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Review
. 2002:56:677-702.
doi: 10.1146/annurev.micro.56.012302.160757. Epub 2002 Jan 30.

Poliovirus cell entry: common structural themes in viral cell entry pathways

James M Hogle  1
Affiliations
Review

Poliovirus cell entry: common structural themes in viral cell entry pathways

James M Hogle. Annu Rev Microbiol. 2002.

Abstract

Structural studies of polio- and closely related viruses have provided a series of snapshots along their cell entry pathways. Based on the structures and related kinetic, biochemical, and genetic studies, we have proposed a model for the cell entry pathway for polio- and closely related viruses. In this model a maturation cleavage of a capsid protein precursor locks the virus in a metastable state, and the receptor acts like a transition-state catalyst to overcome an energy barrier and release the mature virion from the metastable state. This initiates a series of conformational changes that allow the virus to attach to membranes, form a pore, and finally release its RNA genome into the cytoplasm. This model has striking parallels with emerging models for the maturation and cell entry of more complex enveloped viruses such as influenza virus and HIV.

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Figures

Figure 1
Figure 1
Structural changes on maturation and acidification of the influenza A virus hemagglutinin. The hemagglutinin is a homotrimer. (a) The monomer is initially synthesized as a single chain HA0.(b)HA0 is subsequently processed late in assembly to form two chains, HA1 (blue) and HA2 (red). (c) Upon acidification in early endosomes during entry, HA undergoes a significant conformational alteration to a fusogenic form. The newly generated amino terminus of HA2 (yellow) facilitates fusion and is called the fusion peptide. In HA0 the fusion peptide is in an exposed loop near the base of the molecule (indicated by the 1 in Figure 1a). (b) In the mature HA the fusion peptide is buried. The fusion peptide is located near the bottom of the molecule, which would be close to the viral membrane, and some 100Å away from the receptor-binding site (indicated by 2 in Figure 1b). In the fusogenic form (c) the fusion peptide and the C terminus of HA2 (which anchors the molecule in the viral membrane) and the fusion peptide (which is believed to insert into the cell membrane) are both near the top of the molecule. This would bring the viral membrane and cell membrane into close proximity. Figure reproduced from Skehel & Wiley (100), with permission.
Figure 2
Figure 2
The life cycle of poliovirus and related picornaviruses. Infection is initiated by attachment to receptor, which induces conformational changes in the virus that facilitate translocation of the viral RNA into the cytoplasm where it is replicated to yield progeny RNAs and translated to yield viral proteins. Translation produces a long polyprotein that is processed by viral proteases. Assembly of the virus is linked to processing of the polyprotein and proceeds through a series of intermediates including a protomer, a pentamer, an empty capsid, a provirion, and ultimately the virus. Adapted from Principles of Virology, (S.J. Flint, V.R. Racaniello, L.W. Enquist, A.M. Skalka, & R.M. Krug) with permission.
Figure 3
Figure 3
The structure of poliovirus. The virion is composed of 60 copies of 4 proteins, VP1, VP2, VP3, and VP4, arranged on an icosahedral surface. (a) A cartoon representation of the core structure eight-stranded beta-sandwich that is shared by VP1, VP2, and VP3 and the capsid proteins of a number of other icosahedral viruses. (b-d) Ribbon diagrams of VP1, VP2, and VP3 showing the common beta-sandwich core and the unique loops and terminal extensions of each of the subunits. The N-terminal extensions of VP1 and VP3 have been truncated for clarity. (e) An icosahedral framework showing the organization of VP1, VP2, and VP3 with respect to the symmetry axes of the particle. (f) A ribbon diagram representation of a single protomer arranged on a portion of the icosahedral framework, showing VP1 (blue), VP2 (yellow), VP3 (red), and VP4 (green). A fatty acid-like molecule, here modeled as a sphingosine (magenta), binds in the hydrophobic core of VP1.
Figure 4
Figure 4
Radial depth cued view of the surface of poliovirus. The virus has been colored based on the distance of individual atoms from the center of the particle, with atoms closest to the center being dark and those furthest from the center being white. Note the star-shaped mesas at the fivefold axes, the three-bladed propellers at the threefold axes, and the deep canyon that separates the star-shaped mesas from the nearest blades of the propellers.
Figure 5
Figure 5
Network formed by the interaction of VP4 and the N-terminal extensions of VP1, VP2, and VP3 on the inner surface of the protein shell. (a) The network is viewed from the inside looking out. Only the VP4 (green) and N-terminal extensions of VP1 (blue), VP2 (yellow), and VP3 (red) are shown. Note the extensive interactions linking all portions of the structure. (b) A cutaway closeup of a plug formed by the N terminus of VP3 (red) and the N terminus of VP4 (green) that blocks otherwise open channels at the fivefold axes of the viral particle. In this view the inside of the virus is down and the outside is up. Two copies of VP1 flanking one such channel are shown in blue.
Figure 6
Figure 6
Changes on the inner network that occur upon cleavage of VP0. In these panels the view is from the inside of the particle. VP4 (green) and the N-terminal extensions of VP1 (blue), VP2 (yellow), and VP3 (red) are shown as tubes with the bodies of the subunits shown as either (a, b) opaque surfaces or (c) translucent surfaces. (a) The network in the mature virion. The N terminus of VP2 and the C terminus of VP4 (generated by the cleavage of VP0) are indicated by an arrow. (b) The network in the 75S particle prior to VP0 cleavage. The entire N-terminal extension of VP1 and the C terminus of VP4 are disordered, and the N-terminal extension of VP2 is either disordered or rearranged. Only the N-terminal extension of VP3 is intact. The peptide containing the scissile bond of VP0 (green) runs across the bottom center of the panel. The scissile bond is indicated by the arrow. Note that this peptide blocks access of the N-terminal extension of VP1 and the C terminus of VP4 from the site they occupy in the mature virion, and thus prevents the formation of the mature network. (c) A stereo view of the pocket in the inner surface where critical portions of the N terminus of VP1 and the C terminus of VP4 bind in the mature virus. Mutations in these residues suggest that the formation of this portion of the network (which extends otherwise tenuous interactions between VP2 and VP3 within a protomer) is important to viral stability.
Figure 7
Figure 7
The virus-receptor complex. (a) Image reconstruction of the complex between poliovirus and its receptor Pvr. The portion of the reconstruction belonging to the virus is colored red, the remaining surface, which represents the receptor, is blue. There is compelling density for all three Ig-like domains of the receptor. Prominent arms on the density of the middle domain correspond to glycosylation sites. (b) A “roadmap” representation of the footprint of Pvr on the viral surface. A single icosahedral asymmetric unit is shown. The roadmap is color-coded by the distance of residues from the center of the particle with residues closest to the center in blue and those farthest from the center in red. The footprint is in white.(c) A cartoon showing how receptor binding would orient the virus with respect to the cell membrane. Note that the geometry of receptor binding observed in the complex would bring a particle fivefold axis (line with pentagon) in close proximity to the cell membrane. (d) A homology model for Pvr and the atomic model for the virus have been fit to the image reconstruction. Note the good fit to the density, including the fit of a model for glycosylation sites on the second domain to the prominent arms of the receptor reconstruction.
Figure 8
Figure 8
The structures of cell entry intermediates. (a) Models for the virus, (b) the A or 135S particle, and (c) the 80S empty particle have been fit to the reconstruction density, by treating the cores of VP1 (blue), VP2 (yellow), and VP3 (red) as rigid bodies. Note that all three reconstructions contain clear density for the plug formed by the VP3 beta-tube (red, indicated by red arrow). The particle fivefold axes (line with pentagon) and threefold axes (line with triangle) are indicated in each panel. (d) Stereo representations of simplified models for VP1, VP2, and VP3 in the virion (purple), the A particle (green), and the 80S particle (magenta), showing the movement of the proteins during the structural transitions. Umbrella-like motions of the subunits with VP1 pivoting about the fivefold axes and VP2 and VP3 pivoting about the threefold axes produce a flattened appearance of the model in the A or (b) 135S particle. This flattening results in a more angular appearance to the A particle than is readily apparent in reconstruction and in the original micrographs. Reproduced from (9) with permission.
Figure 9
Figure 9
A cartoon representation of a working model for the cell entry mechanism of polio- and related viruses. (a) The virus attaches to the receptor on the membrane of a cell to form an initial complex. The three domains of the receptor are shown in pink with the transmembrane helices (black) anchored in the membrane. The body of the virus is in blue, with the pocket factor in black. The N-terminal extension of VP1 is cyan, the VP3 plug is red, VP4 is green, the myristate is black, and the viral RNA is orange. (b) At physiological temperatures the receptor induces a subtle conformational change that opens the receptor-binding site and presumably displaces the pocket factor to produce a tight-binding complex. (c) The virus undergoes conformational rearrangements that result in the insertion of the amphipathic helices of the N terminus of VP1 (black spirals) and the myristate group of VP4 into the membrane to form a channel. (d) A trigger (perhaps fluxes in Ca+2 concentration) results in the expansion of the particle, the expansion of the pore to form a channel, the temporary removal of the VP3 plug, and the release of the viral RNA into the cell.
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