Tau Binds to Lipid Membrane Surfaces via Short Amphipathic Helices Located in Its Microtubule-Binding Repeats
Tau Binds to Lipid Membrane Surfaces via Short Amphipathic Helices Located in Its Microtubule-Binding Repeats
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DOI：
10.1016/j.bpj.2014.07.046
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发表时间：
2014-09-16
影响因子：
3.4
通讯作者：
Eliezer, David
中科院分区：
文献类型：
--
作者：
Georgieva, Elka R.;Xiao, Shifeng;Eliezer, David
Tau 是一种微管相关蛋白，与痴呆有遗传相关性，并且通过其存在于神经元内的神经原纤维缠结沉积物中而与阿尔茨海默氏病相关，其形式为聚集的成对螺旋丝和直丝。尽管 tau 导致神经退行性变的确切机制尚不清楚，但 tau 聚集通常被认为是 tau 介导的致病性的关键组成部分。然而，tau 蛋白在体内开始聚集的背景尚不清楚。 Tau 富含富含膜的神经元结构，例如轴突和生长锥，并且可以通过中间蛋白和直接通过其微管结合域 (MBD) 与膜相互作用。膜在体外有效促进 tau 聚集，因此可以为体内 tau 聚集成核提供生理相关背景。此外，tau 蛋白与膜的相互作用可能在人们对 tau 蛋白的正常生理功能知之甚少的过程中发挥作用。尽管 tau 蛋白与膜的直接相互作用对于 tau 蛋白病理学和生理学具有潜在的重要性，但这种相互作用背后的结构机制仍有待阐明。在这里，我们采用电子自旋共振光谱来研究三重复 tau 亚型与脂质囊泡和膜模拟物结合时的 MBD 的二级和长程结构特性。我们表明，tau MBD 的膜相互作用是由膜结合状态下每个 MBD 重复序列内形成的短两亲性螺旋介导的。据我们所知，这是在完整脂质双层背景下首次详细阐明螺旋 tau 结构。我们进一步表明，（据我们所知），这些单独的螺旋区域充当由柔性连接区域连接的独立膜结合位点。这些结果代表了（据我们所知）膜结合 tau 蛋白的第一个详细结构视图，并为膜介导 tau 蛋白聚集的潜在机制提供了见解。此外，该结果可能对 tau 微管相互作用和微管介导的 tau 聚集的结构基础产生影响。
Tau is a microtubule-associated protein that is genetically linked to dementia and linked to Alzheimer's disease via its presence in intraneuronal neurofibrillary tangle deposits, where it takes the form of aggregated paired helical and straight filaments. Although the precise mechanisms by which tau contributes to neurodegeneration remain unclear, tau aggregation is commonly considered to be a critical component of tau-mediated pathogenicity. Nevertheless, the context in which tau aggregation begins in vivo is unknown. Tau is enriched in membrane-rich neuronal structures such as axons and growth cones, and can interact with membranes both via intermediary proteins and directly via its microtubule-binding domain (MBD). Membranes efficiently facilitate tau aggregation in vitro, and may therefore provide a physiologically relevant context for nucleating tau aggregation in vivo. Furthermore, tau-membrane interactions may potentially play a role in tau's poorly understood normal physiological functions. Despite the potential importance of direct tau-membrane interactions for tau pathology and physiology, the structural mechanisms that underlie such interactions remain to be elucidated. Here, we employ electron spin resonance spectroscopy to investigate the secondary and long-range structural properties of the MBD of three-repeat tau isoforms when bound to lipid vesicles and membrane mimetics. We show that the membrane interactions of the tau MBD are mediated by short amphipathic helices formed within each of the MBD repeats in the membrane-bound state. To our knowledge, this is the first detailed elucidation of helical tau structure in the context of intact lipid bilayers. We further show, for the first time (to our knowledge), that these individual helical regions behave as independent membrane-binding sites linked by flexible connecting regions. These results represent the first (to our knowledge) detailed structural view of membrane-bound tau and provide insights into potential mechanisms for membrane-mediated tau aggregation. Furthermore, the results may have implications for the structural basis of tau-microtubule interactions and microtubule-mediated tau aggregation.