pH-Dependent Cu(II) Coordination to Amyloid-β Peptide: Impact of Sequence Alterations, Including the H6R and D7N Familial Mutations
pH-Dependent Cu(II) Coordination to Amyloid-β Peptide: Impact of Sequence Alterations, Including the H6R and D7N Familial Mutations
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DOI：
10.1021/ic201739n
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发表时间：
2011-11-07
影响因子：
4.6
通讯作者：
Hureau, Christelle
中科院分区：
文献类型：
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作者：
Alies, Bruno;Eury, Helene;Hureau, Christelle
铜离子被认为参与了与阿尔茨海默病(AD)发展相关的有害过程。作为一个直接的结果，描述铜(II)如何与淀粉样β蛋白(Aβ)肽结合，这是AD中遇到的淀粉样多肽，是至关重要的。在生理pH附近存在两种不同形式的[Cu-II(Aβ)]络合物，通常被称为组分I和II，其性质在文献中仍有广泛的争论，特别是对于II。在本报告中，用EPR、CD和核磁共振技术对铜(II)与Aβ和10个突变体的配位进行了唯象的pH依赖研究。虽然对铜(II)与突变多肽结合的研究只能获得间接的见解，但它们对更好地确定天然Aβ多肽中的铜(II)配位部位非常有用。在pH 6~12范围内鉴定出4个组分，即组分I、II、III和IV，其中主要的Cu(II)赤道中心是{-NH2，CO(As1-Al2)，N-im(His6)，N-im(His13或His14)}，{-NH2，N-(Asp1-Al2)，CO(Ala2-Glu3)，N-im}，{-NH2，N-(As1-Al2)，N-(Al2-Gl3)，N-im}和{-NH2，N-(Asp1-Al2)，N-(Ala2-Glu3)，N-(Glu3-Phe4)}，与经典的pH诱导铜(II)多肽络合物形成中肽骨架的去质子化相一致。结合文献中报道的另一种配位模型，讨论了组分II的结构，即{CO(Ala2-Glu3)，3N-im}。还研究了铜(II)与H6R-Aβ和D7N-Aβ多肽的结合，其中家族性H6R和D7N突变与AD的早期发病有关。在H6R突变的情况下，一些不同的结构特征(与天然的[铜-II(Aβ)]物种相比)已被证明，并预计对H6R-Aβ多肽在铜(II)存在下的聚集特性是重要的。
Copper ions have been proposed to intervene in deleterious processes linked to the development of Alzheimer's disease (AD). As a direct consequence, delineating how Cu(II) can be bound to amyloid-beta (A beta) peptide, the amyloidogenic peptide encountered in AD, is of paramount importance. Two different forms of [Cu-II(A beta)] complexes are present near physiological pH, usually noted components I and II, the nature of which is still widely debated in the literature, especially for II. In the present report, the phenomenological pH-dependent study of Cu(II) coordination to A beta and to ten mutants by EPR, CD, and NMR techniques is described. Although only indirect insights can be obtained from the study of Cu(II) binding to mutated peptides, they reveal very useful for better defining Cu(II) coordination sites in the native A beta peptide. Four components were identified between pH 6 and 12, namely, components I, II, III and IV, in which the predominant Cu(II) equatorial sites are {-NH2, CO (Asp1-Ala2), N-im (His6), N-im (His13 or His14)}, {-NH2, N- (Asp1-Ala2), CO (Ala2-Glu3), N-im}, {-NH2, N- (Asp1-Ala2), N- (Ala2-Glu3), N-im} and {-NH2, N- (Asp1-Ala2), N- (Ala2-Glu3), N- (Glu3-Phe4)}, respectively, in line with classical pH-induced deprotonation of the peptide backbone encountered in Cu(II) peptidic complexes formation. The structure proposed for component II is discussed with respect to another coordination model reported in the literature, that is, {CO (Ala2-Glu3), 3 N-im}. Cu(II) binding to the H6R-A beta and D7N-A beta peptides, where the familial H6R and D7N mutations have been linked to early onset of AD, has also been investigated. In case of the H6R mutation, some different structural features (compared to those encountered in the native [Cu-II(A beta)] species) have been evidenced and are anticipated to be important for the aggregating properties of the H6R-A beta peptide in presence of Cu(II).