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FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Qamar, Seema 
Wang, GuoZhen 
Randle, Suzanne J 
Ruggeri, Francesco Simone 
Varela, Juan A 

Abstract

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.

Description

Keywords

AFM-IR, arginine methylation, cation-π, citrullination, frontotemporal dementia, membraneless organelle, neuronal ribonucleoprotein granule, phase separation, phase-sensitive fluorescent dyes, synaptic new protein synthesis, Amyotrophic Lateral Sclerosis, Animals, Arginine, Cations, DNA Methylation, Frontotemporal Dementia, Frontotemporal Lobar Degeneration, Humans, Microscopy, Atomic Force, Microscopy, Fluorescence, Molecular Chaperones, Protein Binding, Protein Domains, Protein Processing, Post-Translational, Protein Structure, Secondary, RNA-Binding Protein FUS, Tyrosine, Xenopus laevis

Journal Title

Cell

Conference Name

Journal ISSN

0092-8674
1097-4172

Volume Title

173

Publisher

Elsevier BV
Sponsorship
Royal Society (RP150066)
European Research Council (322817)
Wellcome Trust (203249/Z/16/Z)
Biotechnology and Biological Sciences Research Council (BB/H023917/1)
Engineering and Physical Sciences Research Council (EP/H018301/1)
Medical Research Council (MR/K02292X/1)
Medical Research Council (G0902243)
Medical Research Council (MR/N012453/1)