Redox State Controls Phase Separation of the Yeast Ataxin-2 Protein via Reversible Oxidation of Its Methionine-Rich Low-Complexity Domain

Cell. 2019 Apr 18;177(3):711-721.e8. doi: 10.1016/j.cell.2019.02.044. Epub 2019 Apr 11.


Yeast ataxin-2, also known as Pbp1, senses the activity state of mitochondria in order to regulate TORC1. A domain of Pbp1 required to adapt cells to mitochondrial activity is of low sequence complexity. The low-complexity (LC) domain of Pbp1 forms labile, cross-β polymers that facilitate phase transition of the protein into liquid-like or gel-like states. Phase transition for other LC domains is reliant upon widely distributed aromatic amino acids. In place of tyrosine or phenylalanine residues prototypically used for phase separation, Pbp1 contains 24 similarly disposed methionine residues. Here, we show that the Pbp1 methionine residues are sensitive to hydrogen peroxide (H2O2)-mediated oxidation in vitro and in living cells. Methionine oxidation melts Pbp1 liquid-like droplets in a manner reversed by methionine sulfoxide reductase enzymes. These observations explain how reversible formation of labile polymers by the Pbp1 LC domain enables the protein to function as a sensor of cellular redox state.

Keywords: Ataxin-2; ROS; TORC1; aging; cross-β polymer; low-complexity sequence; methionine; neurodegeneration; oxidative stress; phase separation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Hydrogen Peroxide / pharmacology
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Methionine / chemistry*
  • Methionine / metabolism
  • Methionine Sulfoxide Reductases / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mutagenesis, Site-Directed
  • Oxidation-Reduction
  • Oxidative Stress / drug effects
  • Phase Transition
  • Protein Domains
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*


  • Carrier Proteins
  • PBP1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Methionine
  • Hydrogen Peroxide
  • Methionine Sulfoxide Reductases
  • methionine sulfoxide reductase
  • Mechanistic Target of Rapamycin Complex 1