The structure of the amyloid-β peptide high-affinity copper II binding site in Alzheimer disease
The structure of the amyloid-β peptide high-affinity copper II binding site in Alzheimer disease
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DOI：
10.1529/biophysj.108.134429
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发表时间：
2008-10-01
影响因子：
3.4
通讯作者：
Varghese, Joseph N.
中科院分区：
文献类型：
--
作者：
Streltsov, Victor A.;Titmuss, Stephen J.;Varghese, Joseph N.
在阿尔茨海默病（AD）中观察到的神经变性被认为与主要与铜离子结合的淀粉样β（Ab）蛋白在脑中产生的活性氧（ROS）的毒性有关。A β-Cu氧化还原化学的氧化应激作用的证据仍然不完整。抗体中铜结合位点的详细信息可能对AD的病因学至关重要。在这里，我们提出了确定的结构，结合X射线吸收光谱（XAS）和密度泛函理论分析的抗体肽络合的Cu 2+在溶液中的缓冲条件下的范围。磷酸盐缓冲盐水缓冲盐（NaCl）的浓度不影响高亲和力的铜结合模式，但改变了第二配位球。截短和全长A β-Cu 2+肽的XAS光谱相似。A β-Cu 2+复合物中铜周围的新型扭曲六配位（3 N3 O）几何结构包括三个组氨酸：谷氨酸或/和天冬氨酸，以及轴向水。高亲和性Cu 2+结合位点的结构与以下假设一致：与A β结合的金属离子的氧化还原活性可导致AD中发现的二酪氨酸连接的二聚体的形成。
Neurodegeneration observed in Alzheimer disease (AD) is believed to be related to the toxicity from reactive oxygen species (ROS) produced in the brain by the amyloid-beta (Ab) protein bound primarily to copper ions. The evidence for an oxidative stress role of A beta-Cu redox chemistry is still incomplete. Details of the copper binding site in Ab may be critical to the etiology of AD. Here we present the structure determined by combining x-ray absorption spectroscopy (XAS) and density functional theory analysis of Ab peptides complexed with Cu2+ in solution under a range of buffer conditions. Phosphate-buffered saline buffer salt (NaCl) concentration does not affect the high-affinity copper binding mode but alters the second coordination sphere. The XAS spectra for truncated and full-length A beta-Cu2+ peptides are similar. The novel distorted six-coordinated (3N3O) geometry around copper in the A beta-Cu2+ complexes include three histidines: glutamic, or/and aspartic acid, and axial water. The structure of the high-affinity Cu2+ binding site is consistent with the hypothesis that the redox activity of the metal ion bound to A beta can lead to the formation of dityrosine-linked dimers found in AD.