特定地点和短暂相互作用之间的协同作用驱动了无序,低复杂度域的相分离
Priyesh Mohanty1, Jayakrishna Shenoy2, Azamat Rizuan1
1Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX 77843.
概括
在神经退行性疾病中,TAR DNA 结合蛋白 43 (TDP-43) 聚合是关键. 在TDP-43中含有 metionin和芳香残留物.
科学领域:
- 生物化学和分子生物学
- 神经科学是一个神经科学.
- 生物物理学的生物物理.
背景情况:
- 塔尔DNA结合蛋白43 (TDP-43) 与ALS和FTD等神经退行性疾病有关.
- TDP-43的C端域 (CTD) 容易发生聚合和液体-液体相分离 (LLPS).
- 已知芳香残留物和保存的螺旋区域 (CR) 对TDP-43的相分离 (PS) 具有关键作用.
研究的目的:
- 调查形残留物,特别是氨酸在TDP-43 CTD相分离中的作用.
- 阐明不同类型的残留物在驱动TDP-43寡合化和LLPS之间的协同作用.
- 了解疏水性相互作用在无序蛋白的相分离过程中的被低估的贡献.
主要方法:
- 使用多尺度模拟来建模TDP-43 CTD的行为.
- 进行了体外和度 (c_sat) 测量.
- 核磁共振 (NMR) 实验被用于研究残留物相互作用.
主要成果:
- 芳香和酸 metionin 残留物对于 TDP-43 CTD 阶段分离至关重要.
- 氨酸残留物促进单链紧缩,这是LLPS的先决条件.
- 涉及氨酸和氨酸的过渡性疏水相互作用增强了CR介导的分子间协会.
结论:
- 疏水性相互作用,特别是涉及 metionin 和芳香残留物,对于 TDP-43 CTD 寡合化和 LLPS.至关重要.
- TDP-43 CTD采用一种独特的生物分子识别模式,涉及协同性疏水相互作用.
- 这项研究突出了形残留在无序蛋白域相分离中的低估作用.
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