Structure, function, and evolution of the Orthobunyavirus membrane fusion glycoprotein
Jan Hellert,
Andrea Aebischer,
Ahmed Haouz,
Pablo Guardado-Calvo,
Sven Reiche,
Martin Beer,
Félix A. Rey
Affiliations
Jan Hellert
Structural Virology Unit, Institut Pasteur – Université Paris-Cité, CNRS UMR 3569, 25-28 rue du Dr. Roux, 75015 Paris, France; Centre for Structural Systems Biology (CSSB), Leibniz-Institut für Virologie (LIV), Notkestraße 85, 22607 Hamburg, Germany
Andrea Aebischer
Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald, Germany; Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald, Germany
Ahmed Haouz
Crystallography Platform C2RT, Institut Pasteur, CNRS UMR 3528, 25-28 rue du Dr. Roux, 75015 Paris, France
Pablo Guardado-Calvo
Structural Virology Unit, Institut Pasteur – Université Paris-Cité, CNRS UMR 3569, 25-28 rue du Dr. Roux, 75015 Paris, France
Sven Reiche
Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald, Germany
Martin Beer
Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald, Germany; Corresponding author
Félix A. Rey
Structural Virology Unit, Institut Pasteur – Université Paris-Cité, CNRS UMR 3569, 25-28 rue du Dr. Roux, 75015 Paris, France; Corresponding author
Summary: La Crosse virus, responsible for pediatric encephalitis in the United States, 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 under-studied genus cause CNS infections or fever with debilitating arthralgia/myalgia syndromes, with no effective treatment. The main surface antigen, glycoprotein Gc (∼1,000 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 endoplasmic reticulum (ER) translocation sequence at the GcS-GcF junction. The resulting knowledge provides essential molecular underpinnings for future development of potential therapeutic treatments and vaccines.
