Claudin-9 structures reveal mechanism for toxin-induced gut barrier breakdown.
Alex J VecchioRobert M StroudPublished in: Proceedings of the National Academy of Sciences of the United States of America (2019)
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 Å. 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.
Keyphrases
- endothelial cells
- high glucose
- cell death
- binding protein
- diabetic rats
- cell cycle arrest
- induced apoptosis
- induced pluripotent stem cells
- high resolution
- genome wide
- drug induced
- single cell
- single molecule
- blood brain barrier
- oxidative stress
- staphylococcus aureus
- endoplasmic reticulum stress
- pseudomonas aeruginosa
- wild type