Role of aromatic pi-stacking on the aggregation of human islet amyloid polypeptide (hIAPP)

Human islet amyloid polypeptide (hIAPP) is secreted in the β-cells of the pancreas, which also secretes insulin. In type 2 diabetes mellitus, hIAPP undergoes self-aggregation, forming fibrils. This self-aggregation is cytotoxic and is thought to be linked to type 2 diabetes mellitus by causing β-cell membrane destruction. The N-terminus of hIAPP (1-19) contains a binding site (residues 14-18) for self-aggregation. Aggregation is thought to be mediated by pistacking interactions between phenylalanine residues of hIAPP. In this study, the hIAPP 1-19 sequence was modified by replacing phenylalanine with alanine and naphthylalanine, to study if the modification of the aromatic side chain alters aggregation and membrane destructive activity. The activity of the modified hIAPP sequences was tested against differently charged lipids, using a fluorescent dye leakage assay. Both modified hIAPP 1-19 sequences were found to be less active when compared to the original hIAPP 1-19 sequence. This might be due to lack of aromatic pi-stacking interactions at the 15th position or due to inappropriate structural conformation of the naphthylalanine analog