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.

FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions / Qamar, Seema; Wang, Guozhen; Randle, Suzanne J.; Ruggeri, Francesco Simone; Varela, Juan A.; Lin, Julie Qiaojin; Phillips, Emma C.; Miyashita, Akinori; Williams, Declan; Ströhl, Florian; Meadows, William; Ferry, Rodylyn; Dardov, Victoria J.; Tartaglia, Gian G.; Farrer, Lindsay A.; Kaminski Schierle, Gabriele S.; Kaminski, Clemens F.; Holt, Christine E.; Fraser, Paul E.; Schmitt-Ulms, Gerold; Klenerman, David; Knowles, Tuomas; Vendruscolo, Michele; St George-Hyslop, Peter. - In: CELL. - ISSN 0092-8674. - 173:3(2018), pp. 720-734.e15. [10.1016/j.cell.2018.03.056]

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

Tartaglia, Gian G.;Vendruscolo, Michele;
2018

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.
2018
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; Biochemistry, Genetics and Molecular Biology (all)
01 Pubblicazione su rivista::01a Articolo in rivista
FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions / Qamar, Seema; Wang, Guozhen; Randle, Suzanne J.; Ruggeri, Francesco Simone; Varela, Juan A.; Lin, Julie Qiaojin; Phillips, Emma C.; Miyashita, Akinori; Williams, Declan; Ströhl, Florian; Meadows, William; Ferry, Rodylyn; Dardov, Victoria J.; Tartaglia, Gian G.; Farrer, Lindsay A.; Kaminski Schierle, Gabriele S.; Kaminski, Clemens F.; Holt, Christine E.; Fraser, Paul E.; Schmitt-Ulms, Gerold; Klenerman, David; Knowles, Tuomas; Vendruscolo, Michele; St George-Hyslop, Peter. - In: CELL. - ISSN 0092-8674. - 173:3(2018), pp. 720-734.e15. [10.1016/j.cell.2018.03.056]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1279529
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