Molecular dynamics analyses of CLDN15 pore size and charge selectivity.
Molecular dynamics analyses of CLDN15 pore size and charge selectivity.
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CLDN15 孔径和电荷选择性的分子动力学分析。
DOI：
10.1101/2023.08.16.553400
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Weber,ChristopherR
中科院分区：
文献类型：
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作者：
McGuinness,Sarah;Li,Pan;Li,Ye;Fuladi,Shadi;Konar,Sukanya;Sajjadi,Samaneh;Sidahmed,Mohammed;Li,Yueying;Shen,Le;Araghi,FatemehKhalili;Weber,ChristopherR
Claudin-15（CLDN 15）通道对于胃肠道中的营养物、电解质和水的运输是重要的。我们使用细胞培养研究和分子动力学模拟来阐明其结构和渗透机制。我们提供了一个模型，强调了D55残基在CLDN 15选择性过滤器中的关键作用，它与渗透阳离子相互作用。我们的研究证明了D55残基的大小和电荷影响细胞旁通透性的机制。通过将D55改变为更大的带负电荷的谷氨酸（E）或类似大小的中性天冬酰胺（N），我们分别观察到孔径和选择性的变化。D55 E突变减小了孔径，有利于小离子渗透性而不影响电荷选择性，而D55 N突变导致电荷选择性降低而不显著改变尺寸选择性。这些发现揭示了CLDN 15通道的大小和电荷选择性的复杂相互作用。这些知识可以为开发调节CLDN 15和类似通道功能的策略提供信息，这对健康和疾病中的紧密连接调节具有意义。
The Claudin-15 (CLDN15) channel is important for nutrient, electrolyte, and water transport in the gastrointestinal tract. We used cell culture studies and molecular dynamics simulations to elucidate its structure and permeability mechanisms. We provide a model that underscores the crucial role of the D55 residue in the CLDN15 selectivity filter, which interacts with permeating cations. Our studies demonstrated the mechanisms whereby the size and charge of the D55 residue influence paracellular permeability. By altering D55 to larger, negatively charged glutamic acid (E) or similarly sized neutral asparagine (N), we observed changes in pore size and selectivity, respectively. D55E mutation decreased pore size, favoring small ion permeability without affecting charge selectivity, while D55N mutation led to reduced charge selectivity without markedly altering size selectivity. These findings shed light on the complex interplay of size and charge selectivity of CLDN15 channels. This knowledge can inform the development of strategies to modulate the function of CLDN15 and similar channels, which has implications for tight junction modulation in health and disease.