Coevolution of Residues Provides Evidence of a Functional Heterodimer of 5-HT2AR and 5-HT2CR Involving Both Intracellular and Extracellular Domains
Coevolution of Residues Provides Evidence of a Functional Heterodimer of 5-HT2AR and 5-HT2CR Involving Both Intracellular and Extracellular Domains
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DOI：
10.1016/j.neuroscience.2019.05.013
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发表时间：
2019-08-01
期刊：
影响因子：
3.3
通讯作者：
Kudlicki, Andrzej
中科院分区：
文献类型：
--
作者：
Fongang, Bernard;Cunningham, Kathryn A.;Kudlicki, Andrzej
5-羟色胺是一种神经递质，在调节睡眠、食欲、情绪和物质滥用障碍等活动中发挥作用; 5-羟色胺受体5-HT 2AR和5-HT 2CR在与物质滥用相关的通路中具有活性。有人认为5-HT 2AR和5-HT 2CR可能形成影响行为过程的二聚体。在这里，我们研究了5-HT 2AR和5-HT 2CR中残基的协同进化，以确定这两种蛋白质中残基之间的潜在相互作用。共同进化研究可以检测蛋白质的相互作用，由于这样揭示的相互作用受到进化压力，它们可能是功能性的。我们使用随机系统发育树评估了5-HT 2AR/5-HT 2CR相互作用的显著性，发现协同进化显著（p值= 0.01）。我们还讨论了如何共同表达的受体表明预测的相互作用是功能性的。最后，我们分析了5-HT 2AR和5-HT 2CR基因的几个单核苷酸多态性如何影响它们的相互作用。我们的研究结果是第一次表征5-HT 2AR/5-HT 2CR的结合界面，并表明这两种蛋白质中的SNPs的位置之间的相关性。(C)2019年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Serotonin is a neurotransmitter that plays a role in regulating activities such as sleep, appetite, mood and substance abuse disorders; serotonin receptors 5-HT2AR and 5-HT2CR are active within pathways associated with substance abuse. It has been suggested that 5-HT2AR and 5-HT2CR may form a dimer that affects behavioral processes. Here we study the coevolution of residues in 5-HT2AR and 5-HT2CR to identify potential interactions between residues in both proteins. Coevolution studies can detect protein interactions, and since the thus uncovered interactions are subject to evolutionary pressure, they are likely functional. We assessed the significance of the 5-HT2AR/5-HT2CR interactions using randomized phylogenetic trees and found the coevolution significant (p-value = 0.01). We also discuss how co-expression of the receptors suggests the predicted interaction is functional. Finally, we analyze how several single nucleotide polymorphisms for the 5-HT2AR and 5-HT2CR genes affect their interaction. Our findings are the first to characterize the binding interface of 5-HT2AR/5-HT2CR and indicate a correlation between this interface and location of SNPs in both proteins. (C) 2019 IBRO. Published by Elsevier Ltd. All rights reserved.