ArticleBiophysical journal2022
Modulation of assembly of TDP-43 low-complexity domain by heparin: From droplets to amyloid fibrils.
Article in Biophysical journal, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 30 citations in OpenAlex.
- Protease-Mediated TAR DNA-Binding Protein 43 (TDP-43) Pathogenesis: From Molecular Mechanisms to Therapeutic Opportunities.ACS pharmacology & translational science · 2026Review
- TDP-43 Aggregation: The Healthy-Toxic Balance of the Prion-Like Domain.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- OptoChaperone─A Biohybrid Tool for Regulating Protein Condensates in Cells and In Vitro.Journal of the American Chemical Society · 2026Article
- Direct observation and quantification of single nanocondensates of the low complexity domain of TDP-43.Nature communications · 2026Article
- Understanding liquid-liquid phase separation through TDP-43: fundamental principles, subcellular compartmentalisation, and role of solid inclusion formation.Genome biology · 2026Review
- In-Depth Study of Low-Complexity Domains: From Structural Diversity to Disease Mechanisms.Cells · 2025Review
- Targeting protein disorder: the next hurdle in drug discovery.Nature reviews. Drug discovery · 2025Review
- Functional Biomaterials Derived from Protein Liquid-Liquid Phase Separation and Liquid-to-Solid Transition.Advanced materials (Deerfield Beach, Fla.) · 2025Review
- Probing the Formation and Liquid-to-Solid Transition of FUS Condensates via the Lifetimes of Fluorescent Proteins.The journal of physical chemistry letters · 2025Article
- The Regulation of TDP-43 Structure and Phase Transitions: A Review.The protein journal · 2025Review
- Time-course remodeling and pathology intervention of α-synuclein amyloid fibril by heparin and heparin-like oligosaccharides.Nature structural & molecular biology · 2025Article
- Proteins clump: Mechanics and transport during neurodegeneration.Biophysical journal · 2024Article
- Biophysical characterization of the phase separation of TDP-43 devoid of the C-terminal domain.Cellular & molecular biology letters · 2024Article
- Protective roles of highly conserved motif 1 in tardigrade cytosolic-abundant heat soluble protein in extreme environments.Protein science : a publication of the Protein Society · 2024Article
- Biophysics of biomolecular condensates.Biophysical journal · 2023Article
- Single-molecule techniques to visualize and to characterize liquid-liquid phase separation and phase transition.Acta biochimica et biophysica Sinica · 2023Article
- Liquid-Liquid Phase Separation Promotes Protein Aggregation and Its Implications in Ferroptosis in Parkinson's Disease Dementia.Oxidative medicine and cellular longevity · 2022Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
TAR DNA-binding protein 43 (TDP-43) is an RNA-regulating protein that carries out many cellular functions through liquid-liquid phase separation (LLPS). The LLPS of TDP-43 is mediated by its C-terminal low-complexity domain (TDP43-LCD) corresponding to the region 267-414. In neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia, pathological inclusions of the TDP-43 are found that are rich in the C-terminal fragments of ∼25 and ∼35 kDa, of which TDP43-LCD is a part. Thus, understanding the assembly process of TDP43-LCD is essential, given its involvement in the formation of both functional liquid-like assemblies and solid- or gel-like pathological aggregates. Here, we show that the solution pH and salt modulate TDP43-LCD LLPS. A gradual reduction in the pH below its isoelectric point of 9.8 results in a monotonic decrease of TDP43-LCD LLPS due to charge-charge repulsion between monomers, while at pH 6 and below no LLPS was observed. The addition of heparin to TDP43-LCD solution at pH 6, at a 1:2 heparin-to-TDP43-LCD molar ratio, promotes TDP43-LCD LLPS, while at higher concentration, it disrupts LLPS through a reentrant phase transition. Upon incubation at pH 6, TDP43-LCD undergoes gelation without phase separation. However, in the reentrant regime in the presence of a high heparin concentration, it forms thick amyloid aggregates that are significantly more SDS resistant than the gel. The results indicate that the material nature of the TDP43-LCD assembly products can be modulated by heparin which is significant in the context of liquid-to-solid phase transition observed in TDP-43 proteinopathies. Our findings are also crucial in relation to similar transitions that could occur due to alteration in the molecular level interactions among various multivalent biomolecules involving other LCDs and RNAs.
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