RNA-binding tunes the conformational plasticity and intradomain stability of TDP-43 tandem RNA recognition motifs.

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 towards 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.

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