Hemagglutinin Structure and Activities

Abstract

Hemagglutinins (HAs) are the receptor-binding and membrane fusion glycoproteins of influenza viruses. They recognize sialic acid-containing, cell-surface glycoconjugates as receptors but have limited affinity for them, and, as a consequence, virus attachment to cells requires their interaction with several virus HAs. Receptor-bound virus is transferred into endosomes where membrane fusion by HAs is activated at pH between 5 and 6.5, depending on the strain of virus. Fusion activity requires extensive rearrangements in HA conformation that include extrusion of a buried "fusion peptide" to connect with the endosomal membrane, form a bridge to the virus membrane, and eventually bring both membranes close together. In this review, we give an overview of the structures of the 16 genetically and antigenically distinct subtypes of influenza A HA in relation to these two functions in virus replication and in relation to recognition of HA by antibodies that neutralize infection.

Characterization of changes in the hemagglutinin that accompanied the emergence of H3N2/1968 pandemic influenza viruses

“…These findings suggest a potential functional role of the substitution in position 193 during interspecies transmission. Amino acids Q226 and G228 are critical for the avian HA binding to avian-type receptor motif Neu5Acα2-3Gal (Gamblin et al, 2020;Matrosovich et al, 2006b;Shi et al, 2014). Both codons are under purifying selection in birds, horses and dogs, which share binding preference for Neu5Acα2-3Gal-terminated receptors.…”

“…In the case of H2N2/1957 and H3N2/1968 IAVs, substitutions Q226L and G228S were responsible for this switch in receptor specificity. In the case of H1N1/1918 and H1N1/2009 IAVs, this role was played by substitutions E190D and G225D/E [for recent reviews see (Gamblin et al, 2020;Thompson and Paulson, 2020)]. It remains unexplored whether other substitutions in the HA of pandemic IAVs were required for adaptation to receptors in humans, for example, by adjusting HA interactions with sub-terminal oligosaccharide parts of the receptors and/or modulating binding avidity.…”

Second sialic acid‐binding site of influenza A virus neuraminidase: binding receptors for efficient release

“…All rights reserved IAV particles contain two major surface glycoproteins: hemagglutinin (HA) and NA. HA, of which 16 subtypes exist in aquatic birds (H1-16), is responsible for virus binding to SIA receptors on the cell surface and mediates virus-cell membrane fusion after endocytosis (for recent reviews see [11,12]). The receptor-destroying enzyme NA, of which 9 subtypes are known in wild waterfowl (N1-9), cleaves SIA from glycosylated proteins and lipids.…”

Characterization of changes in the hemagglutinin that accompanied the emergence of H3N2/1968 pandemic influenza viruses

“…In the case of H2N2/1957 and H3N2/1968 IAVs, substitutions Q226L and G228S were responsible for this switch in receptor specificity. In the case of H1N1/1918 and H1N1/2009 IAVs, this role was played by substitutions E190D and G225D/E (for recent reviews, see [ 9 , 10 ]). It remains unexplored whether other substitutions in the HA of pandemic IAVs were required for adaptation to receptors in humans, for example, by adjusting HA interactions with sub-terminal oligosaccharide parts of the receptors and/or modulating binding avidity.…”