Viruses and sialic acids: rules of engagement

Abstract

Viral infections are initiated by specific attachment of a virus particle to receptors at the surface of the host cell. For many viruses, these receptors are glycans that are linked to either a protein or a lipid. Glycans terminating in sialic acid and its derivatives serve as receptors for a large number of viruses, including several human pathogens. In combination with glycan array analyses, structural analyses of complexes of viruses with sialylated oligosaccharides have provided insights into the parameters that underlie each interaction. Here, we compare the currently available structural data on viral attachment proteins in complex with sialic acid and its variants. The objective is to define common parameters of recognition and to provide a platform for understanding the determinants of specificity. This information could be of use for the prediction of the location of sialic acid binding sites in viruses for which structural information is still lacking. An improved understanding of the principles that govern the recognition of sialic acid and sialylated oligosaccharides would also advance efforts to develop efficient antiviral agents.

Figure 1

Interactions of viral attachment proteins with terminal Neu5Ac. (a) Contacts of viral proteins with terminal Neu5Ac. The complex structures shown in panels (b–k) were superposed using the terminal sialic acid residues. The Neu5Ac residues are shown in stick representation, with carbons colored orange, oxygens red, and nitrogens blue. All protein atoms within a 4.0 Å radius of Neu5Ac atoms are displayed as spheres and colored according to the color code depicted in panels (b–k). Hydrogen bonds and salt bridges are represented with black and red dashed lines, respectively. (b–k) Neu5Ac binding sites of Polyoma VP1 (b, pdb 1VPS [29]), Ad37 fiber knob (c, pdb 3N0I [7]), cAd2 fiber knob (d, pdb 2WBV [39]), JCV VP1 (e, pdb 3NXD [8]), SV40 VP1 (f, pdb 3BWR [13]), NDV HN (g, pdb 1USR [31]), Reovirus σ1 (h, pdb 3S6X [41]), Rhesus Rotavirus VP8* (i, pdb 1KQR [30]), Influenza A HA (j, 1HGG [26]), and Influenza B HA (k, pdb 2RFT [34]). In all cases, Neu5Ac is shown in stick representation and colored as in panel (a). The protein surfaces are colored gray, with residues interacting with Neu5Ac shown in stick representation and colored by element. Protein atoms within a 4.0 Å radius around Neu5Ac are highlighted with colored spheres. In cases where the Neu5Ac binding site is formed by two protein chains, one of the chains is denoted with an asterisk.

Figure 2

Interactions of viral attachment proteins with O-acetylated Neu5Ac. (a) Contacts of viral proteins with terminal O-acetylated Neu5Ac. Complex structures were superposed on the terminal substituted Neu5Ac. Interacting protein atoms as well as hydrogen bonds and salt bridges are shown as in Figure 1a. Top view of O-acetylated (b) and unsubstituted (c) Neu5Ac, with contacting protein atoms shown as colored spheres. The views are rotated from those in Figure 1 and (a) by two 90° rotations, one around a horizontal and one around a vertical axis. (d–g) Binding sites for O-acetylated Neu5Ac in Influenza C HEF (d) [27], BCoV HE (e, pdb 3CL5 [35]), PToV HE (f, pdb 3I27 [36]) and BToV HE (g, pdb 3I1L [36]). The structures are displayed as in Figure 1b–k.

Figure 3

Different sialic acid and context specificity of SV40 and JCV VP1. (a) JCV VP1 in complex with LSTc oligosaccharide. (b) SV40 VP1 in complex with GM1 oligosaccharide. The oligosaccharides are shown in stick representation and colored by element, with oxygens in red and nitrogens in blue. Monosaccharides that approach the protein closer than 4.0 Å are colored in bright orange, while those not contacting the protein are colored gray. Oligosaccharide atoms within a 4.0 Å radius around the proteins are highlighted as spheres. The protein surface is shown in gray. Residues that define the different oligosaccharide specificities of the two proteins are shown as sticks and colored blue and pink for SV40 and JCV VP1, respectively. Residues from a different polypeptide chain are denoted with an asterisk.

Figure 4

Binding of GD1a glycan to the Ad37 fiber knob protein. (a) Structure of Ad37 fiber knob in complex with the GD1a oligosaccharide [7]. The three different Ad37 fiber knob protomers are shown in surface representation and are colored gray, light red and blue. The GD1a glycan is drawn in stick representation, with both Neu5Ac residues highlighted in color (carbons in orange, oxygens in red and nitrogens in blue). The bridging glycan residues are shown in dark gray. The third binding site (marked by ‘X’) is blocked due to crystal contacts. The arrow indicates the viewing direction shown in panel (b). (b) Interactions between Ad37 fiber knob residues and GD1a. Two different Ad37 fiber knob protomers are shown in transparent surface representation (white and light red). The third protomer is not shown for clarity. Ad37 residues contacting GD1a are shown in stick representation, with oxygens in red and nitrogens in blue. The GD1a glycan is shown in stick representation, with both terminal Neu5Ac residues highlighted in color (carbons in orange, oxygens in red and nitrogens in blue). The bridging glycan residues are shown in gray. Glycan atoms within a distance of 4 Å to Ad37 protein atoms are drawn as spheres. Hydrogen bonds to GD1a glycan are represented with black dashes. Residues from different protomers are denoted with an asterisk.