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

Paul J F Rider,Misagh Naderi,Konstantin G Kousoulas,Jeremy M Brown,Lyndon M Coghill,Michal Brylinski

doi:10.1038/s41598-019-50490-9

Paul J F Rider, Misagh Naderi + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-50490-9

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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.

Highlights

Alphaherpesviruses are distinguished from the beta and gamma subfamilies by their ability to establish and maintain latency in the central and/or peripheral nervous systems of the host[7]
GK and UL20 are highly conserved among neurotropic alphaherpesviruses. Glycoprotein K (gK) and UL20 have been shown to interact and these interactions are important for virus entry, membrane fusion, cytoplasmic virion envelopment and egress[8,9,10,11,12,13,14,15,16,17,18,19]
We inferred the phylogenetic relationships among 18 species of alphaherpesviruses using a set of genes orthologous to herpes simplex viruses (HSV)-1 gK (Table 1, Fig. 1)

Summary

Introduction

Alphaherpesviruses are distinguished from the beta and gamma subfamilies by their ability to establish and maintain latency in the central and/or peripheral nervous systems of the host[7]. The mechanism by which gK functions to facilitate membrane fusion during virus entry and spread, as well as cytoplasmic virion envelopment, is not well understood and is the focus of ongoing work. An intracellular domain of gK is likely to be involved in virion assembly Given this role, the domain should have experienced a relatively stable set of interactions during the diversification of alphaherpesviruses, and would be expected to evolve slowly in order to maintain the fidelity of these interactions. Structural predictions may suggest that the same domain has a less well-defined structure than other parts of gK, requiring less precision in folding to maintain function In this case, the domain’s primary sequence may evolve relatively quickly. The contrasts between these predictions allow us to elucidate the relative strength of the predictions

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