The C-Terminal Threonine of Aβ43 Nucleates Toxic Aggregation via Structural and Dynamical Changes in Monomers and Protofibrils
The C-Terminal Threonine of Aβ43 Nucleates Toxic Aggregation via Structural and Dynamical Changes in Monomers and Protofibrils
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DOI：
10.1021/bi500131a
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发表时间：
2014-05-20
期刊：
影响因子：
2.9
通讯作者：
Fawzi, Nicolas L.
中科院分区：
文献类型：
--
作者：
Conicella, Alexander E.;Fawzi, Nicolas L.
最近的研究表明，β 淀粉样蛋白 (Aβ) 沉积到寡聚聚集体和原纤维中（阿尔茨海默病的标志）可能是由 Aβ 物质的聚集引发的，而不是经过充分研究的 40 和 42 残基形式（分别为 Aβ 40 和 Aβ 42）。在这里，我们报告了 A beta 43 的关键结构、动态和聚集动力学参数，相对于 A beta 42 在 C 端由单个苏氨酸扩展。使用聚集时间过程实验、电子显微镜和核磁共振测量的组合，包括主链弛豫、暗态交换饱和转移以及化学位移差异和标量耦合常数的量化，我们证明 A beta 43 中的 C 端苏氨酸增加了原纤维的速率和程度聚合并赋予 A beta 43 的单体和原纤维结合形式的缓慢 C 末端运动。相对于邻近的残基，A beta 43 的亲水性 Thr43 比 A beta 40 或 A beta 42 的 C 末端更有利于与原纤维表面直接接触。总而言之，这些结果证明了小的化学修饰有可能影响 A β 结构和聚集的特性，为 A 的潜在作用提供了机制。 β 43 作为阿尔茨海默病中 A β 聚集体的主要成核剂。
Recent studies suggest that deposition of amyloid beta (A beta) into oligomeric aggregates and fibrils, hallmarks of Alzheimer's disease, may be initiated by the aggregation of A beta species other than the well-studied 40- and 42-residue forms, A beta 40 and A beta 42, respectively. Here we report on key structural, dynamic, and aggregation kinetic parameters of A beta 43, extended by a single threonine at the C-terminus relative to A beta 42. 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 A beta 43 increases the rate and extent of protofibril aggregation and confers slow C-terminal motions in the monomeric and protofibril-bound forms of A beta 43. Relative to the neighboring residues, the hydrophilic Thr43 of A beta 43 favors direct contact with the protofibril surface more so than the C-terminus of A beta 40 or A beta 42. Taken together, these results demonstrate the potential of a small chemical modification to affect the properties of A beta structure and aggregation, providing a mechanism for the potential role of A beta 43 as a primary nucleator of A beta aggregates in Alzheimer's disease.