Protein phase separation: physical models and phase-separation- mediated cancer signaling

ABSTRACT Phase separation is a concept well described in physics where a system spontaneously exhibits two or more distinct yet coexisting phases at equilibrium. This review describes several popular physical models that serve as a theoretical framework to understand protein phase separation in biological systems, a burgeoning area of research with many challenges left to be explored. The principles of statistical mechanics and thermodynamics that encompass phase separation are crucial to understanding the biophysical properties of biomolecular condensates. Representative systems of protein phase separation in several naturally occurring cancer fusion proteins and their implications in cancer mechanisms are discussed to highlight the underappreciated biophysical perspective on cancer. This insight into the driving force for protein condensate assembly may help to identify novel disease mechanisms and open opportunities for further innovative therapeutic strategies. Graphical abstract