Biophysical characterization of interactions between the C-termini of peripheral nerve claudins and the PDZ₁ domain of zonula occludens.
Biophysical characterization of interactions between the C-termini of peripheral nerve claudins and the PDZ₁ domain of zonula occludens.
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DOI：
10.1016/j.bbrc.2015.02.075
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发表时间：
2015-03-27
影响因子：
3.1
通讯作者：
Li, Jun
中科院分区：
文献类型：
--
作者：
Wu, Jiawen;Peng, Dungeng;Zhang, Yang;Lu, Zhenwei;Voehler, Markus;Sanders, Charles R.;Li, Jun
关键词：
我们最近的研究表明，包裹神经纤维的髓鞘和外膜/髓周膜中的细胞连接调节周围神经的通透性。这种渗透性可能会影响动作电位的传播。闭锁小带(ZO1或ZO2)的PDZ1结构域与Claudins的C末端之间的直接相互作用对于紧密连接的形成是至关重要的。利用纯化的ZO2的PDZ1结构域和周围神经Claudins的各种C端突变体(Claudin-1、Claudin-2、Claudin-3、Claudin-5在外膜/神经膜；Claudin-19在髓鞘中)，我们利用核磁共振技术确定了3个C端的Claudin残基(位置-2、-1、0)与ZO2的PDZ1相互作用的具体作用。与强调-2和0位残基重要性的经典模型不同，我们的结果表明，对于周围神经Claudins，-1位残基在与PDZ1相关的过程中起着关键作用，而残基0的侧链起着重要的作用，但作用较小。令人惊讶的是，髓鞘中含量最丰富的claudin-19没有与ZO2结合。这些发现表明，Claudin/ZO在外膜/外膜的结合机制不同于非ZO-PDZ蛋白与其配体之间的典型相互作用。这一观察结果为开发针对周围神经外膜/神经外膜紧密连接的药物提供了分子基础。
Our recent study has shown that cellular junctions in myelin and in the epi-/perineruium that encase nerve fibers regulate the permeability of the peripheral nerves. This permeability may affect propagation of the action potential. Direct interactions between the PDZ1 domain of zonula occludens (ZO1 or ZO2) and the C-termini of claudins are known to be crucial for the formation of tight junctions. Using the purified PDZ1 domain of ZO2 and a variety of C-terminal mutants of peripheral nerve claudins (claudin-1, claudin-2, claudin-3, claudin-5 in epi-/perineurium; claudin-19 in myelin), we have utilized NMR spectroscopy to determine specific roles of the 3 C-terminal claudin residues (position -2, -1, 0) for their interactions with PDZ1 of ZO2. In contrast to the canonical model that emphasizes the importance of residues at the -2 and 0 positions, our results demonstrate that, for peripheral nerve claudins, the residue at position -1 plays a critical role in association with PDZ1, while the side-chain of residue 0 plays a significant but lesser role. Surprisingly, claudin-19, the most abundant claudin in myelin, exhibited no binding to ZO2. These findings reveal that the binding mechanism of claudin/ZO in epi-/perineurium is distinct from the canonical interactions between non-ZO PDZ-containing proteins with their ligands. This observation provides the molecular basis for a strategy to develop drugs that target tight junctions in the epi-/perineurium of peripheral nerves.
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三个紧密连接相关的Maguks ZO-1，ZO-2和ZO-3与Claudins的Cooh Termini直接结合。
DOI：
10.1083/jcb.147.6.1351
发表时间：
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期刊：
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影响因子：
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