Turn Plasticity Distinguishes Different Modes of Amyloid-β Aggregation
Turn Plasticity Distinguishes Different Modes of Amyloid-β Aggregation
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DOI：
10.1021/ja411707y
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发表时间：
2014-04-02
影响因子：
15
通讯作者：
Zweckstetter, Markus
中科院分区：
文献类型：
--
作者：
Rezaei-Ghaleh, Nasrollah;Amininasab, Mehriar;Zweckstetter, Markus
阿尔茨海默病(AD)的发病机制与淀粉样β蛋白(Aβ)多肽聚集成寡聚和纤维聚集有关；然而，人们对Aβ聚集成不同组装状态的分子基础知之甚少。在这里，我们证明了丝氨酸26(S26)的磷酸化损害了Aβ的纤溶作用，同时稳定了它的单体和非纤维形态的无毒的可溶性集合体。核磁共振光谱和复制交换分子动力学表明，在26位引入磷酸基团或仿磷基团降低了Aβ形成β-发夹的倾向，使修饰位点周围的区域变硬，并干扰了天冬氨酸23和赖氨酸28之间纤维专一性盐桥的形成。综合数据表明，S26的磷酸化阻止了Aβ聚集向纤维推进所需的不同的构象重排，并为丝氨酸26的磷酸化在AD中可能的作用提供了基础。
Pathogenesis of Alzheimer's disease (AD) is associated with aggregation of the amyloid-beta (A beta) peptide into oligomeric and fibrillar assemblies; however, little is known about the molecular basis of aggregation of A beta into distinct assembly states. Here we demonstrate that phosphorylation at serine 26 (S26) impairs A beta fibrillization while stabilizing its monomers and nontoxic soluble assemblies of nonfibrillar morphology. NMR spectroscopy and replica-exchange molecular dynamics indicate that introduction of a phosphate group or phosphomimetic at position 26 diminishes A beta's propensity to form a beta-hairpin, rigidifies the region around the modification site, and interferes with formation of a fibril-specific salt bridge between aspartic acid 23 and lysine 28. The combined data demonstrate that phosphorylation of S26 prevents a distinct conformational rearrangement that is required for progression of A beta aggregation toward fibrils and provide a basis for a possible role of phosphorylation at serine 26 in AD.