Modulation of biomolecular phase behavior by metal ions

Liquid–liquid phase separation (LLPS) appears to be a newly appreciated aspect of the cellular organization of biomolecules that leads to the formation of membraneless organelles (MLOs). MLOs generate distinct microenvironments where particular biomolecules are highly concentrated compared to those in the surrounding environment. Their thermodynamically driven formation is reversible, and their liquid nature allows them to fuse with each other. Dysfunctional biomolecular condensation is associated with human diseases. Pathological states of MLOs may originate from the mutation of proteins or may be induced by other factors. In most aberrant MLOs, transient interactions are replaced by stronger and more rigid interactions, preventing their dissolution, and causing their uncontrolled growth and dysfunction. For these reasons, there is great interest in identifying factors that modulate LLPS. In this review, we discuss an enigmatic and mostly unexplored aspect of this process, namely, the regulatory effects of metal ions on the phase behavior of biomolecules.