Structure and mechanism of the RalGAP tumor suppressor complex
Abstract The RalGAP (GTPase activating protein) complexes are negative regulators of the Ral GTPases and thus crucial components that counteract oncogenic Ras signaling. However, no structural information on the architecture of this tumor suppressor complex is available hampering a mechanistic under...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61743-9 |
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| _version_ | 1849234630550487040 |
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| author | René Rasche Björn Udo Klink Lisa Helene Apken Esther Michalke Minghao Chen Andrea Oeckinghaus Christos Gatsogiannis Daniel Kümmel |
| author_facet | René Rasche Björn Udo Klink Lisa Helene Apken Esther Michalke Minghao Chen Andrea Oeckinghaus Christos Gatsogiannis Daniel Kümmel |
| author_sort | René Rasche |
| collection | DOAJ |
| description | Abstract The RalGAP (GTPase activating protein) complexes are negative regulators of the Ral GTPases and thus crucial components that counteract oncogenic Ras signaling. However, no structural information on the architecture of this tumor suppressor complex is available hampering a mechanistic understanding of its functionality. Here, we present a cryo-EM structure of RalGAP that reveals an extended 58 nm tetrameric architecture comprising two heterodimers of the RalGAPα and RalGAPβ subunits. We show that the catalytic domain of RalGAPα requires stabilization by a unique domain of RalGAPβ, providing the molecular basis for why RalGAP complexes are obligatory heterodimers. Formation of RalGAP tetramers is not required for activity in vitro, but essential for function of the complex in vivo. Structural analysis of RalGAP subunit variants reported in cancer patients suggests effects on complex formation and thus functional relevance, emphasizing the significance of the obtained structural information for medical research. |
| format | Article |
| id | doaj-art-86fa33bf6072422bba2e4353b038d657 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-86fa33bf6072422bba2e4353b038d6572025-08-20T04:03:06ZengNature PortfolioNature Communications2041-17232025-07-0116111210.1038/s41467-025-61743-9Structure and mechanism of the RalGAP tumor suppressor complexRené Rasche0Björn Udo Klink1Lisa Helene Apken2Esther Michalke3Minghao Chen4Andrea Oeckinghaus5Christos Gatsogiannis6Daniel Kümmel7Institute of Biochemistry, University of MünsterInstitute for Medical Physics and Biophysics, University of MünsterInstitute of Molecular Tumor Biology, University of MünsterInstitute of Molecular Tumor Biology, University of MünsterInstitute for Medical Physics and Biophysics, University of MünsterInstitute of Molecular Tumor Biology, University of MünsterInstitute for Medical Physics and Biophysics, University of MünsterInstitute of Biochemistry, University of MünsterAbstract The RalGAP (GTPase activating protein) complexes are negative regulators of the Ral GTPases and thus crucial components that counteract oncogenic Ras signaling. However, no structural information on the architecture of this tumor suppressor complex is available hampering a mechanistic understanding of its functionality. Here, we present a cryo-EM structure of RalGAP that reveals an extended 58 nm tetrameric architecture comprising two heterodimers of the RalGAPα and RalGAPβ subunits. We show that the catalytic domain of RalGAPα requires stabilization by a unique domain of RalGAPβ, providing the molecular basis for why RalGAP complexes are obligatory heterodimers. Formation of RalGAP tetramers is not required for activity in vitro, but essential for function of the complex in vivo. Structural analysis of RalGAP subunit variants reported in cancer patients suggests effects on complex formation and thus functional relevance, emphasizing the significance of the obtained structural information for medical research.https://doi.org/10.1038/s41467-025-61743-9 |
| spellingShingle | René Rasche Björn Udo Klink Lisa Helene Apken Esther Michalke Minghao Chen Andrea Oeckinghaus Christos Gatsogiannis Daniel Kümmel Structure and mechanism of the RalGAP tumor suppressor complex Nature Communications |
| title | Structure and mechanism of the RalGAP tumor suppressor complex |
| title_full | Structure and mechanism of the RalGAP tumor suppressor complex |
| title_fullStr | Structure and mechanism of the RalGAP tumor suppressor complex |
| title_full_unstemmed | Structure and mechanism of the RalGAP tumor suppressor complex |
| title_short | Structure and mechanism of the RalGAP tumor suppressor complex |
| title_sort | structure and mechanism of the ralgap tumor suppressor complex |
| url | https://doi.org/10.1038/s41467-025-61743-9 |
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