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).
This family belongs to the Membrane Fusion Pore (MFP) Superfamily.
References:
Apellaniz B., Huarte N., Largo E. and Nieva JL. (2014). The three lives of viral fusion peptides. Chem Phys Lipids. 181:40-55.
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.
Kononova, A.A., S.V. Cheresiz, A.V. Chechushkov, Y.V. Razumova, and A.G. Pokrovskii. (2017). Comparative Study of Fusogenic Activity of H1 and H5 Subtypes Influenza Virus Hemagglutinins. Bull Exp Biol Med 164: 85-89.
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.
Luo, M. (2012). Influenza virus entry. Adv Exp Med Biol 726: 201-221.
Michalski, M. and P. Setny. (2022). Membrane-Bound Configuration and Lipid Perturbing Effects of Hemagglutinin Subunit 2 N-Terminus Investigated by Computer Simulations. Front Mol Biosci 9: 826366.
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.
Examples:
TC#	Name	Organismal Type	Example
1.G.1.1.1	The Influenza Virus (Class I) Haemagglutinin (HA) (560aas; HA1-S-S-HA2)	virus	HA of Influenza virus (Q1W0T1)

1.G.1.1.2	Influenza B/Hong Kong hemagglutinin/fusion protein precursor of 582 aas.	Viruses	Polyprotein of Influenza B/Hong Kong

1.G.1.1.3	Hemagglutinin (partial) of 172 aas. The 3-d structure bound to a fusion inhibitor has been determined (PDB 3EYM). Several other structures of these and other peptides have also been determined (Apellániz et al. 2014). From the C-terminal part of 1.G.1.1.1 bearing a C-terminal TMS.	Viruses (Orthomyxoviridae)	Hemagglutinin of human influenza virus (fragment)

1.G.1.1.4	*H5 influenza virus haemagllutinin fusion protein of 568 aas and 2 TMSs, N- and C-terminal (Kononova et al.* 2017).**		*H5 of Influenza A virus* (A/Duck/Hong Kong)**

1.G.1.1.5	*H1 influenza virus haemagllutinin fusion protein of 566 aas and 2 TMSs, N- and C-terminal (Kononova et al.* 2017).**		*H1 of Influenza A virus* (A/Turkey/MO/24093/99(H1N2))**

1.G.1.1.6	Influenza A virus A fusion protein of 562 aas and 2 TMSs at the N- and C-termini. The membrane-bound configuration and lipid perturbing effects of hemagglutinin subunit 2 N-terminushave been studied by computer simulations (Michalski and Setny 2022).		Fusion protein of influenzae A/mallard/Maryland

1.G.1.1.7	Influenza A hemagglutinin of 562 aas. Hemagglutinin of Influenza A, but not of Influenza B and C viruses is acylated by ZDHHC2, 8, 15 and 20.		Hemagglutinin of Influenza A virus (A/Ann Arbor/7/1967(H2N2))