Toward the Molecular Mechanism(s) by Which EGCG Treatment Remodels Mature Amyloid Fibrils
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- 作者：Fernando L. Palhano ; Jiyong Lee ; Neil P. Grimster ; Jeffery W. Kelly
- 刊名：The Journal of the American Chemical Society
- 出版年：2013
- 出版时间：May 22, 2013
- 年：2013
- 卷：135
- 期：20
- 页码：7503-7510
- 全文大小：483K
- 年卷期：v.135,no.20(May 22, 2013)
- ISSN：1520-5126
文摘
Protein misfolding and/or aggregation has been implicated as the cause of several human diseases, such as Alzheimer鈥檚 and Parkinson鈥檚 diseases and familial amyloid polyneuropathy. These maladies are referred to as amyloid diseases, named after the cross-尾-sheet amyloid fibril aggregates or deposits common to these disorders. Epigallocatechin-3-gallate (EGCG), the principal polyphenol present in green tea, has been shown to be effective at preventing aggregation and is able to remodel amyloid fibrils comprising different amyloidogenic proteins, although the mechanistic underpinnings are unclear. Herein, we work toward an understanding of the molecular mechanism(s) by which EGCG remodels mature amyloid fibrils made up of A尾1鈥?0, IAPP8鈥?4, or Sup35NM7鈥?6. We show that EGCG amyloid remodeling activity in vitro is dependent on auto-oxidation of the EGCG. Oxidized and unoxidized EGCG binds to amyloid fibrils, preventing the binding of thioflavin T. This engagement of the hydrophobic binding sites in A尾1鈥?0, IAPP8鈥?4, or Sup35NMAc7鈥?6 Y鈫扚 amyloid fibrils seems to be sufficient to explain the majority of the amyloid remodeling observed by EGCG treatment, although how EGCG oxidation drives remodeling remains unclear. Oxidized EGCG molecules react with free amines within the amyloid fibril through the formation of Schiff bases, cross-linking the fibrils, which may prevent dissociation and toxicity, but these aberrant post-translational modifications do not appear to be the major driving force for amyloid remodeling by EGCG treatment. These insights into the molecular mechanism of action of EGCG provide boundary conditions for exploring amyloid remodeling in more detail.