Cu(II)–Zn(II) Cross-Modulation in Amyloid–Beta Peptide Binding: An X-ray Absorption Spectroscopy Study

Santis, Emiliano De; Minicozzi, Velia; Proux, Olivier; Rossi, G.C.; Silva, K. Ishara; Lawless, Matthew J.; Stellato, Francesco; Saxena, Sunil; Morante, Silvia

doi:10.1021/acs.jpcb.5b10264

Cited by 17 publications

(19 citation statements)

References 49 publications

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“…EXAFS data can give access to the nature, number, and distance of the coordinating atoms. However, in the case of the Aβ peptides, the data recorded suffer from the ill-defined coordination sphere of the Zn(II) ions, and in line with previous observations, 34 , 36 , 37 the number of useful oscillations is limited. This is a common feature of such peptidic species that differ from either Zn metalloprotein 38 or inorganic complexes, 39 for which more insights can be obtained due to a higher number of well-resolved oscillations.…”

Section: Resultssupporting

confidence: 85%

Zinc(II) Binding Site to the Amyloid-β Peptide: Insights from Spectroscopic Studies with a Wide Series of Modified Peptides

et al. 2016

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The Zn(II) ion has been linked to Alzheimer’s disease (AD) due to its ability to modulate the aggregating properties of the amyloid-β (Aβ) peptide, where Aβ aggregation is a central event in the etiology of the disease. Delineating Zn(II) binding properties to Aβ is thus a prerequisite to better grasp its potential role in AD. Because of (i) the flexibility of the Aβ peptide, (ii) the multiplicity of anchoring sites, and (iii) the silent nature of the Zn(II) ion in most classical spectroscopies, this is a difficult task. To overcome these difficulties, we have investigated the impact of peptide alterations (mutations, N-terminal acetylation) on the Zn(Aβ) X-ray absorption spectroscopy fingerprint and on the Zn(II)-induced modifications of the Aβ peptides’ NMR signatures. We propose a tetrahedrally bound Zn(II) ion, in which the coordination sphere is made by two His residues and two carboxylate side chains. Equilibria between equivalent ligands for one Zn(II) binding position have also been observed, the predominant site being made by the side chains of His6, His13 or His14, Glu11, and Asp1 or Glu3 or Asp7, with a slight preference for Asp1.

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Section: Resultssupporting

confidence: 85%

Zinc(II) Binding Site to the Amyloid-β Peptide: Insights from Spectroscopic Studies with a Wide Series of Modified Peptides

et al. 2016

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“…As for Zn/Cu competition, when Zn binds first, Cu does not bind easily, while in the case Cu binding first, Zn can bind. 80 This explanation fits with the confinement of Cu to N-terminus, while Zn is more promiscuous with the C-terminus.…”

Section: Solvation Free Energysupporting

confidence: 55%

Zinc binding promotes greater hydrophobicity inAlzheimer's Aβ42peptide than copper binding: Molecular dynamics and solvation thermodynamics studies

et al. 2020

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The aggregation of Aβ42 peptides is considered as one of the main causes for the development of Alzheimer's disease. In this context, Zn2+ and Cu2+ play a significant role in regulating the aggregation mechanism, due to changes in the structural and the solvation free energy of Aβ42. In practice, experimental studies are not able to determine the latter properties, since the Aβ42–Zn2+ and Aβ42–Cu2+ peptide complexes are intrinsically disordered, exhibiting rapid conformational changes in the aqueous environment. Here, we investigate atomic structural variations and the solvation thermodynamics of Aβ42, Aβ42–Cu2+, and Aβ42–Zn2+ systems in explicit solvent (water) by using quantum chemical structures as templates for a metal binding site and combining extensive all‐atom molecular dynamics (MD) simulations with a thorough solvation thermodynamic analysis. Our results show that the zinc and copper coordination results in a significant decrease of the solvation free energy in the C‐terminal region (Met35‐Val40), which in turn leads to a higher structural disorder. In contrast, the β‐sheet formation at the same C‐terminal region indicates a higher solvation free energy in the case of Aβ42. The solvation free energy of Aβ42 increases upon Zn2+ binding, due to the higher tendency of forming the β‐sheet structure at the Leu17‐Ala42 residues, in contrast to the case of binding with Cu2+. Finally, we find the hydrophobicity of Aβ42–Zn2+ in water is greater than in the case of Aβ42–Cu2+.

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“…Contrary to the study of Damante et al ,51 they also probed a more important contribution of His13 and His14 as ligands for Cu( ii ) in the presence of Zn( ii ) 53. In a further study, they proposed that Zn( ii ) and Cu( ii ) do compete for one binding site 54. However, this is in disagreement with the respective affinity values of Cu( ii ) and Zn( ii ) for the Aβ peptide that differ by at least three orders of magnitude (Fig.…”

Section: Coordination Chemistry Of Cu and Zn To Aβmentioning

confidence: 73%

Mutual interference of Cu and Zn ions in Alzheimer's disease: perspectives at the molecular level

2017

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While metal ions such as copper and zinc are essential in biology, they are also linked to several amyloid-related diseases, including Alzheimer’s disease (AD). Zinc and copper can indeed modify the aggregation pathways of the amyloid-β (Aβ) peptide, the key component encountered in AD. In addition, the redox active copper ions do produce Reactive Oxygen Species (ROS) when bound to the Aβ peptide. While Cu(i) or Cu(ii) or Zn(ii) coordination to the Aβ has been extensively studied in the last ten years, characterization of hetero-bimetallic Aβ complexes is still scarce. This is also true for the metal induced Aβ aggregation and ROS production, for which studies on the mutual influence of the copper and zinc ions are currently appearing. Last but not least, zinc can strongly interfere in therapeutic approaches relying on copper detoxification. This will be exemplified with a biological lead, namely metallothioneins, and with synthetic ligands.

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Cu(II)–Zn(II) Cross-Modulation in Amyloid–Beta Peptide Binding: An X-ray Absorption Spectroscopy Study

Cited by 17 publications

References 49 publications

Zinc(II) Binding Site to the Amyloid-β Peptide: Insights from Spectroscopic Studies with a Wide Series of Modified Peptides

Zinc(II) Binding Site to the Amyloid-β Peptide: Insights from Spectroscopic Studies with a Wide Series of Modified Peptides

Zinc binding promotes greater hydrophobicity inAlzheimer's Aβ42peptide than copper binding: Molecular dynamics and solvation thermodynamics studies

Mutual interference of Cu and Zn ions in Alzheimer's disease: perspectives at the molecular level

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