Hemagglutinin (influenza)

Influenza hemagglutinin (HA) or haemagglutinin (British English) is a homotrimeric glycoprotein found on the surface of influenza viruses and integral to its infectivity. Hemagglutinin is a Class I Fusion Protein, having multifunctional activity as both an attachment factor and membrane fusion protein. Therefore, HA is responsible for binding Influenza virus to sialic acid on the surface of target cells, such as cells in the upper respiratory tract or erythrocytes, following which event the virus is internalised. Secondarily, HA is responsible for the fusion of the viral envelope with the late endosomal membrane once exposed to low pH (5.0-5.5). The name 'hemagglutinin' comes from the protein's ability to cause red blood cells (erythrocytes) to clump together ('agglutinate') in vitro. Hemagglutinin (HA) in influenza A has at least 18 different subtypes. These subtypes are named H1 through H18. H16 was discovered in 2004 on influenza A viruses isolated from black-headed gulls from Sweden and Norway. H17 was discovered in 2012 in fruit bats. Most recently, H18 was discovered in a Peruvian bat in 2013. The first three hemagglutinins, H1, H2, and H3, are found in human influenza viruses. By phylogenic similarity, the HA proteins are divided into 2 groups, with H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, and H18 belonging to group 1 and the rest in group 2. The serotype of influenza A virus is determined by the Hemagglutinin (HA) and Neuraminidase (NA) proteins present on its surface. Neuraminidase (NA) has 11 known subtypes, hence influenza virus is named as H1N1, H5N2 etc., depending on the combinations of HA and NA. A highly pathogenic avian flu virus of H5N1 type has been found to infect humans at a low rate. It has been reported that single amino acid changes in this avian virus strain's type H5 hemagglutinin have been found in human patients that 'can significantly alter receptor specificity of avian H5N1 viruses, providing them with an ability to bind to receptors optimal for human influenza viruses'. This finding seems to explain how an H5N1 virus that normally does not infect humans can mutate and become able to efficiently infect human cells. The hemagglutinin of the H5N1 virus has been associated with the high pathogenicity of this flu virus strain, apparently due to its ease of conversion to an active form by proteolysis. HA is a homotrimeric integral membrane glycoprotein. It is shaped like a cylinder, and is approximately 13.5 nanometres long. HA trimer is made of three identical monomers. Each monomer is made of an intact HA0 single polypeptide chain with HA1 and HA2 regions that are linked by 2 disulfide bridges. Each HA2 region adopts alpha helical coiled coil structure and sits on top of the HA1 region, which is a small globular domain that consists of a mix of α/β structures. The HA trimer is synthesized as inactive precursor protein HA0 to prevent any premature and unwanted fusion activity and must be cleaved by host proteases in order to be infectious. At neutral pH, the 23 residues near the N-terminus of HA2, also known as the fusion peptide that is eventually responsible for fusion between viral and host membrane, is hidden in a hydrophobic pocket between the HA2 trimeric interface. The C-terminus of HA2, also known as the transmembrane domain, spans the viral membrane and anchors protein to the membrane. HA plays two key functions in viral entry. Firstly, it allows the recognition of target vertebrate cells, accomplished through the binding to these cells' sialic acid-containing receptors. Secondly, once bound it facilitates the entry of the viral genome into the target cells by causing the fusion of host endosomal membrane with the viral membrane. Specifically, the HA1 domain of the protein binds to the monosaccharide sialic acid which is present on the surface of its target cells, allowing attachment of viral particle to the host cell surface. HA17 and HA18 have been described to bind MHC class II molecules as a receptor for entry rather than sialic acid. The host cell membrane then engulfs the virus, a process known as endocytosis, and pinches off to form a new membrane-bound compartment within the cell called an endosome. The cell then attempts to begin digesting the contents of the endosome by acidifying its interior and transforming it into a lysosome. Once the pH within the endosome drops to about 5.0 to 6.0, a series of conformational rearrangement occurs to the protein. First, fusion peptide is released from the hydrophobic pocket and HA1 is dissociated from HA2 domain. HA2 domain then undergoes extensive conformation change that eventually bring the two membranes into close contact.