Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute, UCLA, Los Angeles, California 90095, USA.
Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095, USA.
Nat Chem. 2018 Feb;10(2):170-176. doi: 10.1038/nchem.2889. Epub 2017 Nov 20.
Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its aggregation, but inhibitors based on the structure of the VQIVYK segment only partially inhibit full-length tau aggregation and are ineffective at inhibiting seeding by full-length fibrils. Here we show that the VQIINK segment is the more powerful driver of tau aggregation. Two structures of this segment determined by the cryo-electron microscopy method micro-electron diffraction explain its dominant influence on tau aggregation. Of practical significance, the structures lead to the design of inhibitors that not only inhibit tau aggregation but also inhibit the ability of exogenous full-length tau fibrils to seed intracellular tau in HEK293 biosensor cells into amyloid. We also raise the possibility that the two VQIINK structures represent amyloid polymorphs of tau that may account for a subset of prion-like strains of tau.
聚集的 tau 蛋白与 20 多种神经退行性疾病有关，包括阿尔茨海默病。先前的研究表明，tau 的序列片段 VQIINK 和 VQIVYK 驱动其聚集，但基于 VQIVYK 片段结构的抑制剂只能部分抑制全长 tau 的聚集，并且对全长纤维的种子形成无效。在这里，我们表明 VQIINK 片段是 tau 聚集的更强大驱动力。通过低温电子显微镜方法微电子衍射确定的该片段的两个结构解释了其对 tau 聚集的主导影响。具有实际意义的是，这些结构导致了抑制剂的设计，不仅可以抑制 tau 的聚集，还可以抑制外源性全长 tau 纤维在 HEK293 生物传感器细胞中诱导细胞内 tau 形成淀粉样蛋白的能力。我们还提出了这样一种可能性，即这两种 VQIINK 结构代表 tau 的淀粉样蛋白多态体，可能解释了 tau 样朊病毒的一部分。
