Membrane-catalyzed IAPP aggregation is dominated by secondary nucleation

Type II diabetes is characterized by the loss of pancreatic β-cells, which produce insulin. β-Cell death is thought to be a consequence of membrane disruption, caused by the aggregation of islet amyloid polypeptide (IAPP) into amyloid fibrils. However, the molecular mechanisms of IAPP aggregation in the presence of membranes have remained unclear. Global fitting of kinetic data has proven to be a valuable method to reveal the microscopic steps of amyloid formation. Here, we use this methodology to elucidate the aggregation mechanism of IAPP in the presence of mixed zwitterionic and anionic lipid membranes. The results of our kinetic analysis converge to a previously undescribed model, in which aggregation on the membrane is strongly dominated by secondary nucleation, i.e. the formation of new nuclei on the surface of existing fibrils. The critical nucleus consists of a single IAPP molecule, and multiple anionic lipids are involved in catalyzing both primary and secondary nucleation. The elongation rate does not appear to be affected by the presence of anionic lipids. These new insights into the mechanism of IAPP aggregation on membranes may help to understand IAPP toxicity and will be important for the development of therapeutics to prevent β-cell death in type II diabetes.