The molecular basis of distinct aggregation pathways of islet amyloid polypeptide

• Main Authors: Chan-Park, Mary B., Wei, Lei, Jiang, Ping, Xu, Weixin, Li, Hai, Zhang, Hua, Yan, Liang Yu, Liu, Xue-Wei, Tang, Kai, Mu, Yuguang, Pervushin, Konstantin
• Other Authors: School of Materials Science & Engineering
• Format: Article
• Language: English
• Published: 2012
• Subjects: DRNTU::Science::Biological sciences::Biochemistry
• Online Access: https://hdl.handle.net/10356/95683; http://hdl.handle.net/10220/8323
• Institution: Nanyang Technological University

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.