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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Zhang, Zhifen Beilhartz, Greg L. Tam, John Auger, Anick Lacy, D. Borden Melnyk, Roman A. Park, Minyoung |
| Description | Author Affiliation: Zhang Z ( Department of Biochemistry, University of Toronto, Toronto, ON, Canada M5S1A8.); |
| Abstract | Disease associated with Clostridium difficile infection is caused by the actions of the homologous toxins TcdA and TcdB on colonic epithelial cells. Binding to target cells triggers toxin internalization into acidified vesicles, whereupon cryptic segments from within the 1,050-aa translocation domain unfurl and insert into the bounding membrane, creating a transmembrane passageway to the cytosol. Our current understanding of the mechanisms underlying pore formation and the subsequent translocation of the upstream cytotoxic domain to the cytosol is limited by the lack of information available regarding the identity and architecture of the transmembrane pore. Here, through systematic perturbation of conserved sites within predicted membrane-insertion elements of the translocation domain, we uncovered highly sensitive residues--clustered between amino acids 1,035 and 1,107--that when individually mutated, reduced cellular toxicity by as much as >1,000-fold. We demonstrate that defective variants are defined by impaired pore formation in planar lipid bilayers and biological membranes, resulting in an inability to intoxicate cells through either apoptotic or necrotic pathways. These findings along with the unexpected similarities uncovered between the pore-forming 'hotspots' of TcdB and the well-characterized -helical diphtheria toxin translocation domain provide insights into the structure and mechanism of formation of the translocation pore for this important class of pathogenic toxins. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 10 |
| Volume Number | 111 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2014-03-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Bacterial Toxins Genetics Toxicity Clostridium Difficile Pathogenicity Pore Forming Cytotoxic Proteins Amino Acid Sequence Metabolism Fluorescence High-Throughput Screening Assays Models, Molecular Molecular Sequence Data Mutagenesis Mutation Protein Structure, Tertiary Rubidium Radioisotopes Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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