A stepwise mechanism for acetylcholine receptor channel gating
A stepwise mechanism for acetylcholine receptor channel gating
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DOI：
10.1038/nature05721
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发表时间：
2007-04-19
期刊：
影响因子：
64.8
通讯作者：
Auerbach, Anthony
中科院分区：
文献类型：
--
作者：
Purohit, Prasad;Mitra, Ananya;Auerbach, Anthony
肌肉收缩是由脊椎动物神经-肌肉突触处乙酰胆碱受体的开放触发的（1-4）。这种变构膜蛋白的M2螺旋排列在通道上，并包含一个调节离子通过孔的“门”。我们使用单分子动力学分析来探测门控构象变化的过渡状态，并估计小鼠乙酰胆碱受体α亚基中M2运动的相对时间（5）。该分析为给定残基产生了“Phi值”，反映了其在过渡态的开放式与封闭式特征。在这里，我们表明，大多数残基在整个长度的M2具有类似于0.64的Phi值，但一些接近中间具有较低的Phi值0.52或0.31，这表明α M2移动在三个离散的步骤。通道的核心既充当调节离子流的门，又充当引导门控异构化通过乙酰胆碱受体的膜结构域传播的枢纽。
Muscle contraction is triggered by the opening of acetylcholine receptors at the vertebrate nerve - muscle synapse(1-4). The M2 helix of this allosteric membrane protein lines the channel, and contains a 'gate' that regulates the flow of ions through the pore. We used single-molecule kinetic analysis to probe the transition state of the gating conformational change and estimate the relative timing of M2 motions in the alpha-subunit of the murine acetylcholine receptor(5). This analysis produces a 'Phi-value' for a given residue that reflects its open-like versus closed-like character at the transition state. Here we show that most of the residues throughout the length of M2 have a Phi-value of similar to 0.64 but that some near the middle have lower Phi-values of 0.52 or 0.31, suggesting that alpha M2 moves in three discrete steps. The core of the channel serves both as a gate that regulates ion flow and as a hub that directs the propagation of the gating isomerization through the membrane domain of the acetylcholine receptor.