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

Marie-Christine Vaney1, Mariano Dellarole1,2, Stéphane Duquerroy1,3

  • 1Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Unité de Virologie Structurale, Paris, France.

Nature Communications
|June 28, 2022
PubMed

Insights

Flavivirus maturation involves prM/E dimer rearrangement. The prM "pr" part originates from HSP40 chaperones, with the E 150-loop controlling this process and viral fusion.

Area of Science:

  • Virology
  • Structural Biology
  • Cellular Biology

Background:

  • Flavivirus assembly and maturation are critical for infectivity.
  • Immature flavivirus particles bud from the endoplasmic reticulum and mature in the trans-Golgi network.
  • Maturation involves structural rearrangements of envelope glycoproteins (prM and E) and prM cleavage.

Purpose of the Study:

  • To elucidate the origin of the prM
  • moiety during flavivirus maturation.
  • To determine the structural mechanism of flavivirus maturation and fusion activation.

Main Methods:

  • X-ray crystallography of tick-borne encephalitis virus (pr/E)2 dimer at acidic pH.
  • Analysis of protein interactions and structural rearrangements.

Main Results:

  • The prM
  • moiety is derived from an HSP40 cellular chaperonin.
  • The E 150-loop acts as a pH-sensitive hinged lid, exposing a binding pocket for
  • at acidic pH.
  • This interaction induces (prM/E)2 dimer formation and smooth particle generation in the Golgi.
  • Lid closure and pr expulsion occur in the neutral extracellular environment, enabling fusion activation.

Conclusions:

  • The study reveals a novel mechanism for flavivirus maturation involving HSP40 chaperones and pH-dependent structural changes of the E 150-loop.
  • This provides insights into flavivirus entry and potential therapeutic targets.

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