Entry functions and antigenic structure of flavivirus envelope proteins

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• Flavivirus envelope (E) proteins form icosahedral structures on virions, mediating receptor binding and membrane fusion.
• Acidic endosomal pH triggers conformational changes in E proteins, initiating viral membrane fusion.

Purpose of the Study:

• To investigate the molecular mechanisms controlling flavivirus E protein-mediated membrane fusion.
• To identify alternative triggers for fusion and understand the regulation of early and late fusion stages.
• To map antigenic sites on the E protein, including those targeted by neutralizing antibodies.

Main Methods:

• Utilized neutralization escape mutants to study the molecular antigenic structure of the E protein.
• Employed recombinant expression systems to generate virus-like particles for structural analysis.
• Investigated the effects of an alternative trigger on E protein conformational changes and fusion progression.

Main Results:

• An alternative trigger was identified that initiates the first phase of fusion but arrests the process at an intermediate stage.
• Data suggest early and late fusion stages are differentially regulated by intersubunit and intrasubunit constraints.
• Each of the three external domains of the E protein can induce and bind neutralizing antibodies.
• Broadly cross-reactive antibodies target a conserved, cryptic fusion peptide loop on the E protein.

Conclusions:

• Flavivirus fusion is a multi-stage process with distinct regulatory mechanisms for early and late events.
• The fusion peptide loop, though cryptic, is a key target for broadly protective flavivirus antibodies.
• Understanding E protein structure and function is crucial for developing novel antiviral strategies.