Influenza Hemagglutinin

The best-characterized example of a viral fusion protein is influenza hemagglutinin (HA). In fact, the generic events described above derive almost entirely from studies on influenza HA, and it is still the only class I fusion protein for which structures of all relevant stages are available, that is, the unprocessed precursor HA0 as well as the fusion protein itself in the pre- and post-fusion states (Chen et al. 1998; Wilson et al. 1981; Carr and Kim 1993; Bullough et al. 1994). HA0 is cleaved into HA1, the receptor-binding protein, and HA2, the fusion protein, which together form the fusion-competent HA protein. In spite of this proteolytic step, HA1 and HA2 remain covalently connected by a disulfide bridge. HA1 recognizes specific sialic acid residues of glycoproteins and glycolipids in the target host membrane. Organ specificity of viral infection is achieved through differential affinities to the major types of sialic acid-galactose linkages and their differential organ distribution (Ito et al. 1997). Binding of HAj to as yet unidentified target receptors leads to endocytosis of the HA1/HA2 complex by the host cell. The low pH of the late endosome triggers the release of the fusion protein HA2 from the metastable HA1/HA2 complex to initiate membrane fusion (Skehel and Wiley 2000). In vitro, membrane fusion can also be initiated by elevated temperature (Wharton et al. 1986). Recombinantly expressed HA2 lacking the fusion peptide and the C-terminal transmembrane region spontaneously folds into the stable post-fusion conformation, structurally and biochemically indistinguishable from that of full-length HA2 in the post-fusion state (Chen et al. 1995). This indicates that this conformation is the lowest-free-energy state of the molecule, implying that the receptor-binding protein functions as a kinetic trap for the fusion protein, which is released upon lowering pH or raising temperature.

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