Journal Article

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

Yuhei Yokoyama, Aguru Ohtaki, Ibrahim Jantan, Masafumi Yohda and Hitoshi Nakamoto

in The Journal of Biochemistry

Published on behalf of The Japanese Biochemical Society

Volume 157, issue 3, pages 161-168
Published in print March 2015 | ISSN: 0021-924X
Published online October 2014 | e-ISSN: 1756-2651 | DOI: http://dx.doi.org/10.1093/jb/mvu061
Goniothalamin enhances the ATPase activity of the molecular chaperone Hsp90 but inhibits its chaperone activity

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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 Km and kcat 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.

Keywords: cyanobacterium; goniothalamin; Hsp90; Hsp90 activator; molecular chaperone

Journal Article.  5348 words.  Illustrated.

Subjects: Biochemistry

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