ArticleProceedings of the National Academy of Sciences of the United States of America2018
Structural characterization of the D290V mutation site in hnRNPA2 low-complexity-domain polymers.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35 citing papers in PubMed, 62 citations in OpenAlex.
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- A simple method for mapping the location of cross-β-forming regions within protein domains of low sequence complexity.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Conformations of a low-complexity protein in homogeneous and phase-separated frozen solutions.Biophysical journal · 2024Article
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- Conformations of a Low-Complexity Protein in Homogeneous and Phase-Separated Frozen Solutions.bioRxiv : the preprint server for biology · 2024Article
- Protein domains of low sequence complexity-dark matter of the proteome.Genes & development · 2024Article
- Oxidative regulation of TDP-43 self-association by a β-to-α conformational switch.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Single-molecule techniques to visualize and to characterize liquid-liquid phase separation and phase transition.Acta biochimica et biophysica Sinica · 2023Article
- Liquid Droplet Aging and Seeded Fibril Formation of the Cytotoxic Granule Associated RNA Binding Protein TIA1 Low Complexity Domain.Journal of the American Chemical Society · 2023Article
- Protein interactions: anything new?Essays in biochemistry · 2022Article
- Emerging Implications of Phase Separation in Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Review
- Protein condensation diseases: therapeutic opportunities.Nature communications · 2022Review
- ALS mutations in the TIA-1 prion-like domain trigger highly condensed pathogenic structures.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Mutations linked to neurological disease enhance self-association of low-complexity protein sequences.Science (New York, N.Y.) · 2022Article
- Identifying amyloid-related diseases by mapping mutations in low-complexity protein domains to pathologies.Nature structural & molecular biology · 2022Article
- Bioinformatic identification of previously unrecognized amyloidogenic proteins.The Journal of biological chemistry · 2022Article
- How do protein domains of low sequence complexity work?RNA (New York, N.Y.) · 2022Review
- The low-complexity domain of the FUS RNA binding protein self-assembles via the mutually exclusive use of two distinct cross-β cores.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
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6 authors at 2 institutions in 1 country.
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Abstract
Human genetic studies have given evidence of familial, disease-causing mutations in the analogous amino acid residue shared by three related RNA binding proteins causative of three neurological diseases. Alteration of aspartic acid residue 290 of hnRNPA2 to valine is believed to predispose patients to multisystem proteinopathy. Mutation of aspartic acid 262 of hnRNPA1 to either valine or asparagine has been linked to either amyotrophic lateral sclerosis or multisystem proteinopathy. Mutation of aspartic acid 378 of hnRNPDL to either asparagine or histidine has been associated with limb girdle muscular dystrophy. All three of these aspartic acid residues map to evolutionarily conserved regions of low-complexity (LC) sequence that may function in states of either intrinsic disorder or labile self-association. Here, we present a combination of solid-state NMR spectroscopy with segmental isotope labeling and electron microscopy on the LC domain of the hnRNPA2 protein. We show that, for both the wild-type protein and the aspartic acid 290-to-valine mutant, labile polymers are formed in which the LC domain associates into an in-register cross-β conformation. Aspartic acid 290 is shown to be charged at physiological pH and immobilized within the polymer core. Polymers of the aspartic acid 290-to-valine mutant are thermodynamically more stable than wild-type polymers. These observations give evidence that removal of destabilizing electrostatic interactions may be responsible for the increased propensity of the mutated LC domains to self-associate in disease-causing conformations.
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