Evidence of a novel viral membrane fusion mechanism shared by the Hepaci, Pegi and Pestiviruses

Abstract

Enveloped viruses encode specialised glycoproteins that mediate fusion of viral and host membranes. Discovery and understanding of the molecular mechanisms of fusion has been achieved through structural analyses of glycoproteins from many different viruses, and yet the fusion mechanisms of some viral genera remain unknown. We have employed systematic genome annotation and AlphaFold modelling to predict the structures of the E1E2 glycoproteins from sixty viral species in the Hepaci, Pegi and Pestivirus genera. Whilst the predicted structure of E2 varied widely, E1 exhibited a very consistent fold across genera, despite little or no homology at the sequence level. Critically, the structure of E1 is unlike any other known viral glycoprotein. This is the first evidence that the Hepaci, Pegi and Pestiviruses possess a common and novel membrane fusion mechanism. Comparison of E1E2 models from various species reveals recurrent features that are likely to be mechanistically important and sheds light on the evolution of membrane fusion in these viral genera. These findings provide new fundamental understanding of viral membrane fusion and are relevant to structure-guided vaccinology.

GB Virus B and Hepatitis C Virus, Distantly Related Hepaciviruses, Share an Entry Factor, Claudin-1

“…Unlike flavivirus entry protein E, hepaciviral E1E2 proteins are not class II membrane fusion proteins; indeed, structural analyses suggest that hepacivirus E1E2 may represent a novel class of fusion proteins ( 61 – 64 ). To this end, studying GBV-B E1E2 entry may prove to be the more facile path to deciphering the hepaciviral membrane fusion mechanism as it is structurally predicted to have fewer disordered segments than HCV E1E2 ( 65 ). Determining the hepaciviral fusion mechanism could inform structure-guided HCV vaccine design.…”

Viral Membrane Fusion: A Dance Between Proteins and Lipids

“…Hepatitis C virus (HCV) displays an E1E2 complex. While E1 has a predicted fusion peptide, it displays ( 7 ), and E1s of related viruses are predicted to contain ( 8 ), a novel fold. Moreover, HCV E2 also appears to interact with the target membrane ( 9 ).…”