Sultana Tamanna, Mou Sadia Islam, Chatterjee Dipankor, Faruk Md Omar, Hosen Md Ismail
Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka-1000, Bangladesh.
Biochem Biophys Rep. 2024 Apr 1;38:101703. doi: 10.1016/j.bbrep.2024.101703. eCollection 2024 Jul.
The urea transporter UT-B1, encoded by the gene, has been hypothesized to be a significant protein whose deficiency and dysfunction contribute to the pathogenesis of bladder cancer and many other diseases. Several studies reported the association of genetic alterations in the (UT-B1) gene with bladder carcinogenesis, suggesting a need for thorough characterization of the UT-B1 protein's coding and non-coding variants. This study used various computational techniques to investigate the commonly occurring germ-line missense and non-coding SNPs (ncSNPs) of the gene (UT-B1) for their structural, functional, and molecular implications for disease susceptibility and dysfunctionality. missense variants, primarily identified from the ENSEMBL genome browser, were screened through twelve functionality prediction tools leading to two variants D280Y (predicted detrimental by maximum tools) and D280N (high global MAF) for rs1058396. Subsequently, the ConSurf and NetSurf tools revealed the D280 residue to be in a variable site and exposed on the protein surface. According to I-Mutant2.0 and MUpro, both variants are predicted to cause a significant effect on protein stability. Analysis of molecular docking anticipated these two variants to decrease the binding affinity of UT-B1 protein for the examined ligands to a significant extent. Molecular dynamics also disclosed the possible destabilization of the UT-B1 protein due to single nucleotide polymorphism compared to wild-type protein which may result in impaired protein function. Furthermore, several non-coding SNPs were estimated to affect transcription factor binding and regulation of gene expression. Additionally, two ncSNPs were found to affect miRNA-based post-transcriptional regulation by creating new seed regions for miRNA binding. This comprehensive study of gene variants may serve as a springboard for future large-scale investigations examining polymorphisms.
由该基因编码的尿素转运蛋白UT - B1被认为是一种重要蛋白质，其缺乏和功能障碍与膀胱癌及许多其他疾病的发病机制有关。多项研究报道了该（UT - B1）基因的遗传改变与膀胱癌发生之间的关联，这表明需要对UT - B1蛋白的编码和非编码变体进行全面表征。本研究使用了各种计算技术，来研究该基因（UT - B1）常见的种系错义突变和非编码单核苷酸多态性（ncSNP），以了解它们对疾病易感性和功能障碍的结构、功能及分子影响。主要从ENSEMBL基因组浏览器中识别出的错义变体，通过十二种功能预测工具进行筛选，得到了rs1058396的两个变体D280Y（多数工具预测为有害）和D280N（高全球等位基因频率）。随后，ConSurf和NetSurf工具显示D280残基位于可变位点且暴露于蛋白质表面。根据I - Mutant2.0和MUpro预测，这两个变体均会对蛋白质稳定性产生显著影响。分子对接分析预计这两个变体将在很大程度上降低UT - B1蛋白与所检测配体的结合亲和力。分子动力学还揭示，与野生型蛋白相比，单核苷酸多态性可能导致UT - B1蛋白不稳定，这可能会导致蛋白质功能受损。此外，估计有几种非编码SNP会影响转录因子结合和该基因表达的调控。此外，还发现两个ncSNP通过创建新的miRNA结合种子区域来影响基于miRNA的转录后调控。对该基因变体的这项全面研究，可能会成为未来大规模研究该基因多态性的一个跳板。
