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研究揭示梭菌毒素受体特异性的分子基础
作者:小柯机器人 发布时间:2020/6/28 13:56:51

加拿大多伦多大学Mikko Taipale、加拿大病童医院Roman A. Melnyk和Jean-Philippe Julien研究小组合作发现,索氏梭菌致死毒素(TcsL)识别轴突向蛋白揭示了梭菌毒素受体特异性的原理。相关论文于2020年6月25日在线发表于《细胞》杂志。

利用CRISPR / Cas9筛选,研究人员发现轴突向蛋白SEMA6A和SEMA6B是TcsL的受体。研究人员发现重组SEMA6A可以保护小鼠免受TcsL导致的水肿。3.3Å冷冻电镜结构表明TcsL与SEMA6A的结合区域与TcdB中与结构无关卷曲蛋白结合的区域相同。值得注意的是,处在不同进化面上的15个突变足以将TcsL的结合特异性区域转换为TcdB的结合特异性区域。该发现表明轴突向蛋白是TcsL生理相关的受体,并揭示了高度相关毒素之间组织靶向和发病机制差异的分子基础。

据介绍,致病性梭菌属细菌会分泌强效毒素,其可诱导严重的宿主组织损伤。TcsL可诱发与致命性妇科感染相关的中毒性休克综合症。TcsL与艰难梭菌TcdB相似,后者通过结肠上皮细胞的卷曲受体进入宿主细胞。然而,索氏梭菌感染靶向血管内皮细胞,这表明TcsL利用了另一种受体。

附:英文原文

Title: Recognition of Semaphorin Proteins by P. sordellii Lethal Toxin Reveals Principles of Receptor Specificity in Clostridial Toxins

Author: Hunsang Lee, Greg L. Beilhartz, Iga Kucharska, Swetha Raman, Hong Cui, Mandy Hiu Yi Lam, Huazhu Liang, John L. Rubinstein, Daniel Schramek, Jean-Philippe Julien, Roman A. Melnyk, Mikko Taipale

Issue&Volume: 2020-06-25

Abstract: Pathogenic clostridial species secrete potent toxins that induce severe host tissue damage. Paeniclostridium sordellii lethal toxin (TcsL) causes an almost invariably lethal toxic shock syndrome associated with gynecological infections. TcsL is 87% similar to C. difficile TcdB, which enters host cells via Frizzled receptors in colon epithelium. However, P. sordellii infections target vascular endothelium, suggesting that TcsL exploits another receptor. Here, using CRISPR/Cas9 screening, we establish semaphorins SEMA6A and SEMA6B as TcsL receptors. We demonstrate that recombinant SEMA6A can protect mice from TcsL-induced edema. A 3.3 cryo-EM structure shows that TcsL binds SEMA6A with the same region that in TcdB binds structurally unrelated Frizzled. Remarkably, 15 mutations in this evolutionarily divergent surface are sufficient to switch binding specificity of TcsL to that of TcdB. Our findings establish semaphorins as physiologically relevant receptors for TcsL and reveal the molecular basis for the difference in tissue targeting and disease pathogenesis between highly related toxins.

DOI: 10.1016/j.cell.2020.06.005

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30692-9

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/