1.G.1 The Viral Pore-forming Membrane Fusion Protein-1 (VMFP1) Family
Influenza virus hemagglutinin (HA) is a type I (Class I) viral membrane fusion protein (VMFP), best characterized of its class. Like all Class I VMFPs, it requires proteolytic processing to generate the fusion competent form and is found on the virion projecting from the viral membrane as spikes. It is mostly α-helical and forms trimers. The fusion peptide is buried in the subunit interface in the native protein and is near the N-terminus. The membrane-embedded form is also a trimer, both before and after fusion (White et al. 2008). The final conformation of the complete ectodomain of the HA2 subunit of influenza hemagglutinin can by itself drive low pH-dependent fusion and pore formation (Kim et al., 2011). The G13A mutation promotes leaky membranes (Lai and Tamm 2010).
HA contains a fusion peptide, a receptor binding site, a metastable structural motif, and the transmembrane domain. The first step of influenza virus entry is recognition of the host cell receptor molecule, terminal α-sialic acid, by HA. This multivalent attachment by multiple copies of trimetric HA triggers endocytosis of influenza virus that is contained in the endosome. The endosome-trapped virus traffics via a unidirectional pathway to a location near the nucleus. At this location, the interior pH of the endosome becomes acidic that induces a dramatic conformational change in HA to insert the fusion peptide into the host membrane, induce juxtaposition of the two membranes, and form a fusion pore that allows the release of the genome segments of influenza virus (Luo, 2012).