Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
Université Grenoble Alpes, CNRS, CEA, IBS, F-38000, Grenoble, France.
Nat Commun. 2024 Feb 27;15(1):1803. doi: 10.1038/s41467-024-46028-x.
Synaptic receptors respond to neurotransmitters by opening an ion channel across the post-synaptic membrane to elicit a cellular response. Here we use recent Torpedo acetylcholine receptor structures and functional measurements to delineate a key feature underlying allosteric communication between the agonist-binding extracellular and channel-gating transmembrane domains. Extensive mutagenesis at this inter-domain interface re-affirms a critical energetically coupled role for the principal α subunit β1-β2 and M2-M3 loops, with agonist binding re-positioning a key β1-β2 glutamate/valine to facilitate the outward motions of a conserved M2-M3 proline to open the channel gate. Notably, the analogous structures in non-α subunits adopt a locally active-like conformation in the apo state even though each L9' hydrophobic gate residue in each pore-lining M2 α-helix is closed. Agonist binding releases local conformational heterogeneity transitioning all five subunits into a conformationally symmetric open state. A release of conformational heterogeneity provides a framework for understanding allosteric communication in pentameric ligand-gated ion channels.
突触受体通过在突触后膜上打开离子通道来响应神经递质，从而引发细胞反应。在这里，我们使用最近的电鳐乙酰胆碱受体结构和功能测量来描绘配体结合细胞外区域和通道门控跨膜区域之间变构通讯的关键特征。在这个域间界面进行广泛的诱变，再次证实了主要的α亚基β1-β2和 M2-M3 环的关键能量偶联作用，激动剂结合重新定位关键的β1-β2谷氨酸/缬氨酸，以促进保守的 M2-M3 脯氨酸的外向运动，打开通道门。值得注意的是，即使每个孔衬 M2α-螺旋中的每个 L9'疏水性门残基都关闭，非-α亚基中的类似结构在apo 状态下仍采用局部活性样构象。激动剂结合释放局部构象异质性，使所有五个亚基转变为构象对称的开放状态。构象异质性的释放为理解五聚体配体门控离子通道的变构通讯提供了一个框架。
