Understanding of prion aggregation in membrane environment may help to ameliorate neurodegenerative complications caused by the amyloid forms of prions. Here, we investigated the membrane binding induced aggregation of yeast prion protein Sup35. Using the combination of fluorescence correlation spectroscopy (FCS) at single molecule resolution and other biophysical studies, we establish that lipid composition and lipid/protein ratio are key modulators of the aggregation kinetics of Sup35. In the presence of zwitterionic membrane, Sup35 exhibited a novel biphasic aggregation kinetics at lipid/protein ratio ranging between 20:1 and 70:1 (termed here as the Optimum Lipid Concentration, OLC). In ratios below (Low Lipid Concentration, LLC) and above (ELC, Excess Lipid Concentration) that range, the aggregation was found to be monophasic. In contrast, in the presence of negatively charged membrane, we did not observe any bi-phasic aggregation kinetics in the entire range of protein to lipid ratios. The toxicity of the aggregates formed within OLC range was found to be greater. Our results provide a mechanistic description of the role that membrane-concentration/composition-modulated-aggregation may play in neurodegenerative diseases.

中文翻译：

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膜组成和脂蛋白比调节酵母蛋白的淀粉样动力学

理解膜环境中ion病毒的聚集可能有助于缓解淀粉状蛋白形式的pr病毒引起的神经退行性并发症。在这里，我们调查了膜结合诱导酵母病毒蛋白Sup35的聚集。使用单分子分辨率的荧光相关光谱（FCS）和其他生物物理研究的组合，我们建立了脂质成分和脂质/蛋白质比是Sup35聚集动力学的关键调节器。在两性离子膜的存在下，Sup35在脂质/蛋白质比率为20：1到70：1（此处称为最佳脂质浓度，OLC）之间显示出新颖的双相聚集动力学。在低于（低脂质浓度，LLC）和高于（ELC，过量脂质浓度）的比率范围内，发现聚集是单相的。相反，在带负电荷的膜存在下，我们在蛋白质与脂质比例的整个范围内均未观察到任何双相聚集动力学。发现在OLC范围内形成的聚集体的毒性更大。我们的结果提供了一种机制描述膜浓度/组成调节聚集在神经退行性疾病中的作用。