The Aβ40 and Aβ42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation.
The Aβ40 and Aβ42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation.
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DOI：
10.1039/c4sc02517b
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发表时间：
2015-07-01
期刊：
影响因子：
8.4
通讯作者：
Linse S
中科院分区：
文献类型：
--
作者：
Cukalevski R;Yang X;Meisl G;Weininger U;Bernfur K;Frohm B;Knowles TPJ;Linse S
从Aβ40和Aβ42的单体混合物开始的反应网络。初级成核水平上的相互作用只会加速Aβ40原纤维的形成。单独的原纤维形成作为次生成核和伸长是高度特异性的。蛋白质组装成淀粉样蛋白原纤维是几种目前无法治愈的人类疾病的核心现象，是一个高度特异性的过程，通常只容忍组成多肽的低水平序列错配。然而，在许多情况下，易于聚集的多肽以序列长度或翻译后修饰变化的混合物存在；特别是可变长度的β淀粉样蛋白（a β）肽在中枢神经系统中共存，并在阿尔茨海默病和相关痴呆中具有聚集倾向。本文研究了两种主要形式的Aβ， Aβ40和Aβ42的共聚集和交叉播种行为，它们在c端有两个疏水残基。我们发现，通过同位素标记、质谱和电子显微镜，它们在两种肽的混合溶液中形成纤维时优先分离成纯Aβ42和Aβ40结构。虽然没有形成混合原纤维，但一种肽的淀粉样蛋白形成动力学受到另一种形式的存在的影响。特别是单体a β42以浓度依赖的方式强烈加速a β40的聚集。虽然每个肽的聚集是由同一肽的低浓度预先形成的原纤维催化的，但我们观察到当a β42原纤维添加到a β40单体或反之亦然时，效果相对不显著。因此，我们得出结论，原纤维催化的细胞核形成和延伸是高度序列特异性的事件，但Aβ40和Aβ42在初级成核过程中相互作用。这些结果提供了多肽序列变体混合物中同分子和异分子聚集步骤的分子水平描述。
Reaction network starting from monomer mixtures of Aβ40 and Aβ42. Interaction at the level of primary nucleation only accelerates Aβ40 fibril formation. Separate fibrils form as secondary nucleation and elongation are highly specific. The assembly of proteins into amyloid fibrils, a phenomenon central to several currently incurable human diseases, is a process of high specificity that commonly tolerates only a low level of sequence mismatch in the component polypeptides. However, in many cases aggregation-prone polypeptides exist as mixtures with variations in sequence length or post-translational modifications; in particular amyloid β (Aβ) peptides of variable length coexist in the central nervous system and possess a propensity to aggregate in Alzheimer's disease and related dementias. Here we have probed the co-aggregation and cross-seeding behavior of the two principal forms of Aβ, Aβ40 and Aβ42 that differ by two hydrophobic residues at the C-terminus. We find, using isotope-labeling, mass spectrometry and electron microscopy that they separate preferentially into homomolecular pure Aβ42 and Aβ40 structures during fibril formation from mixed solutions of both peptides. Although mixed fibrils are not formed, the kinetics of amyloid formation of one peptide is affected by the presence of the other form. In particular monomeric Aβ42 accelerates strongly the aggregation of Aβ40 in a concentration-dependent manner. Whereas the aggregation of each peptide is catalyzed by low concentrations of preformed fibrils of the same peptide, we observe a comparably insignificant effect when Aβ42 fibrils are added to Aβ40 monomer or vice versa. Therefore we conclude that fibril-catalysed nucleus formation and elongation are highly sequence specific events but Aβ40 and Aβ42 interact during primary nucleation. These results provide a molecular level description of homomolecular and heteromolecular aggregation steps in mixtures of polypeptide sequence variants.
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DOI：
10.1016/j.bbapap.2010.04.001
发表时间：
2010-07
期刊：
Biochimica et biophysica acta
影响因子：
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发表时间：
2005-08-12
影响因子：
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DOI：
10.1073/pnas.1218402110
发表时间：
2013-06-11
影响因子：
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