Hao Ruijie, Li Yang, Guan Liping, Lu Tong, Meng Feihong, Wang Chunyu, Li Fei
State Key Laboratory of Supramolecular Structure and Materials, Jilin University 2699 Qianjin Avenue Changchun 130012 P. R. China
RSC Adv. 2018 Dec 5;8(71):40581-40588. doi: 10.1039/c8ra07310d. eCollection 2018 Dec 4.
The interactions between hIAPP and the pancreatic β-cells are associated with β-cell death in type II diabetes. Cholesterol modulates hIAPP-membrane interaction and hIAPP aggregation. The molecular mechanism underlying this is not well understood. Here we explore the cholesterol-sensing role of F15 in the interactions of hIAPP and hIAPP with various compositions of lipids, including DOPC, DPPC and DOPC/DPPC using NMR, CD, ThT fluorescence and dye leakage assays. We show that both hIAPP and hIAPP are more potent in the disruption to the membranes with cholesterol than they are in the disruption to the membranes without cholesterol. A substitution of F15 by leucine affects the binding and disruption of the peptides to the membranes slightly in the absence of cholesterol, but decreases the activities largely in the presence of cholesterol. F15 also plays a role in accelerating fibrillar assembly of hIAPP, but the function is independent of cholesterol in nature. The promotion of cholesterol to the disruptive potency of hIAPP is more effective in the membrane with raft-like domains than in the membrane with a dispersed distribution of cholesterol. Our results suggest that F15 plays a key role in the cholesterol-sensing binding and disruption of hIAPP to the PC membranes and the distribution of cholesterol in the membranes has an influence on the disruptive activity of hIAPP.
人胰岛淀粉样多肽（hIAPP）与胰腺β细胞之间的相互作用与II型糖尿病中的β细胞死亡有关。胆固醇调节hIAPP与膜的相互作用以及hIAPP的聚集。其潜在的分子机制尚未完全了解。在这里，我们使用核磁共振（NMR）、圆二色性（CD）、硫代黄素T（ThT）荧光和染料泄漏试验，探索F15在hIAPP与各种脂质成分（包括二油酰磷脂酰胆碱（DOPC）、二棕榈酰磷脂酰胆碱（DPPC）和DOPC/DPPC）相互作用中的胆固醇传感作用。我们发现，hIAPP和hIAPP对含胆固醇膜的破坏作用比不含胆固醇的膜更强。在无胆固醇情况下，用亮氨酸取代F15对肽与膜的结合和破坏作用影响较小，但在有胆固醇时会大幅降低其活性。F15在加速hIAPP的纤维状组装中也起作用，但其功能本质上与胆固醇无关。胆固醇对hIAPP破坏能力的促进作用在具有筏样结构域的膜中比在胆固醇分布分散的膜中更有效。我们的结果表明，F15在hIAPP对磷脂酰胆碱（PC）膜的胆固醇传感结合和破坏中起关键作用，并且膜中胆固醇的分布对hIAPP的破坏活性有影响。
