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ESEEM analysis of multi-histidine Cu(II)-coordination in model complexes, peptides, and amyloid-β.

Silva KI, Michael BC, Geib SJ, Saxena S - J Phys Chem B (2014)

Bottom Line: We confirm that component II only contains single histidine coordination, using ESEEM and set of model complexes.The ESEEM experiments carried out on systematically (15)N-labeled peptides reveal that, in component II, His 13 and His 14 are more favored as equatorial ligands compared to His 6.Revealing molecular level details of subcomponents in metal ion coordination is critical in understanding the role of metal ions in Alzheimer's disease etiology.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.

ABSTRACT
We validate the use of ESEEM to predict the number of (14)N nuclei coupled to a Cu(II) ion by the use of model complexes and two small peptides with well-known Cu(II) coordination. We apply this method to gain new insight into less explored aspects of Cu(II) coordination in amyloid-β (Aβ). Aβ has two coordination modes of Cu(II) at physiological pH. A controversy has existed regarding the number of histidine residues coordinated to the Cu(II) ion in component II, which is dominant at high pH (∼8.7) values. Importantly, with an excess amount of Zn(II) ions, as is the case in brain tissues affected by Alzheimer's disease, component II becomes the dominant coordination mode, as Zn(II) selectively substitutes component I bound to Cu(II). We confirm that component II only contains single histidine coordination, using ESEEM and set of model complexes. The ESEEM experiments carried out on systematically (15)N-labeled peptides reveal that, in component II, His 13 and His 14 are more favored as equatorial ligands compared to His 6. Revealing molecular level details of subcomponents in metal ion coordination is critical in understanding the role of metal ions in Alzheimer's disease etiology.

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Comparison of ESEEM spectraof Cu(II)–Aβ(1–16)complex at pH 8.7 and the two-imidazole complex. The inset shows theincrease of component II Cu(II) contribution in the presence of Zn(II).
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fig6: Comparison of ESEEM spectraof Cu(II)–Aβ(1–16)complex at pH 8.7 and the two-imidazole complex. The inset shows theincrease of component II Cu(II) contribution in the presence of Zn(II).

Mentions: The integrationanalysis was used to determine the number of nitrogens coupled tothe Cu(II) ion in Aβ(1–16) in component II. As shownin the inset of Figure 6, Zn(II) selectivelydisplaces Cu(II) coordinated to component I. At excess amounts ofZn(II) (ten equivalents of Zn(II)), component II accounts for ∼65%of the overall coordination (inset of Figure 6), where in the absence of Zn(II) the percentage is only 35%.39 Amyloid aggregates in brain tissues containapproximately three times Zn(II) than Cu(II).46 Hence, component II becomes the dominant Cu(II) coordination modein vivo. Figure 6 shows the comparison betweenthe two-imidazole complex and the Aβ(1–16)–Cu(II)complex at pH 8.7. At pH 8.7 only the component II of Cu(II) coordinationexists.4,43 The integrated intensities tabulated inTable 1 suggest that two 14N nucleusare coupled to the Cu(II) ion. The features of the ESEEM spectrumclearly illustrate the imidazole histidine coordination as shown inFigure 6. The peak around 2.8 MHz is indicativeof backbone coordination.57 The backbonecoordination peak is possibly due to the coupling between the Cu(II)ion with the remote backbone nitrogen nuclei of Glu 3, where Cu(II)is coordinated to the carbonyl oxygen of Ala 2.40 This suggests just a single histidine residue is coordinatedto Cu(II) in component II coordination.


ESEEM analysis of multi-histidine Cu(II)-coordination in model complexes, peptides, and amyloid-β.

Silva KI, Michael BC, Geib SJ, Saxena S - J Phys Chem B (2014)

Comparison of ESEEM spectraof Cu(II)–Aβ(1–16)complex at pH 8.7 and the two-imidazole complex. The inset shows theincrease of component II Cu(II) contribution in the presence of Zn(II).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4120975&req=5

fig6: Comparison of ESEEM spectraof Cu(II)–Aβ(1–16)complex at pH 8.7 and the two-imidazole complex. The inset shows theincrease of component II Cu(II) contribution in the presence of Zn(II).
Mentions: The integrationanalysis was used to determine the number of nitrogens coupled tothe Cu(II) ion in Aβ(1–16) in component II. As shownin the inset of Figure 6, Zn(II) selectivelydisplaces Cu(II) coordinated to component I. At excess amounts ofZn(II) (ten equivalents of Zn(II)), component II accounts for ∼65%of the overall coordination (inset of Figure 6), where in the absence of Zn(II) the percentage is only 35%.39 Amyloid aggregates in brain tissues containapproximately three times Zn(II) than Cu(II).46 Hence, component II becomes the dominant Cu(II) coordination modein vivo. Figure 6 shows the comparison betweenthe two-imidazole complex and the Aβ(1–16)–Cu(II)complex at pH 8.7. At pH 8.7 only the component II of Cu(II) coordinationexists.4,43 The integrated intensities tabulated inTable 1 suggest that two 14N nucleusare coupled to the Cu(II) ion. The features of the ESEEM spectrumclearly illustrate the imidazole histidine coordination as shown inFigure 6. The peak around 2.8 MHz is indicativeof backbone coordination.57 The backbonecoordination peak is possibly due to the coupling between the Cu(II)ion with the remote backbone nitrogen nuclei of Glu 3, where Cu(II)is coordinated to the carbonyl oxygen of Ala 2.40 This suggests just a single histidine residue is coordinatedto Cu(II) in component II coordination.

Bottom Line: We confirm that component II only contains single histidine coordination, using ESEEM and set of model complexes.The ESEEM experiments carried out on systematically (15)N-labeled peptides reveal that, in component II, His 13 and His 14 are more favored as equatorial ligands compared to His 6.Revealing molecular level details of subcomponents in metal ion coordination is critical in understanding the role of metal ions in Alzheimer's disease etiology.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.

ABSTRACT
We validate the use of ESEEM to predict the number of (14)N nuclei coupled to a Cu(II) ion by the use of model complexes and two small peptides with well-known Cu(II) coordination. We apply this method to gain new insight into less explored aspects of Cu(II) coordination in amyloid-β (Aβ). Aβ has two coordination modes of Cu(II) at physiological pH. A controversy has existed regarding the number of histidine residues coordinated to the Cu(II) ion in component II, which is dominant at high pH (∼8.7) values. Importantly, with an excess amount of Zn(II) ions, as is the case in brain tissues affected by Alzheimer's disease, component II becomes the dominant coordination mode, as Zn(II) selectively substitutes component I bound to Cu(II). We confirm that component II only contains single histidine coordination, using ESEEM and set of model complexes. The ESEEM experiments carried out on systematically (15)N-labeled peptides reveal that, in component II, His 13 and His 14 are more favored as equatorial ligands compared to His 6. Revealing molecular level details of subcomponents in metal ion coordination is critical in understanding the role of metal ions in Alzheimer's disease etiology.

Show MeSH
Related in: MedlinePlus