Disruption of Claudin-Made Tight Junction Barriers by Clostridium perfringens Enterotoxin: Insights from Structural Biology.
Disruption of Claudin-Made Tight Junction Barriers by Clostridium perfringens Enterotoxin: Insights from Structural Biology.
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Claudin制造的紧密连接屏障被产气荚膜梭菌肠毒素破坏：来自结构生物学的见解。
DOI：
10.3390/cells11050903
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发表时间：
2022-03-05
期刊：
影响因子：
6
通讯作者：
Vecchio AJ
中科院分区：
文献类型：
--
作者：
Ogbu CP;Roy S;Vecchio AJ
claudin是一个完整的膜蛋白家族，通过定位和驱动紧密连接的形成，使上皮细胞/细胞相互作用。通过在邻近细胞的膜内自组装，它们的细胞外结构域相互作用，形成小分子和离子在细胞旁运输的屏障。产气荚膜梭菌（Clostridium perfringens）在哺乳动物中利用一种针对cladin的肠毒素（enterotoxin, CpE）引起普遍的胃肠道疾病。CpE与肠内紧密连接处或附近的cladin结合，并破坏其屏障功能，可能是通过使其组装失能或通过细胞信号途径-机制尚不清楚。CpE最终通过形成细胞毒性膜穿透β桶孔破坏表达claudin的细胞。通过x射线晶体学获得的CpE、claudin和claudin与CpE片段复合物的结构为claudin和CpE功能提供了结构基础，揭示了CpE介导的claudin紧密连接破坏的潜在机制。这篇综述强调了目前在这一领域的进展——已经发现的和未知的——努力阐明CpE破坏紧密结屏障的分子机制。它进一步强调了通过结构获得的关键见解，这些见解正在应用于开发基于cpe的治疗方法，以对抗过表达cludin的癌症或调节紧密连接屏障。
Claudins are a family of integral membrane proteins that enable epithelial cell/cell interactions by localizing to and driving the formation of tight junctions. Via claudin self-assembly within the membranes of adjoining cells, their extracellular domains interact, forming barriers to the paracellular transport of small molecules and ions. The bacterium Clostridium perfringens causes prevalent gastrointestinal disorders in mammals by employing an enterotoxin (CpE) that targets claudins. CpE binds to claudins at or near tight junctions in the gut and disrupts their barrier function, potentially by disabling their assembly or via cell signaling means—the mechanism(s) remain unclear. CpE ultimately destroys claudin-expressing cells through the formation of a cytotoxic membrane-penetrating β-barrel pore. Structures obtained by X-ray crystallography of CpE, claudins, and claudins in complex with CpE fragments have provided the structural bases of claudin and CpE functions, revealing potential mechanisms for the CpE-mediated disruption of claudin-made tight junctions. This review highlights current progress in this space—what has been discovered and what remains unknown—toward efforts to elucidate the molecular mechanism of CpE disruption of tight junction barriers. It further underscores the key insights obtained through structure that are being applied to develop CpE-based therapeutics that combat claudin-overexpressing cancers or modulate tight junction barriers.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
8
作者：
Berndt, Philipp;Winkler, Lars;Haseloff, Reiner F.
通讯作者：
Haseloff, Reiner F.
影响因子：
--
作者：
BRIEHL, MM;MIESFELD, RL
通讯作者：
MIESFELD, RL
DOI：
10.1016/0005-2795(81)90165-3
发表时间：
1981-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
GRANUM, PE;WHITAKER, JR;SKJELKVALE, R
通讯作者：
SKJELKVALE, R
单个基因产物Claudin -1或-2，在成纤维细胞中重构紧密结合的连接链和新兵。
影响因子：
7.8
作者：
Furuse, M;Sasaki, H;Fujimoto, K;Tsukita, S
通讯作者：
Tsukita, S