Graduate Program in Molecular Biology, Cell Biology, and Biochemistry and ‡Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University , Providence, Rhode Island 02912, United States.
Biochemistry. 2014 May 20;53(19):3095-105. doi: 10.1021/bi500131a. Epub 2014 May 7.
Recent studies suggest that deposition of amyloid β (Aβ) into oligomeric aggregates and fibrils, hallmarks of Alzheimer's disease, may be initiated by the aggregation of Aβ species other than the well-studied 40- and 42-residue forms, Aβ40 and Aβ42, respectively. Here we report on key structural, dynamic, and aggregation kinetic parameters of Aβ43, extended by a single threonine at the C-terminus relative to Aβ42. Using aggregation time course experiments, electron microscopy, and a combination of nuclear magnetic resonance measurements including backbone relaxation, dark-state exchange saturation transfer, and quantification of chemical shift differences and scalar coupling constants, we demonstrate that the C-terminal threonine in Aβ43 increases the rate and extent of protofibril aggregation and confers slow C-terminal motions in the monomeric and protofibril-bound forms of Aβ43. Relative to the neighboring residues, the hydrophilic Thr43 of Aβ43 favors direct contact with the protofibril surface more so than the C-terminus of Aβ40 or Aβ42. Taken together, these results demonstrate the potential of a small chemical modification to affect the properties of Aβ structure and aggregation, providing a mechanism for the potential role of Aβ43 as a primary nucleator of Aβ aggregates in Alzheimer's disease.
最近的研究表明，淀粉样蛋白β（Aβ）寡聚体和纤维的沉积，即阿尔茨海默病的标志，可能是由除了研究充分的 40 个和 42 个残基形式（分别为 Aβ40 和 Aβ42）以外的 Aβ 物种的聚集引发的。在这里，我们报告了 Aβ43 的关键结构、动态和聚集动力学参数，与 Aβ42 相比，Aβ43 在 C 末端延长了一个苏氨酸。通过聚合时间过程实验、电子显微镜以及包括骨架弛豫、暗态交换饱和转移和化学位移差异和标量耦合常数定量的核磁共振测量的组合，我们证明了 Aβ43 的 C 末端苏氨酸增加了原纤维聚集的速度和程度，并赋予了 Aβ43 的单体和原纤维结合形式中的 C 末端缓慢运动。与相邻残基相比，Aβ43 的亲水 Thr43 比 Aβ40 或 Aβ42 的 C 末端更有利于与原纤维表面直接接触。总之，这些结果表明，即使是一个小的化学修饰也可能影响 Aβ 结构和聚集的性质，为 Aβ43 作为阿尔茨海默病中 Aβ 聚集的主要引发剂的潜在作用提供了一种机制。
