title: Structural insights on the potential significance of the twin Asn-residue found at the base of the hemagglutinin 2 stalk in all influenza A H1N1 strains: a computational study with clinical implications.
abstract: Influenza hemagglutinin (HA) is a homotrimeric glycoprotein responsible for binding to sialic acids found in the host cell surface. HA has a prominent 75 Å-long α-helix (HA2 stalk) that contributes to overall HA structural stability. Among the H1N1 strains, a high level of predicted disorder is found at the base of the HA2 stalk, predominantly containing Asn residues. Surprisingly, the significance of Asn residues at the base of the HA2 stalk has not been elucidated. In this study, we analyzed the HA2 stalk base of 2830 amino acid sequences of the influenza H1N1 subtype obtained from human, swine, and avian strains throughout 1918-2012. We detected a structurally conserved twin Asn-residue (N145(2)-N146(2)) present at the HA2 stalk base in all H1N1 strains. In addition, we found that the twin Asn-residue maintains both a 2.13 Å salt bridge and 11.74 Å 110-helix:B-loop distance measurement in all H1N1 strains studied. Both observations were consistent with known HA crystal structures. Interestingly, amino acid substitutions in either or both residues 145(2) and 146(2) were found to alter these measurements and, likewise, shift the empirical distribution of HA amino acid residues. Thus, we hypothesize that both the N145(2) and N146(2) residues found at the HA2 stalk base in all H1N1 strains provide the necessary structural requirements to stabilize the HA protein. More importantly, this would imply that the twin-Asn-residue is an ideal target for anti-influenza therapies.
authors.affiliation: Department of Microbiology, Division of Immunology and Pathobiology, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan. marni.cueno@nihon-u.ac.jp
authors.forename: Marni E
authors.initials: ME
authors.lastname: Cueno
authors.forename: Kenichi
authors.initials: K
authors.lastname: Imai
authors.forename: Kuniyasu
authors.initials: K
authors.lastname: Ochiai
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001216:Asparagine / Q000737:chemistry; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D017433:Protein Structure, Secondary
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D001216:Asparagine