Structural Elements Directing G Proteins and β-Arrestin Interactions with the Human Melatonin Type 2 Receptor Revealed by Natural Variants.
Structural Elements Directing G Proteins and β-Arrestin Interactions with the Human Melatonin Type 2 Receptor Revealed by Natural Variants.
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G蛋白和β-阻滞蛋白与人类褪黑激素2型受体相互作用的结构元件揭示的自然变异。
DOI：
10.1021/acsptsci.1c00239
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发表时间：
2022-02-11
影响因子：
--
通讯作者：
Bouvier, Michel
中科院分区：
文献类型：
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作者：
Plouffe, Bianca;Karamitri, Angeliki;Flock, Tilman;Gallion, Jonathan M;Houston, Shane;Daly, Carole A;Bonnefond, Amelie;Guillaume, Jean-Luc;Le Gouill, Christian;Froguel, Phillipe;Lichtarge, Olivier;Deupi, Xavier;Jockers, Ralf;Bouvier, Michel
G蛋白偶联受体(GPCRs)可以结合不同的信号通路亚群，但这种功能选择性的结构决定因素仍然难以捉摸。GPCRs的自然发生的遗传变异，选择性地影响不同的途径，为探索这一现象提供了机会。我们之前发现了MTNR1B基因的40个编码变种，编码褪黑素MT2受体(MT2)。这些突变对β-arrestin 2的募集、ERK的激活、cAMP的产生以及Gαi1和Gαz的激活有不同的影响。在这项研究中，我们结合功能聚类和结构建模来描述控制MT2功能选择性的分子特征。利用非负矩阵分解，我们分析了40个MT2变体的信号特征，这些变体产生了8个由独特的信号特征定义的簇，并定位于MT2的不同区域。利用计算同源模型，我们描述了特定突变如何选择性地影响信号通路的子集，并提供了自然变异可用于探索和理解GPCR功能选择性的原理证据。
G protein-coupled receptors (GPCRs) can engage distinct subsets of signaling pathways, but the structural determinants of this functional selectivity remain elusive. The naturally occurring genetic variants of GPCRs, selectively affecting different pathways, offer an opportunity to explore this phenomenon. We previously identified 40 coding variants of the MTNR1B gene encoding the melatonin MT2 receptor (MT2). These mutations differently impact the β-arrestin 2 recruitment, ERK activation, cAMP production, and Gαi1 and Gαz activation. In this study, we combined functional clustering and structural modeling to delineate the molecular features controlling the MT2 functional selectivity. Using non-negative matrix factorization, we analyzed the signaling signatures of the 40 MT2 variants yielding eight clusters defined by unique signaling features and localized in distinct domains of MT2. Using computational homology modeling, we describe how specific mutations can selectively affect the subsets of signaling pathways and offer a proof of principle that natural variants can be used to explore and understand the GPCR functional selectivity.