High‐resolution NMR studies of the zinc‐binding site of the Alzheimer's amyloid β‐peptide
Abstract
Metal binding to the amyloid beta-peptide is suggested to be involved in the pathogenesis of Alzheimer's disease. We used high-resolution NMR to study zinc binding to amyloid beta-peptide 1-40 at physiologic pH. Metal binding induces a structural change in the peptide, which is in chemical exchange on an intermediate rate, between the apo-form and the holo-form, with respect to the NMR timescale. This causes loss of NMR signals in the resonances affected by the binding. Heteronuclear correlation experiments, (15)N-relaxation and amide proton exchange experiments on amyloid beta-peptide 1-40 revealed that zinc binding involves the three histidines (residues 6, 13 and 14) and the N-terminus, similar to a previously proposed copper-binding site [Syme CD, Nadal RC, Rigby SE, Viles JH (2004) J Biol Chem 279, 18169-18177]. Fluorescence experiments show that zinc shares a common binding site with copper and that the metals have similar affinities for amyloid beta-peptide. The dissociation constant K(d) of zinc for the fragment amyloid beta-peptide 1-28 was measured by fluorescence, using competitive binding studies, and that for amyloid beta-peptide 1-40 was measured by NMR. Both methods gave K(d) values in the micromolar range at pH 7.2 and 286 K. Zinc also has a second, weaker binding site involving residues between 23 and 28. At high metal ion concentrations, the metal-induced aggregation should mainly have an electrostatic origin from decreased repulsion between peptides. At low…
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The pM values compare favorably with Kd values reported for Cu-Aβ (nM-μM) and Zn-Aβ (μM).
“These pM values represent approximate dissociation constants and compare favorably with the Kd values reported for Cu-Aβ (nM-μM) and Zn-Aβ (μM).26,29,31,57,76,79,80”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [79]
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- Authors
- Danielsson, J., Pierattelli, R., Banci, L., & Gräslund, A.
- Affiliations
- Stockholm University (SE)
- University of Florence (IT)
- Venue
- The FEBS Journal
- Publisher
- Wiley
- Published
- 2006-11-20
- Volume
- 274
- Issue
- 1
- Pages
- 46-59
- ISSN
- 1742-464X (ISSN-L)
- 1742-4658
- OpenAlex
- W2019511555
- Cited by
- 253
- References
- 8
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 10 · 2023: 11 · 2022: 12 · 2021: 9 · 2020: 9 · 2019: 13 · 2018: 15 · 2017: 13 · 2016: 15 · 2015: 12 · 2014: 11 · 2013: 13 · 2012: 20
- FWCI
- 8.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- FEBS Journal (publishedVersion)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Spectroscopy › Advanced NMR Techniques and Applications
- Keywords
- amyloid-beta, zinc binding, Alzheimer's disease, metal binding sites, histidine residues, copper binding site, peptide aggregation, dissociation constant, 15N relaxation, amide proton exchange, competitive binding
- MeSH terms
- Alzheimer Disease, Binding Sites, Circular Dichroism, Copper, Histidine, Humans, Hydrogen-Ion Concentration, Magnetic Resonance Spectroscopy, Peptide Fragments, Spectrometry, Fluorescence, Zinc, Amyloid beta-Peptides
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