Molecular determination of claudin-15 organization and channel selectivity.
Molecular determination of claudin-15 organization and channel selectivity.
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DOI：
10.1085/jgp.201711868
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发表时间：
2018-07-02
期刊：
影响因子：
--
通讯作者：
Khalili-Araghi F
中科院分区：
文献类型：
--
作者：
Samanta P;Wang Y;Fuladi S;Zou J;Li Y;Shen L;Weber C;Khalili-Araghi F
克拉丁家族的成员在相邻的上皮细胞和内皮细胞之间形成紧密的连接。Samanta等人。利用分子动力学模拟建立了Claudin-15的原子模型，得出结论是四个Claudin-15分子各自贡献了一个天冬氨酸残基来形成选择性过滤器。紧密连接是横跨上皮细胞和内皮细胞相邻细胞之间的大分子结构。Claudin家族的成员以电荷和大小选择性的方式确定紧密连接的渗透性。在这里，我们使用分子动力学模拟来建立和改进Claudin-15通道的原子模型，并研究其输运性质。我们的模拟表明，claudin-15为离子和分子形成了明确的通道，并通过疏水相互作用密封了细胞旁空间。根据野生型和突变通道的模拟轨迹计算的离子电流反映了体外测量结果。模拟表明，选择性过滤器是由四个Claudin-15分子贡献的四个天冬氨酸残基(D55)组成的笼子，这产生了有利于阳离子通量而不是阴离子通量的负静电势。D55的电荷反转或电荷消融突变显著降低了硅胶和体外的阳离子通透性，而其他带负电荷的孔道氨基酸残基的突变对通道通透性和选择性的影响要小得多。模拟还表明，水和小离子可以穿过孔道，但较大的阳离子，如四甲基铵，不会穿过孔道。因此，我们的模型提供了Claudin通道的原子视图、它们的传输功能以及其选择性过滤器的潜在三维组织。
Members of the claudin family form tight junctions between adjacent epithelial and endothelial cells. Samanta et al. build an atomic model of claudin-15 using molecular dynamics simulations and conclude that four claudin-15 molecules each contribute an aspartic acid residue to form a selectivity filter. Tight junctions are macromolecular structures that traverse the space between adjacent cells in epithelia and endothelia. Members of the claudin family are known to determine tight junction permeability in a charge- and size-selective manner. Here, we use molecular dynamics simulations to build and refine an atomic model of claudin-15 channels and study its transport properties. Our simulations indicate that claudin-15 forms well-defined channels for ions and molecules and otherwise “seals” the paracellular space through hydrophobic interactions. Ionic currents, calculated from simulation trajectories of wild-type as well as mutant channels, reflect in vitro measurements. The simulations suggest that the selectivity filter is formed by a cage of four aspartic acid residues (D55), contributed by four claudin-15 molecules, which creates a negative electrostatic potential to favor cation flux over anion flux. Charge reversal or charge ablation mutations of D55 significantly reduce cation permeability in silico and in vitro, whereas mutations of other negatively charged pore amino acid residues have a significantly smaller impact on channel permeability and selectivity. The simulations also indicate that water and small ions can pass through the channel, but larger cations, such as tetramethylammonium, do not traverse the pore. Thus, our model provides an atomic view of claudin channels, their transport function, and a potential three-dimensional organization of its selectivity filter.
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影响因子：
5.2
作者：
Irudayanathan, Flaviyan Jerome;Wang, Nan;Nangia, Shikha
通讯作者：
Nangia, Shikha
影响因子：
5.5
作者：
Colegio, OR;Van Itallie, C;Anderson, JM
通讯作者：
Anderson, JM
影响因子：
2.4
作者：
CLAUDE, P
通讯作者：
CLAUDE, P
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
紧密连接链内和之间异质claudin物种相互作用的方式。
影响因子：
7.8
作者：
Furuse, M;Sasaki, H;Tsukita, S
通讯作者：
Tsukita, S