Membrane Remodeling and Stimulation of Aggregation Following α-Synuclein Adsorption to Phosphotidylserine Vesicles
Membrane Remodeling and Stimulation of Aggregation Following α-Synuclein Adsorption to Phosphotidylserine Vesicles
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DOI：
10.1021/acs.jpcb.0c09192
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发表时间：
2021-02-04
影响因子：
3.3
通讯作者：
Murphy, Regina M.
中科院分区：
文献类型：
--
作者：
Hoover, Brandon M.;Shen, Zhizhang;Murphy, Regina M.
α-突触核蛋白是一种本质上无序的蛋白质，丰富存在于神经元的突触前末梢和突触囊泡中。α-突触核蛋白与脂质双层的相互作用不仅对其正常生理功能很重要，而且对其在帕金森病中作为路易体的病理性聚集和沉积也很重要。α-突触核蛋白优先与具有酸性头部基团的脂质和高曲率囊泡结合，并且可以调节膜曲率。蛋白质作为膜曲率传感器和发生器的作用与膜在促进其聚集中的作用之间的关系仍然未知。我们研究了α-突触核蛋白与1，2-二油酰基-sn-甘油-3-磷酸-L-丝氨酸（DOPS）或1，2-二月桂酰基-sn-甘油-3-磷酸-L-丝氨酸（DLPS）囊泡的相互作用。使用纳米粒子跟踪沿着与电子显微镜，我们证明，α-突触核蛋白诱导广泛的囊泡破坏和膜重塑成盘状，小管，带状DLPS囊泡，但不DOPS。粗粒度的分子动力学模拟显示，吸附α-突触核蛋白DLPS，但不DOPS囊泡诱导囊泡伸长和蛋白质的重新分配到更高的曲率，一个过程，可以驱动蛋白质聚集的区域。与此假设一致，DLPS而不是DOPS强烈刺激α-突触核蛋白聚集。我们的研究结果提供了新的见解的关键贡献的双层稳定性的膜响应α-突触核蛋白的吸附和刺激聚集。
alpha-Synuclein is an intrinsically disordered protein abundant in presynaptic terminals in neurons and in synaptic vesicles. alpha-Synuclein's interaction with lipid bilayers is important not only for its normal physiological function but also in its pathological aggregation and deposition as Lewy bodies in Parkinson's disease. alpha-Synuclein binds preferentially to lipids with acidic head groups and to high-curvature vesicles and can modulate membrane curvature. The relationship between the protein's role as a membrane curvature sensor and generator and the role of membranes in facilitating its aggregation remains unknown. We investigated the interaction of alpha-synuclein with vesicles of 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS) or 1,2-dilauroyl-sn-glycero-3-phospho-L-serine (DLPS). Using nanoparticle tracking along with electron microscopy, we demonstrate that alpha-synuclein induces extensive vesicle disruption and membrane remodeling into discoids, tubules, and ribbons with DLPS vesicles but not DOPS. Coarse-grained molecular dynamics simulations revealed that adsorption of alpha-synuclein to DLPS but not DOPS vesicles induced vesicle elongation and redistribution of protein to regions of higher curvature, a process that could drive protein aggregation. In agreement with this hypothesis, DLPS but not DOPS strongly stimulated alpha-synuclein aggregation. Our results provide new insights into the critical contribution of bilayer stability in the membrane response to alpha-synuclein adsorption and in stimulation of aggregation.