Herpes Simplex Virus 1 Entry Glycoproteins Form Complexes before and during Membrane Fusion

Pataki, Zemplen; Viveros, Andrea Rebolledo; Heldwein, Ekaterina E.

doi:10.1128/mbio.02039-22

Cited by 16 publications

(19 citation statements)

References 77 publications

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“…The current model of entry places gH/gL between gD and gB in the sequence of events, with receptor-binding by gD initiating a change in gH/gL that triggers gB to refold to drive fusion. Interactions of all of the glycoprotein combinations (gD-gH/gL, gD-gB, and gH/gL-gB) have been demonstrated using a split-luciferase assay ( 13 ) and bimolecular fluorescence complementation (BiFC) assays ( 10 , 12 ).…”

Section: Discussionmentioning

confidence: 99%

“…Studies of neutralizing antibody epitopes have modeled sites of glycoprotein interaction ( 2 , 4 , 8 , 9 ). Physical interactions among the entry glycoproteins also have been demonstrated ( 10 – 13 ), but glycoprotein complexes are difficult to capture, presumably because the glycoprotein interactions are low affinity and/or transient. gH/gL and gB are conserved among all herpesviruses, so understanding their interaction is particularly important for understanding herpesvirus entry.…”

Section: Introductionmentioning

confidence: 99%

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Multiple Sites on Glycoprotein H (gH) Functionally Interact with the gB Fusion Protein to Promote Fusion during Herpes Simplex Virus (HSV) Entry

Fan

Hippler

Yang

et al. 2023

mBio

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Enveloped viruses enter cells by fusing their envelope with the host cell membrane. Herpes simplex virus 1 (HSV-1) entry requires the coordinated interaction of several viral glycoproteins, including gH/gL and gB. gH/gL and gB are essential for virus replication and both proteins are targets of neutralizing antibodies. gB fuses the membranes after being activated by gH/gL, but the details of how gH/gL activates gB are not known.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multiple Sites on Glycoprotein H (gH) Functionally Interact with the gB Fusion Protein to Promote Fusion during Herpes Simplex Virus (HSV) Entry

Fan

Hippler

Yang

et al. 2023

mBio

View full text Add to dashboard Cite

show abstract

“…The current model of entry places gH/gL between gD and gB in the sequence of events, with receptorbinding by gD initiating a change in gH/gL that triggers gB to refold to drive fusion. Interactions of all of the glycoprotein combinations (gD-gH/gL, gD-gB, and gH/gL-gB) have been demonstrated using a splitluciferase assay (13) and bimolecular fluorescence complementation (BiFC) assays (10,12). Purified forms of the gD and gH/gL ectodomains have been shown to interact directly using surface plasmon resonance (SPR) (8,11).…”

Section: Discussionmentioning

confidence: 99%

“…Studies of neutralizing antibody epitopes have modeled sites of glycoprotein interaction (2,4,8,9). Physical interactions among the entry glycoproteins also have been demonstrated (10)(11)(12)(13), but glycoprotein complexes are difficult to capture, presumably because the glycoprotein interactions are low affinity and/or transient. gH/gL and gB are conserved among all herpesviruses, so understanding their interaction is particularly important for understanding herpesvirus entry.…”

Section: Introductionmentioning

confidence: 99%

Multiple sites on glycoprotein H (gH) functionally interact with the gB fusion protein to promote fusion during herpes simplex virus (HSV) entry

Fan

Hippler

Yang

et al. 2022

Preprint

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Enveloped virus entry requires fusion of the viral envelope with a host cell membrane. Herpes simplex virus type 1 (HSV-1) entry is mediated by a set of glycoproteins that interact to trigger the viral fusion protein glycoprotein B (gB). In the current model, receptor-binding by gD signals a gH/gL heterodimer to trigger a refolding event in gB that fuses the membranes. To explore functional interactions between gB and gH/gL, we used a bacterial artificial chromosome (BAC) to generate two HSV-1 mutants that show a small plaque phenotype due to changes in gB. We passaged the viruses to select for restoration of plaque size and analyzed second-site mutations that arose in gH. HSV-1 gB was replaced either by gB from saimiriine herpesvirus type 1 (SaHV-1) or by a mutant form of HSV-1 gB with three alanine substitutions in domain V (gB3A). To shift the selective pressure away from gB, the gB3A virus was passaged in cells expressing gB3A. Sequencing of passaged viruses identified two interesting mutations in gH, including gH-H789 in domain IV and gH-S830N in the cytoplasmic tail (CT). Characterization of these gH mutations indicated they are responsible for the enhanced plaque size. Rather than being globally hyperfusogenic, both gH mutations partially rescued function of the specific gB version present during their selection. These sites may represent functional interaction sites on gH/gL for gB. gH-H789 may alter the positioning of a membrane-proximal flap in the gH ectodomain, whereas gH-S830 may contribute to an interaction between the gB and gH CTs.

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“…The three glycoproteins, gB, gH, and gL, required for this process are conserved across the Herpesviridae 1,2 . Structure-function studies have revealed that the gB trimer is the primary fusogen and the gH-gL heterodimer has roles in cell tropism and gB regulation [3][4][5][6][7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Caught in the Act: targeted mutagenesis of the herpesvirus fusogen central helix captures transition states

Zhou

Vollmer

Machala

et al. 2022

Preprint

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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. Structure-function studies of the VZV gB DIII central helix were performed targeting residues526EHV528. Critically, a H527P mutation captured 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] were 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.

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Herpes Simplex Virus 1 Entry Glycoproteins Form Complexes before and during Membrane Fusion

Abstract: Herpes simplex virus 1 (HSV-1) infects the majority of humans for life and can cause diseases ranging from painful sores to deadly brain inflammation. No vaccines or curative treatments currently exist.

Cited by 16 publications

References 77 publications

Multiple Sites on Glycoprotein H (gH) Functionally Interact with the gB Fusion Protein to Promote Fusion during Herpes Simplex Virus (HSV) Entry

Multiple Sites on Glycoprotein H (gH) Functionally Interact with the gB Fusion Protein to Promote Fusion during Herpes Simplex Virus (HSV) Entry

Multiple sites on glycoprotein H (gH) functionally interact with the gB fusion protein to promote fusion during herpes simplex virus (HSV) entry

Caught in the Act: targeted mutagenesis of the herpesvirus fusogen central helix captures transition states

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