title: The molecular basis of distinct aggregation pathways of islet amyloid polypeptide.
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.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 639798.
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.forename: Ping
authors.initials: P
authors.lastname: Jiang
authors.forename: Weixin
authors.initials: W
authors.lastname: Xu
authors.forename: Hai
authors.initials: H
authors.lastname: Li
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Liangyu
authors.initials: L
authors.lastname: Yan
authors.forename: Mary B
authors.initials: MB
authors.lastname: Chan-Park
authors.forename: Xue-Wei
authors.initials: XW
authors.lastname: Liu
authors.forename: Kai
authors.initials: K
authors.lastname: Tang
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Mu
authors.forename: Konstantin
authors.initials: K
authors.lastname: Pervushin
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018625:Microscopy, Atomic Force; D019906:Nuclear Magnetic Resonance, Biomolecular; D055503:Protein Multimerization; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D013267:Stilbenes; D000077185:Resveratrol