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Structural and Functional Studies of Influenza Virus A/H6 Hemagglutinin.

Ni F, Kondrashkina E, Wang Q - PLoS ONE (2015)

Bottom Line: Our results revealed that in the presence of HA1 Q226, the triad of HA1 S137, E190 and G228 in GD H6 HA allows the binding to both avian- and human-like receptors with a slight preference for avian receptors.Consequently, TW H6 HA has a slight preference for human receptors, thus may represent an intermediate towards a complete human adaptation.The novel roles of the triad at HA1 137, 190 and 228 of H6 HA in binding to receptors revealed here may also be used by other HA subtypes to achieve human adaptation, which needs to be further tested in laboratory and closely monitored in field surveillance.

View Article: PubMed Central - PubMed

Affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.

ABSTRACT
In June 2013, the first human infection by avian influenza A(H6N1) virus was reported in Taiwan. This incident raised the concern for possible human epidemics and pandemics from H6 viruses. In this study, we performed structural and functional investigation on the hemagglutinin (HA) proteins of the human-infecting A/Taiwan/2/2013(H6N1) (TW H6) virus and an avian A/chicken/Guangdong/S1311/2010(H6N6) (GD H6) virus that transmitted efficiently in guinea pigs. Our results revealed that in the presence of HA1 Q226, the triad of HA1 S137, E190 and G228 in GD H6 HA allows the binding to both avian- and human-like receptors with a slight preference for avian receptors. Its conservation among the majority of H6 HAs provides an explanation for the broader host range of this subtype. Furthermore, the triad of N137, V190 and S228 in TW H6 HA may alleviate the requirement for a hydrophobic residue at HA1 226 of H2 and H3 HAs when binding to human-like receptors. Consequently, TW H6 HA has a slight preference for human receptors, thus may represent an intermediate towards a complete human adaptation. Importantly, the triad observed in TW H6 HA is detected in 74% H6 viruses isolated from Taiwan in the past 14 years, suggesting an elevated threat of H6 viruses from this region to human health. The novel roles of the triad at HA1 137, 190 and 228 of H6 HA in binding to receptors revealed here may also be used by other HA subtypes to achieve human adaptation, which needs to be further tested in laboratory and closely monitored in field surveillance.

No MeSH data available.


Related in: MedlinePlus

The overall structures of GD and TW H6 HAs.a). One monomer of GD H6 HA (in yellow color) with the glycans (in stick model). The receptor-binding site (RBS) is labeled. b). One monomer of TW H6 HA (in blue color) with the glycans (in stick model). c). Superposition of the monomers of GD (in yellow color) and TW (in blue color) H6 HAs. d). Comparison of the receptor-binding sites of GD (in yellow) and TW (in blue) H6 HAs. Highlighted are the residues at or surrounding the receptor-binding site. All residues are in H3 HA numbering. e). Comparison of the receptor-binding sites of GD (in yellow) and TW (in blue) H6 HAs with H1 HA from A/Brevig Mission/1/1918(H1N1) (PDB code: 2WRG; in magenta), H2 HA from A/Singapore/1/1957(H2N2) (PDB code: 2WR7; in orange), H3 HA from A/Aichi/2/68(H3N2) (PDB code: 2YPG; in green), H5 HA from an airborne transmissible mutant of A/Indonesia/5/2005(H5N1) (PDB code: 4K67; in cyan), H7 HA from A/Anhui/1/2013(H7N9) (PDB code: 4BSB; in purple), H9 HA from A/swine/Hong Kong/9/1998(H9N2) (PDB code: 1JSI; in grey), H10 HA from A/Jiangxi/Donghu/346/2013(H10N8) (PDB code: 4QY2; in forest), and H13 HA from A/gull/Maryland/704/1977(H13N6) (PDB code: 4KPS; in pink). The strictly conserved residues among all these HAs within the receptor-binding sites, Y98, W153, H183 and Y195, are shown. Also shown are the main chains of HA1 133 that display different configurations among these structures.
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pone.0134576.g001: The overall structures of GD and TW H6 HAs.a). One monomer of GD H6 HA (in yellow color) with the glycans (in stick model). The receptor-binding site (RBS) is labeled. b). One monomer of TW H6 HA (in blue color) with the glycans (in stick model). c). Superposition of the monomers of GD (in yellow color) and TW (in blue color) H6 HAs. d). Comparison of the receptor-binding sites of GD (in yellow) and TW (in blue) H6 HAs. Highlighted are the residues at or surrounding the receptor-binding site. All residues are in H3 HA numbering. e). Comparison of the receptor-binding sites of GD (in yellow) and TW (in blue) H6 HAs with H1 HA from A/Brevig Mission/1/1918(H1N1) (PDB code: 2WRG; in magenta), H2 HA from A/Singapore/1/1957(H2N2) (PDB code: 2WR7; in orange), H3 HA from A/Aichi/2/68(H3N2) (PDB code: 2YPG; in green), H5 HA from an airborne transmissible mutant of A/Indonesia/5/2005(H5N1) (PDB code: 4K67; in cyan), H7 HA from A/Anhui/1/2013(H7N9) (PDB code: 4BSB; in purple), H9 HA from A/swine/Hong Kong/9/1998(H9N2) (PDB code: 1JSI; in grey), H10 HA from A/Jiangxi/Donghu/346/2013(H10N8) (PDB code: 4QY2; in forest), and H13 HA from A/gull/Maryland/704/1977(H13N6) (PDB code: 4KPS; in pink). The strictly conserved residues among all these HAs within the receptor-binding sites, Y98, W153, H183 and Y195, are shown. Also shown are the main chains of HA1 133 that display different configurations among these structures.

Mentions: The structures of GD and TW H6 HAs are determined to 2.66 and 2.39 Å, respectively (S1Table). HA is a homotrimer, with each monomer containing two polypeptide chains, HA1 and HA2 (for clarity, only one monomer is shown in Fig 1A and 1B). Both GD and TW H6 HAs have a total of six potential glycosylation sites on each monomer, at HA1 21, 33, 169, 291, 296 and HA2 154. In the structures, we observed five glycans (at HA1 21, 33, 169, 291 and HA2 154) for both H6 HAs (Fig 1A and 1B). The glycan at HA1 169 is located at the HA1-HA1 monomer interface, which was reported to protect H6 HA from trypsin cleavage at R201 [42]. The overall structures of GD and TW H6 HAs are very similar, where the root-mean-square deviation (RMSD) for all Cα atoms is at 0.67 Å (Fig 1C).


Structural and Functional Studies of Influenza Virus A/H6 Hemagglutinin.

Ni F, Kondrashkina E, Wang Q - PLoS ONE (2015)

The overall structures of GD and TW H6 HAs.a). One monomer of GD H6 HA (in yellow color) with the glycans (in stick model). The receptor-binding site (RBS) is labeled. b). One monomer of TW H6 HA (in blue color) with the glycans (in stick model). c). Superposition of the monomers of GD (in yellow color) and TW (in blue color) H6 HAs. d). Comparison of the receptor-binding sites of GD (in yellow) and TW (in blue) H6 HAs. Highlighted are the residues at or surrounding the receptor-binding site. All residues are in H3 HA numbering. e). Comparison of the receptor-binding sites of GD (in yellow) and TW (in blue) H6 HAs with H1 HA from A/Brevig Mission/1/1918(H1N1) (PDB code: 2WRG; in magenta), H2 HA from A/Singapore/1/1957(H2N2) (PDB code: 2WR7; in orange), H3 HA from A/Aichi/2/68(H3N2) (PDB code: 2YPG; in green), H5 HA from an airborne transmissible mutant of A/Indonesia/5/2005(H5N1) (PDB code: 4K67; in cyan), H7 HA from A/Anhui/1/2013(H7N9) (PDB code: 4BSB; in purple), H9 HA from A/swine/Hong Kong/9/1998(H9N2) (PDB code: 1JSI; in grey), H10 HA from A/Jiangxi/Donghu/346/2013(H10N8) (PDB code: 4QY2; in forest), and H13 HA from A/gull/Maryland/704/1977(H13N6) (PDB code: 4KPS; in pink). The strictly conserved residues among all these HAs within the receptor-binding sites, Y98, W153, H183 and Y195, are shown. Also shown are the main chains of HA1 133 that display different configurations among these structures.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520562&req=5

pone.0134576.g001: The overall structures of GD and TW H6 HAs.a). One monomer of GD H6 HA (in yellow color) with the glycans (in stick model). The receptor-binding site (RBS) is labeled. b). One monomer of TW H6 HA (in blue color) with the glycans (in stick model). c). Superposition of the monomers of GD (in yellow color) and TW (in blue color) H6 HAs. d). Comparison of the receptor-binding sites of GD (in yellow) and TW (in blue) H6 HAs. Highlighted are the residues at or surrounding the receptor-binding site. All residues are in H3 HA numbering. e). Comparison of the receptor-binding sites of GD (in yellow) and TW (in blue) H6 HAs with H1 HA from A/Brevig Mission/1/1918(H1N1) (PDB code: 2WRG; in magenta), H2 HA from A/Singapore/1/1957(H2N2) (PDB code: 2WR7; in orange), H3 HA from A/Aichi/2/68(H3N2) (PDB code: 2YPG; in green), H5 HA from an airborne transmissible mutant of A/Indonesia/5/2005(H5N1) (PDB code: 4K67; in cyan), H7 HA from A/Anhui/1/2013(H7N9) (PDB code: 4BSB; in purple), H9 HA from A/swine/Hong Kong/9/1998(H9N2) (PDB code: 1JSI; in grey), H10 HA from A/Jiangxi/Donghu/346/2013(H10N8) (PDB code: 4QY2; in forest), and H13 HA from A/gull/Maryland/704/1977(H13N6) (PDB code: 4KPS; in pink). The strictly conserved residues among all these HAs within the receptor-binding sites, Y98, W153, H183 and Y195, are shown. Also shown are the main chains of HA1 133 that display different configurations among these structures.
Mentions: The structures of GD and TW H6 HAs are determined to 2.66 and 2.39 Å, respectively (S1Table). HA is a homotrimer, with each monomer containing two polypeptide chains, HA1 and HA2 (for clarity, only one monomer is shown in Fig 1A and 1B). Both GD and TW H6 HAs have a total of six potential glycosylation sites on each monomer, at HA1 21, 33, 169, 291, 296 and HA2 154. In the structures, we observed five glycans (at HA1 21, 33, 169, 291 and HA2 154) for both H6 HAs (Fig 1A and 1B). The glycan at HA1 169 is located at the HA1-HA1 monomer interface, which was reported to protect H6 HA from trypsin cleavage at R201 [42]. The overall structures of GD and TW H6 HAs are very similar, where the root-mean-square deviation (RMSD) for all Cα atoms is at 0.67 Å (Fig 1C).

Bottom Line: Our results revealed that in the presence of HA1 Q226, the triad of HA1 S137, E190 and G228 in GD H6 HA allows the binding to both avian- and human-like receptors with a slight preference for avian receptors.Consequently, TW H6 HA has a slight preference for human receptors, thus may represent an intermediate towards a complete human adaptation.The novel roles of the triad at HA1 137, 190 and 228 of H6 HA in binding to receptors revealed here may also be used by other HA subtypes to achieve human adaptation, which needs to be further tested in laboratory and closely monitored in field surveillance.

View Article: PubMed Central - PubMed

Affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.

ABSTRACT
In June 2013, the first human infection by avian influenza A(H6N1) virus was reported in Taiwan. This incident raised the concern for possible human epidemics and pandemics from H6 viruses. In this study, we performed structural and functional investigation on the hemagglutinin (HA) proteins of the human-infecting A/Taiwan/2/2013(H6N1) (TW H6) virus and an avian A/chicken/Guangdong/S1311/2010(H6N6) (GD H6) virus that transmitted efficiently in guinea pigs. Our results revealed that in the presence of HA1 Q226, the triad of HA1 S137, E190 and G228 in GD H6 HA allows the binding to both avian- and human-like receptors with a slight preference for avian receptors. Its conservation among the majority of H6 HAs provides an explanation for the broader host range of this subtype. Furthermore, the triad of N137, V190 and S228 in TW H6 HA may alleviate the requirement for a hydrophobic residue at HA1 226 of H2 and H3 HAs when binding to human-like receptors. Consequently, TW H6 HA has a slight preference for human receptors, thus may represent an intermediate towards a complete human adaptation. Importantly, the triad observed in TW H6 HA is detected in 74% H6 viruses isolated from Taiwan in the past 14 years, suggesting an elevated threat of H6 viruses from this region to human health. The novel roles of the triad at HA1 137, 190 and 228 of H6 HA in binding to receptors revealed here may also be used by other HA subtypes to achieve human adaptation, which needs to be further tested in laboratory and closely monitored in field surveillance.

No MeSH data available.


Related in: MedlinePlus