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首页> 外文期刊>Biophysical Chemistry: An International Journal Devoted to the Physical Chemistry of Biological Phenomena >Molecular mechanisms for the destabilization of model membranes by islet amyloid polypeptide
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Molecular mechanisms for the destabilization of model membranes by islet amyloid polypeptide

机译：胰岛淀粉样蛋白多肽模型膜不稳定的分子机制

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摘要

Misfolding of human islet amyloid polypeptide (hIAPP) into insoluble aggregates is associated with Type 2 diabetes. It has been suggested that hIAPP toxicity may be due to its accumulation in pancreatic islets, causing membrane disruption and cell permeabilization, however the molecular basis underlying its lipid association are still unclear. Here, we combine solid-state NMR, fluorescence and bright field microscopy to investigate hIAPP lipid membrane interactions. Real-time microscopy highlights a time-dependent penetration of hIAPP oligomers toward the most buried layers of the lipid vesicles until the membrane disrupts. Deuterium NMR was conducted on liposomes at different hIAPP concentration to probe lipid internal order and thermotropism. The gel-to-fluid phase transition of the lipids is decreased by the presence of hIAPP, and site-specific analysis of the order parameter showed a significant increase of lipid order for the first eight positions of the acyl chain, suggesting a partial insertion of the peptide inside the bilayer. These results offer experimental insight into the membrane destabilization of hIAPP on model membrane vesicles.
机译：人胰岛淀粉样蛋白多肽（HIAPP）误折叠成不溶性聚集体与2型糖尿病有关。已经提出，HIAPP毒性可能是由于其在胰岛中的积累，导致膜破坏和细胞透氧，但其脂质关联的分子基础尚不清楚。在此，我们将固态NMR，荧光和亮场显微镜结合以研究HIAPP脂膜相互作用。实时显微镜突出显示HIAPP低聚物对脂质囊泡最埋的层的时间依赖性渗透，直至膜破坏。在不同的HIAPP浓度下对脂质体进行氘NMR，以探测脂质内部秩序和热熵。脂质的凝胶到流体相转变通过HIAPP的存在而降低，并且订单参数的现场特异性分析显示了酰基链的前八个位置的脂质顺序的显着增加，这表明部分插入双层内的肽。这些结果提供了对模型膜囊泡的HIAPP膜不稳定的实验洞察。

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