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Review
. 2015 May:479-480:518-31.
doi: 10.1016/j.virol.2015.02.037. Epub 2015 Mar 12.

Timing is everything: Fine-tuned molecular machines orchestrate paramyxovirus entry

Sayantan Bose  1 , Theodore S Jardetzky  2 , Robert A Lamb  3
Affiliations
Review

Timing is everything: Fine-tuned molecular machines orchestrate paramyxovirus entry

Sayantan Bose et al. Virology. 2015 May.

Abstract

The Paramyxoviridae include some of the great and ubiquitous disease-causing viruses of humans and animals. In most paramyxoviruses, two viral membrane glycoproteins, fusion protein (F) and receptor binding protein (HN, H or G) mediate a concerted process of recognition of host cell surface molecules followed by fusion of viral and cellular membranes, resulting in viral nucleocapsid entry into the cytoplasm. The interactions between the F and HN, H or G viral glycoproteins and host molecules are critical in determining host range, virulence and spread of these viruses. Recently, atomic structures, together with biochemical and biophysical studies, have provided major insights into how these two viral glycoproteins successfully interact with host receptors on cellular membranes and initiate the membrane fusion process to gain entry into cells. These studies highlight the conserved core mechanisms of paramyxovirus entry that provide the fundamental basis for rational anti-viral drug design and vaccine development.

Keywords: Atomic structure of viral glycoproteins; Fusion protein; Membrane fusion; Membrane glycoproteins; Paramyxovirus entry; Viral envelope proteins; Viral receptors.

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Figures

Fig. 1
Fig. 1
Family Paramyxoviridae. Classification of viruses in the family Paramyxoviridae, showing subfamilies – Paramyxovirinae and Pneumovirinae, along with the various genera and representative examples of each genus.
Fig. 2
Fig. 2
The fusion proteins of paramyxoviruses mediate merger of viral and cellular envelopes through molecular refolding. (A–B) Atomic resolution structures of paramyxovirus F proteins in their prefusion forms, (A) RSV F (PDB ID: 4JHW), B) PIV5 F (PDB ID: 2B9B). The fusion protein domains are colored as follows: domain I, yellow; domain II, red; domain III, purple; fusion peptide, pink; HRB domain, blue. C) Schematic model depicting proposed rearrangements of the activated prefusion F proteins leading to fusion peptide insertion in the target membrane and refolding into a post-fusion form through a series of intermediates, eventually causing membrane merger. (D–F) Atomic resolution structures of paramyxovirus F proteins in their post-fusion forms, (D) RSV F (PDB ID: 3RRT), (E) hPIV3 F (PDB ID: 1ZTM) and (F) NDV F (PDB ID: 3MAW). In addition to the color-coding scheme described above, the HRA domain is colored green for (C–F). (G) Surface representation of the PIV5 F prefusion trimer (PDB ID: 2B9B) showing the potential areas of attachment protein interaction. Positions of mutations in the Ig-like domain and the adjoining hydrophobic cavity and the bordering flexible strap are shown. Various colors mark the residues that are important for interaction of PIV5 F with PIV5 HN (cyan) or MeV F and MeV H (black) (based on sequence alignment) or residues that affect both PIV5 F/HN and CDV F/H interactions (based on sequence alignment) (green) or residues that affect both MeV F/H and PIV5 F/HN interactions (slate) or those that align for all the three F proteins above and disrupt all three pairs of F–HN or F–H interactions (silver). (H) Cartoon depiction of the PIV5 F structure showing the ‘strap’ region composed of beta sheets. The protomers of the F are colored variously. The most dynamic peptides identified by FPOP labeling during the process of F-refolding are marked in red. A region of the strap responsible for transfer of HN specificity between closely related paramyxoviruses is shown in blue. Point mutations that destabilize PIV5 F (green) or MeV F (pink) or CDV F (yellow) are located on this ‘strap’ region or within the adjoining hydrophobic cavity at the junction of two protomers of F.
Fig. 3
Fig. 3
Various observed arrangements of paramyxovirus HN proteins in X-ray crystal atomic structures suggest a molecular mechanism of activation of the fusion protein. (A) NDV HN ‘4 heads down’ arrangement (PDB ID: 3T1E), (B) PIV5 HN ‘2 heads up-2 heads down arrangement (PDB ID: 4JF7) and (C) PIV5 HN receptor binding domains in a ‘4 heads up arrangement’ (PDB ID 1Z4X) placed with respect to the PIV5 HN stalk 4HB domain (PDB ID: 3TSI). (D–E) Variations in interaction surfaces between the globular head domains and the stalk 4HB domains of (D) NDV HN (PDB ID: 3T1E) and (E) PIV5 HN (PDB ID: 4JF7). The respective F-activation domains on the two stalk 4HBs are highlighted in red. The single charged residue that determines specificity between Rubulaviruses is highlighted in blue on the PIV5 HN stalk. (F) Images reconstructed from X-ray crystal structures by aligning the PIV5 HN stalk structure (PDB ID: 3TSI) with the PIV5 HN 4-heads up structure (PDB ID 1Z4X). The 20 ectodomain residues missing from the PIV5-HN stalk structure have been replaced by dotted lines. Cleaved PIV5 F-GCNt (PDB ID: 4GIP) is modeled next to the constructed PIV5 HN ‘4 heads up’ conformation described above to indicate the approximate relative heights of the interacting surfaces of the two glycoproteins.
Fig. 4
Fig. 4
(A–C) Models of receptor-dependent fusion activation for paramyxoviruses of the Paramyxovirinae subfamily. Structural and functional data indicate that the HN, H or G attachment proteins (yellow) of this subfamily are structurally related and have a globular, C-terminal receptor-binding domain (head) that can interact with various types of host receptors, through receptor binding-sites in the globular heads (blue rings). Putative regions of F-interaction on HN, H or G proteins are indicated on the stalk domains in red. The F proteins (purple) fold into a functional, prefusion state in the presence or absence of the attachment proteins, but without requiring the attachment protein as a stabilizing ‘clamp’. The F proteins are cleaved by proteases to release a hydrophobic fusion peptide (light blue). The HRA domain of F, which refolds into elongated helices post triggering is shown in dark green. (A) F and HN proteins are transported individually to the cell surface and biochemical data suggests that the F–HN interaction is transient. Receptor binding by HN heads results in stalk exposure and possibly a ‘induced fit’ mechanism between the F protein head and the exposed F-activating region on the HN stalk that triggers F to undergo refolding. (B) In morbilliviruses, where F and H are intimately associated in fusion complexes during cellular transport, it has been proposed that the H globular head domains maintain the stalk domains in a ‘pre-triggering’ conformation, possibly through H head-stalk contacts. Stalk exposure, coupled with release of the stalk domains from the globular heads, allows the F protein to mediate productive interaction with the F-activating regions of the H stalk. (C) In Henipaviruses, the initial F–G interaction may be mediated through F interacting with the globular head domains of G or the C-terminal upper portion of the G stalk, which prevents premature F activation during cellular transport within F–G complexes. Stalk exposure and a switch of binding interfaces, allows F to undergo productive interaction with the exposed F-activating domains in the G stalk and be triggered to undergo refolding. (D) For Pneumovirinae, the mechanism of F triggering is yet unclear and it is likely that the distinct G protein does not play a role in this process. The F protein is believed to bind specifically to cellular receptors through binding sites in the F globular head (white ring) and the timing of F-cleavage by both cellular and extracellular proteases is believed to play a role in the triggering process for some of the Pneumovirinae.
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References

    1. Adamson P., Thammawat S., Muchondo G., Sadlon T., Gordon D. Diversity in glycosaminoglycan binding amongst hMPV G protein lineages. Viruses. 2012;4:3785–3803. - PMC - PubMed
    1. Ader N., Brindley M., Avila M., Orvell C., Horvat B., Hiltensperger G., Schneider-Schaulies J., Vandevelde M., Zurbriggen A., Plemper R.K., Plattet P. Mechanism for active membrane fusion triggering by morbillivirus attachment protein. J. Virol. 2013;87:314–326. - PMC - PubMed
    1. Ader N., Brindley M.A., Avila M., Origgi F.C., Langedijk J., Orvell C., Vandevelde M., Zurbriggen A., Plemper R.K., Plattet P. Structural rearrangements of the central region of the morbillivirus attachment protein stalk domain trigger F protein refolding for membrane fusion. J. Biol. Chem. 2012;287:16324–16334. - PMC - PubMed
    1. Aguilar H.C., Ataman Z.A., Aspericueta V., Fang A.Q., Stroud M., Negrete O.A., Kammerer R.A., Lee B. A novel receptor-induced activation site in the Nipah virus attachment glycoprotein (G) involved in triggering the fusion glycoprotein (F) J. Biol. Chem. 2009;284:1628–1635. - PMC - PubMed
    1. Aguilar H.C., Matreyek K.A., Filone C.M., Hashimi S.T., Levroney E.L., Negrete O.A., Betrolotti-Ciarlet A., Choi D.Y., McHardy I., Fulcher J.A., Su S.V., Wolf M.C., Kohatsu L., Baum L.G., Lee B. N-glycans on Nipah virus fusion protein protect against neutralization but reduce membrane fusion and viral entry. J. Virol. 2006;80:4878–4889. - PMC - PubMed

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