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== Overview of influenza == | == Overview of influenza == | ||
[[Image:Influenza_glyco_proteins_Biochem.PNG|left|300px|thumb|Figure1: schematic diagram of influenza virus depicting the structure of glycoproteins] ]] | |||
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 glycoprotein. The virus is spherically shaped, ranging from 80 to 120 nm in diameter. The viral particles contain 3 proteins on their outer surface, called: H, N, and M2. It also contains a matrix protein M1 below the outer surface. Each protein has a different function that helps the virus to penetrate and enter the animal’s host cell. The virus also contains eight segments of single stranded negative polarity RNA. Once the virus infects the cell, it will travel to the nucleus to replicate its genome, then the viral mRNA will transfer to the cytoplasm to be translated into viral proteins. Once all the viral proteins are formed, they will all aggregate and get released from the host cell (Shors, 2013). | 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 glycoprotein. The virus is spherically shaped, ranging from 80 to 120 nm in diameter. The viral particles contain 3 proteins on their outer surface, called: H, N, and M2. It also contains a matrix protein M1 below the outer surface. Each protein has a different function that helps the virus to penetrate and enter the animal’s host cell. The virus also contains eight segments of single stranded negative polarity RNA. Once the virus infects the cell, it will travel to the nucleus to replicate its genome, then the viral mRNA will transfer to the cytoplasm to be translated into viral proteins. Once all the viral proteins are formed, they will all aggregate and get released from the host cell (Shors, 2013). | ||
== Hemagglutinin (H) protein == | == Hemagglutinin (H) protein == | ||
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(H) protein is the most important glycoprotein found on the virus surface for that it is responsible for the attachment of the influenza to the cells containing sialic acid receptors, such as cells in the upper respiratory tract. It also helps with the fusion between the viral lipid membrane and the host cell endosomal membrane (Shors, 2013). The H protein is a transmembrane protein consisting of two polypeptides, <scene name='SAndbox_159/Ha1/1'>H1</scene> and <scene name='SAndbox_159/Ha2/2'>H2</scene>, which are linked by a disulfide bond between two cysteines. Full length protein is referred to as H0 (Shors, 2013).The H0 protein is homotrimer protein consists of three identical polypeptide chains, each polypeptide is 550 amino acids long that get glycosylated then cleaved into two chains (<scene name='SAndbox_159/Ha1/1'>H1</scene>,<scene name='SAndbox_159/Ha2/2'>H2</scene>) by the removal of arginine 329 along with a conformational change. <scene name='SAndbox_159/Ha1/1'>H1</scene> and <scene name='SAndbox_159/Ha2/2'>H2</scene> chains are covalently attached by a <scene name='SAndbox_159/Disulfide_bond/2'>disulfide bond</scene> to from one monomer. The one monomer noncovalently associates with two additional monomers to form one hemagglutinin homotrimer molecule (Proteopedia, 2015). | (H) protein is the most important glycoprotein found on the virus surface for that it is responsible for the attachment of the influenza to the cells containing sialic acid receptors, such as cells in the upper respiratory tract. It also helps with the fusion between the viral lipid membrane and the host cell endosomal membrane (Shors, 2013). The H protein is a transmembrane protein consisting of two polypeptides, <scene name='SAndbox_159/Ha1/1'>H1</scene> and <scene name='SAndbox_159/Ha2/2'>H2</scene>, which are linked by a disulfide bond between two cysteines. Full length protein is referred to as H0 (Shors, 2013).The H0 protein is homotrimer protein consists of three identical polypeptide chains, each polypeptide is 550 amino acids long that get glycosylated then cleaved into two chains (<scene name='SAndbox_159/Ha1/1'>H1</scene>,<scene name='SAndbox_159/Ha2/2'>H2</scene>) by the removal of arginine 329 along with a conformational change. <scene name='SAndbox_159/Ha1/1'>H1</scene> and <scene name='SAndbox_159/Ha2/2'>H2</scene> chains are covalently attached by a <scene name='SAndbox_159/Disulfide_bond/2'>disulfide bond</scene> to from one monomer. The one monomer noncovalently associates with two additional monomers to form one hemagglutinin homotrimer molecule (Proteopedia, 2015). | ||
[[Image:A_closer_look_on_the_structure_of_H1_and_H2_subunits_of_Hemagglutinin_protein..PNG|left|200px|thumb|Figure2: A closer look on the structure of H1 and H2 subunits of Hemagglutinin protein.] ]] | |||
The H1 subunit consist of 328 amino acid composing eight stranded beta-sheet associated with little alpha-helix (Proteopedia, 2015). The <scene name='SAndbox_159/Ha1/1'>H1</scene> subunit forms a globular bulb at the top of the structure and contains the sialic acid binding site. The amino acid of the alpha helix and some other beta sheets compose the binding pocket of the sialic acid subunit, and determine the attachment specificity of the virus to the host cell. | The H1 subunit consist of 328 amino acid composing eight stranded beta-sheet associated with little alpha-helix (Proteopedia, 2015). The <scene name='SAndbox_159/Ha1/1'>H1</scene> subunit forms a globular bulb at the top of the structure and contains the sialic acid binding site. The amino acid of the alpha helix and some other beta sheets compose the binding pocket of the sialic acid subunit, and determine the attachment specificity of the virus to the host cell. | ||
The <scene name='SAndbox_159/Ha2/2'>H2</scene> subunit of H0 is called membrane-spanning anchor and it is directly involved in the fusion mechanism. <scene name='SAndbox_159/Ha2/2'>H2</scene> has a hairpin structure composed by two antiparallel alpha-helices. The C- terminal of <scene name='SAndbox_159/Ha2/2'>H2</scene> is embedded in the viral membrane while the N-terminal end contains 10 hydrophobic amino acid forming the fusion peptide (Proteopedia, 2011). | The <scene name='SAndbox_159/Ha2/2'>H2</scene> subunit of H0 is called membrane-spanning anchor and it is directly involved in the fusion mechanism. <scene name='SAndbox_159/Ha2/2'>H2</scene> has a hairpin structure composed by two antiparallel alpha-helices. The C- terminal of <scene name='SAndbox_159/Ha2/2'>H2</scene> is embedded in the viral membrane while the N-terminal end contains 10 hydrophobic amino acid forming the fusion peptide (Proteopedia, 2011). | ||
[[Image:The_change_of_Hemagglutinin_structure_and_subunits_arrangement_due_to_the_drop_of_PH_level.PNG|left|200px|thumb|Figure 3. The change of Hemagglutinin structure and subunits arrangement due to the drop of PH level. A) the separation of H1 bulbs due to the drop of pH level. B) the separation of H1 and H2.] ]] | |||
When H protein attaches to sialic acid residues 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. Then the endosomal vesicle pH level drops and reaches about 5.5 due to the pumping of protons inside the vesicle by the M2 ions channel. As a result, the <scene name='SAndbox_159/Ha1/1'>H1</scene> subuint shifts its position, allowing the <scene name='SAndbox_159/Ha2/2'>H2</scene> subunit 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 are partially but not completely reversible. As the pH decrease to 5.5, the three globular heads start to dissociate due to the protonation of relevant H protein residues. the change in pH facilitate the releasing of the fusion peptides. Also at low pH the short and long alpha-helix are separated(Thoennes et.al 2008). The shifting of <scene name='SAndbox_159/Ha1/1'>H1</scene> subunit plays an important role in H mediated membrane fusion , <scene name='SAndbox_159/Ha1/1'>H1</scene> protein helps the membrane attachment and fusion, which results in the release of viral RNA’s into the cytoplasm and then into the cell’s nucleus for RNA replication (Racanilllo, 2009). | When H protein attaches to sialic acid residues 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. Then the endosomal vesicle pH level drops and reaches about 5.5 due to the pumping of protons inside the vesicle by the M2 ions channel. As a result, the <scene name='SAndbox_159/Ha1/1'>H1</scene> subuint shifts its position, allowing the <scene name='SAndbox_159/Ha2/2'>H2</scene> subunit 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 are partially but not completely reversible. As the pH decrease to 5.5, the three globular heads start to dissociate due to the protonation of relevant H protein residues. the change in pH facilitate the releasing of the fusion peptides. Also at low pH the short and long alpha-helix are separated(Thoennes et.al 2008). The shifting of <scene name='SAndbox_159/Ha1/1'>H1</scene> subunit plays an important role in H mediated membrane fusion , <scene name='SAndbox_159/Ha1/1'>H1</scene> protein helps the membrane attachment and fusion, which results in the release of viral RNA’s into the cytoplasm and then into the cell’s nucleus for RNA replication (Racanilllo, 2009). | ||
[[Image:H-mediated membrane binding and fusion between the viral and endosomal membranes..png|Right|475px|thumb|Figure4 : H-mediated membrane binding and fusion between the viral and endosomal membranes.] ]] | |||
== The Neuraminidase (N) protien == | == The Neuraminidase (N) protien == | ||
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Thoennes, S., Li, Z., Lee, B., Langley, W. A., Skehel, J. J., Russell, R. J., et al. (2008). Analysis of residues near the fusion peptide in the influenza hemagglutinin structure for roles in triggering membrane fusion. Virology,370(2), 403-414. doi:http://dx.doi.org/10.1016/j.virol.2007.08.035 | Thoennes, S., Li, Z., Lee, B., Langley, W. A., Skehel, J. J., Russell, R. J., et al. (2008). Analysis of residues near the fusion peptide in the influenza hemagglutinin structure for roles in triggering membrane fusion. Virology,370(2), 403-414. doi:http://dx.doi.org/10.1016/j.virol.2007.08.035 | ||