The Role of Methionine Residues in the Regulation of Liquid-Liquid Phase Separation

Membraneless organelles are non-stoichiometric supramolecular structures in the micron scale. These structures can be quickly assembled/disassembled in a regulated fashion in response to specific stimuli. Membraneless organelles contribute to the spatiotemporal compartmentalization of the cell, and they are involved in diverse cellular processes often, but not exclusively, related to RNA metabolism. Liquid-liquid phase separation, a reversible event involving demixing into two distinct liquid phases, provides a physical framework to gain insights concerning the molecular forces underlying the process and how they can be tuned according to the cellular needs. Proteins able to undergo phase separation usually present a modular architecture, which favors a multivalency-driven demixing. We discuss the role of low complexity regions in establishing networks of intra- and intermolecular interactions that collectively control the phase regime. Post-translational modifications of the residues present in these domains provide a convenient strategy to reshape the residue–residue interaction networks that determine the dynamics of phase separation. Focus will be placed on those proteins with low complexity domains exhibiting a biased composition towards the amino acid methionine and the prominent role that reversible methionine sulfoxidation plays in the assembly/disassembly of biomolecular condensates.