New Biophysical Approaches Reveal the Dynamics and Mechanics of Type I Viral Fusion Machinery and Their Interplay with Membranes

Abstract

Protein-mediated membrane fusion is a highly regulated biological process essential for cellular and organismal functions and infection by enveloped viruses. During viral entry the membrane fusion reaction is catalyzed by specialized protein machinery on the viral surface. These viral fusion proteins undergo a series of dramatic structural changes during membrane fusion where they engage, remodel, and ultimately fuse with the host membrane. The structural and dynamic nature of these conformational changes and their impact on the membranes have long-eluded characterization. Recent advances in structural and biophysical methodologies have enabled researchers to directly observe viral fusion proteins as they carry out their functions during membrane fusion. Here we review the structure and function of type I viral fusion proteins and mechanisms of protein-mediated membrane fusion. We highlight how recent technological advances and new biophysical approaches are providing unprecedented new insight into the membrane fusion reaction.Viruses 2020, 12, 413 2 of 21 built. Type II fusion proteins are found in viruses including flaviviruses and alphaviruses such as Dengue, Zika, and Chikungunya viruses, and even have been identified in eukaryotic cell-cell fusion systems [9][10][11][12]. Type III fusion proteins are found in rhabdoviruses (such as Rabies and Vesicular Stomatatis virus G glycoproteins), herpesviruses (Herpes Simplex virus 1 gB protein), as well as baculovirus [12][13][14][15][16]. While the individual folds exhibited by these classes are completely different, they share common functional traits in that all adopt a pre-fusion conformation prior to activation in which one terminus of the protein is anchored in the virus membrane by a transmembrane domain and a second membrane active component, either a fusion peptide or loop, is sequestered from interacting with membranes ( Figure 1) [12]. A trigger or set of triggers, such as exposure to low pH in endosomes or receptor binding, spurs the machinery to reorganize into a post-fusion state in which the two membrane active components are colocalized.Until recently, static structures of the pre-and post-fusion states of isolated fusion protein ectodomains and biochemical or spectroscopic measurements were the primary pieces of information that informed our models of membrane fusion. While the static structures provide defined endpoints for the conformational change that drives membrane fusion, they do not tell us how these conformational changes occur or how these proteins interact with and perturb the lipid membrane during fusion. Likewise, fluorescence spectroscopy and circular dichroism studies have shown that HA-fusion activation leads to population of discernable intermediates rather than transitioning directly and irreversibly from pre-to post-fusion states [17][18][19][20]. These studies show that not all HAs respond to activation in the same way and some require different pH conditions to fully activate [20]. While such studies provided valuable information...

SARS-CoV-2 (COVID-19) and cystic fibrosis

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Lipidomics Issues on Human Positive ssRNA Virus Infection: An Update

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Ectodomain Pulling Combines with Fusion Peptide Inserting to Provide Cooperative Fusion for Influenza Virus and HIV

“…Viral fusion proteins are classified into three classes. The fusion proteins of influenza and HIV (hemagglutinin and gp120/gp41, respectively) belong to class I, and both of them form trimers [ 7 ]. Several studies suggest that these proteins should act as a team to accomplish the viral fusion [ 24 , 26 , 27 ].…”

“…The fusion peptide goes out from the hydrophobic pocket of the fusion protein ectodomain to incorporate into the lipid bilayer of the target membrane as an effective anchor. In the ensuing course of continuing conformational rearrangements, the fusion protein refolds back, pulling the target cellular membrane with the incorporated fusion peptide toward the viral membrane [ 7 ]. Upon coming into close contact, these membranes merge, resulting in formation of the fusion pore, via which the viral genome can release into the cytoplasm.…”