Hallegger_Chakrabarti_Lee_TDP-43 condensation properties_Mendeley

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 functions of protein-RNA complexes remains unclear. We created a series of TDP-43 C-terminal domain (CTD) variants, which exhibited a gradient of low to high condensation propensity, as observed in vitro and by nuclear mobility and foci formation. Notably, 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 are required for efficient regulation of a subset of bound transcripts, including autoregulation of TDP-43 mRNA. Thus, 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.