Redox-mediated regulation of an evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain
| العنوان: | Redox-mediated regulation of an evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain |
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| المؤلفون: | Sina Ghaemmaghami, Benjamin P. Tu, Masato Kato, Yi Lin, Xiaoming Zhou, Daifei Liu, Steven L. McKnight |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | National Academy of Sciences, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | TDP-43, medicine.disease_cause, Biochemistry, Polymerization, chemistry.chemical_compound, low-complexity sequence, Protein Domains, medicine, Humans, Amino Acid Sequence, Conserved Sequence, Ataxin-2, chemistry.chemical_classification, Mutation, Multidisciplinary, Methionine, Translation (biology), cross-beta polymers, Biological Sciences, Footprinting, redox sensor, DNA-Binding Proteins, Enzyme, HEK293 Cells, chemistry, neurodegenerative disorders, Self-healing hydrogels, Biophysics, Methionine sulfoxide reductase, Reactive Oxygen Species |
| الوصف: | Significance The TDP43 RNA binding protein is frequently aggregated in the brain tissue of patients suffering from neurodegenerative diseases. Human genetic studies of patients suffering from ALS have identified scores of missense mutations clustered within a localized region of the TDP43 protein. This region is of low sequence complexity and has been thought to exist in a state of structural disorder under conditions of proper TDP43 function. The present study gives evidence that the low complexity domain of TDP43 self-associates into a specific structural conformation that may be important to its normal biological function. Unlike prototypic low complexity domains, that of TDP43 is methionine-rich. Evidence is presented suggestive of the utility of these methionine residues in oxidation-mediated regulation of TDP43 function. A methionine-rich low complexity (LC) domain is found within a C-terminal region of the TDP43 RNA-binding protein. Self-association of this domain leads to the formation of labile cross-β polymers and liquid-like droplets. Treatment with H2O2 caused phenomena of methionine oxidation and droplet melting that were reversed upon exposure of the oxidized protein to methionine sulfoxide reductase enzymes. Morphological features of the cross-β polymers were revealed by H2O2-mediated footprinting. Equivalent TDP43 LC domain footprints were observed in polymerized hydrogels, liquid-like droplets, and living cells. The ability of H2O2 to impede cross-β polymerization was abrogated by the prominent M337V amyotrophic lateral sclerosis-causing mutation. These observations may offer insight into the biological role of TDP43 in facilitating synapse-localized translation as well as aberrant aggregation of the protein in neurodegenerative diseases. |
| اللغة: | English |
| تدمد: | 1091-6490 0027-8424 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e0d5c3965b20fd36931728f1b3335106Test http://europepmc.org/articles/PMC7682574Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e0d5c3965b20fd36931728f1b3335106 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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