Structures of Merkel Cell Polyomavirus VP1 Complexes Define a Sialic Acid Binding Site Required for Infection

PLoS Pathogens

Robert L. Garcea¹  Christopher B. Buck¹  Makoto Kiso¹  Rachel M. Schowalter²  Michel Gilbert³  Thilo Stehle⁴  Hiromune Ando⁵  Niklas Arnberg⁵  Thomas Peters⁵  Bärbel S. Blaum⁶  Holger Hengel⁶  Ursula Neu⁶  Dennis Macejak⁷  Warren W. Wakarchuk⁸  Akihiro Imamura⁸ 

[1] Department of Applied Bioorganic Chemistry, Gifu University, Gifu, Japan;Department of Chemistry, University of Luebeck, Luebeck, Germany;Department of Molecular, Cellular, and Developmental Biology, and the Biofrontiers Institute, University of Colorado at Boulder, Boulder, Colorado, United States of America;Division of Virology, Department of Clinical Microbiology, Umeå University, Umeå, Sweden;Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto, Japan;Interfaculty Institute of Biochemistry, University of Tuebingen, Tuebingen, Germany;Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, Maryland, United States of America;National Research Council Canada, Institute for Biological Sciences, Glycobiology Program, Ottawa, Ontario, Canada

关键词: Sialic acids;    Carbohydrates;    Hydrogen bonding;    Viral packaging;    Polyomaviruses;    SV40;    Sphingolipids;    Cell binding;   

DOI  :  10.1371/journal.ppat.1002738

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The recently discovered human Merkel cell polyomavirus (MCPyV or MCV) causes the aggressive Merkel cell carcinoma (MCC) in the skin of immunocompromised individuals. Conflicting reports suggest that cellular glycans containing sialic acid (Neu5Ac) may play a role in MCPyV infectious entry. To address this question, we solved X-ray structures of the MCPyV major capsid protein VP1 both alone and in complex with several sialylated oligosaccharides. A shallow binding site on the apical surface of the VP1 capsomer recognizes the disaccharide Neu5Ac-α2,3-Gal through a complex network of interactions. MCPyV engages Neu5Ac in an orientation and with contacts that differ markedly from those observed in other polyomavirus complexes with sialylated receptors. Mutations in the Neu5Ac binding site abolish MCPyV infection, highlighting the relevance of the Neu5Ac interaction for MCPyV entry. Our study thus provides a powerful platform for the development of MCPyV-specific vaccines and antivirals. Interestingly, engagement of sialic acid does not interfere with initial attachment of MCPyV to cells, consistent with a previous proposal that attachment is mediated by a class of non-sialylated carbohydrates called glycosaminoglycans. Our results therefore suggest a model in which sialylated glycans serve as secondary, post-attachment co-receptors during MCPyV infectious entry. Since cell-surface glycans typically serve as primary attachment receptors for many viruses, we identify here a new role for glycans in mediating, and perhaps even modulating, post-attachment entry processes.

【 授权许可】

CC BY