Journal of Inorganic Biochemistry
Journal of Inorganic Biochemistry
5 years ago

Zn(II) - pramlintide: Stability, binding sites and unexpected aggregation

Zn(II) - pramlintide: Stability, binding sites and unexpected aggregation
Pramlintide is an antidiabetic drug which mimics amylin – a small peptide co-secreted from pancreatic β-cells together with insulin, one of the hallmarks of type 2 diabetes. In the course of the disease, amylin misfolds into small oligomers or to an aggregated β-sheet amyloid fiber. The misfolding mechanism is not yet quite understood, but it is clear that zinc ions play an important role in the process. This work sheds new light on the role of zinc and pramlintide in the course of the disease, giving a detailed description of the Zn(II)-pramlintide complex, in which the metal ion binds to the imidazole of His18 and the amine group of Lys1, imposing a bend in the peptide between these residues. The most surprising finding is the fact that the initially well-soluble, non-aggregating Zn(II)-pramlintide complex forms fibrillar, oligomeric aggregates after a lag-time of 20h. This raises more questions about the relationship between Zn(II) and amylin/pramlintide: could this zinc-induced change in the complex structure be a partial explanation of the formation of oligomeric aggregates of the complex, which might be much more toxic to β-cells than large fibrillar deposits and if so, is pramlintide the optimal choice of an antidiabetic drug?

Publisher URL: www.sciencedirect.com/science

DOI: S0162013417302088

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