The Hsp90 complex—a super-chaperone machine as a novel drug target

doi:10.1016/S0006-2952(98)00120-8

Biochemical Pharmacology

Volume 56, Issue 6, 15 September 1998, Pages 675-682

https://doi.org/10.1016/S0006-2952(98)00120-8 Get rights and content

Abstract

Cells respond to sudden changes in the environmental temperature with increased synthesis of a distinct number of heat shock proteins (Hsps). Analysis of the function of these proteins in recent years has shown that all the major classes of conserved Hsps are molecular chaperones involved in assisting cellular protein folding and preventing irreversible side-reactions, such as unspecific aggregation. In addition to their function under stress conditions, molecular chaperones also play a critical role under physiological conditions. Hsp90 is one of the most abundant chaperones in the cytosol of eukaryotic cells. It is part of the cell’s powerful network of chaperones to fight the deleterious consequences of protein unfolding caused by nonphysiological conditions. In the absence of stress, however, Hsp90 is an obligate component of fundamental cellular processes such as hormone signaling and cell cycle control. In this context, several key regulatory proteins, such as steroid receptors, cell cycle kinases, and p53, have been identified as substrates of Hsp90. Recently, Hsp90 was shown to be the unique target for geldanamycin, a potent new anti-tumor drug that blocks cell proliferation. Interestingly, under physiological conditions, Hsp90 seems to perform its chaperone function in a complex with a set of partner proteins, suggesting that the Hsp90 complex is a multi-chaperone machine specialized in guiding the maturation of conformationally labile proteins. The regulation of key signaling molecules of the cell by the Hsp90 machinery is a stimulating new concept emerging from these studies, and Hsp90 has become a promising new drug target.

Section snippets

Role of Hsp90 in the conformational regulation of proteins in vivo

The first indication of the cellular function of Hsp90s in higher eukaryotes was the surprising discovery that a major protein coprecipitating with steroid hormone receptors in the absence of hormone was identical to Hsp90 4, 5. These complexes were stable because they survived immunoprecipitation. Later on, it was shown that the addition of steroid hormone causes the apparent dissociation of the complex and the dimerization of the receptor, which is required for DNA binding and transcriptional

Dissection of Hsp90 function

Proteolysis experiments and sequence alignments suggested that Hsp90 is composed of several domains including two highly conserved regions common to all members of the Hsp90 family, separated by a highly charged region of varying length [1](Fig. 1). The function of the charged region remains elusive, since its deletion in yeast Hsp90 did not result in a detectable phenotype in vivo[28]. The structure of the N-terminal domain of Hsp90 has been solved by x-ray crystallography 29, 30, 31. This

Hsp90 as the central platform of distinct multi-chaperone complexes

At least for some non-native proteins such as steroid receptors and kinases, Hsp90 functions in concert with a well-defined set of cofactors (Table 1and Fig. 3), which are essential to drive the cycle of Hsp90–substrate interaction. The existence of these heteroprotein complexes could be demonstrated even in the absence of specific substrate proteins [5], leading to the assumption that they may represent “super chaperone complexes” [37].

In the case of steroid receptor activation, a number of

Hsp90 as the target of the novel anti-tumor drug geldanamycin

Recently, Hsp90 surfaced as the target for a potent new anti-tumor drug. Screens of natural compounds for substances inhibiting the proliferation of tumor cells identified the benzochinone ansamycin GA as a promising candidate 67, 68. GA from Streptomyces hygroscopicus var. geldanus and some natural analogs from various Nocardia species inhibited growth of a large number of cancer cell lines when administered in the sub-micromolar range [69]. Initially, GA was supposed to be an inhibitor for

Conclusion

The first identifications of certain classes of proteins as natural substrates of Hsp90 suggested that, in contrast to the other promiscuous chaperones, Hsp90 is a specific or dedicated chaperone [46]. However, the basis for this potential specificity remains enigmatic since the structures of kinases and steroid receptors do not share obvious common structural elements. Furthermore, this specificity would not explain the necessity of increased Hsp90 expression (up to 15-fold) under stress

Acknowledgements

We thank Christian Mayr and Martina Beissinger for assistance in artwork, Franziska Pirkl and Stefan Bell for critically reading the manuscript, Lawrence Pearl for sharing coordinates, and David Smith for detailed comments on receptor cycles. Work in Dr. Buchner’s laboratory was supported by the Deutsche Forschungs-gemeinschaft, Bundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, and the Fonds der chemischen Industrie.

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Citation Excerpt :
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CommentariesThe Hsp90 complex—a super-chaperone machine as a novel drug target

Abstract

Section snippets

Role of Hsp90 in the conformational regulation of proteins in vivo

Dissection of Hsp90 function

Hsp90 as the central platform of distinct multi-chaperone complexes

Hsp90 as the target of the novel anti-tumor drug geldanamycin

Conclusion

Acknowledgements

Biochem Biophys Res Commun

Pharmacol Ther

J Biol Chem

J Biol Chem

J Biol Chem

Cell

Cell

J Biol Chem

J Biol Chem

Trends Biochem Sci

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

The Hsp90 family—An overview

Hsp82 is an essential protein that is required in higher concentrations for growth of cells at higher temperatures

Mol Cell Biol

The common 90-kd protein component of non-transformed ‘8S’ steroid receptors is a heat-shock protein

EMBO J

Steroid receptor interactions with heat shock protein and immunophilin chaperones

Endocr Rev

Modulation of steroid receptor signal transduction by heat shock proteins

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Commentaries
The Hsp90 complex—a super-chaperone machine as a novel drug target

Interaction of the Rous sarcoma virus protein pp60^src with the cellular proteins pp50 and pp90