The structural basis of paramyxovirus invasion

Abstract

To deliver their genetic material into host cells, enveloped viruses have surface glycoproteins that actively cause the fusion of the viral and cellular membranes. Recently determined X-ray crystal structures of the paramyxovirus fusion (F) protein in its pre-fusion and post-fusion conformations reveal the dramatic structural transformation that this protein undergoes while causing membrane fusion. Conformational changes in key regions of the F protein suggest the mechanism by which the F protein is activated and refolds.

Figure 1

Schematic representation of the paramyxovirus F protein. (a) Domain structure of the F protein. The locations of domain I (yellow), domain II (brown) and domain III (pink) are shown as solid lines above the diagram. The fusion peptide (FP, green), heptad repeat A (red), heptad repeat B (blue), transmembrane domain (TM, dotted line) and cytoplasmic tail (CT, dotted line) are also shown. (b) Model of the pre-fusion structure of the PIV5 F protein. The colors of the domains and regions are the same as in (a). HRA (red) is in a spring-loaded conformation and HRB (blue) forms the coiled-coil stalk. (c) Model of the post-fusion structure of the hPIV3 F protein. In the transition between the pre-fusion and post-fusion structures, domains I and II keep the same fold but reorient within the molecule. Domain III undergoes a dramatic refolding process, which leads to the formation of the coiled-coil hairpin structure that causes membrane fusion. In panels (b) and (c), α-helices are depicted as cylinders and β-strands as colored arrows.

Figure 2

Model of the paramyxovirus-mediated membrane fusion. The F protein is thought to adopt five conformations during membrane fusion: (a) an inactive F₀ precursor protein; (b) a metastable, native conformation of the cleaved F₁+F₂ protein; (c) an early fusion intermediate in which the HRB strands open up; (d) a pre-hairpin intermediate in which HRA forms a triple-stranded coiled coil and the fusion peptide inserts into the target membrane; and (e) the fusogenic hairpin structure that actively brings together the viral and cellular membranes. Ribbon diagrams are included of the pre-fusion PIV5 F₀ protein structure [part (a), modified from [8]] and the post-fusion hPIV3 F protein structure [part (e), modified from [10]]. Conformations of the F protein that have not yet been determined at atomic resolution (b–d) are represented schematically as in Figure 1.