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The N‐Terminal Domain of ALS‐Linked TDP‐43 Assembles without Misfolding
Author(s) -
Tsoi Phoebe S.,
Choi KyoungJae,
Leonard Paul G.,
Sizovs Antons,
Moosa Mahdi Muhammad,
MacKenzie Kevin R.,
Ferreon Josephine C.,
Ferreon Allan Chris M.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201706769
Subject(s) - terminal (telecommunication) , domain (mathematical analysis) , chemistry , microbiology and biotechnology , c terminus , computational biology , computer science , biophysics , biology , biochemistry , computer network , mathematics , amino acid , mathematical analysis
Transactivation response element (TAR) DNA‐binding protein 43 (TDP‐43) misfolding is implicated in several neurodegenerative diseases characterized by aggregated protein inclusions. Misfolding is believed to be mediated by both the N‐ and C‐terminus of TDP‐43; however, the mechanistic basis of the contribution of individual domains in the process remained elusive. Here, using single‐molecule fluorescence and ensemble biophysical techniques, and a wide range of pH and temperature conditions, we show that TDP‐43 NTD is thermodynamically stable, well‐folded and undergoes reversible oligomerization. We propose that, in full‐length TDP‐43, association between folded N‐terminal domains enhances the propensity of the intrinsically unfolded C‐terminal domains to drive pathological aggregation.