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首页> 外文期刊>Cell discovery. >An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology
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An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology

机译：受体活性修饰蛋白在定义GPCR药理学中的变构作用

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G protein-coupled receptors are allosteric proteins that control transmission of external signals to regulate cellular response. Although agonist binding promotes canonical G protein signalling transmitted through conformational changes, G protein-coupled receptors also interact with other proteins. These include other G protein-coupled receptors, other receptors and channels, regulatory proteins and receptor-modifying proteins, notably receptor activity-modifying proteins (RAMPs). RAMPs have at least 11 G protein-coupled receptor partners, including many class B G protein-coupled receptors. Prototypic is the calcitonin receptor, with altered ligand specificity when co-expressed with RAMPs. To gain molecular insight into the consequences of this protein–protein interaction, we combined molecular modelling with mutagenesis of the calcitonin receptor extracellular domain, assessed in ligand binding and functional assays. Although some calcitonin receptor residues are universally important for peptide interactions (calcitonin, amylin and calcitonin gene-related peptide) in calcitonin receptor alone or with receptor activity-modifying protein, others have RAMP-dependent effects, whereby mutations decreased amylin/calcitonin gene-related peptide potency substantially only when RAMP was present. Remarkably, the key residues were completely conserved between calcitonin receptor and AMY receptors, and between subtypes of AMY receptor that have different ligand preferences. Mutations at the interface between calcitonin receptor and RAMP affected ligand pharmacology in a RAMP-dependent manner, suggesting that RAMP may allosterically influence the calcitonin receptor conformation. Supporting this, molecular dynamics simulations suggested that the calcitonin receptor extracellular N-terminal domain is more flexible in the presence of receptor activity-modifying protein 1. Thus, RAMPs may act in an allosteric manner to generate a spectrum of unique calcitonin receptor conformational states, explaining the pharmacological preferences of calcitonin receptor-RAMP complexes. This provides novel insight into our understanding of G protein-coupled receptor-protein interaction that is likely broadly applicable for this receptor class.
机译：G蛋白偶联受体是变构蛋白，可控制外部信号的传递以调节细胞反应。尽管激动剂结合促进通过构象变化传递的经典G蛋白信号传导，但G蛋白偶联受体也与其他蛋白相互作用。这些包括其他G蛋白偶联受体，其他受体和通道，调节蛋白和受体修饰蛋白，特别是受体活性修饰蛋白（RAMP）。 RAMP至少具有11个G蛋白偶联受体伴侣，包括许多B G类蛋白偶联受体。原型是降钙素受体，当与RAMPs共表达时，配体特异性会改变。为了获得对这种蛋白质相互作用的后果的分子了解，我们将分子建模与降钙素受体胞外域的诱变相结合，并在配体结合和功能测定中进行了评估。尽管某些降钙素受体残基对于单独使用降钙素受体或与受体活性修饰蛋白的肽相互作用（降钙素，胰岛淀粉样多肽和降钙素基因相关肽）普遍具有重要意义，但另一些则具有RAMP依赖性作用，从而突变降低了与胰蛋白酶/降钙素基因相关的仅当存在RAMP时，肽的效力才有效。值得注意的是，关键残基在降钙素受体和AMY受体之间以及在具有不同配体偏好的AMY受体亚型之间完全保守。降钙素受体和RAMP之间的界面突变以RAMP依赖的方式影响配体药理学，表明RAMP可能会变构地影响降钙素受体的构象。支持这一点的分子动力学模拟表明，在存在受体活性修饰蛋白1的情况下，降钙素受体的细胞外N端结构域更加灵活。解释降钙素受体-RAMP复合物的药理学偏好。这为我们对G蛋白偶联受体-蛋白相互作用的理解提供了新颖的见解，该理解可能广泛适用于该受体类别。

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