Science:艰难梭菌毒素B如何结合卷曲蛋白以靶向结肠上皮

Science

5/11/18Article

37.205

影响因子

原标题:艰难梭菌毒素B识别卷曲蛋白的结构基础

① 艰难梭菌的主要毒力因子——艰难梭菌毒素B(TcdB)通过结合Wnt受体中的卷曲蛋白(FZD)家族以靶向结肠上皮;② 以2.5埃的分辨率解析TcdB片段与人FZD2的富半胱氨酸结构域结合的复合物晶体结构,揭示了与FZD结合的内源性脂肪酸可作为TcdB结合的共受体;③ 这类脂肪酸占据了FZD中的棕榈油酸结合位点(Wnt与FZD结合的位点);④ TcdB结合将该脂质锁定在适当位置,抑制Wnt结合FZD及Wnt信号通路的激活。

艰难梭菌毒素B 卷曲蛋白

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

DOI:
10.1126/science.aar1999

Abstract & Authors展开

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.

All Authors:
Peng Chen, Liang Tao, Tianyu Wang, Jie Zhang, Aina He, Kwok-ho Lam, Zheng Liu, Xi He, Kay Perry, Min Dong, Rongsheng Jin

First Authors:
Peng Chen, Liang Tao

Correspondence:
Min Dong, Rongsheng Jin

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