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

Related Research Articles

<span class="mw-page-title-main">Lectin</span> Carbohydrate-binding protein

Lectins are carbohydrate-binding proteins that are highly specific for sugar groups that are part of other molecules, so cause agglutination of particular cells or precipitation of glycoconjugates and polysaccharides. Lectins have a role in recognition at the cellular and molecular level and play numerous roles in biological recognition phenomena involving cells, carbohydrates, and proteins. Lectins also mediate attachment and binding of bacteria, viruses, and fungi to their intended targets.

<span class="mw-page-title-main">Hemagglutinin (influenza)</span> Hemagglutinin of influenza virus

Influenza hemagglutinin (HA) or haemagglutinin[p] is a homotrimeric glycoprotein found on the surface of influenza viruses and is integral to its infectivity.

<span class="mw-page-title-main">Sialic acid</span> Class of keto acid sugars

Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone. The term "sialic acid" was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this group is N-acetylneuraminic acid found in animals and some prokaryotes.

<i>Orthomyxoviridae</i> Family of RNA viruses including the influenza viruses

Orthomyxoviridae is a family of negative-sense RNA viruses. It includes seven genera: Alphainfluenzavirus, Betainfluenzavirus, Gammainfluenzavirus, Deltainfluenzavirus, Isavirus, Thogotovirus, and Quaranjavirus. The first four genera contain viruses that cause influenza in birds and mammals, including humans. Isaviruses infect salmon; the thogotoviruses are arboviruses, infecting vertebrates and invertebrates. The Quaranjaviruses are also arboviruses, infecting vertebrates (birds) and invertebrates (arthropods).

Antigenic drift is a kind of genetic variation in viruses, arising from the accumulation of mutations in the virus genes that code for virus-surface proteins that host antibodies recognize. This results in a new strain of virus particles that is not effectively inhibited by the antibodies that prevented infection by previous strains. This makes it easier for the changed virus to spread throughout a partially immune population. Antigenic drift occurs in both influenza A and influenza B viruses.

<span class="mw-page-title-main">Measles virus</span> Species of virus

The measles virus (MV), with scientific name Morbillivirus hominis, is a single-stranded, negative-sense, enveloped, non-segmented RNA virus of the genus Morbillivirus within the family Paramyxoviridae. It is the cause of measles. Humans are the natural hosts of the virus; no animal reservoirs are known to exist.

<span class="mw-page-title-main">Hemagglutination assay</span> Measure of virus or bacteria concentration

The hemagglutination assay or haemagglutination assay (HA) and the hemagglutination inhibition assay were developed in 1941–42 by American virologist George Hirst as methods for quantifying the relative concentration of viruses, bacteria, or antibodies.

<span class="mw-page-title-main">Neuraminidase</span> Glycoside hydrolase enzymes that cleave the glycosidic linkages of neuraminic acids

Exo-α-sialidase is a glycoside hydrolase that cleaves the glycosidic linkages of neuraminic acids:

<span class="mw-page-title-main">Hemagglutinin esterase</span> Glycoprotein present in some enveloped viruses

Hemagglutinin esterase (HEs) is a glycoprotein that certain enveloped viruses possess and use as an invading mechanism. HEs helps in the attachment and destruction of certain sialic acid receptors that are found on the host cell surface. Viruses that possess HEs include influenza C virus, toroviruses, and coronaviruses of the subgenus Embecovirus. HEs is a dimer transmembrane protein consisting of two monomers, each monomer is made of three domains. The three domains are: membrane fusion, esterase, and receptor binding domains.

<i>Influenza C virus</i> Genus of viruses in the family Orthomyxoviridae

Influenza C virus is the only species in the genus Gammainfluenzavirus, in the virus family Orthomyxoviridae, which like other influenza viruses, causes influenza.

<span class="mw-page-title-main">H5N1 genetic structure</span> Genetic structure of Influenza A virus

The genetic structure of H5N1, a highly pathogenic avian influenza virus, is characterized by a segmented RNA genome consisting of eight gene segments that encode for various viral proteins essential for replication, host adaptation, and immune evasion.

<span class="mw-page-title-main">Virosome</span> Drug or vaccine delivery mechanism

A virosome is a drug or vaccine delivery mechanism consisting of unilamellar phospholipid membrane vesicle incorporating virus derived proteins to allow the virosomes to fuse with target cells. Viruses are infectious agents that can replicate in their host organism, however virosomes do not replicate. The properties that virosomes share with viruses are based on their structure; virosomes are essentially safely modified viral envelopes that contain the phospholipid membrane and surface glycoproteins. As a drug or vaccine delivery mechanism they are biologically compatible with many host organisms and are also biodegradable. The use of reconstituted virally derived proteins in the formation of the virosome allows for the utilization of what would otherwise be the immunogenic properties of a live-attenuated virus, but is instead a safely killed virus. A safely killed virus can serve as a promising vector because it won't cause infection and the viral structure allows the virosome to recognize specific components of its target cells.

Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response, making it one of the mechanisms of antigenic escape. It is related to phase variation. Antigenic variation not only enables the pathogen to avoid the immune response in its current host, but also allows re-infection of previously infected hosts. Immunity to re-infection is based on recognition of the antigens carried by the pathogen, which are "remembered" by the acquired immune response. If the pathogen's dominant antigen can be altered, the pathogen can then evade the host's acquired immune system. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates. Antigenic variation can result from gene conversion, site-specific DNA inversions, hypermutation, or recombination of sequence cassettes. The result is that even a clonal population of pathogens expresses a heterogeneous phenotype. Many of the proteins known to show antigenic or phase variation are related to virulence.

<i>Murine respirovirus</i> Sendai virus, virus of rodents

Murine respirovirus, formerly Sendai virus (SeV) and previously also known as murine parainfluenza virus type 1 or hemagglutinating virus of Japan (HVJ), is an enveloped, 150-200 nm–diameter, negative sense, single-stranded RNA virus of the family Paramyxoviridae. It typically infects rodents and it is not pathogenic for humans or domestic animals.

<span class="mw-page-title-main">Spike protein</span> Glycoprotein spike on a viral capsid or viral envelope

In virology, a spike protein or peplomer protein is a protein that forms a large structure known as a spike or peplomer projecting from the surface of an enveloped virus. The proteins are usually glycoproteins that form dimers or trimers.

<span class="mw-page-title-main">Influenza</span> Infectious disease

Influenza, commonly known as the flu, is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms begin one to four days after exposure to the virus and last for about two to eight days. Diarrhea and vomiting can occur, particularly in children. Influenza may progress to pneumonia from the virus or a subsequent bacterial infection. Other complications include acute respiratory distress syndrome, meningitis, encephalitis, and worsening of pre-existing health problems such as asthma and cardiovascular disease.

<span class="mw-page-title-main">Viral neuraminidase</span> InterPro Family

Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell. Neuraminidases are enzymes that cleave sialic acid groups from glycoproteins. Viral neuraminidase was discovered by Alfred Gottschalk at the Walter and Eliza Hall Institute in 1957. Neuraminidase inhibitors are antiviral agents that inhibit influenza viral neuraminidase activity and are of major importance in the control of influenza.

<span class="mw-page-title-main">Hemagglutinin-neuraminidase</span>

Hemagglutinin-neuraminidase refers to a single viral protein that has both hemagglutinin and (endo) neuraminidase EC 3.2.1.18 activity. This is in contrast to the proteins found in influenza, where both functions exist but in two separate proteins. Its neuraminidase domain has the CAZy designation glycoside hydrolase family 83 (GH83).

<span class="mw-page-title-main">George Hirst (virologist)</span> American virologist and science administrator

George Keble Hirst, M.D. was an American virologist and science administrator who was among the first to study the molecular biology and genetics of animal viruses, especially influenza virus. He directed the Public Health Research Institute in New York City (1956–1981), and was also the founding editor-in-chief of Virology, the first English-language journal to focus on viruses. He is particularly known for inventing the hemagglutination assay, a simple method for quantifying viruses, and adapting it into the hemagglutination inhibition assay, which measures virus-specific antibodies in serum. He was the first to discover that viruses can contain enzymes, and the first to propose that virus genomes can consist of discontinuous segments. The New York Times described him as "a pioneer in molecular virology."

<i>Influenza D virus</i> Species of virus

Influenza D virus is a species in the virus genus Deltainfluenzavirus, in the family Orthomyxoviridae, that causes influenza.

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.