2. Academic Validation
  3. Structural basis for recognition of frizzled proteins by Clostridium difficile toxin B

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

  • Science. 2018 May 11;360(6389):664-669. doi: 10.1126/science.aar1999.
Peng Chen 1,  Liang Tao 2,  Tianyu Wang 1,  Jie Zhang 2,  Aina He 2 3,  Kwok-Ho Lam 1,  Zheng Liu 1,  Xi He 4,  Kay Perry 5,  Min Dong 6,  Rongsheng Jin 7
Affiliations

Affiliations

  • 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. [email protected] [email protected].
  • 7 Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA. [email protected] [email protected].
PMID: 29748286 DOI: 10.1126/science.aar1999
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.

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