Protein Phase Separation: A New Phase in Cell Biology

Abstract

Cellular compartments and organelles organize biological matter. Most well-known organelles are separated by a membrane boundary from their surrounding milieu. There are also many so-called membraneless organelles and recent studies suggest that these organelles, which are supramolecular assemblies of proteins and RNA molecules, form via protein phase separation. Recent discoveries have shed light on the molecular properties, formation, regulation, and function of membraneless organelles. A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age-related disorders.

Figure 1

Different Characteristics of Protein Phase Transitions. (A) Material state and dynamics can vary in a wide range from liquid-like to solid states. (B) Example of the protein FUS, which can span the entire range of material states in vitro. Pictures adapted from reference [16]. (C) Examples of membraneless organelles and their reconstituted in vitro counterparts. Pictures adapted from references [48,66,72,87,142] (D) Several membraneless organelles have complex topologies with different subcompartments that may belong to different states. All scale bars 5 μm unless indicated.

Figure 2

Interactions and Regulatory Mechanisms Implicated in Protein Phase Separation. (A) Overview of different kinds of contacts, which have been observed in protein phase separation. (B) Examples of phase separating proteins illustrate the importance of multivalency, highlighted by an array of interaction modules within a single protein. (C) Different mechanisms regulate the material state and nucleation of protein phase separation.