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

Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):28727-28734. doi: 10.1073/pnas.2012216117. Epub 2020 Nov 3.


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.

Keywords: TDP-43; cross-beta polymers; low-complexity sequence; neurodegenerative disorders; redox sensor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Ataxin-2 / metabolism*
  • Conserved Sequence
  • DNA-Binding Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Polymerization
  • Protein Domains
  • Reactive Oxygen Species / metabolism


  • ATXN2 protein, human
  • Ataxin-2
  • DNA-Binding Proteins
  • Reactive Oxygen Species
  • TARDBP protein, human