Rubella virus, the cause of the childhood disease measles, remains a serious health problem in developing countries despite an available and efficient vaccine.
The main vaccine target, which the host immune system recognises, is a viral surface protein called E1. This protein sits in the membranous coat covering the virus (known as viral envelope) and facilitates fusion between virus and cell membranes – the first step in viral entry into a host cell. Recently the structure of this protein has been determined, providing insight into what makes the Rubella vaccine so effective.
In order to find this structure, part of the E1 protein was purified and visualized using X-ray diffraction – a technique that can be used to generate atom-scale models of proteins. Interestingly, the researchers found that while this protein forms trimers (groups of three) in a solution, it arranges into a very organized hexagonal pattern on the surface of spherical membrane bilayers (called liposomes). This hexagon organization is very similar to the envelope protein arrangements seen in other virus families – including both the closely related alphaviruses and more distantly related flaviviruses. In fact – while the individual amino acids making up these envelope proteins vary between these virus families, the overall structures are similar. Surprisingly, the differences in structure were greatest between Rubella and the alphaviruses, despite their taxonomic closeness. The authors speculate that this counterintuitive finding might be due to a difference in the host range of the viruses. Alphaviruses and flaviviruses are transmitted by arthropods (i.e. they are arthropod-borne ‘arboviruses’), replicating alternately in vertebrates and insects, whereas rubella virus is strictly limited to humans. In the end this adaptation to two very different hosts would considerably constrain the evolution of the E1 fusion protein given its critical role in the virus life cycle. Additionally, Rubella virus appears to contain a metal binding site within its E1 protein; while common in cellular proteins, this property is so far unique among viruses.
In addition to these evolutionary insights, the E1 structural data suggest that the primary Rubella epitope – the site most commonly recognised by the antibodies within a vaccine – is located at the E1 trimer interface. This means that, once an antibody binds here, subsequent fusion with the cellular membranes and entry into cells would be prevented. This site is therefore an exciting target for the development of antiviral drugs, which could be used to contain Rubella outbreaks in regions where vaccination programmes are limited.
DuBois RM, et al. (2013) Functional and evolutionary insight from the crystal structure of rubella virus protein E1. Nature 493(7433):552–556