Hemagglutinin

Last updated

Illustration showing influenza virus attaching to cell membrane via the surface protein hemagglutinin CSIRO ScienceImage 354 Influenza Protein Attaching to Cell Membrane.jpg
Illustration showing influenza virus attaching to cell membrane via the surface protein hemagglutinin

Hemagglutinins (alternatively spelt haemagglutinin, from the Greek haima, 'blood' + Latin gluten, 'glue') are homotrimeric glycoproteins present on the protein capsids of viruses in the Paramyxoviridae and Orthomyxoviridae families. [1] [2] [3] Hemagglutinins are responsible for binding to receptors, sialic acid residues, on host cell membranes to initiate virus docking and infection. [4] [5]

Contents

Specifically, they recognize cell-surface glycoconjugates containing sialic acid on the surface of host red blood cells with a low affinity and use them to enter the endosome of host cells. [6] Hemagglutinins tend to recognize α-2,6-linked sialic acids of the host cells in humans and α-2,3-linked sialic acids in avian species, although there is evidence that hemagglutinin specificity can vary. This correlates to the fact that Influenza A typically establishes infections in the upper respiratory tract in humans, where many of these α-2,6-linked sialic acids are present. [7] There are various subtypes of hemagglutinins, in which H1, H2, and H3 are known to have human susceptibility. [8] It is the variation in hemagglutinin (and neuraminidase) subtypes that require health organizations (ex. WHO) to constantly update and surveil the known circulating flu viruses in human and animal populations (ex. H5N1).

In the endosome, hemagglutinins undergo conformational changes due to a pH drop to of 5–6.5 enabling viral attachment through a fusion peptide. [9]

Virologist George K. Hirst discovered agglutination and hemagglutinins in 1941. [10] Alfred Gottschalk proved in 1957 that hemagglutinins bind a virus to a host cell by attaching to sialic acids on carbohydrate side chains of cell-membrane glycoproteins and glycolipids. [11]

The name "hemagglutinin" comes from the protein's ability to cause red blood cells (erythrocytes) to clump together ("agglutinate") in vitro . [12]

Types

Structure

Hemagglutinins are small proteins that extend from the surface of the virus membrane as spikes that are 135 Angstroms (Å) in length and 30-50 Å in diameter. [19] Each spike is composed of three identical monomer subunits, making the protein a homotrimer. These monomers are formed of two glycopeptides, HA1 and HA2, and linked by two disulphide polypeptides, including membrane-distal HA1 and the smaller membrane-proximal HA2. X-ray crystallography, NMR spectroscopy, and cryo-electron microscopy were used to solve the protein's structure, the majority of which is α-helical. [20] In addition to the homotrimeric core structure, hemagglutinins have four subdomains: the membrane-distal receptor binding R subdomain, the vestigial domain E, that functions as a receptor-destroying esterase, the fusion domain F, and the membrane anchor subdomain M. The membrane anchor subdomain forms elastic protein chains linking the hemagglutinin to the ectodomain. [21]

Step-By-Step Mechanism (Influenza Hemagglutinin)

On the viral capsids of influenza types A and B, hemagglutinin is initially inactive. Only when cleaved by host proteins, does each monomer polypeptide of the homotrimer transforms into a dimer – composed of HA1 and HA2 subunits attached by disulfide bridges. [22] The HA1 subunit is responsible for docking the viral capsid onto the host cell by binding to sialic acid residues present on the surface of host respiratory cells. This binding triggers endocytosis. [5] The pH in the endosomal compartment then decreases from proton influx, and this causes a conformational change in HA that forces the HA2 subunit to “flip outward.” The HA2 subunit is responsible for membrane fusion. It binds to the endosomal membrane, pulling the viral capsid membrane and the endosomal membrane tightly together, eventually forming a pore through which the viral genome can enter into the host cell cytoplasm. [3] From here, the virus can use host machinery to proliferate.  

Uses in serology

A schematic diagram of the experimental setup to detect hemagglutination for blood typing. Experimental setup to detect hemagglutination.png
A schematic diagram of the experimental setup to detect hemagglutination for blood typing.

See also

References

  1. ↑ Couch, Robert B. (1996), Baron, Samuel (ed.), "Orthomyxoviruses", Medical Microbiology (4th ed.), Galveston (TX): University of Texas Medical Branch at Galveston, ISBN   978-0-9631172-1-2, PMID   21413353 , retrieved 30 January 2024
  2. ↑ "Paramyxoviridae - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 30 January 2024.
  3. 1 2 Skehel, John J.; Wiley, Don C. (June 2000). "Receptor Binding and Membrane Fusion in Virus Entry: The Influenza Hemagglutinin". Annual Review of Biochemistry. 69 (1): 531–569. doi:10.1146/annurev.biochem.69.1.531. ISSN   0066-4154. PMID   10966468.
  4. ↑ Nobusawa, E. (October 1997). "[Structure and function of the hemagglutinin of influenza viruses]". Nihon Rinsho. Japanese Journal of Clinical Medicine. 55 (10): 2562–2569. ISSN   0047-1852. PMID   9360372.
  5. 1 2 Luo, Ming (8 November 2011), Influenza Virus Entry , Advances in Experimental Medicine and Biology, vol. 726, Boston, MA: Springer US, pp. 201–221, doi:10.1007/978-1-4614-0980-9_9, ISBN   978-1-4614-0979-3 , retrieved 17 November 2024
  6. ↑ Bangaru, Sandhya; Lang, Shanshan; Schotsaert, Michael; Vanderven, Hillary A.; Zhu, Xueyong; Kose, Nurgun; Bombardi, Robin; Finn, Jessica A.; Kent, Stephen J.; Gilchuk, Pavlo; Gilchuk, Iuliia (2019). "A Site of Vulnerability on the Influenza Virus Hemagglutinin Head Domain Trimer Interface". Cell. 177 (5): 1136–1152.e18. doi:10.1016/j.cell.2019.04.011. PMC   6629437 . PMID   31100268.
  7. ↑ Kosik, Ivan (16 April 2019). "Influenza Hemagglutinin and Neuraminidase: Yin–Yang Proteins Coevolving to Thwart Immunity". NCBI.
  8. ↑ "PDB101: Molecule of the Month: Hemagglutinin". RCSB: PDB-101. Retrieved 11 December 2024.
  9. ↑ Medeiros, R.; Escriou, N.; Naffakh, N.; Manuguerra, J. C.; van der Werf, S. (10 October 2001). "Hemagglutinin residues of recent human A(H3N2) influenza viruses that contribute to the inability to agglutinate chicken erythrocytes". Virology. 289 (1): 74–85. doi: 10.1006/viro.2001.1121 . ISSN   0042-6822. PMID   11601919.
  10. ↑ Kolata, Gina (26 January 1994). "George Keble Hirst, 84, Is Dead; A Pioneer in Molecular Virology". The New York Times. ISSN   0362-4331 . Retrieved 14 May 2024.
  11. ↑ Henry, Ronnie; Murphy, Frederick A. (October 2018). "Etymologia: Hemagglutinin and Neuraminidase". Emerging Infectious Diseases. 24 (10): 1849. doi:10.3201/eid2410.ET2410. PMC   6154157 .
  12. ↑ Nelson DL, Cox MM (2005). Lehninger's Principles of Biochemistry (4th ed.). New York: WH Freeman.
  13. ↑ CDC (2 November 2021). "Types of Influenza Viruses". Centers for Disease Control and Prevention. Retrieved 18 October 2022.
  14. ↑ Bi, Yuhai; Yang, Jing; Wang, Liang; Ran, Lin; Gao, George F. (August 2024). "Ecology and evolution of avian influenza viruses". Current Biology. 34 (15): R716 –R721. Bibcode:2024CBio...34.R716B. doi:10.1016/j.cub.2024.05.053. ISSN   0960-9822. PMID   39106825.
  15. ↑ Hashiguchi, Takao; Maenaka, Katsumi; Yanagi, Yusuke (16 December 2011). "Measles Virus Hemagglutinin: Structural Insights into Cell Entry and Measles Vaccine". Frontiers in Microbiology. 2: 247. doi: 10.3389/fmicb.2011.00247 . ISSN   1664-302X. PMC   3267179 . PMID   22319511.
  16. ↑ Pan CH, Jimenez GS, Nair N (21 August 2014) [August, 2008]. "Use of Vaxfectin Adjuvant with DNA Vaccine Encoding the Measles Virus Hemagglutinin and Fusion Proteins Protects Juvenile and Infant Rhesus Macaques against Measles Virus". Clinical and Vaccine Immunology. 15 (8): 1214–1221. doi:10.1128/CVI.00120-08. PMC   2519314 . PMID   18524884.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ↑ Tappert, Mary M.; Porterfield, J. Zachary; Mehta-D'Souza, Padmaja; Gulati, Shelly; Air, Gillian M. (August 2013). "Quantitative Comparison of Human Parainfluenza Virus Hemagglutinin-Neuraminidase Receptor Binding and Receptor Cleavage". Journal of Virology. 87 (16): 8962–8970. doi:10.1128/JVI.00739-13. ISSN   0022-538X. PMC   3754076 . PMID   23740997.
  18. ↑ Kubota, Marie; Hashiguchi, Takao (2020). "Large-Scale Expression and Purification of Mumps Virus Hemagglutinin-Neuraminidase for Structural Analyses and Glycan-Binding Assays". Lectin Purification and Analysis. Methods in Molecular Biology. Vol. 2132. pp. 641–652. doi:10.1007/978-1-0716-0430-4_55. ISBN   978-1-0716-0429-8. ISSN   1940-6029. PMID   32306363. S2CID   216030421.
  19. ↑ Gamblin, Steven J.; Vachieri, Sébastien G.; Xiong, Xiaoli; Zhang, Jie; Martin, Stephen R.; Skehel, John J. (1 October 2021). "Hemagglutinin Structure and Activities". Cold Spring Harbor Perspectives in Medicine. 11 (10): a038638. doi:10.1101/cshperspect.a038638. ISSN   2157-1422. PMC   8485738 . PMID   32513673.
  20. ↑ Gamblin, Steven J.; Vachieri, Sébastien G.; Xiong, Xiaoli; Zhang, Jie; Martin, Stephen R.; Skehel, John J. (1 October 2021). "Hemagglutinin Structure and Activities". Cold Spring Harbor Perspectives in Medicine. 11 (10): a038638. doi:10.1101/cshperspect.a038638. ISSN   2157-1422. PMC   8485738 . PMID   32513673.
  21. ↑ Donald J. Benton, Andrea Nans, Lesley J. Calder, Jack Turner, Ursula Neu, Yi Pu Lin, Esther Ketelaars, Nicole L. Kallewaard, Davide Corti, Antonio Lanzavecchia, Steven J. Gamblin, Peter B. Rosenthal, John J. Skehel (2 October 2018) [Sep 17, 2018]. "Hemagglutinin membrane anchor". Proceedings of the National Academy of Sciences of the United States of America. 115 (40): 10112–10117. doi: 10.1073/pnas.1810927115 . PMC   6176637 . PMID   30224494.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ↑ Tzarum, Netanel; de Vries, Robert P.; Zhu, Xueyong; Yu, Wenli; McBride, Ryan; Paulson, James C.; Wilson, Ian A. (March 2015). "Structure and Receptor Binding of the Hemagglutinin from a Human H6N1 Influenza Virus". Cell Host & Microbe. 17 (3): 369–376. doi:10.1016/j.chom.2015.02.005. ISSN   1931-3128. PMC   4374348 . PMID   25766295.
  23. ↑ Payne, Susan (2017). "Methods to Study Viruses". Viruses. pp. 37–52. doi:10.1016/B978-0-12-803109-4.00004-0. ISBN   978-0-12-803109-4. S2CID   89981392.
  24. ↑ Ashiba, Hiroki; Fujimaki, Makoto; Awazu, Koichi; Fu, Mengying; Ohki, Yoshimichi; Tanaka, Torahiko; Makishima, Makoto (March 2015). "Hemagglutination detection for blood typing based on waveguide-mode sensors". Sensing and Bio-Sensing Research. 3: 59–64. Bibcode:2015SBSR....3...59A. doi: 10.1016/j.sbsr.2014.12.003 .
  25. ↑ Theis, Samuel R.; Hashmi, Muhammad F. (2022), "Coombs Test", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   31613487 , retrieved 16 December 2022
  26. ↑ Focosi, Daniele; Franchini, Massimo; Maggi, Fabrizio (8 March 2022). "Modified Hemagglutination Tests for COVID-19 Serology in Resource-Poor Settings: Ready for Prime-Time?". Vaccines. 10 (3): 406. doi: 10.3390/vaccines10030406 . ISSN   2076-393X. PMC   8953758 . PMID   35335038.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.