Liposome Damage and Modeling of Fragments of Human Islet Amyloid Polypeptide (IAPP) Support a Two-Step Model of Membrane Destruction

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A key factor in the development of Type II diabetes is the loss of insulin-producing beta-cells. Human islet amyloid polypeptide (hIAPP) is believed to play a crucial role in this process by forming small aggregates that disrupt the cellular membrane. During Type II diabetes mellitus, human IAPP (hIAPP) fibrillizes to form amyloid deposits. However, the role of various regions of the 37 amino acid peptide in the process of membrane disruption has yet to be fully elucidated. Therefore, several fragments (10-19, 20-29, 10-29, 1-19) of hIAPP were synthesized and compared to full length hIAPP for their effects on model PC/PS bilayers. These fragments were also modeled using density functional methods and analyzed by circular dichroism, to determine possible correlations between activity and available conformations and charge distribution. Results from dye leakage and Thioflavin T fluorescence assays confirmed that the hIAPP fragments disrupt the lipid bilayer to varying extents, despite their inability to form amyloid fibrils. The longer and more positively charged fragments were most active in the assay (1-19 > 10-29 > 10-19 > 20-29), though none rivaled the activity of the native full length peptide. This may reflect their relative abilities to interact with the negatively charged membrane. Data support a two-step model for membrane disruption: insertion by the N-terminus followed by fibrillization mediated by the middle to C-terminal region.[PUBLICATION ABSTRACT]

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