Amylin peptides are secreted together with insulin and zinc ions from pancreatic β-cells. Under unknown conditions, the amylin peptides aggregate to produce oligomers and fibrils, and in some cases Zn2+ ions can bind to amylin peptides to form Zn2+-aggregate complexes. Consequently, these aggregates lead to the death of the β-cells and a decrease in insulin, which is one of the symptoms of type-2 diabetes (T2D). Therefore, it is crucial to investigate the binding sites of the Zn2+ ions in fibrillary amylin. It was previously found by in vitro and simulation studies that Zn2+ ion binds to two or four His residues in the turn domain of fibrillary amylin. In the current study, we present a new Zn2+ binding site in the N-terminus of fibrillary amylin with three different coordination modes. Our simulations showed that Zn2+ ions bind to polymorphic amylin fibrils with a preference to bind to four Cys residues rather than two Cys residues of two neighboring amylin monomers. The new binding site leads to conformational changes, increases the number of polymorphic states, and demonstrates the existence of competition between various binding sites. Our study provides insight into the molecular mechanisms through which Zn2+ ions that play a critical role in amylin aggregation can bind to amylin and promote amylin aggregation in T2D.
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*E-mail: firstname.lastname@example.org. Fax: +972-86428709. Tel: +972-86428705. ORCID Yifat Miller: 0000-0002-1163-9745 Author Contributions V.W.F performed the simulations, analyzed the data, and contributed to writing the manuscript. Y.M. conceived and designed the research and contributed to writing the manuscript. Funding This research was supported by the Israel Science Foundation (Grant 532/15). Notes The authors declare no competing financial interest.
© 2017 American Chemical Society.
- Zinc binding site
- protein aggregation