Molecular-level examination of Cu2+ binding structure for amyloid fibrils of 40-residue Alzheimer's β by solid-state NMR spectroscopy.
Molecular-level examination of Cu2+ binding structure for amyloid fibrils of 40-residue Alzheimer's β by solid-state NMR spectroscopy.
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DOI：
10.1021/ja1072178
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发表时间：
2011-03-16
影响因子：
15
通讯作者：
Ishii Y
中科院分区：
文献类型：
--
作者：
Parthasarathy S;Long F;Miller Y;Xiao Y;McElheny D;Thurber K;Ma B;Nussinov R;Ishii Y
Cu 2+与淀粉样纤维中的阿尔茨海默氏β（Aβ）肽的结合引起了广泛的关注，因为研究表明，阿尔茨海默氏老年斑中的Cu离子浓度升高，并且Aβ与Cu 2+的这种缔合触发神经毒性活性氧（ROS）如H2 O2的产生。然而，对于Aβ原纤维或Aβ的其他聚集体，Cu 2+与Aβ的详细结合位点和结合结构仍在很大程度上未知。在这项工作中，我们通过检测全长40个残基Aβ（1-40）的1D和2D高分辨率13 C SSNMR中的顺磁信号淬灭，研究了Cu 2+与淀粉样纤维结合的分子细节。在Cu 2+结合的Aβ（1-40）的13 C SSNMR中观察到的选择性淬灭表明，Aβ（1 -40）原纤维中的主要Cu 2+结合位点包括His-13和His-14中的Nε，以及瓦尔-40和Glu侧链（Glu-3、Glu-11和/或Glu-22）中的羧基。13 C化学位移分析表明，在疏水核心区域（残基18-25和30-36）中结合Cu 2+后没有重大结构变化。虽然在Cu 2+存在下通过Met-35氧化产生ROS一直被怀疑，但我们对M35中13 C εH3-S-的SSNMR分析显示，在Cu 2+结合后，Met-35几乎没有变化，排除了单独Cu 2+氧化Met-35的可能性。初步的分子动力学（MD）模拟证实了SSNMR结果提示的结合位点和这种结合的稳定性。分子动力学模拟还表明，Aβ纤维中存在多种独特的Cu 2+结合模式，这些模式是通过分子内和分子间的接触以及由于平行β折叠排列而产生的高度集中的配位位点来实现的。
Cu2+ binding to Alzheimer’s β (Aβ) peptides in amyloid fibrils has attracted broad attention, as it was shown that Cu ion concentration elevates in Alzheimer’s senile plaque and such association of Aβ with Cu2+ triggers the production of neurotoxic reactive oxygen species (ROS) such as H2O2. However, detailed binding sites and binding structures of Cu2+ to Aβ are still largely unknown for Aβ fibrils or other aggregates of Aβ. In this work, we examined molecular details of Cu2+ binding to amyloid fibrils by detecting paramagnetic signal quenching in 1D and 2D high-resolution 13C SSNMR for full-length 40-residue Aβ(1–40). Selective quenching observed in 13C SSNMR of Cu2+-bound Aβ(1–40) suggested that primary Cu2+ binding sites in Aβ(1–40) fibrils include Nε in His-13 and His-14, and carboxyl groups in Val-40 as well as in Glu side chains (Glu-3, Glu-11, and/or Glu-22). 13C chemical shift analysis demonstrated no major structural changes upon Cu2+ binding in the hydrophobic core regions (residues 18–25 and 30–36). Although the ROS production via oxidization of Met-35 in the presence of Cu2+ has been long suspected, our SSNMR analysis of 13CεH3-S- in M35 showed little changes after Cu2+ binding, excluding the possibility of Met-35 oxidization by Cu2+ alone. Preliminary molecular dynamics (MD) simulations on Cu2+-Aβ complex in amyloid fibrils confirmed binding sites suggested by the SSNMR results and the stabilities of such bindings. The MD simulations also indicate the coexistence of a variety of Cu2+-binding modes unique in Aβ fibril, which are realized by both intra- and inter-molecular contacts and highly concentrated coordination sites due to the in-register parallel β-sheet arrangements.
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DOI：
10.1073/pnas.0708460105
发表时间：
2008-11-11
影响因子：
11.1
作者：
Balayssac, Stephane;Bertini, Ivano;Luchinat, Claudio
通讯作者：
Luchinat, Claudio
影响因子：
15
作者：
Chimon, S;Ishii, Y
通讯作者：
Ishii, Y
影响因子：
2
作者：
Antzutkin, ON
通讯作者：
Antzutkin, ON
影响因子：
3.3
作者：
Branco, Ricardo J. F.;Fernandes, Pedro A.;Ramos, Maria J.
通讯作者：
Ramos, Maria J.
影响因子：
15
作者：
Balayssac, Stephane;Bertini, Ivano;Maletta, Massimiliano
通讯作者：
Maletta, Massimiliano