Architecture of the paracellular channels formed by claudins of the blood-brain barrier tight junctions
Architecture of the paracellular channels formed by claudins of the blood-brain barrier tight junctions
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DOI：
10.1111/nyas.13378
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发表时间：
2017-10-01
影响因子：
5.2
通讯作者：
Nangia, Shikha
中科院分区：
文献类型：
--
作者：
Irudayanathan, Flaviyan Jerome;Wang, Nan;Nangia, Shikha
紧密连接（TJ）是决定跨上皮膜和内皮膜的组织特异性细胞旁通透性的关键因素。 Claudin 蛋白是 TJ 结构和功能的主要决定因素，在细胞旁空间中组装形成具有电荷和尺寸选择性的通道和孔。在这里，我们利用分子动力学 (MD) 模拟，阐明了血脑屏障 TJ 的claudin-3 和claudin-5 蛋白的分子组装。尽管具有高度的序列和结构相似性，但这两种紧密蛋白形成不同类型的顺式相互作用。观察到的顺式界面与反式界面的分子对接揭示了两种假定的孔隙模型，这两种模型也在自组装模拟中观察到。观察到的孔隙结构（孔隙 I 和 II）具有先前文献中报道过的孔隙衬里残留物。 pore I 模型与之前报道的claudin-15 模型一致。 pore II模型也与生化结果一致，此前未见报道。使用计算机定点突变进行的进一步分析为 pore II 模型的有效性提供了令人信服的支持。使用定向 MD 和伞式采样，我们计算了水和 α-D-葡萄糖通过孔隙 II 的传输特性。该研究为血脑屏障 TJ 的选择性提供了新的见解。
Tight junctions (TJs) are key players in determining tissue-specific paracellular permeability across epithelial and endothelial membranes. Claudin proteins, the primary determinants of TJs structure and functionality, assemble in paracellular spaces to form channels and pores that are charge and size selective. Here, using molecular dynamics (MD) simulations, we elucidate the molecular assembly of claudin-3 and claudin-5 proteins of blood-brain barrier TJs. Despite having a high degree of sequence and structural similarity, these two claudins form different types of cis-interactions. Molecular docking of the observed cis-interfaces into trans-forms revealed two putative pore models that were also observed in the self-assembly simulations. The observed pore structures (pore I and II) have pore-lining residues that have been previously reported in the literature. The pore I model is consistent with a previously reported claudin-15 model. The pore II model, also consistent with biochemical results, has not been reported previously. Further analysis using in silico site-directed mutations provide convincing support for the validity of the pore II model. Using steered MD and umbrella sampling, we computed the transport properties of water and alpha-D-glucose through pore II. The study offers new insight into the selectivity of blood-brain barrier TJs.