Polyphasic linkage and the impact of ligand binding on the regulation of biomolecular condensates

Cellular matter can be spatially and temporally organized into membraneless biomolecular condensates. The current thinking is that these condensates form and dissolve via phase transitions driven by one or more condensate-specific multivalent macromolecules known as scaffolds. Cells likely regulate condensate formation and dissolution by exerting control over the concentrations of regulatory molecules, which we refer to as ligands. Wyman and Gill introduced the framework of polyphasic linkage to explain how ligands can exert thermodynamic control over phase transitions. This review focuses on describing the concepts of polyphasic linkage and the relevance of such a mechanism for controlling condensate formation and dissolution. We describe how ligand-mediated control over scaffold phase behavior can be quantified experimentally. Further, we build on recent studies to highlight features of ligands that make them suppressors vs drivers of phase separation. Finally, we highlight areas where advances are needed to further understand ligand-mediated control of condensates in complex cellular environments. These advances include understanding the effects of networks of ligands on condensate behavior and how ligands modulate phase transitions controlled by different combinations of homotypic and heterotypic interactions among scaffold macromolecules. Insights gained from the application of polyphasic linkage concepts should be useful for designing novel pharmaceutical ligands to regulate condensates.