proteins within cells are normally present in their native, completely folded form. However, vital processes of protein biogenesis such as protein synthesis and translocation of proteins into intracellular compartments require the protein to exist temporarily in an unfolded or partially folded conformation. As a consequence, regions buried when a polypeptide is in its native conformation become exposed and interact with other proteins causing protein aggregation which is deleterious to the cell. To prevent aggregation as proteins become unfolded, heat‐shock proteins protect these interactive surfaces by binding to them and facilitating the folding of unfolded or nascent polypeptides. In other instances the binding of heat‐shock proteins to interactive surfaces of completely folded proteins is a crucial part of their regulation. As heat shock and other stress conditions cause cellular proteins to become partially unfolded, the ability of heat‐shock proteins to protect cells against the adverse effects of stress becomes a logical extension of their normal function as molecular chaperones.

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“…In addition to various target proteins, Hsp90 binds to other cellular proteins, Hsp90-associated proteins (Hsp90APs), which are thought to act with Hsp90 to modulate target protein function (1,40,56). Hsp90APs can be divided into three subgroups: (i) other known chaperone proteins (e.g., Hsp70), (ii) peptidylprolyl cis-trans isomerases (immunophilins of both the FKBP and cyclophilin classes), and (iii) proteins whose biochemical functions are just beginning to be characterized (e.g., p60, p50, p48, and p23).…”

mentioning

confidence: 99%