Metal effects on the membrane interactions of amyloid-β peptides
Metal effects on the membrane interactions of amyloid-β peptides
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DOI：
10.1007/s00249-007-0251-2
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发表时间：
2008-03-01
影响因子：
2
通讯作者：
Separovic, Frances
中科院分区：
文献类型：
--
作者：
Gehman, John D.;O'Brien, Caitlin C.;Separovic, Frances
β（1-42）肽，作为阿尔茨海默病大脑中的聚集物种被发现，与痴呆症的发作有关。我们详细的P-31和H-2固态核磁共振研究的结果与A β肽和金属离子（Cu 2+和Zn 2+），这是发现集中在淀粉样斑块的影响模型膜。膜结合肽或结合肽对脂质双层和肽结构的影响不同。铜离子单独使脂质双层不稳定并诱导形成较小的囊泡，但当A β（1-42）与双层膜结合时不会。A β（25-35）是来自A β（1-42）的C-末端的片段，其缺乏在全长肽中发现的金属配位位点，对皮质细胞培养物具有神经毒性。添加金属离子对具有A β（25-35）肽的膜双层几乎没有影响。P-31魔角旋转NMR数据表明，A β（1-42）和A β（1-42）-Cu 2+复合物在阴离子磷脂膜表面相互作用。然而，掺入的肽似乎比相关肽更严重地破坏膜。固态C-13 NMR用于比较阴离子磷脂和胆固醇的模型膜系统中A β（1-42）与A β（25-35）的结构变化。当加入磷脂脂质体中时，A β肽在C-末端的β-链结构似乎增加。包含的Cu 2+也影响了观察到的C-末端一半的残基的化学位移，为脂质相关的A β/金属复合物提供了结构线索。结果指出了全长肽毒性的复杂途径。
A beta(1-42) peptide, found as aggregated species in Alzheimer's disease brain, is linked to the onset of dementia. We detail results of P-31 and H-2 solid-state NMR studies of model membranes with A beta peptides and the effect of metal ions (Cu2+ and Zn2+), which are found concentrated in amyloid plaques. The effects on the lipid bilayer and the peptide structure are different for membrane incorporated or associated peptides. Copper ions alone destabilise the lipid bilayer and induce formation of smaller vesicles, but not when A beta(1-42) is associated with the bilayer membrane. A beta(25-35), a fragment from the C-terminal end of A beta(1-42), which lacks the metal coordinating sites found in the full length peptide, is neurotoxic to cortical cortex cell cultures. Addition of metal ions has little effect on membrane bilayers with A beta(25-35) peptides. P-31 magic angle spinning NMR data show that A beta(1-42) and A beta(1-42)-Cu2+ complexes interact at the surface of anionic phospholipid membranes. Incorporated peptides, however, appear to disrupt the membrane more severely than associated peptides. Solid-state C-13 NMR was used to compare structural changes of A beta(1-42) to those of A beta(25-35) in model membrane systems of anionic phospholipids and cholesterol. The A beta peptides appeared to have an increase in beta-strand structure at the C-terminus when added to phospholipid liposomes. The inclusion of Cu2+ also influenced the observed chemical shift of residues from the C-terminal half, providing structural clues for the lipid-associated A beta/metal complex. The results point to the complex pathway(s) for toxicity of the full-length peptide.