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

• DOI: 10.1016/j.cell.2021.07.018
• Publication Date: 2021-08-10T15:48:53Z
• Authors: Martina Hallegger; Anob M. Chakrabarti; Flora C.Y. 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
• Keywords: 0301 basic medicine; amyotrophic lateral sclerosis; 570; TDP-43; iCLIP; RNA-binding protein; kemija; 610; info:eu-repo/classification/udc/5; Gene Expression; Biochemistry & Proteomics; Article; Phase Transition; 03 medical and health sciences; Ecology,Evolution & Ethology; Homeostasis; Humans; Point Mutation; RNA, Messenger; Nucleotide Motifs; 3' Untranslated Regions; Sequence Deletion; Computational & Systems Biology; Cell Nucleus; 0303 health sciences; Base Sequence; FOS: Clinical medicine; Stem Cells; alternative polyadenylation; RNA granules; Neurosciences; RNA-Binding Proteins; Cell Biology; multivalency; Tumour Biology; intrinsically disordered region; DNA-Binding Proteins; condensation; HEK293 Cells; Mutation; RNA; phase separation; Protein Multimerization; Poly A; Genetics & Genomics; HeLa Cells; Protein Binding

Mutations causing amyotrophic lateral sclerosis (ALS) often affect the condensation properties of RNA-binding proteins (RBPs). However, role RBP in specificity and function protein-RNA complexes remains unclear. We created a series TDP-43 C-terminal domain (CTD) variants that exhibited gradient low to high propensity, as observed vitro by nuclear mobility foci formation. Notably, capacity for was required efficient assembly on subsets regions, which contain unusually long clusters motifs characteristic types density. These "binding-region condensates" are promoted homomeric CTD-driven interactions regulation subset bound transcripts, including autoregulation mRNA. establish can occur binding-region-specific manner selectively modulate transcriptome-wide RNA regulation, has implications remodeling networks context signaling, disease, evolution.