Envelope E protein of dengue virus and phospholipid binding to the late endosomal membrane

Flaviviruses include many significant human pathogens, comprising dengue, West Nile, Yellow fever, Japanese encephalitis, Zika and tick-borne encephalitis viruses and many others, affecting millions of people in the world. These viruses have produced important epidemics in the past, they continue to do it and they will undoubtedly continue to do so in the future. Flaviviruses enter into the cells via receptor-mediated endocytosis by fusing its membrane with the endosomal membrane in a pH-dependent manner with the help of the envelope E protein, a prototypical class II membrane fusion protein. The envelope E protein has a conserved fusion peptide at its distal end, which is responsible in the first instance of inserting the protein into the host membrane. Since the participation of other segments of the E protein in the fusion process should not be ruled out, we have used atomistic molecular dynamics to study the binding of the distal end of domain II of the envelope E protein from Dengue virus (DENV) with a complex membrane similar to the late-endosome one. Our work shows that not only the fusion peptide participates directly in the fusion, but also two other sequences of the protein, next to the fusion peptide it in the three-dimensional structure, are jointly wrapped in the fusion process. Overall, these three sequences represent a new target that would make it possible to obtain effective antivirals against DENV in particular and Flaviviruses in general.

Automated summary

Flaviviruses, including dengue and yellow fever, enter host cells through membrane fusion mediated by envelope E protein. Our study reveals that besides the fusion peptide, other segments of the envelope E protein are involved in the fusion process, suggesting a potential target for antiviral drug development against DENV and flaviviruses.