Liquid–liquid phase separation as an organizing principle of intracellular space: overview of the evolution of the cell compartmentalization concept

Antifeeva, Iuliia A.; Fonin, Alexander V.; Fefilova, Anna S.; Stepanenko, Olga V.; Povarova, Olga I.; Silonov, Sergey A.; Kuznetsova, Irina М.; Uversky, Vladimir N.; Turoverov, Konstantin К.

doi:10.1007/s00018-022-04276-4

Cited by 70 publications

(43 citation statements)

References 321 publications

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“…The evolution of eukaryotic cells involved a marked increase in organizational complexity, facilitated by intracellular compartmentalization ( Gabaldón and Pittis, 2015 ; Rout and Field, 2017 ; Antifeeva et al, 2022 ). This was accomplished by the formation of cellular organelles by an endomembrane system and the acquisition of mitochondria, which developed from an alpha-proteobacterium engulfed by a eukaryotic progenitor.…”

Section: Introductionmentioning

confidence: 99%

The Role of Ubiquitin in Regulating Stress Granule Dynamics

2022

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Stress granules (SGs) are dynamic, reversible biomolecular condensates, which assemble in the cytoplasm of eukaryotic cells under various stress conditions. Formation of SGs typically occurs upon stress-induced translational arrest and polysome disassembly. The increase in cytoplasmic mRNAs triggers the formation of a protein-RNA network that undergoes liquid-liquid phase separation when a critical interaction threshold has been reached. This adaptive stress response allows a transient shutdown of several cellular processes until the stress is removed. During the recovery from stress, SGs disassemble to re-establish cellular activities. Persistent stress and disease-related mutations in SG components favor the formation of aberrant SGs that are impaired in disassembly and prone to aggregation. Recently, posttranslational modifications of SG components have been identified as major regulators of SG dynamics. Here, we summarize new insights into the role of ubiquitination in affecting SG dynamics and clearance and discuss implications for neurodegenerative diseases linked to aberrant SG formation.

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Section: Introductionmentioning

confidence: 99%

The Role of Ubiquitin in Regulating Stress Granule Dynamics

2022

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“…The underlying biophysical mechanism for membraneless compartmentalization is liquid–liquid phase separation (LLPS). In the past few years, the LLPS of biomolecules has become a unifying physical mechanism for understanding the principles of intracellular compartmentalization, the formation of membraneless organelles (MLOs), and gene regulation [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. In the LLPS process, the relatively well-mixed solution of biomolecules separates into liquid droplets.…”

Section: Introductionmentioning

confidence: 99%

“…In the LLPS process, the relatively well-mixed solution of biomolecules separates into liquid droplets. The ability of proteins to phase separate appears to be encoded primarily in the peculiarities of their primary sequences, which often contain low-complexity regions and intrinsically disordered regions (IDRs) that are enriched in charged and multivalent interaction centers [ 6 , 7 , 8 , 10 , 11 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. While some general sequence trends have emerged, the quantitative aspects of how amino acid sequences encode and decode phase separation still remain largely unknown [ 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

BIAPSS: A Comprehensive Physicochemical Analyzer of Proteins Undergoing Liquid–Liquid Phase Separation

Badaczewska-Dawid

Uversky

Potoyan

2022

IJMS

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The liquid–liquid phase separation (LLPS) of biomolecules is a phenomenon which is nowadays recognized as the driving force for the biogenesis of numerous functional membraneless organelles and cellular bodies. The interplay between the protein primary sequence and phase separation remains poorly understood, despite intensive research. To uncover the sequence-encoded signals of protein capable of undergoing LLPS, we developed a novel web platform named BIAPSS (Bioinformatics Analysis of LLPS Sequences). This web server provides on-the-fly analysis, visualization, and interpretation of the physicochemical and structural features for the superset of curated LLPS proteins.

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“…The dynamic equilibrium between condensation and dissolution of these membraneless organelles are mainly controlled by the multivalent but weak interactions of constituting proteins and other biomolecules within the organelles [1]. Proteins with intrinsic disordered low complexity domain (LCD) are often the major components forming these membraneless organelles [6,7]. In vitro, these proteins with multivalency could demix from solution and form liquid droplets through a protein liquid-liquid phase separation (LLPS) process, providing us a simplified system to understand the physical and chemical forces driving the protein condensation.…”

Section: Introductionmentioning

confidence: 99%

Different Intermolecular Interactions Drive Nonpathogenic Liquid-Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43

Zeng¹,

Bi²,

Zhuo³

et al. 2022

Preprint

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Liquid-liquid phase separation (LLPS) of proteins has been found ubiquitously in eukaryotic cells, critical in the controlling of many biological processes through forming a temporary condensed phase with different bimolecular components. TDP-43 is recruited to stress granules in cells and is the main component of TDP-43 granules and proteinaceous amyloid inclusions in patients with amyotrophic lateral sclerosis (ALS). TDP-43 low complexity domain (LCD) is able to demix in solution forming the protein condensed droplets. The molecular interactions regulating its LLPS were investigated at the protein fusion equilibrium stage, where the droplets stopped growing. We found the molecules in the droplet were still liquid-like but with enhanced intermolecular helix-helix interaction in the LCD. The protein would start to aggregate after about 200 minutes of lag time and aggregate slower than at the condition when the protein does not phase separate or the molecules have a reduced intermolecular helical interaction. A structural transition intermediate towards protein aggregation was also discovered involving a decrease of the intermolecular helix-helix interaction and a reduction in the helicity. Therefore, LLPS and the intermolecular helical interaction could help maintain the stability of TDP-43 LCD.

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Liquid–liquid phase separation as an organizing principle of intracellular space: overview of the evolution of the cell compartmentalization concept

Cited by 70 publications

References 321 publications

The Role of Ubiquitin in Regulating Stress Granule Dynamics

The Role of Ubiquitin in Regulating Stress Granule Dynamics

BIAPSS: A Comprehensive Physicochemical Analyzer of Proteins Undergoing Liquid–Liquid Phase Separation

Different Intermolecular Interactions Drive Nonpathogenic Liquid-Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43

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