Distance measurement between Tyr10 and Met35 in amyloid β by site-directed spin-labeling ESR spectroscopy:: Implications for the stronger neurotoxicity of Aβ42 than Aβ40
Distance measurement between Tyr10 and Met35 in amyloid β by site-directed spin-labeling ESR spectroscopy:: Implications for the stronger neurotoxicity of Aβ42 than Aβ40
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DOI：
10.1002/cbic.200700240
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发表时间：
2007-12-17
期刊：
影响因子：
3.2
通讯作者：
Irie, Kazuhiro
中科院分区：
文献类型：
--
作者：
Murakami, Kazuma;Hara, Hideyuki;Irie, Kazuhiro
42 聚体和 40 聚体淀粉样蛋白 β 肽（A beta 42 和 A beta 340）的神经毒性与 Tyr10 和 Met35 的自由基化密切相关。 A beta 42 比 A beta 40 具有更强的神经毒性。我们之前对 A beta 42 的结构分析表明，Tyr10 和 Met35 通过位置 22 和 23 处的旋转而更加靠近，并且位置 35 处的 S-氧化自由基阳离子（最终的有毒自由基种类）可以通过位置 10 处的苯氧基自由基的氧化有效产生。为了验证这一想法，通过使用定点自旋标记（MTSSL）测量了它们的分离ESR 光谱。在10位和35位双重或单自旋标记的三种Aβ42衍生物中，只有10,35-MTSR-Aβ42在连续波ESR中表现出明显的偶极耦合；这表明 A beta 42 中位置 10 和 35 的分子内自旋标记位于大约 15 埃内。相比之下，10,35-MTSR-A beta 40 则没有给出这样的信号。通过脉冲ESR光谱法成功测量到10,35-MTSSL-A beta 40中Tyr10和Met35之间的距离为30埃长，A beta 42和A beta 40之间的距离差异可以解释A beta 42与A beta 40相比具有更强的神经毒性。
The neurotoxicity of the 42-mer and 40-mer amyloid beta peptides (A beta 42 and A beta 340) is closely related to the radicalization at both Tyr10 and Met35. A beta 42 is more neurotoxic than A beta 40. Our previous structural analyses of A beta 42 suggested that Tyr10 and Met35 are brought closer together by the turn at positions 22 and 23, and the S-oxidized radical cation at position 35, which is the ultimate toxic radical species, can be produced effectively through oxidation by the phenoxy radical at position 10. To verify this idea, their separation was measured by site-directed spin labeling (MTSSL) by using ESR spectroscopy. Among the three kinds of A beta 42 derivatives, which are doubly or singly spin-labeled at position 10 and 35, only 10,35-MTSR-A beta 42 showed a clear dipole coupling in continuous-wave ESR; this suggests that the intramolecular spin labels at position 10 and 35 in A beta 42 are located within similar to 15 angstrom. In contrast, 10,35-MTSR-A beta 40 did not give such signals. The distance between Tyr10 and Met35 in 10,35-MTSSL-A beta 40, which was successfully measured by pulsed ESR spectroscopy was 30 angstrom long, The difference in the distance between A beta 42 and A beta 40 could explain in port the stronger neurotoxicity of A beta 42 compared to A beta 40.