期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 36, 页码 17817-17824出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1908929116
关键词
claudin; tight junction; membrane protein; X-ray structure; toxin
资金
- NIH [R01GM024485, F32GM103277]
- University of California Office of the President, Multicampus Research Programs and Initiatives [MR-15-338599]
- Program for Breakthrough Biomedical Research
- Sandler Foundation
- US Department of Energy Office of Biological and Environmental Research [DE-AC02-05CH11231]
The human pathogenic bacterium Clostridium perfringens secretes an enterotoxin (CpE) that targets claudins through its C-terminal receptor-binding domain (cCpE). Isoform-specific binding by CpE causes dissociation of claudins and tight junctions (TJs), resulting in cytotoxicity and breakdown of the gut epithelial barrier. Here, we present crystal structures of human claudin-9 (hCLDN-9) in complex with cCpE at 3.2 and 3.3 A. We show that hCLDN-9 is a high-affinity CpE receptor and that hCLDN-9-expressing cells undergo cell death when treated with CpE but not cCpE, which lacks its cytotoxic domain. Structures reveal cCpE-induced alterations to 2 epitopes known to enable claudin self-assembly and expose high-affinity interactions between hCLDN-9 and cCpE that explain isoform-specific recognition. These findings elucidate the molecular bases for hCLDN-9 selective ion permeability and binding by CpE, and provide mechanisms for how CpE disrupts gut homeostasis by dissociating claudins and TJs to affect epithelial adhesion and intercellular transport.
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