FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions
By S. Qamar, Guozhen Wang, Suzanne J Randle, F. Ruggeri, J. Varela, Julie Qiaojin Lin, Emma C. Phillips, A. Miyashita, Declan Williams, Florian Ströhl and 14 more. Cell, 2018
818 citations recorded by the source corpus.
Summary Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles and 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 (FTLD), 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.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/a77559c82b14ae7ed39d53b5061ab6804fb30ab3
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Citations in the corpus
- Liquid-Liquid Phase Separation in Disease. (2019, background): “between arginines and aromatic residues, which drive condensation of FUS (127, 152).”
- Physics-driven coarse-grained model for biomolecular phase separation with near-quantitative accuracy (2021, background): “2d) and experiments 10–12 all suggest that Phe–Phe contacts are weaker than Tyr–Tyr ones.”