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TDP-43 condensation properties specify its RNA-binding and regulatory repertoire.

Cell | 2021

Mutations causing amyotrophic lateral sclerosis (ALS) often affect the condensation properties of RNA-binding proteins (RBPs). However, the role of RBP condensation in the specificity and function of protein-RNA complexes remains unclear. We created a series of TDP-43 C-terminal domain (CTD) variants that exhibited a gradient of low to high condensation propensity, as observed in vitro and by nuclear mobility and foci formation. Notably, a capacity for condensation was required for efficient TDP-43 assembly on subsets of RNA-binding regions, which contain unusually long clusters of motifs of characteristic types and density. These "binding-region condensates" are promoted by homomeric CTD-driven interactions and required for efficient regulation of a subset of bound transcripts, including autoregulation of TDP-43 mRNA. We establish that RBP condensation can occur in a binding-region-specific manner to selectively modulate transcriptome-wide RNA regulation, which has implications for remodeling RNA networks in the context of signaling, disease, and evolution.

Pubmed ID: 34380047 RIS Download

Associated grants

  • Agency: Medical Research Council, United Kingdom
    Id: FC001110
  • Agency: Wellcome Trust, United Kingdom
    Id: 101149/Z/13/A
  • Agency: Cancer Research UK, United Kingdom
    Id: FC001110
  • Agency: Wellcome Trust, United Kingdom
    Id: FC001110
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM132039
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS116176
  • Agency: Wellcome Trust, United Kingdom
  • Agency: Wellcome Trust, United Kingdom
    Id: 103760/Z/14/Z
  • Agency: Wellcome Trust, United Kingdom
    Id: 215593/Z/19/Z
  • Agency: Arthritis Research UK, United Kingdom
    Id: FC001110
  • Agency: Motor Neurone Disease Association, United Kingdom
    Id: HALLEGGER/OCT15/959-799
  • Agency: Wellcome Trust, United Kingdom
    Id: 110292/Z/15/Z

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