The mechanism by which a disordered peptide nucleates and forms amyloid is incompletely understood. A central domain of β-amyloid (Aβ21-30) has been proposed to have intrinsic structural propensities that guide the limited formation of structure in the process of fibrillization. In order to test this hypothesis, we examine several internal fragments of Aβ, and variants of these either cyclized or with an N-terminal Cys. While Aβ21-30 and variants were always monomeric and unstructured (circular dichroism (CD) and nuclear magnetic resonance spectroscopy (NMRS)), we found that the addition of flanking hydrophobic residues in Aβ16-34 led to formation of typical amyloid fibrils. NMR showed no long-range nuclear overhauser effect (nOes) in Aβ21-30, Aβ16-34, or their variants, however. Serial 1 H-15 N-heteronuclear single quantum coherence spectroscopy, 1 H-1 H nuclear overhauser effect spectroscopy, and 1 H-1 H total correlational spectroscopy spectra were used to follow aggregation of Aβ16-34 and Cys-Aβ16-34 at a site-specific level. The addition of an N-terminal Cys residue (in Cys-Aβ16-34) increased the rate of fibrillization which was attributable to disulfide bond formation. We propose a scheme comparing the aggregation pathways for Aβ16-34 and Cys-Aβ16-34, according to which Cys-Aβ16-34 dimerizes, which accelerates fibril formation. In this context, cysteine residues form a focal point that guides fibrillization, a role which, in native peptides, can be assumed by heterogeneous nucleators of aggregation.

中文翻译：

---

β-淀粉样蛋白模型核心肽：疏水物和二硫化物的作用。

紊乱的肽成核并形成淀粉样蛋白的机制尚不完全清楚。已经提出β-淀粉样蛋白（Aβ21-30）的中央结构域具有固有的结构倾向，该固有的结构倾向指导在原纤化过程中有限的结构形成。为了检验这一假设，我们检查了Aβ的几个内部片段，以及这些片段的变体，这些变体是环化的或带有N端Cys。尽管Aβ21-30及其变体始终是单体和非结构化的（圆二色性（CD）和核磁共振波谱（NMRS）），但我们发现Aβ16-34中侧翼的疏水残基的添加导致典型淀粉样原纤维的形成。NMR在Aβ21-30，Aβ16-34或它们的变异体中没有显示出长程核过载效应（nOes）。系列1 H-15 N-异核单量子相干光谱，使用1 H-1 H核超负荷效应光谱和1 H-1 H总相关光谱对特定位置的Aβ16-34和Cys-Aβ16-34进行聚集。N末端Cys残基的添加（在Cys-Aβ16-34中）增加了原纤维化的速率，这归因于二硫键的形成。我们提出一种方案，比较Aβ16-34和Cys-Aβ16-34的聚集途径，据此Cys-Aβ16-34发生二聚化，从而加速原纤维形成。在这种情况下，半胱氨酸残基形成了一个引导原纤维化的焦点，在天然肽中，这种作用可以由聚集的异质成核剂承担。N末端Cys残基的添加（在Cys-Aβ16-34中）增加了原纤维化的速率，这归因于二硫键的形成。我们提出一种方案，比较Aβ16-34和Cys-Aβ16-34的聚集途径，据此Cys-Aβ16-34发生二聚化，从而加速原纤维形成。在这种情况下，半胱氨酸残基形成了一个引导原纤维化的焦点，这种作用在天然肽中可以由聚集的异质成核剂承担。N末端Cys残基的添加（在Cys-Aβ16-34中）增加了原纤维化的速率，这归因于二硫键的形成。我们提出一种方案，比较Aβ16-34和Cys-Aβ16-34的聚集途径，据此Cys-Aβ16-34发生二聚化，从而加速原纤维形成。在这种情况下，半胱氨酸残基形成了一个引导原纤维化的焦点，在天然肽中，这种作用可以由聚集的异质成核剂承担。