The role of intrinsically disordered linkers in defining the physical properties and spatial organization of biomolecular condensates

Biomolecular condensates are composed of molecules containing multivalent protein/protein or protein/nucleic acid interaction elements. These molecules undergo liquid-liquid phase separation and form the physical scaffold of biomolecular condensates. Phase separation of multidomain scaffolds is known to be influenced by the number of protein/protein or protein/nucleic acid interaction domains in the molecules. These interacting domains are typically tethered together by intrinsically disordered linkers. Recent computational studies have suggested that the amino acid sequence and consequent physical properties of the linkers may influence the spatial organization biomolecular condensates, dictating whether they undergo sol-gel transitions and/or macroscopic phase separation. In multi-scaffold systems, the linkers may also control whether the condensed phase is homogeneous or multi-layered, as observed in natural condensates such as nucleoli, Cajal bodies, and stress granules. Using a series of designed multidomain proteins, I am currently investigating how the composition of linkers influences the physical properties and spatial organization of biomolecular condensates.