Neurodegenerative diseases and protein folding governed by copper ion

铜离子控制的神经退行性疾病和蛋白质折叠

• 批准号: 12672084
• 负责人: MIURA Takashi
• 金额: $ 2.11万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672084/
• 关键词: neurodegenerative diseases; Alzheimer's disease; metal; histidine; tyrosine; Raman spectroscopy; 鉄; プリオン; 銅; 折りたたみ

1. Aggregation of amyloid β-peptide (Aβ), a key pathological event in Alzheimer's disease, has been shown in vitro to be profoundly promoted by Zn(II). This fact suggests that some factors in the normal brain protect Aβ from the Zn(II)-induced aggregation. In this study, it has been demonstrated that Cu(II) effectively inhibits the Aβ aggregation by competing with Zn(II) for histidine residues. The Raman spectrum of a metal-Aβ complex in the presence of both Zn(II) and Cu(II) shows that the cross-linking of Aβ through binding of Zn(II) to the Nτ atom of histidine is prevented by chelation of Cu(II) by the Nπ atom of histidine and nearby amide nitrogens. The inhibitory effect is strongest at a Cu/Aβ molar ratio of around four. Above this ratio, Cu(II) itself promotes the Aβ aggregation by binding to the phenolate oxygen of Tyr10. These results emphasize the importance of regulation of Cu(II) levels to inhibit Aβ aggregation, and are consistent with an altered metal homeostasis in Alzheimer's disease.2. The Fe(III) ion binds to Aβ and induces significant aggregation of the peptide. In order to understand the role of Fe(III) in Aβ aggregation, the Fe(III)-binding mode of Aβ has been examined by Raman spectroscopy. The Raman spectra of Fe(III)-Aβ complexes excited at 514.5 nm are dominated by resonance Raman bands of metal-bound tyrosinate, evidencing that the Fe(III) ion primarily binds to Aβ via the phenolic oxygen of Tyr10. On the other hand, histidine ewsidues in the N-terminal hydrophilic region of Aβ do not bind to Fe(III). These results are in sharp contrast to the Zn(II)-induced aggregation of Aβ, in which histidine residues act as the primary metal binding sites.

1.淀粉样β-肽（Aβ）的聚集是阿尔茨海默病中的关键病理事件，已在体外显示出Zn（II）显著促进A β聚集。这一事实表明，正常脑中的某些因素保护Aβ免受Zn（II）诱导的聚集。在这项研究中，已经证明Cu（II）通过与Zn（II）竞争组氨酸残基而有效地抑制Aβ聚集。在Zn（II）和Cu（II）同时存在的情况下，金属-A β络合物的拉曼光谱表明，通过Zn（II）与组氨酸的Nτ原子结合的Aβ交联被组氨酸的Nπ原子和附近的酰胺氮螯合的Cu（II）阻止。Cu/Aβ摩尔比约为4时，抑制作用最强。高于此比例，Cu（II）本身通过与Tyr 10的酚氧结合促进Aβ聚集。这些结果强调了调节Cu（II）水平以抑制Aβ聚集的重要性，并且与阿尔茨海默病中改变的金属稳态一致。Fe（III）离子与Aβ结合并诱导肽的显著聚集。为了了解Fe（III）在Aβ聚集中的作用，通过拉曼光谱检查了Aβ的Fe（III）结合模式。在514.5 nm处激发的Fe（III）-Aβ复合物的拉曼光谱由金属结合酪氨酸的共振拉曼带主导，证明Fe（III）离子主要通过Tyr 10的酚氧与Aβ结合。另一方面，Aβ N端亲水区的组氨酸残基不与Fe（III）结合。这些结果与Zn（II）诱导的Aβ聚集形成鲜明对比，其中组氨酸残基作为主要金属结合位点。

项目成果

Takashi Miura: "Binding of Iron(III) to the Single Tyrosine Residue of Amyloid β-Peptide Probed by Raman Spectroscopy"Journal of Molecular Structure. 598(1). 79-84 (2001)

Takashi Miura：“通过拉曼光谱探测铁 (III) 与淀粉样蛋白 β-肽的单个酪氨酸残基的结合”，分子结构杂志 598(1) (2001)。

Takashi Miura: "Metal binding modes of Alzheimer's amyloid β-peptide in insoluble aggregates and soluble complexes"Biochemistry. 39. 7024-7031 (2000)

Takashi Miura：“阿尔茨海默病淀粉样蛋白 β-肽在不溶性聚集体和可溶性复合物中的金属结合模式”生物化学 39. 7024-7031 (2000)。

Takashi Miura: "Metal binding modes of Alzheimer's amyloid β-peptide in insoluble aggregates and soluble complexes"Biochemistry. 39(23). 7024-7031 (2000)

Takashi Miura：“阿尔茨海默病淀粉样蛋白 β-肽在不溶性聚集体和可溶性复合物中的金属结合模式”生物化学 39(23) (2000)。

Takashi Miura, Kiyoko Suzuki & Hideo Takeuchi: "Binding of Iron(III) to the Single Tyrosine Residue of Amyloid β-peptide Probed by Raman Spectroscopy"Journal of Molecular Structure. 598(1). 79-84 (2001)

Takashi Miura、Kiyoko Suzuki 和 Hideo Takeuchi：“通过拉曼光谱探测铁 (III) 与淀粉样蛋白 β-肽的单个酪氨酸残基的结合”《分子结构杂志》598(1)。

Kiyoko Suzuki: "Inhibitory Effect of Copper(II) on Zinc(II)-Induced Aggregation of Amyloid β-Peptide"Biochemical Biophysical Research Communications. 285. 991-996 (2001)

Kiyoko Suzuki：“铜 (II) 对锌 (II) 诱导的淀粉样蛋白 β-肽聚集的抑制作用”生化生物物理研究通讯。 285. 991-996 (2001)