1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
Download icon

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

  1. Juan Carlos Rengifo-Gonzalez
  2. Krystel El Hage
  3. Marie-Jeanne Clément
  4. Emilie Steiner
  5. Vandana Joshi
  6. Pierrick Craveur
  7. Dominique Durand
  8. David Pastré  Is a corresponding author
  9. Ahmed Bouhss  Is a corresponding author
  1. Université Paris-Saclay, INSERM U1204, Univ Evry, France
  2. SYNSIGHT, France
  3. Université Paris-Saclay, CEA, CNRS, France
Research Article
  • Cited 0
  • Views 765
  • Annotations
Cite this article as: eLife 2021;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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

The following previously published data sets were used

Article and author information

Author details

  1. Juan Carlos Rengifo-Gonzalez

    SABNP, Université Paris-Saclay, INSERM U1204, Univ Evry, Evry, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Krystel El Hage

    Department of Chemistry, Université Paris-Saclay, INSERM U1204, Univ Evry, Evry, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4837-3888
  3. Marie-Jeanne Clément

    SABNP, Université Paris-Saclay, INSERM U1204, Univ Evry, Evry, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Emilie Steiner

    laboratoire structure activité des biomolécules normales et pathologiques, Université Paris-Saclay, INSERM U1204, Univ Evry, Evry, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Vandana Joshi

    laboratoire structure activité des biomolécules normales et pathologiques, Université Paris-Saclay, INSERM U1204, Univ Evry, Evry, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Pierrick Craveur

    SYNSIGHT, Evry, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9274-4944
  7. Dominique Durand

    Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9414-5857
  8. David Pastré

    SABNP, Université Paris-Saclay, INSERM U1204, Univ Evry, Evry, France
    For correspondence
    david.pastre@univ-evry.fr
    Competing interests
    The authors declare that no competing interests exist.
  9. Ahmed Bouhss

    Structure-Activité des Biomolécules Normales et Pathologiques (SABNP), Université Paris-Saclay, INSERM U1204, Univ Evry, Evry, France
    For correspondence
    ahmed.bouhss@univ-evry.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6492-1429

Funding

Genopole (SATURNE 2018-SABNP)

  • Ahmed Bouhss

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Rohit V Pappu, Washington University in St Louis, United States

Publication history

  1. Received: February 16, 2021
  2. Accepted: September 3, 2021
  3. Accepted Manuscript published: September 7, 2021 (version 1)
  4. Accepted Manuscript updated: September 10, 2021 (version 2)

Copyright

© 2021, Rengifo-Gonzalez et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 765
    Page views
  • 205
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Biochemistry and Chemical Biology
    Xavier Portillo et al.
    Research Article Updated

    An RNA polymerase ribozyme that has been the subject of extensive directed evolution efforts has attained the ability to synthesize complex functional RNAs, including a full-length copy of its own evolutionary ancestor. During the course of evolution, the catalytic core of the ribozyme has undergone a major structural rearrangement, resulting in a novel tertiary structural element that lies in close proximity to the active site. Through a combination of site-directed mutagenesis, structural probing, and deep sequencing analysis, the trajectory of evolution was seen to involve the progressive stabilization of the new structure, which provides the basis for improved catalytic activity of the ribozyme. Multiple paths to the new structure were explored by the evolving population, converging upon a common solution. Tertiary structural remodeling of RNA is known to occur in nature, as evidenced by the phylogenetic analysis of extant organisms, but this type of structural innovation had not previously been observed in an experimental setting. Despite prior speculation that the catalytic core of the ribozyme had become trapped in a narrow local fitness optimum, the evolving population has broken through to a new fitness locale, raising the possibility that further improvement of polymerase activity may be achievable.

    1. Biochemistry and Chemical Biology
    Gajanan S Patil et al.
    Research Article Updated

    Fatty acyl-AMP ligases (FAALs) channelize fatty acids towards biosynthesis of virulent lipids in mycobacteria and other pharmaceutically or ecologically important polyketides and lipopeptides in other microbes. They do so by bypassing the ubiquitous coenzyme A-dependent activation and rely on the acyl carrier protein-tethered 4′-phosphopantetheine (holo-ACP). The molecular basis of how FAALs strictly reject chemically identical and abundant acceptors like coenzyme A (CoA) and accept holo-ACP unlike other members of the ANL superfamily remains elusive. We show that FAALs have plugged the promiscuous canonical CoA-binding pockets and utilize highly selective alternative binding sites. These alternative pockets can distinguish adenosine 3′,5′-bisphosphate-containing CoA from holo-ACP and thus FAALs can distinguish between CoA and holo-ACP. These exclusive features helped identify the omnipresence of FAAL-like proteins and their emergence in plants, fungi, and animals with unconventional domain organizations. The universal distribution of FAALs suggests that they are parallelly evolved with FACLs for ensuring a CoA-independent activation and redirection of fatty acids towards lipidic metabolites.