Cu(II) binding to monomeric, oligomeric, and fibrillar forms of the Alzheimer's disease amyloid-β peptide
Cu(II) binding to monomeric, oligomeric, and fibrillar forms of the Alzheimer's disease amyloid-β peptide
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DOI：
10.1021/bi702423h
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发表时间：
2008-04-29
期刊：
影响因子：
2.9
通讯作者：
Szalai, Veronika A.
中科院分区：
文献类型：
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作者：
Karr, Jesse W.;Szalai, Veronika A.
铜已被提出通过与淀粉样蛋白-β（A β）肽的相互作用在阿尔茨海默病中发挥作用。作为Cu：A β化学计量和A β低聚状态的函数的结合铜的配位环境特别有争议。使用低温电子顺磁共振（EPR）光谱，我们光谱区分两个Cu（II）结合位点上的可溶性和纤维状A β（对于网站1，A（平行）= 168 +/- 1 G和g（平行）= 2.268;对于网站2，A（平行）= 157 +/- 2 G和g（平行）= 2.303）。当用超过1当量的Cu（II）孵育的原纤维被洗涤时，第二个Cu（II）离子被去除，表明它仅与原纤维弱结合。Cu（II）配位环境没有变化，通过Cu（II）与A β（1：1比率）的EPR光谱检测到，所述Cu（II）与A β（1：1比率）收集作为A β固定化时间的函数，这表明Cu（II）环境独立于A β低聚状态。最初的Cu（II）-A β络合物继续形成含Cu（II）的A β原纤维。A β原纤维的透射电子显微镜图像之前和之后的Cu（II）添加是相同的，表明一旦纳入，Cu（II）不影响原纤维结构;然而，Cu（II）的存在下出现诱导原纤维-原纤维协会。在我们的研究结果的基础上，我们提出了一个模型，铜（II）结合到A β在fiflusization是独立的肽寡聚状态。
Copper has been proposed to play a role in Alzheimer's disease through interactions with the amyoid-beta (A beta) peptide. The coordination environment of bound copper as a function of Cu:A beta stoichiometry and A beta oligomerization state are particularly contentious. Using low-temperature electron paramagnetic resonance (EPR) spectroscopy, we spectroscopically distinguish two Cu(II) binding sites on both soluble and fibrillar A beta (for site 1, A(parallel to) = 168 +/- 1 G and g(parallel to) = 2.268; for site 2, A(parallel to) = 157 +/- 2 G and g(parallel to) = 2.303). When fibrils that have been incubated with more than 1 equiv of Cu(II) are washed, the second Cu(II) ion is removed, indicating that it is only weakly bound to the fibrils. No change in the Cu(II) coordination environment is detected by EPR spectroscopy of Cu(II) with A beta (1: 1 ratio) collected as a function of A beta fibrillization time, which indicates that the Cu(II) environment is independent of A beta oligomeric state. The initial Cu(II)-A beta complexes go on to form Cu(II)-containing A beta fibrils. Transmission electron microscopy images of A beta fibrils before and after Cu(II) addition are the same, showing that once incorporated, Cu(II) does not affect fibrillar structure; however, the presence of Cu(II) appears to induce fibril-fibril association. On the basis of our results, we propose a model for Cu(II) binding to A beta during fibrillization that is independent of peptide oligomeric state.