Role of the Fourth Transmembrane α Helix in the Allosteric Modulation of Pentameric Ligand-Gated Ion Channels
Role of the Fourth Transmembrane α Helix in the Allosteric Modulation of Pentameric Ligand-Gated Ion Channels
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DOI：
10.1016/j.str.2015.06.020
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发表时间：
2015-09-01
期刊：
影响因子：
5.7
通讯作者：
Baenziger, John E.
中科院分区：
文献类型：
--
作者：
Carswell, Casey L.;Henault, Camille M.;Baenziger, John E.
五聚体配体门控离子通道的门控对多种变构调节剂敏感，所述变构调节剂作用于从激动剂位点通向通道门控的变构途径中所涉及的那些结构的外围结构。其中一种结构，即M4，是脂质、神经类固醇和致病突变的靶点。在这里，我们表明，M4与相邻的跨膜α螺旋，M1和M3的相互作用，调节pLGIC功能。增强的M4相互作用促进通道功能，而无效的相互作用降低通道功能。界面化学控制M4-M1/M3螺旋间相互作用的内在强度，既影响通道门控，又赋予面向脂质的M4先天性肌无力综合征突变的增强效应不同的亲和力。通过芳香取代，功能研究和分子动力学模拟，我们阐明了M4调节通道功能的机制。
The gating of pentameric ligand-gated ion channels is sensitive to a variety of allosteric modulators that act on structures peripheral to those involved in the allosteric pathway leading from the agonist site to the channel gate. One such structure, the lipidexposed transmembrane alpha helix, M4, is the target of lipids, neurosteroids, and disease-causing mutations. Here we show that M4 interactions with the adjacent transmembrane alpha helices, M1 and M3, modulate pLGIC function. Enhanced M4 interactions promote channel function while ineffective interactions reduce channel function. The interface chemistry governs the intrinsic strength of M4-M1/M3 inter-helical interactions, both influencing channel gating and imparting distinct susceptibilities to the potentiating effects of a lipid-facing M4 congenital myasthenic syndrome mutation. Through aromatic substitutions, functional studies, and molecular dynamics simulations, we elucidate a mechanism by which M4 modulates channel function.