Predictive atomic resolution descriptions of intrinsically disordered hTau40 and α-synuclein in solution from NMR and small angle scattering.
Predictive atomic resolution descriptions of intrinsically disordered hTau40 and α-synuclein in solution from NMR and small angle scattering.
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DOI：
10.1016/j.str.2013.10.020
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发表时间：
2014-02
期刊：
影响因子：
5.7
通讯作者：
M. Schwalbe;V. Ozenne;Stefan Bibow;Mariusz Jaremko;L. Jaremko;M. Gajda;M. R. Jensen;J. Biernat;S. Becker;E. Mandelkow;M. Zweckstetter;M. Blackledge
中科院分区：
文献类型：
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作者：
M. Schwalbe;V. Ozenne;Stefan Bibow;Mariusz Jaremko;L. Jaremko;M. Gajda;M. R. Jensen;J. Biernat;S. Becker;E. Mandelkow;M. Zweckstetter;M. Blackledge
内在无序蛋白（IDPs）分子描述的发展对于阐明常见神经退行性疾病特征的构象转变至关重要。我们使用核磁共振、小角散射和分子系综方法来表征IDPs Tau和α-突触核蛋白。由于固有的大量的构象自由度与现有的实验测量相比，IDPs的集合描述是高度不确定的。通过广泛的交叉验证，我们表明，通过选择的集合比统计线圈描述更准确地预测了五种不同类型的独立实验参数。在局部采样偏离统计线圈的区域，改进幅度增加，验证了推导的构象描述。利用这些方法，我们在聚集成核位点发现了增强的聚脯氨酸II采样，支持了这一构象空间区域对聚集很重要的建议。
The development of molecular descriptions of intrinsically disordered proteins (IDPs) is essential for elucidating conformational transitions that characterize common neurodegenerative disorders. We use nuclear magnetic resonance, small angle scattering, and molecular ensemble approaches to characterize the IDPs Tau and α-synuclein. Ensemble descriptions of IDPs are highly underdetermined due to the inherently large number of degrees of conformational freedom compared with available experimental measurements. Using extensive cross-validation we show that five different types of independent experimental parameters are predicted more accurately by selected ensembles than by statistical coil descriptions. The improvement increases in regions whose local sampling deviates from statistical coil, validating the derived conformational description. Using these approaches we identify enhanced polyproline II sampling in aggregation-nucleation sites, supporting suggestions that this region of conformational space is important for aggregation.