4x10 | pdb_00004x10
JC Polyomavirus genotype 3 VP1 in complex with GM2 oligosaccharide
Structural highlights
Publication Abstract from PubMedThe human JC polyomavirus (JCPyV) establishes an asymptomatic, persistent infection in the kidney of the majority of the population, and is the causative agent of the fatal, demyelinating disease progressive multifocal leukoencephalopathy (PML) in immunosuppressed individuals. The Mad-1 strain of JCPyV, a brain isolate, was shown earlier to require alpha2,6-linked sialic acid on the LSTc glycan for attachment to host cells. In contrast, a JCPyV kidney isolate Type 3 strain, "WT3", has been reported to interact with sialic acid-containing gangliosides, but the role of these glycans in JCPyV infection has remained unclear. To help rationalize these findings and probe the effects of strain-specific differences on receptor binding, we performed a comprehensive analysis of the glycan receptor specificities of these two representative JCPyV strains using high-resolution X-ray crystallography and NMR spectroscopy, and correlated these data with infectivity assays. We show here that capsid proteins of Mad-1 and WT3 JCPyV can both engage LSTc as well as multiple sialylated gangliosides. However, the binding affinities exhibit subtle differences, with the highest affinity observed for LSTc. Engagement of LSTc is a prerequisite for functional receptor engagement while the weaker-binding gangliosides are not required for productive infection. Our findings highlight the complexity of virus-carbohydrate interactions and demonstrate that subtle differences in binding affinities, rather than the binding event alone, help determine tissue tropism and viral pathogenesis. IMPORTANCE: Viral infection is initiated by attachment to receptors on host cells, and this event plays an important role in viral disease. We investigated the receptor-binding properties of human JC polyomavirus (JCPyV), a virus that resides in the kidney of the majority of the population and can cause the fatal, demyelinating disease progressive multifocal leukoencephalopathy (PML) in the brain of immunosuppressed individuals. JCPyV has been reported to interact with multiple carbohydrate receptors, and we sought to clarify how the interactions between JCPyV and cellular carbohydrate receptors influenced infection. Here we demonstrate that JCPyV can engage numerous sialylated carbohydrate receptors. However, the virus displays preferential binding to LSTc, and only LSTc mediates a productive infection. Our findings demonstrate that subtle differences in binding affinity, rather than receptor engagement alone, are a key determinant of viral infection. Increased Affinity of JC Polyomavirus Capsid for LSTc Over Other Sialylated Glycans Is a Major Determinant of Infectivity.,Stroh LJ, Maginnis MS, Blaum BS, Nelson CD, Neu U, Gee GV, O'Hara BA, Motamedi N, DiMaio D, Atwood WJ, Stehle T J Virol. 2015 Apr 8. pii: JVI.00489-15. PMID:25855729[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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