Claudin family of transmembrane proteins constitute tight junctions that are important determinants of paracellular permeability. Clostridium perfringens an opportunistic spore forming pathogen releases enterotoxins (CPE) that disrupts intestinal tight junctions. C. perfringens enteropathy is the second leading cause of food borne illness in developed countries. Several members of the claudin family are receptors for the CPE, and they specifically bind to the C-terminal domain of the toxin (cCPE). CPE initially forms a small complex with receptor claudins that has ~90 kDa native PAGE mobility, that later forms a ~450 kDa hexameric pore complex CH-1. The CH-1 complex causes Ca2+ influx and consequently apoptosis. The interaction between the cCPE and claudins are active topics of research for potential translational applications that range from cancer treatment and opening the blood-brain barrier. Crystal structures of the full-length toxin show them to form solvent stabilized trimers in C3 symmetry and more recently, the cCPE complex with claudin-4 was resolved, yet still the molecular and mechanistic details of the pathogenesis still remains to clarified. In this study using multi-scale self-assembly simulations, we show that many claudins (including CPE receptor claudin-3/-4), form C3 mediated symmetric interaction in the membrane, that match the receptor orientation for the trimeric CPE toxin. The trimer arrangements presents an electrostatic interaction site that complements the biding pockets in the CPE. We further performed molecular docking and atomistic molecular dynamics to unravel the mechanism of Claudin-CPE interactions. The results correlate well with the experimental results and will be instrumental in designing translational therapeutics utilizing CPE.

Self-assembly of trimeric receptor complex for the Clostridium perfringens enterotoxin

254th National Meeting (2017)

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