Fig. 1

The flavivirus replication cycle and the fusogenic conformational change in the E protein during cell entry. (A) Viral particles first interact with attachment factors that are required to bind the virion to the cell surface, which is followed by specific interactions with entry receptors. The attachment factors include DC-SIGN, HSP70, GAG, etc. Flaviviruses enter cells mainly through the clathrin-mediated endocytic pathway. In the low-pH environment of the endosome, conformational changes and rearrangements of the E protein of the virus are triggered that allow the fusion of viral and endosomal membranes, resulting in the release of viral RNA into the cytoplasm. The released positive-sense RNA ((+) RNA) initiates translation at the rough ER membrane and produces a single polyprotein. NS2B3 and cellular signal peptidases cleave the co- and posttranslational polyproteins into structural and nonstructural proteins. Nonstructural proteins participate in RNA replication in the replication complex (RC). (+) RNA can be incorporated into viral particles, which occur in the ER. Following the viral assembly step, the maturation of virions containing prM occurs along the release pathway by furin-mediated cleavage of prM. Mature virions are released by exocytosis. The asterisk indicates the lifecycle in which the E protein participates. (B) Schematic of the fusion process. The E dimer anchored in the viral membrane (first panel). The E dimer is separated under the low-pH conditions in endosomes; the fusion peptide is inserted in the endosomal membrane (second panel). Domain III shifts and rotates to create trimer contacts, causing the C-terminal portion of the E protein to fold back towards the fusion loop. The energy released by this refolding causes the membrane to bend (third panel). Generation of the final postfusion structure and opening of the fusion pore (fourth panel). This conformation enables the viral genome to be released into the cytoplasm