Structural basis for recognition of frizzled proteins by Clostridium difficile toxin B

Clostridium difficile infection is the most common cause of antibiotic-associated diarrhea in developed countries. The major virulence factor, C. difficile toxin B (TcdB), targets colonic epithelia by binding to the frizzled (FZD) family of Wnt receptors, but how TcdB recognizes FZDs is unclear. Here, we present the crystal structure of a TcdB fragment in complex with the cysteine-rich domain of human FZD2 at 2.5-angstrom resolution, which reveals an endogenous FZD-bound fatty acid acting as a co-receptor for TcdB binding. This lipid occupies the binding site for Wnt-adducted palmitoleic acid in FZDs. TcdB binding locks the lipid in place, preventing Wnt from engaging FZDs and signaling. Our findings establish a central role of fatty acids in FZD-mediated TcdB pathogenesis and suggest strategies to modulate Wnt signaling.

Source: ScienceNOW - May 10, 2018 Category: Science Authors: Chen, P., Tao, L., Wang, T., Zhang, J., He, A., Lam, K.-h., Liu, Z., He, X., Perry, K., Dong, M., Jin, R. Tags: Biochemistry, Microbiology reports Source Type: news