Islet amyloid polypeptide (IAPP) forms pancreatic amyloid in type-2 diabetes and contributes to beta-cell death in the disease. A body of in vitro biophysical studies with simplified model membranes has led to proposals that membrane interactions are critical for toxicity in vivo. However, common model membranes have very high percentages of negatively charged lipids, lack cholesterol and are symmetric. In sharp contrast, the beta-cell plasma membrane contains cholesterol, is asymmetric, and contains a low percentage of anionic lipids which are found in the inner leaflet. We and others have shown that IAPP membrane interactions strongly depend on membrane composition, especially the fraction of negatively charged lipids and the presence or absence of cholesterol. An asymmetric membrane model system has been developed to study IAPP membrane interactions and reveals that IAPP induces a loss of membrane asymmetry. The process of IAPP induced POPS lipid flip-flop correlates with membrane leakage. Studies with cultured beta-cells demonstrate that IAPP induces lipid flip flop in living cells. These studies provide new insights into the mechanism of IAPP induced membrane damage and reveal limitations with standard model membrane systems.

Turning cell membranes inside out: Mechanism of membrane damage by amyloidogenic proteins

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.