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

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 mRN...

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Autores principales:	Juan Carlos Rengifo-Gonzalez, Krystel El Hage, Marie-Jeanne Clément, Emilie Steiner, Vandana Joshi, Pierrick Craveur, Dominique Durand, David Pastré, Ahmed Bouhss
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	RNA RNA-binding proteins neurodegenerative diseases Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/de0ec8831ecd4f1da1a28a35d038e526
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spelling	oai:doaj.org-article:de0ec8831ecd4f1da1a28a35d038e5262021-11-16T14:22:30ZThe cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation10.7554/eLife.676052050-084Xe67605https://doaj.org/article/de0ec8831ecd4f1da1a28a35d038e5262021-09-01T00:00:00Zhttps://elifesciences.org/articles/67605https://doaj.org/toc/2050-084XTDP-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.Juan Carlos Rengifo-GonzalezKrystel El HageMarie-Jeanne ClémentEmilie SteinerVandana JoshiPierrick CraveurDominique DurandDavid PastréAhmed BouhsseLife Sciences Publications LtdarticleRNARNA-binding proteinsneurodegenerative diseasesMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	RNA RNA-binding proteins neurodegenerative diseases Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	RNA RNA-binding proteins neurodegenerative diseases Medicine R Science Q Biology (General) QH301-705.5 Juan Carlos Rengifo-Gonzalez Krystel El Hage Marie-Jeanne Clément Emilie Steiner Vandana Joshi Pierrick Craveur Dominique Durand David Pastré Ahmed Bouhss The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation
description	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.
format	article
author	Juan Carlos Rengifo-Gonzalez Krystel El Hage Marie-Jeanne Clément Emilie Steiner Vandana Joshi Pierrick Craveur Dominique Durand David Pastré Ahmed Bouhss
author_facet	Juan Carlos Rengifo-Gonzalez Krystel El Hage Marie-Jeanne Clément Emilie Steiner Vandana Joshi Pierrick Craveur Dominique Durand David Pastré Ahmed Bouhss
author_sort	Juan Carlos Rengifo-Gonzalez
title	The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation
title_short	The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation
title_full	The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation
title_fullStr	The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation
title_full_unstemmed	The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation
title_sort	cooperative binding of tdp-43 to gu-rich rna repeats antagonizes tdp-43 aggregation
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/de0ec8831ecd4f1da1a28a35d038e526
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The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation

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