Summary of the organization of flavivirus particles, the three-dimensional structures of the flavivirus envelope protein E, and a model of flavivirus membrane fusion. (A) Schematic diagram of a flavivirus particle in its immature (prM-containing) and mature form after proteolytic cleavage of prM. (B) Schematic of the prefusion E dimer including ribbon diagrams of the TBEV sE ectodomain (top and side view) and those parts for which the atomic structure is not known (stem and anchor). (C) Ribbon diagram of the postfusion TBEV sE trimer (side view). The positions of the histidines conserved in all flavivirus E proteins are indicated by gray balls. (D) Schematic of the proposed flavivirus fusion mechanism showing different steps of the fusion process. (step 1) Metastable E dimer in mature virions. (step 2) Dissociation of the E dimers at acidic pH, outward projection of E monomers, and interaction of the FP with the target membrane. (step 3) Trimerization, DIII relocation, and “zipping up” of the stem. (step 4) Formation of the postfusion trimer and opening of the fusion pore. Red, DI; yellow, DII; blue, DIII; orange, FP; purple, stem (linker between DIII and the transmembrane anchors); gray, transmembrane anchors.