TY - JOUR
T1 - Evolution and activation mechanism of the flavivirus class II membrane-fusion machinery
AU - Vaney, Marie Christine
AU - Dellarole, Mariano
AU - Duquerroy, Stéphane
AU - Medits, Iris
AU - Tsouchnikas, Georgios
AU - Rouvinski, Alexander
AU - England, Patrick
AU - Stiasny, Karin
AU - Heinz, Franz X.
AU - Rey, Félix A.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/6/28
Y1 - 2022/6/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85132980149&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-31111-y
DO - 10.1038/s41467-022-31111-y
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C2 - 35764616
AN - SCOPUS:85132980149
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3718
ER -