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Science. 2018 May 11;360(6389):664-669. doi: 10.1126/science.aar1999.

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

Author information

1
Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
2
Department of Urology, Boston Children's Hospital, Department of Microbiology and Immunobiology and Department of Surgery, Harvard Medical School, Boston, MA, USA.
3
Department of Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, No. 600, Yishan Road, 200233 Shanghai, PRC.
4
F. M. Kirby Neurobiology Center, Boston Children's Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
5
NE-CAT and Department of Chemistry and Chemical Biology, Cornell University, Argonne National Laboratory, Argonne, IL, USA.
6
Department of Urology, Boston Children's Hospital, Department of Microbiology and Immunobiology and Department of Surgery, Harvard Medical School, Boston, MA, USA. r.jin@uci.edu min.dong@childrens.harvard.edu.
7
Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA. r.jin@uci.edu min.dong@childrens.harvard.edu.

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.

PMID:
29748286
PMCID:
PMC6231499
[Available on 2019-05-11]
DOI:
10.1126/science.aar1999
[Indexed for MEDLINE]

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