Hemagglutinin

• UniProt: P03437

Glycoprotein hemagglutinin (HA) of influenza virus A is one of the three integral membrane proteins in the virion and the cell surface of infected cells. Hemagglutinins are also present in other viruses.

Properties

The name hemagglutinin comes from the detection of the time since the influenza virus is capable of clumping red blood cells. This process is called hemagglutination. The then unknown factor that caused this, was called hemagglutinin.

Receptors for hemagglutinin ( anti-receptor ) are large, sialinsäuretragende glycoproteins on the cell surface. On the virus particles can also find the other two integral membrane proteins of the influenza virus A, the proton-conducting ion channel M2 and the enzyme neuraminidase ( NA). Neuraminidases are enzymes that remove sialic acid residues in the early development of the virus particle from the host cell membrane. This cleavage of all sialic acid residues plays a crucial role in the propagation cycle of an influenza virus as the virus particles neuentstandende would otherwise adhere by means of its hemagglutinin to its original host cell, which prevents the spread of the virus.

Construction

Hemagglutinin is a homotrimeric membrane protein that mediates adhesion to the receptor sialic acid to a host cell, and - after proteolytic activation in endosomes - discharged, the inside of the virion ( the ribonucleoprotein ) through the endosomal membrane into the cytosol. It is found to be about 10 nanometers to fourteen long peplomer of the viral envelope, and is in the course of an immune response (eg, a disease or vaccination) recognized by neutralizing antibodies, and therefore the changes to most of the HA serotype each epidemic. HA constitutes about 80 percent of the proteins in the viral envelope.

HA is a trimer of three identical units which are seven- glycosylated, palmitoylated and triple associated with lipid rafts. Each unit is, in turn, by the proteolytic cleavage of two subunits: HA1 and HA2, the. Both subunits are linked by a disulfide bridge. The subunits HA1 and HA2 are shown in the previous HA0 protein. For this, the HA0 of a protease from trypsin - type (preferably clara ) must be cleaved into HA1 and HA2.

HA1

The HA1 consists largely of a globular domain, ie it forms a large head, and this is stabilized by disulfide bonds. This header contains the binding site for the sialic acid. The main binding sites (antigens) for the antibodies of the immune system are also located on the globular head of the HA1. Through the selection pressure that HA1 is therefore subjected to rapid evolution.

The HA1 is responsible for the conformational change of HA, which can trigger the fusion of the viral envelope with the host membrane. To this end, HA1 and HA2 have to separate, causing the fusion domain is activated. This is done before the lowered pH in the endosomes, allowing the virus to penetrate the endosomal membrane. A lowering of the pH caused by protonation of the HA1 subunit is a positive charge. Thus, the HA1 subunits stumble against each other, to dissolve it from the HA2 and thereby activate this. The HA2 then triggers the fusion of the membranes. The HA2 but can be activated only once, after that it is inactive and the virus loses its infectivity.

HA2

The HA2 is largely constructed alphahelikal and contains a large loop region. The HA2 also contains the transmembrane domain and the so-called fusion peptide. The fusion peptide is liberated by cleavage of the HA.

The HA2 is responsible for the fusion of the viral envelope with the cell membrane of the host cell. To trigger fusion, the globular heads of the HA1 need to disconnect from the HA2. This allows the HA2 change its conformation so that it unfolds and the fusion peptide can dip into the host membrane. The fusion peptide acts as an anchor or grappling hooks. Thus the virus is directly connected to the host membrane.

The HA2 is extended unilaterally by the development. Lower portions but are " rolled up " at the same time, so that there is no net increase in the protein. In further steps, the HA folds down and energizes the virus to the host membrane zoom and triggers the fusion of the two membranes.

For the conformation of HA2, the pH also plays a role: the already hydrophobic fusion peptide at low pH by changing the conformation of hydrophobic yet. Also, the " rolling up " the lower part of HA2 is also of the low pH -dependent.

Replication

The virus particle binds via the Neuraminsäurerezeptor of HA1 to a neuraminic acid residue of its host cell. The neuraminic acid is as good as all the cells of the host organism's as part of the glycocalyx in front. Therefore Influenza A can infect all of these cells, provided these cells take the virus particles via endocytosis and perform the proteolytic activation of HA0. The endosome is becoming the lysosome and is acidified it. Falls below the pH at 6.0 to 5.0, such a conformational change of the HA is triggered, which has the fusion of viral and endosome result. Characterized the viral genome enters the host cell. However, this process is not sufficient alone to infect the cell. To the membrane protein M2 is also necessary, which mediates the acidification inside the virion.

Although the virus particles of Influenza A can infect many cell types because of the HA, so can not produce infectious virus particles all cell types. To generate an infectious viral particle, the HA0 must be converted by an extracellular protease of the host cell in the active HA. Without this activation, the viral envelope can not fuse with the membrane of the lysosome of the host: the particle is not infectious and is degraded in the lysosome. This mechanism determines which cell types (and thus which tissue) for the propagation of infectious virus come into question.

Tropism

The hemagglutinins bind depending on the serotype a different linked sialic acids. Thus, the tropism of each serotype is determined.

Pathogenicity

The activation of HA0 by the extracellular protease determined in which tissues of the body of the host, active virus particles are produced and in which not. Normally limited in this way an infection with human influenza on the upper respiratory tract.

Aggressive strains can be activated by different proteases. They have two instead of one port and can produce active virus particles in other tissues and cause damage to the tissue by infection. Aggressive high strains ( eg HPAI ) have even three interfaces and are thereby activated by some cellular serine protease, eg, in a multi -basic cleavage site (MBCS ). Therefore, they can breed throughout the body. Coinfection with bacteria in the lung area can provide these proteases.