Hemagglutinin

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"HA" = Hemagglutinin
Hemagglutinin, as depicted in a simplified molecular model.
Hemagglutinin (HA) in action. HA binds sugars (green), then the cell releases acid molecules making HA refolding in a different way. Red peptide is the fusion peptide, that locks virus near the cell membrane. Yellow portion produces fusion between the two membranes.
Hemagglutinin is a spike-shaped virus surface protein made of two chain types. Blue: subunit for binding of specific human cell surfaces sugars. Orange: subunit for triggering response (PDB code: 1ruz). (more details...)

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Hemagglutinin (HA) or haemagglutinin (BE) is an antigenic glycoprotein found on the surface of the influenza viruses (as well as many other bacteria and viruses). It is responsible for binding the virus to the cell that is being infected. The name "hemagglutinin" comes from the protein's ability to cause red blood cells (erythrocytes) to clump together ("agglutinate") in vitro [1].

Subtypes

There are at least 16 different HA antigens. These subtypes are labeled H1 through H16. The last, H16, was discovered only recently on influenza A viruses isolated from black-headed gulls from Sweden and Norway[2]. The first three hemagglutinins, H1, H2, and H3, are found in human influenza viruses.

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"[3][4]. 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 (Senne 1996, Hatta 2001).

Functions and mechanisms of action

HA has two primary functions:

  1. allowing the recognition of target vertebrate cells, accomplished through the binding of these cells' sialic acid-containing receptors, and
  2. allowing the entry of the viral genome into the target cells by causing the fusion of host endosomal membrane with the viral membrane (White 1997),

Mechanism:

HA binds to an as yet unidentified glycoprotein which is present on the surface of its target cells. This 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 PDB molecule of the month: Hemagglutinin (April 2006))

Structure

HA is a homotrimeric integral membrane glycoprotein. It is shaped like a cylinder, and is approximately 135 Å (angstroms) 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.

Sources and notes

  1. Nelson DL and Cox MM, 2005. Lehninger's Principles of Biochemistry, 4th edition, WH Freeman, New York, NY.
  2. Fouchier RAM, Munster V, Wallensten A, et al, 2005. Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls. J Virol vol 79, issue 5, pp2814-22
  3. Suzuki, Y, 2005. Sialobiology of Influenza: Molecular Mechanism of Host Range Variation of Influenza Viruses in Biological and Pharmaceutical Bulletin, vol 28, pp399-408
  4. Gambaryan A, Tuzikov A, Pazynina G, Bovin N, Balish A, Klimov A, 2006. Evolution of the receptor binding phenotype of influenza A (H5) viruses in Virology vol 344, issue 2, pp432-8
  • Yamada S, Suzuki Y, Suzuki T, et al, 2006 Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature vol 444, issue 7117, pp378-82.
  • Weis WI, Brünger AT, Skehel JJ, et al, 1990. Refinement of the influenza virus hemagglutinin by simulated annealing. J Mol Biol vol 212, pp737-761.
  • White JM, Hoffman LR, Arevalo JH, et al, 1997. Attachment and entry of influenza virus into host cells. Pivotal roles of hemagglutinin. In Structural Biology of Viruses. Chiu W, Burnett RM, and Garcea RL, editors. Oxford University Press, NY. pp80-104.

See also

Further reading

de:Hämagglutinin hr:Hemaglutinin nl:Hemagglutinine fi:Hemagglutiniini



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