Goniothalamin enhances the ATPase activity of the molecular chaperone Hsp90 but inhibits its chaperone activity

Hsp90 is an ATP-dependent molecular chaperone that is involved in important cellular pathways such as signal transduction pathways. It is a potential cancer drug target because it plays a critical role for stabilization and activation of oncoproteins. Thus, small molecule compounds that control the...

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Bibliographic Details
Published in:Journal of biochemistry (Tokyo) 2015-03, Vol.157 (3), p.161-168
Main Authors: Yokoyama, Yuhei, Ohtaki, Aguru, Jantan, Ibrahim, Yohda, Masafumi, Nakamoto, Hitoshi
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - chemistry
Adenosine Triphosphate - chemistry
Animals
Bacterial Proteins - chemistry
Binding, Competitive
Enzyme Activators - chemistry
Glucosephosphate Dehydrogenase - chemistry
HSP90 Heat-Shock Proteins - chemistry
Hydrolysis
Kinetics
Protein Refolding
Pyrones - chemistry
Rabbits
Synechococcus - enzymology
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Summary:Hsp90 is an ATP-dependent molecular chaperone that is involved in important cellular pathways such as signal transduction pathways. It is a potential cancer drug target because it plays a critical role for stabilization and activation of oncoproteins. Thus, small molecule compounds that control the Hsp90 function are useful to elucidate potential lead compounds against cancer. We studied effect of a naturally occurring styryl-lactone goniothalamin on the activity of Hsp90. Although many drugs targeting Hsp90 inhibit the ATPase activity of Hsp90, goniothalamin enhanced rather than inhibited the ATPase activity of a cyanobacterial Hsp90 (HtpG) and a yeast Hsp90. It increased both K(m) and k(cat) of the Hsp90s. Domain competition assays and tryptophan fluorescence measurements with various truncated derivatives of HtpG indicated that goniothalamin binds to the N-terminal domain of HtpG. Goniothalamin did not influence on the interaction of HtpG with a non-native protein or the anti-aggregation activity of HtpG significantly. However, it inhibited the activity of HtpG that assists refolding of a non-native protein in cooperation with the Hsp70 chaperone system. This is the first report to show that a small molecule that binds to the N-terminal domain of Hsp90 activates its ATPase activity, while inhibiting the chaperone function of Hsp90.
ISSN:0021-924X
1756-2651
DOI:10.1093/jb/mvu061