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Review
. 2006 Jan 5;344(1):30-7.
doi: 10.1016/j.virol.2005.09.007.

Paramyxovirus membrane fusion: lessons from the F and HN atomic structures

Robert A Lamb  1 , Reay G Paterson, Theodore S Jardetzky
Affiliations
Review

Paramyxovirus membrane fusion: lessons from the F and HN atomic structures

Robert A Lamb et al. Virology. .

Abstract

Paramyxoviruses enter cells by fusion of their lipid envelope with the target cell plasma membrane. Fusion of the viral membrane with the plasma membrane allows entry of the viral genome into the cytoplasm. For paramyxoviruses, membrane fusion occurs at neutral pH, but the trigger mechanism that controls the viral entry machinery such that it occurs at the right time and in the right place remains to be elucidated. Two viral glycoproteins are key to the infection process-an attachment protein that varies among different paramyxoviruses and the fusion (F) protein, which is found in all paramyxoviruses. For many of the paramyxoviruses (parainfluenza viruses 1-5, mumps virus, Newcastle disease virus and others), the attachment protein is the hemagglutinin/neuraminidase (HN) protein. In the last 5 years, atomic structures of paramyxovirus F and HN proteins have been reported. The knowledge gained from these structures towards understanding the mechanism of viral membrane fusion is described.

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Figures

Fig. 1
Fig. 1
The paramyxovirus fusion protein and class I fusion protein core trimers. (A) Cleavage activation of a prototypical paramyxovirus F protein from parainfluenza virus 5 (PIV5). The position of the signal sequence, the TM domain, the cleavage site, the hydrophobic fusion peptide and the heptad repeats A and B are indicated. 252 amino acid residues separate the two heptad repeats. (B) Similar hairpin structures are formed by fragments of the membrane-anchored polypeptides of the fusion proteins from different viruses. (Modified from Baker et al., 1999.)
Fig. 2
Fig. 2
The N-1 and C-1 peptides inhibit fusion in a temporal manner. CV-1 cells coexpressing PIV5 HN and F protein (FR3) mutated at the cleavage site to prevent intracellular cleavage, were incubated with TPCK-trypsin for 1 h to cleave the F0 precursor to the F1 and F2 subunits. RBCs colabeled with octadecyl rhodamine (R18) (red) and carboxyfluorescein (CF) (green) were bound to the CV-1 cells at 4 °C for 1 h. The samples were incubated at 37 °C for 10 min, reincubated at 4 °C and analyzed for dye transfer by confocal microscopy. Either the N-1 or C-1 peptides were incubated with the samples at the following stages of the assay: (A) no peptide at any stage; (B) peptide before and after cleavage; (C) peptide during RBC binding at 4 °C and (D) peptide during the 37 °C incubation. The samples were washed three times with PBS between each stage. The peptide concentrations were 40 μM. (From Russell et al., 2001 with permission.)
Fig. 3
Fig. 3
Mutants in the PIV5 C-1 extended chain region that pack into the core trimer have little effect on 6-helix bundle stability but have dramatic effects on fusion activation. (A) Schematic diagram of the paramyxovirus fusion (F) protein. The positions of the fusion peptide (FP), HRA (residues 129–184), β-barrel domain (β-barrel), immunoglobin-like domain (Ig-like), HRB (residues 449–477) and TM domain are shown. The locations of the N-1 and C-1 peptides from PIV5 F are indicated. The asterisks denote PIV5 residues P22 and P443 and the NDV mutant L289A which have been implicated previously in HN-independent fusion. (Ito et al., 2000, Paterson et al., 2000, Sergel et al., 2000) (B) Sequence alignment of the N-1 and C-1 peptides derived from PIV5 F with the corresponding residues of F proteins from other paramyxovirus genera. HRSV, human respiratory syncytial virus. The asterisks denote the PIV5 N-1 cavity residues, the C-1 cavity-binding residues L447 and I449 and residue 443 that has a hyperactive fusion phenotype when mutated to a proline residue. (C) High-resolution structure of the PIV5 6-helix bundle (6HB) (Baker et al., 1999). The core N-1 trimer is depicted in a surface representation colored by surface curvature and the antiparallel C-1 monomers are depicted by coil representations (magenta). (D) The packing of L447 and I449 into the hydrophobic N-1 cavity. Three N-1 (green) and one C-1 (magenta) chains are depicted by coil representations. (From Russell et al., 2003 with permission.)
Fig. 4
Fig. 4
Model showing the steps for paramyxovirus F protein fusion conformation changes causing virus–cell fusion. See text for a full description. (From Russell et al., 2003 with permission.)
Fig. 5
Fig. 5
Structure of the hPIV3 solF0 protein. (A) Schematic of the domain structure of the hPIV3 solF0 protein. Domain regions are indicated with hPIV3 sequence numbers shown below and with colors corresponding to those used in Figs. 1B, D and E. (B) Ribbon diagram of the hPIV3 solF0 trimer. The three chains are colored similarly from blue (N-terminus) to red (C-terminus). Residues 95–135 are disordered in all chains. Residue 94 is labeled in one chain and residues 136–140 at the base of the stalk are ordered in one chain due to crystal packing interactions. (C) Surface representation of the solF0 trimer. Each chain is a different color and Domains I–III and HRB for one chain (yellow) are indicated by the DI, DII, DIII and HRB labels. One radial channel is readily apparent below Domain I and II of the yellow chain and above Domain III of the red chain. (D) Ribbon diagram of the solF0 protein monomer colored by domain. The direct distance within one monomer between residue 94 at the end of HRC and residue 142 at the base of the stalk region is 122 Å. (E) Ribbon diagram of the monomer rotated by 90°, indicating the width and height of the solF0 monomer. An arrow at the C-terminus of the HRB segment points towards the likely position of the transmembrane anchor domain that would be present in the full-length protein. (From Yin et al., 2005 with permission.)
Fig. 6
Fig. 6
Atomic structure of the PIV5 hemagglutinin-neuraminidase at 2.6 Å resolution. (A) Construct for expression of HNecto in insect cells. Downward arrows correspond to protease cleavage sites in the pBacgus-3 vector. (B) SDS-PAGE analysis of HNecto and dissolved HNecto crystals under reducing and non-reducing conditions. (C and D) Schematic cartoon showing top and side view of PIV5 HN. Helices are shown in cylinders and β-strands in arrowed belts. The N-terminus is shown in blue and the C-terminus in red. The missing loop from residues 186 to 190 is indicated as dashed blue lines. (E) PIV5 HN tetramers. Active sites are marked by space filling representations of the ligand, sialyllactose. The four subunits are shown in different colors. (Left) Top view of the PIV5 HN tetramer arrangement; (Right) side view of PIV5 HN tetramer arrangement, with a 60° packing angle between dimers. (F) Electron density observed for α2,3-sialyllactose soaked crystal at 2.5 Å resolution. (G) A model for HN tetramer rearrangement upon cell-surface receptor binding. The HN tetramer is primarily stabilized by the N-terminal stalk region and can interact with F protein. Sialic acid receptors are displayed at the cell surface, where binding of the individual HN head (neuraminidase active; NA) domains could perturb the NA tetramer arrangement, consistent with the weak interactions between NA domains. Changes in the HN NA domain tetramer could affect interactions and trigger membrane fusion. (From Yuan et al., 2005 with permission.)
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