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Cell. 2018 Apr 19;173(3):720-734.e15. doi: 10.1016/j.cell.2018.03.056.

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

Author information

1
Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, UK.
2
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
3
Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
4
Tanz Centre for Research in Neurodegenerative Diseases and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 3H2, Canada.
5
Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB3 0AS, UK.
6
Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
7
Centre for Genomic Regulation, the Barcelona Institute for Science and Technology, 08003 Barcelona, Spain; Universitat Pompeu Fabra, 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain.
8
Departments of Medicine, Neurology, and Ophthalmology and Departments of Epidemiology and Biostatistics, Boston University, Boston, MA 02118, USA.
9
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK; Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge CB3 0HE, UK.
10
Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, UK; Tanz Centre for Research in Neurodegenerative Diseases and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 3H2, Canada. Electronic address: p.hyslop@utoronto.ca.

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.

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

PMID:
29677515
PMCID:
PMC5927716
DOI:
10.1016/j.cell.2018.03.056
[Indexed for MEDLINE]
Free PMC Article

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