Structural dynamics of receptor recognition and pH-induced dissociation of full-length Clostridioides difficile Toxin B.
Structural dynamics of receptor recognition and pH-induced dissociation of full-length Clostridioides difficile Toxin B.
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DOI：
10.1371/journal.pbio.3001589
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发表时间：
2022-03
期刊：
影响因子：
9.8
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Jiang M;Shin J;Simeon R;Chang JY;Meng R;Wang Y;Shinde O;Li P;Chen Z;Zhang J
艰难梭菌分泌毒素B（TcdB）作为其主要毒力因子之一，其结合肠上皮和上皮下受体，包括卷曲蛋白和硫酸软骨素蛋白聚糖4（CSPG 4）。在这里，我们提出了全长TcdB的cryo-EM结构与CSPG 4结构域1片段（D1401-560）在胞质pH值和卷曲蛋白2（CRD 2）的富含半胱氨酸的结构域在胞质和酸性pH值的复合物。CSPG 4通过盐桥、疏水和芳香族/脯氨酸相互作用的网络特异性结合TcdB的自动加工和递送结构域，其在酸化后被破坏，最终导致CSPG 4从TcdB急剧解离。相比之下，FZD 2在酸性pH下从TcdB适度解离，最可能是由于其部分解折叠。这些结果揭示了TcdB在其进入核内体酸化前的结构动力学，为开发抗C.艰难感染。艰难梭菌分泌毒素B（TcdB）作为其主要毒力因子之一，其结合肠道受体。TcdB与卷曲蛋白-2和硫酸软骨素蛋白聚糖4复合的结构研究揭示了TcdB如何与人类受体结合并为宿主进入做好准备。
Clostridioides difficile secretes Toxin B (TcdB) as one of its major virulence factors, which binds to intestinal epithelial and subepithelial receptors, including frizzled proteins and chondroitin sulfate proteoglycan 4 (CSPG4). Here, we present cryo-EM structures of full-length TcdB in complex with the CSPG4 domain 1 fragment (D1401-560) at cytosolic pH and the cysteine-rich domain of frizzled-2 (CRD2) at both cytosolic and acidic pHs. CSPG4 specifically binds to the autoprocessing and delivery domains of TcdB via networks of salt bridges, hydrophobic and aromatic/proline interactions, which are disrupted upon acidification eventually leading to CSPG4 drastically dissociating from TcdB. In contrast, FZD2 moderately dissociates from TcdB under acidic pH, most likely due to its partial unfolding. These results reveal structural dynamics of TcdB during its preentry step upon endosomal acidification, which provide a basis for developing therapeutics against C. difficile infections. Clostridioides difficile secretes Toxin B (TcdB) as one of its major virulence factors, which binds to intestinal receptors. This structural study of TcdB in complex with frizzled-2 and chondroitin sulfate proteoglycan 4 reveals how TcdB binds to human receptors and primes itself for host entry.
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