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11 Receptor Binding and Membrane Fusion by Influenza Hemagglutinin

John J. Skehel, David Steinhauer, Steve A. Wharton, Per A. Bullough, Fred M. Hughson, Stan J. Watowich, Don C. Wiley


The influenza component which is involved in receptor recognition and membrane fusion to effect transfer of the RNA genome-transcriptase complex into the cell is the hemagglutinin membrane glycoprotein. The hemagglutinin binds viruses to sialic acid residues on cell-surface glycoconjugates and, following endocytosis of the bound virus, mediates fusion between virus and endosomal membranes. It is a 220-kD trimer of identical subunits, each containing two glycopolypeptides, HA1 and HA2 (Fig. 1). The smaller HA2 chain, from which the carboxy-terminal membrane anchor is removed by bromelain digestion to produce soluble bromelain-released hemagglutinin (BHA) for crystallization, is the major component of a mainly α-helical stem that forms the center of the 140-Å-long molecule. HA1 also contributes to the stem structure but primarily forms a membrane-distal globular domain containing the receptor-binding site surrounded by variable, antigenically important, surface residues (Wiley and Skehel 1987).

Evidence for the location in the hemagglutinin of the receptor-binding site comes primarily from crystallographic studies of hemagglutinin-receptor analog complexes (Weis et al. 1988; Sauter et al. 1992) which indicate that sialic acid is bound in a shallow pocket at the membrane-distal tip of the molecule. The pocket is defined by the presence of a number of conserved amino acid residues: Tyr-98l, Trp-1531, His-1831, and Leu-1941 (residues in HA1 and HA2 are numbered with the appropriate subscript). Interactions between these residues and with the substituents of sialic acid are shown in Figure 2. β-Anomers of sialyl glycosides interact very weakly with HA, suggesting the importance for binding of the...

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