Department of Physics, State Key Laboratory of Surface Physics, and Key Laboratory for Computational Physical Sciences (Ministry of Education), Fudan University, Shanghai 200438, People's Republic of China.
Cryo-EM Center, Southern University of Science and Technology, Shenzhen, 518055, People's Republic of China.
Phys Chem Chem Phys. 2021 Sep 22;23(36):20406-20418. doi: 10.1039/d1cp02651h.
Abnormal aggregation of proteins into pathological amyloid fibrils is implicated in a wide range of devastating human neurodegenerative diseases. Intracellular fibrillary inclusions formed by Tau protein are characterized as the hallmark of tauopathies, including Alzheimer's disease and frontotemporal dementia. Heparin has been often used to trigger Tau aggregation in studies. However, the conformational changes induced by heparin and the underlying mechanism of promotion of Tau aggregation by heparin are not well understood. Structural characterization of Tau oligomers in the early stage of fibrillation is of great importance but remains challenging due to their dynamic and heterogeneous nature. R3, the third microtubule-binding repeat of Tau, contains the fibril-nucleating core (PHF6) and is crucial for Tau aggregation. In this study, utilizing extensive all-atom replica-exchange molecular dynamic simulations, we explored the conformational ensembles of R3 monomer/dimer in the absence and presence of heparin. Our results show that without heparin, both monomeric and dimeric R3 preferentially adopt collapsed β-sheet-containing conformations and PHF6 plays an important role in the formation of interchain β-sheet structures, while in the presence of heparin, R3 can populate relatively extended disordered states where chain dimension is similar to that of R3 in Tau filaments. Through electrostatic, hydrogen-bonding and hydrophobic interactions, heparin has a preference for interacting with residues V306/Q307/K317/K321/H329/H330/K331 which distribute throughout the entire sequence of R3, in turn acting as a template to extend R3 conformations. More importantly, heparin alters intramolecular/intermolecular interaction patterns of R3 and increases the intermolecular contact regions. Our results suggest that heparin remodels the conformations of R3 towards fibril-prone structures by increasing chain dimension and intermolecular contact regions, which may shed light on the atomic mechanism of heparin-induced amyloid fibrillization of Tau protein.
蛋白质异常聚集形成病理性淀粉样纤维在广泛的人类神经退行性疾病中起作用。由 Tau 蛋白形成的细胞内纤维状包涵物是包括阿尔茨海默病和额颞叶痴呆在内的 Tau 病的标志。肝素常被用于研究中诱导 Tau 聚集。然而，肝素诱导的构象变化以及肝素促进 Tau 聚集的潜在机制尚不清楚。 Tau 寡聚体在纤维形成早期的结构特征非常重要，但由于其动态和异质性，仍然具有挑战性。Tau 的第三个微管结合重复序列 R3 包含纤维核（PHF6），对于 Tau 聚集至关重要。在这项研究中，利用广泛的全原子复制交换分子动力学模拟，我们研究了 R3 单体/二聚体在无肝素和有肝素存在下的构象集合。我们的结果表明，没有肝素时，单体和二聚体 R3 都优先采用折叠的 β-片层结构构象，并且 PHF6 在形成链间β-片层结构中起重要作用，而在肝素存在时，R3 可以进入相对伸展的无序状态，此时链的尺寸与 Tau 纤维中的 R3 相似。通过静电、氢键和疏水相互作用，肝素优先与分布在整个 R3 序列中的残基 V306/Q307/K317/K321/H329/H330/K331 相互作用，从而充当扩展 R3 构象的模板。更重要的是，肝素改变了 R3 的分子内/分子间相互作用模式并增加了分子间接触区域。我们的结果表明，肝素通过增加链尺寸和分子间接触区域来重塑 R3 的构象，使其倾向于形成纤维状结构，这可能揭示了肝素诱导 Tau 蛋白淀粉样纤维形成的原子机制。
