Targeted mutagenesis of the herpesvirus fusogen central helix captures transition states
Abstract Herpesviruses remain a burden for animal and human health, including the medically important varicella-zoster virus (VZV). Membrane fusion mediated by conserved core glycoproteins, the fusogen gB and the heterodimer gH-gL, enables herpesvirus cell entry. The ectodomain of gB orthologs has f...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-43011-w |
| _version_ | 1797414698532995072 |
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| author | Momei Zhou Benjamin Vollmer Emily Machala Muyuan Chen Kay Grünewald Ann M. Arvin Wah Chiu Stefan L. Oliver |
| author_facet | Momei Zhou Benjamin Vollmer Emily Machala Muyuan Chen Kay Grünewald Ann M. Arvin Wah Chiu Stefan L. Oliver |
| author_sort | Momei Zhou |
| collection | DOAJ |
| description | Abstract Herpesviruses remain a burden for animal and human health, including the medically important varicella-zoster virus (VZV). Membrane fusion mediated by conserved core glycoproteins, the fusogen gB and the heterodimer gH-gL, enables herpesvirus cell entry. The ectodomain of gB orthologs has five domains and is proposed to transition from a prefusion to postfusion conformation but the functional relevance of the domains for this transition remains poorly defined. Here we describe structure-function studies of the VZV gB DIII central helix targeting residues 526EHV528. Critically, a H527P mutation captures gB in a prefusion conformation as determined by cryo-EM, a loss of membrane fusion in a virus free assay, and failure of recombinant VZV to spread in cell monolayers. Importantly, two predominant cryo-EM structures of gB[H527P] are identified by 3D classification and focused refinement, suggesting they represented gB conformations in transition. These studies reveal gB DIII as a critical element for herpesvirus gB fusion function. |
| first_indexed | 2024-03-09T05:37:20Z |
| format | Article |
| id | doaj.art-fe5390920f5244a09c7274e524f00b90 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T05:37:20Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-fe5390920f5244a09c7274e524f00b902023-12-03T12:28:22ZengNature PortfolioNature Communications2041-17232023-12-0114111510.1038/s41467-023-43011-wTargeted mutagenesis of the herpesvirus fusogen central helix captures transition statesMomei Zhou0Benjamin Vollmer1Emily Machala2Muyuan Chen3Kay Grünewald4Ann M. Arvin5Wah Chiu6Stefan L. Oliver7Department of Pediatrics, Stanford University School of MedicineCentre for Structural Systems Biology (CSSB)Centre for Structural Systems Biology (CSSB)Division of Cryo-EM and Bioimaging SSRL, SLAC National Accelerator LaboratoryCentre for Structural Systems Biology (CSSB)Department of Pediatrics, Stanford University School of MedicineDivision of Cryo-EM and Bioimaging SSRL, SLAC National Accelerator LaboratoryDepartment of Pediatrics, Stanford University School of MedicineAbstract Herpesviruses remain a burden for animal and human health, including the medically important varicella-zoster virus (VZV). Membrane fusion mediated by conserved core glycoproteins, the fusogen gB and the heterodimer gH-gL, enables herpesvirus cell entry. The ectodomain of gB orthologs has five domains and is proposed to transition from a prefusion to postfusion conformation but the functional relevance of the domains for this transition remains poorly defined. Here we describe structure-function studies of the VZV gB DIII central helix targeting residues 526EHV528. Critically, a H527P mutation captures gB in a prefusion conformation as determined by cryo-EM, a loss of membrane fusion in a virus free assay, and failure of recombinant VZV to spread in cell monolayers. Importantly, two predominant cryo-EM structures of gB[H527P] are identified by 3D classification and focused refinement, suggesting they represented gB conformations in transition. These studies reveal gB DIII as a critical element for herpesvirus gB fusion function.https://doi.org/10.1038/s41467-023-43011-w |
| spellingShingle | Momei Zhou Benjamin Vollmer Emily Machala Muyuan Chen Kay Grünewald Ann M. Arvin Wah Chiu Stefan L. Oliver Targeted mutagenesis of the herpesvirus fusogen central helix captures transition states Nature Communications |
| title | Targeted mutagenesis of the herpesvirus fusogen central helix captures transition states |
| title_full | Targeted mutagenesis of the herpesvirus fusogen central helix captures transition states |
| title_fullStr | Targeted mutagenesis of the herpesvirus fusogen central helix captures transition states |
| title_full_unstemmed | Targeted mutagenesis of the herpesvirus fusogen central helix captures transition states |
| title_short | Targeted mutagenesis of the herpesvirus fusogen central helix captures transition states |
| title_sort | targeted mutagenesis of the herpesvirus fusogen central helix captures transition states |
| url | https://doi.org/10.1038/s41467-023-43011-w |
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