ARRESTIN INTERACTIONS WITH G-PROTEIN-COUPLED RECEPTORS - DIRECT BINDING-STUDIES OF WILD-TYPE AND MUTANT ARRESTINS WITH RHODOPSIN, BETA(2)-ADRENERGIC, AND M2-MUSCARINIC CHOLINERGIC RECEPTORS
ARRESTIN INTERACTIONS WITH G-PROTEIN-COUPLED RECEPTORS - DIRECT BINDING-STUDIES OF WILD-TYPE AND MUTANT ARRESTINS WITH RHODOPSIN, BETA(2)-ADRENERGIC, AND M2-MUSCARINIC CHOLINERGIC RECEPTORS
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DOI：
10.1074/jbc.270.2.720
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发表时间：
1995-01-13
影响因子：
4.8
通讯作者：
BENOVIC, JL
中科院分区：
文献类型：
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作者：
GUREVICH, VV;DION, SB;BENOVIC, JL
阻滞素在G蛋白偶联受体启动的猝灭信号转导中起重要作用。为了探索arrestin-受体相互作用的特异性，我们已经表征了各种野生型抑制素与视紫红质、β(2)-肾上腺素能受体(beta(2)AR)和m2 M胆碱能受体(M2 MAChR)的结合能力，视觉arrestin被发现是最具选择性的，因为它最好地区分了被测试的三种不同的受体(与视紫红质的结合最高)，以及受体的磷酸化和激活状态(与任何其他形式的视紫红质相比，与磷酸化的光激活形式的视紫红质的结合比与其他形式的视紫红质高10倍)。虽然β-arrestin和arrestin 3也被发现优先与给定受体的磷酸化激活形式结合，但它们仅在所测试的三种受体中进行了适度的区分。为了探索Arrestin功能中重要的结构特征，我们构造了一系列截断和嵌合的拦阻因子。对各种突变的阻滞素结合特性的分析表明，一个共同的分子机制参与决定受体结合的选择性。参与arrestin结合的结构元件包括：1)C-末端酸性区域，在控制arrestin与受体的磷酸化和活化形式的结合选择性方面起调节作用，而不直接参与受体相互作用；2)碱性N-末端结构域，直接参与受体相互作用，并似乎通过与C-末端酸性区域的分子内相互作用起调节作用；以及3)两个中心定位的区域，直接参与决定受体结合的特异性和选择性。提出了一个比较的结构-功能模型和β-arrestin和arrestin 3与受体相互作用的动力学模型。
Arrestins play an important role in quenching signal transduction initiated by G protein-coupled receptors. To explore the specificity of arrestin-receptor interaction, we have characterized the ability of various wildtype arrestins to bind to rhodopsin, the beta(2)-adrenergic receptor (beta(2)AR), and the m2 muscarinic cholinergic receptor (m2 mAChR), Visual arrestin was found to be the most selective arrestin since it discriminated best between the three different receptors tested (highest binding to rhodopsin) as web as between the phosphorylation and activation state of the receptor (>10-fold higher binding to the phosphorylated Light-activated form of rhodopsin compared to any other form of rhodopsin). While beta-arrestin and arrestin 3 were also found to preferentially bind to the phosphorylated activated form of a given receptor, they only modestly discriminated among the three receptors tested. To explore the structural characteristics important in arrestin function, we constructed a series of truncated and chimeric arrestins. Analysis of the binding characteristics of the various mutant arrestins suggests a common molecular mechanism involved in determining receptor binding selectivity. Structural elements that contribute to arrestin binding include: 1) a C-terminal acidic region that serves a regulatory role in controlling arrestin binding selectivity toward the phosphorylated and activated form of a receptor, without directly participating in receptor interaction; 2) a basic N-terminal domain that directly participates in receptor interaction and appears to serve a regulatory role via intramolecular interaction with the C-terminal acidic region; and 3) two centrally localized domains that are directly involved in determining receptor binding specificity and selectivity. A comparative structure-function model of all arrestins and a kinetic model of beta-arrestin and arrestin 3 interaction with receptors are proposed.