气候变化领域集成服务门户(CCPortal): Structural basis for Clostridium perfringens enterotoxin targeting of claudins at tight junctions in mammalian gut

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DOI	10.1073/pnas.2024651118
	Structural basis for Clostridium perfringens enterotoxin targeting of claudins at tight junctions in mammalian gut
	Vecchio A.J.; Rathnayake S.S.; Stroud R.M.
发表日期	2021
ISSN	00278424
卷号	118 期号:15
英文摘要	The bacterium Clostridium perfringens causes severe, sometimes lethal gastrointestinal disorders in humans, including enteritis and enterotoxemia. Type F strains produce an enterotoxin (CpE) that causes the third most common foodborne illness in the United States. CpE induces gut breakdown by disrupting barriers at cell-cell contacts called tight junctions (TJs), which are formed and maintained by claudins. Targeted binding of CpE to specific claudins, encoded by its C-terminal domain (cCpE), loosens TJ barriers to trigger molecular leaks between cells. Cytotoxicity results from claudin-bound CpE complexes forming pores in cell membranes. In mammalian tissues, ∼24 claudins govern TJ barriers-but the basis for CpE's selective targeting of claudins in the gut was undetermined. We report the structure of human claudin-4 in complex with cCpE, which reveals that enterotoxin targets a motif conserved in receptive claudins and how the motif imparts high-affinity CpE binding to these but not other subtypes. The structural basis of CpE targeting is supported by binding affinities, kinetics, and half-lives of claudin-enterotoxin complexes and by the cytotoxic effects of CpE on claudin-expressing cells. By correlating the binding residence times of claudin-CpE complexes we determined to claudin expression patterns in the gut, we uncover that the primary CpE receptors differ in mice and humans due to sequence changes in the target motif. These findings provide the molecular and structural element CpE employs for subtype-specific targeting of claudins during pathogenicity of C. perfringens in the gut and a framework for new strategies to treat CpE-based illnesses in domesticated mammals and humans. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Claudin; Enterotoxin; Membrane protein; Tight junction; X-ray structure
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179862
作者单位	Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, United States; Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE 68588, United States; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, United States
推荐引用方式 GB/T 7714	Vecchio A.J.,Rathnayake S.S.,Stroud R.M.. Structural basis for Clostridium perfringens enterotoxin targeting of claudins at tight junctions in mammalian gut[J],2021,118(15).
APA	Vecchio A.J.,Rathnayake S.S.,&Stroud R.M..(2021).Structural basis for Clostridium perfringens enterotoxin targeting of claudins at tight junctions in mammalian gut.Proceedings of the National Academy of Sciences of the United States of America,118(15).
MLA	Vecchio A.J.,et al."Structural basis for Clostridium perfringens enterotoxin targeting of claudins at tight junctions in mammalian gut".Proceedings of the National Academy of Sciences of the United States of America 118.15(2021).