Intrinsically disordered protein regions and phase separation: sequence determinants of assembly or lack thereof

Intrinsically disordered protein regions (IDRs) — regions that do not fold into a fixed three-dimensional structure but instead exist in a heterogeneous ensemble of conformations — have recently entered mainstream cell biology in the context of liquid–liquid phase separation (LLPS). IDRs are frequently found to be enriched in phase-separated compartments. Due to this observation, the presence of an IDR in a protein is frequently assumed to be diagnostic of its ability to phase separate. In this review, we clarify the role of IDRs in biological assembly and explore the physical principles through which amino acids can confer the attractive molecular interactions that underlie phase separation. While some disordered regions will robustly drive phase separation, many others will not. We emphasize that rather than ‘disorder' driving phase separation, multivalency drives phase separation. As such, whether or not a disordered region is capable of driving phase separation will depend on the physical chemistry encoded within its amino acid sequence. Consequently, an in-depth understanding of that physical chemistry is a prerequisite to make informed inferences on how and why an IDR may be involved in phase separation or, more generally, in protein-mediated intermolecular interactions.