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Hsp90: a specialized but essential protein-folding tool.

Young JC, Moarefi I, Hartl FU - J. Cell Biol. (2001)

Bottom Line: Hsp90 is unique among molecular chaperones.The majority of its known substrates are signal transduction proteins, and recent work indicates that it uses a novel protein-folding strategy.

View Article: PubMed Central - PubMed

Affiliation: Cellular Biochemistry, Max Planck Institute for Biochemistry, Martinsried D-82152, Germany.

ABSTRACT
Hsp90 is unique among molecular chaperones. The majority of its known substrates are signal transduction proteins, and recent work indicates that it uses a novel protein-folding strategy.

Show MeSH
Different modes of Hsp90 action in signaling pathways. (A) Inactive steroid hormone receptors are folded by the Hsp90 machinery. Folded receptors either are stabilized and activated by hormone binding or remain unstable and are rebound by chaperones (Smith, 1993; Pratt and Toft, 1997). (B) Ecdysone receptor with its partner USP can bind hormone but requires folding by the Hsp90 machinery to become active for DNA binding (Arbeitman and Hogness, 2000). (C) Monomeric HSF1 is sequestered by Hsp90. Under stress conditions, misfolded proteins compete for Hsp90, and HSF1 is displaced from Hsp90 and can form the active trimer (Zou et al., 1998).
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fig3: Different modes of Hsp90 action in signaling pathways. (A) Inactive steroid hormone receptors are folded by the Hsp90 machinery. Folded receptors either are stabilized and activated by hormone binding or remain unstable and are rebound by chaperones (Smith, 1993; Pratt and Toft, 1997). (B) Ecdysone receptor with its partner USP can bind hormone but requires folding by the Hsp90 machinery to become active for DNA binding (Arbeitman and Hogness, 2000). (C) Monomeric HSF1 is sequestered by Hsp90. Under stress conditions, misfolded proteins compete for Hsp90, and HSF1 is displaced from Hsp90 and can form the active trimer (Zou et al., 1998).

Mentions: The best characterized example of an Hsp90-dependent signaling pathway is that of the steroid hormone receptors (Pratt and Toft, 1997) (Fig. 3 A). Interaction of the glucocorticoid receptor with Hsp90 is essential for its activity (Picard et al., 1990), and the unstable ligand-binding domain of the receptor is sufficient for this interaction (Young and Hartl, 2000). Monomeric glucocorticoid receptor and the closely related progesterone receptor are loaded onto Hsp90 by the Hsp70/Hop-dependent mechanism described above and attain their hormone-binding conformation after binding to Hsp90. Once the folded monomeric receptor has been released from the chaperones, it either binds the appropriate steroid hormone, resulting in dimerization and activation, or remains unstable and is recognized again by the chaperone machinery (Smith, 1993). Recently, progesterone receptor and glucocorticoid receptor have been used to reconstitute the typical multichaperone complexes with purified mammalian Hsp90, Hsc70, Hop, and p23. Although the requirement for cochaperones in vitro is still controversial (Morishima et al., 2000; Rajapandi et al., 2000), the ATP-dependent function of Hsp90 in steroid receptor maturation has been demonstrated (Grenert et al., 1999).


Hsp90: a specialized but essential protein-folding tool.

Young JC, Moarefi I, Hartl FU - J. Cell Biol. (2001)

Different modes of Hsp90 action in signaling pathways. (A) Inactive steroid hormone receptors are folded by the Hsp90 machinery. Folded receptors either are stabilized and activated by hormone binding or remain unstable and are rebound by chaperones (Smith, 1993; Pratt and Toft, 1997). (B) Ecdysone receptor with its partner USP can bind hormone but requires folding by the Hsp90 machinery to become active for DNA binding (Arbeitman and Hogness, 2000). (C) Monomeric HSF1 is sequestered by Hsp90. Under stress conditions, misfolded proteins compete for Hsp90, and HSF1 is displaced from Hsp90 and can form the active trimer (Zou et al., 1998).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2150759&req=5

fig3: Different modes of Hsp90 action in signaling pathways. (A) Inactive steroid hormone receptors are folded by the Hsp90 machinery. Folded receptors either are stabilized and activated by hormone binding or remain unstable and are rebound by chaperones (Smith, 1993; Pratt and Toft, 1997). (B) Ecdysone receptor with its partner USP can bind hormone but requires folding by the Hsp90 machinery to become active for DNA binding (Arbeitman and Hogness, 2000). (C) Monomeric HSF1 is sequestered by Hsp90. Under stress conditions, misfolded proteins compete for Hsp90, and HSF1 is displaced from Hsp90 and can form the active trimer (Zou et al., 1998).
Mentions: The best characterized example of an Hsp90-dependent signaling pathway is that of the steroid hormone receptors (Pratt and Toft, 1997) (Fig. 3 A). Interaction of the glucocorticoid receptor with Hsp90 is essential for its activity (Picard et al., 1990), and the unstable ligand-binding domain of the receptor is sufficient for this interaction (Young and Hartl, 2000). Monomeric glucocorticoid receptor and the closely related progesterone receptor are loaded onto Hsp90 by the Hsp70/Hop-dependent mechanism described above and attain their hormone-binding conformation after binding to Hsp90. Once the folded monomeric receptor has been released from the chaperones, it either binds the appropriate steroid hormone, resulting in dimerization and activation, or remains unstable and is recognized again by the chaperone machinery (Smith, 1993). Recently, progesterone receptor and glucocorticoid receptor have been used to reconstitute the typical multichaperone complexes with purified mammalian Hsp90, Hsc70, Hop, and p23. Although the requirement for cochaperones in vitro is still controversial (Morishima et al., 2000; Rajapandi et al., 2000), the ATP-dependent function of Hsp90 in steroid receptor maturation has been demonstrated (Grenert et al., 1999).

Bottom Line: Hsp90 is unique among molecular chaperones.The majority of its known substrates are signal transduction proteins, and recent work indicates that it uses a novel protein-folding strategy.

View Article: PubMed Central - PubMed

Affiliation: Cellular Biochemistry, Max Planck Institute for Biochemistry, Martinsried D-82152, Germany.

ABSTRACT
Hsp90 is unique among molecular chaperones. The majority of its known substrates are signal transduction proteins, and recent work indicates that it uses a novel protein-folding strategy.

Show MeSH