Coiled-coils as emerging drivers of liquid–liquid phase separation

Liquid-liquid phase separation (LLPS) is a fundamental organizing principle in biology, driving the formation of membraneless compartments and thereby orchestrating a vast array of biochemical reactions in a spatiotemporal manner. LLPS is mediated by weak, multivalent interactions between biomolecules. While intrinsically disordered regions (IDRs) are widely recognized as major drivers of LLPS, coiled-coils, one of the most ubiquitous protein motifs, are emerging as functionally distinct, versatile contributors. This review systematically explores the multifaceted roles of coiled-coils in LLPS, highlighting their capabilities that contrast with those of IDRs. A key feature distinguishing coiled-coils is their ability to span an exceptionally broad range of interaction affinities, from picomolar to millimolar levels. This vast dynamic range allows them to operate across a continuous functional spectrum-from serving as high-affinity oligomerization platforms to acting as modules that mediate weak, transient interactions-a functional duality not recapitulated by IDRs. Through this inherent tunability, coiled-coils can play a pivotal role in modulating both the propensity for phase separation and the material properties of the resultant condensates.