Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, United States.
J Chem Inf Model. 2023 Feb 27;63(4):1351-1361. doi: 10.1021/acs.jcim.2c01597. Epub 2023 Feb 14.
In tauopathies such as Alzheimer's disease (AD), aberrant phosphorylation causes the dissociation of tau proteins from microtubules. The dissociated tau then aggregates into sequent forms from soluble oligomers to paired helical filaments and insoluble neurofibrillary tangles (NFTs). NFTs is a hallmark of AD, while oligomers are found to be the most toxic form of the tau aggregates. Therefore, understanding tau oligomerization with regard to abnormal phosphorylation is important for the therapeutic development of AD. In this study, we investigated the impact of phosphorylated Ser289, one of the 40 aberrant phosphorylation sites of full-length tau proteins, on monomeric and dimeric structures of tau repeat R2 peptides. We carried out intensive replica exchange molecular dynamics simulation with a total simulation time of up to 0.1 ms. Our result showed that the phosphorylation significantly affected the structures of both the monomer and the dimer. For the monomer, the phosphorylation enhanced ordered-disordered structural transition and intramolecular interaction, leading to more compactness of the phosphorylated R2 compared to the wild-type one. As to the dimer, the phosphorylation increased intermolecular interaction and β-sheet formation, which can accelerate the oligomerization of R2 peptides. This result suggests that the phosphorylation at Ser289 is likely to promote tau aggregation. We also observed a phosphorylated Ser289-Na-phosphorylated Ser289 bridge in the phosphorylated R2 dimer, suggesting an important role of cation ions in tau aggregation. Our findings suggest that phosphorylation at Ser289 should be taken into account in the inhibitor screening of tau oligomerization.
在 tau 病，如阿尔茨海默病（AD）中，异常磷酸化导致 tau 蛋白从微管中解离。然后，游离的 tau 聚集成连续的形式，从可溶性寡聚体到配对螺旋丝和不溶性神经原纤维缠结（NFTs）。NFTs 是 AD 的标志，而寡聚体被发现是 tau 聚集物中最具毒性的形式。因此，了解异常磷酸化对 tau 寡聚化的影响对于 AD 的治疗开发很重要。在这项研究中，我们研究了全长 tau 蛋白的 40 个异常磷酸化位点之一 Ser289 的磷酸化对 tau 重复 R2 肽单体和二聚体结构的影响。我们进行了长达 0.1 毫秒的密集复制交换分子动力学模拟。我们的结果表明，磷酸化显著影响单体和二聚体的结构。对于单体，磷酸化增强了有序-无序结构转变和分子内相互作用，导致磷酸化的 R2 比野生型的 R2 更紧凑。对于二聚体，磷酸化增加了分子间相互作用和β-折叠形成，这可以加速 R2 肽的寡聚化。这一结果表明，Ser289 的磷酸化可能促进 tau 聚集。我们还观察到磷酸化的 R2 二聚体中存在 Ser289-Na-磷酸化的 Ser289 桥，这表明阳离子在 tau 聚集中的重要作用。我们的研究结果表明，在 tau 寡聚化抑制剂筛选中应考虑 Ser289 的磷酸化。
