Review
Hsp90 & Co. – a holding for folding

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Abstract

Hsp90 is an abundant molecular chaperone that is involved in the folding of a defined set of signalling molecules including steroid-hormone receptors and kinases. Recent in vitro experiments suggest that Hsp90 contains two different binding sites for non-native proteins, which allow it to combine the properties of a promiscuous chaperone with those of a dedicated folding-helper protein. Significant progress has been made in analysing co-chaperones, which form defined, substrate-dependent complexes with Hsp90 in vivo. Structural studies have identified the ATP-binding site in the N-terminal domain of Hsp90, which can be blocked by high-affinity inhibitors. Although a detailed understanding of the mechanism of Hsp90 action is still lacking, recent advances suggest that the protein is the centre of a dynamic, multifunctional and multicomponent chaperone machinery that extends the limits of protein folding in the cell.

Section snippets

Hsp90 structure

Sequence alignments and proteolytic digests have shown that Hsp90 has a modular structure in which two well-conserved regions are connected by a highly charged linker of variable length (Fig. 1a). The native protein is an elongated dimer; the association sites lie in the extreme C-terminal region of the protein4 (Fig. 1b). Electron microscopy, together with antibody-binding studies, suggests that the C-terminal parts of the protein meet in the middle and that the N-terminal domains point in

Hsp90 function

Interestingly, high levels of Hsp90 are not required to support growth: a reduction to 5% of the normal concentration is tolerated in yeast under physiological conditions11, 12. In response to stress, expression of Hsp90 increases up to tenfold both in prokaryotes and in eukaryotes. Genetic analysis in yeast established that high concentrations of Hsp90p are required for growth at high temperatures. Thus, physiological levels of Hsp90 under normal conditions probably act as a buffer to protect

Hsp90 substrates

The best-studied in vivo substrates of Hsp90 are SHRs15. Unlike most other receptor proteins, SHRs are soluble intracellular proteins that shuttle between the cytosol and the nucleus. Hsp90 binds specifically to SHRs in the absence of steroid hormones. Addition of the hormone causes dissociation of the Hsp90–SHR complex and dimerization of the receptors, which allows them to bind to specific DNA sequences and regulate transcription14. In the presence of Hsp90, most aporeceptors are inactive

Changing partners during the chaperone cycle

In recent years, analysis of Hsp90-dependent SHR activation has focused on the identification of components of the Hsp90 chaperone cycle (Table 3)15, 30. Interestingly, yeast, plant and mammalian cells all seem to contain a similar set of partner proteins; this suggests that the function of Hsp90–partner-protein complexes is conserved throughout eukaryotes. The Hsp90 chaperone machinery comprises numerous partner proteins and complexes; compared with the Hsp70 and GroE enterprises, it is like a

Functions of Hsp90-partner proteins

Despite enormous progress in characterizing the composition of Hsp90–partner-protein complexes, we know little about the function of these partner proteins – either individually or as part of the complex. These proteins can be divided into two functional classes: (1) scaffold proteins for the Hsp90 complexes; and (2) cofactors that assist protein folding directly. Note that this is a rather crude classification; more information on the structure–function relationships of Hsp90-partner proteins

Hsp90: the target of the anti-tumour drugs geldanamycin and radicicol

Specific inhibitors identified in screens for natural substances that inhibit proliferation of tumour cells are important new tools for analysis of Hsp90 function in vivo and in vitro. One of these, geldanamycin (GA; see Fig. 2c)39, initially seemed to decrease the activity of certain cell-cycle kinases. It was therefore thought to be a kinase inhibitor. Surprisingly, however, the only cellular protein to which GA binds is Hsp90 (Ref. 40). The effect of GA on kinase activity is thus indirect

Hsp90 – chaperone properties

The term ‘molecular chaperone’ has been used incorrectly sometimes and applied to any substance (including lipids and even buffer additives such as glycerol) that alters protein structure. It is therefore valuable to recapitulate the chaperone concept: chaperones are a functionally related collection of highly conserved and ubiquitous proteins that specifically recognize non-native proteins. Thus, chaperones prevent unwanted inter-and intra-molecular interactions and influence the partitioning

Perspectives

Studies of stable interactions between Hsp90 and SHRs, and Hsp90 and kinases, have allowed rapid progress in elucidating the composition of different Hsp90 complexes and their importance during the chaperone cycle. The picture that is beginning to emerge is one in which Hsp90 and partner proteins work together as chaperones to control the activation of, and prevent the aggregation or collapse of, partially folded, unstable forms of specific substrates. It is tempting to speculate that Hsp90

Acknowledgements

I thank Laurence Pearl for sharing coordinates for Hsp90 and GA, Didier Picard, David Smith, David Toft and Ichiro Yahara for unpublished data, Martina Beissinger and Christian Mayr for artwork, Adina Breimann, Priti Krishna and Jan Miernick for information on Hsp90-partner proteins in plants, and Martina Beissinger, Brian Freeman, Hauke Lilie, Chris Nicchitta, Didier Picard, Thomas Scheibel, David Smith, David Toft and, especially, Rick Morimoto for comments on the manuscript. I thank the

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