Low pH acts as inhibitor of membrane damage induced by human islet amyloid polypeptide

Human islet amyloid polypeptide (IAPP) is the major component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus. After synthesis, IAPP is stored in the β-cell granules of the pancreas at a pH of approximately 5.5 and released into the extracellular compartment at a pH of 7.4. To gain insight into the possible consequences of pH differences for properties and membrane interaction of IAPP, we here compared the aggregational and conformational behavior of IAPP as well as IAPP-membrane interactions at pH 5.5 and pH 7.4. Our data reveal that a low pH decreases the rate of fibril formation both in solution and in the presence of membranes. We observed by CD spectroscopy that these differences in kinetics are directly linked to changes in the conformational behavior of the peptide. Mechanistically, the processes that occur at pH 5.5 and pH 7.4 appear to be similar. At both pH values, we found that the kinetic profile of IAPP fibril growth matches the kinetic profile of IAPP-induced membrane damage, and that both are characterized by a lag phase and a sigmoidal transition. Furthermore, monolayer studies as well as solid-state NMR experiments indicate that the differences in kinetics and conformational behavior as function of pH are not due to a different mode of membrane insertion. Our study suggests that a low pH prevents aggregation and membrane damage of IAPP in the secretory granules, most likely by affecting the ionization properties of the peptide.