Tau mutants bind tubulin heterodimers with enhanced affinity
Tau mutants bind tubulin heterodimers with enhanced affinity
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DOI：
10.1073/pnas.1315983111
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发表时间：
2014-04-29
影响因子：
11.1
通讯作者：
Rhoades, Elizabeth
中科院分区：
文献类型：
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作者：
Elbaum-Garfinkle, Shana;Cobb, Garrett;Rhoades, Elizabeth
Tau是一种微管结合蛋白，在阿尔茨海默病和其他Tau蛋白病的脑中形成病理性聚集体。疾病病因被认为是由于tau和微管之间的天然相互作用的丧失，以及与tau聚集相关的毒性的获得引起的，尽管这两种机制都没有很好地理解。在这里，我们使用疾病相关和疾病动机的tau突变体来研究功能和疾病之间的联系。我们发现，突变为高度保守的脯氨酸残基的重复2和3的微管结合结构域的tau结合微管蛋白和能力的tau，以增强微管蛋白聚合有不同的影响。值得注意的是，这些残基的突变导致对微管蛋白二聚体的亲和力增加，同时对与稳定化微管的结合具有可忽略的影响。我们测量了tau蛋白与微管蛋白结合时的构象变化，为观察到的亲和力和功能改变提供了结构框架。此外，我们发现这些突变不一定会增强聚集，这可能对仅专注于寻找tau聚集抑制剂的tau治疗策略具有重要意义。我们提出了一个模型，描述了tau结合微管蛋白二聚体和疾病相关的改变tau影响其功能的机制。总之，这些结果引起了人们对tau蛋白和游离微管蛋白之间的相互作用的关注，因为它们在tau蛋白病理学机制中发挥着重要作用。
Tau is a microtubule binding protein that forms pathological aggregates in the brain in Alzheimer's disease and other tauopathies. Disease etiology is thought to arise from loss of native interactions between tau and microtubules, as well as from gain of toxicity tied to tau aggregation, although neither mechanism is well understood. Here we investigate the link between function and disease using disease-associated and disease-motivated mutants of tau. We find that mutations to highly conserved proline residues in repeats 2 and 3 of the microtubule binding domain have differential effects on tau binding to tubulin and the capacity of tau to enhance tubulin polymerization. Notably, mutations to these residues result in an increased affinity for tubulin dimers while having a negligible effect on binding to stabilized microtubules. We measure conformational changes in tau on binding to tubulin that provide a structural framework for the observed altered affinity and function. Additionally, we find that these mutations do not necessarily enhance aggregation, which could have important implications for tau therapeutic strategies that focus solely on searching for tau aggregation inhibitors. We propose a model that describes tau binding to tubulin dimers and a mechanism by which disease-relevant alterations to tau impact its function. Together, these results draw attention to the interaction between tau and free tubulin as playing an important role in mechanisms of tau pathology.