The Effect of Cholesterol on Membrane-Bound Islet Amyloid Polypeptide.
The Effect of Cholesterol on Membrane-Bound Islet Amyloid Polypeptide.
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DOI：
10.3389/fmolb.2021.657946
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发表时间：
2021
影响因子：
5
通讯作者：
Schiøtt B
中科院分区：
文献类型：
--
作者：
Christensen M;Berglund NA;Schiøtt B
胰岛淀粉样多肽（IAPP）是II型糖尿病患者β细胞质量减少的原因。细胞膜的分子组成对于调节IAPP细胞毒性和聚集是重要的。胆固醇以高浓度存在于胰腺β细胞中，体外实验表明，胆固醇通过直接相互作用或通过改变膜的性质来影响IAPP的淀粉样蛋白形成。在这项研究中，我们应用原子，无偏分子动力学模拟在微秒的时间尺度上研究胆固醇对膜结合IAPP的影响。用胆固醇、磷脂酰胆碱（PC）和磷脂酰丝氨酸（PS）脂质的各种组合进行模拟。在所有模拟中，单体IAPP的螺旋结构通过膜稳定。我们发现，胆固醇降低插入深度的IAPP相比，纯磷脂膜，而PS脂质抵消胆固醇的影响。聚集倾向先前已被提出与插入深度的IAPP，我们发现，减少与增加的有序的脂质诱导胆固醇。胆固醇在IAPP附近耗尽，因此我们的结果表明胆固醇的影响是间接的。
Islet amyloid polypeptide (IAPP) is a proposed cause of the decreased beta-cell mass in patients with type-II diabetes. The molecular composition of the cell-membrane is important for regulating IAPP cytotoxicity and aggregation. Cholesterol is present at high concentrations in the pancreatic beta-cells, and in-vitro experiments have indicated that it affects the amyloid formation of IAPP either by direct interactions or by changing the properties of the membrane. In this study we apply atomistic, unbiased molecular dynamics simulations at a microsecond timescale to investigate the effect of cholesterol on membrane bound IAPP. Simulations were performed with various combinations of cholesterol, phosphatidylcholine (PC) and phosphatidylserine (PS) lipids. In all simulations, the helical structure of monomer IAPP was stabilized by the membrane. We found that cholesterol decreased the insertion depth of IAPP compared to pure phospholipid membranes, while PS lipids counteract the effect of cholesterol. The aggregation propensity has previously been proposed to correlate with the insertion depth of IAPP, which we found to decrease with the increased ordering of the lipids induced by cholesterol. Cholesterol is depleted in the vicinity of IAPP, and thus our results suggest that the effect of cholesterol is indirect.
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