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首页> 外文期刊>Journal of Molecular Biology >Mechanistic and Structural Origins of the Asymmetric Barrier to Prion-like Cross-Seeding between Tau-3R and Tau-4R
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Mechanistic and Structural Origins of the Asymmetric Barrier to Prion-like Cross-Seeding between Tau-3R and Tau-4R

机译：TAU-3R和TAU-4R之间的非对称障碍的非对称障碍的机械和结构起源

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摘要

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.
机译：通过朊病毒机制在脑中的传染性纤维蛋白聚集体的涂布和沉积是各种神经变性疾病的病理生理学中的关键组分，包括薄膜病变。在TauOpathies中，发现含有三个和四个微管结合重复的Tau的两种同种型，并且聚集体中存在的同种型的类型决定了TauOpathy的类型。两个Tau同种型之间的交叉播种受到类似于类似物种屏障的不对称屏障，这些屏障限制了跨种类的朊病毒传播，其起源仍然不清楚。在该研究中，可以通过两步迈克利斯 - 麦片样模型描述Tau原纤维的生长。作为Michaelis-Menten的机制的机制划分是对TAU，TAU-K18和TAU-K19的两种同种型之间存在的不对称播种屏障的定量理解（其分别不同于含有四个和三个微管结合重复） ），其中Tau-K18原纤维不能播种Tau-K19单体。此外，两种同种型的高分辨率结构分析表明，结构芯在TAU-K19中比在TAU-K18中更具秩序。因此，目前的作品为不对称播种屏障提供了动力学和结构理性，特别是两个TAU同种型。 （c）2018年elestvier有限公司保留所有权利。

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