title: Goniothalamin enhances the ATPase activity of the molecular chaperone Hsp90 but inhibits its chaperone activity.
abstract: 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.
authors.affiliation: Molecular Biology Course, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan; Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia; and Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Yokoyama
authors.affiliation: Molecular Biology Course, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan; Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia; and Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan.
authors.forename: Aguru
authors.initials: A
authors.lastname: Ohtaki
authors.affiliation: Molecular Biology Course, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan; Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia; and Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Jantan
authors.affiliation: Molecular Biology Course, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan; Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia; and Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yohda
authors.affiliation: Molecular Biology Course, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan; Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia; and Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan nakamoto@mail.saitama-u.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakamoto
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry*; D001667:Binding, Competitive; D020536:Enzyme Activators / Q000737:chemistry*; D005954:Glucosephosphate Dehydrogenase / Q000737:chemistry; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry*; D006868:Hydrolysis; D007700:Kinetics; D058849:Protein Refolding; D011753:Pyrones / Q000737:chemistry*; D011817:Rabbits; D046940:Synechococcus / Q000201:enzymology
chemical_list: D001426:Bacterial Proteins; D020536:Enzyme Activators; D018841:HSP90 Heat-Shock Proteins; D011753:Pyrones; C066720:HtpG protein, bacteria; C103280:goniothalamin; D000255:Adenosine Triphosphate; D005954:Glucosephosphate Dehydrogenase; D000251:Adenosine Triphosphatases
keywords: Hsp90; Hsp90 activator; cyanobacterium; goniothalamin; molecular chaperone