Identification of Key Regions Mediating Human Melatonin Type 1 Receptor Functional Selectivity Revealed by Natural Variants,ACS Pharmacology & Translational Science

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Identification of Key Regions Mediating Human Melatonin Type 1 Receptor Functional Selectivity Revealed by Natural Variants
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2021-09-01 , DOI: 10.1021/acsptsci.1c00157
Alan Hegron _{1,

2,

3} , Eunna Huh ₄ , Xavier Deupi _{5,

6} , Badr Sokrat _{2,

3} , Wenwen Gao ₁ , Christian Le Gouill ₃ , Mickaël Canouil _{7,

8} , Mathilde Boissel _{7,

8} , Guillaume Charpentier ₉ , Ronan Roussel _{10,

11,

12} , Beverley Balkau _{13,

14} , Philippe Froguel _{7,

8,

15} , Bianca Plouffe _{2,

3} , Amélie Bonnefond _{7,

8,

15} , Olivier Lichtarge _{4,

16} , Ralf Jockers ₁ , Michel Bouvier _{2,

3}

Affiliation

Université de Paris, Institut Cochin, CNRS, INSERM, F-75014 Paris, France.
Department of Biochemistry and Molecular Medicine, University de Montréal, Montreal, Quebec, H3T 1J4 Canada.
Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, H3T 1J4 Canada.
Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, United States of America.
Laboratory of Biomolecular Research, Paul Scherrer Institute (PSI), 5232 Villigen, Switzerland.
Condensed Matter Theory group, Paul Scherrer Institute (PSI), 5232 Villigen, Switzerland.
Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, 59000, France.
University of Lille, Lille University Hospital, Lille, 59000, France.
Centre d'Étude et de Recherche pour l'Intensification du Traitement du Diabète, 91000, Evry, France.
Department of Diabetology Endocrinology Nutrition, Hôpital Bichat, DHU FIRE, Assistance Publique Hôpitaux de Paris, 75004 Paris, France.
Inserm U1138, Centre de Recherche des Cordeliers, 75006 Paris, France.
UFR de Médecine, University Paris Diderot, Sorbonne Paris Cité, 75006 Paris, France.
Inserm U1018, Center for Research in Epidemiology and Population Health, 94805 Villejuif, France.
University Paris-Saclay, University Paris-Sud, 94270 Villejuif, France.
Department of Metabolism, Imperial College London, London, W12 0NN, United Kingdom.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, United States.

Melatonin is a hormone mainly produced by the pineal gland and MT₁ is one of the two G protein-coupled receptors (GPCRs) mediating its action. Despite an increasing number of available GPCR crystal structures, the molecular mechanism of activation of a large number of receptors, including MT₁, remains poorly understood. The purpose of this study is to elucidate the structural elements involved in the process of MT₁’s activation using naturally occurring variants affecting its function. Thirty-six nonsynonymous variants, including 34 rare ones, were identified in MTNR1A (encoding MT₁) from a cohort of 8687 individuals and their signaling profiles were characterized using Bioluminescence Resonance Energy Transfer-based sensors probing 11 different signaling pathways. Computational analysis of the experimental data allowed us to group the variants in clusters according to their signaling profiles and to analyze the position of each variant in the context of the three-dimensional structure of MT₁ to link functional selectivity to structure. MT₁ variant signaling profiles revealed three clusters characterized by (1) wild-type-like variants, (2) variants with selective defect of βarrestin-2 recruitment, and (3) severely defective variants on all pathways. Our structural analysis allows us to identify important regions for βarrestin-2 recruitment as well as for Gα12 and Gα15 activation. In addition to identifying MT₁ domains differentially controlling the activation of the various signaling effectors, this study illustrates how natural variants can be used as tools to study the molecular mechanisms of receptor activation.

中文翻译：

天然变体揭示的介导人类褪黑激素 1 型受体功能选择性的关键区域的鉴定

褪黑激素是一种主要由松果体产生的激素，MT ₁是介导其作用的两种 G 蛋白偶联受体 (GPCR) 之一。尽管可用的 GPCR 晶体结构越来越多，但对包括 MT ₁在内的大量受体激活的分子机制仍知之甚少。本研究的目的是利用影响其功能的自然发生的变体来阐明参与 MT ₁激活过程的结构元件。从 8687 名个体的MTNR1A （编码 MT ₁ ）中鉴定出 36 个非同义变异，包括 34 个罕见变异，并使用基于生物发光共振能量转移的传感器探测 11 种不同的信号传导途径来表征它们的信号传导谱。对实验数据的计算分析使我们能够根据其信号传导谱将变体分组，并分析每个变体在 MT ₁三维结构中的位置，以将功能选择性与结构联系起来。 MT ₁变异信号传导谱揭示了三个簇，其特征在于 (1) 野生型样变异、(2) βarrestin-2 招募选择性缺陷的变异、以及 (3) 所有途径上严重缺陷的变异。我们的结构分析使我们能够识别 βarrestin-2 招募以及 Gα12 和 Gα15 激活的重要区域。除了识别差异控制各种信号传导效应器激活的 MT ₁结构域外，本研究还说明了如何使用自然变体作为研究受体激活分子机制的工具。

更新日期：2021-10-08

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