9CMH

Cryo-EM structure of human claudin-4 complex with Clostridium perfringens enterotoxin

Summary for 9CMH

• Entry DOI: 10.2210/pdb9cmh/pdb
• EMDB information: 45748
• Descriptor: Claudin-4, Heat-labile enterotoxin B chain (2 entities in total)
• Functional Keywords: claudin, enterotoxin, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 55234.91

Authors

Vecchio, A.J. (deposition date: 2024-07-15, release date: 2024-07-24, Last modification date: 2024-11-27)

Primary citation

Rathnayake, S.S.,Erramilli, S.K.,Kossiakoff, A.A.,Vecchio, A.J.
Cryo-EM structures of Clostridium perfringens enterotoxin bound to its human receptor, claudin-4.
Structure, 32:1936-, 2024

PubMed Abstract: 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.

PubMed: 39383874
DOI: 10.1016/j.str.2024.09.015

Experimental method

ELECTRON MICROSCOPY (4 Å)