Evolution and activation mechanism of the flavivirus class II membrane-fusion machinery

The flavivirus envelope glycoproteins prM and E drive the assembly of icosahedral, spiky immature particles that bud across the membrane of the endoplasmic reticulum. Maturation into infectious virions in the trans-Golgi network involves an acid-pH-driven rearrangement into smooth particles made of (prM/E)(2) dimers exposing a furin site for prM cleavage into pr and M. Here we show that the prM pr moiety derives from an HSP40 cellular chaperonin. Furthermore, the X-ray structure of the tick-borne encephalitis virus (pr/E)(2) dimer at acidic pH reveals the E 150-loop as a hinged-lid that opens at low pH to expose a positively-charged pr-binding pocket at the E dimer interface, inducing (prM/E)(2) dimer formation to generate smooth particles in the Golgi. Furin cleavage is followed by lid-closure upon deprotonation in the neutral-pH extracellular environment, expelling pr while the 150-loop takes the relay in fusion loop protection, thus revealing the elusive flavivirus mechanism of fusion activation. The mechanism of flavivirus activation for membrane fusion is not yet understood. Here, Vaney et al. describe how the viral pr protein, derived from an HSP40/DnaJ chaperonin, interacts with a pH sensing loop in the envelope protein E for fusogenic activation.

Automated summary

The flavivirus envelope proteins prM and E are involved in the assembly of immature particles and their maturation into infectious virions. The HSP40 chaperonin is responsible for the generation of the prM moiety. The X-ray structure of the tick-borne encephalitis virus reveals the mechanism of fusion activation involving the pH sensing loop and pr-binding pocket.