Influenza virus hemagglutinin (HA) mediates virus entry by binding to cell surface receptors and fusing the viral and endosomal membranes following uptake by endocytosis. The acidic environment of endosomes triggers a large-scale conformational change in the transmembrane subunit of HA (HA2) involving a loop (B loop)-to-helix transition, which releases the fusion peptide at the HA2 N terminus from an interior pocket within the HA trimer. Subsequent insertion of the fusion peptide into the endosomal membrane initiates fusion. The acid stability of HA is influenced by residues in the fusion peptide, fusion peptide pocket, coiled-coil regions of HA2, and interactions between the surface (HA1) and HA2 subunits, but details are not fully understood and vary among strains. Current evidence suggests that the HA from the circulating pandemic 2009 H1N1 influenza A virus [A(H1N1)pdm09] is less stable than the HAs from other seasonal influenza virus strains. Here we show that residue 205 in HA1 and residue 399 in the B loop of HA2 (residue 72, HA2 numbering) in different monomers of the trimeric A(H1N1)pdm09 HA are involved in functionally important intermolecular interactions and that a conserved histidine in this pair helps regulate HA stability. An arginine-lysine pair at this location destabilizes HA at acidic pH and mediates fusion at a higher pH, while a glutamate-lysine pair enhances HA stability and requires a lower pH to induce fusion. Our findings identify key residues in HA1 and HA2 that interact to help regulate H1N1 HA stability and virus infectivity. IMPORTANCE Influenza virus hemagglutinin (HA) is the principal antigen in inactivated influenza vaccines and the target of protective antibodies. However, the influenza A virus HA is highly variable, necessitating frequent vaccine changes to match circulating strains.Sequence changes in HA affect not only antigenicity but also HA stability, which has important implications for vaccine production, as well as viral adaptation to hosts. HA from the pandemic 2009 H1N1 influenza A virus is less stable than other recent seasonal influenza virus HAs, but the molecular interactions that contribute to HA stability are not fully understood. Here we identify molecular interactions between specific residues in the surface and transmembrane subunits of HA that help regulate the HA conformational changes needed for HA stability and virus entry. These findings contribute to our understanding of the molecular mechanisms controlling HA function and antigen stability. T he influenza virus envelope protein, hemagglutinin (HA), is organized as a noncovalently associated homotrimer on the viral surface. Each monomer of HA is posttranslationally cleaved into HA1 and HA2 subunits that are disulfide linked. The HA trimer consists of a large membrane-distal, globular domain formed only by HA1 and an elongated membrane-proximal stem domain comprised of HA2 and the N-and C-terminal segments of HA1. HA1 mediates virus binding to cell surface sialic acid receptors to initiate viral e...
Critical for cellular function, ions of the transition metal copper need to reach multiple specific destinations inside cells in an efficient manner. That they do is taken for granted. Yet, how exactly does an ion of 11Å3 find binding sites of ~1000Å3 in a volume of 30,000,000,000,000Å3 that is accessible to diffusible species within the cytosol of even a small organism like yeast? The odds for this to happen through simple 3D‐random walks and diffusion are staggeringly low, and yet, live goes on as though this problem did not exist. Studying the mechanisms of cellular copper acquisition and distribution, we recently made the discovery that cells overcome the odds associated with targeted copper delivery by reducing the dimensionality of the search problem through exploitation of cellular membranes as scaffolding components. Specifically, our studies showed that cellular copper chaperones are able to associate with membranes and that this novel property of the chaperones is important for initial copper loading into the chaperone’s copper binding site. Taken together, our findings blend into a novel paradigm in which cellular membranes play a pivotal role in the intracellular distribution of copper ions.
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