Phase separation of low-complexity domains in cellular function and disease.

In this review, we discuss the ways in which recent studies of low-complexity (LC) domains have challenged our understanding of the mechanisms underlying cellular organization. LC sequences, long believed to function in the absence of a molecular structure, are abundant in the proteomes of all eukaryotic organisms. Over the past decade, the phase separation of LC domains has emerged as a fundamental mechanism driving dynamic multivalent interactions of many cellular processes. We review the key evidence showing the role of phase separation of individual proteins in organizing cellular assemblies and facilitating biological function while implicating the dynamics of phase separation as a key to biological validity and functional utility. We also highlight the evidence showing that pathogenic LC proteins alter various phase separation-dependent interactions to elicit debilitating human diseases, including cancer and neurodegenerative diseases. Progress in understanding the biology of phase separation may offer useful hints toward possible therapeutic interventions to combat the toxicity of pathogenic proteins.