Modulating liquid–liquid phase separation of FUS: mechanisms and strategies

Ji, Yanglimin; Fen, LI; Qiao, Yan

doi:10.1039/d2tb01688e

Cited by 22 publications

(14 citation statements)

References 117 publications

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“…Both the N-terminal LC domain (FUS-LC) and the C-terminal RGG-rich domain (FUS-RGG) exhibit high capability for LLPS . The FUS-LC has a large number of tyrosine which may direct its LLPS by π–π interaction, while the FUS-RGG is enriched in arginine, which can form cation−π interaction with tyrosine of FUS-LC to drive LLPS of full-length FUS .…”

Section: Resultsmentioning

confidence: 99%

Graphene Quantum Dots Modulate Stress Granule Assembly and Prevent Abnormal Phase Transition of Fused in Sarcoma Protein

Zhou

Zhang

et al. 2023

ACS Nano

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Protein liquid−liquid phase separation (LLPS) plays a crucial role in mediating dynamic assembly of different membraneless organelles such as stress granules (SGs). Dysregulation of dynamic protein LLPS leads to aberrant phase transition and amyloid aggregation which is closely associated with neurodegenerative diseases. In this study, we found that three types of graphene quantum dots (GQDs) exhibit potent activity in preventing SG formation and promoting SG disassembly. We next demonstrate that GQDs can directly interact with the SGs-containing protein fused in sarcoma (FUS), inhibit and reverse FUS LLPS, and prevent its abnormal phase transition. Moreover, GQDs display superior activity in preventing amyloid aggregation of FUS and disaggregating preformed FUS fibrils. Mechanistic study further demonstrates that GQDs with different edge-site exhibit distinct binding affinity to FUS monomers and fibrils, which accounts for their distinct activities in modulating FUS LLPS and fibrillation. Our work reveals the potent capability of GQDs in modulating SG assembly, protein LLPS, and fibrillation and sheds light on rational design of GQDs as effective modulators of protein LLPS for therapeutics application.

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Section: Resultsmentioning

confidence: 99%

Graphene Quantum Dots Modulate Stress Granule Assembly and Prevent Abnormal Phase Transition of Fused in Sarcoma Protein

Zhou

Zhang

et al. 2023

ACS Nano

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“…Based on this, proteins can be grouped into five different regions according to the diagram of states (Supplementary Figure 2 ). The tick-GRP77 sequence falls in the region of weak polyampholytes and polyelectrolytes, similar to many well-characterized phase-separating IDR-containing proteins like FUS 42 and viral nucleocapsid 43 . Cumulatively, our bioinformatic analysis indicated a strong inclination for tick-GRP77 to undergo LLPS.…”

Section: Resultsmentioning

confidence: 91%

Phase Separation and Ageing of Glycine-Rich Protein from Tick Adhesive

Ganar

Turbina

Nandy

et al. 2023

Preprint

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Hard ticks feed on their host for multiple days. To ensure firm attachment, they secrete a protein-rich saliva that eventually forms a solid cement cone. The underlying mechanism of this liquid-to-solid transition is not yet understood. This study focuses on the phase transitions of a disordered glycine-rich protein (GRP) that is prominent in tick saliva. We show that GRP undergoes liquid-liquid phase separation via simple coacervation to form biomolecular condensates in salty environments. Cation-pi and pi-pi interactions near the C-terminus promote coacervation while a negatively charged N-terminus prolongs its onset through electrostatic repulsion. Interestingly, GRP condensates exhibit ageing and undergo liquid-to-gel transition to form viscoelastic networks as well as solid-like condensates. Lastly, we provide evidence for protein-rich condensates in natural tick saliva. Our findings provide a starting point to gain insights into the bioadhesion of ticks, develop novel tick control strategies, and towards biomedical applications such as tissue sealants.

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“…Moreover, there are lots of studies revealed that the presence of IDRs with large and highly hydrophobic residues, plays an important role in LLPS formation and RNA binding processes of some important key RNA granule proteins (e.g., FUS 17,18 and DDX6 19 ). The similarity indicates LLPS proteins and RNA granule proteins could undergo phase separation, a process where a homogeneous solution separates into two distinct phases.…”

Section: Differential Features Of Rna Granule Proteins With the Human...mentioning

confidence: 99%

Unravelling biomolecular and community grammars of RNA granules via machine learning

Ban,

Yan,

Dawson

2024

Preprint

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RNA granules are dynamic compartments within cells that play a crucial role in posttranscriptional regulation of gene expression. They are associated with a variety of human neurodegenerative diseases. While RNA granules play vital roles in cellular functions, the comprehension of their assembly has remained elusive.In this study, we employed robust machine learning models combining residue content and physicochemical features to accurately identify potential RNA granule (i.e.,stress granule and P-body) proteome within the human proteome. Our models achieved good performance with high areas under the receiver operating characteristic curve of up to 0.88, outperforming previous liquid-liquid phase separation models. Intriguingly, the predicted RNA granule proteome reveals a significant enrichment in biological functions and domains associated with RNA granule-related processes, mirroring findings from observed high-confidence RNA granule protein datasets. Furthermore, our analysis unveils critical physicochemical attributes, notably hydrophobicity, influencing the formation of RNA granules.Using the constructed model, we uncovered the central roles of RNA granule proteins with high propensities within the comprehensive RNA granule protein-protein interaction (PPI) network and their commonality in diverse RNA granules. Furthermore, we identified prominent clusters with dense PPIs, significantly contributing to critical biological processes within diverse RNA granules, including translation, mRNA decay, rRNA processing, and mRNA splicing. This analysis proposes a hypothesis: dense PPI clusters are integral functional subunits, constituting relatively stable ‘cores’ within diverse RNA granules.In conclusion, this study provides a comprehensive molecular and community-based foundation for understanding the importance of PPIs in the stability of RNA granule formation and functionality. This analysis contributes to a deeper and more comprehensive understanding of the intricate nature of RNA granules and opens avenues for future research and therapeutic interventions targeting RNA granule- related diseases.

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Modulating liquid–liquid phase separation of FUS: mechanisms and strategies

Abstract: This review summarizes the regulations of liquid–liquid phase separation involving fused in sarcoma protein (FUS) by physical stimuli, biochemical modulators and protein structural modifications.

Cited by 22 publications

References 117 publications

Graphene Quantum Dots Modulate Stress Granule Assembly and Prevent Abnormal Phase Transition of Fused in Sarcoma Protein

Graphene Quantum Dots Modulate Stress Granule Assembly and Prevent Abnormal Phase Transition of Fused in Sarcoma Protein

Phase Separation and Ageing of Glycine-Rich Protein from Tick Adhesive

Unravelling biomolecular and community grammars of RNA granules via machine learning

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