We underline that phase separation of a liquid system does not necessarily imply a change in material properties ( e.g., a change from liquid to solid), although the latter can take place during the “maturation” of liquid-like condensates ( 21, 22). If the separated phases maintain their liquidity, the demixing is called liquid-liquid phase separation (LLPS). The miscibility is strongly dependent on the components’ concentrations, temperature, pressure, pH, and crowding agents. The thermodynamics of a multi-component system can be explained by a tug of war between entropy and enthalpy demixing occurs if the energy gain for demixing is greater than the entropic loss for demixing ( 19, 20). PRINCIPLES OF LIQUID-LIQUID PHASE SEPARATIONĪ multi-component system like cellular cytoplasm can exist as a homogeneous, well-mixed mixture or a soup of distinct phases (phase separation), depending on the interactions of the constituent molecules including the solvent. We collected recent publications (specifically published in two years) related to biomolecular LLPS, and found that the four topics mentioned above can summarize the field well. We start with a brief introduction of the major principles of LLPS (Section 2), and move to the recent advancement in the field (Section 3): new biomolecular condensates and their functions in the cytosol (Section 3.1) and nuclei (Section 3.2), studies on mole-cular principles of biomolecular LLPS (Section 3.3), design and engineering of artificial condensates (Section 3.4), and implications of LLPS in diseases (Section 3.5). In this review, we highlight the recent findings on the underlying mechanisms of phase separation driven by proteins and the effects of nucleic acid on this process. In addition, LLPS even has implications for the pathogenesis of cancer and many neurodegenerative such as Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis ( 16- 18). LLPS is also observed in many processes such as miRISC assembly ( 10), innate immune signalling ( 11), stress granule assembly ( 12), autophagy ( 13), nucleolus formation ( 14), and transcription ( 15). Hence, biomolecular condensates have a significant role in a wide range of cellular functions including cell signalling, ribosomal biogenesis ( 5), cytoskeletal regulation ( 6), stress response ( 7), cell polarization ( 8), and cytoplasmic branching ( 9). Cells can use this mechanism to quickly respond to abrupt environmental changes. Moreover, due to their liquid-like properties, biomolecular condensates can quickly recruit specific molecules in response to perturbations such as temperature changes. Many cellular reactions can be triggered by a change in the concentrations of specific molecules, in which cases LLPS can be utilized for efficient cell functioning as it can dramatically increase the local concentration of the recruited molecules ( 4, 5). This demixing had been a mystery, but recently it was found that it can occur spontaneously via liquid-liquid phase separation (LLPS), a phenomenon that has been known in physics and chemistry for more than a century ( 3). Although biomolecular condensates do not enclose their components within a membrane, the components do not mix with their surroundings. The membrane-bound organelles (such as nucleus, endoplasmic reticulum, Golgi apparatus, mitochondria, and lysosomes) have been known for many decades and studied extensively, but our knowledge of the membrane-less organelles, often called biomolecular condensates, was limited until recently ( 2). Some of them are surrounded by a membrane, while others float inside the cell as spherical droplets made of proteins, nucleic acids, lipids, and other small molecules ( 1). A living cell is an assembly of various organelles.
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