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

Authors:
Open Access
Publisher website
Google Scholar
Abstract
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.
Funding Information
  • Agence Nationale de la Recherche (ANR-10-LABX-62-10 IBEID)
  • Wellcome Trust (collaborative grant (UNS22082))
  • Institut Pasteur (recurring support)
  • Austrian Science Fund (I1378-B13 and P27501-B21)

This publication has 65 references indexed in Scilit: