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

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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 languageEnglish
Article numbere15
Pages (from-to)720-734
JournalCell
Volume173
Issue number3
DOIs
Publication statusPublished - 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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  • 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

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