Oral 1 STRUCTURE AND ACTIVATION OF PARAMYXOVIRUS FUSION GLYCOPROTEINS

Fusion of the lipid envelope of paramyxoviruses with the host cell plasma membrane during virus entry is mediated by the F protein, a trimeric extracellular transmembrane-anchored glycoprotein. During F-mediated fusion, its fusion peptide inserts into the host cell membrane, followed by large-scale refolding from a largely globular pre-fusion conformation to a golf tee-shaped postfusion conformation. For most paramyxoviruses, the F conformational change is triggered by binding of the attachment glycoprotein (HN/H or G) to cellular receptors, which is thought to enable an interaction of F with the Nterminal stalk domain of the attachment protein. However, for Respiratory Syncytial virus (RSV) and Metapneumovirus (MPV), activation of the F protein does not require the attachment glycoprotein, suggesting a fundamentally different mechanism for fusion activation. Here we will present negative stain EM and crystal structure analyses of the prefusion conformation of the Hendra virus F protein, a member of the henipavirus genus that is known to cause disease in horses and humans with high mortality rate. The overall fold of the Hendra F protein is remarkably similar to that of parainfluenzavirus 5 F, despite their low homology (~27% identify). The most notable differences in secondary structure occur on the Hendra F protein surface. By contrast, comparisons to the RSV F prefusion structure show more significant structural differences. These larger structural differences between RSV and Hendra/PIV5 F proteins may be linked to their different modes of activation. Structural features in key areas of the henipavirus F structure, such as the fusion peptide cleavage site, the heptad repeat A region, and the putative interaction site for G will be discussed, along with their implications for understanding the mechanism of F activation. Disclosure of Interest: None declared