Normal mode analysis suggests a quaternary twist model for the nicotinic receptor gating mechanism
Normal mode analysis suggests a quaternary twist model for the nicotinic receptor gating mechanism
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DOI：
10.1529/biophysj.104.050229
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发表时间：
2005-06-01
影响因子：
3.4
通讯作者：
Changeux, JP
中科院分区：
文献类型：
--
作者：
Taly, A;Delarue, M;Changeux, JP
我们提出了一个三维模型的同型五聚体α 7烟碱乙酰胆碱受体（nAChR），其中包括细胞外和膜结构域，通过比较建模的基础上：1），X射线晶体结构的蜗牛乙酰胆碱结合蛋白，同源物的细胞外结构域的nAChR;和2），在纹电鳐nAChRs上收集的膜结构域的冷冻电子显微镜数据。我们对完整的三维模型进行了正常模式分析，以探索蛋白质的灵活性。在前10个最低频率模式中，只有第一种模式产生与通道门控相容的结构重组：由蛋白质的协调对称四元扭曲运动与上部（细胞外）和下部（跨膜）结构域的相反旋转引起的通道孔的宽开口。尽管如此，在每个亚基内观察到显著的重组，其涉及它们在结构域界面处的弯曲，构成胞外结构域的两个β-折叠之间的角度增加，内部β-折叠与M2 α-螺旋片段的运动显著相关。五聚体蛋白复合物的这种全局对称扭转运动，类似于其他多聚体离子通道的开放过渡，合理地解释了现有的实验数据，因此可能描述了nAChR门控过程。
We present a three-dimensional model of the homopentameric alpha 7 nicotinic acetylcholine receptor ( nAChR), that includes the extracellular and membrane domains, developed by comparative modeling on the basis of: 1), the x-ray crystal structure of the snail acetylcholine binding protein, an homolog of the extracellular domain of nAChRs; and 2), cryo-electron microscopy data of the membrane domain collected on Torpedo marmorata nAChRs. We performed normal mode analysis on the complete three-dimensional model to explore protein flexibility. Among the first 10 lowest frequency modes, only the first mode produces a structural reorganization compatible with channel gating: a wide opening of the channel pore caused by a concerted symmetrical quaternary twist motion of the protein with opposing rotations of the upper (extracellular) and lower ( transmembrane) domains. Still, significant reorganizations are observed within each subunit, that involve their bending at the domain interface, an increase of angle between the two beta-sheets composing the extracellular domain, the internal beta-sheet being significantly correlated to the movement of the M2 alpha-helical segment. This global symmetrical twist motion of the pentameric protein complex, which resembles the opening transition of other multimeric ion channels, reasonably accounts for the available experimental data and thus likely describes the nAChR gating process.