Targeted mutagenesis of the herpesvirus fusogen central helix captures transition states

Momei Zhou (), Benjamin Vollmer, Emily Machala, Muyuan Chen, Kay Grünewald, Ann M. Arvin, Wah Chiu and Stefan L. Oliver
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Momei Zhou: Stanford University School of Medicine
Benjamin Vollmer: Centre for Structural Systems Biology (CSSB)
Emily Machala: Centre for Structural Systems Biology (CSSB)
Muyuan Chen: SLAC National Accelerator Laboratory
Kay Grünewald: Centre for Structural Systems Biology (CSSB)
Ann M. Arvin: Stanford University School of Medicine
Wah Chiu: SLAC National Accelerator Laboratory
Stefan L. Oliver: Stanford University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43011-w

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