Polymorphism of Alzheimer's Aβ17-42 (p3) Oligomers: The Importance of the Turn Location and Its Conformation

被引:87
作者
Miller, Yifat
Ma, Buyong [1 ]
Nussinov, Ruth [1 ,2 ]
机构
[1] NCI, Basic Res Program, SAIC Frederick, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA
[2] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel
基金
美国国家卫生研究院;
关键词
BETA-AMYLOID PEPTIDE; MOLECULAR-DYNAMICS SIMULATIONS; PARTICLE MESH EWALD; SOLID-STATE NMR; FIBRIL FORMATION; IN-VITRO; PRECURSOR PROTEIN; COMMON MECHANISM; STRUCTURAL BASIS; PRION STRAINS;
D O I
10.1016/j.bpj.2009.05.042
中图分类号
Q6 [生物物理学];
学科分类号
071011 ;
摘要
A beta(17-42) (so-called p3) amyloid is detected in vivo in the brains of individuals with Alzheimer's disease or Down's syndrome. We investigated the polymorphism of A beta(17-42) oligomers based on experimental data from steady-state NMR measurements, electron microscopy, two-dimensional hydrogen exchange, and mutational studies, using all-atom molecular-dynamics simulation with explicit solvent. We assessed the structural stability and the populations. Our results suggest that conformational differences in the U-turn of A beta(17-42) lead to polymorphism in beta-sheet registration and retention of an ordered beta-strand organization at the termini. Further, although the parallel A beta(17-42) oligomer organization is the most stable of the conformers investigated here, different antiparallel A beta(17-42) organizations are also stable and compete with the parallel architectures, presenting a polymorphic population. In this study we propose that 1), the U-turn conformation is the primary factor leading to polymorphism in the assembly of A beta(17-42) Oligomers, and is also coupled to oligomer growth; and 2), both parallel A beta(17-42) Oligomers and an assembly of A beta(17-42) oligomers that includes both parallel and antiparallel organizations contribute to amyloid fibril formation. Finally, since a U-turn motif generally appears in amyloids formed by full proteins or long fragments, and since to date these have been shown to exist only in parallel architectures, our results apply to a broad range of oligomers and fibrils.
引用
收藏
页码:1168 / 1177
页数:10
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