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Review
. 2013:372:83-104.
doi: 10.1007/978-3-642-38919-1_4.

Structure and function of respiratory syncytial virus surface glycoproteins

Jason S McLellan  1 , William C Ray, Mark E Peeples
Affiliations
Review

Structure and function of respiratory syncytial virus surface glycoproteins

Jason S McLellan et al. Curr Top Microbiol Immunol. 2013.

Abstract

The two major glycoproteins on the surface of the respiratory syncytial virus (RSV) virion, the attachment glycoprotein (G) and the fusion glycoprotein (F), control the initial phases of infection. G targets the ciliated cells of the airways, and F causes the virion membrane to fuse with the target cell membrane. The F protein is the major target for antiviral drug development, and both G and F glycoproteins are the antigens targeted by neutralizing antibodies induced by infection. In this chapter, we review the structure and function of the RSV surface glycoproteins, including recent X-ray crystallographic data of the F glycoprotein in its pre- and postfusion conformations, and discuss how this information informs antigen selection and vaccine development.

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Figures

Figure 1
Figure 1. Refolding the F protein to initiate fusion
In the prefusion form of the F1 protein the fusion peptide (FP) at the N terminus of F1 (turquoise) is followed by 4 short α-helices (blue) connected by 3 non-helical peptides. Triggering causes these non-helical connecting peptides to refold into α-helices, completing a single long HRA α-helix that thrusts the FP into the target cell membrane. The long HRA α-helices trimerize, the molecule folds in half, and the HRB α-helices (red) insert into the grooves between the HRA units forming a stable 6-helix bundle (6HB). As a result, the virion and cell membranes are brought together and initiate membrane fusion. The central region of the F protein does not rearrange during triggering and refolding and, therefore, is not represented here. It would be positioned at the bend in the molecule.
Figure 2
Figure 2. Crystal structures of RSV F in pre- and postfusion conformations
Binding of antibody D25 locks the F glycoprotein in the prefusion conformation. Two of the prefusion F protomers are shown in surface representation and colored pink and green, while the third protomer is shown as ribbons colored blue to red, from the N-terminus of F2 to the C-terminus of F1, respectively. Three D25 Fabs are shown, with the heavy chain colored dark red and the light chain colored white. The Fab shown as ribbons is bound primarily to the F protomer shown as ribbons, while the other two Fabs are shown in surface representation. The two middle images show a pre- and postfusion protomer in ribbons, with labeled secondary structure elements. Antigenic sites Ø, I, II and IV are labeled.
Figure 3
Figure 3. Schematic of the RSV G protein
The RSV A2 strain G protein is 298 amino acids long and consists of two heavily glycosylated mucin-like regions, separated by a central conserved, unglycosylated cysteine noose (yellow-green loop at the top) that is stabilized by a pair of disulfide bonds. The unglycosylated N terminus includes the cytoplasmic and transmembrane domains (blue). To approximate the structure, a linear α-helical prototype of the G protein was subjected to steered molecular dynamics (NAMD), pulling the central noose perpendicular to the backbone until mucin-like region 1 (green) and 2 (orange) arrived in a near-parallel arrangement. This simulation resulted in the loss of α-helical structure over much of each mucin domain, primarily due to the abundant prolines, without affecting the helical structure in the TM and N-terminal domains. Complex glycans were positioned at each of the 4 N-linked sites (yellow side chains), and simple glycans (grey) were positioned at each O-linked site predicted by NetOGlyc3.1. The glycans in this representation have slightly higher-than-biological mass to reflect the probable space they would occupy.
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