Key Points Enveloped animal viruses deliver their genetic contents into host cells by a fusion reaction between the virus membrane, which is derived from the host-cell membrane during virus budding, and the host-cell membrane. Studying the molecular mechanisms of virus membrane-fusion reactions is important, as they are paradigms for cellular membrane-fusion reactions and potential targets for antiviral therapies. The fusion reactions are driven by virus membrane-fusion proteins, which undergo a major conformational change that is triggered by interactions with the target cell. Currently, two classes of virus membrane-fusion proteins are known — class I and class II. Class I proteins have been well characterized and refold to a hairpin conformation that drives membrane fusion. The class II membrane-fusion proteins are considered in detail, using the E1 protein of the alphavirus Semliki Forest virus (SFV) and the E protein of the flavivirus tick-borne encephalitis virus (TBE) as examples. In spite of the lack of any detectable amino-acid-sequence similarity, the ectodomains of the alphavirus (E1) and flavivirus (E) fusion proteins have remarkably similar secondary and tertiary structures. Both proteins fold co-translationally with a companion protein, p62 and prM, respectively. One important difference between the viruses is that different budding sites are used — new alphavirus virions bud from the plasma membrane, whereas flavivirus particles bud into the endoplasmic reticulum as immature virions, which are then transported via the exocytic pathway. The structure of the E1 and E proteins is considered in detail, as are the conformational changes that occur during target-membrane insertion and fusion. Unlike class I fusion proteins, which are already in trimeric form before fusion, class II proteins are dimers that must rearrange during fusion to form a stable membrane-inserted homotrimer. However, despite the fact that class I and class II proteins have very different structures, both classes refold during fusion to give a similar overall 'hairpin' conformation. Evidence suggests that class II trimers interact cooperatively during membrane insertion and fusion. A model for five-fold interactions at the fusion site, including the formation of a transient hemifusion intermediate, is proposed. It is likely that class I and II fusion proteins use the same overall mechanism, suggesting that there could be a universal mechanism of membrane fusion. The possibility that there could be further classes of membrane-fusion proteins in addition to class I and class II is discussed.
