Redox-mediated regulation of an evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33144500.
- Also identified by DOI 10.1073/pnas.2012216117 and PMC identifier 7682574.
- Licence recorded as CC BY-NC-ND.
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Abstract
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 H<sub>2</sub>O<sub>2</sub> 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 H<sub>2</sub>O<sub>2</sub>-mediated footprinting. Equivalent TDP43 LC domain footprints were observed in polymerized hydrogels, liquid-like droplets, and living cells. The ability of H<sub>2</sub>O<sub>2</sub> 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.
Medical subject headings
- Ataxin-2
- DNA-Binding Proteins