Mutational analysis of the ability of resveratrol to inhibit amyloid formation by islet amyloid polypeptide: Critical evaluation of the importance of aromatic-inhibitor and histidine-inhibitor interactions

Ling Hsien Tu, Lydia M. Young, Amy G. Wong, Alison E. Ashcroft, Sheena E. Radford, Daniel P. Raleigh

研究成果: 雜誌貢獻文章

31 引文 斯高帕斯(Scopus)

摘要

The process of amyloid formation by the normally soluble hormone islet amyloid polypeptide (IAPP) contributes to β-cell death in type 2 diabetes and in islet transplants. There are no clinically approved inhibitors of islet amyloidosis, and the mode of action of existing inhibitors is not well-understood. Resveratrol, a natural polyphenol, has been reported to inhibit amyloid formation by IAPP and by the Alzheimer's disease Aβ peptide. The mechanism of action of this compound is not known, nor is its mode of interaction with IAPP. In this study, we use a series of IAPP variants to examine possible interactions between resveratrol and IAPP. Fluorescence assays, transmission electron microscopy, and mass spectrometry demonstrate that resveratrol is much less effective as an inhibitor of IAPP amyloid formation than the polyphenol (-)-epigallocatechin 3-gallate (EGCG) and, unlike EGCG, does not significantly disaggregate preformed IAPP amyloid fibrils. Resveratrol is also shown to interfere with thioflavin-T assays. His-18 mutants, a truncation mutant, mutants of each of the aromatic residues, and mutants of Arg-11 of IAPP were examined. Mutation of His to Gln or Leu weakens the ability of resveratrol to inhibit amyloid formation by IAPP, as do mutations of Arg-11, Phe-15, or Tyr-37 to Leu, and truncation to form the variant Ac 8-37-IAPP, which removes the first seven residues to eliminate Lys-1 and the N-terminal amino group. In contrast, replacement of Phe-23 with Leu has a smaller effect. The data highlight Phe-15, His-18, and Tyr-37 as being important for IAPP-resveratrol interactions and are consistent with a potential role of the N-terminus and Arg-11 in polypeptide-resveratrol interactions. (Graph Presented).

原文英語
頁(從 - 到)666-676
頁數11
期刊Biochemistry
54
發行號3
DOIs
出版狀態已發佈 - 2015 一月 27

    指紋

ASJC Scopus subject areas

  • Biochemistry

引用此