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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Arginine / chemistry*
  • Cations
  • DNA Methylation
  • Frontotemporal Dementia / metabolism
  • Frontotemporal Lobar Degeneration / metabolism
  • Humans
  • Microscopy, Atomic Force
  • Microscopy, Fluorescence
  • Molecular Chaperones / chemistry*
  • Protein Binding
  • Protein Domains
  • Protein Processing, Post-Translational
  • Protein Structure, Secondary
  • RNA-Binding Protein FUS / chemistry*
  • RNA-Binding Protein FUS / metabolism
  • Tyrosine / chemistry
  • Xenopus laevis


  • Cations
  • FUS protein, human
  • Molecular Chaperones
  • RNA-Binding Protein FUS
  • Tyrosine
  • Arginine