title: Zinc as chaperone-mimicking agent for retardation of amyloid β peptide fibril formation.
abstract: Metal ions have emerged to play a key role in the aggregation process of amyloid β (Aβ) 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 Aβ-Zn(2+) binding features as well as how Zn(2+) modulates the nucleation mechanism of the aggregation process. Our results show that, under near-physiological conditions, substoichiometric amounts of Zn(2+) effectively retard the generation of amyloid fibrils. A global kinetic profile analysis reveals that in the absence of zinc Aβ40 aggregation is driven by a monomer-dependent secondary nucleation process in addition to fibril-end elongation. In the presence of Zn(2+), the elongation rate is reduced, resulting in reduction of the aggregation rate, but not a complete inhibition of amyloid formation. We show that Zn(2+) 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 Zn(2+) ion, forming a marginally stable, short-lived folded Aβ40 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 Aβ40-Zn(2+) 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 Aβ40.
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, 106 91 Stockholm, Sweden.
authors.forename: Axel
authors.initials: A
authors.lastname: Abelein
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, 106 91 Stockholm, Sweden.
authors.forename: Astrid
authors.initials: A
authors.lastname: Gräslund
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, 106 91 Stockholm, Sweden jensd@dbb.su.se.
authors.forename: Jens
authors.initials: J
authors.lastname: Danielsson
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D066329:Protein Aggregates; D017434:Protein Structure, Tertiary; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018832:Molecular Chaperones; D010446:Peptide Fragments; D066329:Protein Aggregates; C078592:amyloid beta-protein (1-40); D015032:Zinc
keywords: Alzheimer’s disease; NMR relaxation; aggregation kinetics; amyloid beta peptide; zinc ion interactions
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