The influenza viral Hemagglutinin (HA) protein is a homo trimer with a receptor binding pocket on the globular head of each monomer. Hemagglutinin (HA) protein is translated in cells as a single protein, HA0, or hemagglutinin precursor protein. For viral activation, hemagglutinin precursor protein (HA0) must be cleaved by a trypsin-like serine endoprotease at a specific site, normally coded for by a single basic amino acid (usually arginine) between the HA1 and HA2 domains of the protein. After cleavage, the two disulfide-bonded protein domains produce the mature form of the protein subunits as a prerequisite for the conformational change necessary for fusion and hence viral infectivity.
The hemagglutinin (HA) membrane glycoprotein of influenza virus is a trimer of identical subunits that are formed of two disulfide-linked polypeptides:
• Membrane-distal, HA1
• Membrane-proximal, HA2
The two domain are also called a triple-stranded coiled-coil of alpha-helices extends 76 A from the membrane and a globular region of antiparallel beta-sheet, which contains the receptor binding site and the variable antigenic determinants, is positioned on top of this stem. Each subunit has an unusual loop-like topology, starting at the membrane, extending 135 A distally and folding back to enter the membrane.
Influenza type A viruses into 16 HA (H1–H16) subtypes. Phylogenetically, there are two groups of HAs: group 1 contains H1, H2, H5, H6, H8, H9, H11, H12, H13, and H16, and group 2 contains H3, H4, H7, H10, H14, and H15
• Gold and silver: two of the monomers from each trimer
• The subunits that make up the third monomer are colored as follows:
blue: receptor binding
yellow: vestigial esterase
magenta and red: fusion subdomains
• Phylogenetic tree:
16 subtypes of HA that fall into two distinct groups
Hemagglutinin (HA) has two functions in virus infection:
• Receptor binding
• Membrane fusion
Hemagglutinin (HA) mediates binding of the virus particle to the host-cell membrane and catalyzes fusion of the viral membrane with that of the host. HA is therefore a major target in the development of antiviral strategies.
Viruses are bound by HAs to cell-surface sialic acid receptors and are taken into cells by endocytosis. This activity is the target of antibodies that block infection. The HA1 domain of hemagglutinin binds to the monosaccharide sialic acid which is present on the surface of its target cells. Many strain-specific antibodies bind in or near the HA1, membrane-distal, receptor-binding site. By contrast, a number of cross-reactive anti-HA antibodies have been described that bind to the membrane proximal regions of HA and block membrane fusion.
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