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

eLife

Pierrick Craveur¹  Dominique Durand²  Emilie Steiner³  Ahmed Bouhss³  Marie-Jeanne Clément³  Juan Carlos Rengifo-Gonzalez³  Vandana Joshi³  Krystel El Hage³  David Pastré³ 

[1] SYNSIGHT, Evry-Courcouronnes, France;Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France;Université Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP), Evry-Courcouronnes, France;

关键词: RNA;    RNA-binding proteins;    neurodegenerative diseases;    Human;   

DOI  :  10.7554/eLife.67605

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY