Investigating the Effect of Insulin on Amylin Aggregation in Type 2 Diabetes

The self-assembly of amylin peptide is associated with amylin aggregation in type 2 Diabetes (T2D). Under unknown conditions, amylin peptides aggregate into oligomers which are known as toxic species to β-cells, lead to their loss, consequently to the decreasing of insulin and eventually to the progression of T2D. Insulin shares the same secretory pathway in the β-cells and thus may interact with amylin.

The self-assembly of amylin has been recently investigated in our group. [1] A previous in vitro study suggested that a specific domain in insulin B chain binds to a specific domain in amylin. [2] It has been proposed that the aromatic amino acid Tyr16 in insulin B chain is forming π-π stacking interaction with the Phe15 in amylin, mediate amylin-insulin recognition and therefore play important role in inhibition of amylin aggregation. Yet, the role of these aromatic amino acids in amylin-insulin recognition has not been proved by experimental and computational tools.

In this work we combined experimental and computational studies to approve that the Tyr16 in chain B of insulin is forming π-π interactions with the Phe15 in amylin oligomer. Furthermore, our research shows that these interactions decrease the self-assembly of amylin and therefore inhibit amylin aggregation. The mutation of Tyr16 to Ala in insulin resulted in new groups of aromatic interactions between the mutated insulin and the wt-amylin and consequently leads to the promotion of amylin aggregation.

References:

[1] V. Wineman-fisher, Y. Atsmon-Raz, and Y. Miller, “Orientations of Residues along the β - Arch of Self-Assembled Amylin Fibril-Like Structures Lead to Polymorphism,” Biomacromolecules., 16, 156-65, 2015.

[2] S. Gilead, H. Wolfenson, and E. Gazit, “Molecular mapping of the recognition interface between the islet amyloid polypeptide and insulin.,” Angew. Chem. Int. Ed. Engl., 45, 6476–80, 2006.