期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：17
页码：5407-5412
DOI：10.1073/pnas.1421961112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceOne histologic hallmark of Alzheimer's disease is the self-assembly of amyloid {beta} peptide (A{beta}) into insoluble amyloid aggregates. This aggregation process is strongly dependent on environmental conditions and metal ions, such as zinc, have been shown to modulate A{beta} aggregation. To understand the underlying molecular mechanism of how zinc affects fibril formation we analyzed the aggregation kinetics and could conclude that zinc causes a significant reduction in elongation rate (i.e., monomer addition to the fibril ends). We used NMR methods to elucidate the details of zinc binding and we found that the N terminus of A{beta} transiently folds around the zinc ion, forming a metastable dynamic complex. Metal ions have emerged to play a key role in the aggregation process of amyloid {beta} (A{beta}) peptide that is closely related to the pathogenesis of Alzheimer's disease. A detailed understanding of the underlying mechanistic process of peptide-metal interactions, however, has been challenging to obtain. By applying a combination of NMR relaxation dispersion and fluorescence kinetics methods we have investigated quantitatively the thermodynamic A{beta}-Zn2+ binding features as well as how Zn2+ modulates the nucleation mechanism of the aggregation process. Our results show that, under near-physiological conditions, substoichiometric amounts of Zn2+ effectively retard the generation of amyloid fibrils. A global kinetic profile analysis reveals that in the absence of zinc A{beta}40 aggregation is driven by a monomer-dependent secondary nucleation process in addition to fibril-end elongation. In the presence of Zn2+, the elongation rate is reduced, resulting in reduction of the aggregation rate, but not a complete inhibition of amyloid formation. We show that Zn2+ transiently binds to residues in the N terminus of the monomeric peptide. A thermodynamic analysis supports a model where the N terminus is folded around the Zn2+ ion, forming a marginally stable, short-lived folded A{beta}40 species. This conformation is highly dynamic and only a few percent of the peptide molecules adopt this structure at any given time point. Our findings suggest that the folded A{beta}40-Zn2+ complex modulates the fibril ends, where elongation takes place, which efficiently retards fibril formation. In this conceptual framework we propose that zinc adopts the role of a minimal antiaggregation chaperone for A{beta}40.
