Interactions between Tau and Different Conformations of Tubulin: Implications for Tau Function and Mechanism
Interactions between Tau and Different Conformations of Tubulin: Implications for Tau Function and Mechanism
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DOI：
10.1016/j.jmb.2017.03.018
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发表时间：
2017-05-05
影响因子：
5.6
通讯作者：
Goodson, Holly V.
中科院分区：
文献类型：
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作者：
Duan, Aranda R.;Jonasson, Erin M.;Goodson, Holly V.
Tau 是一种多面神经元蛋白，可稳定微管 (MT)，但这种活性的机制仍知之甚少。问题包括 Tau 是否横向或纵向结合 MT，以及 Tau 的结合亲和力是否取决于微管蛋白的核苷酸状态。我们观察到 Tau 与 Dolastatin-10 微管蛋白环紧密结合，并促进 Dolastatin-10 环堆叠的形成，这意味着 Tau 可以横向交联 MT 原丝。此外，我们发现 Tau 更喜欢 GDP 样微管蛋白构象，这意味着 Tau 与 MT 表面的结合偏向远离动态富含 GTP 的 MT 尖端。为了研究这些 Tau 活性对 MT 稳定性的潜在影响，我们将它们纳入我们之前开发的 MT 动力学二聚体规模计算模型中。我们发现横向交联活动对 MT 稳定性的影响比纵向交联活动大得多，并且引入 GDP 微管蛋白的偏差对观察到的 MT 稳定性几乎没有影响。为了解决 Tau 为何偏向 GDP 微管蛋白的问题，我们测试了 Tau 是否可能影响 + TIP EB1 的 MT 结合。我们证实了最近的报道，即 Tau 直接与 EB1 结合，并且 Tau 与 EB1 竞争 MT 结合。我们的结果得出了一个概念模型，其中 Tau 通过加强原丝之间的横向相互作用来稳定 MT 晶格。我们提出 Tau 的 GDP 偏好允许细胞独立调节 MT 尖端的动力学和晶格的稳定性。 (C) 2017 年由爱思唯尔有限公司出版。
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.