How Islet Amyloid Polypeptide Damages Lipid Bilayers

Abstract

A leading hypothesis for the attrition of insulin-producing beta-cells in type 2 diabetes attributes the cause to islet amyloid polypeptide (IAPP) for its deleterious effects on the cell membranes. This idea has initiated extensive investigations on human IAPP (hIAPP) and its interactions with lipid bilayers. However, it is still difficult to correlate its modes of interactions with its effects on islet cells in culture, which indeed induce cell death. HIAPP fibrils demonstrably interact with lipids and damage lipid bilayers, but appear to have no effect on islet cells in culture. Thus a modified amyloid hypothesis assumes that the toxicity is caused by hIAPP oligomers which are not pre-amyloid fibrils or protofibrils. But so far such oligomers have not been isolated or identified. HIAPP monomers also bind to lipid bilayers, but the mode of interaction is not clear. Here we performed two types of experiments that have not been done before. First we used X-ray diffraction, in conjunction with CD measurement, to reveal the location of the peptide bound in a lipid bilayer. We then observed the effects of hIAPP, either in its fibril form or in its monomeric form, on giant unilamellar vesicles. The results show that the peptide binds to the headgroup-chain interface only in its alpha-helical form. Once the peptides transform to beta-aggregates, the latter come out of the interfacial binding region and bind or attach to the surface of lipid bilayers. The process of hIAPP transforming from the bound alpha-helices to beta-aggregates extracts lipid molecules to become part of the aggregation. We believe that this process also creates defects in the lipid bilayer that allow transmembrane ion conduction as a possible damage to cell membranes.