New findings challenge our understanding of the alpha virus structure and fusion mechanism. It is evident from recent work in electron cryomicroscopy, cryoEM, that the external domains of the membrane-anchored glycoproteins, E1 and E2, form a shell at some distance above the membrane. From there, the glycoproteins protrude further outwards as three-lobed spikes. They present a receptor-binding site residing in E2 at their outermost domains, distal to the center of the spike. The ectodomain of the fusion protein, the E1, has an elongated shape, as revealed by X-ray crystallography. Fitted in the cryoEM structure of the virus, the C-terminal and central parts of the E1 ectodomain fill the major portion of the shell, while the fusion peptide loop hides under the receptor-binding domain in the spike. With this structural background, the alphaviruses represent an intriguing new fusion principle, differing in many aspects from the established influenza model. This mechanism is now on its way to be revealed.
