title: The cholesterol-dependent cytolysin family of gram-positive bacterial toxins.
abstract: The cholesterol-dependent cytolysins (CDCs) are a family of beta-barrel pore-forming toxins secreted by Gram-positive bacteria. These toxins are produced as water-soluble monomeric proteins that after binding to the target cell oligomerize on the membrane surface forming a ring-like pre-pore complex, and finally insert a large beta-barrel into the membrane (about 250 A in diameter). Formation of such a large transmembrane structure requires multiple and coordinated conformational changes. The presence of cholesterol in the target membrane is absolutely required for pore-formation, and therefore it was long thought that cholesterol was the cellular receptor for these toxins. However, not all the CDCs require cholesterol for binding. Intermedilysin, secreted by Streptoccocus intermedius only binds to membranes containing a protein receptor, but forms pores only if the membrane contains sufficient cholesterol. In contrast, perfringolysin O, secreted by Clostridium perfringens, only binds to membranes containing substantial amounts of cholesterol. The mechanisms by which cholesterol regulates the cytolytic activity of the CDCs are not understood at the molecular level. The C-terminus of perfringolysin O is involved in cholesterol recognition, and changes in the conformation of the loops located at the distal tip of this domain affect the toxin-membrane interactions. At the same time, the distribution of cholesterol in the membrane can modulate toxin binding. Recent studies support the concept that there is a dynamic interplay between the cholesterol-binding domain of the CDCs and the excess of cholesterol molecules in the target membrane.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA 01003, USA. heuck@biochem.umass.edu
authors.forename: Alejandro P
authors.initials: AP
authors.lastname: Heuck
authors.forename: Paul C
authors.initials: PC
authors.lastname: Moe
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Johnson
mesh_terms: D001427:Bacterial Toxins / Q000378:metabolism; D001430:Bacteriocins / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D003603:Cytotoxins / Q000737:chemistry / Q000378:metabolism*; D006460:Hemolysin Proteins / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
chemical_list: D001427:Bacterial Toxins; D001430:Bacteriocins; D003603:Cytotoxins; D006460:Hemolysin Proteins; D008081:Liposomes; D008563:Membrane Lipids; C403910:intermedilysin protein, Streptococcus intermedius; C020452:Clostridium perfringens theta-toxin; D002784:Cholesterol