Structural insight into tight junction disassembly by Clostridium perfringens enterotoxin

Abstract

The C-terminal region of Clostridium perfringens enterotoxin (C-CPE) can bind to specific claudins, resulting in the disintegration of tight junctions (TJs) and an increase in the paracellular permeability across epithelial cell sheets. Here we present the structure of mammalian claudin-19 in complex with C-CPE at 3.7 Å resolution. The structure shows that C-CPE forms extensive hydrophobic and hydrophilic interactions with the two extracellular segments of claudin-19. The claudin-19/C-CPE complex shows no density of a short extracellular helix that is critical for claudins to assemble into TJ strands. The helix displacement may thus underlie C-CPE-mediated disassembly of TJs.

Intestinal permeation enhancers for oral peptide delivery

“…PEs that bind either the first (Claudin-1 53-80 peptide [123], C 1 C 2 [124] and C-CPE [125]) or second (C-CPE [102]) extracellular CAR motifs interfere in TJ formation leading to an increase in paracellular permeability (Table S1). …”

Viral interactions with the blood-brain barrier: old dog, new tricks

“…73,74 Using crystallography, Saitoh and colleagues have resolved the 3D crystal structure of the motif in claudin-19 that binds to CPE via hydrophobic interactions. 75 The CPE binding motif is conserved across different claudin species and made of 4 amino acid residues located in the second extracellular loop domain (ECL2) of claudin, e.g. NPSTP (amino acid number: 150-154) in claudin-19 (Fig.…”

Molecular basis of claudin-17 anion selectivity

“…H154 points to the opposite side in the turn region of the ECL2. After a crystal structure of mouse Cldn19 (63 % sequence similarity to Cldn17) was released recently (PDB: 3X29; [20]), an additional homology model was generated based on this Cldn19 template. In both models, the residues mutated in this study were positioned in a similar manner supporting the validity of the models (Fig.…”

“…However, a more detailed structural understanding of barrier and channel formation was limited due to the lack of 3D structure information for claudins. Recently, however, the first claudin crystal structures have been published for Cldn15 and Cldn19 [19,20]. This now allows more detailed homology modeling of other classic claudins and investigation of the molecular mechanisms responsible for channel formation.…”