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Structure of the glycoprotein of Mokola virus in its post-fusion conformation
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International audience. Mokola virus (MOKV) is a rhabdovirus belonging to the lyssavirus genus close to the rabies virus (RABV). MOKV, like all members of this genus, causes fatal encephalitis in mammals. Entry of MOKV into host cells is mediated by its transmembrane glycoprotein G. First, G binds cellular receptors, triggering endocytosis of the virus. Then, in the acidic environment of the endosome, G undergoes a conformational change from a pre- to a post-fusion state, which catalyzes the fusion of the viral and endosomal membranes. We solved the crystalline structure of MOKV G ectodomain. In the crystal, MOKV G monomer is similar to the protomer of the G trimeric post-fusion state of vesicular stomatitis virus (VSV). Electron microscopy observations on VSV particles pseudotyped with MOKV G show that MOKV G can adopt the trimeric post-fusion conformation on the viral surface. We also showed that MOKV G can reorganize into regular arrays at acidic pH. Sequence alignment of MOKV G with RABV G allows the localization of RABV G antigenic sites on MOKV G. Repositioning of MOKV G domains on the pre-fusion structure of VSV G reveals that the antigenic sites are located in the most exposed part of G and are therefore highly accessible to antibodies. Finally, analysis of MOKV G structure allows the identification of pH-sensitive molecular switches. In particular, a long helix, which constitutes the core of the post-fusion trimer for class III fusion glycoproteins, contains several conserved acidic residues localized at the trimeric interface. Most of them are aligned along this helix and point toward the 3-fold axis. These residues must be protonated in the post-fusion trimer of MOKV G to be stable. At high pH, when negatively charged, these acidic residues destabilize the interface, which explains the reversibility of the conformational change. This structure of a rabies-related virus glycoprotein paves the way for the development of a pan-lyssavirus vaccine.
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