The Control Centers of Biomolecular Phase Separation: How Membrane Surfaces, PTMs, and Active Processes Regulate Condensation

Abstract

Biomolecular condensation is emerging as an essential process for cellular compartmentalization. The formation of biomolecular condensates can be driven by liquid-liquid phase separation, which arises from weak, multivalent interactions among proteins and nucleic acids. A substantial body of recent work has revealed that diverse cellular processes rely on biomolecular condensation and that aberrant phase separation may cause disease. Many proteins display an intrinsic propensity to undergo phase separation. However, the mechanisms by which cells regulate phase separation to build functional condensates at the appropriate time and location are only beginning to be understood. Here, we review three key cellular mechanisms that enable the control of biomolecular phase separation: membrane surfaces, post-translational modifications, and active processes. We discuss how these mechanisms may function in concert to provide robust control over biomolecular condensates and suggest new research avenues that will elucidate how cells build and maintain these key centers of cellular compartmentalization.

Keywords: biomolecular condensates; membranes; molecular chaperones; phase separation; post-translational modifications.

Figure 1.

Overview of how membrane surfaces, post-translational modifications, and active processes regulate biomolecular phase separation.

Figure 2.

Membrane surfaces regulate biomolecular phase separation in time and space. (A) By restricting molecular diffusion to a two-dimensional plane, membrane surfaces reduce the concentration threshold to phase separation in comparison to free-diffusing molecules in solution. (B) Membrane contact interfaces between apposed organelles or organelles and the plasma membrane may control condensate assembly. Condensates may further regulate these interfaces to mediate material exchange and signaling. (C) Biomolecular condensates may couple with lipid phase separation to help organize membrane surfaces.

Figure 3.

PTMs provide a complex network of regulation over biomolecular phase separation. (A) PTMs can drive dissolution of some condensates by inhibiting cation-π, electrostatic, and other types of interactions. Some key PTMs and relevant proteins are indicated in red. (B) Phosphorylation can drive phase separation of Tau by promoting electrostatic interactions. (C) Phosphorylation can increase valency to promote phase separation, for example in the nephrin-Nck-N-WASP network.