Structural basis for Clostridium perfringens enterotoxin targeting of claudins at tight junctions in mammalian gut

Significance Clostridium perfringens causes gas gangrene and is a leading cause of bacterial food poisoning, with 1,000,000 US cases annually. Food-poisoning strains produce an enterotoxin (CpE) that breaks apart tight junctions, protein assemblies composed of claudins that fortify the gut barrier. CpE selectively targets claudins via its C-terminal domain (cCpE) to disrupt the gut barrier—the basis for targeting was unknown. Here, we determine the structure of cCpE bound to human claudin-4, discover the structural origin of CpE targeting, and reveal that the primary CpE receptors differ in mice and humans. These insights elucidate CpE’s mechanism for selective targeting of claudins in mammalian gut and can be applied to aid design of new CpE-based therapeutics to treat claudin-linked diseases.