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: Lei Wei, Ping Jiang, Weixin Xu, Hai Li, Hua Zhang, Liangyu Yan, Mary B Chan-Park, Xue-Wei Liu, Kai Tang, Yuguang Mu, Konstantin Pervushin
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 8 Pg. 6291-300 (Feb 25 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21148563 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid
• Islet Amyloid Polypeptide
• Stilbenes
• Resveratrol

Topics

• Amyloid (chemistry, genetics, metabolism)
• Diabetes Mellitus, Type 2 (genetics, metabolism)
• Humans
• Islet Amyloid Polypeptide (chemistry, genetics, metabolism)
• Microscopy, Atomic Force
• Nuclear Magnetic Resonance, Biomolecular
• Protein Multimerization
• Resveratrol
• Stilbenes (chemistry)