title: Structural Basis for Receptor Recognition by the Human CD59-Responsive Cholesterol-Dependent Cytolysins.
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.
authors: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
authors: Sara L
authors: SL
authors: Lawrence
authors: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
authors: Michael A
authors: MA
authors: Gorman
authors: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
authors: Susanne C
authors: SC
authors: Feil
authors: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia.
authors: Terrence D
authors: TD
authors: Mulhern
authors: Victorian Life Sciences Computation Initiative, The University of Melbourne, Parkville, VIC 3010, Australia.
authors: Michael J
authors: MJ
authors: Kuiper
authors: Departments of Pediatrics and Microbiology, New York University School of Medicine, New York, NY 10016, USA.
authors: Adam J
authors: AJ
authors: Ratner
authors: Department of Microbiology and Immunology, University of Oklahoma, Health Sciences Center, Oklahoma City, OK 73104, USA.
authors: Rodney K
authors: RK
authors: Tweten
authors: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
authors: Craig J
authors: CJ
authors: Morton
authors: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: mparker@svi.edu.au.
authors: Michael W
authors: MW
authors: Parker
mesh_terms: D020816:Amino Acid Motifs; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001427:Bacterial Toxins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001430:Bacteriocins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D018957:CD59 Antigens / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D001430:Bacteriocins; D018957:CD59 Antigens; D011994:Recombinant Proteins; C403910:intermedilysin protein, Streptococcus intermedius; C542392:vaginolysin, Gardnerella vaginalis; C051590:CD59 protein, human; D002784:Cholesterol