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.
journal_name
Proc Natl Acad Sci U S Aauthors
Lin Y,Zhou X,Kato M,Liu D,Ghaemmaghami S,Tu BP,McKnight SLdoi
10.1073/pnas.2012216117subject
Has Abstractpub_date
2020-11-17 00:00:00pages
28727-28734issue
46eissn
0027-8424issn
1091-6490pii
2012216117journal_volume
117pub_type
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