Chatterjee Rupsa, Kolli Vidyalatha, Sarkar Nandini
Department of Biotechnology and Medical Engineering, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India.
Protein J. 2017 Apr;36(2):138-146. doi: 10.1007/s10930-017-9705-2.
Many degenerative disorder such as Parkinsons, Alzheimers, Huntingtons disease, etc are caused due to the deposition of amyloid fibrils, formed due to the ordered aggregation of misfolded/unfolded proteins. Misfolded or unfolded proteins aggregate mostly through hydrophobic interactions which are unexposed in native state, but become exposed upon unfolding. To counteract amyloid related diseases, inhibition of the protein self assembly into fibril is a potential therapeutic strategy. The study aims at investigating the effect of selected compounds, namely trehalose and magnesium chloride hexahydrate towards inhibition and disaggregation of amyloid fibrils using Hen Egg White Lysozyme as a model. We further attempted to understand the mechanism of action with the help of various biophysical, microscopic as well as computational studies. A common mechanism of action was identified where the selected compounds exert their anti-amyloidogenic effects by altering HEWL conformations characterized by reduction in the beta sheet content and decrease in exposed hydrophobic surfaces. The altered conformation seems to have lesser amyloidogenic propensity leading to inhibition as well as disaggregation of amyloids.
许多退行性疾病，如帕金森病、阿尔茨海默病、亨廷顿舞蹈症等，是由于淀粉样原纤维的沉积所致，这些原纤维是由错误折叠/未折叠蛋白质的有序聚集形成的。错误折叠或未折叠的蛋白质大多通过疏水相互作用聚集，这些疏水相互作用在天然状态下是隐藏的，但在蛋白质展开时会暴露出来。为了对抗与淀粉样蛋白相关的疾病，抑制蛋白质自组装成原纤维是一种潜在的治疗策略。本研究旨在以鸡蛋清溶菌酶为模型，研究所选化合物海藻糖和六水合氯化镁对淀粉样原纤维的抑制和解聚作用。我们还借助各种生物物理、显微镜以及计算研究试图了解其作用机制。我们确定了一种共同的作用机制，即所选化合物通过改变溶菌酶的构象发挥抗淀粉样蛋白生成作用，其特征是β-折叠含量减少和暴露的疏水表面减少。改变后的构象似乎具有较低的淀粉样蛋白生成倾向，从而导致淀粉样蛋白的抑制和解聚。
