Ali Abid, Zhaliazka Kiryl, Holman Aidan P, Kurouski Dmitry
Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, USA.
Department of Biomedical Engineering, Texas A&M University, College Station, Texas, USA.
Proteins. 2024 Mar;92(3):411-417. doi: 10.1002/prot.26622. Epub 2023 Nov 1.
A progressive aggregation of misfolded proteins is a hallmark of numerous pathologies including diabetes Type 2, Alzheimer's disease, and Parkinson's disease. As a result, highly toxic protein aggregates, which are known as amyloid fibrils, are formed. A growing body of evidence suggests that phospholipids can uniquely alter the secondary structure and toxicity of amyloid aggregates. However, the role of phosphatidic acid (PA), a unique lipid that is responsible for cell signaling and activation of lipid-gated ion channels, in the aggregation of amyloidogenic proteins remains unclear. In this study, we investigate the role of the length and degree of unsaturation of fatty acids (FAs) in PA in the structure and toxicity of lysozyme fibrils formed in the presence of this lipid. We found that both the length and saturation of FAs in PA uniquely altered the secondary structure of lysozyme fibrils. However, these structural differences in PA caused very little if any changes in the morphology of lysozyme fibrils. We also utilized cell toxicity assays to determine the extent to which the length and degree of unsaturation of FAs in PA altered the toxicity of lysozyme fibrils. We found that amyloid fibrils formed in the presence of PA with C18:0 FAs exerted significantly higher cell toxicity compared to the aggregates formed in the presence of PA with C16:0 and C18:1 FAs. These results demonstrated that PA can be an important player in the onset and spread of amyloidogenic diseases.
错误折叠蛋白的逐步聚集是包括2型糖尿病、阿尔茨海默病和帕金森病在内的众多病症的一个标志。结果，形成了被称为淀粉样原纤维的剧毒蛋白聚集体。越来越多的证据表明，磷脂可以独特地改变淀粉样聚集体的二级结构和毒性。然而，磷脂酸（PA）这种负责细胞信号传导和脂质门控离子通道激活的独特脂质，在淀粉样蛋白生成过程中的作用仍不清楚。在本研究中，我们研究了PA中脂肪酸（FAs）的长度和不饱和度在这种脂质存在下形成的溶菌酶原纤维的结构和毒性中的作用。我们发现，PA中FAs的长度和饱和度都独特地改变了溶菌酶原纤维的二级结构。然而，PA中的这些结构差异对溶菌酶原纤维的形态几乎没有影响。我们还利用细胞毒性试验来确定PA中FAs的长度和不饱和度在多大程度上改变了溶菌酶原纤维的毒性。我们发现，与在含有C16:0和C18:1 FAs的PA存在下形成的聚集体相比，在含有C18:0 FAs的PA存在下形成的淀粉样原纤维具有显著更高的细胞毒性。这些结果表明，PA可能在淀粉样疾病的发生和传播中起重要作用。
