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

Marie Christine Vaney, Mariano Dellarole, Stéphane Duquerroy, Iris Medits, Georgios Tsouchnikas, Alexander Rouvinski, Patrick England, Karin Stiasny*, Franz X. Heinz*, Félix A. Rey*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageAmerican English
Article number3718
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - 28 Jun 2022

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