Influenza Hemagglutinin (HA) Protein

Influenza hemagglutinin is a viral surface protein that binds to sialic acid receptors on the host cell, resulting in receptor-mediated endocytosis. The proton pumps which typically pump hydrogen ions to the exterior of the cell now pump H+ into the endosome. The resulting drop in pH causes the hemagglutinin protein to undergo a dramatic conformational change, leading to membrane fusion and viral infection. Students explore this fascinating molecular story with physical models and animations.

:: Physical models - coming soon to the MSOE Model Lending Library!

  • hemagglutinin modelInfluenza virus hemagglutinin (HA) protein
  • HA2 protein at pH 7 (left) and pH 5 (right) Schematic depicting HA protein on the surface of the virus Collection of HA models

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:: Hemagglutinin References

influenza hemagglutinin trimerAir, Gillian M. 1981. Sequence relationships among the hemagglutinin genes of 12 subtypes of influenza A virus. PNAS 78(12): 7639-7643.

Both, G.W., Sleigh, M.J., Cox, N.J. and Kendal, A.P. 1983. Antigenic drift in influenza virus H3 hemagglutinin from 1968 to 1980: multiple evolutionary pathways and sequential amino acid changes at key antigenic sites. J. Virol. 48(1): 52-60.

Bullough, Per A., Hughson, Frederick M., Skehel, John J. and Wiley, Don C. 2002. Structure of influenza haemagglutinin at the pH of membrane fusion. Nature 371:37-43.

Carr, Chavela M., Chaudhry, Charu and Kim, Peter S. 1997. Influenza hemagglutinin is spring-loaded by a metastable native conformation. PNAS 94: 14306-14313.

Chen, Jue, Lee, Hon Ho, Steinhauer, David A., Stevens, David J, Skehel, John J. and Wiley, Don C. 1998. Structure of the Hemagglutinin Precursor Cleavage Site, a Determinant of Influenza Pathogenicity and the Origin of the Labile Conformation. Cell 95:409-417.

Chernomordik, Leonid, V., Frolov, Vadim A., Leikina, Eugenia, Bronk, Peter and Zimmerberg, Joshua. 1998. The Pathway of Membrane Fusion Catalyzed by Influenza Hemagglutinin: Restriction of Lipids, Hemifusion, and Lipidic Fusion Pore Formation. J. Cell Biol. 140(6):1369-1382.

Connor, Robert J., Kawaoka, Yoshihiro, Webster, Robert G. and Paulson, James C. 1994. Receptor specificity in human, avian, and equine H2 and H3 influenza virus isolates. Virol. 205(1):17-23.

Couceiro, J.Nelson, Paulson, James C. and Baum, Linda G. 1993. Influenza virus strains selectively recognize sialyloligosaccharides on human respiratory epithelium; the role of the host cell in selection of hemagglutinin receptor specificity.Virus Res. 29(2):155-165.

Doms, Robert W., Helenius, Ari and White, Judy. 1985. Membrane Fusion Activity of the Influenza Virus Hemagglutinin: The Low pH-Induced Conformational Change. J. Biol. Chem. 260(5):2973-2981.

Gamblin, S.J., Haire, L.F., Russell, R.J., Stevens, D.J., Xiao, B., Ha, Y., Visisht, N., Steinhauer, D.A., Daniels, R.S., Elliot, A., Wiley, D.C. and Skehel, J.J. 2004. The Structure and Receptor Binding Properties of the 1918 Influenza Hemagglutinin. Science 303:1838-1842.

Han, Xing, Bushweller, John H., Cafiso, Davis S. and Tamm, Lukas K. 2001. Membrane structure and fusion-triggering conformational change of the fusion domain from influenza hemagglutinin. Nature Struct. Biol. 8(8):715-720.

Hoffman, Lucas R., Kuntz, I.D. and White, Judith M. 1997. Structure-Based Identification of an Inducer of the Low-pH Conformational Change in the Influenza Virus Hemagglutinin: Irreversible Inhibition of Infectivity. J. Virol. 71(11): 8808-8820.

Kawaoka, Yoshihiro, Trauss, Scott and Webster, Robert G. 1989. Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics. J. Virol. 63(11):4603-4608.

Krystal, Mark, Elliott, Richard M., Benz, Edmund W., Jr., Young, James F. and Palese, Peter. 1982. Evolution of influenza A and B viruses: conservation of structural features in the hemagglutinin genes. PNAS 79(15):4800-4804.

Nakada, Susumu, Creager, Richard S., Krystal, Mark, Aaronson, Robert P. and Palese, Peter. 1984. Influenza C virus hemagglutinin: comparison with influenza A and B virus hemagglutinins. J. Virol. 50(1): 118-124.

Plotkin, Joshua B., Dushoff, Jonathan and Levin, Simon A. 2002. Hemagglutinin sequence clusters and the antigenic evolution of influenza A virus. PNAS 99(9):6263-6268.

Reid, Ann H., Fanning, Thomas G., Hultin, Johan V., and Taubenberger, Jeffery K. 1999. Origin and evolution of the 1918 "Spanish" influenza virus hemagglutinin gene. PNAS 96(4):1651-1656.

Skehel, J.J., Bayley, P.M., Brown, E.B., Martin, S.R., Waterfield, M.D., White, J.M., Wilson, I.A. and Wiley, D.C. 1982. Changes in the conformation of influenza virus hemagglutinin at the pH optimum of virus-mediated membrane fusion. PNAS 79:968-972.

Skehel, John J. and Wiley, Don C. 2000. Receptor Binding and Membrane Fusion in Virus Entry: The Influenza Hemagglutinin. Ann. Rev. Biochem. 69:531-569.

Stevens, James, Corper, Adam L., Basler, Christopher F., Taubenberger, Jeffery K., Palese, Peter and Wilson, Ian A. 2004. Structure of the Uncleaved Human H1 Hemagglutinin from the Extinct 1918 Influenza Virus. Science 303:1866-1870.

Stevens, James, Blizt, Ola, Tumpey, Terrence M., Taubenberger, Jeffery K., Paulson, James C. and Wilson, Ian A. 2006. Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus. Science 312:404-410.

Stuart, David. 1994. Docking Mission Accomplished. (News and Views) Nature 371:19-20.

Tamm, Lukas K. 2003. Hypothesis: spring-loaded boomerang mechanism of influenza hemagglutinin-mediated membrane fusion. Biochim. Biophys. Acta 1614:14-23.

Tamm, Lukas K., Crane, Jonathan and Kiessling, Volker. 2003. Membrane fusion: a structural perspective on the interplay of lipids and proteins. Curr. Opin. Struct. Biol. 13:4.

Tatulian, Suren A., Hinterdorfer, Peter, Baber, Gwen and Tamm, Lukas K. 1995. Influenza hemagglutinin assumes a tilted conformation during membrane fusion as determined by attenuated total reflection FTIR spectroscopy. The EMBO J. 14(22):5514-5523.

Tumpey, Terrence M., Basler, Christopher F., Aguilar, Patricia V., Zeng, Hui, Solórzano, Alicia, Swayne, David E., Cox, Nancy J., Katz, Jacqueline M., Taubenberger, Jeffery K., Palese, Peter and García-Sastre, Adolfo. 2005. Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus. Science 310:77-80.

Webster, Robert G., Bean, William J., Gorman, Owen T., Chambers, Thomas M. and Kawaoka, Yoshihiro. 1992. Evolution and Ecology of Influenza A Viruses. Microb. Rev. 56(1):152-179.

Wharton, S.A., Calder, L.J. Ruigrok, R.W.H, Skehel, J.J., Steinhauer, D.A. and Wiley. D.C. 1995. Electron microscopy of antibody complexes of influenza virus haemagglutinin in the fusion pH conformation. The EMBO J. 14(2):240-246.

Whittaker, Gary R. 2001. Intracellular trafficking of influenza virus: clinical implications for molecular medicine. Exp. Rev. Mol. Med. 8 February.

Wiley, D. C. and Skehel, J.J. 1987. The Structure and Function of the Hemagglutinin Membrane Glycoprotein of Influenza Virus. Ann. Rev. Biochem. 56:365-394.

Wiley, D.C, Wilson, I.A. and Skehel, J.J. 1981. Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation. Nature 289:373-378.

Yamada, Shinya, Suzuki, Yasuo, Suzuki, Takashi, Le, Mai Q., Nidom, Chairul A., Sakai-Tagawa, Yuko, Muramoto, Yukiko, Ito, Mutsumi, Kiso, Maki, Horimoto, Taisuke, Shinya, Kyoko, Sawada, Toshihiko, Kiso, Makoto, Usui, Taiichi, Murata, Takeomi, Lin, Yipu, Hay, Alan, Haire, Lesley F., Stevens, David J., Russell, Rupert J., Gamblin, Stven J., Skehel, John J. and Kawaoka, Yoshihiro. 2006. Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature 444:378-380.