Bali Sofia, Singh Ruhar, Wydorski Pawel M, Wosztyl Aleksandra, Perez Valerie A, Chen Dailu, Rizo Josep, Joachimiak Lukasz A
Molecular Biophysics Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas.
Res Sq. 2024 Jan 16:rs.3.rs-3796916. doi: 10.21203/rs.3.rs-3796916/v1.
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. 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 design tau sequences that stabilize its structural ensemble. Our findings reveal that substitutions near the conserved 'PGGG' beta-turn motif can modulate local conformation, more stably engaging in interactions with the VQIVYK amyloid motif to decrease aggregation in vitro and in cells. Designed tau sequences maintain microtubule binding and explain why 3R isoforms of tau exhibit reduced pathogenesis over 4R isoforms. We propose a simple mechanism to reduce the formation of pathogenic species while preserving biological function, offering insights for therapeutic strategies aimed at reducing 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。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，来设计稳定其结构整体的tau序列。我们的研究结果表明，保守的“PGGG”β-转角基序附近的取代可以调节局部构象，更稳定地与VQIVYK淀粉样基序相互作用，以减少体外和细胞内的聚集。设计的tau序列保持微管结合，并解释了为什么tau的3R异构体比4R异构体表现出更低的发病机制。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，为旨在减少神经退行性疾病中蛋白质错误折叠的治疗策略提供了见解。
