Collagen VI microfibril structure reveals mechanism for molecular assembly and clustering of inherited pathogenic mutations
Abstract Collagen VI links the cell surface to the extracellular matrix to provide mechanical strength to most mammalian tissues, and is linked to human diseases including muscular dystrophy, fibrosis, cardiovascular disease and osteoarthritis. Collagen VI assembles from heterotrimers of three diffe...
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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/s41467-025-62923-3 |
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| author | Alan R. F. Godwin Mark H. Becker Rana Dajani Matthew Snee Alan M. Roseman Clair Baldock |
| author_facet | Alan R. F. Godwin Mark H. Becker Rana Dajani Matthew Snee Alan M. Roseman Clair Baldock |
| author_sort | Alan R. F. Godwin |
| collection | DOAJ |
| description | Abstract Collagen VI links the cell surface to the extracellular matrix to provide mechanical strength to most mammalian tissues, and is linked to human diseases including muscular dystrophy, fibrosis, cardiovascular disease and osteoarthritis. Collagen VI assembles from heterotrimers of three different α-chains into microfibrils, but there are many gaps in our knowledge of the molecular assembly process. Here, we determine the structures of both heterotrimeric mini-collagen VI constructs and collagen VI microfibrils, from mammalian tissue, using cryogenic-electron microscopy. These structures reveal a cysteine-rich coiled coil region involved in trimerisation as well as microfibril assembly. Furthermore, our structures show that pathogenic mutations are located at interaction sites involved in different steps of collagen VI assembly, from the trimeric-coiled coil region that mediates heterotrimerisation, to clusters of mutations in the triple-helical region involved in microfibril formation. Our microfibril structure provides a template for understanding supramolecular assembly, and offers a platform for rationale design of therapeutics for collagen VI pathologies. |
| format | Article |
| id | doaj-art-c525984a65444d0abcdf126f77bd5daf |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c525984a65444d0abcdf126f77bd5daf2025-08-20T04:03:00ZengNature PortfolioNature Communications2041-17232025-08-0116111710.1038/s41467-025-62923-3Collagen VI microfibril structure reveals mechanism for molecular assembly and clustering of inherited pathogenic mutationsAlan R. F. Godwin0Mark H. Becker1Rana Dajani2Matthew Snee3Alan M. Roseman4Clair Baldock5Division of Cell-Matrix Biology and Regenerative Medicine, Manchester Cell-Matrix Centre, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterDivision of Cell-Matrix Biology and Regenerative Medicine, Manchester Cell-Matrix Centre, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterDivision of Cell-Matrix Biology and Regenerative Medicine, Manchester Cell-Matrix Centre, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterDivision of Cell-Matrix Biology and Regenerative Medicine, Manchester Cell-Matrix Centre, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterDivision of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterDivision of Cell-Matrix Biology and Regenerative Medicine, Manchester Cell-Matrix Centre, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterAbstract Collagen VI links the cell surface to the extracellular matrix to provide mechanical strength to most mammalian tissues, and is linked to human diseases including muscular dystrophy, fibrosis, cardiovascular disease and osteoarthritis. Collagen VI assembles from heterotrimers of three different α-chains into microfibrils, but there are many gaps in our knowledge of the molecular assembly process. Here, we determine the structures of both heterotrimeric mini-collagen VI constructs and collagen VI microfibrils, from mammalian tissue, using cryogenic-electron microscopy. These structures reveal a cysteine-rich coiled coil region involved in trimerisation as well as microfibril assembly. Furthermore, our structures show that pathogenic mutations are located at interaction sites involved in different steps of collagen VI assembly, from the trimeric-coiled coil region that mediates heterotrimerisation, to clusters of mutations in the triple-helical region involved in microfibril formation. Our microfibril structure provides a template for understanding supramolecular assembly, and offers a platform for rationale design of therapeutics for collagen VI pathologies.https://doi.org/10.1038/s41467-025-62923-3 |
| spellingShingle | Alan R. F. Godwin Mark H. Becker Rana Dajani Matthew Snee Alan M. Roseman Clair Baldock Collagen VI microfibril structure reveals mechanism for molecular assembly and clustering of inherited pathogenic mutations Nature Communications |
| title | Collagen VI microfibril structure reveals mechanism for molecular assembly and clustering of inherited pathogenic mutations |
| title_full | Collagen VI microfibril structure reveals mechanism for molecular assembly and clustering of inherited pathogenic mutations |
| title_fullStr | Collagen VI microfibril structure reveals mechanism for molecular assembly and clustering of inherited pathogenic mutations |
| title_full_unstemmed | Collagen VI microfibril structure reveals mechanism for molecular assembly and clustering of inherited pathogenic mutations |
| title_short | Collagen VI microfibril structure reveals mechanism for molecular assembly and clustering of inherited pathogenic mutations |
| title_sort | collagen vi microfibril structure reveals mechanism for molecular assembly and clustering of inherited pathogenic mutations |
| url | https://doi.org/10.1038/s41467-025-62923-3 |
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