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

Nat Commun. 2022 Jun 28;13(1):3718. doi: 10.1038/s41467-022-31111-y.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Encephalitis Viruses, Tick-Borne*
  • Furin*
  • Membrane Fusion
  • Viral Envelope Proteins / chemistry
  • Virion

Substances

  • Viral Envelope Proteins
  • Furin