ArticleProceedings of the National Academy of Sciences of the United States of America2021
An intrinsically disordered pathological prion variant Y145Stop converts into self-seeding amyloids via liquid-liquid phase separation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29 citing papers in PubMed, 83 citations in OpenAlex.
- Engineering short-sequence elements for condensate-like assemblies by de novo design.Synthetic and systems biotechnology · 2027Article
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- [Mechanisms of RNA-binding protein phase separation in steroid-associated necrosis of the femoral head].Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2026Review
- RNA-seq analyses reveal the relevance of RNAs involved in ribosomal complex to induce mammalian prion protein aggregation and phase separationRNA biology · 2025Article
- Coacervates Composed of Low-Molecular-Weight Compounds- Molecular Design, Stimuli Responsiveness, Confined Reaction.Advanced biology · 2025Review
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- Topological confinement by a membrane anchor suppresses phase separation into protein aggregates: Implications for prion diseases.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- RNA-dependent RNA polymerase of predominant human norovirus forms liquid-liquid phase condensates as viral replication factories.Science advances · 2024Article
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- Intermolecular energy migration via homoFRET captures the modulation in the material property of phase-separated biomolecular condensates.Nature communications · 2024Article
- RNA-dependent RNA polymerase of predominant human norovirus forms liquid-liquid phase condensates as viral replication factories.bioRxiv : the preprint server for biology · 2024Article
- Fundamental Aspects of Phase-Separated Biomolecular Condensates.Chemical reviews · 2024Review
- Raman spectroscopy in the study of amyloid formation and phase separation.Biochemical Society transactions · 2024Review
- Active learning of the thermodynamics-dynamics trade-off in protein condensates.Science advances · 2024Article
- Excess PrPNature communications · 2023Article
- Single-molecule FRET unmasks structural subpopulations and crucial molecular events during FUS low-complexity domain phase separation.Nature communications · 2023Article
- Copper drives prion protein phase separation and modulates aggregation.Science advances · 2023Article
- Biomolecular condensates modulate membrane lipid packing and hydration.Nature communications · 2023Article
- Biomolecular condensates: Formation mechanisms, biological functions, and therapeutic targets.MedComm · 2023Review
- Heterotypic electrostatic interactions control complex phase separation of tau and prion into multiphasic condensates and co-aggregates.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
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4 authors at 1 institution in 1 country.
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Abstract
Biomolecular condensation via liquid-liquid phase separation of intrinsically disordered proteins/regions (IDPs/IDRs) along with other biomolecules is proposed to control critical cellular functions, whereas aberrant phase transitions are associated with a range of neurodegenerative diseases. Here, we show that a disease-associated stop codon mutation of the prion protein (PrP) at tyrosine 145 (Y145Stop), resulting in a truncated, highly disordered, N-terminal IDR, spontaneously phase-separates into dynamic liquid-like droplets. Phase separation of this highly positively charged N-terminal segment is promoted by the electrostatic screening and a multitude of weak, transient, multivalent, intermolecular interactions. Single-droplet Raman measurements, in conjunction with an array of bioinformatic, spectroscopic, microscopic, and mutagenesis studies, revealed a highly mobile internal organization within the liquid-like condensates. The phase behavior of Y145Stop is modulated by RNA. Lower RNA:protein ratios promote condensation at a low micromolar protein concentration under physiological conditions. At higher concentrations of RNA, phase separation is abolished. Upon aging, these highly dynamic liquid-like droplets gradually transform into ordered, β-rich, amyloid-like aggregates. These aggregates formed via phase transitions display an autocatalytic self-templating characteristic involving the recruitment and binding-induced conformational conversion of monomeric Y145Stop into amyloid fibrils. In contrast to this intrinsically disordered truncated variant, the wild-type full-length PrP exhibits a much lower propensity for both condensation and maturation into amyloids, hinting at a possible protective role of the C-terminal domain. Such an interplay of molecular factors in modulating the protein phase behavior might have much broader implications in cell physiology and disease.
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