The three lives of viral fusion peptides

Abstract

Fusion peptides comprise conserved hydrophobic domains absolutely required for the fusogenic activity of glycoproteins from divergent virus families. After 30 years of intensive research efforts, the structures and functions underlying their high degree of sequence conservation are not fully elucidated. The long-hydrophobic viral fusion peptide (VFP) sequences are structurally constrained to access three successive states after biogenesis. Firstly, the VFP sequence must fulfill the set of native interactions required for (meta) stable folding within the globular ectodomains of glycoprotein complexes. Secondly, at the onset of the fusion process, they get transferred into the target cell membrane and adopt specific conformations therein. According to commonly accepted mechanistic models, membrane-bound states of the VFP might promote the lipid bilayer remodeling required for virus-cell membrane merger. Finally, at least in some instances, several VFPs co-assemble with transmembrane anchors into membrane integral helical bundles, following a locking movement hypothetically coupled to fusion-pore expansion. Here we review different aspects of the three major states of the VFPs, including the functional assistance by other membrane-transferring glycoprotein regions, and discuss briefly their potential as targets for clinical intervention.

A Coiled-Coil Peptide Shaping Lipid Bilayers upon Fusion

“…In the docked state K can bind as monomer to the membranes and adopt its second role. It acts as a membrane active agent supporting the membrane deformation and rupture, comparable with the suggested role of certain fusion peptides during viral entry (78). Unlike in neuronal vesicle fusion where primed, i.e., docked vesicles proceed rapidly to full fusion specifically triggered by Ca 2þ influx, we propose that in the E/K system the slow accumulation of membrane-bound K at the docking site by diffusion and/or dissociation of the complex causes the further progression to full fusion nonspecifically.…”

Alteration of a Second Putative Fusion Peptide of Structural Glycoprotein E2 of Classical Swine Fever Virus Alters Virus Replication and Virulence in Swine

“…1), was found within a region where the corresponding Kyte-Doolittle hydropathy plot was flat. This trend is typically observed within class II IFPs, which insert into the external leaflet of the target membrane (25,32). The class II fusion glycoproteins share a fold composed of ␤-domains I, II, and III (34).…”

“…In comparison with most class I FPs, class II IFPs are shorter, less hydrophobic sequences (usually lacking aliphatic residues) and are comparatively enriched in aromatics (25). Besides these features, class II IFPs follow common patterns of interaction with membranes.…”

“…Besides these features, class II IFPs follow common patterns of interaction with membranes. These interactions are defined by the stabilization of the short loop conformation upon membrane association, shallow insertion, and a high dose requirement for generating lipid bilayer perturbations (25). In this regard, the conformations adopted by representative synthetic peptides (compatible with ␤-type structures), their capacities for inserting into lipid monolayers and for partitioning from water solution into lipid bilayers, their membrane penetration depth, and their scored membraneperturbing activity levels ( Fig.…”

“…To perform these experiments, synthetic peptides spFPII.wt, spFPII.2, and spFPII.5 were tagged with the fluorophore 7-nitrobenz-2-oxa-l,3-diazole-4 (NBD) at the N terminus and membranes were labeled by inclusion of PE-Rho in the lipid composition. (25). These loops are enriched in Gly residues and often stabilized through DiS bridges.…”