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

Elife. 2021 Sep 7:10:e67605. doi: 10.7554/eLife.67605.

Abstract

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.

Keywords: RNA; RNA-binding proteins; biochemistry; chemical biology; human; molecular biophysics; neurodegenerative diseases; structural biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytoplasmic Granules*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Escherichia coli
  • Humans
  • RNA / metabolism*
  • RNA Recognition Motif
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*

Substances

  • DNA-Binding Proteins
  • RNA-Binding Proteins
  • TARDBP protein, human
  • RNA