An allosteric link connecting the lipid-protein interface to the gating of the nicotinic acetylcholine receptor.
An allosteric link connecting the lipid-protein interface to the gating of the nicotinic acetylcholine receptor.
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DOI：
10.1038/s41598-018-22150-x
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发表时间：
2018-03-01
影响因子：
4.6
通讯作者：
Baenziger JE
中科院分区：
文献类型：
--
作者：
Domville JA;Baenziger JE
膜蛋白对脂质敏感的机制具有重要的生物学意义。一个统一的机制问题是如何在脂质-蛋白质界面的结构变化是通过跨膜结构域翻译影响蛋白质功能的关键结构。烟碱乙酰胆碱受体（nAChR）的门控对其脂质环境敏感。为了了解脂质-蛋白质界面的变化如何影响门控，我们检查了M4跨膜α-螺旋最外层面向脂质表面上418位的突变如何改变M4与跨膜结构域其余部分之间的能量耦合。人类肌肉nAChR对位置418处的突变敏感，其中Cys-to-Trp突变导致功能增强16倍，从而导致先天性肌无力综合征。M4和Cys环之间的能量耦合，门控中涉及的关键结构，不随C418 W而改变。相反，Trp 418和相邻的残基与M1跨膜α-螺旋上的残基能量偶联，导致M1重新定向，稳定开放状态。因此，我们确定了连接nAChR的脂质-蛋白质界面改变通道功能的变构链接。
The mechanisms underlying lipid-sensing by membrane proteins is of considerable biological importance. A unifying mechanistic question is how a change in structure at the lipid-protein interface is translated through the transmembrane domain to influence structures critical to protein function. Gating of the nicotinic acetylcholine receptor (nAChR) is sensitive to its lipid environment. To understand how changes at the lipid-protein interface influence gating, we examined how a mutation at position 418 on the lipid-facing surface of the outer most M4 transmembrane α-helix alters the energetic couplings between M4 and the remainder of the transmembrane domain. Human muscle nAChR is sensitive to mutations at position 418, with the Cys-to-Trp mutation resulting in a 16-fold potentiation in function that leads to a congenital myasthenic syndrome. Energetic coupling between M4 and the Cys-loop, a key structure implicated in gating, do not change with C418W. Instead, Trp418 and an adjacent residue couple energetically with residues on the M1 transmembrane α-helix, leading to a reorientation of M1 that stabilizes the open state. We thus identify an allosteric link connecting the lipid-protein interface of the nAChR to altered channel function.
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