ArticleThe Journal of biological chemistry2014
Folding of the RNA recognition motif (RRM) domains of the amyotrophic lateral sclerosis (ALS)-linked protein TDP-43 reveals an intermediate state.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 51 citations in OpenAlex.
- Prion-like Protein TDP-43: Mechanisms, Diagnosis, and Therapeutic Prospects.Pathogens (Basel, Switzerland) · 2026Review
- Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.BMC medicine · 2026Review
- Investigating the effect of progressive truncations at the ALS-linked protein TDP-43 RRM2 on its aggregation mechanism.Frontiers in molecular biosciences · 2026Article
- Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses.Cells · 2025Review
- Hydrogen-Deuterium Exchange Mass Spectrometry Reveals Mechanistic Insights into RNA Oligonucleotide-Mediated Inhibition of TDP-43 Aggregation.Journal of the American Chemical Society · 2024Article
- A Hydrophobic Core Stabilizes the Residual Structure in the RRM2 Intermediate State of the ALS-linked Protein TDP-43.Journal of molecular biology · 2024Article
- RNA binding tunes the conformational plasticity and intradomain stability of TDP-43 tandem RNA recognition motifs.Biophysical journal · 2024Article
- Review
- Cooperativity boosts affinity and specificity of proteins with multiple RNA-binding domains.NAR genomics and bioinformatics · 2023Article
- Altered TDP-43 Structure and Function: Key Insights into Aberrant RNA, Mitochondrial, and Cellular and Systemic Metabolism in Amyotrophic Lateral Sclerosis.Metabolites · 2022Review
- A Computational Approach to Investigate TDP-43 RNA-Recognition Motif 2 C-Terminal Fragments Aggregation in Amyotrophic Lateral Sclerosis.Biomolecules · 2021Article
- RNA Is a Double-Edged Sword in ALS Pathogenesis.Frontiers in cellular neuroscience · 2021Review
- Zinc Binds to RRM2 Peptide of TDP-43.International journal of molecular sciences · 2020Article
- Insight into the Folding and Dimerization Mechanisms of the N-Terminal Domain from Human TDP-43.International journal of molecular sciences · 2020Article
- Structure of an Unfolding Intermediate of an RRM Domain of ETR-3 Reveals Its Native-like Fold.Biophysical journal · 2020Article
- Characterization of TDP-43 RRM2 Partially Folded States and Their Significance to ALS Pathogenesis.Biophysical journal · 2018Article
- Keys to Amyloid City: Computation and NMR Reveal Potential TDP-43 ALS Intermediates.Biophysical journal · 2018Article
- TDP-43 self-interaction is modulated by redox-active compounds Auranofin, Chelerythrine and Riluzole.Scientific reports · 2018Article
- The RNA-Recognition Motifs of TAR DNA-Binding Protein 43 May Play a Role in the Aberrant Self-Assembly of the Protein.Frontiers in molecular neuroscience · 2018Article
- A method for the unbiased and efficient segmental labelling of RNA-binding proteins for structure and biophysics.Scientific reports · 2017Article
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5 authors at 1 institution in 1 country.
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Abstract
Pathological alteration of TDP-43 (TAR DNA-binding protein-43), a protein involved in various RNA-mediated processes, is a hallmark feature of the neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Fragments of TDP-43, composed of the second RNA recognition motif (RRM2) and the disordered C terminus, have been observed in cytoplasmic inclusions in sporadic amyotrophic lateral sclerosis cases, suggesting that conformational changes involving RRM2 together with the disordered C terminus play a role in aggregation and toxicity. The biophysical data collected by CD and fluorescence spectroscopies reveal a three-state equilibrium unfolding model for RRM2, with a partially folded intermediate state that is not observed in RRM1. Strikingly, a portion of RRM2 beginning at position 208, which mimics a cleavage site observed in patient tissues, increases the population of this intermediate state. Mutually stabilizing interactions between the domains in the tethered RRM1 and RRM2 construct reduce the population of the intermediate state and enhance DNA/RNA binding. Despite the high sequence homology of the two domains, a network of large hydrophobic residues in RRM2 provides a possible explanation for the increased stability of RRM2 compared with RRM1. The cluster analysis suggests that the intermediate state may play a functional role by enhancing access to the nuclear export signal contained within its sequence. The intermediate state may also serve as a molecular hazard linking productive folding and function with pathological misfolding and aggregation that may contribute to disease.
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