Amyloid formation has been implicated in a wide range of human diseases, and the interaction of amyloidogenic proteins with membranes are believed to be important for many of them. In type-2 diabetes, human islet amyloid polypeptide (IAPP) forms amyloids, which contribute to β-cell death and dysfunction in the disease. IAPP–membrane interactions are potential mechanisms of cytotoxicity. In vitro studies have shown that cholesterol significantly modulates the ability of model membranes to induce IAPP amyloid formation and IAPP-mediated membrane damage. It is not known if this is due to the general effects of cholesterol on membranes or because of specific sterol–IAPP interactions. The effects of replacing cholesterol with eight other sterols/steroids on IAPP binding to model membranes, membrane disruption, and membrane-mediated amyloid formation were examined. The primary effect of the sterols/steroids on the IAPP–membrane interactions was found to reflect their effect upon membrane order as judged by fluorescence anisotropy measurements. Specific IAPP–sterol/steroid interactions have smaller effects. The fraction of vesicles that bind IAPP was inversely correlated with the sterols/steroids’ effect on membrane order, as was the extent of IAPP-induced membrane leakage and the time to form amyloids. The correlation between the fraction of vesicles binding IAPP and membrane leakage was particularly tight, suggesting the restriction of IAPP to a subset of vesicles is responsible for incomplete leakage.

中文翻译：

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甾醇结构强烈调节膜-胰岛淀粉样多肽相互作用。

淀粉样蛋白的形成与多种人类疾病有关，并且淀粉样蛋白原蛋白与膜的相互作用被认为对其中许多重要。在2型糖尿病中，人胰岛淀粉样多肽（IAPP）形成淀粉样蛋白，导致该疾病的β细胞死亡和功能障碍。IAPP-膜相互作用是细胞毒性的潜在机制。体外研究表明，胆固醇显着调节模型膜诱导IAPP淀粉样蛋白形成和IAPP介导的膜损伤的能力。目前尚不清楚这是由于胆固醇对膜的一般作用还是由于特定的固醇-IAPP相互作用。用其他八种固醇/类固醇替代胆固醇对IAPP与模型膜结合，膜破裂，并检查了膜介导的淀粉样蛋白的形成。发现固醇/类固醇对IAPP-膜相互作用的主要作用反映了其对膜顺序的影响，这是通过荧光各向异性测量法判断的。特定的IAPP-固醇/类固醇相互作用的影响较小。结合IAPP的囊泡比例与固醇/类固醇对膜顺序的影响呈负相关，IAPP诱导的膜渗漏程度和形成淀粉样蛋白的时间也与之相反。结合IAPP的囊泡分数与膜渗漏之间的关系特别紧密，这表明将IAPP限制在一部分囊泡中是造成渗漏不完全的原因。发现固醇/类固醇对IAPP-膜相互作用的主要作用反映了其对膜顺序的影响，这通过荧光各向异性测量来判断。特定的IAPP-固醇/类固醇相互作用的影响较小。结合IAPP的囊泡比例与固醇/类固醇对膜顺序的影响呈负相关，IAPP诱导的膜渗漏程度和形成淀粉样蛋白的时间也与之相反。结合IAPP的囊泡分数与膜渗漏之间的关系特别紧密，这表明将IAPP限制在一部分囊泡中是造成渗漏不完全的原因。发现固醇/类固醇对IAPP-膜相互作用的主要作用反映了其对膜顺序的影响，这是通过荧光各向异性测量法判断的。特定的IAPP-固醇/类固醇相互作用的影响较小。结合IAPP的囊泡比例与固醇/类固醇对膜顺序的影响呈负相关，IAPP诱导的膜渗漏程度和形成淀粉样蛋白的时间也与之相反。结合IAPP的囊泡分数与膜渗漏之间的相关性特别紧密，这表明将IAPP限制在一部分囊泡中是造成渗漏不完全的原因。结合IAPP的囊泡比例与固醇/类固醇对膜顺序的影响呈负相关，IAPP诱导的膜渗漏程度和形成淀粉样蛋白的时间也与之相反。结合IAPP的囊泡分数与膜渗漏之间的相关性特别紧密，这表明将IAPP限制在一部分囊泡中是造成渗漏不完全的原因。结合IAPP的囊泡比例与固醇/类固醇对膜顺序的影响呈负相关，IAPP诱导的膜渗漏程度和形成淀粉样蛋白的时间也与之相反。结合IAPP的囊泡分数与膜渗漏之间的相关性特别紧密，这表明将IAPP限制在一部分囊泡中是造成渗漏不完全的原因。