The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue eLife Année : 2021

The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation

Résumé

TDP-43 is a nuclear RNA-binding protein that forms neuronal cytoplasmic inclusions in two major neurodegenerative diseases, ALS and FTLD. While the self-assembly of TDP-43 by its structured N-terminal and intrinsically disordered C-terminal domains has been widely studied, the mechanism by which mRNA preserves TDP-43 solubility in the nucleus has not been addressed. Here, we demonstrate that tandem RNA Recognition Motifs of TDP-43 bind to long GU-repeats in a cooperative manner through intermolecular interactions. Moreover, using mutants whose cooperativity is impaired, we found that the cooperative binding of TDP-43 to mRNA may be critical to maintain the solubility of TDP-43 in the nucleus and the miscibility of TDP-43 in cytoplasmic stress granules. We anticipate that the knowledge of a higher order assembly of TDP-43 on mRNA may clarify its role in intron processing and provide a means of interfering with the cytoplasmic aggregation of TDP-43.
Fichier principal
Vignette du fichier
elife-67605-v3.pdf (17.21 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-03343496 , version 1 (25-10-2021)

Identifiants

Citer

Juan Carlos Rengifo-Gonzalez, Krystel El Hage, Marie-Jeanne Clément, Emilie Steiner, Vandana Joshi, et al.. The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation. eLife, 2021, 10, pp.e.67605. ⟨10.7554/eLife.67605⟩. ⟨hal-03343496⟩
77 Consultations
9 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More