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首页> 美国卫生研究院文献>Protein Science : A Publication of the Protein Society >Structural transitions in tau k18 on micelle binding suggest a hierarchy in the efficacy of individual microtubule-binding repeats in filament nucleation
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Structural transitions in tau k18 on micelle binding suggest a hierarchy in the efficacy of individual microtubule-binding repeats in filament nucleation

机译：tau k18在胶束结合上的结构转变表明细丝成核中单个微管结合重复序列的功效具有层次结构

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摘要

The protein tau is found in an aggregated filamentous state in the intraneuronal paired helical filament deposits characteristic of Alzheimer's disease and other related dementias and mutations in tau protein and mRNA cause frontotemproal dementia. Tau isoforms include a microtubule-binding domain containing either three or four imperfect tandem microtubule binding repeats that also form the core of tau filaments and contain hexapaptide motifs that are critical for tau aggregation. The tau microtubule-binding domain can also engage in direct interactions with detergents, fatty acids, or membranes, which can greatly facilitate tau aggregation and may also mediate some tau functions. Here, we show that the alternatively spliced second microtubule-binding repeat exhibits significantly different structural characteristics compared with the other three repeats in the context of the intact repeat domain. Most notably, the PHF6* hexapeptide motif located at the N-terminus of repeat 2 has a lower propensity to form strand-like structure than the corresponding PHF6 motif in repeat 3, and unlike PHF6 converts to partially helical structure in the micelle-bound state. Interestingly, the behavior of the Module-B motif, located at the beginning of repeat 4, resembles that of PHF6* rather than PHF6. Our observations, combined with previous results showing that PHF6* and Module-B are both less effective than PHF6 in nucleating tau aggregation, suggest a hierarchy in the efficacy of these motifs in nucleating tau aggregation that originates in differences in their intrinsic propensities for extended strand-like structure and the resistance of these propensities to changes in tau's environment.
机译：在阿尔茨海默氏病和其他相关痴呆的特征性神经元内配对螺旋丝沉积物中发现了tau蛋白聚集的丝状状态，tau蛋白和mRNA的突变引起额颞叶痴呆。 Tau同工型包括一个微管结合结构域，该结构域包含三个或四个不完美的串联微管结合重复序列，这些重复序列也形成tau细丝的核心，并含有对tau聚集至关重要的六肽基序。 tau微管结合域也可以与去污剂，脂肪酸或膜直接相互作用，这可以极大地促进tau聚集，还可以介导一些tau功能。在这里，我们显示，在完整重复域的背景下，与其他三个重复序列相比，第二个微管结合重复片段的剪接结构具有明显不同的结构特征。最值得注意的是，与重复序列3中相应的PHF6基序相比，位于重复序列2 N端的PHF6 *六肽基序具有更低的形成链状结构的倾向，并且与PHF6在胶束结合状态下转变成部分螺旋结构不同。有趣的是，位于重复4开头的Module-B基序的行为类似于PHF6 *，而不是PHF6。我们的观察结果与先前的结果相结合，表明PHF6 *和Module-B在成核tau聚集方面均不如PHF6有效，表明这些基序在成核tau聚集中的功效等级是由其对延长链的内在倾向的差异引起的类结构以及这些倾向对tau环境变化的抵抗力。

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