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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2021-09-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/67605 |
| _version_ | 1811199396098867200 |
|---|---|
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T01:48:50Z |
| format | Article |
| id | doaj.art-de0ec8831ecd4f1da1a28a35d038e526 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:48:50Z |
| publishDate | 2021-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-de0ec8831ecd4f1da1a28a35d038e5262022-12-22T03:53:01ZengeLife Sciences Publications LtdeLife2050-084X2021-09-011010.7554/eLife.67605The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregationJuan Carlos Rengifo-Gonzalez0Krystel El Hage1Marie-Jeanne Clément2Emilie Steiner3Vandana Joshi4Pierrick Craveur5Dominique Durand6https://orcid.org/0000-0001-9414-5857David Pastré7https://orcid.org/0000-0002-3348-9514Ahmed Bouhss8https://orcid.org/0000-0002-6492-1429Université Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP), Evry-Courcouronnes, FranceUniversité Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP), Evry-Courcouronnes, FranceUniversité Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP), Evry-Courcouronnes, FranceUniversité Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP), Evry-Courcouronnes, FranceUniversité Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP), Evry-Courcouronnes, FranceSYNSIGHT, Evry-Courcouronnes, FranceUniversité Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, FranceUniversité Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP), Evry-Courcouronnes, FranceUniversité Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP), Evry-Courcouronnes, FranceTDP-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.https://elifesciences.org/articles/67605RNARNA-binding proteinsneurodegenerative diseases |
| spellingShingle | 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 eLife RNA RNA-binding proteins neurodegenerative diseases |
| title | 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_short | 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 |
| topic | RNA RNA-binding proteins neurodegenerative diseases |
| url | https://elifesciences.org/articles/67605 |
| work_keys_str_mv | AT juancarlosrengifogonzalez thecooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT krystelelhage thecooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT mariejeanneclement thecooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT emiliesteiner thecooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT vandanajoshi thecooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT pierrickcraveur thecooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT dominiquedurand thecooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT davidpastre thecooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT ahmedbouhss thecooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT juancarlosrengifogonzalez cooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT krystelelhage cooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT mariejeanneclement cooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT emiliesteiner cooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT vandanajoshi cooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT pierrickcraveur cooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT dominiquedurand cooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT davidpastre cooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation AT ahmedbouhss cooperativebindingoftdp43togurichrnarepeatsantagonizestdp43aggregation |