TDP-43 condensation properties specify its RNA-binding and regulatory repertoire.
journal contributionposted on 03.09.2021, 09:34 authored by Martina Hallegger, Anob M Chakrabarti, Flora CY 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 M Luscombe, Jernej Ule
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.