Intrinsically disordered linkers determine the interplay between phase separation and gelation in multivalent proteins

Abstract Many intracellular membraneless bodies appear to form via reversible phase transitions of multivalent proteins. Two relevant types of phase transitions are sol-gel transitions (gelation) and phase separation plus gelation. Gelation refers to the formation of a system spanning molecular network. This can either be enabled by phase separation or it can occur independently. Despite relevance for the formation and selectivity of compositionally distinct protein and RNA assemblies, the determinants of gelation as opposed to phase separation plus gelation remain unclear. Here, we focus on linear multivalent proteins that consist of interaction domains that are connected by disordered linkers. Using results from computer simulations and theoretical analysis we show that the lengths and sequence-specific features of disordered linkers determine the coupling between phase separation and gelation. Thus, the precise nature of phase transitions for linear multivalent proteins should be biologically tunable through genetic encoding of or post-translational modifications to linker sequences.