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. 2013 Nov;446(1-2):112-22.
doi: 10.1016/j.virol.2013.07.035. Epub 2013 Aug 27.

Structural basis for the divergent evolution of influenza B virus hemagglutinin

Fengyun Ni  1 , Elena Kondrashkina, Qinghua Wang
Affiliations

Structural basis for the divergent evolution of influenza B virus hemagglutinin

Fengyun Ni et al. Virology. 2013 Nov.

Abstract

Influenza A and B viruses are responsible for the severe morbidity and mortality worldwide in annual influenza epidemics. Currently circulating influenza B virus belongs to the B/Victoria or B/Yamagata lineage that was diverged from each other about 30-40 years ago. However, a mechanistic understanding of their divergent evolution is still lacking. Here we report the crystal structures of influenza B/Yamanashi/166/1998 hemagglutinin (HA) belonging to B/Yamagata lineage and its complex with the avian-like receptor analogue. Comparison of these structures with those of undiverged and diverged influenza B virus HAs, in conjunction with sequence analysis, reveals the molecular basis for the divergent evolution of influenza B virus HAs. Furthermore, HAs of diverged influenza B virus strains display much stronger molecular interactions with terminal sialic acid of bound receptors, which may allow for a different tissue tropism for current influenza B viruses, for which further investigation is required.

Keywords: Divergent evolution; Hemagglutinin; Influenza B virus; Positive selective pressure; Receptor binding; Sialic acid receptors.

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Figures

Fig. 1
Fig. 1
Structure of B/Yamanashi/98 HA. (a) Ribbon diagram of B/Yamanashi/98 HA structure with three subunits differently colored (grey, blue and green). The receptor-binding site (RBS) is highlighted in red color. Glycans resolved in the crystal structure are also shown. (b) Structure of a B/Yamanashi/98 HA subunit. HA1 and HA2 are in yellow and green color, respectively. The two major helices on HA2, helix A and helix B, are also labelled. Disulfide bonds on each subunit are shown as space-filling models in purple, and seven sugar residues are in ball-and-stick models. The RBS is labelled in red. (c) Comparison of the fusion peptide between B/Yamanashi/98 HA and influenza A/H3 virus HA (PDB code: 3HMG). The helix A and helix B and fusion peptide from each subunit are shown in different colors: green, blue and grey for B/Yamanashi/98 HA, and red, yellow and cyan for influenza A/H3 virus HA. It is clear that the fusion peptide of B/Yamanashi/98 HA points away from its helix A and helix B and interacts with the helices from a neighbouring subunit. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
Comparison of known influenza B virus HA structures. Pairwise structural comparison ((a), (c), (e) and (g)) and the corresponding Cα-RMSD ((b), (d), (f) and (h)). The pairs are: (a) and (b) B/Brisbane/08 and B/HK/73 HAs in the range of HA133–324; ((c) and (d)). B/Yamanashi/98 and B/HK/73 HAs in the range of HA133–324; (e) and (f) B/Florida/06 and B/HK/73 HAs in the range of HA191–281; (g) and (h) B/Yamanashi/98 and B/Yamanashi/98-LSTa HAs in the range of HA133–324.
Fig. 3
Fig. 3
Antigenic structure of influenza B virus HA. (a) Surface presentation of the globular domain of B/Yamanashi/98 HA. Residues with large structural variations between B/Yamanashi/98 or B/Brisbane/08 relative to B/HK/73 HA (Cα-RMSD greater than 1.0 Å) are highlighted based on their spatial location (120-loop region in cyan, 150-loop in green, 160-loop in blue and 190-helix region in red). (b)–(e) Amino-acid substitutions in B/Brisbane/08 HA (purple), B/Yamanashi/98 HA (green) relative to B/HK/73 HA (yellow) for the 120-loop region (b), 150-loop (c), 160-loop (d) and 190-helix region (e). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 4
Fig. 4
Receptor binding of influenza B virus HA. (a) Comparison of receptor-binding sites between B/Yamanashi/98 (green) and B/HK/73 (grey) HAs. Important residues are highlighted according to the atom types with the exception that carbon atoms are colored in yellow for B/HK/73 HA and in cyan for B/Yamanashi/98 HA. (b) Comparison of receptor-binding sites between B/Yamanashi/98 (green) and B/Brisbane/08 (purple) HAs. Important residues are highlighted according to the atom types with the exception that carbon atoms are colored in cyan for B/Yamanashi/98 HA and in purple for B/Brisbane/08 HA. (c) Molecular interactions between B/Yamanashi/98 HA and avian-like receptor analogue LSTa. Dashed lines are for hydrogen bonds listed in Table 4. (d) Comparison of LSTa in the receptor-binding sites of B/Yamanashi/98 and B/HK/73 HAs. The coloring scheme is the same as in (a). (e) Crystal contacts around the LSTa ligand in the structure of B/Yamanashi/98 HA. Two neighboring HA molecules are shown in green and light grey, and their bound LSTa in cyan and grey, respectively. It is clear that in this conformation, LSTa does not have crystal clashes. (f) Crystal contracts around the LSTa ligand in the structure of B/Yamanashi/98 HA if LSTa were in a conformation as found in B/HK/73 HA. It is clear that LSTa in this conformation will have steric clashes, providing an explanation why LSTa adopts the unusual conformation as found in B/Yamanashi/98 HA-LSTa. Coloring scheme is the same as in (e). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 5
Fig. 5
The Lys206→Asn mutation of HAs in B/Yamagata lineage. (a) The stabilization of the HA1–HA1 interface by three new hydrogen bonds between Asn-206 and Asn-168 shown as dashed lines with the distances labeled. The coloring scheme is the same as in Fig. 3. (b) Zoom-in of the hydrogen bond between Subunits B and C. (c) The residues at the HA1–HA1 interface in B/Yamanashi/98 HA structure. Residues Lys-209 and His-220 interact with each other at the 3-fold axis of the structure and are the major stabilizing force. Three HA subunits are colored as green, blue and light grey, respectively. (d) pH-dependent hemolysis of B/Brisbane/08 virus. Shown are averaged values and standard deviations from at least three independent measurements. (e) pH-dependent hemolysis of B/Yamanashi/98 virus. Shown are averaged values and standard deviations from at least three independent measurements. (f) Comparison of the rate of hemolysis between B/Brisbane/08 virus and B/Yamanashi/98 virus at pH 4.8. Shown are averaged values and standard deviations from at least three independent measurements. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
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