TDP-43 condensation properties specify its RNA-binding and regulatory repertoire
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Martina Hallegger Anob Chakrabarti Flora Lee Bo Lim Lee Aram G Amalietti Hana M Odeh Katie E Copley Jack D Rubien Bede Portz Klara Kuret Ina Huppertz Frédérique Rau Rickie Patani Nicolas L Fawzi James Shorter Nicholas Luscombe Jernej UleAbstract
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.
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Journal Cell
Volume 184
Issue number 18
Pages 4680-4696.e22
Available online
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Publisher website (DOI) 10.1016/j.cell.2021.07.018
Europe PubMed Central 34380047
Pubmed 34380047
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