TDP-43 condensation properties specify its RNA-binding and regulatory repertoire
Martina Hallegger, Anob M. Chakrabarti, Flora Lee, Bo Lim Lee, Aram Gustav 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
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.