School of Nano Science , Institute for Research in Fundamental Sciences (IPM) , Tehran 1958914875 , Iran.
Department of Medical Biotechnologies , University of Siena , Siena 53100 , Italy.
J Phys Chem B. 2018 Apr 26;122(16):4407-4417. doi: 10.1021/acs.jpcb.7b12453. Epub 2018 Apr 11.
Calcium release-activated calcium (CRAC) channels open upon depletion of Ca from the endoplasmic reticulum, and when open, they are permeable to a selective flux of calcium ions. The atomic structure of Orai, the pore domain of CRAC channels, from Drosophila melanogaster has revealed many details about conduction and selectivity in this family of ion channels. However, it is still unclear how residues on the third transmembrane helix can affect the conduction properties of the channel. Here, molecular dynamics and Brownian dynamics simulations were employed to analyze how a conserved glutamate residue on the third transmembrane helix (E262) contributes to selectivity. The comparison between the wild-type and mutated channels revealed a severe impact of the mutation on the hydration pattern of the pore domain and on the dynamics of residues K270, and Brownian dynamics simulations proved that the altered configuration of residues K270 in the mutated channel impairs selectivity to Ca over Na. The crevices of water molecules, revealed by molecular dynamics simulations, are perfectly located to contribute to the dynamics of the hydrophobic gate and the basic gate, suggesting a possible role in channel opening and in selectivity function.
钙释放激活钙 (CRAC) 通道在细胞质内质网中钙耗尽时打开，并且当打开时，它们对钙离子的选择性流是可渗透的。来自黑腹果蝇的 Orai 的原子结构，即 CRAC 通道的孔域，揭示了该离子通道家族中关于传导和选择性的许多细节。然而，目前尚不清楚第三跨膜螺旋上的残基如何影响通道的传导特性。在这里，使用分子动力学和布朗动力学模拟来分析第三跨膜螺旋上的保守谷氨酸残基 (E262) 如何有助于选择性。野生型和突变型通道之间的比较表明，该突变对孔域的水合模式以及残基 K270 的动力学具有严重影响，布朗动力学模拟证明了突变通道中残基 K270 的改变构型会损害钙对钠的选择性。分子动力学模拟揭示的水分子缝隙完美地位于贡献疏水门和碱性门的动力学，这表明其可能在通道开放和选择性功能中发挥作用。
