Departments of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.
Neurodegeneration, H. Lundbeck A/S, DK-2500, Valby, Denmark.
Sci Rep. 2018 Apr 18;8(1):6209. doi: 10.1038/s41598-018-24276-4.
Tau antibodies have shown therapeutic potential for Alzheimer's disease and several are in clinical trials. As a microtubule-associated protein, tau relies on dynamic phosphorylation for its normal functions. In tauopathies, it becomes hyperphosphorylated and aggregates into toxic assemblies, which collectively lead to neurodegeneration. Of the phospho-epitopes, the region around Ser396 has received particular attention because of its prominence and stability in tauopathies. Here we report the first structure of a monoclonal tau antibody in complex with the pathologically important phospho-Ser396 residue. Its binding region reveals tau residues Tyr394 to phospho-Ser396 stabilized in a β-strand conformation that is coordinated by a phospho-specific antigen binding site. These details highlight a molecular switch that defines this prominent conformation of tau and ways to target it. Overall, the structure of the antibody-antigen complex clarifies why certain phosphorylation sites in tau are more closely linked to neurodegeneration than others.
tau 抗体在阿尔茨海默病的治疗中显示出了潜力，目前已有多种抗体处于临床试验阶段。tau 作为一种微管相关蛋白，其正常功能依赖于动态磷酸化。在 tau 病中，tau 会过度磷酸化并聚集成毒性组装体，从而导致神经退行性变。在磷酸化表位中，Ser396 周围的区域因其在 tau 病中的突出性和稳定性而受到特别关注。在这里，我们报告了第一个与病理上重要的磷酸化 Ser396 残基结合的单克隆 tau 抗体的结构。其结合区域揭示了 tau 残基 Tyr394 到磷酸化 Ser396 的稳定，形成了一个由磷酸特异性抗原结合位点协调的 β-折叠构象。这些细节突出了一个分子开关，该开关定义了 tau 的这种突出构象以及靶向它的方法。总的来说，抗体-抗原复合物的结构阐明了为什么 tau 中的某些磷酸化位点比其他位点与神经退行性变的关系更密切。
