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Zinc as chaperone-mimicking agent for retardation of amyloid beta peptide fibril formation
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.ORCID-id: 0000-0002-6048-6896
2015 (Engelska)Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 17, s. 5407-5412Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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).

Ort, förlag, år, upplaga, sidor
2015. Vol. 112, nr 17, s. 5407-5412
Nyckelord [en]
Alzheimer's disease, amyloid beta peptide, aggregation kinetics, zinc ion interactions, NMR relaxation
Nationell ämneskategori
Biologiska vetenskaper Medicinska och farmaceutiska grundvetenskaper
Identifikatorer
URN: urn:nbn:se:su:diva-117444DOI: 10.1073/pnas.1421961112ISI: 000353554000052PubMedID: 25825723OAI: oai:DiVA.org:su-117444DiVA, id: diva2:813011
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AuthorCount:3;

Tillgänglig från: 2015-05-21 Skapad: 2015-05-19 Senast uppdaterad: 2022-02-23Bibliografiskt granskad

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Abelein, AxelGräslund, AstridDanielsson, Jens

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Abelein, AxelGräslund, AstridDanielsson, Jens
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Proceedings of the National Academy of Sciences of the United States of America
Biologiska vetenskaperMedicinska och farmaceutiska grundvetenskaper

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