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== External links ==
== External links ==
*[http://www.callutheran.edu/Academic_Programs/Departments/BioDev/omm/jmol/flu_div/start.html Jmol tutorial of influenza hemagglutinin structure and activity.]{{dead link|date=March 2015}}
*[http://web.archive.org/web/20160106191826/http://www.callutheran.edu/Academic_Programs/Departments/BioDev/omm/jmol/flu_div/start.html Jmol tutorial of influenza hemagglutinin structure and activity.]
* {{PDB Molecule of the Month|76|Hemagglutinin}} (April 2006)
* {{PDB Molecule of the Month|76|Hemagglutinin}} (April 2006)
*[http://www.fludb.org Influenza Research Database] Database of influenza protein sequences and structures
*[http://www.fludb.org Influenza Research Database] Database of influenza protein sequences and structures

Revision as of 11:38, 28 February 2016

Hemagglutinin
Identifiers
SymbolHemagglutinin
PfamPF00509
InterProIPR001364
SCOP21hgd / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1eo8​, 1ha0​, 1hgd​, 1hge​, 1hgf​, 1hgg​, 1hgh​, 1hgi​, 1hgj​, 1htm​, 1ibn​, 1ibo​, 1jsd​, 1jsh​, 1jsi​, 1jsm​, 1jsn​, 1jso​, 1ken​, 1mql​, 1mqm​, 1mqn​, 1qfu​, 1qu1​, 1rd8​, 1ru7​, 1ruy​, 1ruz​, 1rv0​, 1rvt​, 1rvx​, 1rvz​, 1ti8​, 1xoo​, 1xop​, 2dci​, 2fk0​, 2hmg​, 2ibx​, 2rft​, 2rfu​, 2vir​, 2vis​, 2vit​, 2viu​, 3bt6​, 3eyj​, 3eyk​, 3eym​, 3fku​, 3gbm​, 3gbn​, 3hmg​, 4hmg​, 5hmg​
Influenza C hemagglutinin stalk
x-ray structure of the haemagglutinin-esterase-fusion glycoprotein of influenza c virus
Identifiers
SymbolHema_stalk
PfamPF08720
InterProIPR014831
SCOP21flc / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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.[1] 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.[2]

Subtypes

Structure of influenza, showing neuraminidase marked as NA and hemagglutinin as HA.

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.[3][4] Most recently, H18 was discovered in a Peruvian bat in 2013.[5] The first three hemagglutinins, H1, H2, and H3, are found in human influenza viruses.

Viral neuraminidase (NA) is another protein found on the surface of influenza. Influenza viruses are characterized by the type of HA and NA that they carry; hence H1N1, H5N2 etc.

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".[6][7] 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.[8][9]

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.[10]

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.[11]

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.[citation needed]

Structure

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.

Neutralizing antibodies

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:

  1. Inhibition of attachment to target cells
  2. Inhibition of membrane fusion (entry)

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 at right) and physically block the interaction with sialic acid receptors on target cells.[12] 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).[13] Most of these antibodies, like the human antibodies F10,[14] FI6,[15] CR6261, recognize sites in the stem/stalk region (orange region in figure at right), far away from the receptor binding site.[16][17]

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. However, 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.[18]

See also

References

  1. ^ 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. doi:10.1073/pnas.0807142105. PMC 2584702. PMID 19004788.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Nelson DL, Cox MM (2005). Lehninger's Principles of Biochemistry (4th ed.). New York: WH Freeman.
  3. ^ 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. doi:10.1128/JVI.79.5.2814-2822.2005. PMC 548452. PMID 15709000.
  4. ^ Unique new flu virus found in bats http://www.nhs.uk/news/2012/03march/Pages/cdc-finds-h17-bat-influenza.aspx
  5. ^ Suxiang Tong; et al. (October 2013). "New World Bats Harbor Diverse Influenza A Viruses". PLoS Pathogens. 9 (10): e1003657. doi:10.1371/journal.ppat.1003657. PMC 3794996. PMID 24130481.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ Suzuki Y (March 2005). "Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses". Biol. Pharm. Bull. 28 (3): 399–408. doi:10.1248/bpb.28.399. PMID 15744059.
  7. ^ 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. doi:10.1016/j.virol.2005.08.035. PMID 16226289.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ 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. doi:10.1126/science.1062882. PMID 11546875.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ 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. doi:10.2307/1592241. JSTOR 1592241. PMID 8790895.
  10. ^ 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 (ed.). Structural Biology of Viruses. Oxford University Press. pp. 80–104.{{cite book}}: CS1 maint: multiple names: editors list (link)
  11. ^ 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
  12. ^ 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. (26 November 2013). "Molecular Mechanisms of Inhibition of Influenza by Surfactant Protein D Revealed by Large-Scale Molecular Dynamics Simulation". Biochemistry. 52 (47): 8527–8538. doi:10.1021/bi4010683. ISSN 0006-2960. PMC 3927399. PMID 24224757.
  13. ^ 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. doi:10.1038/nm.3443. PMC 3966466. PMID 24412922.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ 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. doi:10.1038/nsmb.1566. PMC 2692245. PMID 19234466.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ 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. doi:10.1126/science.1205669. PMID 21798894.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ 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. doi:10.1371/journal.pone.0003942. PMC 2596486. PMID 19079604.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  17. ^ 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. doi:10.1126/science.1171491. PMC 2758658. PMID 19251591.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ 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. doi:10.1006/viro.2001.1320. PMID 11886266.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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