tetano
Editor, Senior Moderator
J Virol. 2016 Nov 9. pii: JVI.00868-16. [Epub ahead of print]
[h=1]An amino acid in the stalk domain of N1 neuraminidase is critical for enzymatic activity.[/h] Zanin M[SUP]1[/SUP], Duan S[SUP]2[/SUP], Wong SS[SUP]1[/SUP], Kumar G[SUP]3[/SUP], Baviskar P[SUP]1[/SUP], Collin E[SUP]4[/SUP], Russell C[SUP]1[/SUP], Barman S[SUP]1[/SUP], Hause B[SUP]5[/SUP], Webby R[SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Neuraminidase (NA) is a sialidase expressed on the surface of influenza A viruses that releases progeny viruses from the surface of infected cells and prevents viruses becoming trapped in mucus. It is a homo-tetramer with each monomer consisting of a transmembrane region, a stalk and a globular head with sialidase activity. We recently characterized two swine viruses of the pandemic H1N1 lineage; A/swine/Virginia/1814-1/2012 (pH1N1[SUB]low[/SUB]-1) and A/swine/Virginia/1814-2/2012 (pH1N1[SUB]low[/SUB]-2) with almost undetectable NA enzymatic activity compared to the highly homologous A/swine/Pennsylvania/2436/2012 (pH1N1-1) and A/swine/Minnesota/2499/2012 (pH1N1-2) viruses. pH1N1-1 transmitted to aerosol contact ferrets but pH1N1[SUB]low[/SUB]-1 did not. The aim of this study was to identify the molecular determinants associated with low NA activity as potential markers of aerosol transmission. We identified the shared unique substitutions M19V, A232V, D248N and I436V (N1 numbering) in pH1N1[SUB]low[/SUB]-1 and pH1N1[SUB]low[/SUB]-2. pH1N1[SUB]low[/SUB]-1 also had the unique Y66D substitution in the stalk domain, where 66Y was highly conserved in N1 NAs. Restoration of 66Y was critical for the NA activity of pH1N1[SUB]low[/SUB]-1 NA, although 19M or 248D in conjunction with 66Y was required to recover activity to that of pH1N1 viruses. Studies of NA stability and molecular modeling revealed that 66Y likely stabilized the NA homotetramer. Therefore, 66Y in the stalk domain of N1 NA was critical for the stability of the NA tetramer and, subsequently, for NA enzymatic activity.
[h=4]IMPORTANCE:[/h] Neuraminidase (NA) is a sialidase that is one of the major surface glycoproteins of influenza A viruses and the target for the influenza drugs oseltamivir and zanamivir. NA is important as it releases progeny viruses from the surface of infected cells and prevents viruses becoming trapped in mucus. Mutations in the globular head domain that decrease enzymatic activity but confer resistance to NA inhibitors have been characterized, however the importance of specific mutations in the stalk domain are unknown. We identified 66Y (N1 numbering), a highly conserved amino acid that was critical for the stability of the NA tetramer and, subsequently, for NA enzymatic activity.
Copyright ? 2016, American Society for Microbiology. All Rights Reserved.
PMID: 27847354 DOI: 10.1128/JVI.00868-16
[PubMed - as supplied by publisher]
[h=1]An amino acid in the stalk domain of N1 neuraminidase is critical for enzymatic activity.[/h] Zanin M[SUP]1[/SUP], Duan S[SUP]2[/SUP], Wong SS[SUP]1[/SUP], Kumar G[SUP]3[/SUP], Baviskar P[SUP]1[/SUP], Collin E[SUP]4[/SUP], Russell C[SUP]1[/SUP], Barman S[SUP]1[/SUP], Hause B[SUP]5[/SUP], Webby R[SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Neuraminidase (NA) is a sialidase expressed on the surface of influenza A viruses that releases progeny viruses from the surface of infected cells and prevents viruses becoming trapped in mucus. It is a homo-tetramer with each monomer consisting of a transmembrane region, a stalk and a globular head with sialidase activity. We recently characterized two swine viruses of the pandemic H1N1 lineage; A/swine/Virginia/1814-1/2012 (pH1N1[SUB]low[/SUB]-1) and A/swine/Virginia/1814-2/2012 (pH1N1[SUB]low[/SUB]-2) with almost undetectable NA enzymatic activity compared to the highly homologous A/swine/Pennsylvania/2436/2012 (pH1N1-1) and A/swine/Minnesota/2499/2012 (pH1N1-2) viruses. pH1N1-1 transmitted to aerosol contact ferrets but pH1N1[SUB]low[/SUB]-1 did not. The aim of this study was to identify the molecular determinants associated with low NA activity as potential markers of aerosol transmission. We identified the shared unique substitutions M19V, A232V, D248N and I436V (N1 numbering) in pH1N1[SUB]low[/SUB]-1 and pH1N1[SUB]low[/SUB]-2. pH1N1[SUB]low[/SUB]-1 also had the unique Y66D substitution in the stalk domain, where 66Y was highly conserved in N1 NAs. Restoration of 66Y was critical for the NA activity of pH1N1[SUB]low[/SUB]-1 NA, although 19M or 248D in conjunction with 66Y was required to recover activity to that of pH1N1 viruses. Studies of NA stability and molecular modeling revealed that 66Y likely stabilized the NA homotetramer. Therefore, 66Y in the stalk domain of N1 NA was critical for the stability of the NA tetramer and, subsequently, for NA enzymatic activity.
[h=4]IMPORTANCE:[/h] Neuraminidase (NA) is a sialidase that is one of the major surface glycoproteins of influenza A viruses and the target for the influenza drugs oseltamivir and zanamivir. NA is important as it releases progeny viruses from the surface of infected cells and prevents viruses becoming trapped in mucus. Mutations in the globular head domain that decrease enzymatic activity but confer resistance to NA inhibitors have been characterized, however the importance of specific mutations in the stalk domain are unknown. We identified 66Y (N1 numbering), a highly conserved amino acid that was critical for the stability of the NA tetramer and, subsequently, for NA enzymatic activity.
Copyright ? 2016, American Society for Microbiology. All Rights Reserved.
PMID: 27847354 DOI: 10.1128/JVI.00868-16
[PubMed - as supplied by publisher]