Center for Theoretical Biological Physics, Rice University, Houston, TX 77005.
Department of Chemistry, Rice University, Houston, TX 77005.
Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4125-4130. doi: 10.1073/pnas.1921702117. Epub 2020 Feb 6.
Filaments made up of different isoforms of tau protein are associated with a variety of neurodegenerative diseases. Filaments made up of the 4R-tau isoform, which has four repeat regions (R1 to R4), are found in patients suffering from Alzheimer's disease, while filaments made of the 3R-tau isoform, which contains only three repeat units (R1, R3, and R4), are found in patients with Pick's disease (frontotemporal dementia). In this work, a predictive coarse-grained protein force field, the associative memory water-mediated structure and energy model (AWSEM), is used to study the energy landscapes of nucleation of the two different fibrils derived from patients with Pick's and Alzheimer's diseases. The landscapes for nucleating both fibril types contain amorphous oligomers leading to branched structures as well as prefibrillar oligomers. These two classes of oligomers differ in their structural details: The prefibrillar oligomers have more parallel in-register β-strands, which ultimately lead to amyloid fibrils, while the amorphous oligomers are characterized by a near random β-strand stacking, leading to a distinct amorphous phase. The landscape topography suggests that there must be significant structural reordering, or "backtracking," to transit from the amorphous aggregation channel to the fibrillization channel. Statistical mechanical perturbation theory allows us to evaluate the effects of changing concentration on the aggregation free-energy landscapes and to predict the effects of phosphorylation, which is known to facilitate the aggregation of tau repeats.
由不同的 tau 蛋白异构体组成的纤维与多种神经退行性疾病有关。由含有四个重复区（R1 到 R4）的 4R-tau 异构体组成的纤维存在于患有阿尔茨海默病的患者中，而由仅含有三个重复单元（R1、R3 和 R4）的 3R-tau 异构体组成的纤维存在于患有 Pick 病（额颞叶痴呆）的患者中。在这项工作中，使用了一种预测性的粗粒蛋白质力场，即关联记忆水介导的结构和能量模型（AWSEM），来研究源自 Pick 病和阿尔茨海默病患者的两种不同纤维的成核的能量景观。两种纤维类型的成核景观都包含无定形寡聚物，导致分支结构以及原纤维寡聚物。这两类寡聚物在其结构细节上有所不同：原纤维寡聚物具有更多平行的在位β-链，最终导致淀粉样纤维，而无定形寡聚物的特征是近随机的β-链堆积，导致明显的无定形相。景观地形表明，必须有显著的结构重排，或“回溯”，才能从无定形聚集通道过渡到纤维化通道。统计力学微扰理论使我们能够评估浓度变化对聚集自由能景观的影响，并预测磷酸化的影响，磷酸化已知可促进 tau 重复的聚集。
