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Structure of murine polyomavirus complexed with an oligosaccharide receptor fragment
T Stehle1, Y Yan, T L Benjamin
1Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138.
Abstract:
The polyomaviruses are non-enveloped, icosahedrally symmetrical particles with circular double-stranded DNA genomes. The outer shell of the virion contains 360 copies of viral protein VP1 (M(r) approximately 42K) arranged in pentamers. We report here the structure at 3.65 A resolution of murine polyomavirus ('polyoma') complexed with an oligosaccharide receptor fragment. This structure has been determined using the previously described model of simian virus 40 (SV40). Although very similar in structure to SV40, polyoma has interesting biological differences. Cell-surface N-acetyl neuraminic acid (sialic acid) is required for polyoma infectivity, but not for SV40. Polyoma attaches to the surface of susceptible cells by stereospecific recognition of oligosaccharides terminating in (alpha 2,3)-linked sialic acid. Studies of pathogenicity show that the specificity of viral binding to such oligosaccharides is an important determinant of the virus' ability to establish a disseminated infection and to induce tumours in the natural host. The complex described here show how polyoma recognizes the receptor fragment and how strains with different receptor specificities can distinguish between alternative ligands. The results also suggest an explanation for the large disparity in pathogenicity exhibited by strains differing in only one amino-acid residue of VP1.
Insights
Murine polyomavirus binds to sialic acid on host cells, a key step for infection. Structural analysis reveals how this binding specificity influences viral pathogenicity and tumor induction.
Area of Science:
- Virology
- Structural Biology
- Molecular Interactions
Background:
- Polyomaviruses are non-enveloped viruses with double-stranded DNA genomes.
- The viral protein VP1 forms the outer shell of the polyomavirus virion.
- Murine polyomavirus (polyoma) and simian virus 40 (SV40) share structural similarities but exhibit distinct biological properties.
Purpose of the Study:
- To determine the high-resolution structure of murine polyomavirus complexed with an oligosaccharide receptor fragment.
- To elucidate the mechanism of polyomavirus attachment to host cells via sialic acid recognition.
- To understand how variations in receptor specificity and VP1 structure affect viral pathogenicity.
Main Methods:
- X-ray crystallography at 3.65 A resolution.
- Utilizing a previously determined simian virus 40 (SV40) model.
- Analysis of viral-host cell interactions and pathogenicity studies.
Main Results:
- The structure reveals the stereospecific recognition of oligosaccharides terminating in (alpha 2,3)-linked sialic acid by polyomavirus.
- Cell-surface sialic acid is essential for polyomavirus infectivity, unlike SV40.
- Differences in receptor binding specificity correlate with the ability to establish disseminated infections and induce tumors.
Conclusions:
- The structure provides insights into polyomavirus-receptor interactions at the molecular level.
- Sialic acid binding specificity is a critical determinant of polyomavirus pathogenicity.
- Subtle changes in VP1 structure can lead to significant differences in viral infectivity and disease outcome.