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Modulation of adenosine A2a receptor oligomerization by receptor activation and PIP2 interactions
Structure ( IF 5.7 ) Pub Date : 2021-07-15 , DOI: 10.1016/j.str.2021.06.015
Wanling Song 1 , Anna L Duncan 1 , Mark S P Sansom 1
Affiliation  

GPCRs have been shown to form oligomers, which generate distinctive signaling outcomes. However, the structural nature of the oligomerization process remains uncertain. We have characterized oligomeric configurations of the adenosine A2a receptor (A2aR) by combining large-scale molecular dynamics simulations with Markov state models. These oligomeric structures may also serve as templates for studying oligomerization of other class A GPCRs. Our simulation data revealed that receptor activation results in enhanced oligomerization, more diverse oligomer populations, and a more connected oligomerization network. The active state conformation of the A2aR shifts protein-protein association interfaces to those involving intracellular loop ICL3 and transmembrane helix TM6. Binding of PIP2 to A2aR stabilizes protein-protein interactions via PIP2-mediated association interfaces. These results indicate that A2aR oligomerization is responsive to the local membrane lipid environment. This, in turn, suggests a modulatory effect on A2aR whereby a given oligomerization profile favors the dynamic formation of specific supramolecular signaling complexes.



中文翻译:

通过受体激活和 PIP2 相互作用调节腺苷 A2a 受体寡聚化

GPCR 已被证明可以形成寡聚体,从而产生独特的信号转导结果。然而,低聚过程的结构性质仍然不确定。我们通过将大规模分子动力学模拟与马尔可夫状态模型相结合,对腺苷 A2a 受体 (A2aR) 的寡聚构型进行了表征。这些寡聚结构也可以作为研究其他 A 类 GPCR 寡聚化的模板。我们的模拟数据表明,受体激活会导致寡聚化增强、寡聚体群体更加多样化以及寡聚化网络连接更加紧密。A2aR 的活性状态构象将蛋白质-蛋白质结合界面转移到涉及细胞内环 ICL3 和跨膜螺旋 TM6 的界面。PIP 2的绑定A2aR 通过 PIP 2介导的关联界面稳定蛋白质-蛋白质相互作用。这些结果表明 A2aR 寡聚化对局部膜脂质环境有反应。这反过来又表明对 A2aR 的调节作用,由此给定的寡聚化特征有利于特定超分子信号复合物的动态形成。

更新日期:2021-07-15
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