Structure of the parainfluenza virus 5 F protein in its metastable, prefusion conformation

Abstract

Enveloped viruses have evolved complex glycoprotein machinery that drives the fusion of viral and cellular membranes, permitting entry of the viral genome into the cell. For the paramyxoviruses, the fusion (F) protein catalyses this membrane merger and entry step, and it has been postulated that the F protein undergoes complex refolding during this process. Here we report the crystal structure of the parainfluenza virus 5 F protein in its prefusion conformation, stabilized by the addition of a carboxy-terminal trimerization domain. The structure of the F protein shows that there are profound conformational differences between the pre- and postfusion states, involving transformations in secondary and tertiary structure. The positions and structural transitions of key parts of the fusion machinery, including the hydrophobic fusion peptide and two helical heptad repeat regions, clarify the mechanism of membrane fusion mediated by the F protein.

Supplementary information

The online version of this article (doi:10.1038/nature04322) contains supplementary material, which is available to authorized users.

Viral membrane fusion

Infection of a cell by enveloped viruses such as influenza, HIV and paramyxoviruses requires the fusion of viral and cellular membranes. Many of the viral proteins involved in this process are highly specialized. At first they adopt a metastable shape that stores the energy needed for entry into cells, then irreversible changes in the protein shape catalyse membrane fusion. The crystal structure of pre-fusion parainfluenza virus 5 F fusion protein has now been determined. The extensive differences between pre- and post-fusion states reveal details of the mechanism of membrane fusion which could be of value for developing novel approaches to preventing viral infections.

Supplementary information

The online version of this article (doi:10.1038/nature04322) contains supplementary material, which is available to authorized users.