Class II Fusion Proteins

Abstract

Enveloped viruses rely on fusion proteins in their envelope to fuse the viral membrane to the host-cell membrane. This key step in viral entry delivers the viral genome into the cytoplasm for replication. Although class II fusion proteins are genetically and structurally unrelated to class I fusion proteins, they use the same physical principles and topology as other fusion proteins to drive membrane fusion. Exposure of a fusion loop first allows it to insert into the host-cell membrane. Conserved hydrophobic residues in the fusion loop act as an anchor, which penetrates only partway into the outer bilayer leaflet of the host-cell membrane. Subsequent folding back of the fusion protein on itself directs the C-terminal viral transmembrane anchor towards the fusion loop. This fold-back forces the host-cell membrane (held by the fusion loop) and the viral membrane (held by the C-terminal transmembrane anchor) against each other, resulting in membrane fusion. In class II fusion proteins, the fold-back is triggered by the reduced pH of an endosome, and is accompanied by the assembly of fusion protein monomers into trimers. The fold-back occurs by domain rearrangement rather than by an extensive refolding of secondary structure, but this domain rearrangement and the assembly of monomers into trimers together bury a large surface area. The energy that is thus released exerts a bending force on the apposed viral and cellular membranes, causing them to bend towards each other and, eventually, to fuse.

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

“…This similarity suggested that rGc had adopted its predicted post-fusion conformation, as recently evidenced for Andes virus Gc by sucrose sedimentation in an in vitro system [46]. Because attempts to crystallize the membrane inserted form of rGc failed, we introduced a mutation in the predicted fusion loop, which caused rosette formation upon concentration after detergent solubilization (in line with the model for insertion of trimeric post-fusion class II proteins into membranes, reviewed in [47, 48]). The fusion loop mutation was inspired by a recent report showing that the trimeric post-fusion form of the flavivirus class II fusion protein E could be crystallized in its post-fusion, trimeric form in the absence of detergent by replacing Trp 101 by histidine, as this residue is prominently exposed at the membrane facing-end of the post-fusion trimer [49].…”

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

“…It has been shown that in class II membrane fusion proteins there is a hinge motion between domain I and II [reviewed in [19]], and mutations at that region affect the pH threshold for fusion. However it seems that in phlebovirus G C this region is more rigid [25].…”

“…In both routes, however, the virus is directed to an endosomal compartment where the glycoproteins respond to the reduced pH of the compartment with a sequence of conformational changes [17]. These conformational changes expose a hydrophobic motif, which is inserted into the endosomal membrane [18, 19]. The glycoprotein then folds back on itself, forcing the cell membrane (held by the fusion motif) and the viral membrane (held by a transmembrane anchor) to proximity, inducing the viral and endosomal membranes to fuse [20–22].…”

KDEL Receptors Assist Dengue Virus Exit from the Endoplasmic Reticulum

“…for replication or extracellular milieu for another infection round), and is delivered in the form of trafficking vesicles (Humphries and Way, 2013;Modis, 2013;Rothman and Orci, 1992;Sun et al, 2013). Therefore, KDELR can be considered as intracellular receptors for DENV/RSP trafficking, whose function is akin to the role played by cell surface proteins in mediating viral entry.…”