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Angew Chem Int Ed Engl. 2017 Oct 2;56(41):12590-12593. doi: 10.1002/anie.201706769. Epub 2017 Sep 5.

The N-Terminal Domain of ALS-Linked TDP-43 Assembles without Misfolding.

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Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, USA.
Department of Genomic Medicine and Core for Biomolecular Structure and Function, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.


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-43NTD 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.


amyotrophic lateral sclerosis; misfolding; neurodegenerative diseases; protein phase diagram; smFRET

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