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[210826 Àú³Î¹ßÇ¥] TDP-43 condensation properties specify its RNA-binding and regulatory repertoire

À̵¿ÁØ ¦¢ 2021-08-24

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2021 Aug 6;S0092-8674(21)00877-1.
 doi: 10.1016/j.cell.2021.07.018. Online ahead of print.

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

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Abstract

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.

Keywords: RNA granules; RNA-binding protein; TDP-43; alternative polyadenylation; amyotrophic lateral sclerosis; condensation; iCLIP; intrinsically disordered region; multivalency; phase separation.




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