Receptor Binding and Membrane Fusion in Virus Entry: The Influenza Hemagglutinin

Abstract

Hemagglutinin (HA) is the receptor-binding and membrane fusion glycoprotein of influenza virus and the target for infectivity-neutralizing antibodies. The structures of three conformations of the ectodomain of the 1968 Hong Kong influenza virus HA have been determined by X-ray crystallography: the single-chain precursor, HA0; the metastable neutral-pH conformation found on virus, and the fusion pH-induced conformation. These structures provide a framework for designing and interpreting the results of experiments on the activity of HA in receptor binding, the generation of emerging and reemerging epidemics, and membrane fusion during viral entry. Structures of HA in complex with sialic acid receptor analogs, together with binding experiments, provide details of these low-affinity interactions in terms of the sialic acid substituents recognized and the HA residues involved in recognition. Neutralizing antibody-binding sites surround the receptor-binding pocket on the membrane-distal surface of HA, and the structures of the complexes between neutralizing monoclonal Fabs and HA indicate possible neutralization mechanisms. Cleavage of the biosynthetic precursor HA0 at a prominent loop in its structure primes HA for subsequent activation of membrane fusion at endosomal pH (Figure 1). Priming involves insertion of the fusion peptide into a charged pocket in the precursor; activation requires its extrusion towards the fusion target membrane, as the N terminus of a newly formed trimeric coiled coil, and repositioning of the C-terminal membrane anchor near the fusion peptide at the same end of a rod-shaped molecule. Comparison of this new HA conformation, which has been formed for membrane fusion, with the structures determined for other virus fusion glycoproteins suggests that these molecules are all in the fusion-activated conformation and that the juxtaposition of the membrane anchor and fusion peptide, a recurring feature, is involved in the fusion mechanism. Extension of these comparisons to the soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) protein complex of vesicle fusion allows a similar conclusion.

Isolation, sequencing and phylogenetic analysis of the hemagglutinin, neuraminidase and nucleoprotein genes of the Chilean equine influenza virus subtypes H7N7 and H3N8

“…With respect to the HA of subtype H3, in agreement with results in the literature [26] most amino acid substitutions in Sa85 are found in the protein's globular region. This globular region, whose three-dimensional structure is known [36], contains all the known antigenic sites.…”

Synthetic Multivalent Ligands as Probes of Signal Transduction

“…[54][55][56] Ligand binding can transduce signals by directly stabilizing or destabilizing protein assemblies. [57][58][59] For example, data collected from diverse experiments suggest that attractant binding to a single MCP can impact signaling from nearby MCP partners. [46] [60][61][62][63][64] Similarly, crossphosphorylation of some growth factor receptors is facilitated by ligand-induced contacts.…”

Viral membrane fusion: is glycoprotein G of rhabdoviruses a representative of a new class of viral fusion proteins?

“…The best-studied low pH-activated viral fusion protein is the influenza virus glycoprotein hemagglutinin (HA). The X-ray structure of influenza virus HA was determined at both neutral and fusogenic pH (5). The conformational changes observed suggest that the hydrophobic fusion peptide moves to the tip of the molecule and is delivered toward the target membrane.…”