Structure of the primed paramyxovirus fusion protein

Abstract

Viruses with lipid envelopes must fuse their membranes with those of host cells to transfer their genomes and initiate infection. Depending on the virus, the membrane fusion process can occur at the plasma membrane, or at intracellular membranes following the internalization of virus particles. Not surprisingly, the viral proteins responsible for membrane fusion are highly diverse, as are the mechanisms by which the fusion processes can be triggered; however, common themes have emerged as our understanding of membrane fusion has developed. In particular, an expanding repertoire of high-resolution structures of viral fusion proteins (F proteins; VFPs) in pre- and postfusion conformations has driven the field forward. From these, we know that many VFPs undergo substantial conformational changes during fusion, forming highly stable rod-like structures to draw the membranes together (1⇓–3). Despite this, for VFPs other than influenza HA (4⇓⇓–7), high-resolution structures for all three major static conformations adopted during the virus life cycle, uncleaved prefusion, primed prefusion and postfusion, have remained incomplete. These limitations have hindered our development of insights into the fusion mechanism of viruses that, unlike influenza virus, enter cells at the plasma membrane at neutral pH. In a groundbreaking report in PNAS (8), Welch et al. solve the high-resolution X-ray crystal structure of the cleaved, prefusion form of the F protein of parainfluenza virus 5 (PIV5). This alters the state of affairs by providing an essential missing link in the understanding of paramyxovirus entry. In conjunction with previous work by these laboratories (9, 10), the new structure now affords us with a complete set of all three major static conformations of paramyxovirus F proteins (Fig. 1), a tour de force representing many years of effort …