Department of Physics, Emory University, Atlanta, Georgia 30322, United States.
ACS Chem Neurosci. 2023 Nov 1;14(21):3905-3912. doi: 10.1021/acschemneuro.3c00470. Epub 2023 Oct 20.
The roles of α-synuclein in neurotransmitter release in brain neurons and in the Parkinson's disease condition have challenged comprehensive description. To gain insight into molecular mechanistic properties that actuate α-synuclein function and dysfunction, the coupled protein and solvent dynamics of oligomer and fibril forms of human α-synuclein are examined in a low-temperature system that allows control of confinement and localization of a motionally sensitive electron paramagnetic resonance spin probe in the coupled solvent-protein regions. The rotational mobility of the spin probe resolves two distinct α-synuclein-associated solvent components for oligomers and fibrils, as for globular proteins, but with dramatically higher fluidities at each temperature, that are comparable to low-confinement, aqueous-cryosolvent mesophases. In contrast to the temperature-independent volumes of the solvent phases that surround globular and condensate-forming proteins, the higher-fluidity mesophase volume of α-synuclein oligomers and fibrils decreases with decreasing temperature, signaling a compression of this phase. This unique property and thermal hysteresis in the mobilities and component weights, together with previous high-resolution structural characterizations, suggest a model in which the dynamically disordered C-terminal domain of α-synuclein creates a compressible phase that maintains high fluidity under confinement. Robust dynamics and compressibility are fundamental molecular mechanical properties of α-synuclein oligomers and fibrils, which may contribute to dysfunction and inform about function.
α-突触核蛋白在脑神经元中神经递质释放以及帕金森病中的作用一直难以全面描述。为深入了解促使α-突触核蛋白功能和功能障碍的分子机制特性，在允许控制运动敏感电子顺磁共振自旋探针在耦合溶剂-蛋白质区域中的局域化和限制的低温系统中，研究了人α-突触核蛋白的寡聚物和原纤维形式的耦合蛋白质和溶剂动力学。旋转流动性的自旋探针为寡聚物和原纤维解析了两个不同的与α-突触核蛋白相关的溶剂成分，与球状蛋白一样，但在每个温度下的流动性都大大提高，与低限制、水-结晶溶剂中间相相当。与围绕球状和凝结形成蛋白质的溶剂相的温度独立体积相反，α-突触核蛋白寡聚物和原纤维的较高流动性中间相体积随温度降低而降低，表明该相压缩。这种独特的性质和流动性以及组成权重的热滞，加上以前的高分辨率结构特征，表明了一个模型，其中动态无序的 C 末端结构域的α-突触核蛋白创建了一个可压缩的相，在限制下保持高流动性。动态性和可压缩性是α-突触核蛋白寡聚物和原纤维的基本分子力学特性，这可能导致功能障碍，并提供有关功能的信息。
