TcdA TcdB.pptxVIP

Structure and mode of action of clostridial glucosylating toxins: the ABCD model Thomas Jank and Klaus Aktories Institut fur Experimentelle und Klinische Pharmakologie und Toxikologie der Albert-Ludwigs Universitat Freiburg,Otto-Krayer-Haus, Albertstrasse 25, D-79104 Freiburg, Germany Cell IF=31.3 Background Toxins A and B, which are the major virulence factors of antibiotic-associated diarrhea and pseudomembranous colitis caused by Clostridium difficile, are the prototypes of the family of clostridial glucosylating toxins. Antibiotic-associated diarrhea and pseudomembranous colitis induced by Clostridium difficile have emerged as important nosocomial infections. During the past decade, these diseases seem to have become more serious and more frequently refractory to therapy Clostridial glucosylating toxins Toxins with multimodular structure biological activity cutting, delivery binding; Interaction of toxin B with Rho GTPases Structure Mode of action Topic 1 toxins with multimodular structure TcdA -----------2710 amino acid 308kDa TcdB----------- 2366 amino acid 269.6kDa AB model -------------------ABCD model A, biological activity; B, binding; C, cutting; D,delivery 1. the C terminus binds to target cell membranes Toxin A folds in a sole-noid-like structure with 32 small repeats consisting of 15–21 residues and seven large repeats of 30 residues. Solenoid structures increase the surface area of proteins and enable protein–protein or protein carbohydrate interactions The junction of a large repeat and the hairpin turn forms carbohydrate-binding groove A glycoprotein or glycosphingolipid comprises the intestinal receptor of TcdA remains to be clarified The nature of the receptor of C. difficile toxin B is even further from being defined. 2. toxin uptake: a question of cutting and delivery receptor binding endocytosis translocate through the early endosomal membrane into the cytosol 转膜 加工 释放 Clostridial glucosylating toxins bind to the cel