Cryo-EM structures of Clostridium perfringens enterotoxin bound to its human receptor, claudin-4

Clostridium perfringens enterotoxin (CpE) causes prevalent and deadly gastrointestinal disorders. CpE binds to receptors called claudins on the apical surfaces of small intestinal epithelium. Claudins normally regulate paracellular transport but are hijacked from doing so by CpE and are instead led to form claudin/CpE complexes. Claudin/CpE complexes are the building blocks of oligomeric β-barrel pores that penetrate the plasma membrane and induce gut cytotoxicity. Here, we present the structures of CpE in complex with its native claudin receptor in humans, claudin-4, using cryogenic electron microscopy. The structures reveal the architecture of the claudin/CpE complex, the residues used in binding, the orientation of CpE relative to the membrane, and CpE-induced changes to claudin-4. Further, structures and modeling allude to the biophysical procession from claudin/CpE complexes to cytotoxic β-barrel pores during pathogenesis. In full, this work proposes a model of claudin/CpE assembly and provides strategies to obstruct its formation to treat CpE diseases. [Display omitted] •Cryo-EM structures of claudin-4/CpE complexes with and without a Fab are presented•CpE binds in a consensus conformation and induces targeted changes to claudin-4•A model for claudin-4/CpE complex integration into pre-cytotoxic assemblies is proposed•Potential mechanism of CpE-induced gastrointestinal disease Vecchio et al. determine the cryo-EM structure of Clostridium perfringens enterotoxin bound to its human receptor claudin-4. The enterotoxin causes common gastrointestinal diseases that are difficult to treat. This work clarifies the structure and assembly of this complex and provides strategies to prevent its formation to treat disease.