Structural correlates of human muscle nicotinic acetylcholine receptor subunit assembly mediated by d(+) interface residues
Structural correlates of human muscle nicotinic acetylcholine receptor subunit assembly mediated by d(+) interface residues
复制标题
d()界面残基介导的人肌肉烟碱乙酰胆碱受体亚基组装的结构相关性
DOI：
10.1101/2020.06.11.145466
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Epstein M
中科院分区：
文献类型：
--
作者：
Epstein M
肌肉烟碱乙酰胆碱受体是一类异戊二胺配体门控阳离子通道，其组成亚基采用固定的化学计量排列。然而，控制亚基排序的特定氨基酸残基仅被部分理解。通过整合嵌合nAChR亚基的全原子分子动力学模拟、生物信息学、双电极电压钳电生理学和125i -α-bungarotoxin检测，我们确定了δ亚基的细胞外、跨膜和延伸的M4螺旋上的残基，这些残基形成了有助于不妥协组装规则的结构特征。此外，在α2δ2β受体中观察到的功能差异可以通过在激动剂结合位点表现出的动力学行为变化来解释。
Muscle nicotinic acetylcholine receptors are a class of heteropentameric ligand-gated cation channels with constituent subunits adopting a fixed stoichiometric arrangement. The specific amino acid residues that govern subunit ordering are however, only partially understood. By integrating all-atom molecular dynamics simulations, bioinformatics, two-electrode voltage clamp electrophysiology and125I-α-bungarotoxin assays of chimeric nAChR subunits, we identify residues across the extracellular, transmembrane and extended M4 helix of the δ subunit that make structural signatures that contribute to intransigent assembly rules. Furthermore, functional differences observed in α2δ2β receptors can be rationalized by changes in dynamical behavior that manifest themselves at the agonist binding site.