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.



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.


TC#NameOrganismal TypeExample
1.G.1.1.1The Influenza Virus (Class I) Haemagglutinin (HA) (560aas; HA1-S-S-HA2)virusHA of Influenza virus (Q1W0T1)

Influenza B/Hong Kong hemagglutinin/fusion protein precursor of 582 aas.


Polyprotein of Influenza B/Hong Kong


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)


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)


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))


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


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))