Thakur Sumit, Singh Balvinder, Singh Ranvir
Department cum National Centre of Human Genome Studies and Research, Panjab University, Chandigarh, India.
Bioinformatics Center, Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh, India.
Biochem Biophys Rep. 2025 Aug 5;43:102190. doi: 10.1016/j.bbrep.2025.102190. eCollection 2025 Sep.
Apolipoprotein E (Apo E) is involved in lipid metabolism and plays a crucial role in maintaining the balance of lipoprotein interactions within the body. Mutations in the Apo E protein have been associated with Hyperlipoproteinemia type III, which is characterized by abnormal lipid accumulation in the body. This work explores the structural and functional consequences of seven missense mutations (R154C, R154S, R160C, R163C, R163H, K164E, and K164Q) of Apo E protein associated with Hyperlipoproteinemia type III. Through computational methods such as homology modelling, pathogenicity prediction, Molecular docking and Molecular dynamics, we have investigated the impact of single-point mutations on protein structure, stability, and dynamics. Molecular dynamics simulation studies of wild type Apo E and modelled mutants provided insights into the conformational changes and flexibility of Apo E mutants, giving insights into mechanistic aspect of the influence of mutations on the receptor binding domain and protein structure. The results demonstrate that most of the studied mutations disrupt critical stabilizing interactions and alter domain flexibility thus destabilizing the protein structure and function affecting its interaction with Low-Density Lipoprotein receptor 1 (LDLR1). These molecular insights into how the mutations affect Apo E's conformation and its interaction with the LDL receptor 1 (LDLR1) will help to contribute to a deeper understanding of the pathogenesis of Hyperlipoproteinemia type III.
载脂蛋白E（Apo E）参与脂质代谢，在维持体内脂蛋白相互作用平衡方面发挥关键作用。Apo E蛋白的突变与III型高脂蛋白血症相关，其特征是体内脂质异常蓄积。这项工作探究了与III型高脂蛋白血症相关的Apo E蛋白七个错义突变（R154C、R154S、R160C、R163C、R163H、K164E和K164Q）的结构和功能后果。通过同源建模、致病性预测、分子对接和分子动力学等计算方法，我们研究了单点突变对蛋白质结构、稳定性和动力学的影响。野生型Apo E和建模突变体的分子动力学模拟研究揭示了Apo E突变体的构象变化和灵活性，深入了解了突变对受体结合域和蛋白质结构影响的机制方面。结果表明，大多数研究的突变破坏了关键的稳定相互作用并改变了结构域的灵活性，从而使蛋白质结构和功能不稳定，影响其与低密度脂蛋白受体1（LDLR1）的相互作用。这些关于突变如何影响Apo E构象及其与低密度脂蛋白受体1（LDLR1）相互作用的分子见解将有助于更深入地理解III型高脂蛋白血症的发病机制。
