Alharethi Salem Hussain, Kamal Tahseen, Alharbi Bandar, Alhassan Hassan H, Hakami Mohammed Ageeli, Alotaibi Bader Saud, Rub Malik Abdul, Marwani Hadi M, Alamry Khalid A, Asiri Abdullah M, Azum Naved
Department of Biological Science, College of Arts and Science, Najran University, Najran, Saudi Arabia.
Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, Saudi Arabia.
OMICS. 2023 Apr;27(4):171-179. doi: 10.1089/omi.2023.0020.
Signal transducer and activator of transcription 6 (STAT6) is a multifunctional protein that plays critical functions in cell proliferation, apoptosis, differentiation, and angiogenesis. Mutations in STAT6 may contribute to the development of certain complex diseases such as cancer. This study examined single amino acid substitutions in STAT6 to pinpoint deleterious variants and their related structural and functional impairments. Data on STAT6 mutations were obtained from the Ensembl database and analyzed to evaluate the selected mutations for their pathogenicity and destabilizing or harmful effects. Specifically, we analyzed aggregation propensity, nonpacking density, and accessible surface area on the chosen mutations. The results suggest that seven out of eight mutations are less soluble, which might lead to aggregation, disrupt ordered helices, and alter strand propensity. Four mutations lay in the conserved regions of the protein, as revealed by the Consurf analysis. We found that three mutations, E318G, L365F, and R562H, change hydrophobic contacts and lead to frustration of STAT6, which can alter its stability, contributing to disease progression in cancer. In conclusion, these findings inform how single amino acid changes can destabilize STAT6. This has implications for cancer progression which warrants further experimental research.
信号转导及转录激活因子6（STAT6）是一种多功能蛋白，在细胞增殖、凋亡、分化和血管生成中发挥关键作用。STAT6中的突变可能促成某些复杂疾病如癌症的发生。本研究检测了STAT6中的单氨基酸替换，以确定有害变异及其相关的结构和功能损伤。从Ensembl数据库获取STAT6突变数据，并进行分析以评估所选突变的致病性以及其去稳定化或有害作用。具体而言，我们分析了所选突变的聚集倾向、非堆积密度和可及表面积。结果表明，八个突变中有七个的溶解性较差，这可能导致聚集、破坏有序螺旋并改变链倾向。Consurf分析显示，四个突变位于该蛋白的保守区域。我们发现，E318G、L365F和R562H这三个突变改变了疏水接触并导致STAT6功能紊乱，这会改变其稳定性，促使癌症疾病进展。总之，这些发现揭示了单氨基酸变化如何使STAT6去稳定化。这对癌症进展具有启示意义，值得进一步开展实验研究。
