Molecular basis for amyloid-β polymorphism
Molecular basis for amyloid-β polymorphism
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DOI：
10.1073/pnas.1112600108
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发表时间：
2011-10-11
影响因子：
11.1
通讯作者：
Eisenberg, David
中科院分区：
文献类型：
--
作者：
Colletier, Jacques-Philippe;Laganowsky, Arthur;Eisenberg, David
淀粉样蛋白-β（A β）聚集体是老年斑的主要成分，老年斑是阿尔茨海默病的组织学标志。β分子形成含有β折叠的结构，其组装成各种多晶型低聚物、原纤维和纤维，其表现出一系列寿命和细胞毒性。A β的这种多态性使其生物物理特性、结构决定和我们对其病理机制的理解受挫。为了阐明A β多态性的原子细节，我们确定了八个新的微晶结构的纤维形成部分的A β。这些结构都是短的、自我互补的β折叠对，称为空间拉链，揭示了A β自我缔合的各种模式。将这些原子结构与以前的NMR研究相结合，使我们能够提出几种纤维模型，为A β可访问的多分散结构的一些库提供分子模型。这些结构和分子模型为理解A β多态性性质和发病机制提供了基础信息。
Amyloid-beta (A beta) aggregates are the main constituent of senile plaques, the histological hallmark of Alzheimer's disease. A beta molecules form beta-sheet containing structures that assemble into a variety of polymorphic oligomers, protofibers, and fibers that exhibit a range of lifetimes and cellular toxicities. This polymorphic nature of A beta has frustrated its biophysical characterization, its structural determination, and our understanding of its pathological mechanism. To elucidate A beta polymorphism in atomic detail, we determined eight new microcrystal structures of fiber-forming segments of A beta. These structures, all of short, self-complementing pairs of beta-sheets termed steric zippers, reveal a variety of modes of self-association of A beta. Combining these atomic structures with previous NMR studies allows us to propose several fiber models, offering molecular models for some of the repertoire of polydisperse structures accessible to A beta. These structures and molecular models contribute fundamental information for understanding A beta polymorphic nature and pathogenesis.