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

• Published in: Nature communications Vol. 13; no. 1; p. 3718
• Main Authors: Vaney, Marie-Christine, Dellarole, Mariano, Duquerroy, Stéphane, Medits, Iris, Tsouchnikas, Georgios, Rouvinski, Alexander, England, Patrick, Stiasny, Karin, Heinz, Franz X., Rey, Félix A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.06.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/326/596/1282; 631/326/596/2116; 631/535/1266; 692/308/575; 82/80; 82/83; 9/10; Cellular structure; Cleavage; Dengue fever; Dimers; Encephalitis; Encephalitis Viruses, Tick-Borne; Endoplasmic reticulum; Env protein; Furin; Glycoproteins; Golgi apparatus; Hsp40 protein; Humanities and Social Sciences; Life Sciences; Membrane Fusion; Membranes; Molecular structure; multidisciplinary; pH effects; Protein E; Proteins; Science; Science (multidisciplinary); Tick-borne encephalitis; Tropical diseases; Viral envelope proteins; Viral Envelope Proteins - chemistry; Virion; Virions; Viruses; West Nile virus
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31111-y

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.