Structural Impact of Tau Phosphorylation at Threonine 231
Structural Impact of Tau Phosphorylation at Threonine 231
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DOI：
10.1016/j.str.2015.06.002
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发表时间：
2015-08-04
期刊：
影响因子：
5.7
通讯作者：
Zweckstetter, Markus
中科院分区：
文献类型：
--
作者：
Schwalbe, Martin;Kadavath, Harindranath;Zweckstetter, Markus
微管相关蛋白Tau的磷酸化影响微管的组装和稳定，并在一些神经退行性疾病中被解除调控。然而，Tau的高度灵活性阻碍了对其磷酸化诱导的结构变化的原子水平描述。利用一组广泛的距离和方向限制条件以及一种新的系综计算方法，我们确定了非磷酸化状态下Tau片段的构象系综，以及当T231/S235或T231/S235/S237/S238处磷酸化时，阿尔茨海默病中四个重要的磷酸化位点。分子集成的比较表明，调节T231的磷酸化并不干扰近端微管结合(225)KVAVVR(230)基序的骨架构象。相反，磷酸化的T231选择性地与R230形成盐桥，这可以与微管蛋白的分子间盐桥的形成竞争。我们的研究提供了一个系综的描述，这将有助于分析Tau和其他内在无序蛋白质的构象转变。
Phosphorylation of the microtubule-associated protein Tau influences the assembly and stabilization of microtubules and is deregulated in several neuro-degenerative diseases. The high flexibility of Tau, however, has prevented an atomic-level description of its phosphorylation-induced structural changes. Employing an extensive set of distance and orientational restraints together with a novel ensemble calculation approach, we determined conformational ensembles of Tau fragments in the non-phosphorylated state and, when phosphorylated at T231/S235 or T231/S235/S237/S238, four important sites of phosphorylation in Alzheimer disease. Comparison of the molecular ensembles showed that phosphorylation of the regulatory T231 does not perturb the backbone conformation of the proximal microtubule-binding (225)KVAVVR(230) motif. Instead, phosphorylated T231 selectively engages in a salt bridge with R230 that can compete with the formation of intermolecular salt bridges to tubulin. Our study provides an ensemble description which will be useful for the analysis of conformational transitions in Tau and other intrinsically disordered proteins.