Document Detail


Binary actin-ADP-ribosylating toxins and their use as molecular Trojan horses for drug delivery into eukaryotic cells.
MedLine Citation:
PMID:  18289001     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Binary bacterial toxins are unique AB-type toxins, composed of two non-linked proteins that act as a binding/translocation component and an enzyme component. All known actin-ADP-ribosylating toxins from clostridia possess this binary structure. This toxin family is comprised of the prototypical Clostridium botulinum C2 toxin, Clostridium perfringens iota toxin, Clostridium difficile CDT, and Clostridium spiroforme toxin. Once in the cytosol of host cells, these toxins transfer an ADP-ribose moiety from nicotinamide-adenosine-dinucleotide onto G-actin that then leads to depolymerization of actin filaments. In recent years much progress has been made towards understanding the cellular uptake mechanism of binary actin-ADP-ribosylating toxins, and in particular that of C2 toxin. Both components act in a precisely concerted manner to intoxicate eukaryotic cells. The binding/translocation (B-) component forms a complex with the enzyme (A-) component and mediates toxin binding to a cell-surface receptor. Following receptor-mediated endocytosis, the enzyme component escapes from acidic endosomes into the cytosol. Acidification of endosomes triggers pore formation by the binding/translocation component in endosomal membranes and the enzyme component subsequently translocates through the pore. This step requires a host cell chaperone, Hsp90. Due to their unique structure, binary toxins are naturally "tailor made" for transporting foreign proteins into the cytosol of host cells. Several highly specific and cell-permeable recombinant fusion proteins have been designed and successfully used in experimental cell research. This review will focus on the recent progress in studying binary actin ADP-ribosylating toxins as highly effective virulence factors and innovative tools for cell physiology as well as pharmacology.
Authors:
Holger Barth; Bradley G Stiles
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Current medicinal chemistry     Volume:  15     ISSN:  0929-8673     ISO Abbreviation:  Curr. Med. Chem.     Publication Date:  2008  
Date Detail:
Created Date:  2008-02-21     Completed Date:  2008-05-01     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9440157     Medline TA:  Curr Med Chem     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  459-69     Citation Subset:  IM    
Affiliation:
Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, D-89081 Ulm, Germany. holger.barth@uni-ulm.de
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MeSH Terms
Descriptor/Qualifier:
ADP Ribose Transferases / administration & dosage
Actins / administration & dosage*,  metabolism
Adenosine Diphosphate Ribose / administration & dosage*
Animals
Antigens, Bacterial / administration & dosage
Bacterial Toxins / administration & dosage*
Botulinum Toxins / administration & dosage
Drug Delivery Systems*
Endocytosis / physiology
Enterotoxins / administration & dosage
Humans
Protein Transport
Recombinant Fusion Proteins / administration & dosage
Chemical
Reg. No./Substance:
0/Actins; 0/Antigens, Bacterial; 0/Bacterial Toxins; 0/Botulinum Toxins; 0/Enterotoxins; 0/Recombinant Fusion Proteins; 0/anthrax toxin; 0/botulinum toxin type C; 0/iota toxin, Clostridium perfringens; 0/iota toxin, Clostridium spiroforme; 0/tcdA protein, Clostridium difficile; 20762-30-5/Adenosine Diphosphate Ribose; EC 2.4.2.-/ADP Ribose Transferases

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