Mia Md Arzo, Uddin Md Nasir, Akter Yasmin, Wal Marzan Lolo
Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong, Bangladesh.
Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, Bangladesh.
Bioinform Biol Insights. 2022 Jun 9;16:11779322221104308. doi: 10.1177/11779322221104308. eCollection 2022.
The sodium-dependent serotonin transporter (solute carrier family 6 member 4) gene encodes an intrinsic membrane protein that transmits the serotonin neurotransmitter from synaptic clefts into presynaptic neurons. The product of the gene is related to the regulation of mood and social behavior, sleep, appetite, memory, digestion, and sexual desire. This protein is a target for antidepressant and psychostimulant drugs, thus prolonged neurotransmitter signaling remains blocked. In this study, the functional consequences of nsSNPs in the human gene were explored through computational tools: PhD-SNP, SIFT, Align GVGD, PROVEAN, PMut, nsSNP Analyzer, SNPs&GO, SNAP2, PolyPhen2, and PANTHER to identify the most deleterious and damaging nsSNPs. Then the mutant protein stabilities were assessed using I-Mutant, MUpro, and MutPred2; amino acid conservation using ConSurf, and posttranslational modification analysis using MusiteDEEP and PROSPER. Furthermore, the 3-dimensional (3D) model of the mutated proteins was predicted and validated using SPARKS-X, Verify3D, and PROCHECK. The protein-ligand binding sites were analyzed using the COACH meta-server. Results from this study predicted that T192M, G342E, R607C, W282S, R104C, P131L, P156L, and N351S were the most structurally and functionally significant nsSNPs in the human gene. Arg607 and Pro156 were the predicted sites for posttranslational modifications, and Thr192 and Try282 were the ligand-binding sites in the human gene. The analyzed data also suggested that R104C, P131L, P156L, T192M, G342E, and W282S mutants might affect the binding of sodium ions with this protein. Taken together, this study provided important information on structurally and functionally important nsSNPs of the human gene for further experimental validation. In the future, these damaging nsSNPs of the gene have the potential to be evaluated as prognostic biomarkers for -related disorder diagnosis and research.
钠依赖性5-羟色胺转运体（溶质载体家族6成员4）基因编码一种内在膜蛋白，该蛋白可将5-羟色胺神经递质从突触间隙转运到突触前神经元中。该基因的产物与情绪和社会行为、睡眠、食欲、记忆、消化及性欲的调节有关。这种蛋白是抗抑郁药和精神兴奋药的作用靶点，因此神经递质信号的延长传递仍被阻断。在本研究中，通过PhD-SNP、SIFT、Align GVGD、PROVEAN、PMut、nsSNP Analyzer、SNPs&GO、SNAP2、PolyPhen2和PANTHER等计算工具，探索了人类该基因中非同义单核苷酸多态性（nsSNPs）的功能后果，以识别最具有害性和破坏性的nsSNPs。然后，使用I-Mutant、MUpro和MutPred2评估突变蛋白的稳定性；使用ConSurf评估氨基酸保守性，使用MusiteDEEP和PROSPER进行翻译后修饰分析。此外，使用SPARKS-X、Verify3D和PROCHECK预测并验证了突变蛋白的三维（3D）模型。使用COACH元服务器分析蛋白质-配体结合位点。本研究结果预测，T192M、G342E、R607C、W282S、R104C、P131L、P156L和N351S是人类该基因中在结构和功能上最具重要意义的nsSNPs。Arg607和Pro156是预测的翻译后修饰位点，Thr192和Try282是人类该基因中的配体结合位点。分析数据还表明，R104C、P131L、P156L、T192M、G342E和W282S突变体可能会影响钠离子与该蛋白的结合。综上所述，本研究提供了关于人类该基因在结构和功能上重要的nsSNPs的重要信息，以供进一步实验验证。未来，该基因的这些有害nsSNPs有可能被评估为相关疾病诊断和研究的预后生物标志物。
