Structures of Merkel cell polyomavirus VP1 complexes define a sialic acid binding site required for infection
| Autor: | Baerbel S. Blaum, Holger Hengel, Rachel M. Schowalter, Warren W. Wakarchuk, Makoto Kiso, Hiromune Ando, Christopher B. Buck, Ursula Neu, Dennis Macejak, Thomas Peters, Niklas Arnberg, Robert L. Garcea, Thilo Stehle, Akihiro Imamura, Michel Gilbert |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular crystallization Protein Conformation Glycobiology Merkel cell polyomavirus Oligosaccharides virus entry medicine.disease_cause Crystallography X-Ray n acetylneuraminic acid Biochemistry polyomavirus infection chemistry.chemical_compound protein purification Emerging Viral Diseases Biomacromolecule-Ligand Interactions lcsh:QH301-705.5 Glycosaminoglycans 0303 health sciences biology Merkel cell carcinoma virus mutation Antivirals capsid protein 3. Good health Oncology sialic acid Receptors Virus Medicine Oncology Agents virus morphology Polyomavirus mutagenesis Research Article virus DNA lcsh:Immunologic diseases. Allergy Glycan Viral protein ligand binding Immunology Virus Attachment Sialic acid binding Viral Structure chemistry Microbiology virus receptor Microbiology in the medical area Cell Line VP1 protein polyomavirus 03 medical and health sciences complex formation Virology glycosaminoglycan Genetics medicine Mikrobiologi inom det medicinska området oligosaccharide Humans protein structure protein expression Molecular Biology Biology 030304 developmental biology Polyomavirus Infections Binding Sites binding site 030306 microbiology Proteins cell adhesion nucleotide sequence X ray crystallography Virus Internalization biology.organism_classification medicine.disease N-Acetylneuraminic Acid Sialic acid carbohydrates (lipids) Epitope mapping lcsh:Biology (General) Viruses and Cancer physiology DNA Viral Mutation chemical structure biology.protein Parasitology Capsid Proteins Miridae protein VP1 lcsh:RC581-607 metabolism N-Acetylneuraminic acid Epitope Mapping |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 8, Iss 7, p e1002738 (2012) |
| ISSN: | 1553-7374 |
| Popis: | 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. Author Summary Viruses must interact with specific receptor molecules on their host cells in order to first attach to the cell and second gain entry into it. Therefore, a viral entry pathway is a sequence of precisely regulated binding events between viral proteins and their cellular receptors, which can be proteins or other biomolecules. In the present study, we investigated the human Merkel cell polyomavirus (MCPyV or MCV) and show that it uses complex carbohydrates containing sialic acid as receptors for entry. MCPyV was discovered in 2008, is widespread in humans and can cause aggressive skin tumors termed Merkel cell carcinomas in immunosuppressed individuals. We determined the crystal structures of the MCPyV capsid protein bound to sialylated carbohydrates, describing the contacts needed for receptor recognition in molecular detail. When we introduced targeted mutations that abolished sialic acid binding into the virus, it was unable to infect cells although it could still attach to them. Earlier studies showed that the virus uses a different group of carbohydrates called glycosaminoglycans for initial attachment to the cell surface. Thus, its entry pathway involves sequential binding to two distinct classes of carbohydrates. Our structures can be used as a starting point to develop antivirals against MCPyV. |
| Databáze: | OpenAIRE |
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