Mechanistic and Structural Origins of the Asymmetric Barrier to Prion-like Cross-Seeding between Tau-3R and Tau-4R
Mechanistic and Structural Origins of the Asymmetric Barrier to Prion-like Cross-Seeding between Tau-3R and Tau-4R
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DOI：
10.1016/j.jmb.2018.09.010
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发表时间：
2018-12-07
影响因子：
5.6
通讯作者：
Udgaonkar, Jayant B.
中科院分区：
文献类型：
--
作者：
Kumar, Harish;Udgaonkar, Jayant B.
感染性纤维蛋白聚集体通过类朊病毒机制在大脑中传播和沉积，是包括 tau 病在内的各种神经退行性疾病病理生理学的关键组成部分。在 tau 蛋白病中，含有 3 个和 4 个微管结合重复序列的 tau 蛋白的两种异构体被发现聚集，并且聚集体中存在的异构体类型决定了 tau 蛋白病的类型。两种 tau 亚型之间的交叉播种受到不对称屏障的限制，该不对称屏障类似于限制朊病毒跨物种传播的物种屏障，其起源仍不清楚。在这项研究中，tau 原纤维的生长可以通过两步米氏模型来描述。将该机制描述为类似 Michaelis-Menten 的机制，使得人们能够定量了解 tau 的两种同种型 tau-K18 和 tau-K19（其不同之处分别包含四个和三个微管结合重复序列）之间存在的不对称播种屏障，其中 tau-K18 原纤维不能播种 tau-K19 单体。此外，两种异构体的高分辨率结构分析表明，tau-K19 的结构核心比 tau-K18 更加有序。因此，当前的工作为一般的不对称播种屏障，特别是两种 tau 亚型提供了动力学和结构原理。 (C) 2018 Elsevier Ltd. 保留所有权利。
The spread and deposition of infectious fibrillar protein aggregates in the brain via a prion-like mechanism is a critical component in the patho-physiology of various neurodegenerative diseases, including the tauopathies. In tauopathies, two isoforms of tau, containing three and four microtubule binding repeats, are found to aggregate, and the type of isoform present in aggregates determines the type of tauopathy. Cross-seeding between the two tau isoforms is limited by an asymmetric barrier similar to the species barrier that restricts prion transmission across species, whose origin has remained unclear. In this study, the growth of the tau fibrils is shown to be describable by a two-step Michaelis-Menten-like model. Delineation of the mechanism as a Michaelis-Menten-like mechanism has enabled a quantitative understanding of the asymmetric seeding barrier that exists between two isoforms of tau, tau-K18 and tau-K19 (which differ in containing four and three microtubule binding repeats, respectively), wherein tau-K18 fibrils cannot seed tau-K19 monomer. Furthermore, high-resolution structural analysis of the two isoforms shows that the structural core is more ordered in tau-K19 than in tau-K18. Hence, the current work provides kinetic and structural rationales for asymmetric seeding barriers in general and for the two tau isoforms in particular. (C) 2018 Elsevier Ltd. All rights reserved.