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Redox-mediated regulation of an evolutionarily conserved cross-? structure formed by the TDP43 low complexity domain.

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-? 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-? 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-? 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.

SUBMITTER: Lin Y

PROVIDER: S-EPMC7682574 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Redox-mediated regulation of an evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain.

Lin Yi Y Zhou Xiaoming X Kato Masato M Liu Daifei D Ghaemmaghami Sina S Tu Benjamin P BP McKnight Steven L SL

Proceedings of the National Academy of Sciences of the United States of America 20201103 46

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 H2</s ...[more]

PMID: 33144500

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Project description:Despite the sequence homology between acid-sensing ion channels (ASICs) and epithelial sodium channel (ENaCs), these channel families display very different functional characteristics. Whereas ASICs are gated by protons and show a relatively low degree of selectivity for sodium over potassium, ENaCs are constitutively active and display a remarkably high degree of sodium selectivity. To decipher if some of the functional diversity originates from differences within the transmembrane helices (M1 and M2) of both channel families, we turned to a combination of computational and functional interrogations, using statistical coupling analysis and mutational studies on mouse ASIC1a. The coupling analysis suggests that the relative position of M1 and M2 in the upper part of the pore domain is likely to remain constant during the ASIC gating cycle, whereas they may undergo relative movements in the lower part. Interestingly, our data suggest that to account for coupled residue pairs being in close structural proximity, both domain-swapped and nondomain-swapped ASIC M2 conformations need to be considered. Such conformational flexibility is consistent with structural work, which suggested that the lower part of M2 can adopt both domain-swapped and nondomain-swapped conformations. Overall, mutations to residues in the middle and lower pore were more likely to affect gating and/or ion selectivity than those in the upper pore. Indeed, disrupting the putative interaction between a highly conserved Trp/Glu residue pair in the lower pore is detrimental to gating and selectivity, although this interaction might occur in both domain-swapped and nonswapped conformations. Finally, our results suggest that the greater number of larger, aromatic side chains in the ENaC M2 helix may contribute to the constitutive activity of these channels at a resting pH. Together, the data highlight differences in the transmembrane domains of these closely related ion channels that may help explain some of their distinct functional properties.

Dataset Information

Redox-mediated regulation of an evolutionarily conserved cross-? structure formed by the TDP43 low complexity domain.

Publications

Redox-mediated regulation of an evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain.

Similar Datasets

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