Amyloid-β(25-35) peptides aggregate into cross-β sheets in unsaturated anionic lipid membranes at high peptide concentrations.
Amyloid-β(25-35) peptides aggregate into cross-β sheets in unsaturated anionic lipid membranes at high peptide concentrations.
复制标题
在高肽浓度下，淀粉样蛋白-β(25-35) 肽在不饱和阴离子脂质膜中聚集成交叉β片层。
作者：
Jennifer Tang;R. Alsop;M. Backholm;Hannah Dies;A. Shi;M. Rheinstädter
阿尔茨海默病的标志之一是大脑中形成蛋白质斑块，其主要由不同长度的淀粉样β肽组成。虽然这些斑块在疾病病理学中的作用尚不清楚，但肽聚集背后的机制是一个深入研究和讨论的话题。由于其简单性，合成膜是有前途的模型系统，可用于识别所涉及的基本过程。我们制备了由 1-棕榈酰-2-油酰-sn-甘油-磷酸胆碱 (POPC) 和 1,2-二肉豆蔻酰-sn-甘油-3-磷酸-l-丝氨酸 (DMPS) 制成的不饱和两性离子/阴离子脂质膜，POPC/3 mol% DMPS 的浓度包含 0 mol%、3 mol%、10 mol% 和 20 mol% 淀粉样蛋白-β25-35 肽。在肽浓度为 10 mol% 和 20 mol% 时观察到膜嵌入的肽簇，典型簇大小为 ∼11 μm。簇密度随着肽浓度的增加而增加，从每毫米(2) 59 (±3) 个簇增加到每毫米(2) 920 (±64) 个簇。虽然单体肽在低肽浓度下嵌入脂质双层时呈 α 螺旋状态，但肽簇中的肽被发现形成交叉 β 片层，并在 X 射线实验中显示出特征模式。肽的存在伴随着双层的弹性变形，这可以诱导肽之间的长程相互作用。实验观察到的簇模式与长程相互作用肽的蒙特卡罗模拟非常吻合。这种相互作用可能是膜中交叉β折叠形成的基本过程，这些折叠可以作为进一步生长成淀粉样原纤维的种子。
One of the hallmarks of Alzheimer's disease is the formation of protein plaques in the brain, which mainly consist of amyloid-β peptides of different lengths. While the role of these plaques in the pathology of the disease is not clear, the mechanism behind peptide aggregation is a topic of intense research and discussion. Because of their simplicity, synthetic membranes are promising model systems to identify the elementary processes involved. We prepared unsaturated zwitterionic/anionic lipid membranes made of 1-palmitoyl-2-oleoyl-sn-glycero-phosphocholine (POPC) and 1,2-dimyristoyl-sn-glycero-3-phospho-l-serine (DMPS) at concentrations of POPC/3 mol% DMPS containing 0 mol%, 3 mol%, 10 mol%, and 20 mol% amyloid-β25-35 peptides. Membrane-embedded peptide clusters were observed at peptide concentrations of 10 and 20 mol% with a typical cluster size of ∼11 μm. Cluster density increased with peptide concentration from 59 (±3) clusters per mm(2) to 920 (±64) clusters per mm(2), respectively. While monomeric peptides take an α-helical state when embedded in lipid bilayers at low peptide concentrations, the peptides in peptide clusters were found to form cross-β sheets and showed the characteristic pattern in X-ray experiments. The presence of the peptides was accompanied by an elastic distortion of the bilayers, which can induce a long range interaction between the peptides. The experimentally observed cluster patterns agree well with Monte Carlo simulations of long-range interacting peptides. This interaction may be the fundamental process behind cross-β sheet formation in membranes and these sheets may serve as seeds for further growth into amyloid fibrils.
登录
查看更多内容
影响因子：
3.4
作者：
Chang-chun Lee;Yen Sun;Huey W. Huang
通讯作者：
Chang-chun Lee;Yen Sun;Huey W. Huang
影响因子：
56.9
作者：
COHEN, C;PARRY, DAD
通讯作者：
PARRY, DAD
影响因子：
2.9
作者：
Huang, HW
通讯作者：
Huang, HW
影响因子：
3.4
作者：
Ding, Hao;Schauerte, Joseph A.;Gafni, Ari
通讯作者：
Gafni, Ari
影响因子：
3.4
作者：
Mills, Thalia T.;Toombes, Gilman E. S.;Nagle, John F.
通讯作者：
Nagle, John F.