J Am Chem Soc. 2021 Nov 17;143(45):18899-18906. doi: 10.1021/jacs.1c05344. Epub 2021 Nov 8.
The neuronal protein α-synuclein, linked to Parkinson's disease, binds to negatively charged vesicles adopting a partial α-helix structure, but helix arrangement at the vesicle surface is not fully understood. Using linear dichroism spectroscopy (LD), we study the interaction of monomeric α-synuclein with large unilamellar vesicles of 1,2-dioleoyl--glycero-3-phospho-l-serine (DOPS), 1-palmitoyl-2-oleoyl--glycero-3-phospho-l-serine (POPS), and 1,2-dioleoyl--glycero-3-phospho-(1'--glycerol) (DOPG) under mild shear flow. The LD data of oriented lipid vesicles show that the long axis of the protein helix is oriented preferentially perpendicular to the membrane normal but deviates from a uniform in-plane distribution. Upon initial binding, a fraction of helices are oriented in the direction of least curvature for all ellipsoid-shaped vesicles at a lipid:protein molar ratio of 100. However, at a lower protein concentration the helices distribute uniformly on DOPS and POPS vesicles. In all cases, the α-synuclein helices rearrange with time (minute time scale) in the shear flow and begin to tilt into the vesicle membrane. Faster reorientation kinetics in the presence of flow suggests that modulation of membrane dynamics, by thermal or shear-dynamic activation, may overcome steric barriers by what may be called "flow catalysis".
神经元蛋白α-突触核蛋白与帕金森病有关，它与带负电荷的囊泡结合，形成部分α-螺旋结构，但囊泡表面的螺旋排列方式尚不完全清楚。我们使用线二色性光谱（LD）研究单体α-突触核蛋白与 1,2-二油酰基-sn-甘油-3-磷酸-l-丝氨酸（DOPS）、1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸-l-丝氨酸（POPS）和 1,2-二油酰基-sn-甘油-3-磷酸-(1'-甘油)（DOPG）的大单室囊泡的相互作用，在温和的剪切流条件下进行。定向脂质囊泡的 LD 数据表明，蛋白质螺旋的长轴优先垂直于膜法线取向，但偏离了平面内的均匀分布。在初始结合时，对于所有各向异性囊泡，在脂质：蛋白质摩尔比为 100 的情况下，一部分螺旋沿最小曲率的方向取向。然而，在较低的蛋白质浓度下，DOPS 和 POPS 囊泡上的螺旋呈均匀分布。在所有情况下，α-突触核蛋白螺旋随时间（分钟时间尺度）在剪切流中重新排列，并开始倾斜进入囊泡膜。在存在流动的情况下更快的重取向动力学表明，通过热或剪切动力学激活来调节膜动力学，可能通过所谓的“流动催化”克服空间位阻。
