3D structure of Alzheimer's amyloid-beta(1-42) fibrils.
3D structure of Alzheimer's amyloid-beta(1-42) fibrils.
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发表时间：
2005
影响因子：
11.1
通讯作者：
Thorsten Lührs;C. Ritter;M. Adrian;Dominique Riek-Loher;B. Bohrmann;H. Döbeli;D. Schubert;R. Riek
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作者：
Thorsten Lührs;C. Ritter;M. Adrian;Dominique Riek-Loher;B. Bohrmann;H. Döbeli;D. Schubert;R. Riek
阿尔茨海默病是最致命的神经退行性疾病，其中淀粉样蛋白-β（Abeta）淀粉样蛋白生成的过程似乎是致病的。在这里，我们提出了包含Abeta（1-42）的原纤维的3D结构，该结构是通过使用来自淬灭氢/氘交换NMR的氢键约束、来自成对诱变研究的侧链包装约束以及来自先前固态NMR研究的平行、配准β-片层排列获得的。虽然残基1-17是无序的，但残基18-42形成β链-转角-β链基序，其包含由残基18-26（β 1）和31-42（β 2）形成的两个分子间平行的对齐β片层。至少需要两个Abeta（1-42）分子才能获得原丝的重复结构。在第n个分子的β 1链的奇数残基和第（n - 1）个分子的β 2链的偶数残基之间形成分子间侧链接触。这种相互作用模式导致在原纤维末端的部分未配对的β链，这解释了序列选择性、协同性和Abeta原纤维生长的表观单向性。它也为纤维化抑制剂提供了结构基础。
Alzheimer's disease is the most fatal neurodegenerative disorder wherein the process of amyloid-beta (Abeta) amyloidogenesis appears causative. Here, we present the 3D structure of the fibrils comprising Abeta(1-42), which was obtained by using hydrogen-bonding constraints from quenched hydrogen/deuterium-exchange NMR, side-chain packing constraints from pairwise mutagenesis studies, and parallel, in-register beta-sheet arrangement from previous solid-state NMR studies. Although residues 1-17 are disordered, residues 18-42 form a beta-strand-turn-beta-strand motif that contains two intermolecular, parallel, in-register beta-sheets that are formed by residues 18-26 (beta1) and 31-42 (beta2). At least two molecules of Abeta(1-42) are required to achieve the repeating structure of a protofilament. Intermolecular side-chain contacts are formed between the odd-numbered residues of strand beta1 of the nth molecule and the even-numbered residues of strand beta2 of the (n - 1)th molecule. This interaction pattern leads to partially unpaired beta-strands at the fibrillar ends, which explains the sequence selectivity, the cooperativity, and the apparent unidirectionality of Abeta fibril growth. It also provides a structural basis for fibrillization inhibitors.