Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore

Zhifen Zhang; Minyoung Park; John TamAnick AugerGreg L. BeilhartzD. Borden LacyRoman A. Melnyk

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore

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Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore

机译：Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore

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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 wellcharacterized α-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.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第10期|3721-3726|共6页
作者
Zhifen Zhang; Minyoung Park; John TamAnick AugerGreg L. BeilhartzD. Borden LacyRoman A. Melnyk;
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作者单位

Department of Biochemistry, University of Toronto, Toronto, ON, Canada M5S1A8;

Molecular Structure and Function, The Hospital for Sick Children, Toronto, ON, Canada M5G0A4;

Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Translocation; mutations; pore;

Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore

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