Journal Article

Molecular interactions underlying liquid−liquid phase separation of the FUS low-complexity domain

Dignon, Gregory L, Parekh, Sapun H, Fawzi, Nicolas L, Zerze, Gül H, Kan, Yelena, Murthy, Anastasia C, Mittal, Jeetain

2019

Overview

The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid−liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that heterogeneous interactions involving all residue types underlie LLPS of human FUS LC. We find no evidence that FUS LC adopts conformations with traditional secondary structure elements in the condensed phase; rather, it maintains conformational heterogeneity. We show that hydrogen bonding, π/sp2, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.

• Publisher: Nature Publishing Group
• Subject: Complexity / Computer simulation / Engineering / FUS protein / Glutamine / Heterogeneity / Hydrogen bonding / Hydrophobicity / Liquid phases / Molecular biology / Molecular interactions / Mutagenesis / NMR / Nuclear magnetic resonance / Phase separation / Polypeptides / Protein structure / Proteins / Raman spectroscopy / Residues / Ribonucleic acid / RNA / RNA polymerase / RNA-binding protein / Secondary structure / Spectrum analysis / Tyrosine