Identification and Visualization of Functionally Important Domains and Residues in Herpes Simplex Virus Glycoprotein K(gK) Using a Combination of Phylogenetics and Protein Modeling

Abstract

Alphaherpesviruses are a subfamily of herpesviruses that include the significant human pathogens herpes simplex viruses (HSV) and varicella zoster virus (VZV). Glycoprotein K (gK), conserved in all alphaherpesviruses, is a multi-membrane spanning virion glycoprotein essential for virus entry into neuronal axons, virion assembly, and pathogenesis. Despite these critical functions, little is known about which gK domains and residues are most important for maintaining these functions across all alphaherpesviruses. Herein, we employed phylogenetic and structural analyses including the use of a novel model for evolutionary rate variation across residues to predict conserved gK functional domains. We found marked heterogeneity in the evolutionary rate at the level of both individual residues and domains, presumably as a result of varying selective constraints. To clarify the potential role of conserved sequence features, we predicted the structures of several gK orthologs. Congruent with our phylogenetic analysis, slowly evolving residues were identified at potentially structurally significant positions across domains. We found that using a quantitative measure of amino acid rate variation combined with molecular modeling we were able to identify amino acids predicted to be critical for gK protein structure/function. This analysis yields targets for the design of anti-herpesvirus therapeutic strategies across all alphaherpesvirus species that would be absent from more traditional analyses of conservation.

Novel Oncolytic Herpes Simplex Virus 1 VC2 Promotes Long-Lasting, Systemic Anti-melanoma Tumor Immune Responses and Increased Survival in an Immunocompetent B16F10-Derived Mouse Melanoma Model

“…The inability to enter neurons abolishes the establishment and maintenance of a latent infection and thus greatly improves its safety profile. This virus, VC2, possesses a deletion of 38 amino acids in the N terminus of the viral envelope glycoprotein K (gK), which is highly conserved among all alphaherpesviruses ( 34 ). We have shown that this mutation in the N terminus of gK precludes entry by fusion and forces the virus to enter cells via endocytosis ( 35 ).…”

Rational Design of Live-Attenuated Vaccines against Herpes Simplex Viruses

“…The majority of mutations that cause enhanced virus-induced cell fusion are found within gK mediated primarily by interactions between gK and the amino terminus of gB [ 41 , 42 , 43 , 44 ]. Together gK and UL20 are highly conserved among neurotrophic alphaherpesviruses indicating highly conserved functions within this virus family [ 45 , 46 , 47 ]. Additionally, the amino terminus of gK is required for the interaction between gB and the cellular protein Akt.…”

Two Sides to Every Story: Herpes Simplex Type-1 Viral Glycoproteins gB, gD, gH/gL, gK, and Cellular Receptors Function as Key Players in Membrane Fusion

“…Although gK may not directly bind to HSV-1 receptors, overexpression of gK increases expression of 3-OS-HS, PILR alpha, nectin-1, and nectin-2 receptors and severity of corneal scarring, highlighting its role in viral pathogenesis [ 59 ]. gK is highly conserved among all neurotropic alphaherpesviruses, and thus, it is hypothesized to play important roles in neuronal infection and neuropathogenesis [ 28 ]. HSV mutant viruses overexpressing gK were reported to exacerbate mouse corneal scaring attributed at least in part to an amino-terminal 8 amino acid peptide.…”