Functional Analysis of Glycoprotein L (gL) from Rhesus Lymphocryptovirus in Epstein-Barr Virus-Mediated Cell Fusion Indicates a Direct Role of gL in gB-Induced Membrane Fusion

Plate, Aileen E.; Smajlovic, Jasmina; Jardetzky, Theodore S.; Longnecker, Richard

doi:10.1128/jvi.00457-09

Cited by 39 publications

(48 citation statements)

References 50 publications

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“…The deleterious mutations of L65A and L69A may disrupt interactions with gL and the proper folding of D-I. The monoclonal antibody E1D1 recognizes an epitope generated by both gH and gL, and its binding to the L65A mutant is diminished, consistent with an al- We have recently shown that two gL residues (54 and 94) determine the specificity of gB activation in membrane fusion (32), potentially through direct interactions with gB. Rhesus LCV gL (Rh-gL) and EBV gL are highly homologous (82% identity) (Fig.…”

Section: Resultsmentioning

confidence: 62%

“…The gL subunit is important for gH folding (28,30,31) and is implicated in the specificity of EBV gB activation (32). In EBV gH/gL, gL (residues 24-131) plays a key structural role in D-I (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…4C), potentially defining an extended surface region important to gH/gL function in EBV entry. gL residues that regulate the specificity of gB activation (32) have been mapped to the surface of D-I (Q54) and to the D-I/D-II interface (K94). Q54 is surface-exposed and surrounded by other prominently displayed D-I residues, which together could form a gB binding site.…”

Section: Resultsmentioning

confidence: 99%

“…(Fig. 3A) (32,33). Mutants in leucine residues in gH were generated in the Nterminal region spanning residues 54-74, which are found in D-I or the helical junction to D-II (34).…”

Section: Resultsmentioning

confidence: 99%

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Crystal structure of the Epstein-Barr virus (EBV) glycoprotein H/glycoprotein L (gH/gL) complex

Matsuura

Kirschner

Longnecker

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The Epstein-Barr virus (EBV) is a γ-herpesvirus that infects B cells and epithelial cells and that has been linked to malignancies in both cell types in vivo. EBV, like other herpesviruses, has three glycoproteins, glycoprotein B (gB), gH, and gL, that form the core membrane fusion machinery mediating viral penetration into the cell. The gH and gL proteins associate to form a heterodimeric complex, which is necessary for efficient membrane fusion and also implicated in direct binding to epithelial cell receptors required for viral entry. To gain insight into the mechanistic role of gH/gL, we determined the crystal structure of the EBV gH/gL complex. The structure is comprised of four domains organized along the longest axis of the molecule. Comparisons with homologous HSV-2 gH/gL and partial pseudorabies virus gH structures support the domain boundaries determined for the EBV gH/gL structure and illustrate significant differences in interdomain packing angles. The gL subunit and N-terminal residues of gH form a globular domain at one end of the structure, implicated in interactions with gB and activation of membrane fusion. The C-terminal domain of gH, proximal to the viral membrane, is also implicated in membrane fusion. The gH/gL structure locates an integrin binding motif, implicated in epithelial cell entry, on a prominent loop in the central region of the structure. Multiple regions of gH/gL, including its two extreme ends, are functionally important, consistent with the multiple roles of gH/gL in EBV entry.

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Section: Resultsmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…(Fig. 3A) (32,33). Mutants in leucine residues in gH were generated in the Nterminal region spanning residues 54-74, which are found in D-I or the helical junction to D-II (34).…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Crystal structure of the Epstein-Barr virus (EBV) glycoprotein H/glycoprotein L (gH/gL) complex

Matsuura

Kirschner

Longnecker

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

151

205

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“…Interestingly, the same face of gH/gL is implicated for gB binding in EBV, albeit more N-terminal on the heterodimer, within gL (23,24). Another anti-HSV neutralizing antibody, 52S, inhibits cell-cell fusion and binds to gH at H2/H3 border (21).…”

Section: Significancementioning

confidence: 99%

Mechanism for neutralizing activity by the anti-CMV gH/gL monoclonal antibody MSL-109

Fouts¹,

Comps-Agrar²,

Stengel

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cytomegalovirus (CMV) is a widespread opportunistic pathogen that causes birth defects when transmitted transplacentally and severe systemic illness in immunocompromised individuals. MSL-109, a human monoclonal IgG isolated from a CMV seropositive individual, binds to the essential CMV entry glycoprotein H (gH) and prevents infection of cells. Here, we suggest a mechanism for neutralization activity by MSL-109. We define a genetic basis for resistance to MSL-109 and have generated a structural model of gH that reveals the epitope of this neutralizing antibody. Using surface-based, time-resolved FRET, we demonstrate that gH/gL interacts with glycoprotein B (gB). Additionally, we detect homodimers of soluble gH/gL heterodimers and confirm this novel oligomeric assembly on full-length gH/gL expressed on the cell surface. We show that MSL-109 perturbs the dimerization of gH/gL:gH/gL, suggesting that dimerization of gH/gL may be required for infectivity. gH/gL homodimerization may be conserved between alpha-and betaherpesviruses, because both CMV and HSV gH/gL demonstrate self-association in the FRET system. This study provides evidence for a novel mechanism of action for MSL-109 and reveals a previously undescribed aspect of viral entry that may be susceptible to therapeutic intervention.H uman CMV is a β-group herpesvirus that causes severe complications in immunocompromised individuals. CMV infects between 60% and 80% of the adult population worldwide (1). As with other herpesviruses, CMV establishes a lifelong latency in the host but is largely asymptomatic among infected immunocompetent individuals (2). However, during severe immunosuppression (e.g., in the setting of hematopoietic stem cell transplantation and solid organ transplantation, or advanced HIV/AIDS), CMV reactivation or primary infection can result in life-threatening disease. In addition, the acquisition of primary CMV infection during pregnancy, although of little consequence to the mother, can have severe clinical consequences in the developing fetus (3, 4). The current therapy for CMV disease is treatment with either ganciclovir or valganciclovir, which are associated with significant toxicity and not approved for use in pregnant women or for congenitally damaged infants (5). CMV hyperimmunoglobulin (CMV-HIG; pooled human IgG from CMV-positive individuals) has demonstrated efficacy in certain solid organ transplant recipients and more recently found to show limited success in protecting infants from congenital CMV disease (1, 6, 7). These findings suggest that more potent or differently targeted antibody therapy may prove to be an effective and safe alternative to the current forms of CMV therapy.Like other herpesviruses, CMV uses multiprotein entry complexes to initiate infection of host cells. Three glycoproteins, gB, gH, and gL, known as the "core fusion machinery," are conserved in all herpesviruses and are required for entry (8,9). gB, the most conserved of these glycoproteins, exists as a homotrimer and catalyzes membrane fusion during vira...

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GB and gH/gL fusion machinery: a promising target for vaccines to prevent Epstein-Barr virus infection

Liu,

Li,

Qiao

et al. 2024

Arch Virol

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Functional Analysis of Glycoprotein L (gL) from Rhesus Lymphocryptovirus in Epstein-Barr Virus-Mediated Cell Fusion Indicates a Direct Role of gL in gB-Induced Membrane Fusion

Cited by 39 publications

References 50 publications

Crystal structure of the Epstein-Barr virus (EBV) glycoprotein H/glycoprotein L (gH/gL) complex

Crystal structure of the Epstein-Barr virus (EBV) glycoprotein H/glycoprotein L (gH/gL) complex

Mechanism for neutralizing activity by the anti-CMV gH/gL monoclonal antibody MSL-109

GB and gH/gL fusion machinery: a promising target for vaccines to prevent Epstein-Barr virus infection

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