N -Glycolyl GM1 Ganglioside as a Receptor for Simian Virus 40

Abstract

Carbohydrate microarrays have emerged as powerful tools in analyses of microbe-host interactions. Using a microarray with 190 sequence-defined oligosaccharides in the form of natural glycolipids and neoglycolipids representative of diverse mammalian glycans, we examined interactions of simian virus 40 (SV40) with potential carbohydrate receptors. While the results confirmed the high specificity of SV40 for the ganglioside GM1, they also revealed that N-glycolyl GM1 ganglioside [GM1(Gc)], which is characteristic of simian species and many other nonhuman mammals, is a better ligand than the N-acetyl analog [GM1(Ac)] found in mammals, including humans. After supplementing glycolipid-deficient GM95 cells with GM1(Ac) and GM1(Gc) gangliosides and the corresponding neoglycolipids with phosphatidylethanolamine lipid groups, it was found that GM1(Gc) analogs conferred better virus binding and infectivity. Moreover, we visualized the interaction of NeuGc with VP1 protein of SV40 by molecular modeling and identified a conformation for GM1(Gc) ganglioside in complex with the virus VP1 pentamer that is compatible with its presentation as a membrane receptor. Our results open the way not only to detailed studies of SV40 infection in relation to receptor expression in host cells but also to the monitoring of changes that may occur with time in receptor usage by the virus.

Structural basis of GM1 ganglioside recognition by simian virus 40

“…There are two possible energetically favorable conformations of the CH 2 -OH group, both of which would result in additional hydrogen bond formation and stabilizing van der Waals interactions. Because these interactions would occur in a partly hydrophobic environment, they would nicely explain the observed stronger interaction between SV40 and NeuNGc-GM1 compared with NeuNAc-GM1 (16). Although it is, of course, possible that NeuNGc-GM1 and NeuNAc-GM1 have totally different modes of binding, we consider this possibility unlikely.…”

“…However, it was recently shown that SV40 binds to NeuNGc-GM1 more strongly than to NeuNAc-GM1, indicating that NeuNGc-GM1 is the natural receptor of this virus (16). The N-acetyl group of NeuNAc faces toward a deep oval cavity, which is formed by the BC1-loop of one subunit and the BC2-loop of its clockwise neighbor (Fig.…”

“…15). Both GM1 variants can serve as receptors for SV40, but the presence of NeuNGc considerably increases binding (16). Structural studies with Polyoma (17)(18)(19) reveal that the VP1 protein binds the oligosaccharide portion of gangliosides in shallow surface pockets on top of the pentamer, corresponding to the outer edge of the capsid.…”

Lipid-Mediated Endocytosis

“…In the case of SV40, it is interesting to note in this context that a single atom in the carbohydrate moiety can make a difference. Thus N-acetyl sialic acid in human GM1 provides less efficient binding to cells and less efficient infection than the N-glycolyl group present in simian GM1 (Campanero-Rhodes et al 2007). …”

“…Interestingly, the binding of cholera toxin to GM1 strongly reduces the diffusion of other lipid molecules in the same membrane (Forstner et al 2006). The binding interface between CTX and SV40 pentamers and the membrane is quite tight, with the protein surface contacting the top bilayer leaflet (Campanero-Rhodes et al 2007;Neu et al 2008). This may be important for the inclusion into membrane microdomains or for trans-bilayer coupling.…”