Hemagglutinin | |||||||||
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Identifiers | |||||||||
Symbol | Hemagglutinin | ||||||||
Pfam | PF00509 | ||||||||
InterPro | IPR001364 | ||||||||
SCOP | 1hgd | ||||||||
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Influenza C hemagglutinin stalk | |||||||||
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x-ray structure of the haemagglutinin-esterase-fusion glycoprotein of influenza c virus | |||||||||
Identifiers | |||||||||
Symbol | Hema_stalk | ||||||||
Pfam | PF08720 | ||||||||
InterPro | IPR014831 | ||||||||
SCOP | 1flc | ||||||||
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Influenza hemagglutinin (HA) or haemagglutinin (British English) is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected. HA proteins bind to cells with sialic acid on the membranes, such as cells in the upper respiratory tract or erythrocytes.[1]
The name "hemagglutinin" comes from the protein's ability to cause red blood cells (erythrocytes) to clump together ("agglutinate") in vitro.[2]
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There are at least 16 different HA antigens. These subtypes are named H1 through H16. The last, H16, was discovered only in 2004 on influenza A viruses isolated from black-headed gulls from Sweden and Norway.[3] The first three hemagglutinins, H1, H2, and H3, are found in human influenza viruses.
Viral neuraminidase (NA) is another protein found on the surface of influenza. Influenza viruses are characterised by the type of HA and NA that they carry; hence H1N1, H5N2 etc.
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".[4][5] 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.[6][7]
HA has two functions. Firstly, it allows the recognition of target vertebrate cells, accomplished through the binding of 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.[8]
HA binds to the monosaccharide sialic acid which is present on the surface of its target cells, which causes the viral particles to stick to the cell's surface. The cell membrane then engulfs the virus and the portion of the membrane that encloses it pinches off to form a new membrane-bound compartment within the cell called an endosome, which contains the engulfed virus. The cell then attempts to begin digesting the contents of the endosome by acidifying its interior and transforming it into a lysosome. However, as soon as the pH within the endosome drops to about 6.0, the original folded structure of the HA molecule becomes unstable, causing it to partially unfold, and releasing a very hydrophobic portion of its peptide chain that was previously hidden within the protein.
This so-called "fusion peptide" acts like a molecular grappling hook by inserting itself into the endosomal membrane and locking on. Then, when the rest of the HA molecule refolds into a new structure (which is more stable at the lower pH), it "retracts the grappling hook" and pulls the endosomal membrane right up next to the virus particle's own membrane, causing the two to fuse together. Once this has happened, the contents of the virus, including its RNA genome, are free to pour out into the cell's cytoplasm. (see Molecule of the Month at the RCSB Protein Data Bank: Hemagglutinin (April 2006))
HA is a homotrimeric integral membrane glycoprotein. It is shaped like a cylinder, and is approximately 13.5 nanometres long. The three identical monomers that constitute HA are constructed into a central α helix coil; three spherical heads contain the sialic acid binding sites. HA monomers are synthesized as precursors that are then glycosylated and cleaved into two smaller polypeptides: the HA1 and HA2 subunits. Each HA monomer consists of a long, helical chain anchored in the membrane by HA2 and topped by a large HA1 globule.
Since hemagglutinin is the major surface protein of the influenza A virus and is essential to the entry process, it is the primary target of neutralizing antibodies. Neutralizing antibodies against flu have been found to act by two different mechanisms, mirroring the dual functions of hemagglutinin:
Most commonly, antibodies against hemagglutinin act by inhibiting attachment. This is because these antibodies bind near the top of the hemagglutinin "head" (blue region in figure at right) and physically block the interaction with sialic acid receptors on target cells. In contrast, some antibodies have been found to have no effect on attachment. Instead, this latter group of antibodies acts by preventing membrane fusion. Most of these antibodies, like the human antibody CR6261, recognize sites in the stem/stalk region region (orange region in figure at right), far away from the receptor binding site [9][10] The stem (also called HA2), contains most of the membrane fusion machinery of the hemagglutinin protein, and antibodies targeting this region block key structural changes that drive the membrane fusion process. However, at least one fusion-inhibiting antibody was found to bind closer to the top of hemagglutinin, and is thought to work by cross-linking the heads together, the opening of which is thought to be the first step in the membrane fusion process.[11]
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