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Abstract

The Bunyaviridae family of enveloped RNA viruses includes five genuses, orthobunyaviruses, hantaviruses, phleboviruses, nairoviruses and tospoviruses. It has not been determined which Bunyavirus protein mediates virion:cell membrane fusion. Class II viral fusion proteins (betapenetrenes), encoded by members of the Alphaviridae and Flaviviridae, are comprised of three antiparallel beta sheet domains with an internal fusion peptide located at the end of domain II. Proteomics computational analyses indicate that the carboxyl terminal glycoprotein (Gc) encoded by Sandfly fever virus (SAN), a phlebovirus, has a significant amino acid sequence similarity with envelope protein 1 (E1), the class II fusion protein of Sindbis virus (SIN), an Alphavirus. Similar sequences and common structural/functional motifs, including domains with a high propensity to interface with bilayer membranes, are located collinearly in SAN Gc and SIN E1. Gc encoded by members of each Bunyavirus genus share several sequence and structural motifs. These results suggest that Gc of Bunyaviridae, and similar proteins of Tenuiviruses and a group of Caenorhabditis elegans retroviruses, are class II viral fusion proteins. Comparisons of divergent viral fusion proteins can reveal features essential for virion:cell fusion, and suggest drug and vaccine strategies.

Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc

“…They heterodimerize in the ER and are then transported to the site of budding, which is the Golgi apparatus for a number of bunyaviruses [13], although some hantaviruses were reported to bud at the plasma membrane [14, 15]. The bunyavirus Gc glycoproteins were predicted to adopt a “class II” fold using proteomic computational analyses [16], and Gc from Andes virus (a hantavirus endemic in South America) was modeled using the flavivirus E protein as template [17], thereby predicting the location of the “fusion loop”, which was later functionally confirmed as important for fusion by site directed mutagenesis [18]. Similarly, for La Crosse virus in the Orthobunyavirus genus, mutagenesis of the predicted fusion loop region—deduced by comparison to the alphavirus fusion glycoprotein E1—confirmed the importance of this region for entry [19].…”

Crystal Structure of Glycoprotein C from a Hantavirus in the Post-fusion Conformation

“…Based on bioinformatic studies and in vitro experiments using synthetic peptides it was postulated that hantavirus G C adopts a class II membrane fusion protein fold [23, 24]. Until recently, viral class II fusion proteins were thought to be restricted to members of the Flavivirus genus (family: Flaviviridae ) and the Togaviridae .…”

Thrips and tospoviruses come of age: Mapping determinants of insect transmission

“…Sin et al (1) validate the hypothesis that, like the animal-infecting bunyaviruses, the GPs encoded by plant-infecting members of the family are necessary for infection of animal host cells. Modeling the structure of a bunyavirus G C protein revealed that the GPs may be class II fusion proteins, and sequence comparisons showed TSWV G N protein shares sequence similarity with another viral attachment protein, sindbis virus E2 (23). These data are supported by findings that TSWV G N likely plays a role in virus attachment to thrips midgut epithelial cells (10), and that G C is cleaved at acidic pH, consistent with it serving as a fusion protein activated at low pH (24).…”