Abstract

Mokola virus (MOKV) belongs to the lyssavirus genus. As other genus members-including rabies virus (RABV)-it causes deadly encephalitis in mammals. MOKV entry into host cells is mediated by its transmembrane glycoprotein G. First, G binds cellular receptors, triggering virion endocytosis. Then, in the acidic endosomal environment, G undergoes a conformational change from its pre- toward its post-fusion state that catalyzes the merger of the viral and endosomal membranes. Here, we have determined the crystal structure of a soluble MOKV G ectodomain in which the hydrophobic fusion loops have been replaced by more hydrophilic sequences. The crystal structure corresponds to a monomer that is similar to the protomer of the trimeric post-fusion state of vesicular stomatitis virus (VSV) G. However, by electron microscopy, we show that, at low pH, at the surface of pseudotyped VSV, MOKV spikes adopt the trimeric post-fusion conformation and have a tendency to reorganize into regular arrays. Sequence alignment between MOKV G and RABV G allows a precise location of RABV G antigenic sites. Repositioning MOKV G domains on VSV G pre-fusion structure reveals that antigenic sites are located in the most exposed part of the molecule in its pre-fusion conformation and are therefore very accessible to antibodies. Furthermore, the structure allows the identification of pH-sensitive molecular switches. Specifically, the long helix, which constitutes the core of the post-fusion trimer for class III fusion glycoproteins, contains many acidic residues located at the trimeric interface. Several of them, aligned along the helix, point toward the trimer axis. They have to be protonated for the post-fusion trimer to be stable. At high pH, when they are negatively charged, they destabilize the interface, which explains the conformational change reversibility. Finally, the present structure will be of great help to perform rational mutagenesis on lyssavirus glycoproteins.

Highlights

  • IntroductionAll lyssaviruses cause acute progressive encephalitis (rabies disease) in mammals and are transmitted between susceptible individuals directly by bites, scratches, or contamination of mucous membranes with infected saliva

  • Lyssavirus is a genus of the Rhabdoviridae family, which consists of 16 species

  • The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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Summary

Introduction

All lyssaviruses cause acute progressive encephalitis (rabies disease) in mammals and are transmitted between susceptible individuals directly by bites, scratches, or contamination of mucous membranes with infected saliva They have been classified into three phylogroups: the prototype of phylogroup I is rabies virus (RABV), the prototype of phylogroup II is Mokola virus (MOKV), and the prototype of phylogroup III is West Caucasian bat lyssavirus (WCBV) [1]. The acidic environment of the endosome induces a huge conformational change of G from a native (or pre-fusion) state toward a final (or post-fusion) state that catalyzes fusion of the viral envelope with the endosomal membrane [10] This results in the release of the nucleocapsid in the cytoplasm for the subsequent steps of infection

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