Amino Acids

, Volume 41, Issue 5, pp 1159–1163 | Cite as

Molecular mechanisms of flavivirus membrane fusion

  • Karin Stiasny
  • Richard Fritz
  • Karen Pangerl
  • Franz X. Heinz
Review Article


Flaviviruses comprise a number of important human pathogens including yellow fever, dengue, West Nile, Japanese encephalitis and tick-borne encephalitis viruses. They are small enveloped viruses that enter cells by receptor-mediated endocytosis and release their nucleocapsid into the cytoplasm by fusing their membrane with the endosomal membrane. The fusion event is triggered by the acidic pH in the endosome and is mediated by the major envelope protein E. Based on the atomic structures of the pre- and post-fusion conformations of E, a fusion model has been proposed that includes several steps leading from the metastable assembly of E at the virion surface to membrane merger and fusion pore formation trough conversion of E into a stable trimeric post-fusion conformation. Using recombinant subviral particles of tick-borne encephalitis virus as a model, we have defined individual steps of the molecular processes underlying the flavivirus fusion mechanisms. This includes the identification of a conserved histidine as being part of the pH sensor in the fusion protein that responds to the acidic pH and thus initiates the structural transitions driving fusion.


Flavivirus Membrane fusion Viral fusion protein Fusion trigger Histidine 



This work was supported by the Austrian Science Fund (FWF; P19843-B13).


  1. Allison SL, Schalich J, Stiasny K, Mandl CW, Heinz FX (2001) Mutational evidence for an internal fusion peptide in flavivirus envelope protein E. J Virol 75:4268–4275PubMedCrossRefGoogle Scholar
  2. Backovic M, Jardetzky TS (2009) Class III viral membrane fusion proteins. Curr Opin Struct Biol 19:189–196PubMedCrossRefGoogle Scholar
  3. Bressanelli S, Stiasny K, Allison SL, Stura EA, Duquerroy S, Lescar J, Heinz FX, Rey FA (2004) Structure of a flavivirus envelope glycoprotein in its low-pH-induced membrane fusion conformation. EMBO J 23:728–738PubMedCrossRefGoogle Scholar
  4. Campadelli-Fiume G, Amasio M, Avitabile E, Cerretani A, Forghieri C, Gianni T, Menotti L (2007) The multipartite system that mediates entry of herpes simplex virus into the cell. Rev Med Virol 17:313–326PubMedCrossRefGoogle Scholar
  5. Chernomordik LV, Kozlov MM (2008) Mechanics of membrane fusion. Nat Struct Mol Biol 15:675–683PubMedCrossRefGoogle Scholar
  6. Corver J, Ortiz A, Allison SL, Schalich J, Heinz FX, Wilschut J (2000) Membrane fusion activity of tick-borne encephalitis virus and recombinant subviral particles in a liposomal model system. Virology 269:37–46PubMedCrossRefGoogle Scholar
  7. DeLano WL (2002) The pymol molecular graphics system.
  8. Ferlenghi I, Clarke M, Ruttan T, Allison SL, Schalich J, Heinz FX, Harrison SC, Rey FA, Fuller SD (2001) Molecular organization of a recombinant subviral particle from tick-borne encephalitis virus. Mol Cell 7:593–602PubMedCrossRefGoogle Scholar
  9. Fritz R, Stiasny K, Heinz FX (2008) Identification of specific histidines as pH sensors in flavivirus membrane fusion. J Cell Biol 183:353–361PubMedCrossRefGoogle Scholar
  10. Gubler D, Kuno G, Markhoff L (2006) Flaviviruses. In: Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, Roizman B, Straus SE (eds) Fields virology, 5th edn. Lippincott, Philadelphia, pp 1153–1252Google Scholar
  11. Harrison SC (2008a) The pH sensor for flavivirus membrane fusion. J Cell Biol 183:177–179PubMedCrossRefGoogle Scholar
  12. Harrison SC (2008b) Viral membrane fusion. Nat Struct Mol Biol 15:690–698PubMedCrossRefGoogle Scholar
  13. Kampmann T, Mueller DS, Mark AE, Young PR, Kobe B (2006) The role of histidine residues in low-pH-mediated viral membrane fusion. Structure 14:1481–1487PubMedCrossRefGoogle Scholar
  14. Kanai R, Kar K, Anthony K, Gould LH, Ledizet M, Fikrig E, Marasco WA, Koski RA, Modis Y (2006) Crystal structure of west nile virus envelope glycoprotein reveals viral surface epitopes. J Virol 80:11000–11008PubMedCrossRefGoogle Scholar
  15. Kielian M (2006) Class II virus membrane fusion proteins. Virology 344:38–47PubMedCrossRefGoogle Scholar
  16. Kielian M, Rey FA (2006) Virus membrane-fusion proteins: more than one way to make a hairpin. Nat Rev Microbiol 4:67–76PubMedCrossRefGoogle Scholar
  17. Kuhn RJ, Zhang W, Rossmann MG, Pletnev SV, Corver J, Lenches E, Jones CT, Mukhopadhyay S, Chipman PR, Strauss EG, Baker TS, Strauss JH (2002) Structure of dengue virus: implications for flavivirus organization, maturation, and fusion. Cell 108:717–725PubMedCrossRefGoogle Scholar
  18. Martens S, McMahon HT (2008) Mechanisms of membrane fusion: disparate players and common principles. Nat Rev Mol Cell Biol 9:543–556PubMedCrossRefGoogle Scholar
  19. Modis Y, Ogata S, Clements D, Harrison SC (2003) A ligand-binding pocket in the dengue virus envelope glycoprotein. Proc Natl Acad Sci USA 100:6986–6991PubMedCrossRefGoogle Scholar
  20. Modis Y, Ogata S, Clements D, Harrison SC (2004) Structure of the dengue virus envelope protein after membrane fusion. Nature 427:313–319PubMedCrossRefGoogle Scholar
  21. Modis Y, Ogata S, Clements D, Harrison SC (2005) Variable surface epitopes in the crystal structure of dengue virus type 3 envelope glycoprotein. J Virol 79:1223–1231PubMedCrossRefGoogle Scholar
  22. Moss B (2006) Poxvirus entry and membrane fusion. Virology 344:48–54PubMedCrossRefGoogle Scholar
  23. Mueller DS, Kampmann T, Yennamalli R, Young PR, Kobe B, Mark AE (2008) Histidine protonation and the activation of viral fusion proteins. Biochem Soc Trans 36:43–45PubMedCrossRefGoogle Scholar
  24. Mukhopadhyay S, Kim BS, Chipman PR, Rossmann MG, Kuhn RJ (2003) Structure of West Nile virus. Science 302:248PubMedCrossRefGoogle Scholar
  25. Nayak V, Dessau M, Kucera K, Anthony K, Ledizet M, Modis Y (2009) Crystal structure of dengue virus type 1 envelope protein in the postfusion conformation and its implications for membrane fusion. J Virol 83:4338–4344PubMedCrossRefGoogle Scholar
  26. Nelson S, Poddar S, Lin TY, Pierson TC (2009) Protonation of individual histidine residues is not required for the pH-dependent entry of West Nile virus: evaluation of the “histidine-switch” hypothesis. J Virol. doi: 10.1128/JVI.01072-09
  27. Nybakken GE, Nelson CA, Chen BR, Diamond MS, Fremont DH (2006) Crystal structure of the West Nile virus envelope glycoprotein. J Virol 80:11467–11474PubMedCrossRefGoogle Scholar
  28. Qin ZL, Zheng Y, Kielian M (2009) Role of conserved histidine residues in the low-pH dependence of the Semliki Forest virus fusion protein. J Virol 83:4670–4677PubMedCrossRefGoogle Scholar
  29. Rey FA, Heinz FX, Mandl C, Kunz C, Harrison SC (1995) The envelope glycoprotein from tick-borne encephalitis virus at 2 A resolution. Nature 375:291–298PubMedCrossRefGoogle Scholar
  30. Roche S, Albertini AA, Lepault J, Bressanelli S, Gaudin Y (2008) Structures of vesicular stomatitis virus glycoprotein: membrane fusion revisited. Cell Mol Life Sci 65:1716–1728PubMedCrossRefGoogle Scholar
  31. Roussel A, Lescar J, Vaney MC, Wengler G, Wengler G, Rey FA (2006) Structure and interactions at the viral surface of the envelope protein E1 of Semliki Forest virus. Structure 14:75–86PubMedCrossRefGoogle Scholar
  32. Schalich J, Allison SL, Stiasny K, Mandl CW, Kunz C, Heinz FX (1996) Recombinant subviral particles from tick-borne encephalitis virus are fusogenic and provide a model system for studying flavivirus envelope glycoprotein functions. J Virol 70:4549–4557PubMedGoogle Scholar
  33. Sollner TH (2004) Intracellular and viral membrane fusion: a uniting mechanism. Curr Opin Cell Biol 16:429–435PubMedCrossRefGoogle Scholar
  34. Srivastava J, Barber DL, Jacobson MP (2007) Intracellular pH sensors: design principles and functional significance. Physiology 22:30–39PubMedCrossRefGoogle Scholar
  35. Stevens J, Corper AL, Basler CF, Taubenberger JK, Palese P, Wilson IA (2004) Structure of the uncleaved human H1 hemagglutinin from the extinct 1918 influenza virus. Science 303:1866–1870PubMedCrossRefGoogle Scholar
  36. Stiasny K, Heinz FX (2006) Flavivirus membrane fusion. J Gen Virol 87:2755–2766PubMedCrossRefGoogle Scholar
  37. Weissenhorn W, Hinz A, Gaudin Y (2007) Virus membrane fusion. FEBS Lett 581:2150–2155PubMedCrossRefGoogle Scholar
  38. White JM, Delos SE, Brecher M, Schornberg K (2008) Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme. Crit Rev Biochem Mol Biol 43:189–219PubMedCrossRefGoogle Scholar
  39. Zhang Y, Zhang W, Ogata S, Clements D, Strauss JH, Baker TS, Kuhn RJ, Rossmann MG (2004) Conformational changes of the flavivirus E glycoprotein. Structure 12:1607–1618PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Karin Stiasny
    • 1
  • Richard Fritz
    • 1
  • Karen Pangerl
    • 1
  • Franz X. Heinz
    • 1
  1. 1.Institute of VirologyMedical University of ViennaViennaAustria

Personalised recommendations