Hemagglutinin (influenza virus A)
| Hemagglutinin (influenza virus A) | ||
|---|---|---|
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| Hemagglutinin molecule | ||
| Mass / length primary structure | 549 = 321 + 228 amino acids | |
| Secondary to quaternary structure | 3 * (HA1 + HA2) homotrimer | |
| Precursor | Pre-HA (566 AS) | |
| Identifier | ||
| External IDs | ||
Hemagglutinin (HA) is a glycoprotein of the influenza A virus . It is one of the three integral membrane proteins in the virion and on the cell surface of infected cells. Hemagglutinins are also found in other viruses.
properties
The name of hemagglutinin comes from the discovery that the influenza virus is able to clump together red blood cells. This process is called hemagglutination . The then unknown factor that did this was called hemagglutinin.
Receptors for hemagglutinins (antireceptors) are large, sialic acid-bearing glycoproteins on the cell surface. The two other integral membrane proteins of influenza virus A, the proton-conducting ion channel M2 and the enzyme neuraminidase (NA) are also located on the virus particles . Neuraminidases are enzymes that remove sialic acid residues from the host cell membrane in the early development of the virus particle. This splitting off of all sialic acid residues plays a decisive role within the replication cycle of an influenza virus, since the newly emerging virus particle would otherwise adhere to its original host cell by means of its hemagglutinin, which prevents the virus from spreading. The hemagglutinin also serves as a fusogenic protein for penetration of the endosome when the cell enters.
construction
Hemagglutinin is a homotrimeric membrane protein that binds to the neuraminic acid receptor on a host cell and - after proteolytic activation in the endosome - transports the interior of the virion (the ribonucleoprotein ) through the endosome membrane into the cytosol . It protrudes from the virus envelope as a 10 to fourteen nanometer long peplomer and is recognized by neutralizing antibodies in the course of an immune reaction (e.g. in the event of an illness or vaccination ) , which is why the serotype of HA changes after almost every epidemic . HA makes up about 80 percent of the proteins in the virus envelope.
The HA is a trimer of three identical units that are seven-fold glycosylated , three-fold palmitoylated and associated with lipid rafts . After the proteolytic cleavage, each unit consists in turn of two subunits: the HA1 and the HA2 . Both subunits are connected to one another by a disulphide bridge. The subunits HA1 and HA2 arise from the predecessor protein HA0 . For this purpose, the HA0 must be cleaved into HA1 and HA2 by a protease of the trypsin type (preferably clara ).
HA1
The HA1 consists mainly of a globular domain, ie it forms a large head, which is stabilized by disulfide bridges. This head contains the binding site for neuraminic acid. The most important binding sites ( antigens ) for the antibodies of the immune system are also located on the globular head of the HA1. Due to the selection pressure, the HA1 is therefore subject to rapid evolution.
The HA1 is responsible for the conformational change of the HA, which can trigger the fusion of the virus envelope with the host membrane. To do this, HA1 and HA2 must separate, which activates the fusion domain . This happens before the lowered pH value in the endosome allows the virus to penetrate the endosome membrane. A decrease in the pH value causes a positive charge through protonation of the HA1 subunits. As a result, the HA1 subunits repel each other, detach themselves from the HA2 and activate it. The HA2 then triggers the fusion of the membranes. The HA2 can only be activated once, after which it is inactive and the virus loses its ability to infect.
HA2
The HA2 is mostly built up alphahelically and contains a large loop region. The HA2 also contains the transmembrane domain and the so-called fusion peptide . The fusion peptide is released by cleaving the HA.
The HA2 is responsible for the fusion of the virus envelope with the cell membrane of the host cell. To trigger the fusion, the globular heads of HA1 must separate from HA2. This allows the HA2 to change its conformation so that it can unfold and immerse the fusion peptide in the host membrane. The fusion peptide acts like an anchor or grappling hook. As a result, the virus is directly connected to the host membrane.
The HA2 is extended on one side by the unfolding. However, lower areas are simultaneously "rolled up" so that there is no net increase in the protein. In further steps, the HA flips over and thus pulls the virus to the host membrane and triggers the fusion of both membranes.
The pH value also plays a role in the conformational change of HA2: the already hydrophobic fusion peptide becomes even more hydrophobic at low pH due to a change in conformation. The "curling up" of the lower part of the HA2 is also dependent on the low pH.
Replication
The virus particle binds to a neuraminic acid residue of its host cell via the neuraminic acid receptor of HA1 . Neuraminic acid occurs as a component of the glycocalyx in almost all cells of the host organism. Influenza A can therefore also attack all these cells, provided that these cells also take up the virus particle via the endocytosis and carry out the proteolytic activation of the HA0. The endosome develops into a lysosome and is acidified in the process. If the pH falls below a value of 6.0 to 5.0, a conformational change of the HA is triggered, which results in the fusion of the virus and endosome membrane. This brings the virus genome into the host cell. However, this process alone is not enough to infect the cell. This also requires the membrane protein M2 , which mediates the acidification inside the virion.
Although the virus particle of influenza A can infect a large number of cell types because of the HA , not all cell types can produce infectious virus particles. In order to generate an infectious virus particle, the HA0 must be converted into the active HA by an extracellular protease of the host cell. Without this activation, the virus envelope cannot fuse with the membrane of the host's lysosome: the particle is not infectious and is broken down in the lysosome. This mechanism determines which cell types (and thus which tissue) are suitable for the replication of infectious viruses.
Tropism
The hemagglutinins bind a differently linked sialic acid depending on the serotype . This determines the tropism of the respective serotype.
Pathogenicity
The activation of the HA0 by the extracellular protease determines in which tissue of the host's body active virus particles can and in which not. Typically, in this way, human influenza infection is limited to the upper respiratory tract.
Aggressive strains can be activated by various proteases. They have two interfaces instead of one and can thus generate active virus particles in other tissues and damage them through the infection. Highly aggressive strains (e.g. HPAI ) even have three interfaces and are thereby activated by some cellular serine proteases , e.g. B. in a multi-basic cleavage site (MBCS). Because of this, they can multiply throughout the body. A co-infection with bacteria in the lung area can provide these proteases.
literature
Milton J. Schlesinger and Sondra Schlesinger: Domains of Virus Glycoproteins. II. Influenza Virus Hemagglutinin . In: Karl Maramorosch, Kenneth M. Smith, Frederick A. Murphy, Max A. Lauffer, Aaron J. Shatkin (Eds.): Advances in Virus Research . tape 33 . Academic Press, 2007, ISBN 0-12-039833-8 , pp. 2 ff .
Individual evidence
Web links
- Jennifer McDowall / Interpro: Protein Of The Month: Bird flu - Haemagglutinin. (engl.)
- Hemagglutinin inhibitors as a new class of drugs in avian flu