Insight into the Metal Binding Sites in Amylin Aggregates

Abstract

Amylin peptide consists of 37 residues. The aggregation of Amylin is one of the symptoms of type 2 diabetes (T2D). Amylin's oligomers that are toxic lead to β-cells death and thus to decreasing of insulin's release to the blood and to progressing of T2D. The factors that affect Amylin aggregation are elusive, however it is known that Amylin peptides are found with insulin and zinc ions in the pancreatic β-cells and that zinc ions bind to Amylin oligomers and may inhibit Amylin aggregation. So far, it is unknown how zinc ions bind Amylin oligomers at the atomic resolution. Understanding the mechanism of zinc-binding sites in amylin oligomers is important for effective drug design to prevent and alleviate aggregation. We constructed Amylin oligomers based on ssNMR and x-ray crystallography. These experimental studies illustrate four different Amylin oligomeric models, which differ in the orientation of His18 in accordance of the core domain of Amylin. Other ssNMR study proposed that the binding site of zinc ions is His18. We applied molecular dynamics simulations to examine our constructed models. Two main conclusions had been obtained from our simulations. First, the binding site of zinc in Amylin is His18 which is located outside the core domain. Second, the zinc:Amylin ratio is 1:2.