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Activation Microswitches in Adenosine Receptor A2A Function as Rheostats in the Cell Membrane
Biochemistry ( IF 2.9 ) Pub Date : 2020-10-15 , DOI: 10.1021/acs.biochem.0c00626
Ning Ma 1 , Sangbae Lee 1 , Nagarajan Vaidehi 1
Affiliation  

Although multiple components of the cell membrane modulate the stability and activation of G protein-coupled receptors (GPCRs), insights into the dynamics of GPCR structures come from biophysical studies conducted in detergents. This is because of the challenges of studying activation in a multicomponent lipid bilayer. To understand the role of cellular membrane lipids and cations in GPCR activation, we performed multiscale molecular dynamics simulations (56 μs) on three different conformational states of adenosine receptor A2AR, in both the cell membrane-like lipid bilayer and in detergent micelles. Molecular dynamics (MD) simulations show that the phosphatidylinositol bisphosphate (PIP2) interacts with the basic residues in the intracellular regions of A2AR, thereby reducing the flexibility of the receptor in the inactive state and limiting the transition to the active-intermediate state. In the G protein-coupled fully active state, PIP2 stabilizes the GPCR:G protein complex. Such stiffening effects are absent in non-ionic detergent micelles, and therefore, more transitions have been observed in detergents. The inter-residue distances that change significantly upon GPCR activation are known as activation microswitches. The activation microswitches show different levels of activation in the cell membrane, in the pure POPC bilayer, and in detergents. Thus, the temporal heat map of different activation microswitches calculated from the MD simulations suggests a rheostat model of GPCR activation microswitches rather than the binary switch model. These simulation results connect the chemistry of cell membrane lipids to receptor activity, which is useful for the design of detergents mimicking the cell membrane.

中文翻译:

腺苷受体 A2A 中的激活微开关充当细胞膜中的变阻器

尽管细胞膜的多种成分调节 G 蛋白偶联受体 (GPCR) 的稳定性和激活,但对 GPCR 结构动态的深入了解来自于在洗涤剂中进行的生物物理研究。这是因为研究多组分脂质双层的激活存在挑战。为了了解细胞膜脂质和阳离子在 GPCR 激活中的作用,我们对细胞膜样脂质双层和洗涤剂胶束中腺苷受体 A 2A R 的三种不同构象状态进行了多尺度分子动力学模拟 (56 μs)。分子动力学(MD)模拟表明,磷脂酰肌醇二磷酸(PIP2)与A 2A R细胞内区域的碱性残基相互作用,从而降低受体在非活性状态下的灵活性并限制向活性中间状态的转变。在 G 蛋白偶联完全激活状态下,PIP2 稳定 GPCR:G 蛋白复合物。非离子洗涤剂胶束不存在这种硬化效应,因此,在洗涤剂中观察到更多的转变。GPCR 激活后显着变化的残基间距离称为激活微开关。激活微开关在细胞膜、纯 POPC 双层和洗涤剂中显示出不同程度的激活。因此,根据 MD 模拟计算出的不同激活微开关的时间热图表明 GPCR 激活微开关的变阻器模型而不是二进制开关模型。这些模拟结果将细胞膜脂质的化学性质与受体活性联系起来,这对于设计模拟细胞膜的去垢剂非常有用。
更新日期:2020-10-28
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