Li Ruiting, Singh Ruhar, Kashav Tara, Yang ChunMin, Sharma Ravi Datta, Lynn Andrew M, Prasad Rajendra, Prakash Amresh, Kumar Vijay
School of Engineering, Guangzhou College of Technology and Business, Guangzhou, China.
School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi, India.
Front Mol Neurosci. 2022 Apr 25;15:822863. doi: 10.3389/fnmol.2022.822863. eCollection 2022.
TDP-43 proteinopathies is a disease hallmark that characterizes amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The N-terminal domain of TDP-43 (NTD) is important to both TDP-43 physiology and TDP-43 proteinopathy. However, its folding and dimerization process is still poorly characterized. In the present study, we have investigated the folding/unfolding of NTD employing all-atom molecular dynamics (MD) simulations in 8 M dimethylsulfoxide (DMSO) at high temperatures. The MD results showed that the unfolding of the NTD at high temperature evolves through the formation of a number of conformational states differing in their stability and free energy. The presence of structurally heterogeneous population of intermediate ensembles was further characterized by the different extents of solvent exposure of Trp80 during unfolding. We suggest that these non-natives unfolded intermediate ensembles may facilitate NTD oligomerization and subsequently TDP-43 oligomerization, which might lead to the formation of irreversible pathological aggregates, characteristics of disease pathogenesis.
TDP - 43蛋白病是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTLD）的疾病标志。TDP - 43的N端结构域（NTD）对TDP - 43的生理功能和TDP - 43蛋白病都很重要。然而，其折叠和二聚化过程仍未得到很好的表征。在本研究中，我们采用全原子分子动力学（MD）模拟，研究了在高温下8 M二甲基亚砜（DMSO）中NTD的折叠/去折叠过程。MD结果表明，高温下NTD的去折叠通过形成许多稳定性和自由能不同的构象状态而发生。在去折叠过程中，Trp80不同程度的溶剂暴露进一步表征了中间集合体结构异质群体的存在。我们认为，这些非天然去折叠的中间集合体可能促进NTD的寡聚化，进而促进TDP - 43的寡聚化，这可能导致形成不可逆的病理聚集体，这是疾病发病机制的特征。
