Structural basis of mammalian glycan targeting by Vibrio cholerae cytolysin and biofilm proteins
| Autor: | Rich Olson, Brandon C Case, Swastik De, Katherine Kaus, Shada Sinclair |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular genetic structures medicine.disease_cause Pathology and Laboratory Medicine Toxicology Crystallography X-Ray Biochemistry Lectins Medicine and Health Sciences Toxins Vibrio cholerae lcsh:QH301-705.5 Crystallography biology Organic Compounds Cytotoxins Physics Biofilm matrix Condensed Matter Physics Bacterial Pathogens Chemistry Medical Microbiology Physical Sciences Crystal Structure Rabbits Pathogens Research Article lcsh:Immunologic diseases. Allergy Glycan Virulence Factors Recombinant Fusion Proteins 030106 microbiology Immunology Toxic Agents Carbohydrates Virulence Receptors Cell Surface Microbiology 03 medical and health sciences Polysaccharides Virology Genetics medicine Solid State Physics Animals Protein Interaction Domains and Motifs Amino Acid Sequence Molecular Biology Microbial Pathogens Vibrio Binding Sites Blood Cells Bacteria Sequence Homology Amino Acid Perforin Organic Chemistry Biofilm Organisms Chemical Compounds Biology and Life Sciences Proteins Bacteriology biology.organism_classification Mammalian Glycan Peptide Fragments Kinetics 030104 developmental biology Amino Acid Substitution lcsh:Biology (General) Biofilms Mutation biology.protein Parasitology Cytolysin Bacterial Biofilms lcsh:RC581-607 Mannose Sequence Alignment |
| Zdroj: | PLoS Pathogens, Vol 14, Iss 2, p e1006841 (2018) PLoS Pathogens |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | Vibrio cholerae is an aquatic gram-negative microbe responsible for cholera, a pandemic disease causing life-threatening diarrheal outbreaks in populations with limited access to health care. Like most pathogenic bacteria, V. cholerae secretes virulence factors to assist colonization of human hosts, several of which bind carbohydrate receptors found on cell-surfaces. Understanding how pathogenic virulence proteins specifically target host cells is important for the development of treatment strategies to fight bacterial infections. Vibrio cholerae cytolysin (VCC) is a secreted pore-forming toxin with a carboxy-terminal β-prism domain that targets complex N-glycans found on mammalian cell-surface proteins. To investigate glycan selectivity, we studied the VCC β-prism domain and two additional β-prism domains found within the V. cholerae biofilm matrix protein RbmC. We show that the two RbmC β-prism domains target a similar repertoire of complex N-glycan receptors as VCC and find through binding and modeling studies that a branched pentasaccharide core (GlcNAc2-Man3) represents the likely footprint interacting with these domains. To understand the structural basis of V. cholerae β-prism selectivity, we solved high-resolution crystal structures of fragments of the pentasaccharide core bound to one RbmC β-prism domain and conducted mutagenesis experiments on the VCC toxin. Our results highlight a common strategy for cell-targeting utilized by both toxin and biofilm matrix proteins in Vibrio cholerae and provide a structural framework for understanding the specificity for individual receptors. Our results suggest that a common strategy for disrupting carbohydrate interactions could affect multiple virulence factors produced by V. cholerae, as well as similar β-prism domains found in other vibrio pathogens. Author summary Bacterial pathogens secrete multiple virulence factors to aid in infection including adhesion molecules, effector proteins, enzymes, toxins and biofilm proteins. To increase the potency and specificity of these molecules, many factors contain binding sites for host cell-surface receptors. This study involves two such factors from the human pathogen Vibrio cholerae: a toxin that forms cytotoxic pores in the cell-membranes of target cells (most likely immune cells like neutrophils) and biofilm matrix proteins that help form a protective sheath around growing bacterial colonies. We show that both factors utilize similar carbohydrate receptors to recognize cell surfaces. Uncovering the structural basis for how host cells are targeted is important in understanding how V. cholerae and similar organisms cause disease. |
| Databáze: | OpenAIRE |
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