scholarly journals FG-nucleoporins caught in the act of liquid–liquid phase separation

2019 ◽  
Vol 219 (1) ◽  
Author(s):  
Dorothee Dormann
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Barrier Properties ◽  
Liquid Phase Separation ◽  
Nuclear Pore ◽  
Permeability Barrier ◽  
Nuclear Pore Complexes ◽  
Liquid Droplets ◽  
Pore Complexes ◽  
Liquid Liquid Phase Separation

The interior of nuclear pore complexes (NPCs) is densely filled with FG-nucleoporins that form a permeability barrier of a still-obscure nature. Celetti et al. (2019. J. Cell Biol.https://doi.org/10.1083/jcb.201907157) now reveal that FG-nucleoporins can undergo liquid–liquid phase separation and form liquid droplets that mimic permeability barrier properties of intact NPCs.

scholarly journals Perturbation of liquid droplets of P-granule protein LAF-1 by the antimicrobial peptide LL-III

2020 ◽  
Vol 56 (78) ◽  
pp. 11577-11580
Author(s):  
Rosario Oliva ◽  
Sanjib K. Mukherjee ◽  
Zamira Fetahaj ◽  
Simone Möbitz ◽  
Roland Winter
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Antimicrobial Peptides ◽  
Antimicrobial Peptide ◽  
Droplet Formation ◽  
Liquid Phase Separation ◽  
Liquid Droplets ◽  
Cellular Organization ◽  
P Protein ◽  
Liquid Liquid Phase Separation

Protein/RNA droplet formation by liquid–liquid phase separation has emerged as a key mechanism for cellular organization. We show that binding of antimicrobial peptides such as LL-III can lead to loss of droplet function.

scholarly journals Dynamic Formation of Liquid Droplets Triggered by Sequential Enzymatic Reactions

2020 ◽  
Author(s):  
Tomoto Ura ◽  
Shunsuke Tomita ◽  
Kentaro Shiraki
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Enzyme Reaction ◽  
Model System ◽  
Liquid Phase Separation ◽  
Enzymatic Reactions ◽  
Liquid Droplets ◽  
Dynamic Formation ◽  
Liquid Liquid Phase Separation

<p>A model system was developed that dynamically generates two different liquid droplets via liquid–liquid phase separation coupled with a sequential glycolytic reaction. The sequential two-enzyme reaction triggers the formation/dissolution of the liquid droplets. The droplets, in turn, compartmentalize each enzymatic step and generate feedback to accelerate the overall reaction.</p>

Dynamic behavior of liquid droplets with enzyme compartmentalization triggered by sequential glycolytic enzyme reactions

2021 ◽  
Author(s):  
Tomoto Ura ◽  
Shunsuke Tomita ◽  
Kentaro Shiraki
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Dynamic Behavior ◽  
Droplet Formation ◽  
Glycolytic Enzyme ◽  
Liquid Phase Separation ◽  
Biological Processes ◽  
Liquid Droplets ◽  
Enzyme Reactions ◽  
Liquid Liquid Phase Separation

Dynamic droplet formation via liquid-liquid phase separation (LLPS) is believed to be involved in the regulation of various biological processes. Here, a model LLPS system coupled with a sequential glycolytic...

A Short Peptide Synthon for Liquid-Liquid Phase Separation

2020 ◽  
Author(s):  
Manzar Abbas ◽  
Wojciech P. Lipiński ◽  
Karina K. Nakashima ◽  
Wilhelm T.S. Huck ◽  
Evan Spruijt
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Living Cells ◽  
Liquid Phase Separation ◽  
Disordered Proteins ◽  
Liquid Droplets ◽  
Short Peptide ◽  
Peptide Analogues ◽  
Single Peptide ◽  
Liquid Liquid Phase Separation

Liquid-liquid phase separation of disordered proteins has emerged as a ubiquitous route to membraneless compartments in living cells, and similar coacervates may have played a role when the first cells formed. However, existing coacervates are typically made of multiple macromolecular components, and designing short peptide analogues capable of self-coacervation has proven difficult. Here, we present a short peptide synthon for phase separation, made of only two dipeptide stickers linked via a flexible, hydrophilic spacer. These small-molecule compounds self-coacervate into micrometre-sized liquid droplets at sub-mM concentrations, which retain up to 75 weight-% water. The design is general and we derive guidelines for the required sticker hydrophobicity and spacer polarity. To illustrate their potential as protocells, we create a disulphide-linked derivative that undergoes reversible compartmentalisation controlled by redox chemistry. The resulting coacervates sequester and melt nucleic acids, and act as microreactors that catalyse two different anabolic reactions yielding molecules of increasing complexity. This provides a stepping stone for new protocells made of single peptide species.<br>

A Short Peptide Synthon for Liquid-Liquid Phase Separation

2020 ◽  
Author(s):  
Manzar Abbas ◽  
Wojciech P. Lipiński ◽  
Karina K. Nakashima ◽  
Wilhelm T.S. Huck ◽  
Evan Spruijt
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Living Cells ◽  
Liquid Phase Separation ◽  
Disordered Proteins ◽  
Liquid Droplets ◽  
Short Peptide ◽  
Peptide Analogues ◽  
Single Peptide ◽  
Liquid Liquid Phase Separation

Liquid-liquid phase separation of disordered proteins has emerged as a ubiquitous route to membraneless compartments in living cells, and similar coacervates may have played a role when the first cells formed. However, existing coacervates are typically made of multiple macromolecular components, and designing short peptide analogues capable of self-coacervation has proven difficult. Here, we present a short peptide synthon for phase separation, made of only two dipeptide stickers linked via a flexible, hydrophilic spacer. These small-molecule compounds self-coacervate into micrometre-sized liquid droplets at sub-mM concentrations, which retain up to 75 weight-% water. The design is general and we derive guidelines for the required sticker hydrophobicity and spacer polarity. To illustrate their potential as protocells, we create a disulphide-linked derivative that undergoes reversible compartmentalisation controlled by redox chemistry. The resulting coacervates sequester and melt nucleic acids, and act as microreactors that catalyse two different anabolic reactions yielding molecules of increasing complexity. This provides a stepping stone for new protocells made of single peptide species.<br>

scholarly journals Small molecules as potent biphasic modulators of protein liquid-liquid phase separation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
W. Michael Babinchak ◽  
Benjamin K. Dumm ◽  
Sarah Venus ◽  
Solomiia Boyko ◽  
Andrea A. Putnam ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Small Molecules ◽  
Rational Design ◽  
De Novo ◽  
Liquid Phase Separation ◽  
Disulfonic Acid ◽  
Liquid Droplets ◽  
Small Molecule Modulators ◽  
Liquid Liquid Phase Separation

Abstract Liquid-liquid phase separation (LLPS) of proteins that leads to formation of membrane-less organelles is critical to many biochemical processes in the cell. However, dysregulated LLPS can also facilitate aberrant phase transitions and lead to protein aggregation and disease. Accordingly, there is great interest in identifying small molecules that modulate LLPS. Here, we demonstrate that 4,4’-dianilino-1,1’-binaphthyl-5,5’-disulfonic acid (bis-ANS) and similar compounds are potent biphasic modulators of protein LLPS. Depending on context, bis-ANS can both induce LLPS de novo as well as prevent formation of homotypic liquid droplets. Our study also reveals the mechanisms by which bis-ANS and related compounds modulate LLPS and identify key chemical features of small molecules required for this activity. These findings may provide a foundation for the rational design of small molecule modulators of LLPS with therapeutic value.

scholarly journals Regulatory mechanisms of tau protein fibrillation under the conditions of liquid–liquid phase separation

2020 ◽  
Vol 117 (50) ◽  
pp. 31882-31890
Author(s):  
Solomiia Boyko ◽  
Krystyna Surewicz ◽  
Witold K. Surewicz
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Tau Protein ◽  
Phenotypic Variability ◽  
Total Concentration ◽  
Liquid Phase Separation ◽  
Liquid Droplets ◽  
Tau Isoforms ◽  
Protein Fibrillation ◽  
Liquid Liquid Phase Separation

One of the hallmarks of Alzheimer’s disease and several other neurodegenerative disorders is the aggregation of tau protein into fibrillar structures. Building on recent reports that tau readily undergoes liquid–liquid phase separation (LLPS), here we explored the relationship between disease-related mutations, LLPS, and tau fibrillation. Our data demonstrate that, in contrast to previous suggestions, pathogenic mutations within the pseudorepeat region do not affect tau441’s propensity to form liquid droplets. LLPS does, however, greatly accelerate formation of fibrillar aggregates, and this effect is especially dramatic for tau441 variants with disease-related mutations. Most important, this study also reveals a previously unrecognized mechanism by which LLPS can regulate the rate of fibrillation in mixtures containing tau isoforms with different aggregation propensities. This regulation results from unique properties of proteins under LLPS conditions, where total concentration of all tau variants in the condensed phase is constant. Therefore, the presence of increasing proportions of the slowly aggregating tau isoform gradually lowers the concentration of the isoform with high aggregation propensity, reducing the rate of its fibrillation. This regulatory mechanism may be of direct relevance to phenotypic variability of tauopathies, as the ratios of fast and slowly aggregating tau isoforms in brain varies substantially in different diseases.

scholarly journals Tau conformers in FTLD-MAPT undergo liquid-liquid phase separation and perturb the nuclear envelope

2020 ◽  
Author(s):  
Sang-Gyun Kang ◽  
Zhuang Zhuang Han ◽  
Nathalie Daude ◽  
Emily McNamara ◽  
Serene Wohlgemuth ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Nuclear Envelope ◽  
Solid Phase ◽  
Critical Mass ◽  
Liquid Phase Separation ◽  
Liquid Droplets ◽  
Cytoplasmic Transport ◽  
End Stage ◽  
Liquid Liquid Phase Separation

AbstractRecent studies show that a single MAPT gene mutation can promote alternative tau misfolding pathways engendering divergent forms of frontotemporal dementia and that under conditions of molecular crowding, the repertoire of tau forms can include liquid-liquid phase separation (LLPS). We show here that following pathogenic seeding, tau condenses on the nuclear envelope (NE) and disrupts nuclear-cytoplasmic transport (NCT). Interestingly, NE fluorescent tau signals and small fluorescent inclusions behaved as demixed liquid droplets in living cells. Thioflavin S-positive intracellular aggregates were prevalent in tau-derived inclusions with a size bigger than 3 μm2, indicating that a threshold of critical mass in the liquid state condensation may drive liquid-solid phase transitions. Our findings indicate that tau undergoing LLPS is more toxic amongst a spectrum of alternative conformers; LLPS droplets on the NE that disrupt NCT serve to trigger cell death and can act as nurseries for fibrillar structures abundantly detected in end-stage disease.

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