Copper Coordination to Native N-Terminally Modified versus Full-Length Amyloid-β: Second-Sphere Effects Determine the Species Present at Physiological pH
Copper Coordination to Native N-Terminally Modified versus Full-Length Amyloid-β: Second-Sphere Effects Determine the Species Present at Physiological pH
复制标题
DOI：
10.1021/ic302097d
复制
发表时间：
2012-12-03
影响因子：
4.6
通讯作者：
Hureau, Christelle
中科院分区：
文献类型：
--
作者：
Alies, Bruno;Bijani, Christian;Hureau, Christelle
阿尔茨海默病的特征在于老年斑，其中金属离子（铜、锌和铁）与聚集形式的不同序列的淀粉样蛋白-β肽共定位。除了全长肽（A β 1-40/42）之外，已经提出N-末端截短的A β 3-40/42形式及其焦谷氨酸盐对应物A β p3-40/42在聚集过程中起关键作用，导致老年斑。此外，它们已被证明比全长A β更具毒性，这使它们成为治疗方法的中心靶点。为了更好地解开金属离子在聚集过程中的可能作用，铜（II）的全长淀粉样肽的配位在过去几年中已被广泛研究。然而，关于在位置3处的N-末端修饰形式，知之甚少。因此，铜（I）和铜（II）的协调，这些肽已在本报告中使用各种互补技术和pH值的函数进行了研究。铜（I）的协调不受影响的N-末端修饰。与此相反，铜（II）的协调是不同于先前报道的全长肽。在焦谷氨酸盐形式的情况下，这是由于排除了N-末端胺结合。在N-末端截短形式的情况下，铜（II）配位的改变是由第二球效应引起的，第二球效应影响第一结合壳和各种[Cu（肽）]络合物的pH依赖性再分配。这种第二球效应预计将适用于各种金属离子和肽，其改变第一结合壳层的重要性尚未得到充分认识。
Alzheimer's disease is characterized by senile plaques in which metallic ions (copper, zinc, and iron) are colocalized with amyloid-beta peptides of different sequences in aggregated forms. In addition to the full-length peptides (A beta 1-40/42), N-terminally truncated A beta 3-40/42 forms and their pyroglutamate counterparts, A beta p3-40/42, have been proposed to play key features in the aggregation process, leading to the senile plaques. Furthermore, they have been shown to be more toxic than the full-length A beta, which made them central targets for therapeutic approaches. In order to better disentangle the possible role of metallic ions in the aggregation process, copper(II) coordination to the full-length amyloid peptides has been extensively studied in the last years. However, regarding the N-terminally modified forms at position 3, very little is known. Therefore, copper(I) and copper(II) coordination to those peptides have been investigated in the present report using a variety of complementary techniques and as a function of pH. Copper(I) coordination is not affected by the N-terminal modifications. In contrast, copper(II) coordination is different from that previously reported for the full-length peptide. In the case of the pyroglutamate form, this is due to preclusion of N-terminal amine binding. In the case of the N-terminally truncated form, alteration in copper(II) coordination is caused by second-sphere effects that impact the first binding shell and the pH-dependent repartition of the various [Cu(peptide)] complexes. Such second-sphere effects are anticipated to apply to a variety of metal ions and peptides, and their importance on changing the first binding shell has not been fully recognized yet.