ArticleNature communications2025
Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed.
- Protease-Mediated TAR DNA-Binding Protein 43 (TDP-43) Pathogenesis: From Molecular Mechanisms to Therapeutic Opportunities.ACS pharmacology & translational science · 2026Review
- Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice.Nature aging · 2026Article
- Site-Specific Raman Probes Reveal Droplet Aging and Residue-Level Fibril Polymorphism in TDP-43Journal of the American Chemical Society · 2026Article
- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration.Science (New York, N.Y.) · 2026Article
- An ALS-associated mutation in the C-terminal α-helix of TDP-43 uncouples condensate formation and amyloid assembly.Protein science : a publication of the Protein Society · 2026Article
- Stability and Dynamics of the N‑Terminal Domain of TDP-43 and the Effect of Point Mutations.ACS omega · 2026Article
- Breaking β-sheets in FUS prion-like domain preserves phase separation and function but prevents aggregation and toxicity.bioRxiv : the preprint server for biology · 2026Article
- Understanding liquid-liquid phase separation through TDP-43: fundamental principles, subcellular compartmentalisation, and role of solid inclusion formation.Genome biology · 2026Review
- Beyond structures: solution NMR as the quantitative engine of integrated structural biology.Frontiers in molecular biosciences · 2026Review
- Site-specific methionine oxidation alters structure and phase separation of TDP-43 C-terminal domain.bioRxiv : the preprint server for biology · 2025Article
- Solid trouble: tau and TDP-43 interaction in aggregation and pathology.The EMBO journal · 2025Article
- Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain.Nature communications · 2025Article
- Repulsive vs Attractive Crowding Distinctly Regulate TDP-43 Condensates through Region-specific Structural Dynamics.JACS Au · 2025Article
- Amino acid transfer free energies reveal thermodynamic driving forces in biomolecular condensate formation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Multiscale simulations elucidate the mechanism of polyglutamine aggregation and the role of flanking domains in fibril polymorphism.bioRxiv : the preprint server for biology · 2025Article
- Hydrogen-Deuterium Exchange Mass Spectrometry Reveals Mechanistic Insights into RNA Oligonucleotide-Mediated Inhibition of TDP-43 Aggregation.Journal of the American Chemical Society · 2024Article
- Amino Acid Transfer Free Energies Reveal Thermodynamic Driving Forces in Biomolecular Condensate Formation.bioRxiv : the preprint server for biology · 2024Article
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16 authors.
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Abstract
Pathological inclusions of the C-terminal domain (CTD) of TAR DNA binding protein-43 (TDP-43) are neurodegenerative hallmarks in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, yet CTD's aggregation propensity complicates structural characterization of native TDP-43. Here we propose structural models for the physiological multimerization of TDP-43 CTD's conserved region (CR) essential for TDP-43 RNA processing. Using NMR spectroscopy, we establish that the native state of TDP-43 CR at physiological conditions is α-helical. Hydrophobic residues drive CR helix-helix assembly, phase separation, and TDP-43 nuclear retention, while polar residues down regulate these processes. An integrative approach combining analytical ultracentrifugation, NMR-derived contacts, AlphaFold2-Multimer modeling, and all-atom molecular dynamics simulations together suggest that TDP-43 CR forms dynamic, multimeric helical assemblies stabilized by a methionine-rich core with specific contributions from a tryptophan/leucine pair. These structures show how ALS-associated mutations disrupt TDP-43 function and provide pharmacologically targetable structures to prevent its conversion into pathogenic β-sheet aggregates.
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