Agonist-receptor-arrestin, an alternative ternary complex with high agonist affinity
Agonist-receptor-arrestin, an alternative ternary complex with high agonist affinity
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DOI：
10.1074/jbc.272.46.28849
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发表时间：
1997-11-14
影响因子：
4.8
通讯作者：
Onorato, JJ
中科院分区：
文献类型：
--
作者：
Gurevich, VV;PalsRylaarsdam, R;Onorato, JJ
对持续刺激的反应的迅速降低，通常称为脱敏，是一种广泛的生物学现象。许多G蛋白偶联受体的信号转导似乎通过惊人的统一的两步机制终止，最广泛的特征是β（2）-肾上腺素能受体（β（2）AR），m2毒蕈碱胆碱能受体（m2 muscarinic cholinergic receptor，m2 AR）。该模型预测激活的受体最初被磷酸化，然后紧密结合抑制蛋白，其有效地阻断进一步的G蛋白相互作用，在这里，我们报告说，复合物的β（2）AR-抑制蛋白和m2 mAChR-抑制蛋白有更高的亲和力，激动剂（但不是拮抗剂）比受体不与抑制蛋白复合。在完全激动剂存在下，这种高亲和力状态下磷酸化β 2 AR的百分比随不同的抑制蛋白而变化，并通过抑制蛋白的选择性突变而增强。高亲和力位点的百分比也与激动剂的内在活性成比例，并且比例系数随不同的抑制蛋白而变化。某些突变的抑制蛋白可以与未磷酸化的受体形成这些高亲和力复合物。增强激动剂-受体-抑制蛋白复合物形成的突变应该提供用于操纵信号传导效率和受体内化的速率和特异性的有用工具。
The rapid decrease of a response to a persistent stimulus, often termed desensitization, is a widespread biological phenomenon, Signal transduction by numerous G protein-coupled receptors appears to be terminated by a strikingly uniform two-step mechanism, most extensively characterized for the beta(2)-adrenergic receptor (beta(2)AR), m2 muscarinic cholinergic receptor (m2 mAChR), and rhodopsin, The model predicts that activated receptor is initially phosphorylated and then tightly binds an arrestin protein that effectively blocks further G protein interaction, Here we report that complexes of beta(2)AR-arrestin and m2 mAChR-arrestin have a higher affinity for agonists (but not antagonists) than do receptors not complexed with arrestin. The percentage of phosphorylated beta(2)AR in this high affinity state in the presence of full agonists varied with different arrestins and was enhanced by selective mutations in arrestins, The percentage of high affinity sites also was proportional to the intrinsic activity of an agonist, and the coefficient of proportionality varies for different arrestin proteins. Certain mutant arrestins can form these high affinity complexes with unphosphorylated receptors, Mutations that enhance formation of the agonist-receptor-arrestin complexes should provide useful tools for manipulating both the efficiency of signaling and rate and specificity of receptor internalization.