Hemagglutinins (alternatively spelt haemagglutinin, from the Greek haima, 'blood' + Latin gluten, 'glue') are homotrimeric glycoproteins present on the protein capsids of viruses in the Paramyxoviridae and Orthomyxoviridae families. Hemagglutinins are responsible for binding to receptors, sialic acid residues, on host cell membranes to initiate virus docking and infection. Specifically, they 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. In the endosome, hemagglutinins undergo conformational changes due to a pH drop to of 5–6.5 enabling viral attachment through a fusion peptide. Virologist George K. Hirst discovered agglutination and hemagglutinins in 1941. 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. The name "hemagglutinin" comes from the protein's ability to cause red blood cells (erythrocytes) to clump together ("agglutinate") in vitro.

Types

Structure

Hemagglutinins are small proteins that extend from the surface of the virus membrane as spikes that are 135 Angstroms (Å) in length and 30-50 Å in diameter. Each spike is composed 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, NMR spectroscopy, and cryo-electron microscopy were used to solve the protein's structure, the majority of which is α-helical. 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.

Step-By-Step Mechanism (Influenza Hemagglutinin)

On the viral capsids of influenza types A and B, hemagglutinin is initially inactive. Only when cleaved by host proteins, does each monomer polypeptide of the homotrimer transforms into a dimer – composed of HA1 and HA2 subunits attached by disulfide bridges. The HA1 subunit is responsible for docking the viral capsid onto the host cell by binding to sialic acid residues present on the surface of host respiratory cells. This binding triggers endocytosis. The pH in the endosomal compartment then decreases from proton influx, and this causes a conformational change in HA that forces the HA2 subunit to “flip outward.” The HA2 subunit is responsible for membrane fusion. It binds to the endosomal membrane, pulling the viral capsid membrane and the endosomal membrane tightly together, eventually forming a pore through which the viral genome can enter into the host cell cytoplasm. From here, the virus can use host machinery to proliferate.

Uses in serology