Tackling microtubule-tau interactions Alzheimer's disease is a major cause of death in the elderly. Disease progression is associated with the accumulation of neurofibrillary tangles composed of tau, a protein important for neuronal development and function. Tangle formation is preceded by phosphorylation events that cause tau to dissociate from its native binding partner, microtubules. Microtubule-tau interactions have been mysterious. Kellogg et al. used cryo–electron microscopy and molecular modeling to show how tau interacts with the outer surface of the microtubule, stapling together tubulin subunits and thus stabilizing the polymer. A key tau amino acid within the tightly bound segment between tubulin subunits corresponds to a clinically relevant site of tau phosphorylation, explaining the competition between microtubule interaction and tau aggregation. Science, this issue p. 1242 A near-atomic model of microtubule-bound tau provides an explanation for disease-associated phosphorylation data. Tau is a developmentally regulated axonal protein that stabilizes and bundles microtubules (MTs). Its hyperphosphorylation is thought to cause detachment from MTs and subsequent aggregation into fibrils implicated in Alzheimer’s disease. It is unclear which tau residues are crucial for tau-MT interactions, where tau binds on MTs, and how it stabilizes them. We used cryo–electron microscopy to visualize different tau constructs on MTs and computational approaches to generate atomic models of tau-tubulin interactions. The conserved tubulin-binding repeats within tau adopt similar extended structures along the crest of the protofilament, stabilizing the interface between tubulin dimers. Our structures explain the effect of phosphorylation on MT affinity and lead to a model of tau repeats binding in tandem along protofilaments, tethering together tubulin dimers and stabilizing polymerization interfaces.

中文翻译：

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微管-tau 相互作用的近原子模型

解决微管-tau 相互作用 阿尔茨海默病是老年人死亡的主要原因。疾病进展与由 tau 组成的神经原纤维缠结的积累有关，tau 是一种对神经元发育和功能很重要的蛋白质。缠结形成之前是磷酸化事件，导致 tau 与其天然结合伙伴微管分离。微管-tau 相互作用一直很神秘。凯洛格等人。使用低温电子显微镜和分子建模来显示 tau 如何与微管的外表面相互作用，将微管蛋白亚基钉在一起，从而稳定聚合物。微管蛋白亚基之间紧密结合的片段内的关键 tau 氨基酸对应于 tau 磷酸化的临床相关位点，解释了微管相互作用和 tau 聚集之间的竞争。科学，本期第 3 页。1242 微管结合 tau 的近原子模型为疾病相关的磷酸化数据提供了解释。Tau 是一种发育调节的轴突蛋白，可稳定和捆绑微管 (MT)。它的过度磷酸化被认为会导致与 MT 脱离并随后聚集成与阿尔茨海默病有关的原纤维。目前尚不清楚哪些 tau 残基对 tau-MT 相互作用至关重要，tau 与 MT 结合的位置，以及它如何稳定它们。我们使用低温电子显微镜来可视化 MT 上的不同 tau 结构，并使用计算方法生成 tau-微管蛋白相互作用的原子模型。tau 内保守的微管蛋白结合重复序列沿原丝的顶部采用类似的延伸结构，从而稳定了微管蛋白二聚体之间的界面。我们的结构解释了磷酸化对 MT 亲和力的影响，并产生了一个 tau 重复序列沿原丝串联结合的模型，将微管蛋白二聚体连接在一起并稳定聚合界面。