Structure, Function, and Evolution of the Orthobunyavirus Membrane Fusion Glycoprotein  : [Preprint]

SummaryLa Crosse virus, responsible for pediatric encephalitis in the USA, and Schmallenberg virus, a highly teratogenic veterinary virus in Europe, belong to the large Orthobunyavirus genus of zoonotic arthropod-borne pathogens distributed worldwide. Viruses in this understudied genus cause CNS infections or fever with debilitating arthralgia/myalgia syndromes, with no effective treatment. The main surface antigen, glycoprotein Gc (1000 residues), has a variable N-terminal half (GcS) targeted by the patients’ antibody response, and a conserved C-terminal moiety (GcF) responsible for membrane fusion during cell entry. Here we report the X-ray structure of post-fusion La Crosse and Schmallenberg virus GcF, revealing the molecular determinants for hairpin formation and trimerization required to drive membrane fusion. We further experimentally confirm the role of residues in the fusion loops and in a vestigial ERtranslocation sequence at the GcS-GcF junction. The resulting knowledge provides essential molecular underpinnings for the future development of potential therapeutic treatments and vaccines.

Funding Information: This research was performed as part of the Zoonoses Anticipation and Preparedness Initiative (ZAPI project; IMI Grant Agreement n°115760), with the assistance and financial support of IMI and the European Commission, and in-kind contributions from EFPIA partners. Additional funding was provided by Institut Pasteur, CNRS and grant ANR-10-LABX-62-IBEID to F.A.R. J.H. received the Pasteur-Cantarini fellowship for 24 months and was further supported by the Région Ile de France (Domaine d’intêret majeur innovative technologies for life sciences, DIM 1HEALTH).



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