Structural Basis for Receptor Recognition by the Human CD59-Responsive Cholesterol-Dependent Cytolysins

Structure. 2016 Sep 6;24(9):1488-98. doi: 10.1016/j.str.2016.06.017. Epub 2016 Aug 4.


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.

MeSH terms

  • Amino Acid Motifs
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Bacterial Toxins / chemistry*
  • Bacterial Toxins / genetics
  • Bacterial Toxins / metabolism
  • Bacteriocins / chemistry*
  • Bacteriocins / genetics
  • Bacteriocins / metabolism
  • Binding Sites
  • CD59 Antigens / chemistry*
  • CD59 Antigens / genetics
  • CD59 Antigens / metabolism
  • Cholesterol / chemistry*
  • Cholesterol / metabolism
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression
  • Humans
  • Molecular Dynamics Simulation
  • Mutation
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Scattering, Small Angle
  • X-Ray Diffraction


  • Bacterial Proteins
  • Bacterial Toxins
  • Bacteriocins
  • CD59 Antigens
  • Recombinant Proteins
  • intermedilysin protein, Streptococcus intermedius
  • vaginolysin, Gardnerella vaginalis
  • CD59 protein, human
  • Cholesterol