4D structural biology–quantitative dynamics in the eukaryotic RNA exosome complex
Abstract Molecular machines play pivotal roles in all biological processes. Most structural methods, however, are unable to directly probe molecular motions. Here, we demonstrate that dedicated NMR experiments can provide quantitative insights into functionally important dynamic regions in very larg...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62982-6 |
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| author | Jobst Liebau Daniela Lazzaretti Torben Fürtges Anna Bichler Michael Pilsl Till Rudack Remco Sprangers |
| author_facet | Jobst Liebau Daniela Lazzaretti Torben Fürtges Anna Bichler Michael Pilsl Till Rudack Remco Sprangers |
| author_sort | Jobst Liebau |
| collection | DOAJ |
| description | Abstract Molecular machines play pivotal roles in all biological processes. Most structural methods, however, are unable to directly probe molecular motions. Here, we demonstrate that dedicated NMR experiments can provide quantitative insights into functionally important dynamic regions in very large asymmetric protein complexes. We establish this for the 410 kDa eukaryotic RNA exosome complex that contains ten distinct protein chains. Methyl-group and fluorine NMR experiments reveal site-specific interactions among subunits and with an RNA substrate. Furthermore, we extract quantitative insights into conformational changes within the complex in response to substrate and subunit binding for regions that are invisible in static cryo-EM and crystal structures. In particular, we identify a flexible plug region that can block an aberrant route for RNA towards the active site. Based on molecular dynamics simulations and NMR data, we provide a model that shows how the flexible plug is structured in the open and closed conformations. Our work thus demonstrates that a combination of state-of-the-art structural biology methods can provide quantitative insights into large molecular machines that go significantly beyond the well-resolved and static images of biomolecular complexes, thereby adding the time domain to structural biology. |
| format | Article |
| id | doaj-art-d368406c96aa4e5eb54bf7f6c6195dc8 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d368406c96aa4e5eb54bf7f6c6195dc82025-08-24T11:39:45ZengNature PortfolioNature Communications2041-17232025-08-0116111610.1038/s41467-025-62982-64D structural biology–quantitative dynamics in the eukaryotic RNA exosome complexJobst Liebau0Daniela Lazzaretti1Torben Fürtges2Anna Bichler3Michael Pilsl4Till Rudack5Remco Sprangers6Department of Biophysics I, Regensburg Center for Biochemistry, University of RegensburgDepartment of Biophysics I, Regensburg Center for Biochemistry, University of RegensburgStructural Bioinformatics Group, Regensburg Center for Biochemistry, University of RegensburgDepartment of Biophysics I, Regensburg Center for Biochemistry, University of RegensburgStructural Biochemistry Group, Regensburg Center for Biochemistry, University of RegensburgStructural Bioinformatics Group, Regensburg Center for Biochemistry, University of RegensburgDepartment of Biophysics I, Regensburg Center for Biochemistry, University of RegensburgAbstract Molecular machines play pivotal roles in all biological processes. Most structural methods, however, are unable to directly probe molecular motions. Here, we demonstrate that dedicated NMR experiments can provide quantitative insights into functionally important dynamic regions in very large asymmetric protein complexes. We establish this for the 410 kDa eukaryotic RNA exosome complex that contains ten distinct protein chains. Methyl-group and fluorine NMR experiments reveal site-specific interactions among subunits and with an RNA substrate. Furthermore, we extract quantitative insights into conformational changes within the complex in response to substrate and subunit binding for regions that are invisible in static cryo-EM and crystal structures. In particular, we identify a flexible plug region that can block an aberrant route for RNA towards the active site. Based on molecular dynamics simulations and NMR data, we provide a model that shows how the flexible plug is structured in the open and closed conformations. Our work thus demonstrates that a combination of state-of-the-art structural biology methods can provide quantitative insights into large molecular machines that go significantly beyond the well-resolved and static images of biomolecular complexes, thereby adding the time domain to structural biology.https://doi.org/10.1038/s41467-025-62982-6 |
| spellingShingle | Jobst Liebau Daniela Lazzaretti Torben Fürtges Anna Bichler Michael Pilsl Till Rudack Remco Sprangers 4D structural biology–quantitative dynamics in the eukaryotic RNA exosome complex Nature Communications |
| title | 4D structural biology–quantitative dynamics in the eukaryotic RNA exosome complex |
| title_full | 4D structural biology–quantitative dynamics in the eukaryotic RNA exosome complex |
| title_fullStr | 4D structural biology–quantitative dynamics in the eukaryotic RNA exosome complex |
| title_full_unstemmed | 4D structural biology–quantitative dynamics in the eukaryotic RNA exosome complex |
| title_short | 4D structural biology–quantitative dynamics in the eukaryotic RNA exosome complex |
| title_sort | 4d structural biology quantitative dynamics in the eukaryotic rna exosome complex |
| url | https://doi.org/10.1038/s41467-025-62982-6 |
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