In molecular biology, hemagglutinins (alternatively spelled haemagglutinin, from the Greek haima, 'blood' + Latin gluten, 'glue') are receptor-binding membrane fusion glycoproteins produced by viruses in the Paramyxoviridae and Orthomyxoviridae families.[1][2] Hemagglutinins are responsible for binding to receptors on red blood cells to initiate viral attachment and infection.[3] The agglutination of red cells occurs when antibodies on one cell bind to those on others, causing amorphous aggregates of clumped cells.
Hemagglutinins recognize cell-surface glycoconjugates containing sialic acid on the surface of host red blood cells with a low affinity, and use them to enter the endosome of host cells.[4] In the endosome, hemagglutinins are activated at a pH of 5–6.5 to undergo conformational changes that enable viral attachment through a fusion peptide.[5]
Virologist George K. Hirst discovered agglutination and hemagglutinins in 1941.[6] Alfred Gottschalk proved in 1957 that hemagglutinins bind a virus to a host cell by attaching to sialic acids on carbohydrate side chains of cell-membrane glycoproteins and glycolipids.[7]
Hemagglutinins are small proteins that project from the virus membrane surface as 135 Angstrom (Å) long spikes with a diameter of 30–50 Å.[13] Each spike is made up of three identical monomer subunits, making the protein a homotrimer. These monomers are formed of two glycopeptides, HA1 and HA2, and linked by two disulphide polypeptides, including membrane-distal HA1 and the smaller membrane-proximal HA2. X-ray crystallography and spectroscopy were used to identify that the majority of the protein structures is made of α-helical proteins.[14] In addition to the homotrimeric core structure, hemagglutinins have four subdomains: the membrane-distal receptor binding R subdomain, the vestigial domain E, that functions as a receptor-destroying esterase, the fusion domain F, and the membrane anchor subdomain M. The membrane anchor subdomain forms elastic protein chains linking the hemagglutinin to the ectodomain.[15]