The E protein mediates virus-membrane fusion by refolding to a hairpin-like E homotrimer with the fusion loops and TM domains at the same end [21, 22] . This reaction involves low pH-triggered dissociation of the homodimer, fusion loop insertion into the endosome membrane, formation of a core trimer composed of DI and DII, and the foldback of the DIII and stem regions towards the target membrane and their packing against the core trimer. The prefusion and postfusion conformations of the flavivirus E fusion protein are structurally and functionally similar to those of the E1 fusion protein from the alphavirus Semliki Forest virus (SFV) [23, 24, 25] , and these fusion proteins are often referred to as ''class II'' [26, 27, 28] . In addition to the ectodomains whose trimer structures are described above, truncated fusion proteins composed of domains I and II (DI/II) can reconstitute SFV and DENV core trimer formation on target membranes [29, 30] . Such core trimers act as specific targets for DIII binding, thus recapitulating the protein-protein interactions during class II trimerization and hairpin formation.