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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.

Author information

1
Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, USA.
2
Department of Genomic Medicine and Core for Biomolecular Structure and Function, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
3
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.

Abstract

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.

KEYWORDS:

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

PMID:
28833982
DOI:
10.1002/anie.201706769
[Indexed for MEDLINE]

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