Mechanism of Nucleated Conformational Conversion of Aβ42
Mechanism of Nucleated Conformational Conversion of Aβ42
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DOI：
10.1021/acs.biochem.5b00467
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发表时间：
2015-07-14
期刊：
影响因子：
2.9
通讯作者：
Smith, Steven
中科院分区：
文献类型：
--
作者：
Fu, Ziao;Aucoin, Darryl;Smith, Steven
A β 42肽的可溶性寡聚体和原纤维是单体A β 42转化为与阿尔茨海默病相关的淀粉样纤维的神经毒性中间体。核磁共振和傅里叶变换红外光谱，沿着与单触摸原子力显微镜，用于建立参与原纤维形成的结构转变。我们表明，在有利于成核构象转换的条件下，A β 42肽聚集成大部分非结构化的低分子量（MW）低聚物，这些低聚物能够堆叠形成高分子量低聚物，并横向缔合形成原纤维。β-折叠二级结构在低聚物的不可逆横向缔合期间形成。这种转化的第一步是形成通过单体内氢键稳定的反平行β-发夹。然后，反平行的β-发夹与具有单体间氢键的平行且对齐的β-链结合成交叉β-折叠结构。
Soluble oligorners and protofibrils of the A beta 42 peptide are neurotoxic intermediates in the conversion of monomeric A beta 42 into the amyloid fibrils associated with Alzheimer's disease. Nuclear magnetic resonance and Fourier transform infrared spectroscopy, along with single-touch atomic force microscopy, are used to establish the structural transitions involved in fibril formation. We show that under conditions favorable for the nucleated conformation conversion, the A beta 42 peptide aggregates into largely unstructured low-molecular weight (MW) oligomers that are able to stack to form high-MW oligomers and to laterally associate to form protofibrils. beta-Sheet secondary structure develops during the irreversible lateral association of the oligomers. The first step in this conversion is the formation of an antiparallel beta-hairpin stabilized by intramonomer hydrogen bonding. The antiparallel beta-hairpins then associate into a cross beta-sheet structure with parallel and in-register beta-strands having intermonomer hydrogen bonding.