11 Receptor Binding and Membrane Fusion by Influenza Hemagglutinin

Abstract

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).

RECEPTOR BINDING
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-98_l, 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...