A novel membrane fusion protein family in Flaviviridae?

•Viral membrane fusion proteins fall into three distinct structural classes (I–III).•In 2013, the E2 glycoproteins of pesti- and hepaciviruses were found to have novel folds.•E1 and E2 proteins of pesti- and hepaciviruses define a new class of fusion machinery.•Structural data suggest that fusion proteins evolved by host–virus or virus–virus transfer.

Enveloped viruses must fuse their lipid membrane to a cellular membrane to deliver their genome into the cytoplasm for replication. Viral envelope proteins catalyze this critical membrane fusion event. They fall into three distinct structural classes. In 2013, envelope proteins from a pestivirus and hepatitis C virus were found to have two distinct novel folds. This was unexpected because these viruses are in the same family as flaviviruses, which have class II fusion proteins. We propose that the membrane fusion machinery of the closely related pestiviruses and hepatitis C virus defines a new structural class. This and other recently identified structural relationships between viral fusion proteins shift the paradigm for how these proteins evolved.