Faculty of Biochemistry and Molecular Biology and Biocenter Oulu, University of Oulu, Oulu, 90220, Finland.
Department of Molecular Enzymology, University of Potsdam, 14476, Potsdam, Germany.
Sci Rep. 2018 Apr 30;8(1):6752. doi: 10.1038/s41598-018-25237-7.
Coronary artery disease is the most common cause of death globally and is linked to a number of risk factors including serum low density lipoprotein, high density lipoprotein, triglycerides and lipoprotein(a). Recently two proteins, angiopoietin-like protein 3 and 4, have emerged from genetic studies as being factors that significantly modulate plasma triglyceride levels and coronary artery disease. The exact function and mechanism of action of both proteins remains to be elucidated, however, mutations in these proteins results in up to 34% reduction in coronary artery disease and inhibition of function results in reduced plasma triglyceride levels. Here we report the crystal structures of the fibrinogen-like domains of both proteins. These structures offer new insights into the reported loss of function mutations, the mechanisms of action of the proteins and open up the possibility for the rational design of low molecular weight inhibitors for intervention in coronary artery disease.
冠状动脉疾病是全球范围内最常见的死亡原因，与多种危险因素有关，包括血清低密度脂蛋白、高密度脂蛋白、甘油三酯和脂蛋白(a)。最近，两项遗传研究表明，两种蛋白质——血管生成素样蛋白 3 和 4——是显著调节血浆甘油三酯水平和冠状动脉疾病的因素。这两种蛋白质的确切功能和作用机制仍有待阐明，然而，这些蛋白质的突变会导致冠状动脉疾病减少高达 34%，并且抑制其功能会导致血浆甘油三酯水平降低。在这里，我们报告了这两种蛋白质的纤维蛋白原样结构域的晶体结构。这些结构为报道的功能丧失突变、蛋白质的作用机制提供了新的见解，并为合理设计用于干预冠状动脉疾病的小分子抑制剂开辟了可能性。
