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Proteolytic Activation of Flavivirus Envelope Proteins

  • Franz X. Heinz
  • Karin Stiasny
Chapter

Abstract

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.

Keywords

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 

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Center for VirologyMedical University of ViennaViennaAustria

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