ArticleScientific reports2021
Tethering-induced destabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1.
Article in Scientific reports, 2021. 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, 25 citations in OpenAlex.
- Regulation of RNA-binding proteins by small biomolecules.Nature reviews. Molecular cell biology · 2026Review
- TDP-43 in neurodegeneration and cancer: Decoding the mechanism of mRNA localization and translation.Biochemistry and biophysics reports · 2026Review
- ATP Can Act as a Stabilizer on Neutral Macromolecules.The journal of physical chemistry letters · 2025Article
- Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation.Scientific reports · 2025Article
- Stress granules: emerging players in neurodegenerative diseases.Translational neurodegeneration · 2025Review
- Regulation of gene expression through protein-metabolite interactions.npj metabolic health and disease · 2025Review
- Liquid-Liquid Phase Separation Associated with Intrinsically Disordered Proteins: Experimental and Computational Tools.Current protein & peptide science · 2025Review
- Molecular Mechanisms of Phase Separation and Amyloidosis of ALS/FTD-linked FUS and TDP-43.Aging and disease · 2024Review
- Mechanistic insights into lanthipeptide modification by a distinct subclass of LanKC enzyme that forms dimers.Nature communications · 2024Article
- Adenosine Triphosphate: The Primordial Molecule That Controls Protein Homeostasis and Shapes the Genome-Proteome Interface.Biomolecules · 2024Review
- Adenosine Triphosphate (ATP) and Protein Aggregation in Age-Related Vision-Threatening Ocular Diseases.Metabolites · 2023Article
- ATP and nucleic acids competitively modulate LLPS of the SARS-CoV2 nucleocapsid protein.Communications biology · 2023Article
- Nonspecific Binding of Adenosine Tripolyphosphate and Tripolyphosphate Modulates the Phase Behavior of Lysozyme.Journal of the American Chemical Society · 2023Article
- Sequence- and structure-specific RNA oligonucleotide binding attenuates heterogeneous nuclear ribonucleoprotein A1 dysfunction.Frontiers in molecular biosciences · 2023Article
- Arg/Lys-containing IDRs are cryptic binding domains for ATP and nucleic acids that interplay to modulate LLPS.Communications biology · 2022Article
- A review of the effects of ATP and hydroxychloroquine on the phase separation of the SARS-CoV-2 nucleocapsid protein.Biophysical reviews · 2022Review
- Adenosine triphosphate energy-independently controls protein homeostasis with unique structure and diverse mechanisms.Protein science : a publication of the Protein Society · 2021Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
TDP-43 and hnRNPA1 contain tandemly-tethered RNA-recognition-motif (RRM) domains, which not only functionally bind an array of nucleic acids, but also participate in aggregation/fibrillation, a pathological hallmark of various human diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), alzheimer's disease (AD) and Multisystem proteinopathy (MSP). Here, by DSF, NMR and MD simulations we systematically characterized stability, ATP-binding and conformational dynamics of TDP-43 and hnRNPA1 RRM domains in both tethered and isolated forms. The results reveal three key findings: (1) upon tethering TDP-43 RRM domains become dramatically coupled and destabilized with Tm reduced to only 49 °C. (2) ATP specifically binds TDP-43 and hnRNPA1 RRM domains, in which ATP occupies the similar pockets within the conserved nucleic-acid-binding surfaces, with the affinity slightly higher to the tethered than isolated forms. (3) MD simulations indicate that the tethered RRM domains of TDP-43 and hnRNPA1 have higher conformational dynamics than the isolated forms. Two RRM domains become coupled as shown by NMR characterization and analysis of inter-domain correlation motions. The study explains the long-standing puzzle that the tethered TDP-43 RRM1-RRM2 is particularly prone to aggregation/fibrillation, and underscores the general role of ATP in inhibiting aggregation/fibrillation of RRM-containing proteins. The results also rationalize the observation that the risk of aggregation-causing diseases increases with aging.
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