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Lysophosphatidylcholine modulates the aggregation of human islet amyloid polypeptide
Physical Chemistry Chemical Physics ( IF 2.9 ) Pub Date : 2017-11-01 00:00:00 , DOI: 10.1039/c7cp06670h
Yanting Xing 1, 2, 3, 4 , Emily H. Pilkington 5, 6, 7, 8, 9 , Miaoyi Wang 5, 6, 7, 8, 9 , Cameron J. Nowell 6, 7, 8, 9 , Aleksandr Kakinen 5, 6, 7, 8, 9 , Yunxiang Sun 1, 2, 3, 4 , Bo Wang 1, 2, 3, 4 , Thomas P. Davis 5, 6, 7, 8, 9 , Feng Ding 1, 2, 3, 4 , Pu Chun Ke 5, 6, 7, 8, 9
Affiliation  

Amyloid aggregation of human islet amyloid polypeptide (IAPP) is a hallmark of type 2 diabetes (T2D), a metabolic disease and a global epidemic. Although IAPP is synthesized in pancreatic β-cells, its fibrils and plaques are found in the extracellular space indicating a causative transmembrane process. Numerous biophysical studies have revealed that cell membranes as well as model lipid vesicles promote the aggregation of amyloid-β (associated with Alzheimer's), α-synuclein (associated with Parkinson's) and IAPP, through electrostatic and hydrophobic interactions between the proteins/peptides and lipid membranes. Using a thioflavin T kinetic assay, transmission electron microscopy, circular dichroism spectroscopy, discrete molecular dynamics simulations as well as free energy calculations here we show that micellar lysophosphatidylcholine (LPC), the most abundant lysophospholipid in the blood, inhibited the amyloid aggregation of IAPP through nonspecific interactions while elevating the α-helical peptide secondary structure. This surprising finding suggests a native protective mechanism against IAPP aggregation in vivo.

中文翻译:

溶血磷脂酰胆碱调节人胰岛淀粉样多肽的聚集

人胰岛淀粉样多肽(IAPP)的淀粉样聚集是2型糖尿病(T2D),代谢疾病和全球流行的标志。尽管IAPP是在胰腺β细胞中合成的,但在细胞外空间中发现了其原纤维和噬菌斑,表明存在跨膜过程。大量的生物物理研究表明,细胞膜以及模型脂质囊泡通过蛋白质/肽与脂质之间的静电和疏水相互作用,促进了淀粉样蛋白-β(与阿尔茨海默氏症相关),α-突触核蛋白(与帕金森氏症相关)和IAPP的聚集。膜。使用硫代黄素T动力学分析,透射电子显微镜,圆二色光谱,离散分子动力学模拟以及自由能计算在这里我们表明,胶束溶血磷脂酰胆碱(LPC)是血液中最丰富的溶血磷脂,通过非特异性相互作用抑制了IAPP的淀粉样聚集,同时提高了α-螺旋肽的二级结构。这一令人惊讶的发现表明,针对IAPP聚集的天然保护机制体内
更新日期:2017-11-22
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