Abstract
Cholesterol-dependent cytolysins (CDCs) are a family of pore-forming toxins that punch holes in the outer membrane of eukaryotic cells. Cholesterol serves as the receptor, but a subclass of CDCs first binds to human CD59. Here we describe the crystal structures of vaginolysin and intermedilysin complexed to CD59. These studies, together with small-angle X-ray scattering, reveal that CD59 binds to each at different, though overlapping, sites, consistent with molecular dynamics simulations and binding studies. The CDC consensus undecapeptide motif, which for the CD59-responsive CDCs has a proline instead of a tryptophan in the motif, adopts a strikingly different conformation between the structures; our data suggest that the proline acts as a selectivity switch to ensure CD59-dependent CDCs bind their protein receptor first in preference to cholesterol. The structural data suggest a detailed model of how these water-soluble toxins assemble as prepores on the cell surface.
Copyright © 2016 Elsevier Ltd. All rights reserved.
MeSH terms
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Amino Acid Motifs
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Bacterial Proteins / chemistry*
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Bacterial Toxins / chemistry*
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Bacterial Toxins / genetics
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Bacterial Toxins / metabolism
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Bacteriocins / chemistry*
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Bacteriocins / genetics
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Bacteriocins / metabolism
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Binding Sites
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CD59 Antigens / chemistry*
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CD59 Antigens / genetics
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CD59 Antigens / metabolism
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Cholesterol / chemistry*
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Cholesterol / metabolism
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Cloning, Molecular
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Crystallography, X-Ray
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Escherichia coli / genetics
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Escherichia coli / metabolism
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Gene Expression
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Humans
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Molecular Dynamics Simulation
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Mutation
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Protein Binding
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Protein Conformation, alpha-Helical
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Protein Conformation, beta-Strand
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Protein Interaction Domains and Motifs
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Protein Multimerization
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Scattering, Small Angle
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X-Ray Diffraction
Substances
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Bacterial Proteins
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Bacterial Toxins
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Bacteriocins
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CD59 Antigens
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Recombinant Proteins
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intermedilysin protein, Streptococcus intermedius
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vaginolysin, Gardnerella vaginalis
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CD59 protein, human
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Cholesterol