Summary: Influenza C hemagglutinin stalk
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Hemagglutinin (influenza) Edit Wikipedia article
|Influenza C hemagglutinin stalk|
x-ray structure of the haemagglutinin-esterase-fusion glycoprotein of influenza c virus
Influenza hemagglutinin (HA) or haemagglutinin (British English) is a glycoprotein found on the surface of influenza viruses. It is responsible for binding the virus to cells with sialic acid on the membranes, such as cells in the upper respiratory tract or erythrocytes. It is also responsible for the fusion of the viral envelope with the endosome membrane, after the pH has been reduced. The name "hemagglutinin" comes from the protein's ability to cause red blood cells (erythrocytes) to clump together ("agglutinate") in vitro.
HA has at least 18 different antigens. These subtypes are named H1 through H18. H16 was discovered in 2004 on influenza A viruses isolated from black-headed gulls from Sweden and Norway. H17 was discovered in 2012 in fruit bats. Most recently, H18 was discovered in a Peruvian bat in 2013. 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". 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.
Function and mechanism
HA has two functions. Firstly, it allows the recognition of target vertebrate cells, accomplished through the binding to these cells' sialic acid-containing receptors. Secondly, once bound it facilitates the entry of the viral genome into the target cells by causing the fusion of host endosomal membrane with the viral membrane.
HA binds to the monosaccharide sialic acid which is present on the surface of its target cells, which 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 release 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.
HA is a homotrimeric integral membrane glycoprotein. It is shaped like a cylinder, and is approximately 13.5 nanometres 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.
Since hemagglutinin is the major surface protein of the influenza A virus and is essential to the entry process, it is the primary target of neutralizing antibodies. Neutralizing antibodies against flu have been found to act by two different mechanisms, mirroring the dual functions of hemagglutinin:
Most commonly, antibodies against hemagglutinin act by inhibiting attachment. This is because these antibodies bind near the top of the hemagglutinin "head" (blue region in figure above) and physically block the interaction with sialic acid receptors on target cells. In contrast, some antibodies have been found to have no effect on attachment. Instead, this latter group of antibodies acts by preventing membrane fusion (only in vitro; the efficacy of these antibodies in vivo is believed to be a result of Antibody-Dependent Cell-Mediated Cytotoxicity and the Complement system). Most of these antibodies, like the human antibodies F10, FI6, CR6261, recognize sites in the stem/stalk region (orange region in figure at right), far away from the receptor binding site.
The stem (also called HA2), contains most of the membrane fusion machinery of the hemagglutinin protein, and antibodies targeting this region block key structural changes that drive the membrane fusion process. At least one fusion-inhibiting antibody was found to bind closer to the top of hemagglutinin, and is thought to work by cross-linking the heads together, the opening of which is thought to be the first step in the membrane fusion process.
In 2015 researchers designed an immunogen mimicking the HA stem, specifically the area where the antibody ties to the virus of the antibody CR9114. Rodent and nonhuman primate models given the immunogen produced antibodies that could bind with HAs in many influenza subtypes, including H5N1. When the HA head is present, the immune system does not make bNAbs (broadly neutralizing antibodies). Without the head, the whole protein becomes unrecognizable to antibodies. One team designed self-assembling HA-stem nanoparticles, using a protein called ferritin to hold the HA together. Another replaced and added amino acids to stabilize a mini-HA lacking a proper head.
- FI6 antibody
- Antigenic shift
- Sialic acid
- H5N1 genetic structure
- Russell RJ, Kerry PS, Stevens DJ, Steinhauer DA, Martin SR, Gamblin SJ, Skehel JJ (November 2008). "Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion". Proc. Natl. Acad. Sci. U.S.A. 105 (46): 17736–41. PMC . PMID 19004788. doi:10.1073/pnas.0807142105.
- Nelson DL, Cox MM (2005). Lehninger's Principles of Biochemistry (4th ed.). New York: WH Freeman.
- Fouchier RA, Munster V, Wallensten A, et al. (March 2005). "Characterization of a Novel Influenza A Virus Hemagglutinin Subtype (H16) Obtained from Black-Headed Gulls". J. Virol. 79 (5): 2814–22. PMC . PMID 15709000. doi:10.1128/JVI.79.5.2814-2822.2005.
- Unique new flu virus found in bats http://www.nhs.uk/news/2012/03march/Pages/cdc-finds-h17-bat-influenza.aspx
- Suxiang Tong; et al. (October 2013). "New World Bats Harbor Diverse Influenza A Viruses". PLoS Pathogens. 9 (10): e1003657. PMC . PMID 24130481. doi:10.1371/journal.ppat.1003657.
- Suzuki Y (March 2005). "Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses". Biol. Pharm. Bull. 28 (3): 399–408. PMID 15744059. doi:10.1248/bpb.28.399.
- Gambaryan A, Tuzikov A, Pazynina G, Bovin N, Balish A, Klimov A (January 2006). "Evolution of the receptor binding phenotype of influenza A (H5) viruses". Virology. 344 (2): 432–8. PMID 16226289. doi:10.1016/j.virol.2005.08.035.
- Hatta M, Gao P, Halfmann P, Kawaoka Y (September 2001). "Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses". Science. 293 (5536): 1840–2. PMID 11546875. doi:10.1126/science.1062882.
- Senne DA, Panigrahy B, Kawaoka Y, et al. (1996). "Survey of the hemagglutinin (HA) cleavage site sequence of H5 and H7 avian influenza viruses: amino acid sequence at the HA cleavage site as a marker of pathogenicity potential". Avian Dis. 40 (2): 425–37. JSTOR 1592241. PMID 8790895. doi:10.2307/1592241.
- White JM, Hoffman LR, Arevalo JH, et al. (1997). "Attachment and entry of influenza virus into host cells. Pivotal roles of hemagglutinin". In Chiu W, Burnett RM, Garcea RL. Structural Biology of Viruses. Oxford University Press. pp. 80–104.
- Stegmann T, Booy, P.F., Wilschut, J. Dec 1987, "Effects of Low pH on Influenza Virus" The Journal of Biological Chemistry, Vol. 262, No. 36, pp. 17744-17749, 1987
- Goh, Boon Chong; Rynkiewicz, Michael J.; Cafarella, Tanya R.; White, Mitchell R.; Hartshorn, Kevan L.; Allen, Kimberly; Crouch, Erika C.; Calin, Oliviana; Seeberger, Peter H. (2013-11-26). "Molecular Mechanisms of Inhibition of Influenza by Surfactant Protein D Revealed by Large-Scale Molecular Dynamics Simulation". Biochemistry. 52 (47): 8527–8538. ISSN 0006-2960. PMC . PMID 24224757. doi:10.1021/bi4010683.
- Dilillo DJ, Tan GS, Palese P, Ravetch JV (February 2014). "Broadly neutralizing hemagglutinin stalk-specific antibodies require FcγR interactions for protection against influenza virus in vivo". Nature Medicine. 20 (2): 143–51. PMC . PMID 24412922. doi:10.1038/nm.3443.
- Sui J, Hwang WC, Perez S, Wei G, Aird D, Chen LM, Santelli E, Stec B, Cadwell G, Ali M, Wan H, Murakami A, Yammanuru A, Han T, Cox NJ, Bankston LA, Donis RO, Liddington RC, Marasco WA (March 2009). "Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses". Nat. Struct. Mol. Biol. 16 (3): 265–73. PMC . PMID 19234466. doi:10.1038/nsmb.1566.
- Corti D, Voss J, Gamblin SJ, Codoni G, Macagno A, Jarrossay D, Vachieri SG, Pinna D, Minola A, Vanzetta F, Silacci C, Fernandez-Rodriguez BM, Agatic G, Bianchi S, Giacchetto-Sasselli I, Calder L, Sallusto F, Collins P, Haire LF, Temperton N, Langedijk JP, Skehel JJ, Lanzavecchia A (August 2011). "A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins". Science. 333 (6044): 850–6. PMID 21798894. doi:10.1126/science.1205669.
- Throsby M, van den Brink E, Jongeneelen M, Poon LL, Alard P, Cornelissen L, Bakker A, Cox F, van Deventer E, Guan Y, Cinatl J, ter Meulen J, Lasters I, Carsetti R, Peiris M, de Kruif J, Goudsmit J (2008). "Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells". PLoS ONE. 3 (12): e3942. PMC . PMID 19079604. doi:10.1371/journal.pone.0003942.
- Ekiert DC, Bhabha G, Elsliger MA, Friesen RH, Jongeneelen M, Throsby M, Goudsmit J, Wilson IA (April 2009). "Antibody recognition of a highly conserved influenza virus epitope". Science. 324 (5924): 246–51. PMC . PMID 19251591. doi:10.1126/science.1171491.
- Barbey-Martin C, Gigant B, Bizebard T, Calder LJ, Wharton SA, Skehel JJ, Knossow M (March 2002). "An antibody that prevents the hemagglutinin low pH fusogenic transition". Virology. 294 (1): 70–4. PMID 11886266. doi:10.1006/viro.2001.1320.
- MICU, ALEXANDRU (2015-08-25). "Universal flue vaccine: research moves closer". ZME Science. Retrieved 2016-06-10.
- "Scientists Get One Step Closer to a Universal Flu Vaccine". WIRED. Retrieved 2016-06-12.
- Jmol tutorial of influenza hemagglutinin structure and activity.
- PDB Molecule of the Month Hemagglutinin (April 2006)
- Influenza Research Database Database of influenza protein sequences and structures
- 3D macromolecular structures of influenza hemagglutinin from the EM Data Bank(EMDB)
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Influenza C hemagglutinin stalk Provide feedback
This domain corresponds to the stalk segment of hemagglutinin in influenza C virus. It forms a coiled coil structure .
Rosenthal PB, Zhang X, Formanowski F, Fitz W, Wong CH, Meier-Ewert H, Skehel JJ, Wiley DC; , Nature. 1998;396:92-96.: Structure of the haemagglutinin-esterase-fusion glycoprotein of influenza C virus. PUBMED:9817207 EPMC:9817207
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR014831
Haemagglutinin (HA) is one of two main surface fusion glycoproteins embedded in the envelope of influenza viruses, the other being neuraminidase (NA). There are sixteen known HA subtypes (H1-H16) and nine NA subtypes (N1-N9), which together are used to classify influenza viruses (e.g. H5N1). The antigenic variations in HA and NA enable the virus to evade host antibodies made to previous influenza strains, accounting for recurrent influenza epidemics [PUBMED:16178512]. The HA glycoprotein is present in the viral membrane as a single polypeptide (HA0), which must be cleaved by the host's trypsin-like proteases to produce two peptides (HA1 and HA2) in order for the virus to be infectious. Once HA0 is cleaved, the newly exposed N-terminal of the HA2 peptide then acts to fuse the viral envelope to the cellular membrane of the host cell, which allows the viral negative-stranded RNA to infect the host cell. The type of host protease can influence the infectivity and pathogenicity of the virus.
The haemagglutinin glycoprotein is a trimer containing three structurally distinct regions: a globular head consisting of anti-parallel beta-sheets that form a beta-sandwich with a jelly-roll fold (contains the receptor binding site and the HA1/HA2 cleavage site); a triple-stranded, coiled-coil, alpha-helical stalk; and a globular foot composed of anti-parallel beta-sheets [PUBMED:16543414, PUBMED:15475582]. Each monomer consists of an intact HA0 polypeptide with the HA1 and HA2 regions linked by disulphide bonds. The N terminus of HA1 provides the central strand in the 5-stranded globular foot, while the rest of the HA1 chain makes its way to the 8-stranded globular head. HA2 provides two alpha helices, which form part of the triple-stranded coiled-coil that stabilises the trimer, its C terminus providing the remaining strands of the 5-stranded globular foot.
This entry represents the stalk segment of haemagglutinin in influenza C virus. It forms a coiled coil structure [PUBMED:9817207].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||viral envelope (GO:0019031)|
|Molecular function||host cell surface receptor binding (GO:0046789)|
|Biological process||fusion of virus membrane with host plasma membrane (GO:0019064)|
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Number in seed:||1|
|Number in full:||1|
|Average length of the domain:||175.00 aa|
|Average identity of full alignment:||100 %|
|Average coverage of the sequence by the domain:||26.72 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||9|
|Download:||download the raw HMM for this family|
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The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Hema_stalk domain has been found. There are 12 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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