6esc | pdb_00006esc
Crystal structure of Pseudorabies virus glycoprotein B
Structural highlights
Function[G3G8X1_9ALPH] Envelope glycoprotein that forms spikes at the surface of virion envelope. Essential for the initial attachment to heparan sulfate moities of the host cell surface proteoglycans. Involved in fusion of viral and cellular membranes leading to virus entry into the host cell. Following initial binding to its host receptors, membrane fusion is mediated by the fusion machinery composed at least of gB and the heterodimer gH/gL. May be involved in the fusion between the virion envelope and the outer nuclear membrane during virion egress.[HAMAP-Rule:MF_04032] Publication Abstract from PubMedConserved across the Herpesviridae family, glycoprotein B (gB) is responsible for driving fusion of the viral envelope with the host cell membrane for entry upon receptor binding and activation by the viral gH/gL complex. Although crystal structures of the gB ectodomain of several herpesviruses have been reported, the membrane fusion mechanism has remained elusive. Here, we report the X-ray structure of the Pseudorabies virus (PrV) gB ectodomain, revealing a typical class III post-fusion trimer that binds membranes via its fusion loops (FLs) in a cholesterol-dependent manner. Mutagenesis of FL residues allowed us to dissect those interacting with distinct sub-regions of the lipid bilayer and their role for membrane interactions. We tested 15 gB variants for their ability to bind to liposomes, and further investigated a subset of them in functional assays. We found that PrV gB FL residues Trp187, Tyr192, Phe275 and Tyr276, which were essential for liposome binding and for fusion in a cellular and viral context, form a continuous hydrophobic patch at the gB trimer surface. Together with reported results from other alpha-herpesvirus gBs, our data suggest a model in which Phe275 from the tip of FL2 protrudes deeper into the hydrocarbon core of the lipid bilayer, while the side chains of Trp187, Tyr192 and Tyr276 form a rim that inserts into the more superficial, interfacial region of the membrane to catalyze the fusion process. Comparative analysis with gB from beta- and gamma-herpesviruses suggest that this membrane-interaction mode is valid for gB from all herpesviruses.IMPORTANCE Herpesviruses are common human and animal pathogens, which infect cells by entering via fusion of viral and cellular membranes and which cause life-long and incurable infections. Central to the membrane fusion event for entry is glycoprotein B (gB), which is the most conserved envelope protein across the herpesvirus family. Like other viral fusion proteins, gB anchors itself into the target membrane via two polypeptide segments called fusion loops (FL). The molecular details of how gB FLs insert into the lipid bilayer have not been described. We provide here structural and functional data regarding key FL residues of gB from Pseudorabies virus, a porcine herpesvirus of veterinary concern, which allows us to propose, for the first time, a molecular model to understand how the initial interactions by gB from all herpesviruses with target membranes are established. Structure-function dissection of the Pseudorabies virus glycoprotein B fusion loops.,Vallbracht M, Brun D, Tassinari M, Vaney MC, Pehau-Arnaudet G, Guardado-Calvo P, Haouz A, Klupp BG, Mettenleiter TC, Rey FA, Backovic M J Virol. 2017 Oct 18. pii: JVI.01203-17. doi: 10.1128/JVI.01203-17. PMID:29046441[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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