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

被引：107

作者：

Chen, Peng ^{[1
]}

Tao, Liang ^{[2
,3
]}

Wang, Tianyu ^{[1
]}

Zhang, Jie ^{[2
,3
]}

He, Aina ^{[2
,3
,4
]}

Lam, Kwok-ho ^{[1
]}

Liu, Zheng ^{[1
]}

He, Xi ^{[5
]}

Perry, Kay ^{[6
,7
]}

Dong, Min ^{[2
,3
]}

Jin, Rongsheng ^{[1
]}

机构：

[1] Univ Calif Irvine, Dept Physiol & Biophys, Irvine, CA 92717 USA

[2] Harvard Med Sch, Boston Childrens Hosp, Dept Urol, Dept Microbiol & Immunobiol, Boston, MA 02115 USA

[3] Harvard Med Sch, Dept Surg, Boston, MA 02115 USA

[4] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Oncol, 600 Yishan Rd, Shanghai 200233, Peoples R China

[5] Harvard Med Sch, Dept Neurol, Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA USA

[6] Cornell Univ, Argonne Natl Lab, NE CAT, Argonne, IL USA

[7] Cornell Univ, Argonne Natl Lab, Dept Chem & Chem Biol, Argonne, IL USA

来源：

SCIENCE | 2018年 / 360卷 / 6389期

关键词：

GLUCOSYLATING TOXINS; RECEPTORS; VIRULENCE; DISEASE;

D O I：

10.1126/science.aar1999

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：664 / 669

页数：6

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