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首页> 外文期刊>Biochemistry >Molecular Basis of Association of Receptor Activity-Modifying Protein 3 with the Family B G Protein-Coupled Secretin Receptor
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Molecular Basis of Association of Receptor Activity-Modifying Protein 3 with the Family B G Protein-Coupled Secretin Receptor

机译：受体活性修饰蛋白3与家族B G蛋白偶联的促胰液素受体的关联的分子基础。

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The three receptor activity-modifying proteins (RAMPs) have been recognized as being importantnfor the trafficking and function of a subset of family B G protein-coupled receptors, although the structuralnbasis for this has not been well established. In the current work, we use morphological fluorescencentechniques, bioluminescence resonance energy transfer, and bimolecular fluorescence complementation tondemonstrate that the secretin receptor associates specifically with RAMP3, but not with RAMP1 or RAMP2.nWe use truncation constructs, peptide competition experiments, and chimeric secretin-GLP1 receptornconstructs to establish that this association is structurally specific, dependent on the intramembranous regionnof the RAMP and TM6 and TM7 of this receptor. There were no observed changes in secretin-stimulatedncAMP, intracellular calcium, ERK1/2 phosphorylation, or receptor internalization in receptor-bearing COSnor CHO-K1 cells in the presence or absence of exogenous RAMP transfection, although the secretin receptorntrafficks normally to the cell surface in these cells in a RAMP-independent manner, resulting in both free andnRAMP-associated receptor on the cell surface. RAMP3 association with this receptor was shown to bencapable of rescuing a receptor mutant (G241C) that is normally trapped intracellularly in the biosyntheticnmachinery. Similarly, secretin receptor expression had functional effects on adrenomedullin activity, withnincreasing secretin receptor expression competing for RAMP3 association with the calcitonin receptor-likenreceptor to yield a functional adrenomedullin receptor. These data provide important new insights into thenstructural basis for RAMP3 interaction with a family B G protein-coupled receptor, potentially providing anhighly selective target for drug action. This may be representative of similar interactions between othernmembers of this receptor family and RAMP proteins.
机译：三种受体活性修饰蛋白（RAMPs）被认为对B G蛋白偶联受体家族的一个子集的运输和功能很重要，尽管其结构基础尚未得到很好的确立。在当前的工作中，我们使用形态荧光技术，生物发光共振能量转移和双分子荧光互补技术来证明促胰液素受体与RAMP3特异性结合，但与RAMP1或RAMP2无关.n我们使用截短构建体，肽竞争实验和嵌合促胰液素-GLP1受体n可建立这种联系的结构特异性，取决于该受体的RAMP和TM6和TM7的膜内区域。在存在或不存在外源性RAMP转染的情况下，在未接受受体的COSnor CHO-K1细胞中，未观察到促胰液素刺激的ncAMP，细胞内钙，ERK1 / 2磷酸化或受体内在化的变化，尽管促胰液素受体通常在细胞表面向细胞表面转移。这些细胞以独立于RAMP的方式产生，从而在细胞表面产生游离和nRAMP相关的受体。与该受体的RAMP3缔合被证明不能拯救通常在生物合成机械中细胞内捕获的受体突变体（G241C）。类似地，促胰液素受体表达对肾上腺髓质素活性具有功能作用，增加的促胰液素受体表达与降钙素受体样受体竞争RAMP3缔合，从而产生功能性肾上腺髓质素受体。这些数据为RAMP3与家族B G蛋白偶联受体相互作用的结构基础提供了重要的新见解，可能为药物作用提供高度选择性的靶标。这可以代表该受体家族的其他成员与RAMP蛋白之间的相似相互作用。

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