Biological phase separation: cell biology meets biophysics

Abstract

Progress in development of biophysical analytic approaches has recently crossed paths with macromolecule condensates in cells. These cell condensates, typically termed liquid-like droplets, are formed by liquid-liquid phase separation (LLPS). More and more cell biologists now recognize that many of the membrane-less organelles observed in cells are formed by LLPS caused by interactions between proteins and nucleic acids. However, the detailed biophysical processes within the cell that lead to these assemblies remain largely unexplored. In this review, we evaluate recent discoveries related to biological phase separation including stress granule formation, chromatin regulation, and processes in the origin and evolution of life. We also discuss the potential issues and technical advancements required to properly study biological phase separation.

Phase Transitions by an Abundant Protein in the Anammox Extracellular Matrix Mediate Cell-to-Cell Aggregation and Biofilm Formation

“…We further show that the C terminus of the surface protein contains two repeat regions of approximately 100 amino acids that are intrinsically disordered. Low-complexity or intrinsically disordered domains (IDDs), which are regions of the protein without three-dimensional order, have been implicated in biologically regulated phase separation of macromolecules into liquid-phase condensates (14). Phase separation occurs due to their tendency toward weak and transient interactions.…”

Fused in Sarcoma (FUS) in DNA Repair: Tango with Poly(ADP-ribose) Polymerase 1 and Compartmentalisation of Damaged DNA

“…Even though the nucleus, unlike the cytoplasm, does not contain membrane-bound organelles, the nucleus is a highly organised structure with separate proteinaceous and nucleic-acid–rich subnuclear compartments that have special morphology and specific composition of protein–nucleic acid complexes and are functionally specialised [ 105 ]. It was recently proposed that many DNA- or RNA-containing structures in the nucleus are assembled through a physicochemical process called LLPS [ 30 , 105 , 106 , 107 ]. In fact, LLPS of protein or protein–nucleic acid mixtures is now regarded as the principal mechanism behind the formation of protein-rich membrane-less compartments in the cell [ 29 , 105 , 106 , 107 , 108 ].…”

“…It was recently proposed that many DNA- or RNA-containing structures in the nucleus are assembled through a physicochemical process called LLPS [ 30 , 105 , 106 , 107 ]. In fact, LLPS of protein or protein–nucleic acid mixtures is now regarded as the principal mechanism behind the formation of protein-rich membrane-less compartments in the cell [ 29 , 105 , 106 , 107 , 108 ]. In eukaryotes, an abundant group of RBPs—that are intrinsically disordered proteins (IDPs) with prion-like properties—represents key factors that contribute to the creation of these compartments in the cell through the phase separation mechanism [ 30 , 64 , 65 , 67 ].…”

Interface Engineering in Multiphase Systems toward Synthetic Cells and Organelles: From Soft Matter Fundamentals to Biomedical Applications

“…[62] In addition, the recent discovery of macromolecule crowding in living cells may contribute to the high efficiency of intracellular/ subcellular enzymatic reactions, thus stimulating enormous interests of coacervate droplets. [31][32][33][34][35][36][37][63][64][65][66][67][68][69] Moreover, the development in cell-inspired novel carriers for therapeutic nuclei acids and proteins has been progressed excitingly with translational successes. For a prosperous and interdisciplinary field like synthetic cells, there are reviews summarizing from specific aspects, for instance, tailoring appearance of synthetic cells, [2,[70][71][72] elucidating specific functions of synthetic cell modules, [2,71,73] which include adhesion, [58] growth, [57] energy regeneration/conversion, [4,[59][60][61] gene circuits, [56,74] and cellular interactions, [75][76][77] exclusively focusing on applications of synthetic compartments such as delivery carriers [10,18,[78][79][80][81][82][83][84][85]…”