Department for NMR-Based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.
Biophys J. 2011 Sep 7;101(5):1202-11. doi: 10.1016/j.bpj.2011.06.062.
Assembly of β-amyloid (Aβ) peptide into toxic oligomers is widely believed to initiate Alzheimer's disease pathogenesis. Under in vitro physiological conditions, zinc (Zn(II)) can bind to Aβ and redirect its assembly from amyloid fibrillar toward less toxic amorphous aggregation. Propensity of Aβ to go toward a specific form of aggregate state is determined by structural and dynamical properties of the initial monomeric as well as the aggregate state. Here we probe the structural and dynamical impact of binding of Zn(II) to monomeric Aβ40 using NMR spectroscopy. To obtain further support for the importance of intrinsic dynamics in the aggregation precursor, (15)N relaxation measurements were also performed for Aβ42, the more fibrillar aggregation-prone variant of Aβ. The combined data suggest that, upon Zn(II)-binding to the N-terminus of Aβ40, a relatively rigid turnlike structure is induced at residues Val(24)-Lys(28) whereas the residues flanking this region become more mobile on the picosecond-to-nanosecond timescale. This is in contrast to the increased rigidity of Aβ42 at the C-terminus, and proposed to be linked to the higher propensity of Zn(II)-bound peptide to form amorphous aggregates with less entropic penalties than their fibrillar counterparts.
β-淀粉样蛋白 (Aβ) 肽的组装形成毒性寡聚体，被广泛认为是引发阿尔茨海默病发病机制的原因。在体外生理条件下，锌 (Zn(II)) 可以与 Aβ 结合，并将其组装从淀粉样纤维状转向毒性较低的无定形聚集。Aβ 倾向于形成特定形式的聚集态，这取决于初始单体以及聚集态的结构和动力学特性。在这里，我们使用 NMR 光谱法研究了 Zn(II)与单体 Aβ40 结合对其结构和动力学的影响。为了进一步支持固有动力学在聚集前体中的重要性，还对 Aβ42（Aβ 的更易形成纤维状聚集的变体）进行了 (15)N 弛豫测量。综合数据表明，Zn(II)与 Aβ40 的 N 端结合后，在残基 Val(24)-Lys(28)处诱导形成相对刚性的环肽结构，而该区域周围的残基在皮秒到纳秒时间尺度上变得更加移动。这与 Aβ42 在 C 端的刚性增加形成对比，并且与 Zn(II)结合的肽形成无定形聚集体的倾向更高有关，与纤维状聚集体相比，其具有更少的熵罚。
