Large clostridial cytotoxins: cellular biology of Rho/Ras-glucosylating toxins.
Mono-O-glycosylation of eukaryotic target proteins is the molecular mechanism of bacterial protein toxins of the family of large clostridial cytotoxins. This toxin family encompasses several high molecular mass proteins (>250 kDa) of various Clostridia species that are implicated in severe human diseases. Toxin A and toxin B from Clostridium difficile are the causative agents of pseudomembranous colitis and antibiotic-associated diarrhea. Lethal toxin and hemorrhagic toxin from Clostridium sordellii as well as alpha-toxin from Clostridium novyi are involved in the gas gangrene syndrome. The common mode of action of large clostridial cytotoxins is elicited by specific glycosylation of small GTP-binding proteins in the cytosol of target cells using activated nucleotide sugars as cosubstrates. Specific modification at a single threonine residue in the small GTPases renders these important key players of various signaling pathways inactive. This minireview intends to give an overview on structure-function analysis and mode of action of the large clostridial cytotoxins, as well as on the resulting functional consequences of glycosylation of target proteins.
Schirmer
Jörg
J
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität Freiburg, Otto-Krayer-Haus, Albertstrasse 25, D-79104 Freiburg, Germany.
Aktories
Klaus
K
D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000737:chemistry / Q000378:metabolism*; D003013:Clostridium / Q000378:metabolism* / Q000472:pathogenicity; D003603:Cytotoxins / Q000737:chemistry / Q000378:metabolism*; D004768:Enterotoxins / Q000378:metabolism; D005057:Eukaryotic Cells / Q000378:metabolism / Q000382:microbiology; D006031:Glycosylation; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D003603:Cytotoxins; D004768:Enterotoxins; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; D018631:ras Proteins; D020741:rho GTP-Binding Proteins