Heterogeneous Tau-Tubulin Complexes Accelerate Microtubule Polymerization
Heterogeneous Tau-Tubulin Complexes Accelerate Microtubule Polymerization
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DOI：
10.1016/j.bpj.2017.05.006
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发表时间：
2017-06-20
影响因子：
3.4
通讯作者：
Rhoades, Elizabeth
中科院分区：
文献类型：
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作者：
Li, Xiao-Han;Rhoades, Elizabeth
Tau是一种内在紊乱的蛋白质，在许多神经退行性疾病的病理中起着核心作用。Tau蛋白通常起稳定神经元的作用。微管，尽管这种功能的机制还没有被很好地理解。值得注意的是，tau蛋白和可溶性微管蛋白之间的相互作用，这对理解tau蛋白的功能及其在疾病中的作用都有意义，但尚未得到充分的探索。在这里，我们研究tau微管蛋白复合物的异质性和tau功能之间的关系。具体来说，我们创建了一系列截断和乱序的tau结构，并表征了在非聚合条件下形成的tau-微管蛋白复合物的大小和异质性。通过微管蛋白聚合实验验证了构建体的功能。我们发现，令人惊讶的是，位于tau核心微管结合区域两侧的tau的伪重复区域在很大程度上有助于形成大型的异质tau微管蛋白复合物；其他独立的微管蛋白结合位点存在于微管结合域的重复序列2和3中。特别有趣的是，我们发现配合物的大小和异质性与tau促进微管聚合的速率呈正相关。我们认为tau-微管蛋白可以被描述为一个“模糊”复合物，我们的结果证明了异质复合物在tau功能中的重要性。这项工作为tau的功能机制提供了基本的见解，并且更广泛地强调了异质性和动态复合物在内在无序蛋白质功能中的相关性。
Tau is an intrinsically disordered protein with a central role in the pathology of a number of neurodegenerative diseases. Tau normally functions to stabilize neuronal. microtubules, although the mechanism underlying this function is not well understood. Of note is that the interaction between tau and soluble tubulin, which has implications both in understanding tau function as well as its role in disease, is underexplored. Here we investigate the relationship between heterogeneity in tautubulin complexes and tau function. Specifically, we created a series of truncated and scrambled tau constructs and characterized the size and heterogeneity of the tau-tubulin complexes formed under nonpolymerizing conditions. Function of the constructs was verified by tubulin polymerization assays. We find that, surprisingly, the pseudo-repeat region of tau, which flanks the core micro tubule-binding domain of tau, contributes largely to the formation of large, heterogeneous tau tubulin complexes; additional independent tubulin binding sites exist in repeats two and three of the microtubule binding domain. Of particular interest is that we find positive correlation between the size and heterogeneity of the complexes and rate of tau-promoted microtubule polymerization. We propose that tau-tubulin can be described as a "fuzzy" complex, and our results demonstrate the importance of heterogeneous complexformation in tau function. This work provides fundamental insights into the functional mechanism of tau, and more broadly underscores the relevance of heterogeneous and dynamic complexes in the functions of intrinsically disordered proteins.