Relating structure to evolution in class II viral membrane fusion proteins

• Until 2013, class II proteins had only been found in flaviviruses and alphaviruses.
• A class II fusion protein was recently discovered in the unrelated phlebovirus genus.
• Within the same family as alphaviruses, rubella virus has a divergent class II fold.
• Pestiviruses, although they are Flaviviridae, have fusion proteins from a novel class.
• Viral class II proteins may originate from cellular class II fusion protein ancestors.

Enveloped viruses must fuse their lipid membrane to a cellular membrane to deliver the viral genome into the cytoplasm for replication. Viral envelope proteins catalyze this critical membrane fusion event. They fall into at least three distinct structural classes. Class II fusion proteins have a conserved three-domain architecture and are found in many important viral pathogens. Until 2013, class II proteins had only been found in flaviviruses and alphaviruses. However, in 2013 a class II fusion protein was discovered in the unrelated phlebovirus genus, and two unexpectedly divergent envelope proteins were identified in families that also contain prototypical class II proteins. The structural relationships of newly identified class II proteins, reviewed herein, shift the paradigm for how these proteins evolved.

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