The influenza virus is a common virus found in many places around the world and comes in three different subtypes A,B, and C. Influenza A subtype is the most infectious subtype. It causes pandemics with significant mortalities in affected young people for that it has a wide host range including human, pigs, horses, and birds. All the three influenza subtypes contains the same segmental genome and enveloped glycoproteins. The virus is spherically shaped, ranging from 80 to 120 nm in diameter. It contain 3 proteins on their outer surface, H, N, and M2. It also contains a matrix protein M1 below the outer surface. Every protein have different function that helps the virus to penetrate and insert the animal’s cells. The virus also contains eight segments of single stranded negative polarity RNA. Once the virus infect the cell , it will travel to the nucleus to replicate its genome, then the viral mRNA will transfer to the cytoplasm for translation into viral proteins. Once all the viral proteins are formed, they will all aggregate and get released from the host cell (Shors, 2013).Reza Mortazavi/Sandbox 1. Click above on edit this page to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia [1] or to the article describing Jmol [2] to the rescue.
Functions
Hemagglutinin (H) protein is the most important glycoprotein found on the cell surface for that it is responsible for the attachment of the influenza to the epithelial cell receptor (sialic acid) as well as helping with the fusion between the viral lipid membrane and the host cell endosomal membrane.(Shors, 2013). The H protein consist of three identical polypeptides, each polypeptide is 550 amino acids long that get glycosylated then cleaved into two chains (H1,H2). The cleavage of the polypeptide is done by removal of arginine 329 along with a conformational change. H1 and H2 chains are covalently attached by disulfide bonds and form one monomer, then they noncovalently associate with two of the same monomers and form a homotrimer (Proteopedia 2015).
The H protein is a transmembrane protein consist of two polypeptides, H1 and H2, which are linked by a disulfide bond. The full length of the protein is referred to as H0. The H1 subunit (382 Amino Acid) is composed of of eight stranded β sheet associated with little α helix (Proteopedia,2015).The H1 portion forms a globular bulb at the top of the structure which is composed of an eight-stranded beta-sheet, associated with a little alpha-helix, separating the strands 3 and 4. H1 proteins contain the sialic acid binding site for attachment to the host cell. The amino acid of the alpha helix and some other beta sheets compose the binding pocket of the receptor subunit, and determine the attachment specificity of the virus to the host cell (Proteopedia,2011). The H2 portion of H0 is called membrane-spanning anchor and it is directly involved in the fusion mechanism. H2 has a hairpin structure composed by two antiparallel alpha-helices. The C- terminal of H2 is embedded in the the viral membrane while the hydrophobic N-terminal end contains 10 hydrophobic amino acid forming the fusion peptide (proteopedia, 2011).
When H protein attaches to sialic acid residues that are present on glycoproteins of the ciliated columnar epithelial cell lining the sinuses and airways, the bound virus is endocytosed by the cell and the virions enter the cell within the endosomal vesicle. When the endosomal pH level drops and reaches about 5.5 which happens due to the pumping of protons inside the nucleosome by the M2 ions channel, the H1 protein shifts its position, allowing the H2 protein to become embedded in the host cell membrane. Additionally, the C-terminus embedded in the viral membrane rearranges, bringing the two membranes closer together and facilitation fusion (Wilson et. al 1981). The pH induced conformational changes is partially, but not completely reversible, it involve the loss of confirmation of 15-25 β sheet residues, therefore membrane bound H1 subunit becomes more rigid at low pH. The quaternary structural change in H1 subunit during membrane fusion involves the introduction of disulfide bonds. Overall, the shifting of H1 subunit plays an important role in H mediated membrane fusion that results in the release of viral RNA’s into the cytoplasm and then into the cell’s nucleus for RNA replication (Racanilllo, 2009)
https://www.nature.com/nature/journal/v289/n5796/pdf/289366a0.pdf
The N protein (neuraminidase), is one of the main antigenic determinants present at the outer surface along with other transmembrane glycoproteins, and it aids in the viral budding process. The N protein is homotetramer with the substrate binding site containing only single protein. The secondary structure mostly consist of several beta sheets and three short alpha helices (Proteopedia, 2014). The neuraminidase is an enzyme that cleaves sialic acid from the haemagglutinin molecule, neuraminidase molecules, glycoproteins and glycolipids at the cell’s surface. The sialic acid cleavage helps the virus to bud off from the surface of the infected cell (Gürtler, 2006).
The M1 protein, also known as the matrix protein, surrounds the viral proteins and the constructs the matrix of the influenza virus. This matrix layer is covered by the lipid layer, which contains the main transmembrane glycoproteins in one side of the virus, and affinity for the viral ribonucleotide complex molecules on the other side. the structure of M1 protein has two domain protein with an N-terminal domain containing residues 1–164 and a C-terminal domain with residues 165–252. https://www.sciencedirect.com/science/article/pii/S0168170203003216
the N terminus of M1 has a polybasic sequence at the one side of the molecule, this polybasic sequence sometimes is beta strand and sometimes is alpha helix https://www.sciencedirect.com/science/article/pii/S0042682299901344. Thus,M1 protein function as self polymerisation, M1 proteins must bind to both the membrane as well as the viral RNA simultaneously. However, even though the M1 protein binds to the viral RNA, the binding is not specific. Some other functions include a role in the export of the viral ribonucleoproteins from the host cell nucleus,M1 protein enters the nucleus through its own nuclear localization signal which is needed for the export for the newly formed ribonucleoproteins. there is protein that involved in this export process, NS2 or NEP for nuclear export protein https://www.sciencedirect.com/science/article/pii/S0168170203003216, inhibition of viral transcription, and in the virus assembly and budding, which is a form of asexual reproduction that the influenza virus practices (Holsinger et. al 1994).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC236612/
The structure of the M2 protein consists of a four-helix bundle with a 25 degree tilt (online source). Once the H protein undergoes a conformational change, M2 proteins act as an ion channel by allowing the proton ions to penetrate the viron. The pumping of the protons will weakens the interaction between the viral matrix proteins and the viral RNA and nucleoproteins. The eight segments of the viral ribonuclease are then released into the cytoplasm and exported to the nucleus. the ability of opening and closing the M2 ion channel depends on the action of single transmembrane domain residue Trp 41.when the pH exceed pH7 the channel will be closed. while when the pH is lower than pH 6.5 the channel will be opened. Trp 41 is a key residue in opening and closing ion channel pore (Pinto, Lamb 2006).
Treatment
There are two antiviral treatments nowadays that triggers the M2 channel and stops its function, Amantadine and Rimantadine (Shors, 2013). By stopping the function of M2 proteins, the release of the viral genome and proteins will be incomplete or terminally stopped. As a result, the uncoating process and the spread of the viral genome will be infrared and the virus replication will be stopped. This can be done by changing the formation of the ion channel or stopping the M2 protein function entirely. In addition to the above treatments, there are other antiviral drugs which targets the sialic acid receptor, the RNA dependent RNA polymerase, Neuraminidase (N) protein.
- ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:https://dx.doi.org/10.1002/ijch.201300024
- ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
