Journal
INORGANIC CHEMISTRY
Volume 58, Issue 9, Pages 6294-6311Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.inorgchem.9b00507
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Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- National Institutes of Health [GM065790]
- NSERC
- Province of Saskatchewan
- University of Saskatchewan
- Collaborative Innovation Development grant from the Saskatchewan Health Research Foundation
- U.S. Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences [DE-AG02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
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Alzheimer's disease (AD) is the main cause of age-related dementia and currently affects approximately 5.7 million Americans. Major brain changes associated with AD pathology include accumulation of amyloid beta (A beta) protein fragments and formation of extracellular amyloid plaques. Redox-active metals mediate oligomerization of A beta, and the resultant metal-bound oligomers have been implicated in the putative formation of harmful, reactive species that could contribute to observed oxidative damage. In isolated plaque cores, Cu(II) is bound to A beta via histidine residues. Despite numerous structural studies of Cu(II) binding to synthetic A beta in vitro, there is still uncertainty surrounding Cu(II) coordination in A beta. In this study, we used X-ray absorption spectroscopy (XAS) and high energy resolution fluorescence detected (HERFD) XAS to investigate Cu(II) coordination in A beta(1-42) under various solution conditions. We found that the average coordination environment in Cu(II)A beta(1-42) is sensitive to X-ray photoreduction, changes in buffer composition, peptide concentration, and solution pH. Fitting of the extended X-ray absorption fine structure (EXAFS) suggests Cu(II) is bound in a mixture of coordination environments in monomeric A beta(1-42) under all conditions studied. However, it was evident that on average only a single histidine residue coordinates Cu(II) in monomeric A beta(1-42) at pH 6.1, in addition to 3 other oxygen or nitrogen ligands. Cu(II) coordination in A beta(1-42) at pH 7.4 is similarly 4-coordinate with oxygen and nitrogen ligands, although an average of 2 histidine residues appear to coordinate at this pH. At pH 9.0, the average Cu(II) coordination environment in A beta(1-42) appears to be 5-coordinate with oxygen and nitrogen ligands, including two histidine residues.
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