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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

Structural comparison of H6 HAs in binding to avian receptor analogues.a). GD H6 HA-LSTa complex. GD H6 HA structure is shown in yellow and LSTa is in green. The composite omit 2Fo-Fc electron density map for the receptor is shown at 1σ. The hydrogen bonds detected by LIGPLOT are shown as black dashed lines. b). TW H6 HA-LSTa complex. TW H6 HA structure is shown in blue and LSTa is in green. The composite omit 2Fo-Fc electron density map for the receptor is shown at 1σ. The hydrogen bonds detected by LIGPLOT are shown as black dashed lines. c). Comparison of LSTa interaction with GD (in yellow) and TW (in blue) H6 HAs. The hydrogen bonds different between these two complexes are shown as dashed lines (yellow dashed lines for hydrogen bonds unique to GD H6 HA-LSTa; blue dashed lines for hydrogen bonds unique to TW H6 HA-LSTa). Highlighted by arrows are the different sitting positions of the LSTa Sia-1 moiety in the receptor-binding sites of GD and TW H6 HAs. d). Comparison of avian receptor analogues in GD H6 HA (in yellow) with avian H1 HA from A/WDK/JX/12416/2005(H1N1) (PDB code: 3HTP; in green). e). Comparison of avian receptor analogues in GD H6 HA (in yellow) with avian H5 HA from A/Indonesia/5/2005(H5N1) (PDB code: 4K63; in grey). f). Comparison of avian receptor analogues in TW H6 HA (in blue) and H5 HA from an airborne transmissible mutant of A/Indonesia/5/2005(H5N1) (PDB codes: 4K66; in red). g). Comparison of avian receptor analogues in TW H6 HA (in blue) and H5 HA from a transmissible mutant of A/Vietnam/1203/2004(H5N1) (PDB code: 4BH4; in cyan).
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pone.0134576.g002: Structural comparison of H6 HAs in binding to avian receptor analogues.a). GD H6 HA-LSTa complex. GD H6 HA structure is shown in yellow and LSTa is in green. The composite omit 2Fo-Fc electron density map for the receptor is shown at 1σ. The hydrogen bonds detected by LIGPLOT are shown as black dashed lines. b). TW H6 HA-LSTa complex. TW H6 HA structure is shown in blue and LSTa is in green. The composite omit 2Fo-Fc electron density map for the receptor is shown at 1σ. The hydrogen bonds detected by LIGPLOT are shown as black dashed lines. c). Comparison of LSTa interaction with GD (in yellow) and TW (in blue) H6 HAs. The hydrogen bonds different between these two complexes are shown as dashed lines (yellow dashed lines for hydrogen bonds unique to GD H6 HA-LSTa; blue dashed lines for hydrogen bonds unique to TW H6 HA-LSTa). Highlighted by arrows are the different sitting positions of the LSTa Sia-1 moiety in the receptor-binding sites of GD and TW H6 HAs. d). Comparison of avian receptor analogues in GD H6 HA (in yellow) with avian H1 HA from A/WDK/JX/12416/2005(H1N1) (PDB code: 3HTP; in green). e). Comparison of avian receptor analogues in GD H6 HA (in yellow) with avian H5 HA from A/Indonesia/5/2005(H5N1) (PDB code: 4K63; in grey). f). Comparison of avian receptor analogues in TW H6 HA (in blue) and H5 HA from an airborne transmissible mutant of A/Indonesia/5/2005(H5N1) (PDB codes: 4K66; in red). g). Comparison of avian receptor analogues in TW H6 HA (in blue) and H5 HA from a transmissible mutant of A/Vietnam/1203/2004(H5N1) (PDB code: 4BH4; in cyan).

Mentions: In order to investigate the atomic interactions of H6 HAs with avian-like receptors, we used the pentasaccharide, α(2,3)-linked lactoseries tetrasaccharide a (LSTa), for crystallographic study [43]. The Sia-1, Gal-2 and GlcNAc-3 of the LSTa are clearly visualized in both GD and TW H6 HA structures (Fig 2A and 2B). Using LIGPLOT [44], a total of nine hydrogen bonds are detected between GD H6 HA and LSTa and seven hydrogen bonds between TW H6 HA and LSTa (Table 3, Fig 2A and 2B). The stronger interactions between GD H6 HA and LSTa are consistent with their relatively higher binding affinity compared to TW H6 HA with LSTa (Table 2). Most noticeably, the residues in the receptor-binding sites that differ between TW and GD H6 HAs interact differentially with bound receptors. For instance, the side chain of N137 in TW H6 HA makes one strong hydrogen bond with the O1A atom of Sia-1, which is absent between S137 in GD H6 HA and Sia-1 (Table 3). In addition, the side-chain hydroxyl group of S228 in TW H6 HA contributes a strong hydrogen bond with the O9 atom of Sia-1 (Table 3, Fig 2B and 2C). On the other hand, different from the small hydrophobic residue V190 in TW H6 HA, GD H6 HA has a large hydrophilic residue E190 that interacts with the O9 atom of Sia-1 (Table 3, Fig 2A and 2C).


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

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

Structural comparison of H6 HAs in binding to avian receptor analogues.a). GD H6 HA-LSTa complex. GD H6 HA structure is shown in yellow and LSTa is in green. The composite omit 2Fo-Fc electron density map for the receptor is shown at 1σ. The hydrogen bonds detected by LIGPLOT are shown as black dashed lines. b). TW H6 HA-LSTa complex. TW H6 HA structure is shown in blue and LSTa is in green. The composite omit 2Fo-Fc electron density map for the receptor is shown at 1σ. The hydrogen bonds detected by LIGPLOT are shown as black dashed lines. c). Comparison of LSTa interaction with GD (in yellow) and TW (in blue) H6 HAs. The hydrogen bonds different between these two complexes are shown as dashed lines (yellow dashed lines for hydrogen bonds unique to GD H6 HA-LSTa; blue dashed lines for hydrogen bonds unique to TW H6 HA-LSTa). Highlighted by arrows are the different sitting positions of the LSTa Sia-1 moiety in the receptor-binding sites of GD and TW H6 HAs. d). Comparison of avian receptor analogues in GD H6 HA (in yellow) with avian H1 HA from A/WDK/JX/12416/2005(H1N1) (PDB code: 3HTP; in green). e). Comparison of avian receptor analogues in GD H6 HA (in yellow) with avian H5 HA from A/Indonesia/5/2005(H5N1) (PDB code: 4K63; in grey). f). Comparison of avian receptor analogues in TW H6 HA (in blue) and H5 HA from an airborne transmissible mutant of A/Indonesia/5/2005(H5N1) (PDB codes: 4K66; in red). g). Comparison of avian receptor analogues in TW H6 HA (in blue) and H5 HA from a transmissible mutant of A/Vietnam/1203/2004(H5N1) (PDB code: 4BH4; in cyan).
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Related In: Results  -  Collection

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pone.0134576.g002: Structural comparison of H6 HAs in binding to avian receptor analogues.a). GD H6 HA-LSTa complex. GD H6 HA structure is shown in yellow and LSTa is in green. The composite omit 2Fo-Fc electron density map for the receptor is shown at 1σ. The hydrogen bonds detected by LIGPLOT are shown as black dashed lines. b). TW H6 HA-LSTa complex. TW H6 HA structure is shown in blue and LSTa is in green. The composite omit 2Fo-Fc electron density map for the receptor is shown at 1σ. The hydrogen bonds detected by LIGPLOT are shown as black dashed lines. c). Comparison of LSTa interaction with GD (in yellow) and TW (in blue) H6 HAs. The hydrogen bonds different between these two complexes are shown as dashed lines (yellow dashed lines for hydrogen bonds unique to GD H6 HA-LSTa; blue dashed lines for hydrogen bonds unique to TW H6 HA-LSTa). Highlighted by arrows are the different sitting positions of the LSTa Sia-1 moiety in the receptor-binding sites of GD and TW H6 HAs. d). Comparison of avian receptor analogues in GD H6 HA (in yellow) with avian H1 HA from A/WDK/JX/12416/2005(H1N1) (PDB code: 3HTP; in green). e). Comparison of avian receptor analogues in GD H6 HA (in yellow) with avian H5 HA from A/Indonesia/5/2005(H5N1) (PDB code: 4K63; in grey). f). Comparison of avian receptor analogues in TW H6 HA (in blue) and H5 HA from an airborne transmissible mutant of A/Indonesia/5/2005(H5N1) (PDB codes: 4K66; in red). g). Comparison of avian receptor analogues in TW H6 HA (in blue) and H5 HA from a transmissible mutant of A/Vietnam/1203/2004(H5N1) (PDB code: 4BH4; in cyan).
Mentions: In order to investigate the atomic interactions of H6 HAs with avian-like receptors, we used the pentasaccharide, α(2,3)-linked lactoseries tetrasaccharide a (LSTa), for crystallographic study [43]. The Sia-1, Gal-2 and GlcNAc-3 of the LSTa are clearly visualized in both GD and TW H6 HA structures (Fig 2A and 2B). Using LIGPLOT [44], a total of nine hydrogen bonds are detected between GD H6 HA and LSTa and seven hydrogen bonds between TW H6 HA and LSTa (Table 3, Fig 2A and 2B). The stronger interactions between GD H6 HA and LSTa are consistent with their relatively higher binding affinity compared to TW H6 HA with LSTa (Table 2). Most noticeably, the residues in the receptor-binding sites that differ between TW and GD H6 HAs interact differentially with bound receptors. For instance, the side chain of N137 in TW H6 HA makes one strong hydrogen bond with the O1A atom of Sia-1, which is absent between S137 in GD H6 HA and Sia-1 (Table 3). In addition, the side-chain hydroxyl group of S228 in TW H6 HA contributes a strong hydrogen bond with the O9 atom of Sia-1 (Table 3, Fig 2B and 2C). On the other hand, different from the small hydrophobic residue V190 in TW H6 HA, GD H6 HA has a large hydrophilic residue E190 that interacts with the O9 atom of Sia-1 (Table 3, Fig 2A and 2C).

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