TAR DNA binding protein 43 (TDP-43) is a nuclear RNA/DNA-binding protein with pivotal roles in RNA-related processes such as splicing, transcription, transport, and stability. The high binding affinity and specificity of TDP-43 toward its cognate RNA sequences (GU-rich) is mediated by highly conserved residues in its tandem RNA recognition motif (RRM) domains (aa: 104–263). Importantly, the loss of RNA binding to the tandem RRMs caused by physiological stressors and chemical modifications promotes cytoplasmic mislocalization and pathological aggregation of TDP-43. Despite the substantial implications of RNA binding in TDP-43 function and pathology, its precise effects on the intradomain stability, and conformational dynamics of the tandem RRMs is not properly understood. Here, we employed all-atom molecular dynamics (MD) simulations to assess the effect of RNA binding on the conformational landscape and intradomain stability of TDP-43 tandem RRMs. RNA limits the overall conformational space of the tandem RRMs and promotes intradomain stability through a combination of specific base stacking interactions and transient electrostatic interactions. In contrast, tandem RRMs exhibit a high intrinsic conformational plasticity in the absence of RNA, which, surprisingly, is accompanied by a tendency of RRM1 to adopt partially unfolded conformations. Overall, our simulations reveal how RNA binding dynamically tunes the structural and conformational landscape of TDP-43 tandem RRMs, contributing to physiological function and mitigating pathological aggregation.

中文翻译：

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RNA 结合可调节 TDP-43 串联 RNA 识别基序的构象可塑性和结构域内稳定性


TAR DNA 结合蛋白 43 （TDP-43） 是一种核 RNA/DNA 结合蛋白，在 RNA 相关过程（如剪接、转录、转运和稳定性）中起关键作用。TDP-43 对其同源 RNA 序列（富含 GU）的高结合亲和力和特异性是由其串联 RNA 识别基序 （RRM） 结构域中高度保守的残基介导的 （aa： 104–263）。重要的是，由生理应激源和化学修饰引起的 RNA 与串联 RRM 结合的缺失促进了 TDP-43 的细胞质错误定位和病理聚集。尽管 RNA 结合在 TDP-43 功能和病理学中具有重大意义，但其对串联 RRM 的结构域内稳定性和构象动力学的确切影响尚未得到正确理解。在这里，我们采用全原子分子动力学 （MD） 模拟来评估 RNA 结合对 TDP-43 串联 RRM 的构象景观和结构域内稳定性的影响。RNA 限制了串联 RRM 的整体构象空间，并通过特异性碱基堆叠相互作用和瞬态静电相互作用的组合促进结构域内稳定性。相比之下，串联 RRM 在没有 RNA 的情况下表现出较高的内在构象可塑性，令人惊讶的是，这伴随着 RRM1 采用部分展开构象的趋势。总体而言，我们的模拟揭示了 RNA 结合如何动态调节 TDP-43 串联 RRM 的结构和构象景观，从而促进生理功能并减轻病理聚集。