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Molecular modeling and phylogenetic analyses highlight the role of amino acid 347 of the N1 subtype neuraminidase in influenza virus host range and interspecies adaptation
The N1 neuraminidases (NAs) of avian and pandemic human influenza viruses contain tyrosine and asparagine, respectively, at position 347 on the rim of the catalytic site; the biological significance of this difference is not clear. Here, we used molecular dynamics simulation to model the effects...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Philipps-Universität Marburg
2023
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| Subjects: | |
| Online Access: | PDF Full Text |
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| Summary: | The N1 neuraminidases (NAs) of avian and pandemic human influenza viruses
contain tyrosine and asparagine, respectively, at position 347 on the rim of the
catalytic site; the biological significance of this difference is not clear. Here, we used
molecular dynamics simulation to model the effects of amino acid 347 on N1 NA
interactions with sialyllacto-N-tetraoses 6’SLN-LC and 3’SLN-LC, which represent
NA substrates in humans and birds, respectively. Our analysis predicted that Y347
plays an important role in the NA preference for the avian-type substrates. The
Y347N substitution facilitates hydrolysis of human-type substrates by resolving
steric conflicts of the Neu5Ac2–6Gal moiety with the bulky side chain of Y347,
decreasing the free energy of substrate binding, and increasing the solvation of
the Neu5Ac2–6Gal bond. Y347 was conserved in all N1 NA sequences of avian
influenza viruses in the GISAID EpiFlu database with two exceptions. First, the
Y347F substitution was present in the NA of a specific H6N1 poultry virus lineage
and was associated with the substitutions G228S and/or E190V/L in the receptorbinding
site (RBS) of the hemagglutinin (HA). Second, the highly pathogenic
avian H5N1 viruses of the Gs/Gd lineage contained sporadic variants with the NA
substitutions Y347H/D, which were frequently associated with substitutions in the
HA RBS. The Y347N substitution occurred following the introductions of avian
precursors into humans and pigs with N/D347 conserved during virus circulation
in these hosts. Comparative evolutionary analysis of site 347 revealed episodic
positive selection across the entire tree and negative selection within most
host-specific groups of viruses, suggesting that substitutions at NA position 347
occurred during host switches and remained under pervasive purifying selection
thereafter. Our results elucidate the role of amino acid 347 in NA recognition of
sialoglycan substrates and emphasize the significance of substitutions at position
347 as a marker of host range and adaptive evolution of influenza viruses. |
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| Item Description: | Gefördert durch den Open-Access-Publikationsfonds der UB Marburg. |
| DOI: | 10.3389/fmicb.2023.1309156 |