Chaperone fusion proteins aid entropy-driven maturation of class II viral fusion proteins

• The viral fusion protein has more than one native state: prefusion and postfusion.
• Class II viral fusion proteins depend on their chaperones for their folding and function.
• Maturation processes of flaviviruses and alphaviruses bear much resemblance.
• Dengue virus (DENV) maturation is unidirectional, driven by entropy-increasing events.

Class II viral fusion proteins are present on the envelope of flaviviruses and togaviruses, viruses that often cause tropical and subtropical diseases. These proteins use a second membrane protein as a molecular chaperone to assist their folding and to ensure proper function during viral assembly, maturation, and infection. Recent progress in structural studies of dengue viruses has revealed how the chaperone pre-membrane (prM) protein guides viral maturation and how pH is sensed in both the maturation and infection processes. Drastic conformation changes and reorganization of these viral membrane proteins occur during the transition from their metastable to stable structural states in a unidirectional, entropy-driven process.