a Department of Biochemistry & Molecular Pharmacology , New York University School of Medicine , New York , NY , USA.
b Departments of Neuroscience & Physiology, & Psychiatry , New York University School of Medicine , New York , NY , USA.
MAbs. 2019 Apr;11(3):477-488. doi: 10.1080/19420862.2019.1574530. Epub 2019 Feb 26.
Targeting tau with immunotherapies is currently the most common approach taken in clinical trials of patients with Alzheimer's disease. The most prominent pathological feature of tau is its hyperphosphorylation, which may cause the protein to aggregate into toxic assemblies that collectively lead to neurodegeneration. Of the phospho-epitopes, the region around Ser/Ser has received particular attention for therapeutic targeting because of its prominence and stability in diseased tissue. Herein, we present the antigen-binding fragment (Fab)/epitope complex structures of three different monoclonal antibodies (mAbs) that target the pSer tau epitope region. Most notably, these structures reveal an antigen conformation similar to a previously described pathogenic tau epitope, pSer, which was shown to have a β-strand structure that may be linked to the seeding core in tau oligomers. In addition, we have previously reported on the similarly ordered conformation observed in a pSer epitope, which is in tandem with pSer. Our data are the first Fab structures of mAbs bound to this epitope region of the tau protein and support the existence of proteopathic tau conformations stabilized by specific phosphorylation events that are viable targets for immune modulation.
针对 tau 的免疫疗法是目前阿尔茨海默病患者临床试验中最常用的方法。tau 的最突出的病理特征是过度磷酸化，这可能导致蛋白质聚集成有毒的聚集物，从而导致神经退行性变。在磷酸化表位中，Ser/Ser 周围的区域因其在病变组织中的突出性和稳定性而受到特别关注，作为治疗靶点。在此，我们展示了针对 pSer tau 表位区域的三种不同单克隆抗体 (mAb) 的抗原结合片段 (Fab)/表位复合物结构。最值得注意的是，这些结构揭示了一种类似于先前描述的致病性 tau 表位 pSer 的抗原构象，该表位具有 β-折叠结构，可能与 tau 寡聚体中的种子核心有关。此外，我们之前还报道了在与 pSer 串联的 pSer 表位中观察到的类似有序构象。我们的数据是首次报道与 tau 蛋白该表位区域结合的 mAb 的 Fab 结构，并支持存在由特定磷酸化事件稳定的蛋白病变 tau 构象，这些构象是免疫调节的可行靶点。
