Zinc ions promote Alzheimer Aβ aggregation via population shift of polymorphic states
- 6 May 2010
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (21), 9490-9495
- https://doi.org/10.1073/pnas.0913114107
Abstract
Although a key factor in Alzheimer’s disease etiology is enrichment of Zn2+ in aggregates, and there are data suggesting that zinc promotes aggregation, how Zn2+-Aβ coordination promotes aggregation is elusive. Here we probe the structures and mechanisms through which Zn2+ can affect amyloidosis. By covalently linking fragments (that have experiment-based coordinates) we observed that, in oligomeric Zn2+-Aβ42, Zn2+ can simultaneously coordinate intra- and intermolecularly, bridging two peptides. Zinc coordination significantly decreases the solvation energy for large Zn2+-Aβ42 oligomers and thus enhances their aggregation tendency. Zn2+ binding does not change the β-sheet association around the C-terminal hydrophobic region; however, it shifts the relative population of the preexisting amyloid polymorphic ensembles. As a result, although a parallel β-sheet arrangement is still preferred, antiparallel and other less structured assemblies are stabilized, also becoming major species. Overall, Zn2+ coordination promotes Aβ42 aggregation leading to less uniform structures. Our replica exchange molecular dynamics simulations further reproduced an experimental observation that the increasing Zn2+ concentration could slow down the aggregation rate, even though the aggregation rates are still much higher than in Zn2+-free solution.This publication has 50 references indexed in Scilit:
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