FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions

Seema Qamar; GuoZhen Wang; Suzanne J Randle; Francesco Simone Ruggeri; Juan A Varela; Julie Qiaojin Lin; Emma C Phillips; Akinori Miyashita; Declan Williams; Florian Ströhl; William Meadows; Rodylyn Ferry; Victoria J Dardov; Gian G Tartaglia; Lindsay A Farrer; Gabriele S Kaminski Schierle; Clemens F Kaminski; Christine E Holt; Paul E Fraser; Gerold Schmitt-Ulms; David Klenerman; Tuomas Knowles; Michele Vendruscolo; Peter St George-Hyslop

doi:10.1016/j.cell.2018.03.056

FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions

Seema Qamar, GuoZhen Wang, Suzanne J Randle, Francesco Simone Ruggeri, Juan A Varela, Julie Qiaojin Lin, Emma C Phillips, Akinori Miyashita, Declan Williams, Florian Ströhl, William Meadows, Rodylyn Ferry, Victoria J Dardov, Gian G Tartaglia, Lindsay A Farrer, Gabriele S Kaminski Schierle, Clemens F Kaminski, Christine E Holt, Paul E Fraser, Gerold Schmitt-UlmsDavid Klenerman, Tuomas Knowles, Michele Vendruscolo, Peter St George-Hyslop

School of Biology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	e15
Pages (from-to)	720-734
Journal	Cell
Volume	173
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2018.03.056
Publication status	Published - 19 Apr 2018

Keywords

Phase separation
Neuronal ribonucleoprotein granule
Synaptic new protein synthesis
Membraneless organelle
Cation-π
arginine methylation
Citrullination
Frontotemporal dementia
AFM-IR
Phase-sensitive fluorescent dyes

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10.1016/j.cell.2018.03.056Licence: CC BY

Qamar_2018_Cell_FUSphaseseparation_CC
Copyright © 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 5.63 MBLicence: CC BY

Juan Alberto Varela
- jv32st-andrews.acuk
Person: Academic

Raw data for Qamar et al, FUS Phase Separation, Cell-D-17-01483
Qamar, S. (Creator), Wang, G. (Creator), Randle, S. J. (Creator), Ruggeri, F. S. (Creator), Varela, J. A. (Creator), Lin, J. Q. (Creator), Phillips, E. C. (Creator), Miyashita, A. (Creator), Williams, D. (Creator), Ströhl, F. (Creator), Meadows, W. (Creator), Ferry, R. (Creator), Dardov, V. J. (Creator), Tartaglia, G. G. (Creator), Farrer, L. A. (Creator), Kaminski Schierle, G. S. (Creator), Kaminski, C. F. (Creator), Holt, C. E. (Creator), Fraser, P. E. (Creator), Schmitt-Ulms, G. (Creator), Klenerman, D. (Creator), Knowles, T. (Creator), Vendruscolo, M. (Creator) & St George-Hyslop, P. (Creator), Mendeley Data, 30 Mar 2018
DOI: 10.17632/4mjh8y579j.1
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Qamar, S., Wang, G., Randle, S. J., Ruggeri, F. S., Varela, J. A., Lin, J. Q., Phillips, E. C., Miyashita, A., Williams, D., Ströhl, F., Meadows, W., Ferry, R., Dardov, V. J., Tartaglia, G. G., Farrer, L. A., Kaminski Schierle, G. S., Kaminski, C. F., Holt, C. E., Fraser, P. E., ... St George-Hyslop, P. (2018). FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions. Cell, 173(3), 720-734. Article e15. https://doi.org/10.1016/j.cell.2018.03.056

@article{ec2c620950a940f5ab68d327ca765fb9,

title = "FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions",

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 = "Phase separation, Neuronal ribonucleoprotein granule, Synaptic new protein synthesis, Membraneless organelle, Cation-π, arginine methylation, Citrullination, Frontotemporal dementia, AFM-IR, Phase-sensitive fluorescent dyes",

author = "Seema Qamar and GuoZhen Wang and Randle, {Suzanne J} and Ruggeri, {Francesco Simone} and Varela, {Juan A} and Lin, {Julie Qiaojin} and Phillips, {Emma C} and Akinori Miyashita and Declan Williams and Florian Str{\"o}hl and William Meadows and Rodylyn Ferry and Dardov, {Victoria J} and Tartaglia, {Gian G} and Farrer, {Lindsay A} and {Kaminski Schierle}, {Gabriele S} and Kaminski, {Clemens F} and Holt, {Christine E} and Fraser, {Paul E} and Gerold Schmitt-Ulms and David Klenerman and Tuomas Knowles and Michele Vendruscolo and {St George-Hyslop}, Peter",

note = "This work was supported by the Canadian Consortium on Neurodegeneration and Aging of the Canadian Institutes of Health Research (to P.S.H.), Wellcome Trust (to P.S.H., M.V., D.K., T.K., C.F.K., and G.S.K.S.), a European Research Council starting grant (RIBOMYLOME_309545) (to G.G.T.), a European Research Council grant (322817) (to C.E.H.), the Swiss National Foundation for Science (to F.S.R.), and the ALS Society of Canada/Brain Canada (to P.S.H.).",

year = "2018",

month = apr,

day = "19",

doi = "10.1016/j.cell.2018.03.056",

language = "English",

volume = "173",

pages = "720--734",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "3",

}

Qamar, S, Wang, G, Randle, SJ, Ruggeri, FS, Varela, JA, Lin, JQ, Phillips, EC, Miyashita, A, Williams, D, Ströhl, F, Meadows, W, Ferry, R, Dardov, VJ, Tartaglia, GG, Farrer, LA, Kaminski Schierle, GS, Kaminski, CF, Holt, CE, Fraser, PE, Schmitt-Ulms, G, Klenerman, D, Knowles, T, Vendruscolo, M & St George-Hyslop, P 2018, 'FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions', Cell, vol. 173, no. 3, e15, pp. 720-734. https://doi.org/10.1016/j.cell.2018.03.056

TY - JOUR

T1 - FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions

AU - Qamar, Seema

AU - Wang, GuoZhen

AU - Randle, Suzanne J

AU - Ruggeri, Francesco Simone

AU - Varela, Juan A

AU - Lin, Julie Qiaojin

AU - Phillips, Emma C

AU - Miyashita, Akinori

AU - Williams, Declan

AU - Ströhl, Florian

AU - Meadows, William

AU - Ferry, Rodylyn

AU - Dardov, Victoria J

AU - Tartaglia, Gian G

AU - Farrer, Lindsay A

AU - Kaminski Schierle, Gabriele S

AU - Kaminski, Clemens F

AU - Holt, Christine E

AU - Fraser, Paul E

AU - Schmitt-Ulms, Gerold

AU - Klenerman, David

AU - Knowles, Tuomas

AU - Vendruscolo, Michele

AU - St George-Hyslop, Peter

N1 - This work was supported by the Canadian Consortium on Neurodegeneration and Aging of the Canadian Institutes of Health Research (to P.S.H.), Wellcome Trust (to P.S.H., M.V., D.K., T.K., C.F.K., and G.S.K.S.), a European Research Council starting grant (RIBOMYLOME_309545) (to G.G.T.), a European Research Council grant (322817) (to C.E.H.), the Swiss National Foundation for Science (to F.S.R.), and the ALS Society of Canada/Brain Canada (to P.S.H.).

PY - 2018/4/19

Y1 - 2018/4/19

N2 - 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.

AB - 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.

KW - Phase separation

KW - Neuronal ribonucleoprotein granule

KW - Synaptic new protein synthesis

KW - Membraneless organelle

KW - Cation-π

KW - arginine methylation

KW - Citrullination

KW - Frontotemporal dementia

KW - AFM-IR

KW - Phase-sensitive fluorescent dyes

U2 - 10.1016/j.cell.2018.03.056

DO - 10.1016/j.cell.2018.03.056

M3 - Article

C2 - 29677515

SN - 0092-8674

VL - 173

SP - 720

EP - 734

JO - Cell

JF - Cell

IS - 3

M1 - e15

ER -

FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions

Abstract

Keywords

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Raw data for Qamar et al, FUS Phase Separation, Cell-D-17-01483

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