The entry machinery of flaviviruses

Area of Science:

• Virology
• Molecular Biology
• Structural Biology

Background:

• Tick-borne encephalitis virus (TBEV) utilizes its envelope protein E, a class II fusion protein, to mediate membrane fusion.
• The flavivirus envelope protein E undergoes conformational changes from a dimer to a trimer at acidic pH within endosomes.

Purpose of the Study:

• To investigate the molecular mechanisms of membrane fusion mediated by the flavivirus envelope protein E.
• To compare flavivirus fusion mechanisms with those of alphaviruses and other viral fusion protein classes.

Main Methods:

• Utilizing TBEV as a model system for studying viral fusion.
• Analyzing conformational changes of the envelope protein E.
• Investigating interactions with lipids, particularly cholesterol.

Main Results:

• Flavivirus envelope protein E transitions from a metastable dimer to a stable trimer at acidic pH, releasing a fusion peptide.
• This process drives interaction with the endosomal membrane and subsequent fusion.
• Flavivirus fusion involves specific interactions with cholesterol's 3beta-hydroxyl group, similar to alphaviruses.

Conclusions:

• The conformational flexibility of flavivirus envelope protein E is key to its efficient membrane fusion.
• Class II fusion proteins, like TBEV's E protein, exhibit distinct mechanisms compared to class I fusion proteins.
• Understanding these mechanisms provides insights into viral entry and potential therapeutic targets.