Copper selectively triggers β-sheet assembly of an N-terminally truncated amyloid β-peptide beginning with Glu3
Copper selectively triggers β-sheet assembly of an N-terminally truncated amyloid β-peptide beginning with Glu3
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DOI：
10.1016/j.jinorgbio.2003.10.008
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发表时间：
2004
影响因子：
3.9
通讯作者：
T. Miura;Sayoko Mitani;Chiho Takanashi;Nobuhiro Mochizuki
中科院分区：
文献类型：
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作者：
T. Miura;Sayoko Mitani;Chiho Takanashi;Nobuhiro Mochizuki
金属离子可诱导淀粉样β-肽（Aβ）聚集，这是阿尔茨海默病的一个重要环节。然而，直接证据表明，具体的金属-肽相互作用是负责淀粉样蛋白的形成以前没有提供。在这里，我们提出了第一个例子，金属诱导的淀粉样蛋白形成的Aβ片段，这表现出明确的依赖于氨基酸序列。Aβ3- 9氨基酸残基的七肽EFRHDSG在与Cu（II）结合时发生构象转变，从不规则构象转变为β折叠，并自缔合形成不溶性聚集体。Cu（II）-Aβ3- 9复合物的拉曼光谱分析和突变Aβ3- 9肽的聚集试验表明，His 6的咪唑侧链、Glu 3和Asp 7的羧基以及N端的氨基的协同Cu（II）配位对于淀粉样蛋白的形成是必需的。虽然Aβ1- 9和Aβ2- 9也含有金属结合位点，但这两种肽在Cu（II）存在下均不形成淀粉样沉积。这项研究的结果可能不仅提供了新的见解的淀粉样蛋白形成的机制，但也是重要的一步，建设的蛋白质材料具有特定功能的控制下的铜（II）。
Metal ions have been suggested to induce aggregation of amyloid β-peptide (Aβ), which is a key event in Alzheimer’s disease. However, direct evidence that specific metal–peptide interactions are responsible for the amyloid formation has not previously been provided. Here we present the first example of the metal-induced amyloid formation by an Aβ fragment, which exhibits a clear-cut dependence on the amino acid sequence. A heptapeptide, EFRHDSG, corresponding to the amino acid residues 3–9 of Aβ (Aβ3–9) undergoes a conformational transition from irregular to β-sheet and self-associates into insoluble aggregates upon Cu(II) binding. A Raman spectrum analysis of the Cu(II)–Aβ3–9complex and aggregation assays of mutated Aβ3–9peptides demonstrated that a concerted Cu(II) coordination of the imidazole side chain of His6, the carboxyl groups of Glu3 and Asp7, and the amino group at the N-terminus is essential for the amyloid formation. Although Aβ1–9and Aβ2–9also contain the metal binding sites, neither of these peptides forms amyloid depositions in the presence of Cu(II). The results of this study may not only provide new insight into the mechanism of amyloid formation, but also be important as a step toward the construction of proteinaceous materials with a specific function under the control of Cu(II).