Tau assembly: the dominant role of PHF6 (VQIVYK) in microtubule binding region repeat R3.
Tau assembly: the dominant role of PHF6 (VQIVYK) in microtubule binding region repeat R3.
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Tau组装：PHF6（VQIVYK）在微管结合区域重复R3中的主要作用。
DOI：
10.1021/acs.jpcb.5b00175
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发表时间：
2015-04-02
影响因子：
3.3
通讯作者：
Shea, Joan-Emma
中科院分区：
文献类型：
--
作者：
Ganguly, Pritam;Do, Thanh D.;Larini, Luca;LaPointe, Nichole E.;Sercel, Alexander J.;Shade, Madeleine F.;Feinstein, Stuart C.;Bowers, Michael T.;Shea, Joan-Emma
微管结合蛋白Tau的自聚集降低了其功能，并且与Tau相关疾病（称为Tau病）紧密相关。Tau聚集还与两个成核六残基片段，即PHF 6（VQIVYK）和PHF 6 *（VQIINK）强烈相关。在本文中，我们使用实验和计算建模，研究了含有PHF 6 *（R2/wt; 273 GKVQIINKKLDL 284）和PHF 6（R3/wt; 306 VQIVYKPVDLSK 317）的Tau片段的单个和二元混合物的自组装，以及与神经退行性Tau病变相关的突变体R2/ΔK280。通过离子迁移率质谱法探测聚集的初始阶段，用硫磺素T测定法监测聚集的动力学，并通过透射电子显微镜观察聚集体的形态。洞察到早期聚集体的结构和稳定的聚集体的因素是从副本交换分子动力学模拟。我们的数据表明，R3/wt具有比R2/wt或R2/ΔK280强得多的聚集倾向。含有R3/wt的异源二聚体比R3/wt同源二聚体更不稳定，但比R2/wt和R2/ΔK280的同源二聚体稳定得多，表明PHF 6 */PHF 6相互作用在引发全长Tau聚集中的可能作用。最后，R2/ΔK280与R3/wt的结合比与R2/wt的结合更强，表明正常Tau功能的病理性丧失的可能机制。
Self-aggregation of the microtubule-binding protein Tau reduces its functionality and is tightly associated with Tau-related diseases, termed tauopathies. Tau aggregation is also strongly associated with two nucleating six-residue segments, namely PHF6 (VQIVYK) and PHF6* (VQIINK). In this paper, using experiments and computational modeling, we study the self-assembly of individual and binary mixtures of Tau fragments containing PHF6* (R2/wt; 273GKVQIINKKLDL284) and PHF6 (R3/wt; 306VQIVYKPVDLSK317), and a mutant R2/ΔK280 associated with a neurodegenerative tauopathy. The initial stage of aggregation is probed by ion-mobility mass spectrometry, the kinetics of aggregation monitored with Thioflavin T assays and the morphology of aggregates visualized by transmission electron microscopy. Insights into the structure of early aggregates and the factors stabilizing the aggregates are obtained from replica exchange molecular dynamics simulations. Our data suggest that R3/wt has a much stronger aggregation propensity than either R2/wt or R2/ΔK280. Heterodimers containing R3/wt are less stable than R3/wt homodimers but much more stable than homodimers of R2/wt and R2/ΔK280, suggesting a possible role of PHF6*/PHF6 interactions in initiating the aggregation of full length Tau. Lastly, R2/ΔK280 binds stronger to R3/wt than R2/wt suggesting a possible mechanism for a pathological loss of normal Tau function.
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