The N-Terminal Domain of ALS-Linked TDP-43 Assembles without Misfolding.
Angew Chem Int Ed Engl
; 56(41): 12590-12593, 2017 10 02.
Article
em En
| MEDLINE
| ID: mdl-28833982
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dobramento de Proteína
/
Proteínas de Ligação a DNA
/
Esclerose Lateral Amiotrófica
Limite:
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos