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Zn(II) ions substantially perturb Cu(II) ion coordination in amyloid-? at physiological pH.

ABSTRACT: The interaction of Cu(II) and Zn(II) ions with amyloid-? (A?) plays an important role in the etiology of Alzheimer's disease. We describe the use of electron spin resonance (ESR) to measure metal-binding competition between Cu(II) and Zn(II) in amyloid-? at physiological pH. Continuous wave ESR measurements show that the affinity of Cu(II) toward A?(1-16) is significantly higher than that of Zn(II) at physiological pH. Importantly, of the two known Cu(II) coordination modes in A?, component I and component II, Zn(II) displaces Cu(II) only from component I. Our results indicate that at excess amounts of Zn(II) component II becomes the most dominant coordination mode. This observation is important as A? aggregates in the brain contain a high Zn(II) ion concentration. In order to determine details of the metal ion competition, electron spin echo envelope modulation experiments were carried out on A? variants that were systematically (15)N labeled. In the presence of Zn(II), most peptides use His 14 as an equatorial ligand to bind Cu(II) ions. Interestingly, Zn(II) ions completely substitute Cu(II) ions that are simultaneously coordinated to His 6 and His 13. Furthermore, in the presence of Zn(II), the proportion of Cu(II) ions that are simultaneously coordinated to His 13 and His 14 is increased. On the basis of our results we suggest that His 13 plays a critical role in modulating the morphology of A? aggregates.

SUBMITTER: Silva KI

PROVIDER: S-EPMC3775258 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Zn(II) ions substantially perturb Cu(II) ion coordination in amyloid-β at physiological pH.

Silva K Ishara KI Saxena Sunil S

The journal of physical chemistry. B 20130731 32

The interaction of Cu(II) and Zn(II) ions with amyloid-β (Aβ) plays an important role in the etiology of Alzheimer's disease. We describe the use of electron spin resonance (ESR) to measure metal-binding competition between Cu(II) and Zn(II) in amyloid-β at physiological pH. Continuous wave ESR measurements show that the affinity of Cu(II) toward Aβ(1-16) is significantly higher than that of Zn(II) at physiological pH. Importantly, of the two known Cu(II) coordination modes in Aβ, component I an ...[more]

PMID: 23841511

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Project description:The main aim of this study was the analysis of the interaction between humic acids (HAs) from different soils and Zn(II) ions at wide concentration ranges and at two different pHs, 5 and 7, by using fluorescence and FTIR spectroscopy, as well as potentiometric measurements. The presence of a few areas of HAs structures responsible for Zn(II) complexing was revealed. Complexation at ?-sites (low humified structures of low-molecular weight and aromatic polycondensation) and ?-sites (weakly humified structures) was stronger at pH 7 than 5. This trend was not observed for ?-sites (structures with linearly-condensed aromatic rings, unsaturated bonds and large molecular weight). The amount of metal complexed at pH5 and 7 by ? and ?-structures increased with a decrease in humification and aromaticity of HAs, contrary to ?-areas where complexation increased with increasing content of carboxylic groups. The stability of complexes was higher at pH 7 and was the highest for ?-structures. At pH 5, stability decreased with C/N increase for ?-areas and -COOH content increase for ?-sites; stability increased with humification decrease for ?-structures. The stability of complexes at ? and ?-areas at pH 7 decreased with a drop in HAs humification. FTIR spectra at pH 5 revealed that the most-humified HAs tended to cause bidentate bridging coordination, while in the case of the least-humified HAs, Zn caused bidentate bridging coordination at low Zn additions and bidentate chelation at the highest Zn concentrations. Low Zn doses at pH 7 caused formation of unidentate complexes while higher Zn doses caused bidentate bridging. Such processes were noticed for HAs characterized by high oxidation degree and high oxygen functional group content; where these were low, HAs displayed bidentate bridging or even bidentate chelation. To summarize, the above studies have showed significant impact of Zn concentration, pH and some properties of HAs on complexation reactions of humic acids with zinc.

Project description:The interaction of amyloid-? (A?) peptide with Cu(II) appears to play an important role in the etiology of Alzheimer's disease. At physiological pH, the Cu(II) coordination in A? is heterogeneous, and there exist at least two binding modes in which Cu(II) is coordinated by histidine residues. Electron spin resonance studies have revealed a picture of the Cu(II) binding at a higher or lower pH, where only one of the two binding modes is almost exclusively present. We describe a procedure to directly examine the coordination of Cu(II) to each histidine residue in the dominant binding mode at physiological pH. We use nonlabeled and residue-specifically (15)N-labeled A?(1-16). For quantitative analysis, the intensities of three-pulse electron spin-echo envelope modulation (ESEEM) spectra are analyzed. Spectral simulations show that ESEEM intensities provide information about the contribution of each histidine residue. Indeed, the ESEEM experiments at pH 6.0 confirm the dominant contribution of His6 to the Cu(II) coordination as expected from the work of other researchers. Interestingly, however, the ESEEM data obtained at pH 7.4 reveal that the contributions of the three residues to the Cu(II) coordination are in the order of His14 ? His6 > His13 in the dominant binding mode. The order indicates a significant contribution from the simultaneous coordination by His13 and His14 at physiological pH, which has been underappreciated. These findings are supported by hyperfine sublevel correlation spectroscopy experiments. The simultaneous coordination by the two adjacent residues is likely to be present in a non-?-sheet structure. The coexistence of different secondary structures is possibly the molecular origin for the formation of amorphous aggregates rather than fibrils at relatively high concentrations of Cu(II). Through our approach, precise and useful information about Cu(II) binding in A?(1-16) at physiological pH is obtained without any side-chain modification, amino acid residue replacement, or pH change, each of which might lead to an alteration in the peptide structure or the coordination environment.

Dataset Information

Zn(II) ions substantially perturb Cu(II) ion coordination in amyloid-? at physiological pH.

Publications

Zn(II) ions substantially perturb Cu(II) ion coordination in amyloid-β at physiological pH.

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