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

ABSTRACT: 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.

SUBMITTER: Chen P

PROVIDER: S-EPMC6231499 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Chen Peng P Tao Liang L Wang Tianyu T Zhang Jie J He Aina A Lam Kwok-Ho KH Liu Zheng Z He Xi X Perry Kay K Dong Min M Jin Rongsheng R

Science (New York, N.Y.) 20180501 6389

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 ...[more]

PMID: 29748286

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