Murine polyomavirus (MuPyV) causes
tumors of various origins in newborn mice and hamsters.
Infection is initiated by attachment of the virus to
ganglioside receptors at the cell surface. Single
amino acid exchanges in the receptor-binding pocket of the major
capsid protein VP1 are known to drastically alter tumorigenicity and spread in closely related MuPyV strains. The virus represents a rare example of differential receptor recognition directly influencing viral pathogenicity, although the factors underlying these differences remain unclear. We performed structural and functional analyses of three MuPyV strains with strikingly different pathogenicities: the low-tumorigenicity strain RA, the high-pathogenicity strain PTA, and the rapidly growing, lethal laboratory isolate strain LID. Using
ganglioside deficient mouse embryo fibroblasts, we show that addition of specific
gangliosides restores infectability for all strains, and we uncover a complex relationship between virus attachment and
infection. We identify a new infectious
ganglioside receptor that carries an additional linear [α-2,8]-linked
sialic acid. Crystal structures of all three strains complexed with representative
oligosaccharides from the three main pathways of
ganglioside biosynthesis provide the molecular basis of receptor recognition. All strains bind to a range of sialylated
glycans featuring the central [α-2,3]-linked
sialic acid present in the established receptors GD1a and GT1b, but the presence of additional
sialic acids modulates binding. An extra [α-2,8]-linked
sialic acid engages a
protein pocket that is conserved among the three strains, while another, [α-2,6]-linked branching
sialic acid lies near the strain-defining
amino acids but can be accommodated by all strains. By comparing electron density of the
oligosaccharides within the binding pockets at various concentrations, we show that the [α-2,8]-linked
sialic acid increases the strength of binding. Moreover, the
amino acid exchanges have subtle effects on their affinity for the validated receptor GD1a. Our results indicate that both receptor specificity and affinity influence MuPyV pathogenesis.