The Impact of Mutation L138F/L210F on the Orai Channel: A Molecular Dynamics Simulation Study.
The Impact of Mutation L138F/L210F on the Orai Channel: A Molecular Dynamics Simulation Study.
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突变 L138F/L210F 对 Orai 通道的影响：分子动力学模拟研究
DOI：
10.3389/fmolb.2021.755247
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发表时间：
2021
影响因子：
5
通讯作者：
Song C
中科院分区：
文献类型：
--
作者：
Zhang X;Yu H;Liu X;Song C
由奥赖通道和STIM蛋白组成的钙释放激活钙通道（CRAC）在维持细胞内钙离子浓度方面起着至关重要的作用。先前的研究表明，人类Orai1中的L138F突变产生了一个独立于STIM的组成性开放通道，导致严重的肌病，但L138F突变如何激活Orai1仍不清楚。本文基于果蝇奥赖（d奥赖）的晶体结构，对野生型（WT）和L210 F（对应于人Orai 1中的L138 F）突变体进行了分子动力学模拟，研究了它们的结构和动力学性质。结果表明，L210F dOrai突变体倾向于具有更多的水合疏水区域（V174至F171），以及更多的扩张碱性区域（K163至R155）和选择性过滤器（E178）。钠离子位于更深的突变体比野生型。进一步的分析揭示了两个局部但本质的构象变化，这可能是激活的关键。发现F210的旋转（先前未描述的特征）导致K163门通过疏水相互作用打开。与此同时，F171的逆时针旋转在突变体中发生得更频繁，导致更宽的疏水门和更多的水合作用。最终，两个门的打开可以促进独立于STIM的奥赖通道的打开。
The calcium release-activated calcium (CRAC) channel, composed of the Orai channel and the STIM protein, plays a crucial role in maintaining the Ca2+ concentration in cells. Previous studies showed that the L138F mutation in the human Orai1 creates a constitutively open channel independent of STIM, causing severe myopathy, but how the L138F mutation activates Orai1 is still unclear. Here, based on the crystal structure of Drosophila melanogaster Orai (dOrai), molecular dynamics simulations for the wild-type (WT) and the L210F (corresponding to L138F in the human Orai1) mutant were conducted to investigate their structural and dynamical properties. The results showed that the L210F dOrai mutant tends to have a more hydrated hydrophobic region (V174 to F171), as well as more dilated basic region (K163 to R155) and selectivity filter (E178). Sodium ions were located deeper in the mutant than in the WT. Further analysis revealed two local but essential conformational changes that may be the key to the activation. A rotation of F210, a previously undescribed feature, was found to result in the opening of the K163 gate through hydrophobic interactions. At the same time, a counter-clockwise rotation of F171 occurred more frequently in the mutant, resulting in a wider hydrophobic gate with more hydration. Ultimately, the opening of the two gates may facilitate the opening of the Orai channel independent of STIM.
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影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
DOI：
10.1126/science.1228757
发表时间：
2012-12-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hou X;Pedi L;Diver MM;Long SB
通讯作者：
Long SB
影响因子：
64.8
作者：
McNally, Beth A.;Somasundaram, Agila;Yamashita, Megumi;Prakriya, Murali
通讯作者：
Prakriya, Murali
影响因子：
7.3
作者：
Frischauf I;Litviňuková M;Schober R;Zayats V;Svobodová B;Bonhenry D;Lunz V;Cappello S;Tociu L;Reha D;Stallinger A;Hochreiter A;Pammer T;Butorac C;Muik M;Groschner K;Bogeski I;Ettrich RH;Romanin C;Schindl R
通讯作者：
Schindl R
影响因子：
4.5
作者：
Feske, Stefan
通讯作者：
Feske, Stefan