Glycan-induced structural activation softens the human papillomavirus capsid for entry through reduction of intercapsomere flexibility
Abstract High-risk human papillomaviruses (HPVs) cause various cancers. While type-specific prophylactic vaccines are available, additional anti-viral strategies are highly desirable. Initial HPV cell entry involves receptor-switching induced by structural capsid modifications. These modifications a...
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| Format: | Article |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54373-0 |
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| author | Yuzhen Feng Dominik van Bodegraven Alan Kádek Ignacio L. B. Munguira Laura Soria-Martinez Sarah Nentwich Sreedeepa Saha Florian Chardon Daniel Kavan Charlotte Uetrecht Mario Schelhaas Wouter H. Roos |
| author_facet | Yuzhen Feng Dominik van Bodegraven Alan Kádek Ignacio L. B. Munguira Laura Soria-Martinez Sarah Nentwich Sreedeepa Saha Florian Chardon Daniel Kavan Charlotte Uetrecht Mario Schelhaas Wouter H. Roos |
| author_sort | Yuzhen Feng |
| collection | DOAJ |
| description | Abstract High-risk human papillomaviruses (HPVs) cause various cancers. While type-specific prophylactic vaccines are available, additional anti-viral strategies are highly desirable. Initial HPV cell entry involves receptor-switching induced by structural capsid modifications. These modifications are initiated by interactions with cellular heparan sulphates (HS), however, their molecular nature and functional consequences remain elusive. Combining virological assays with hydrogen/deuterium exchange mass spectrometry, and atomic force microscopy, we investigate the effect of capsid-HS binding and structural activation. We show how HS-induced structural activation requires a minimal HS-chain length and simultaneous engagement of several binding sites by a single HS molecule. This engagement introduces a pincer-like force that stabilizes the capsid in a conformation with extended capsomer linkers. It results in capsid enlargement and softening, thereby likely facilitating L1 proteolytic cleavage and subsequent L2-externalization, as needed for cell entry. Our data supports the further devising of prophylactic strategies against HPV infections. |
| format | Article |
| id | doaj-art-ad05749e2602467997b382ccd9878f0a |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ad05749e2602467997b382ccd9878f0a2024-11-24T12:35:14ZengNature PortfolioNature Communications2041-17232024-11-0115111510.1038/s41467-024-54373-0Glycan-induced structural activation softens the human papillomavirus capsid for entry through reduction of intercapsomere flexibilityYuzhen Feng0Dominik van Bodegraven1Alan Kádek2Ignacio L. B. Munguira3Laura Soria-Martinez4Sarah Nentwich5Sreedeepa Saha6Florian Chardon7Daniel Kavan8Charlotte Uetrecht9Mario Schelhaas10Wouter H. Roos11Moleculaire Biofysica, Zernike Instituut, Rijksuniversiteit GroningenInstitute of Cellular Virology, ZMBE, University of MünsterCSSB Centre for Structural Systems Biology, Deutsches Elektronen-Synchrotron DESY & Leibniz Institute of Virology (LIV), Notkestraße 85Moleculaire Biofysica, Zernike Instituut, Rijksuniversiteit GroningenInstitute of Cellular Virology, ZMBE, University of MünsterCSSB Centre for Structural Systems Biology, Deutsches Elektronen-Synchrotron DESY & Leibniz Institute of Virology (LIV), Notkestraße 85Institute of Cellular Virology, ZMBE, University of MünsterInstitute of Cellular Virology, ZMBE, University of MünsterInstitute of Microbiology of the Czech Academy of Sciences, Videnska 1083CSSB Centre for Structural Systems Biology, Deutsches Elektronen-Synchrotron DESY & Leibniz Institute of Virology (LIV), Notkestraße 85Institute of Cellular Virology, ZMBE, University of MünsterMoleculaire Biofysica, Zernike Instituut, Rijksuniversiteit GroningenAbstract High-risk human papillomaviruses (HPVs) cause various cancers. While type-specific prophylactic vaccines are available, additional anti-viral strategies are highly desirable. Initial HPV cell entry involves receptor-switching induced by structural capsid modifications. These modifications are initiated by interactions with cellular heparan sulphates (HS), however, their molecular nature and functional consequences remain elusive. Combining virological assays with hydrogen/deuterium exchange mass spectrometry, and atomic force microscopy, we investigate the effect of capsid-HS binding and structural activation. We show how HS-induced structural activation requires a minimal HS-chain length and simultaneous engagement of several binding sites by a single HS molecule. This engagement introduces a pincer-like force that stabilizes the capsid in a conformation with extended capsomer linkers. It results in capsid enlargement and softening, thereby likely facilitating L1 proteolytic cleavage and subsequent L2-externalization, as needed for cell entry. Our data supports the further devising of prophylactic strategies against HPV infections.https://doi.org/10.1038/s41467-024-54373-0 |
| spellingShingle | Yuzhen Feng Dominik van Bodegraven Alan Kádek Ignacio L. B. Munguira Laura Soria-Martinez Sarah Nentwich Sreedeepa Saha Florian Chardon Daniel Kavan Charlotte Uetrecht Mario Schelhaas Wouter H. Roos Glycan-induced structural activation softens the human papillomavirus capsid for entry through reduction of intercapsomere flexibility Nature Communications |
| title | Glycan-induced structural activation softens the human papillomavirus capsid for entry through reduction of intercapsomere flexibility |
| title_full | Glycan-induced structural activation softens the human papillomavirus capsid for entry through reduction of intercapsomere flexibility |
| title_fullStr | Glycan-induced structural activation softens the human papillomavirus capsid for entry through reduction of intercapsomere flexibility |
| title_full_unstemmed | Glycan-induced structural activation softens the human papillomavirus capsid for entry through reduction of intercapsomere flexibility |
| title_short | Glycan-induced structural activation softens the human papillomavirus capsid for entry through reduction of intercapsomere flexibility |
| title_sort | glycan induced structural activation softens the human papillomavirus capsid for entry through reduction of intercapsomere flexibility |
| url | https://doi.org/10.1038/s41467-024-54373-0 |
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