Chemistry-School of Natural and Environmental Sciences, Newcastle University, Newcastle NE1 7RU, UK.
Newcastle University Centre for Cancer, Newcastle University, Newcastle NE1 7RU, UK.
Int J Mol Sci. 2021 May 22;22(11):5466. doi: 10.3390/ijms22115466.
Cholinergic α7 nicotinic receptors encoded by the gene are ligand-gated ion channels directly related to memory and immunomodulation. Exons 5-7 in can be duplicated and fused to exons A-E of , resulting in a hybrid gene known as , unique to humans. Its product, denoted herein as Dupα7, is a truncated subunit where the N-terminal 146 residues of the ligand binding domain of the α7 receptor have been replaced by 27 residues from FAM7. Dupα7 negatively affects the functioning of α7 receptors associated with neurological disorders, including Alzheimer's diseases and schizophrenia. However, the stoichiometry for the α7 nicotinic receptor containing dupα7 monomers remains unknown. In this work, we developed computational models of all possible combinations of wild-type α7 and dupα7 pentamers and evaluated their stability via atomistic molecular dynamics and coarse-grain simulations. We assessed the effect of dupα7 subunits on the Ca conductance using free energy calculations. We showed that receptors comprising of four or more dupα7 subunits are not stable enough to constitute a functional ion channel. We also showed that models with dupα7/α7 interfaces are more stable and are less detrimental for the ion conductance in comparison to dupα7/dupα7 interfaces. Based on these models, we used protein-protein docking to evaluate how such interfaces would interact with an antagonist, α-bungarotoxin, and amyloid Aβ. Our findings show that the optimal stoichiometry of dupα7/α7 functional pentamers should be no more than three dupα7 monomers, in favour of a dupα7/α7 interface in comparison to a homodimer dupα7/dupα7 interface. We also showed that receptors bearing dupα7 subunits are less sensitive to Aβ effects, which may shed light on the translational gap reported for strategies focused on nicotinic receptors in 'Alzheimer's disease research.
乙酰胆碱能α7 烟碱型受体由 基因编码，是与记忆和免疫调节直接相关的配体门控离子通道。 基因的外显子 5-7 可以重复并融合到 基因的外显子 A-E 中，从而产生一种独特的人类杂交基因，称为 。其产物，在此表示为 Dupα7，是一种截断的亚基，其中α7 受体配体结合域的 N 端 146 个残基被 FAM7 的 27 个残基取代。Dupα7 会对与神经紊乱相关的α7 受体的功能产生负面影响，包括阿尔茨海默病和精神分裂症。然而，包含 dupα7 单体的α7 烟碱受体的化学计量比仍然未知。在这项工作中，我们开发了所有可能的野生型α7 和 dupα7 五聚体组合的计算模型，并通过原子分子动力学和粗粒化模拟对其稳定性进行了评估。我们使用自由能计算评估了 dupα7 亚基对 Ca 电导的影响。我们表明，由四个或更多 dupα7 亚基组成的受体不够稳定，无法构成功能性离子通道。我们还表明，与 dupα7/dupα7 界面相比，具有 dupα7/α7 界面的模型更稳定，并且对离子电导率的损害更小。基于这些模型，我们使用蛋白质-蛋白质对接来评估这些界面将如何与拮抗剂α-银环蛇毒素和淀粉样蛋白 Aβ 相互作用。我们的研究结果表明，dupα7/α7 功能性五聚体的最佳化学计量比不应超过三个 dupα7 单体，与 dupα7/α7 界面相比，dupα7/dupα7 界面更有利于形成二聚体。我们还表明，携带 dupα7 亚基的受体对 Aβ 效应的敏感性较低，这可能有助于解释在“阿尔茨海默病研究”中针对烟碱受体的策略所报道的转化差距。
