Metal binding modes of Alzheimer's amyloid β-peptide in insoluble aggregates and soluble complexes
Metal binding modes of Alzheimer's amyloid β-peptide in insoluble aggregates and soluble complexes
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DOI：
10.1021/bi0002479
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发表时间：
2000-06-13
期刊：
影响因子：
2.9
通讯作者：
Takeuchi, H
中科院分区：
文献类型：
--
作者：
Miura, T;Suzuki, K;Takeuchi, H
淀粉样β-肽（A β）聚集成不溶性纤维是阿尔茨海默病的关键病理事件。Zn（II）诱导A β聚集在酸性至中性pH值，而Cu（TI）是一个有效的诱导剂，只有在温和的酸性pH值。我们已经研究了Zn（II）和Cu（II）的结合模式的A β和它们的pH依赖性的拉曼光谱。拉曼光谱清楚地表明，在N-末端亲水区域的三个组氨酸残基提供了主要的金属结合位点，并且金属-A β络合物的溶解度与金属结合模式相关。Zn（TI）与组氨酸咪唑环的N-tau原子结合，并且肽通过分子间His（N-tau）-Zn（II）-His（N-tau）桥聚集。N-tau-金属连接也发生在Cu（II）诱导的A β聚集在温和的酸性pH值。然而，在中性pH值，Cu（II）结合到N-π，其他氮的组氨酸咪唑环，和去质子化的酰胺氮的肽主链。组氨酸和主链酰胺基团对Cu（II）的螯合作用导致可溶性Cu（II）-A β络合物。在正常生理条件下，预期Cu（II）通过与Zn（TI）竞争A β的组氨酸残基来保护A β免受Zn（II）诱导的聚集。
Aggregation of the amyloid beta-peptide (A beta) into insoluble fibrils is a key pathological event in Alzheimer's disease. Zn(II) induces the A beta aggregation at acidic-to-neutral pH, while Cu(TI) is an effective inducer only at mildly acidic pH. We have examined Zn(II) and Cu(II) binding modes of A beta and their pH dependence by Raman spectroscopy. The Raman spectra dearly demonstrate that three histidine residues in the N-terminal hydrophilic region provide primary metal binding sites and the solubility of the metal-A beta complex is correlated with the metal binding mode. Zn(TI) binds to the N-tau atom of the histidine imidazole ring and the peptide aggregates through intermolecular His(N-tau)-Zn(II)-His(N-tau) bridges. The N-tau-metal ligation also occurs in Cu(II)-induced A beta aggregation at mildly acidic pH. At neutral pH, however, Cu(II) binds to N-pi, the other nitrogen of the histidine imidazole ring, and to deprotonated amide nitrogens of the peptide main chain. The chelation of Cu(II) by histidine and main-chain amide groups results in soluble Cu(II)-A beta complexes. Under normal physiological conditions, Cu(II) is expected to protect A beta against Zn(II)-induced aggregation by competing with Zn(TI) for histidine residues of A beta.