Bioinformatics Division, School of Biosciences and Technology, VIT University, Tamilnadu, 632014, India.
Gene. 2012 Oct 25;508(2):211-20. doi: 10.1016/j.gene.2012.07.066. Epub 2012 Aug 8.
Serotonin (5-HT) and its receptors have been involved in critical signal transduction mechanism and deregulation implicated in mood-related disorders. 5-HT activities are mediated through a family of transmembrane spanning serotonin receptors. Both within the family and species, 5-HT receptor protein sequence diversity and 7-transmembrane structural homogeneity have long been intriguing. In this study, we have analyzed the codon site constraint in 5-HT1 subclass receptors from 13 orthologous mammalian mRNA coding sequence. Further, the study was extended to computationally investigate the impact of non-synonymous sites with respect to function and structural significance through sequence homology algorithm and molecular dynamics simulation (MDS). Codon sites with significant posterior probability were observed in 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptor indicating variations in site constraint within the 5-HT1 sub-class genes. In 5-HT(1A) receptor, seven sites were detected at the functional intracellular loop(3) (ICL(3)) with higher substitution rate through Codeml program. Sequence homology algorithm identifies that these sites were functionally tolerant within the mammals representing a selectively relaxed constraint at this domain. On the other hand, the root mean square deviation (rmsd) values from MDS suggest differences in structural conformation of ICL(3) models among the species. Specifically, the human ICL(3) model fluctuation was comparatively more stable than other species. Hence, we argue that these sites may have varying influence in G-proteins coupling and activation of effectors systems through downstream interacting accessory proteins of cell among the species. However, further experimental studies are required to elucidate the precise role and the seeming difference of these sites in 5-HT receptors between species.
血清素（5-HT）及其受体参与了关键的信号转导机制，其失调与情绪相关障碍有关。5-HT 活性是通过一组跨膜 5-HT 受体来介导的。在家族内和物种间，5-HT 受体蛋白序列的多样性和 7 次跨膜结构的同质性一直令人着迷。在这项研究中，我们分析了来自 13 个同源哺乳动物 mRNA 编码序列的 5-HT1 亚类受体的密码子位点约束。此外，该研究还通过序列同源性算法和分子动力学模拟（MDS）扩展到计算研究非同义位点对功能和结构意义的影响。在 5-HT1A、5-HT1B 和 5-HT1D 受体中观察到具有显著后验概率的密码子位点，表明 5-HT1 亚类基因内的位点约束存在差异。在 5-HT1A 受体中，通过 Codeml 程序在功能细胞内环 3（ICL3）中检测到七个具有较高取代率的位点。序列同源性算法确定，这些位点在哺乳动物中具有功能耐受性，代表该结构域选择性松弛的约束。另一方面，MDS 的均方根偏差（rmsd）值表明物种间 ICL3 模型的结构构象存在差异。具体来说，人类 ICL3 模型的波动比其他物种更稳定。因此，我们认为这些位点可能通过细胞下游相互作用的辅助蛋白在不同物种中对 G 蛋白偶联和效应子系统的激活产生不同的影响。然而，需要进一步的实验研究来阐明这些位点在不同物种 5-HT 受体中的精确作用和明显差异。
