Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity
Abstract The mitochondrial chaperone TRAP1 is a key regulator of cellular homeostasis and its activity has important implications in neurodegeneration, ischemia and cancer. Recent evidence has indicated that TRAP1 mutations are involved in several disorders, even though the structural basis for the...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-03-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07467-6 |
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| author | Claudio Laquatra Alessia Magro Federica Guarra Matteo Lambrughi Lavinia Ferrone Giulio Fracasso Melissa Bacchin Martina La Spina Elisabetta Moroni Elena Papaleo Giorgio Colombo Andrea Rasola |
| author_facet | Claudio Laquatra Alessia Magro Federica Guarra Matteo Lambrughi Lavinia Ferrone Giulio Fracasso Melissa Bacchin Martina La Spina Elisabetta Moroni Elena Papaleo Giorgio Colombo Andrea Rasola |
| author_sort | Claudio Laquatra |
| collection | DOAJ |
| description | Abstract The mitochondrial chaperone TRAP1 is a key regulator of cellular homeostasis and its activity has important implications in neurodegeneration, ischemia and cancer. Recent evidence has indicated that TRAP1 mutations are involved in several disorders, even though the structural basis for the impact of point mutations on TRAP1 functions has never been studied. By exploiting a modular structure-based framework and molecular dynamics simulations, we investigated the effect of five TRAP1 mutations on its structure and stability. Each mutation differentially impacts long-range interactions, intra and inter-protomer dynamics and ATPase activity. Changes in these parameters influence TRAP1 functions, as revealed by their effects on the activity of the TRAP1 interactor succinate dehydrogenase (SDH). In keeping with this, TRAP1 point mutations affect the growth and migration of aggressive sarcoma cells, and alter sensitivity to a selective TRAP1 inhibitor. Our work provides new insights on the structure-activity relationship of TRAP1, identifying crucial amino acid residues that regulate TRAP1 proteostatic functions and pro-neoplastic activity. |
| format | Article |
| id | doaj-art-b2573b22e46a46b6a64a87c72b7392bf |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-b2573b22e46a46b6a64a87c72b7392bf2025-08-20T02:56:20ZengNature Publishing GroupCell Death and Disease2041-48892025-03-0116111210.1038/s41419-025-07467-6Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activityClaudio Laquatra0Alessia Magro1Federica Guarra2Matteo Lambrughi3Lavinia Ferrone4Giulio Fracasso5Melissa Bacchin6Martina La Spina7Elisabetta Moroni8Elena Papaleo9Giorgio Colombo10Andrea Rasola11Department of Biomedical Sciences, University of PadovaDepartment of Biomedical Sciences, University of PadovaDepartment of Chemistry, University of PaviaCancer Structural Biology, Danish Cancer InstituteDepartment of Biomedical Sciences, University of PadovaDepartment of Biomedical Sciences, University of PadovaDepartment of Biomedical Sciences, University of PadovaDepartment of Biomedical Sciences, University of PadovaSCITEC-CNRCancer Structural Biology, Danish Cancer InstituteDepartment of Chemistry, University of PaviaDepartment of Biomedical Sciences, University of PadovaAbstract The mitochondrial chaperone TRAP1 is a key regulator of cellular homeostasis and its activity has important implications in neurodegeneration, ischemia and cancer. Recent evidence has indicated that TRAP1 mutations are involved in several disorders, even though the structural basis for the impact of point mutations on TRAP1 functions has never been studied. By exploiting a modular structure-based framework and molecular dynamics simulations, we investigated the effect of five TRAP1 mutations on its structure and stability. Each mutation differentially impacts long-range interactions, intra and inter-protomer dynamics and ATPase activity. Changes in these parameters influence TRAP1 functions, as revealed by their effects on the activity of the TRAP1 interactor succinate dehydrogenase (SDH). In keeping with this, TRAP1 point mutations affect the growth and migration of aggressive sarcoma cells, and alter sensitivity to a selective TRAP1 inhibitor. Our work provides new insights on the structure-activity relationship of TRAP1, identifying crucial amino acid residues that regulate TRAP1 proteostatic functions and pro-neoplastic activity.https://doi.org/10.1038/s41419-025-07467-6 |
| spellingShingle | Claudio Laquatra Alessia Magro Federica Guarra Matteo Lambrughi Lavinia Ferrone Giulio Fracasso Melissa Bacchin Martina La Spina Elisabetta Moroni Elena Papaleo Giorgio Colombo Andrea Rasola Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity Cell Death and Disease |
| title | Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity |
| title_full | Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity |
| title_fullStr | Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity |
| title_full_unstemmed | Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity |
| title_short | Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity |
| title_sort | point mutations of the mitochondrial chaperone trap1 affect its functions and pro neoplastic activity |
| url | https://doi.org/10.1038/s41419-025-07467-6 |
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