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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).

References associated with 1.G.1 family:

Apellaniz B., Huarte N., Largo E. and Nieva JL. (2014). The three lives of viral fusion peptides. Chem Phys Lipids. 181:40-55. 24704587
Kim, C.S., R.F. Epand, E. Leikina, R.M. Epand, and L.V. Chernomordik. (2011). The final conformation of the complete ectodomain of the HA2 subunit of influenza hemagglutinin can by itself drive low pH-dependent fusion. J. Biol. Chem. 286: 13226-13234. 21292763
Lai, A.L. and L.K. Tamm. (2010). Shallow boomerang-shaped influenza hemagglutinin G13A mutant structure promotes leaky membrane fusion. J. Biol. Chem. 285: 37467-37475. 20826788
Luo, M. (2012). Influenza virus entry. Adv Exp Med Biol 726: 201-221. 22297515
White, J.M., S.E. Delos, M. Brecher, and K. Schornberg. (2008). Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme. Crit. Rev. Biochem. Mol. Biol. 43: 189-219. 18568847