Abstract
Divalent cations Cu2+ and Zn2+ can prevent the viral growth in mammalian cells during influenza infection, and viral titers decrease significantly on a copper surface. The underlying mechanisms include DNA damage by radicals, modulation of viral protease, M1 or neuraminidase, and morphological changes in viral particles. However, the molecular mechanisms underlying divalent cation-mediated antiviral activities are unclear. An unexpected observation of this study was that a Zn2+ ion is bound by Glu68 and His137 residues at the head regions of two neighboring trimers in the crystal structure of hemagglutinin (HA) derived from A/Thailand/CU44/2006. The binding of Zn2+ at high concentrations induced multimerization of HA and decreased its acid stability. The acid-induced conformational change of HA occurred even at neutral pH in the presence of Zn2+. The fusion of viral and host endosomal membranes requires substantial conformational changes in HA upon exposure to acidic pH. Therefore, our results suggest that binding of Zn2+ may facilitate the conformational changes of HA, analogous to that induced by acidic pH.
Highlights
Divalent cations Cu2+ and Zn2+ can prevent the viral growth in mammalian cells during influenza infection, and viral titers decrease significantly on a copper surface
The divalent cation in the crystal structure appeared to enhance the stability of HA, but significantly decreased the melting temperature Tm of the CU44 HA, depending on the Zn2+ concentrations
The mutations largely accounted for reduced exposure of hydrophobic amino acid residues on the surface and increased hydrophobic residues at the monomer–monomer interface within the trimer. They were expressed in insect cell culture, purified, and characterized by differential scanning fluorimetry (DSF)
Summary
Divalent cations Cu2+ and Zn2+ can prevent the viral growth in mammalian cells during influenza infection, and viral titers decrease significantly on a copper surface. The HA plays a critical role for acidic pH-induced membrane fusion in viral fitness[8,9] and involves the dissociation of the head regions and the extension of central coiled-coil domains in the stem regions. In this context, the stability of HA is an important attribute of influenza viral fitness, which regulates and enhances viral growth and p athogenesis[10,11]. The divalent cation in the crystal structure appeared to enhance the stability of HA, but significantly decreased the melting temperature Tm of the CU44 HA, depending on the Zn2+ concentrations. We report the structure of HA bound to Z n2+ ions and the effects of the divalent cation on pH-dependent conformational changes of HA
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