A Lipid-dependent Uncoupled Conformation of the Acetylcholine Receptor
A Lipid-dependent Uncoupled Conformation of the Acetylcholine Receptor
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DOI：
10.1074/jbc.m900030200
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发表时间：
2009-06-26
影响因子：
4.8
通讯作者：
Baenziger, John E.
中科院分区：
文献类型：
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作者：
daCosta, Corrie J. B.;Baenziger, John E.
脂质影响Cys-loop受体对神经递质结合的反应能力，但其潜在机制尚不清楚。利用来自鱼雷的尼古丁乙酰胆碱受体（nAChR），目前的模型表明脂质调节静止和脱敏构象之间的自然平衡。我们发现脂质失活的nAChR并没有脱敏，相反，它采用了一种新的构象，其神经递质结合位点和跨膜孔之间的变构偶联丧失了。解偶联伴随着先前埋藏残基的揭开，表明结构完整的激动剂结合和跨膜结构域之间的关联减弱。这些数据结合大量关于cys环受体-脂质相互作用的文献表明，M4跨膜螺旋作为脂质传感器起着关键作用，将双层性质转化为改变的nAChR功能。
Lipids influence the ability of Cys-loop receptors to gate open in response to neurotransmitter binding, but the underlying mechanisms are poorly understood. With the nicotinic acetylcholine receptor (nAChR) from Torpedo, current models suggest that lipids modulate the natural equilibrium between resting and desensitized conformations. We show that the lipid-inactivated nAChR is not desensitized, instead it adopts a novel conformation where the allosteric coupling between its neuro-transmitter-binding sites and transmembrane pore is lost. The uncoupling is accompanied by an unmasking of previously buried residues, suggesting weakened association between structurally intact agonist-binding and transmembrane domains. These data combined with the extensive literature on Cys-loop receptor-lipid interactions suggest that the M4 transmembrane helix plays a key role as a lipid-sensor, translating bilayer properties into altered nAChR function.