Bali Sofia, Singh Ruhar, Wydorski Pawel M, Van Nuland Nico E, Wosztyl Aleksandra, Perez Valerie A, Chen Dailu, Chen Jie, Rizo Josep, Joachimiak Lukasz A
bioRxiv. 2025 Feb 13:2023.12.13.571598. doi: 10.1101/2023.12.13.571598.
The microtubule-associated protein tau is implicated in neurodegenerative diseases characterized by amyloid formation. Mutations associated with frontotemporal dementia increase tau aggregation propensity and disrupt its endogenous microtubule-binding activity. However, the structural relationship between aggregation propensity and biological activity remains unclear. We employed a multi-disciplinary approach, including computational modeling, NMR, cross-linking mass spectrometry, and cell models to engineer tau sequences that modulate its structural ensemble. Our findings show that substitutions near the conserved 'PGGG' β-turn motif informed by tau isoform context reduce tau aggregation in vitro and cells and can even counteract aggregation induced by turn destabilizing disease-associated proline-to-serine mutations. Engineered tau sequences maintain microtubule binding and explain why 3R isoforms exhibit reduced pathogenesis compared to 4R. We propose a simple mechanism to reduce the formation of pathogenic species while preserving biological function, thus offering insights for therapeutic strategies aimed at reducing tau protein misfolding in neurodegenerative diseases.
微管相关蛋白tau与以淀粉样蛋白形成为特征的神经退行性疾病有关。与额颞叶痴呆相关的突变会增加tau的聚集倾向，并破坏其内源性微管结合活性。然而，聚集倾向与生物活性之间的结构关系仍不清楚。我们采用了多学科方法，包括计算建模、核磁共振、交联质谱和细胞模型，来设计能够调节tau结构整体的序列。我们的研究结果表明，根据tau异构体背景，在保守的“PGGG”β-转角基序附近进行的替换可减少tau在体外和细胞中的聚集，甚至可以抵消由破坏转角稳定性的疾病相关脯氨酸到丝氨酸突变诱导的聚集。工程化的tau序列保持微管结合能力，并解释了为什么3R异构体与4R相比发病机制降低。我们提出了一种在保留生物功能的同时减少致病物种形成的简单机制，从而为旨在减少神经退行性疾病中tau蛋白错误折叠的治疗策略提供了见解。
