Liquid–liquid phase separation (LLPS) has increasingly been found to play pivotal roles in a number of intracellular events and reactions, and has introduced a new paradigm in cell biology to explain protein–protein and enzyme–ligand interactions beyond conventional molecular and biochemical theories. LLPS is driven by the cumulative effects of weak and promiscuous interactions, including electrostatic, hydrophobic and cation–π interactions, among polypeptides containing intrinsically disordered regions (IDRs) and describes the macroscopic behaviours of IDR-containing proteins in an intracellular milieu. Recent studies have revealed that interactions between ‘charge blocks’ – clusters of like charges along the polypeptide chain – strongly induce LLPS and play fundamental roles in its spatiotemporal regulation. Introducing a new parameter, termed ‘charge blockiness’, into physicochemical models of disordered polypeptides has yielded a better understanding of how the intrinsic amino acid sequence of a polypeptide determines the spatiotemporal occurrence of LLPS within a cell. Charge blockiness might also explain why some post-translational modifications segregate within IDRs and how they regulate LLPS. In this Review, we summarise recent progress towards understanding the mechanism and biological roles of charge block-driven LLPS and discuss how this new characteristic parameter of polypeptides offers new possibilities in the fields of structural biology and cell biology.

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