6OV3

Crystal structure of human claudin-9 in complex with Clostridium perfringens entertoxin C-terminal domain in open form

Summary for 6OV3

• Entry DOI: 10.2210/pdb6ov3/pdb
• Related: 6OV2
• Descriptor: Claudin-9, Heat-labile enterotoxin B chain (2 entities in total)
• Functional Keywords: claudin, enterotoxin, tight junction protein, transmembrane protein, cell adhesion
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 37657.77

Authors

Vecchio, A.J.,Stroud, R.M. (deposition date: 2019-05-06, release date: 2019-09-04, Last modification date: 2024-10-09)

Primary citation

Vecchio, A.J.,Stroud, R.M.
Claudin-9 structures reveal mechanism for toxin-induced gut barrier breakdown.
Proc.Natl.Acad.Sci.USA, 116:17817-17824, 2019

PubMed Abstract: The human pathogenic bacterium 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.

PubMed: 31434788
DOI: 10.1073/pnas.1908929116

Experimental method

X-RAY DIFFRACTION (3.25 Å)