Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands.
Science for Life, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands.
Nat Commun. 2020 Jan 29;11(1):571. doi: 10.1038/s41467-019-13745-7.
Aggregation of the Tau protein into fibrils defines progression of neurodegenerative diseases, including Alzheimer's Disease. The molecular basis for potentially toxic reactions of Tau aggregates is poorly understood. Here we show that π-stacking by Arginine side-chains drives protein binding to Tau fibrils. We mapped an aggregation-dependent interaction pattern of Tau. Fibrils recruit specifically aberrant interactors characterised by intrinsically disordered regions of atypical sequence features. Arginine residues are key to initiate these aberrant interactions. Crucial for scavenging is the guanidinium group of its side chain, not its charge, indicating a key role of π-stacking chemistry for driving aberrant fibril interactions. Remarkably, despite the non-hydrophobic interaction mode, the molecular chaperone Hsp90 can modulate aberrant fibril binding. Together, our data present a molecular mode of action for derailment of protein-protein interaction by neurotoxic fibrils.
Tau 蛋白聚集成纤维定义了神经退行性疾病的进展，包括阿尔茨海默病。Tau 聚集物潜在毒性反应的分子基础理解得很差。在这里，我们表明精氨酸侧链的π-堆积驱动蛋白质与 Tau 纤维的结合。我们绘制了 Tau 的依赖于聚集的相互作用模式图。纤维特异性募集由内在无序区域具有非典型序列特征的异常相互作用子。精氨酸残基是引发这些异常相互作用的关键。胍基侧链对清除至关重要，而不是其电荷，这表明π-堆积化学在驱动异常纤维相互作用中起着关键作用。值得注意的是，尽管非疏水相互作用模式，分子伴侣 Hsp90 可以调节异常纤维结合。总之，我们的数据为神经毒性纤维使蛋白质-蛋白质相互作用脱轨提供了一种作用模式。
