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Proc Natl Acad Sci U S A. 2019 Sep 3;116(36):17817-17824. doi: 10.1073/pnas.1908929116. Epub 2019 Aug 21.

Claudin-9 structures reveal mechanism for toxin-induced gut barrier breakdown.

Author information

1
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.
2
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158 stroud@msg.ucsf.edu.

Abstract

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.

KEYWORDS:

X-ray structure; claudin; membrane protein; tight junction; toxin

PMID:
31434788
PMCID:
PMC6731655
[Available on 2020-02-21]
DOI:
10.1073/pnas.1908929116

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