Corrigendum: Structural Insights Into TDP-43 and Effects of Post-translational Modifications

François‐Moutal, Liberty; Perez‐Miller, Samantha; Scott, David D.; Miranda, Victor G.; Mollasalehi, Niloufar; Khanna, May

doi:10.3389/fnmol.2020.00045

Cited by 2 publications

(1 citation statement)

References 7 publications

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“…TDP-43 is stratified into four canonical domains – the N-terminal domain, which is involved in oligomerization of the protein, two RNA recognition motifs, and the C-terminal, intrinsically-disordered LCD (Prasad et al 2019; François-Moutal et al 2019). In the context of neurodegenerative diseases, the LCD has received particular attention, as patient-derived inclusions are enriched in C-terminal fragments containing this domain (Neumann et al 2006; Arai et al 2006; Igaz et al 2008; Arseni et al 2022).…”

Section: Introductionmentioning

confidence: 99%

Pathological C-terminal phosphomimetic substitutions alter the mechanism of liquid-liquid phase separation of TDP-43 low complexity domain

Haider,

Shipley,

Surewicz

et al. 2024

Preprint

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C-terminally phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) marks the proteinaceous inclusions that characterize a number of age-related neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration and Alzheimer's disease. TDP-43 phosphorylation at S403/S404, and especially at S409/S410, is in fact accepted as a biomarker of proteinopathy. These residues are located within the low complexity domain (LCD), which also drives the protein's liquid-liquid phase separation (LLPS). The impact of phosphorylation at these LCD sites on phase separation of the protein is a topic of great interest, as these post-translational modifications and LLPS are both implicated in proteinopathies. Here, we employed a combination of experimental and simulation-based approaches to explore this question on a phosphomimetic model of the TDP-43 LCD. Our turbidity and fluorescence microscopy data show that Ser-to-Asp substitutions at residues S403, S404, S409 and S410 alter the LLPS behavior of TDP-43 LCD. In particular, in contrast to the unmodified protein, the phosphomimetic variants display a biphasic dependence on salt concentration. Through coarse-grained modeling, we find that this biphasic salt dependence is derived from an altered mechanism of phase separation, in which LLPS-driving short-range intermolecular hydrophobic interactions are modulated by long-range attractive electrostatic interactions. Overall, this in vitro and in silico study provides a physiochemical foundation for understanding the impact of pathologically-relevant C-terminal phosphorylation on the LLPS of the TDP-43 in a more complex cellular environment.

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