Molecular Hairpin: A Possible Model for Inhibition of Tau Aggregation by Tannic Acid

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• 作者：Junliang Yao ; Xing Gao ; Wenliang Sun ; Tianming Yao ; Shuo Shi ; Liangnian Ji
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：March 19, 2013
• 年：2013
• 卷：52
• 期：11
• 页码：1893-1902
• 全文大小：689K
• 年卷期：v.52,no.11(March 19, 2013)
• ISSN：1520-4995

文摘

Inhibition of anomalous aggregation of tau protein would be an attractive therapeutic target for Alzheimer鈥檚 disease (AD). In this study, tannic acid (TA), a polymeric plant polyphenol, and its monomer, gallic acid (GA), were introduced as the references to afford a molecular framework that integrates tau binding properties and inhibitory effects. Using a thioflavin S fluorescence assay and electron microscopy, we demonstrated that TA could competently inhibit the in vitro aggregation of tau peptide R3, corresponding to the third repeat unit of the microtubule-binding domain, with an IC₅₀ of 3.5 渭M, while GA鈥檚 inhibition was comparatively piddling (with an IC₅₀ of 92 渭M). In the isothermal titration calorimetry experiment, we found that TA could strongly bind to R3 with a large amount of heat released. Circular dichroism spectra showed TA dose-dependently suppressed the conformational transition of R3 from a random coil structure to a 尾-sheet structure during the aggregation process. Finally, a structural model was built using molecular docking simulation to elucidate the possible binding sites for TA on the tau peptide surface. Our results suggest that TA recognizably interacts with tau peptide by forming a hairpin binding motif, a key framework required for inhibiting tau polymerization, in addition to hydrogen bonding, hydrophilic鈥揾ydrophobic interactions, and static electrical interactions, as reported previously. The inhibitory effect of TA on human full-length tau protein (tau₄₄₁) was also verified by electron microscopy. This finding hints at the possibility of TA as a leading compound of anti-AD drugs and offers a new stratagem for the rational molecular design of a tau aggregation inhibitor.