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The molecular basis of distinct aggregation pathways of islet amyloid polypeptide

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The molecular basis of distinct aggregation pathways of islet amyloid polypeptide

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Title: The molecular basis of distinct aggregation pathways of islet amyloid polypeptide
Author: Wei, Lei; Jiang, Ping; Xu, Weixin; Li, Hai; Zhang, Hua; Yan, Liang Yu; Chan-Park, Mary B.; Liu, Xue-Wei; Tang, Kai; Mu, Yuguang; Pervushin, Konstantin
Copyright year: 2011
Abstract: Abnormal aggregation of islet amyloid polypeptide (IAPP) into amyloid fibrils is a hallmark of type 2 diabetes. In this study, we investigated the initial oligomerization and subsequent addition of monomers to growing aggregates of human IAPP at the residue-specific level using NMR, atomic force microscopy, mass spectroscopy, and computational simulations. We found that in solution IAPPs rapidly associate into transient low-order oligomers such as dimers and trimers via interactions between histidine 18 and tyrosine 37. This initial event is proceeded by slow aggregation into higher-order spherical oligomers and elongated fibrils. In these two morphologically distinct types of aggregates IAPPs adopt structures with markedly different residual flexibility. Here we show that the anti-amyloidogenic compound resveratrol inhibits oligomerization and amyloid formation via binding to histidine 18, supporting the finding that this residue is crucial for on-pathway oligomer formation.
Subject: DRNTU::Science::Biological sciences::Biochemistry.
Type: Journal Article
Series/ Journal Title: Journal of Biological Chemistry
School: School of Materials Science and Engineering
Rights: © 2011 The American Society for Biochemistry and Molecular Biology. This is the author created version of a work that has been peer reviewed and accepted for publication by Journal of Biological Chemistry, The American Society for Biochemistry and Molecular Biology. It incorporates referee’s comments but changes resulting from the publishing process, such as copyediting, structural formatting, may not be reflected in this document. The published version is available at: [http://dx.doi.org/10.1074/jbc.M110.166678].
Version: Accepted version

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