Claudin-9 structures reveal mechanism for toxin-induced gut barrier breakdown.
Claudin-9 structures reveal mechanism for toxin-induced gut barrier breakdown.
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Claudin-9 结构揭示了毒素诱导肠道屏障破坏的机制。
DOI：
10.1073/pnas.1908929116
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发表时间：
2019
影响因子：
11.1
通讯作者：
Stroud,RobertM
中科院分区：
文献类型：
--
作者：
Vecchio,AlexJ;Stroud,RobertM
人类致病菌产气荚膜梭菌分泌一种肠毒素（CpE），通过其C末端受体结合结构域（cCpE）靶向claudin。CpE的同种型特异性结合导致紧密连接蛋白和紧密连接（TJ）的解离，导致细胞毒性和肠上皮屏障的破坏。在这里，我们呈现了与cCpE在3.2和3.3 nm处复合的人密蛋白-9（hCLDN-9）的晶体结构。我们表明，hCLDN-9是一种高亲和力的CpE受体，hCLDN-9表达细胞经历细胞死亡时，处理与CpE，但不cCpE，缺乏其细胞毒性结构域。结构揭示了cCpE诱导的2个表位的改变，已知这些表位能够使密蛋白自组装，并暴露hCLDN-9和cCpE之间的高亲和力相互作用，这解释了亚型特异性识别。这些发现阐明了hCLDN-9选择性离子渗透性和CpE结合的分子基础，并提供了CpE如何通过解离密封蛋白和TJ影响上皮粘附和细胞间转运来破坏肠道稳态的机制。
The human pathogenic bacteriumClostridium perfringenssecretes an enterotoxin (CpE) that targets claudins through its C-terminal receptor-binding domain (cCpE). Isoform-specific binding by CpE causes dissociation of claudins and tight junctions (TJs), resulting in cytotoxicity and breakdown of the gut epithelial barrier. Here, we present crystal structures of human claudin-9 (hCLDN-9) in complex with cCpE at 3.2 and 3.3 Å. We show that hCLDN-9 is a high-affinity CpE receptor and that hCLDN-9–expressing cells undergo cell death when treated with CpE but not cCpE, which lacks its cytotoxic domain. Structures reveal cCpE-induced alterations to 2 epitopes known to enable claudin self-assembly and expose high-affinity interactions between hCLDN-9 and cCpE that explain isoform-specific recognition. These findings elucidate the molecular bases for hCLDN-9 selective ion permeability and binding by CpE, and provide mechanisms for how CpE disrupts gut homeostasis by dissociating claudins and TJs to affect epithelial adhesion and intercellular transport.