Featured Article - March 2014
Short description: The crystal structure of HA antigen from H17N10 bat influenza virus shows how its receptor binding site has diverged from human flu strains.
Influenza virus infection has two surface antigens, hemagglutinin (HA) and neuraminidase (NA). HA initiates viral entry by binding sialic acid moieties of receptors on the cell surface, while NA removes sialic acid from surface glycoproteins and glycolipids of viral progeny to promote their release from the host cell and enhance infectivity. Circulating influenza viruses are classified into subtypes according to the unique combinations of HA and NA proteins they bear, which also determines the range of avian and mammalian species they can infect.
The recent identification of a seventeenth HA subtype from the H17N10 virus that infects bats expanded the known host range of type A influenza viruses and raised the possibility that bats may provide a reservoir of viruses with the potential to prime a human influenza outbreak. To determine whether the H17 HA from A/little yellow-shouldered bat/Guatemala/060/2010 shared the receptor-binding properties of human viral HAs, Wilson (PSI JCSG) and colleagues determined the crystal structure of the recombinant protein at 3.18-Å resolution.
Consistent with its ∼50% sequence conservation with group 1 HAs, H17 forms a trimer with a membrane-distal receptor binding site (RBS) comprised of 190-helix, 130-loop and 220-loop structures characteristic of HAs. However, multiple substitutions of HA residues involved in receptor binding have created an acidic RBS interface that is incompatible with sialic acid binding, including an Asp substitution of Ser/Thr 136 that would interfere with the binding of sialic acid's carboxyl group. Indeed, glycan microarray analysis revealed that H17 has no binding activity for a large panel of sialosides. Moreover, HA proteins undergo large conformational changes at low pH to release a peptide that triggers membrane fusion. Although the fusion peptide sequence is conserved in H17, it appears to be refractory to pH-induced trypsin digestion in vitro, again suggesting that divergent substitutions have caused a loss of low pH-induced membrane fusion function by altering protein properties.
These findings complement previous reports that the N10 NA homolog of H17N10 virus was similarly unable to interact with and cleave sialic acid off host cell receptors to promote viral release. Together, this body of work suggests that, despite the conservation of HA and NA proteins, H17N10 viruses require a distinct membrane receptor for host infection.
X. Zhu et al. Hemagglutinin homologue from H17N10 bat influenza VIRUS exhibits divergent receptor-binding and pH-dependent fusion activities.
Proc Natl Acad Sci U S A. 110, 1458-63 (2013). doi:10.1073/pnas.1218509110
X. Zhu et al. Crystal structures of two subtype N10 neuraminidase-like proteins from bat influenza A viruses reveal a diverged putative active site.
Proc Natl Acad Sci U S A. 109, 18903-8 (2012). doi:10.1073/pnas.1212579109
Q. Li et al. Structural and functional characterization of neuraminidase-like molecule N10 derived from bat influenza A virus.
Proc Natl Acad Sci U S A. 109, 18897-902 (2012). doi:10.1073/pnas.1211037109