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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Interplay Of α-synuclein Binding And Conformational Switching Probed By Single-molecule Fluorescence
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Interplay Of α-synuclein Binding And Conformational Switching Probed By Single-molecule Fluorescence

机译：单分子荧光探测α-突触核蛋白结合与构象转换的相互作用

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We studied the coupled binding and folding of α-synuclein, an intrinsically disordered protein linked with Parkinson's disease. Using single-molecule fluorescence resonance energy transfer and correlation methods, we directly probed protein membrane association, structural distributions, and dynamics. Results revealed an intricate energy landscape on which binding of α-synuclein to amphiphilic small molecules or membrane-like partners modulates conformational transitions between a natively unfolded state and multiple α-helical structures. α-Synuclein conformation is not continuously tunable, but instead partitions into 2 main classes of folding landscape structural minima. The switch between a broken and an extended helical structure can be triggered by changing the concentration of binding partners or by varying the curvature of the binding surfaces presented by micelles or bilayers composed of the lipid-mimetic SDS. Single-molecule experiments with lipid vesicles of various composition showed that a low fraction of negatively charged lipids, similar to that found in biological membranes, was sufficient to drive α-synuclein binding and folding, resulting here in the induction of an extended helical structure. Overall, our results imply that the 2 folded structures are preen-coded by the α-synuclein amino acid sequence, and are tunable by small-molecule supramolecular states and differing membrane properties, suggesting novel control elements for biological and amyloid regulation of α-synuclein.
机译：我们研究了α-突触核蛋白（一种与帕金森氏病相关的内在失调的蛋白质）的结合结合和折叠。使用单分子荧光共振能量转移和相关方法，我们直接探测了蛋白质膜的缔合，结构分布和动力学。结果揭示了复杂的能量格局，在该格局上，α-突触核蛋白与两亲小分子或膜样伴侣的结合调节了天然展开状态和多个α-螺旋结构之间的构象转变。 α-突触核蛋白构象不是连续可调的，而是分为折叠景观结构极小值的两个主要类别。断裂的螺旋结构和延伸的螺旋结构之间的转换可以通过改变结合配偶体的浓度或改变由模拟脂质的SDS组成的胶束或双层所呈现的结合表面的曲率来触发。用各种组成的脂质囊泡进行的单分子实验表明，与生物膜中发现的负电荷脂质类似，低比例的带负电荷的脂质足以驱动α-突触核蛋白结合和折叠，从而导致了螺旋结构的延伸。总体而言，我们的结果表明2个折叠结构是由α-突触核蛋白氨基酸序列预先编码的，并且可以通过小分子超分子状态和不同的膜特性进行调节，这暗示了α-突触核蛋白的生物学和淀粉样调节的新型控制元件。 。

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