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Review
. 2013 Jun;5(9):1059-71.
doi: 10.4155/fmc.13.88.

Contributions of co-chaperones and post-translational modifications towards Hsp90 drug sensitivity

Annerleim Walton-Diaz  1 , Sahar Khan, Dimitra Bourboulia, Jane B Trepel, Len Neckers, Mehdi Mollapour
Affiliations
Review

Contributions of co-chaperones and post-translational modifications towards Hsp90 drug sensitivity

Annerleim Walton-Diaz et al. Future Med Chem. 2013 Jun.

Abstract

Hsp90 is a molecular chaperone and important driver of stabilization and activation of several oncogenic proteins that are involved in the malignant transformation of tumor cells. Therefore, it is not surprising that Hsp90 has been reported to be a promising target for the treatment of several neoplasias, such as non-small-cell lung cancer and HER2-positive breast cancer. Hsp90 chaperone function depends on its ability to bind and hydrolyze ATP and Hsp90 inhibitors have been shown to compete with nucleotides for binding to Hsp90. Multiple factors, such as co-chaperones and post-translational modification, are involved in regulating Hsp90 ATPase activity. Here, the impact of post-translational modifications and co-chaperones on the efficacy of Hsp90 inhibitors are reviewed.

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Figures

Figure 1.
Figure 1.. Two sides to Hsp90 function.
Hsp90 looks after proteins that are involved in normal cellular function. Hsp90 also chaperones clients that are crucial for the maintenance of each of the proposed hallmarks of cancer.
Figure 2.
Figure 2.. Hsp90 chaperone function.
ATP binding to the N-terminal domain of Hsp90 promotes transient dimerization of the N-domains. The co-chaperone Aha1 enhances Hsp90 ATPase activity by promoting various conformational changes, while Hop/Sti1 and Hsp90 inhibitors such as geldanamycin or radicicol exert the opposite effect by inhibiting N-domain dimerization. p23 slows ATP hydrolysis at a late stage of the chaperone cycle.
Figure 3.
Figure 3.
Hsp90 N- and C-domain inhibitors.
Figure 4.
Figure 4.. Post-translational modification residues on human Hsp90α.
Domain location of phosphorylated serine (S), theronine (T) and tyrosine (Y) sites for which kinases are known. Acetylated lysine (K) residues, S-nitrosylated cysteine (†) and cysteine oxidation sites (‡) on human Hsp90α. Phosphorylation and acetylation sites that enhance sensitivity to Hsp90 inhibitors are also marked in bold.
Figure 5.
Figure 5.. Post-translational modifications and co-chaperones fine-tune Hsp90 chaperone machinery.
The Hsp90 chaperone cycle is regulated by the interplay between ATP binding to Hsp90 and the regulated association/dissociation of various co-chaperones. The Hsp90 chaperone machine is also regulated by a number of diverse post-translational modifications of Hsp90 and co-chaperones, including phosphorylation, S-nitrosylation, oxidation, acetylation and ubiquitination. Hsp90 inhibitors effectively displace ATP from its binding pocket in the N-domain of Hsp90, disrupt this complex mechanism and prevent chaperone cycling.
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Website

    1. Updated list of Hsp90 clients. www.picard.ch/downloads/downloads.html.

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