The structure of an infectious immature flavivirus redefines viral architecture and maturation

Area of Science:

• Virology
• Structural Biology
• Molecular Biology

Background:

• Flaviviruses are significant human pathogens transmitted by arthropods like mosquitoes and ticks.
• Viral entry into host cells relies on a fusion mechanism that must be tightly regulated during virus assembly and release.
• The premembrane (prM) protein acts as a molecular chaperone, maintaining flaviviruses in an immature, non-infectious state.

Purpose of the Study:

• To determine the structural basis of flavivirus immaturity and the role of the prM protein.
• To elucidate the mechanism of viral fusion activation and its regulation.

Main Methods:

• Cryo-electron microscopy was used to determine the structure of an immature flavivirus particle.
• Analysis of the interaction between the prM chaperone and the viral spike proteins.

Main Results:

• The first structure of an immature flavivirus with a complete spike was determined.
• The prM protein forms a supporting pillar, holding the spike in an upright, asymmetric conformation.
• This structure is primed for conformational changes upon acidification, leading to spike collapse and fusion.

Conclusions:

• The prM chaperone is critical for maintaining flavivirus immaturity by stabilizing the viral spike.
• A revised model for flavivirus architecture and fusion activation is proposed, involving prM-mediated spike collapse.
• This mechanism is likely conserved across the Flaviviridae family, offering potential therapeutic targets.