Proteolytic Activation of Flavivirus Envelope Proteins

  • Franz X. HeinzEmail author
  • Karin Stiasny


Flaviviruses comprise a number of important human vector-borne pathogens, including yellow fever, dengue, Zika, West Nile, Japanese encephalitis, and tick-borne encephalitis viruses. New technologies for determining high-resolution structures of viral particles have provided unprecedented insights into the molecular organization of this group of enveloped, icosahedral viruses in different stages of assembly and maturation. The viral fusion protein E forms a metastable herringbone-like array at the surface of mature viruses, spring-loaded to mediate membrane fusion upon encountering the acidic pH in endosomes. The E protein does not require proteolytic cleavage for activation, but an accessory protein (prM), associated tightly with E in the initially assembled noninfectious immature viruses, has to be cleaved by furin in the trans-Golgi network during virus release, thus priming E for fusion. A complex interplay of pH sensors in E and prM trigger sequential conformational changes at different steps of the viral life cycle to control virus maturation and membrane fusion. There is increasing evidence that incomplete proteolytic cleavage of prM, leading to mosaic particles with patches of envelope proteins in both their immature as well as mature conformations, may be an important factor for certain biological properties of flaviviruses. Dynamic motions of the envelope proteins (“virus breathing”) further increase deviations from a picture of static icosahedral structures. The resulting particle heterogeneity causes the presentation of otherwise inaccessible sites for interactions at the surface of infectious virions that can modulate viral attachment to cells and influence the induction of antibodies as well as virus neutralization.


Flaviviruses Tick-borne encephalitis virus Yellow fever virus Dengue virus Zika virus West Nile virus Japanese encephalitis virus Fusion protein E Accessory protein prM Furin Virus maturation Virus breathing 


  1. Acosta EG, Kumar A, Bartenschlager R. Revisiting dengue virus–host cell interaction: new insights into molecular and cellular virology. In: Karl M, Frederick AM, editors. Advances in virus research, vol. vol 88. San Diego: Academic Press; 2014. p. 1–109. Scholar
  2. Amara A, Mercer J. Viral apoptotic mimicry. Nat Rev Microbiol. 2015;13(8):461–9. Scholar
  3. Apte-Sengupta S, Sirohi D, Kuhn RJ. Coupling of replication and assembly in flaviviruses. Curr Opin Virol. 2014;9:134–42. Scholar
  4. Beltramello M, Williams KL, Simmons CP, Macagno A, Simonelli L, Quyen NT, Sukupolvi-Petty S, Navarro-Sanchez E, Young PR, de Silva AM, Rey FA, Varani L, Whitehead SS, Diamond MS, Harris E, Lanzavecchia A, Sallusto F. The human immune response to Dengue virus is dominated by highly cross-reactive antibodies endowed with neutralizing and enhancing activity. Cell Host Microbe. 2010;8(3):271–83. Scholar
  5. Blitvich BJ, Firth AE. Insect-specific flaviviruses: a systematic review of their discovery, host range, mode of transmission, superinfection exclusion potential and genomic organization. Virus. 2015;7(4):1927–59. Scholar
  6. Böttcher-Friebertshäuser E, Klenk HD, Garten W. Activation of influenza viruses by proteases from host cells and bacteria in the human airway epithelium. Pathog Dis. 2013;69(2):87–100. Scholar
  7. Chao LH, Klein DE, Schmidt AG, Peña JM, Harrison SC. Sequential conformational rearrangements in flavivirus membrane fusion. eLife. 2014;3:e04389. Scholar
  8. Cherrier MV, Kaufmann B, Nybakken GE, Lok SM, Warren JT, Chen BR, Nelson CA, Kostyuchenko VA, Holdaway HA, Chipman PR, Kuhn RJ, Diamond MS, Rossmann MG, Fremont DH. Structural basis for the preferential recognition of immature flaviviruses by a fusion-loop antibody. EMBO J. 2009;28(20):3269–76. Scholar
  9. Costin JM, Jenwitheesuk E, Lok S-M, Hunsperger E, Conrads KA, Fontaine KA, Rees CR, Rossmann MG, Isern S, Samudrala R, Michael SF. Structural optimization and de novo design of dengue virus entry inhibitory peptides. PLoS Negl Trop Dis. 2010;4(6):e721. Scholar
  10. Coyne CB, Lazear HM. Zika virus—reigniting the TORCH. Nat Rev Microbiol. 2016;14(11):707–15. Scholar
  11. Cruz-Oliveira C, Freire JM, Conceicao TM, Higa LM, Castanho MA, Da Poian AT. Receptors and routes of dengue virus entry into the host cells. FEMS Microbiol Rev. 2015;39(2):155–70. Scholar
  12. Davis CW, Mattei LM, Nguyen H-Y, Ansarah-Sobrinho C, Doms RW, Pierson TC. The location of asparagine-linked glycans on West Nile virions controls their interactions with CD209 (dendritic cell-specific ICAM-3 grabbing nonintegrin). J Biol Chem. 2006;281(48):37183–94. Scholar
  13. de Alwis R, Williams KL, Schmid MA, Lai C-Y, Patel B, Smith SA, Crowe JE, Wang W-K, Harris E, de Silva AM. Dengue viruses are enhanced by distinct populations of serotype cross-reactive antibodies in human immune sera. PLoS Pathog. 2014;10(10):e1004386. Scholar
  14. Dejnirattisai W, Jumnainsong A, Onsirisakul N, Fitton P, Vasanawathana S, Limpitikul W, Puttikhunt C, Edwards C, Duangchinda T, Supasa S, Chawansuntati K, Malasit P, Mongkolsapaya J, Screaton G. Cross-reacting antibodies enhance dengue virus infection in humans. Science. 2010;328(5979):745–8. Scholar
  15. Doms RW. What came first—the virus or the egg? Cell. 2017;168(5):755–7. Scholar
  16. Dowd KA, DeMaso CR, Pierson TC. Genotypic differences in dengue virus neutralization are explained by a single amino acid mutation that modulates virus breathing. MBio. 2015;6(6):e01559-15. Scholar
  17. Dowd KA, Mukherjee S, Kuhn RJ, Pierson TC. Combined effects of the structural heterogeneity and dynamics of flaviviruses on antibody recognition. J Virol. 2014;88(20):11726–37. Scholar
  18. Dowd KA, Pierson TC. Antibody-mediated neutralization of flaviviruses: a reductionist view. Virology. 2011;411(2):306–15. Scholar
  19. Elshuber S, Allison SL, Heinz FX, Mandl CW. Cleavage of protein prM is necessary for infection of BHK-21 cells by tick-borne encephalitis virus. J Gen Virol. 2003;84(Pt 1):183–91.CrossRefPubMedGoogle Scholar
  20. Elshuber S, Mandl CW. Resuscitating mutations in a furin cleavage-deficient mutant of the flavivirus tick-borne encephalitis virus. J Virol. 2005;79(18):11813–23. Scholar
  21. Fédry J, Liu Y, Péhau-Arnaudet G, Pei J, Li W, Tortorici MA, Traincard F, Meola A, Bricogne G, Grishin NV, Snell WJ, Rey FA, Krey T. The ancient gamete fusogen HAP2 is a eukaryotic class II fusion protein. Cell. 2017;168(5):904–915.e910. Scholar
  22. Fibriansah G, Ng TS, Kostyuchenko VA, Lee J, Lee S, Wang J, Lok SM. Structural changes in dengue virus when exposed to a temperature of 37°C. J Virol. 2013;87(13):7585–92. Scholar
  23. Fischl W, Elshuber S, Schrauf S, Mandl CW. Changing the protease specificity for activation of a flavivirus, tick-borne encephalitis virus. J Virol. 2008;82(17):8272–82. Scholar
  24. Fritz R, Stiasny K, Heinz FX. Identification of specific histidines as pH sensors in flavivirus membrane fusion. J Cell Biol. 2008;183(2):353–61.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Ge P, Zhou ZH. Chaperone fusion proteins aid entropy-driven maturation of class II viral fusion proteins. Trends Microbiol. 2014;22(2):100–6. Scholar
  26. Goo L, VanBlargan LA, Dowd KA, Diamond MS, Pierson TC. A single mutation in the envelope protein modulates flavivirus antigenicity, stability, and pathogenesis. PLoS Pathog. 2017;13(2):e1006178. Scholar
  27. Guirakhoo F, Bolin RA, Roehrig JT. The Murray Valley encephalitis virus prM protein confers acid resistance to virus particles and alters the expression of epitopes within the R2 domain of E glycoprotein. Virology. 1992;191(2):921–31. Scholar
  28. Halstead SB. Dengue antibody-dependent enhancement: knowns and unknowns. Microbiol Spectr. 2014;2(6).
  29. Halstead SB, Mahalingam S, Marovich MA, Ubol S, Mosser DM. Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet Infect Dis. 2010;10(10):712–22. Scholar
  30. Harrison SC. Viral membrane fusion. Virology. 2015;479–480:498–507. Scholar
  31. Heinz FX, Stiasny K, Puschner-Auer G, Holzmann H, Allison SL, Mandl CW, Kunz C. Structural changes and functional control of the tick-borne encephalitis virus glycoprotein E by the heterodimeric association with protein prM. Virology. 1994;198(1):109–17.CrossRefPubMedGoogle Scholar
  32. Jarmer J, Zlatkovic J, Tsouchnikas G, Vratskikh O, Strauss J, Aberle JH, Chmelik V, Kundi M, Stiasny K, Heinz FX. Variation of the specificity of the human antibody responses after tick-borne encephalitis virus infection and vaccination. J Virol. 2014;88(23):13845–57. Scholar
  33. Junjhon J, Edwards TJ, Utaipat U, Bowman VD, Holdaway HA, Zhang W, Keelapang P, Puttikhunt C, Perera R, Chipman PR, Kasinrerk W, Malasit P, Kuhn RJ, Sittisombut N. Influence of pr-M cleavage on the heterogeneity of extracellular dengue virus particles. J Virol. 2010;84(16):8353–8. Scholar
  34. Junjhon J, Lausumpao M, Supasa S, Noisakran S, Songjaeng A, Saraithong P, Chaichoun K, Utaipat U, Keelapang P, Kanjanahaluethai A, Puttikhunt C, Kasinrerk W, Malasit P, Sittisombut N. Differential modulation of prM cleavage, extracellular particle distribution, and virus infectivity by conserved residues at nonfurin consensus positions of the dengue virus pr-M junction. J Virol. 2008;82(21):10776–91.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Katzelnick LC, Coloma J, Harris E. Dengue: knowledge gaps, unmet needs, and research priorities. Lancet Infect Dis. 2017;17(3):e88–e100. Scholar
  36. Keelapang P, Sriburi R, Supasa S, Panyadee N, Songjaeng A, Jairungsri A, Puttikhunt C, Kasinrerk W, Malasit P, Sittisombut N. Alterations of pr-M cleavage and virus export in pr-M junction chimeric dengue viruses. J Virol. 2004;78(5):2367–81. Scholar
  37. Kindhauser MK, Allen T, Frank V, Santhana R, Dye C. Zika: the origin and spread of a mosquito-borne virus. Bull World Health Organ. 2016;94(9):675–686C. Scholar
  38. Kostyuchenko VA, Chew PL, Ng TS, Lok SM. Near-atomic resolution cryo-electron microscopic structure of dengue serotype 4 virus. J Virol. 2014;88(1):477–82. Scholar
  39. Kostyuchenko VA, Lim EXY, Zhang S, Fibriansah G, Ng T-S, Ooi JSG, Shi J, Lok S-M. Structure of the thermally stable Zika virus. Nature. 2016;533(7603):425–8. Scholar
  40. Kostyuchenko VA, Zhang Q, Tan JL, Ng TS, Lok SM. Immature and mature dengue serotype 1 virus structures provide insight into the maturation process. J Virol. 2013;87(13):7700–7. Scholar
  41. Kuhn RJ, Dowd KA, Beth Post C, Pierson TC. Shake, rattle, and roll: Impact of the dynamics of flavivirus particles on their interactions with the host. Virology. 2015;479–480C:508–17. Scholar
  42. Kuhn RJ, Zhang W, Rossmann MG, Pletnev SV, Corver J, Lenches E, Jones CT, Mukhopadhyay S, Chipman PR, Strauss EG, Baker TS, Strauss JH. Structure of dengue virus: implications for flavivirus organization, maturation, and fusion. Cell. 2002;108(5):717–25.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Lai CY, Tsai WY, Lin SR, Kao CL, Hu HP, King CC, Wu HC, Chang GJ, Wang WK. Antibodies to envelope glycoprotein of dengue virus during the natural course of infection are predominantly cross-reactive and recognize epitopes containing highly conserved residues at the fusion loop of domain II. J Virol. 2008;82(13):6631–43. Scholar
  44. Li L, Lok SM, Yu IM, Zhang Y, Kuhn RJ, Chen J, Rossmann MG. The flavivirus precursor membrane-envelope protein complex: structure and maturation. Science. 2008;319(5871):1830–4.CrossRefPubMedGoogle Scholar
  45. Lindenbach BD, Murray CL, Thiel HJ, Rice CM. Flaviviridae. In: Knipe DM, Howley PM, Cohen JI, et al., editors. Fields virology. 6th ed. Philadelphia: Lippincott, Williams & Wilkins; 2013. p. 712–46.Google Scholar
  46. Lorenz IC, Allison SL, Heinz FX, Helenius A. Folding and dimerization of tick-borne encephalitis virus envelope proteins prM and E in the endoplasmic reticulum. J Virol. 2002;76(11):5480–91.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Luo Y-Y, Feng J-J, Zhou J-M, Yu Z-Z, Fang D-Y, Yan H-J, Zeng G-C, Jiang L-F. Identification of a novel infection-enhancing epitope on dengue prM using a dengue cross-reacting monoclonal antibody. BMC Microbiol. 2013;13:194. Scholar
  48. Martín CS-S, Liu CY, Kielian M. Dealing with low pH: entry and exit of alphaviruses and flaviviruses. Trends Microbiol. 2009;17(11):514–21. Scholar
  49. Meertens L, Carnec X, Lecoin MP, Ramdasi R, Guivel-Benhassine F, Lew E, Lemke G, Schwartz O, Amara A. The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry. Cell Host Microbe. 2012;12(4):544–57. Scholar
  50. Miner JJ, Diamond MS. Zika virus pathogenesis and tissue tropism. Cell Host Microbe. 2017;21(2):134–42. Scholar
  51. Morrison TE, Diamond MS. Animal models of Zika virus infection, pathogenesis, and immunity. J Virol. 2017;91(8):pii: e00009-17. Scholar
  52. Moureau G, Cook S, Lemey P, Nougairede A, Forrester NL, Khasnatinov M, Charrel RN, Firth AE, Gould EA, de Lamballerie X. New insights into flavivirus evolution, taxonomy and biogeographic history, extended by analysis of canonical and alternative coding sequences. PLoS One. 2015;10(2):e0117849. Scholar
  53. Mukherjee S, Dowd KA, Manhart CJ, Ledgerwood JE, Durbin AP, Whitehead SS, Pierson TC. Mechanism and significance of cell type-dependent neutralization of flaviviruses. J Virol. 2014;88(13):7210–20. Scholar
  54. Mukherjee S, Lin TY, Dowd KA, Manhart CJ, Pierson TC. The infectivity of prM-containing partially mature West Nile virus does not require the activity of cellular furin-like proteases. J Virol. 2011;85(22):12067–72. Scholar
  55. Mukherjee S, Sirohi D, Dowd KA, Chen Z, Diamond MS, Kuhn RJ, Pierson TC. Enhancing dengue virus maturation using a stable furin over-expressing cell line. Virology. 2016;497:33–40. Scholar
  56. Nelson S, Jost CA, Xu Q, Ess J, Martin JE, Oliphant T, Whitehead SS, Durbin AP, Graham BS, Diamond MS, Pierson TC. Maturation of West Nile virus modulates sensitivity to antibody-mediated neutralization. PLoS Pathog. 2008;4(5):e1000060.CrossRefPubMedPubMedCentralGoogle Scholar
  57. Nelson S, Poddar S, Lin T-Y, Pierson TC. 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. 2009;83(23):12631–5. Scholar
  58. Perera-Lecoin M, Meertens L, Carnec X, Amara A. Flavivirus entry receptors: an update. Virus. 2014;6(1):69–88. Scholar
  59. Pérez-Vargas J, Krey T, Valansi C, Avinoam O, Haouz A, Jamin M, Raveh-Barak H, Podbilewicz B, Rey Félix A. Structural basis of eukaryotic cell-cell fusion. Cell. 2014;157(2):407–19. Scholar
  60. Pierson TC, Diamond MS. Degrees of maturity: the complex structure and biology of flaviviruses. Curr Opin Virol. 2012;2(2):168–75. Scholar
  61. Pierson TC, Diamond MS. Flaviviruses. In: Knipe DM, Howley PM, Cohen JI, et al., editors. Fields virology. 6th ed. Philadelphia: Lippincott, Williams & Wilkins; 2013. p. 747–94.Google Scholar
  62. Pierson TC, Xu Q, Nelson S, Oliphant T, Nybakken GE, Fremont DH, Diamond MS. The stoichiometry of antibody-mediated neutralization and enhancement of West Nile virus infection. Cell Host Microbe. 2007;1(2):135.CrossRefPubMedPubMedCentralGoogle Scholar
  63. Plevka P, Battisti AJ, Junjhon J, Winkler DC, Holdaway HA, Keelapang P, Sittisombut N, Kuhn RJ, Steven AC, Rossmann MG. Maturation of flaviviruses starts from one or more icosahedrally independent nucleation centres. EMBO Rep. 2011;12(6):602–6. Scholar
  64. Plevka P, Battisti AJ, Sheng J, Rossmann MG. Mechanism for maturation-related reorganization of flavivirus glycoproteins. J Struct Biol. 2014;185(1):27–31. Scholar
  65. Prasad VM, Miller AS, Klose T, Sirohi D, Buda G, Jiang W, Kuhn RJ, Rossmann MG. Structure of the immature Zika virus at 9 A resolution. Nat Struct Mol Biol. 2017;24(2):184–6. Advance online publicationCrossRefPubMedPubMedCentralGoogle Scholar
  66. Randolph VB, Winkler G, Stollar V. Acidotropic amines inhibit proteolytic processing of flavivirus prM protein. Virology. 1990;174(2):450–8.CrossRefPubMedGoogle Scholar
  67. Rey FA, Stiasny K, Heinz FX. Flavivirus structural heterogeneity: implications for cell entry. Curr Opin Virol. 2017;24:132–9.CrossRefPubMedPubMedCentralGoogle Scholar
  68. Richard AS, Shim B-S, Kwon Y-C, Zhang R, Otsuka Y, Schmitt K, Berri F, Diamond MS, Choe H. AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses. Proc Natl Acad Sci U S A. 2017;114(8):2024–9. Scholar
  69. Rodenhuis-Zybert IA, van der Schaar HM, da Silva Voorham JM, van der Ende-Metselaar H, Lei HY, Wilschut J, Smit JM. Immature dengue virus: a veiled pathogen? PLoS Pathog. 2010;6(1):e1000718. Scholar
  70. Sapparapu G, Fernandez E, Kose N, Bin C, Fox JM, Bombardi RG, Zhao H, Nelson CA, Bryan AL, Barnes T, Davidson E, Mysorekar IU, Fremont DH, Doranz BJ, Diamond MS, Crowe JE. Neutralizing human antibodies prevent Zika virus replication and fetal disease in mice. Nature. 2016;540(7633):443–7. Scholar
  71. Schmidt AG, Yang PL, Harrison SC. Peptide inhibitors of dengue-virus entry target a late-stage fusion intermediate. PLoS Pathog. 2010;6(4):e1000851. Scholar
  72. Simmons G, Zmora P, Gierer S, Heurich A, Pöhlmann S. Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research. Antivir Res. 2013;100(3):605–14. Scholar
  73. Sirohi D, Chen Z, Sun L, Klose T, Pierson TC, Rossmann MG, Kuhn RJ. The 3.8 Å resolution cryo-EM structure of Zika virus. Science. 2016;352(6284):467–70.CrossRefPubMedPubMedCentralGoogle Scholar
  74. Smit JM, Moesker B, Rodenhuis-Zybert I, Wilschut J. Flavivirus cell entry and membrane fusion. Virus. 2011;3(2):160–71. Scholar
  75. Smith EC, Popa A, Chang A, Masante C, Dutch RE. Viral entry mechanisms: the increasing diversity of paramyxovirus entry. FEBS J. 2009;276(24):7217–27. Scholar
  76. Smith SA, de Alwis AR, Kose N, Jadi RS, de Silva AM, Crowe JE Jr. Isolation of dengue virus-specific memory B cells with live virus antigen from human subjects following natural infection reveals the presence of diverse novel functional groups of antibody clones. J Virol. 2014;88(21):12233–41. Scholar
  77. Smith SA, Nivarthi UK, de Alwis R, Kose N, Sapparapu G, Bombardi R, Kahle KM, Pfaff JM, Lieberman S, Doranz BJ, de Silva AM, Crowe JE Jr. Dengue virus prM-specific human monoclonal antibodies with virus replication-enhancing properties recognize a single immunodominant antigenic site. J Virol. 2016;90(2):780–9. Scholar
  78. Smith SA, Zhou Y, Olivarez NP, Broadwater AH, de Silva AM, Crowe JE Jr. Persistence of circulating memory B cell clones with potential for dengue virus disease enhancement for decades following infection. J Virol. 2012;86(5):2665–75. Scholar
  79. Stadler K, Allison SL, Schalich J, Heinz FX. Proteolytic activation of tick-borne encephalitis virus by furin. J Virol. 1997;71(11):8475–81.PubMedPubMedCentralGoogle Scholar
  80. Stiasny K, Heinz FX. Flavivirus membrane fusion. J Gen Virol. 2006;87(10):2755–66. Scholar
  81. Thomas G. Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol. 2002;3(10):753–66.CrossRefPubMedPubMedCentralGoogle Scholar
  82. Vratskikh O, Stiasny K, Zlatkovic J, Tsouchnikas G, Jarmer J, Karrer U, Roggendorf M, Roggendorf H, Allwinn R, Heinz FX. Dissection of antibody specificities induced by yellow fever vaccination. PLoS Pathog. 2013;9(6):e1003458. Scholar
  83. Wang L, Valderramos SG, Wu A, Ouyang S, Li C, Brasil P, Bonaldo M, Coates T, Nielsen-Saines K, Jiang T, Aliyari R, Cheng G. From mosquitos to humans: genetic evolution of Zika virus. Cell Host Microbe. 2016;19(5):561–5. Scholar
  84. Wang Z, Li L, Pennington JG, Sheng J, Yap ML, Plevka P, Meng G, Sun L, Jiang W, Rossmann MG. Obstruction of dengue virus maturation by Fab fragments of the 2H2 antibody. J Virol. 2013;87(16):8909–15. Scholar
  85. White JM, Whittaker GR. Fusion of enveloped viruses in endosomes. Traffic. 2016;17(6):593–614. Scholar
  86. Wilder-Smith A, Gubler DJ, Weaver SC, Monath TP, Heymann DL, Scott TW. Epidemic arboviral diseases: priorities for research and public health. Lancet Infect Dis. 2017;17(3):e101–6. Scholar
  87. Yu IM, Holdaway HA, Chipman PR, Kuhn RJ, Rossmann MG, Chen J. Association of the pr peptides with dengue virus at acidic pH blocks membrane fusion. J Virol. 2009;83(23):12101–7. Scholar
  88. Yu IM, Zhang W, Holdaway HA, Li L, Kostyuchenko VA, Chipman PR, Kuhn RJ, Rossmann MG, Chen J. Structure of the immature dengue virus at low pH primes proteolytic maturation. Science. 2008;319(5871):1834–7.CrossRefPubMedGoogle Scholar
  89. Zaitseva E, Yang S-T, Melikov K, Pourmal S, Chernomordik LV. Dengue virus ensures its fusion in late endosomes using compartment-specific lipids. PLoS Pathog. 2010;6(10):e1001131. Scholar
  90. Zhang W, Kaufmann B, Chipman PR, Kuhn RJ, Rossmann MG. Membrane curvature in flaviviruses. J Struct Biol. 2013a;183(1):86–94. Scholar
  91. Zhang X, Ge P, Yu X, Brannan JM, Bi G, Zhang Q, Schein S, Zhou ZH. Cryo-EM structure of the mature dengue virus at 3.5-A resolution. Nat Struct Mol Biol. 2013b;20(1):105–10. Scholar
  92. Zhang Y, Corver J, Chipman PR, Zhang W, Pletnev SV, Sedlak D, Baker TS, Strauss JH, Kuhn RJ, Rossmann MG. Structures of immature flavivirus particles. EMBO J. 2003;22(11):2604–13.CrossRefPubMedPubMedCentralGoogle Scholar
  93. Zheng A, Yuan F, Kleinfelter LM, Kielian M. A toggle switch controls the low pH-triggered rearrangement and maturation of the dengue virus envelope proteins. Nat Commun. 2014;5:3877. Scholar
  94. Zicari S, Arakelyan A, Fitzgerald W, Zaitseva E, Chernomordik LV, Margolis L, Grivel J-C. Evaluation of the maturation of individual dengue virions with flow virometry. Virology. 2016;488:20–7. Scholar
  95. Zybert IA, van der Ende-Metselaar H, Wilschut J, Smit JM. Functional importance of dengue virus maturation: infectious properties of immature virions. J Gen Virol. 2008;89(Pt 12):3047–51. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Center for VirologyMedical University of ViennaViennaAustria

Personalised recommendations