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首页> 外文期刊>Journal of Molecular Biology >Interactions between Tau and Different Conformations of Tubulin: Implications for Tau Function and Mechanism
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Interactions between Tau and Different Conformations of Tubulin: Implications for Tau Function and Mechanism

机译：TAU与微管蛋白不同构象之间的相互作用：TAU功能的影响和机制

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Tau is a multifaceted neuronal protein that stabilizes microtubules (MTs), but the mechanism of this activity remains poorly understood. Questions include whether Tau binds MTs laterally or longitudinally and whether Tau's binding affinity depends on the nucleotide state of tubulin. We observed that Tau binds tightly to Dolastatin-10 tubulin rings and promotes the formation of Dolastatin-10 ring stacks, implying that Tau can crosslink MT protofilaments laterally. In addition, we found that Tau prefers GDP-like tubulin conformations, which implies that Tau binding to the MT surface is biased away from the dynamic GTP-rich MT tip. To investigate the potential impact of these Tau activities on MT stabilization, we incorporated them into our previously developed dimer-scale computational model of MT dynamics. We found that lateral crosslinking activities have a much greater effect on MT stability than do longitudinal crosslinking activities, and that introducing a bias toward GDP tubulin has little impact on the observed MT stabilization. To address the question of why Tau is GDP-tubulin-biased, we tested whether Tau might affect MT binding of the + TIP EB1. We confirmed recent reports that Tau binds directly to EB1 and that Tau competes with EB1 for MT binding. Our results lead to a conceptual model where Tau stabilizes the MT lattice by strengthening lateral interactions between protofilaments. We propose that Tau's GDP preference allows the cell to independently regulate the dynamics of the MT tip and the stability of the lattice. (C) 2017 Published by Elsevier Ltd.
机译：Tau是一种稳定微管（MTS）的多方面的神经元蛋白，但该活动的机制仍然尚不清楚。问题包括TAU是否横向或纵向结合MT，以及TAU的结合亲和力取决于管蛋白的核苷酸状态。我们观察到Tau紧紧地结合Dolastatin-10微管蛋白环并促进了偶极菌蛋白-10环堆的形成，这意味着Tau可以横向交联MT原子丝。此外，我们发现Tau喜欢类似GDP的微管蛋白构象，这意味着TAU与MT表面的TAU与动态GTP的MT尖端偏置。为了调查这些TAU活动对MT稳定的潜在影响，我们将它们纳入我们以前开发的MT动态的二聚体计算模型。我们发现横向交联剂对MT稳定性的影响比纵向交联活动更大，并且引入GDP小管蛋白的偏差对观察到的MT稳定性影响几乎没有影响。为了解决为什么Tau是GDP-Timulin-偏见的问题，我们测试了TAU是否可能影响+提示EB1的MT绑定。我们确认了最近的报告称Tau直接与EB1结合，而Tau与EB1竞争MT绑定。我们的结果导致概念模型，Tau通过强化原子丝之间的横向相互作用来稳定Mt晶格。我们提出Tau的GDP优先允许电池独立地调节MT尖端的动态和晶格的稳定性。 （c）2017年由elestvier有限公司出版

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