Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils.
Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils.
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DOI：
10.1021/jacs.6b05129
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发表时间：
2016-08-03
影响因子：
15
通讯作者：
Griffin RG
中科院分区：
文献类型：
--
作者：
Colvin MT;Silvers R;Ni QZ;Can TV;Sergeyev I;Rosay M;Donovan KJ;Michael B;Wall J;Linse S;Griffin RG
淀粉样蛋白-β (a β)是一种由淀粉样前体蛋白（APP）裂解产生的39-42残基蛋白，随后聚集形成交叉β淀粉样蛋白原纤维，这是阿尔茨海默病（AD）的标志。Aβ最突出的形式是Aβ1 - 40和Aβ1 - 42，它们在c端有两个氨基酸（I和A）的区别。然而，a - β42具有更强的神经毒性，对阿尔茨海默病的病因至关重要。本文研究了a - β m01 - 42淀粉样原纤维的原子分辨率结构，该结构来源于500多个13C - 13C， 13C - 15N距离和主角结构约束，这些约束来自高场魔角自旋核磁共振光谱。结构（PDB ID: 5KK3）表明，原纤维核心由a β42分子二聚体组成，每个分子含有4条s型淀粉样蛋白折叠的β链，并以一种方式排列，产生两个疏水核心，这些核心被盐桥覆盖在链的末端。单体的外表面对溶剂呈现亲水性侧链。二聚体单体之间的界面显示一个分子的M35与另一个分子的L17和Q15之间有明显的接触。分子间13C - 15N约束表明淀粉样蛋白原纤维在寄存器上是平行的。主链结构（Q15-A42）的RMSD为0.71±0.12 Å，所有重原子的RMSD为1.07±0.08 Å。该结构为设计与原纤维表面结合从而干扰二次成核的药物以及减轻a β42聚集的其他治疗方法提供了一个出发点。
Amyloid-β (Aβ) is a 39–42 residue protein produced by the cleavage of the amyloid precursor protein (APP), which subsequently aggregates to form cross-β amyloid fibrils that are a hallmark of Alzheimer’s disease (AD). The most prominent forms of Aβ are Aβ1–40 and Aβ1–42, which differ by two amino acids (I and A) at the C-terminus. However, Aβ42 is more neurotoxic and essential to the etiology of AD. Here, we present an atomic resolution structure of a monomorphic form of AβM01–42 amyloid fibrils derived from over 500 13C−13C, 13C−15N distance and backbone angle structural constraints obtained from high field magic angle spinning NMR spectra. The structure (PDB ID: 5KK3) shows that the fibril core consists of a dimer of Aβ42 molecules, each containing four β-strands in a S-shaped amyloid fold, and arranged in a manner that generates two hydrophobic cores that are capped at the end of the chain by a salt bridge. The outer surface of the monomers presents hydrophilic side chains to the solvent. The interface between the monomers of the dimer shows clear contacts between M35 of one molecule and L17 and Q15 of the second. Intermolecular 13C−15N constraints demonstrate that the amyloid fibrils are parallel in register. The RMSD of the backbone structure (Q15–A42) is 0.71 ± 0.12 Å and of all heavy atoms is 1.07 ± 0.08 Å. The structure provides a point of departure for the design of drugs that bind to the fibril surface and therefore interfere with secondary nucleation and for other therapeutic approaches to mitigate Aβ42 aggregation.