Figure 4. Flavivirus E: proposed sequence of fusogenic conformational changes.

(a) The packing of 180 E subunits (90 dimers) in an icosahedral array on the surface of a flavivirus particle³¹. The red, yellow and blue parts of each subunit correspond respectively to domains I, II and III of the ectodomain. (b) 'Side view' of the pre-fusion, dimeric conformation of the E protein, based on the crystal structure of dengue E (residues 1–395)¹⁰, supplemented by a representation of the 'stem' segment (two helices linked by a short loop, lying in the plane of the membrane head groups) and the transmembrane anchor (a helical hairpin), derived from a cryo-EM reconstruction of the virion³¹. The domains in one of the two subunits are colored as in a; the other subunit is in gray. The fusion loop is at the tip of domain II, on the far right of the colored subunit, buried at the contact with domain III of the dimer partner. (c) Monomeric transition between the pre-fusion dimer and the trimeric extended intermediate. The three subunits that will associate into the extended intermediate in d are not yet in contact. The drawing embodies the suggestion that domains I and II have swung outward, while domain III and the stem remain oriented against the membrane roughly as in the pre-fusion state. The fusion loop is now at the top of the diagram and is shown already interacting with the target bilayer. (d) Extended intermediate. Domains I and II have associated into the trimeric core of the post-fusion conformation, but domain III has not yet flipped over (upper arrows) to dock against them⁴⁷. To indicate that the stem segment must then zip back along the trimer core (lower arrows), the stem is represented by loops 'poised' to reconfigure. (e) Post-fusion conformation. Domain III has reoriented, and the stem (dashed line, as there is no direct structural information on its conformation or exact position in the post-fusion trimer) connects it to the transmembrane anchor, now brought together with the fusion loop in the single, fused bilayer. The post-fusion conformation is shown in a 'horizontal' orientation, to correspond to the sequence in Figure 1.