Reentrant transitions in protein phase-separation: segregation vs. association

In the past decade, a large body of research has highlighted the biological significance of liquid-liquid phase separation (LLPS) in the formation of cellular, membraneless organelles. Such organelles are usually formed by a protein (“scaffold”) that phase separates in aqueous solution due to self-attractive interactions. In biological systems, additional solutes (“clients”), that bind the scaffold proteins are localized in the scaffold rich phase to form a distinct biochemical environment with unique functions. We use Flory Huggins theory to predict the phase diagrams of scaffold-client-solvent ternary solutions. We find that the phase diagram may exhibit reentrant LLPS as the interaction of the scaffold and client increases, leading to a transition from LLPS in which the scaffold and client are segregated, to LLPS in which the scaffold and client jointly phase-separate. We suggest this change of the composition of the dense phase as a possible mechanism underlying neurodegenerative diseases that show aberrant LLPS and are associated with mutations that affect the scaffold-client interaction energy.