Phase Separation of FUS is Modulated by Methylation State of Cation-π Interactions and Interaction with TNPO1
Accepted version
Peer-reviewed
Repository URI
Repository DOI
Change log
Authors
Abstract
Reversible phase separation, which underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles, is in part driven by the intrinsically disordered low complexity (LC) domain of FUS. Here, we report that cooperative cation-π interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation. Indeed, significant hypomethylation, which occurs in FUS-associated frontotemporal lobar degeneration, induces FUS condensation into stable intermolecular β-sheet-rich hydrogels that disrupt RNP granule function and impair new protein synthesis in neuron terminals. We show that transportin acts as a physiological molecular chaperone of FUS in neuron terminals, reducing phase separation and gelation of methylated and hypomethylated FUS, and rescuing protein synthesis. These results demonstrate how FUS condensation is physiologically regulated, and how perturbations in these mechanisms can lead to disease.
Description
Keywords
Journal Title
Conference Name
Journal ISSN
Volume Title
Publisher
Publisher DOI
Sponsorship
Wellcome Trust (089703/Z/09/Z)
Medical Research Council (MR/K02292X/1)
Medical Research Council (MR/N012453/1)