On the interaction of Clostridium perfringens enterotoxin with claudins

Abstract

Clostridium perfringens causes one of the most common foodborne illnesses, which is largely mediated by the Clostridium perfringens enterotoxin (CPE). The toxin consists of two functional domains. The N-terminal region mediates the cytotoxic effect through pore formation in the plasma membrane of the mammalian host cell. The C-terminal region (cCPE) binds to the second extracellular loop of a subset of claudins. Claudin-3 and claudin-4 have been shown to be receptors for CPE with very high affinity. The toxin binds with weak affinity to claudin-1 and -2 but contribution of these weak binding claudins to CPE-mediated disease is questionable. cCPE is not cytotoxic, however, it is a potent modulator of tight junctions. This review describes recent progress in the molecular characterization of the cCPE-claudin interaction using mutagenesis, in vitro binding assays and permeation studies. The results promote the development of recombinant cCPE-proteins and CPE-based peptidomimetics to modulate tight junctions for improved drug delivery or to treat tumors overexpressing claudins.

Keywords: Claudins; Clostridium perfringens enterotoxin; drug delivery; tight junction.

Figure 1

(a) Homologous helix-turn-helix model of the ECL2 of mouse Cld3 based on the fragment of PDB code 2BDV in front view. Residues F146 to R157 and M160 are shown (ball and stick), key residues for CPE-claudin interaction N148 and L150 [37] are given in red. M160 (green) was also reported to be involved in CPE-claudin interaction [44]. Residues F146, Y147 (grey), and R157 (blue) correspond to aromatic residues F147, Y148, and Y158 in Cld5, which were found to be important for trans–interaction. Heteroatoms are red (oxygen), dark blue (nitrogen), white (hydrogen), and yellow (sulfur). Black dashed lines: hydrogen bonds, grey dashed line: cell-membrane. (b) Supposed spatial regions of interaction between binding sensitive residues (Y306, Y310, Y312, and L315 from literature [60]) visualized at the CPE194–319 x-ray structure (PDB code 2QUO) and residues (148NPLVP, Q155) in Cld3. Key-residues for the CPE-claudin interaction are highlighted in red.