Identification of an aggregation-prone structure of tau.
Identification of an aggregation-prone structure of tau.
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DOI：
10.1021/ja305206m
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发表时间：
2012-10-10
影响因子：
15
通讯作者：
Rhoades, Elizabeth
中科院分区：
文献类型：
--
作者：
Elbaum-Garfinkle, Shana;Rhoades, Elizabeth
正常可溶性蛋白质的聚集和沉积是几种破坏性神经退行性疾病的标志。对于阿尔茨海默病中的tau蛋白和帕金森病中的α-突触核蛋白等蛋白质，聚集涉及从固有无序单体到高度结构化纤维的转变。虽然理解这些蛋白质在神经变性中的作用需要阐明自缔合的结构基础，但无序蛋白质的构象异质性使其结构表征具有内在的挑战性。在这里，我们使用单分子Förster共振能量转移来测量在肝素存在和不存在的情况下tau蛋白的构象集合，以确定与聚集起始相关的关键构象变化。我们发现，不同的结构域的tau蛋白显示不同的构象特性是强烈相关的，与他们的无序程度，这可能涉及到他们的聚集作用。此外，我们观察到，肝素结合诱导一个独特的两个状态的结构转变tau描述的损失的远程接触和随之而来的压缩的微管结合域。我们的研究结果描述了tau的构象中间体，其先于聚集体的形成，并且可以作为tau聚焦疗法的靶点。
The aggregation and deposition of normally soluble proteins is the hallmark of several devastating neurodegenerative disorders. For proteins such as tau in Alzheimer’s disease and α-synuclein in Parkinson’s disease, aggregation involves a transition from an intrinsically disordered monomer to a highly structured fiber. While understanding the role of these proteins in neurodegeneration requires elucidation of the structural basis of self-association, the conformational heterogeneity of disordered proteins makes their structural characterization inherently challenging. Here we use single molecule Förster resonance energy transfer to measure the conformational ensemble of tau in the absence and presence of heparin to identify critical conformational changes relevant to the initiation of aggregation. We find that different domains of tau display distinct conformational properties that are strongly correlated with their degree of disorder and which may relate to their roles in aggregation. Moreover, we observe that heparin binding induces a distinct two-state structural transition in tau described by a loss of long-range contacts and a concomitant compaction of the microtubule binding domain. Our results describe a conformational intermediate of tau that precedes the formation of aggregates and could serve as a target for tau-focused therapeutics.
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DOI：
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发表时间：
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影响因子：
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