Fichou Yann, Schirò Giorgio, Gallat François-Xavier, Laguri Cedric, Moulin Martine, Combet Jérôme, Zamponi Michaela, Härtlein Michael, Picart Catherine, Mossou Estelle, Lortat-Jacob Hugues, Colletier Jacques-Philippe, Tobias Douglas J, Weik Martin
Université Grenoble Alpes, CNRS, and Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Institut de Biologie Structurale, 38044 Grenoble, France;
Life Sciences Group, Institut Laue-Langevin, 38000 Grenoble, France;
Proc Natl Acad Sci U S A. 2015 May 19;112(20):6365-70. doi: 10.1073/pnas.1422824112. Epub 2015 Apr 27.
The paired helical filaments (PHF) formed by the intrinsically disordered human protein tau are one of the pathological hallmarks of Alzheimer disease. PHF are fibers of amyloid nature that are composed of a rigid core and an unstructured fuzzy coat. The mechanisms of fiber formation, in particular the role that hydration water might play, remain poorly understood. We combined protein deuteration, neutron scattering, and all-atom molecular dynamics simulations to study the dynamics of hydration water at the surface of fibers formed by the full-length human protein htau40. In comparison with monomeric tau, hydration water on the surface of tau fibers is more mobile, as evidenced by an increased fraction of translationally diffusing water molecules, a higher diffusion coefficient, and increased mean-squared displacements in neutron scattering experiments. Fibers formed by the hexapeptide (306)VQIVYK(311) were taken as a model for the tau fiber core and studied by molecular dynamics simulations, revealing that hydration water dynamics around the core domain is significantly reduced after fiber formation. Thus, an increase in water dynamics around the fuzzy coat is proposed to be at the origin of the experimentally observed increase in hydration water dynamics around the entire tau fiber. The observed increase in hydration water dynamics is suggested to promote fiber formation through entropic effects. Detection of the enhanced hydration water mobility around tau fibers is conjectured to potentially contribute to the early diagnosis of Alzheimer patients by diffusion MRI.
由内在无序的人类蛋白质tau形成的双螺旋丝（PHF）是阿尔茨海默病的病理标志之一。PHF是具有淀粉样性质的纤维，由刚性核心和无结构的模糊外壳组成。纤维形成的机制，特别是水合水可能发挥的作用，仍然知之甚少。我们结合蛋白质氘化、中子散射和全原子分子动力学模拟，研究全长人类蛋白质htau40形成的纤维表面水合水的动力学。与单体tau相比，tau纤维表面的水合水更具流动性，这在中子散射实验中表现为平移扩散水分子的比例增加、扩散系数更高以及均方位移增加。由六肽（306）VQIVYK（311）形成的纤维被用作tau纤维核心的模型，并通过分子动力学模拟进行研究，结果表明纤维形成后核心结构域周围的水合水动力学显著降低。因此，有人提出模糊外壳周围水动力学的增加是整个tau纤维周围实验观察到的水合水动力学增加的起源。观察到的水合水动力学增加被认为通过熵效应促进纤维形成。推测检测tau纤维周围增强的水合水流动性可能有助于通过扩散磁共振成像对阿尔茨海默病患者进行早期诊断。
