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

Yi Lin, Xiaoming Zhou, Masato Kato, Daifei Liu, Sina Ghaemmaghami, Benjamin P. Tu, Steven L. McKnight

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)28727-28734
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number46
DOIs
StatePublished - Nov 17 2020

Keywords

  • Low-complexity sequence cross-beta polymers | TDP-43 | redox sensor | neurodegenerative disorders

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Redox-mediated regulation of an evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain'. Together they form a unique fingerprint.

Cite this