ArticlePLoS biology2019
A unified mechanism for LLPS of ALS/FTLD-causing FUS as well as its modulation by ATP and oligonucleic acids.
Article in PLoS biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 143 citations in OpenAlex.
- Valosin-containing protein counteracts ATP-driven dissolution of FUS condensates through its ATPase activity in vitro.FEBS letters · 2026Article
- Phase separation in neurodegenerative disorders: a metabolic perspective on protein aggregation and therapeutic targeting.Translational neurodegeneration · 2026Review
- Adenosine triphosphate as a modulator of protein interactions and stability.FEBS open bio · 2026Review
- Protein arginine methyltransferases as regulators of phase separation: implications in cancer and neurodegenerative diseases.European biophysics journal : EBJ · 2026Review
- RNA G-quadruplexes function as a tunable switch of FUS phase separation.Nucleic acids research · 2026Article
- Short autoinhibitory sequences control phase separation of an essential bacterial transcription termination factor.The EMBO journal · 2026Article
- Amyloid-β, Tau Protein, α-Synuclein, TDP-43, and FUS in Mixed Pathology: And Intrinsic Disorder to Rule Them All.International journal of molecular sciences · 2026Review
- Assessing the performance of multimodal large language models in experimental information extraction from liquid-liquid phase separation literature.Scientific reports · 2026Article
- Understanding liquid-liquid phase separation through TDP-43: fundamental principles, subcellular compartmentalisation, and role of solid inclusion formation.Genome biology · 2026Review
- N-terminal modifications as fate switches in neurodegeneration: a mechanistic review.Frontiers in aging neuroscience · 2026Review
- ATP and small amphiphilic molecules act as molecular matchmakers to fine-tune FET protein clusters.Communications chemistry · 2025Article
- RNA G-Quadruplexes Function as a Tunable Switch of FUS Phase Separation.bioRxiv : the preprint server for biology · 2025Article
- ATP Can Act as a Stabilizer on Neutral Macromolecules.The journal of physical chemistry letters · 2025Article
- Elucidation of the Molecular Interaction Network Underlying Full-Length FUS Conformational Transitions and Its Phase Separation Using Atomistic Simulations.The journal of physical chemistry. B · 2025Article
- Biomolecular Condensates as Emerging Biomaterials: Functional Mechanisms and Advances in Computational and Experimental Approaches.Advanced materials (Deerfield Beach, Fla.) · 2025Review
- Biomolecular phase separation in tumorigenesis: from aberrant condensates to therapeutic vulnerabilities.Molecular cancer · 2025Review
- Aberrant phase separation of two PKA RIβ neurological disorder mutants leads to mechanistically distinct signaling deficits.Cell reports · 2025Article
- Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.Science advances · 2025Article
- Selective phase separation of transcription factors is driven by orthogonal molecular grammar.Nature communications · 2025Article
- Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
526-residue Fused in sarcoma (FUS) undergoes liquid-liquid phase separation (LLPS) for its functions, which can further transit into pathological aggregation. ATP and nucleic acids, the universal cellular actors, were shown to modulate LLPS of FUS in a unique manner: enhancement and then dissolution. Currently, the driving force for LLPS of FUS is still under debate, while the mechanism for the modulation remains completely undefined. Here, by NMR and differential interference contrast (DIC) imaging, we characterized conformations, dynamics, and LLPS of FUS and its domains and subsequently their molecular interactions with oligonucleic acids, including one RNA and two single-stranded DNA (ssDNA) molecules, as well as ATP, Adenosine monophosphate (AMP), and adenosine. The results reveal 1) both a prion-like domain (PLD) rich in Tyr but absent of Arg/Lys and a C-terminal domain (CTD) abundant in Arg/Lys fail to phase separate. By contrast, the entire N-terminal domain (NTD) containing the PLD and an Arg-Gly (RG)-rich region efficiently phase separate, indicating that the π-cation interaction is the major driving force; 2) despite manifesting distinctive NMR observations, ATP has been characterized to modulate LLPS by specific binding as oligonucleic acids but with much lower affinity. Our results together establish a unified mechanism in which the π-cation interaction acts as the major driving force for LLPS of FUS and also serves as the target for modulation by ATP and oligonucleic acids through specific binding. This mechanism predicts that a myriad of proteins unrelated to RNA-binding proteins (RBPs) but with Arg/Lys-rich disordered regions could be modulated by ATP and nucleic acids, thus rationalizing the pathological association of Amyotrophic lateral sclerosis (ALS)-causing C9ORF72 dipeptides with any nucleic acids to manifest cytotoxicity.
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