Jahanfar Farhad, Hamishehkar Hamed
Biotechnology Research Center and Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
J Mol Graph Model. 2018 Mar;80:52-58. doi: 10.1016/j.jmgm.2017.12.023. Epub 2018 Jan 4.
The polymorphism rs10490924 (A69S) in the age-related maculopathy susceptibility 2 (ARMS2) gene is highly associated with age-related macular degeneration, which is the leading cause of blindness among the elderly population. ARMS2 gene encodes a putative small (11 kDa) protein, which the function and localization of the ARMS2 protein remain under debate. For a better understanding of functional impacts of A69S mutation, we performed a detailed analysis of an ARMS2 sequence with a broad set of bioinformatics tools. In silico analysis was followed to predict the tertiary structure, putative binding site regions, and binding site residues. Also, the effects of this mutation on protein stability, aggregation propensity, and homodimerization were analyzed. Next, a molecular dynamic simulation was carried out to understand the dynamic behavior of wild-type, A69S, and phosphorylated A69S structures. The results showed alterations in the putative post-translational modification sites on the ARMS2 protein, due to the mutation. Furthermore, the stability of protein and putative homodimer conformations were affected by the mutation. Molecular dynamic simulation results revealed that A69S mutation enhances the rigidity of the ARMS2 structure and residue serine at position 69 is buried and may not be phosphorylated; however, phosphorylated serine enhances the flexibility of the ARMS2 structure. In conclusion, our study provides new insights into the deleterious effects of A69S mutation on the ARMS2 structure.
年龄相关性黄斑病变易感基因2（ARMS2）中的多态性rs10490924（A69S）与年龄相关性黄斑变性高度相关，而年龄相关性黄斑变性是老年人群失明的主要原因。ARMS2基因编码一种假定的小蛋白（11 kDa），但其功能和定位仍存在争议。为了更好地理解A69S突变的功能影响，我们使用一系列生物信息学工具对ARMS2序列进行了详细分析。随后进行了计算机模拟分析，以预测三级结构、假定的结合位点区域和结合位点残基。此外，还分析了该突变对蛋白质稳定性、聚集倾向和同二聚化的影响。接下来，进行了分子动力学模拟，以了解野生型、A69S和磷酸化A69S结构的动态行为。结果表明，由于该突变，ARMS2蛋白假定的翻译后修饰位点发生了改变。此外，蛋白质稳定性和假定的同二聚体构象受到该1突变的影响。分子动力学模拟结果显示，A69S突变增强了ARMS2结构的刚性，69位的丝氨酸残基被掩埋且可能无法被磷酸化；然而，磷酸化的丝氨酸增强了ARMS2结构的灵活性。总之，我们的研究为A69S突变对ARMS2结构的有害影响提供了新的见解。
