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Pleomorphic copper coordination by Alzheimer's disease amyloid-beta peptide.
J Am Chem Soc. 2009 Jan 28; 131(3):1195-207.JA

Abstract

Numerous conflicting models have been proposed regarding the nature of the Cu(2+) coordination environment of the amyloid beta (Abeta) peptide, the causative agent of Alzheimer's disease. This study used multifrequency CW-EPR spectroscopy to directly resolve the superhyperfine interactions between Cu(2+) and the ligand nuclei of Abeta, thereby avoiding ambiguities associated with introducing point mutations. Using a library of Abeta16 analogues with site-specific (15)N-labeling at Asp1, His6, His13, and His14, numerical simulations of the superhyperfine resonances delineated two independent 3N1O Cu(2+) coordination modes, {N(a)(D1), O, N(epsilon)(H6), N(epsilon)(H13)} (component Ia) and {N(a)(D1), O, N(epsilon)(H6), N(epsilon)(H14)} (component Ib), between pH 6-7. A third coordination mode (component II) was identified at pH 8.0, and simulation of the superhyperfine resonances indicated a 3N1O coordination sphere involving nitrogen ligation by His6, His13, and His14. No differences were observed upon (17)O-labeling of the phenolic oxygen of Tyr10, confirming it is not a key oxygen ligand in the physiological pH range. Hyperfine sublevel correlation (HYSCORE) spectroscopy, in conjunction with site-specific (15)N-labeling, provided additional support for the common role of His6 in components Ia and Ib, and for the assignment of a {O, N(epsilon)(H6), N(epsilon)(H13), N(epsilon)(H14)} coordination sphere to component II. HYSCORE studies of a peptide analogue with selective (13)C-labeling of Asp1 revealed (13)C cross-peaks characteristic of equatorial coordination by the carboxylate oxygen of Asp1 in component Ia/b coordination. The direct resolution of Cu(2+) ligand interactions, together with the key finding that component I is composed of two distinct coordination modes, provides valuable insight into a range of conflicting ligand assignments and highlights the complexity of Cu(2+)/Abeta interactions.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Drew SC
Department of Pathology, The University of Melbourne, Victoria 3010, Australia. sdrew@unimelb.edu.au
Noble CJ
No affiliation info available
Masters CL
No affiliation info available
Hanson GR
No affiliation info available
Barnham KJ
No affiliation info available

MeSH

Alzheimer DiseaseAmyloid beta-PeptidesCopperElectron Spin Resonance SpectroscopyMolecular StructurePeptide Fragments

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19119811

Citation

Drew, Simon C., et al. "Pleomorphic Copper Coordination By Alzheimer's Disease Amyloid-beta Peptide." Journal of the American Chemical Society, vol. 131, no. 3, 2009, pp. 1195-207.
Drew SC, Noble CJ, Masters CL, et al. Pleomorphic copper coordination by Alzheimer's disease amyloid-beta peptide. J Am Chem Soc. 2009;131(3):1195-207.
Drew, S. C., Noble, C. J., Masters, C. L., Hanson, G. R., & Barnham, K. J. (2009). Pleomorphic copper coordination by Alzheimer's disease amyloid-beta peptide. Journal of the American Chemical Society, 131(3), 1195-207. https://doi.org/10.1021/ja808073b
Drew SC, et al. Pleomorphic Copper Coordination By Alzheimer's Disease Amyloid-beta Peptide. J Am Chem Soc. 2009 Jan 28;131(3):1195-207. PubMed PMID: 19119811.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pleomorphic copper coordination by Alzheimer's disease amyloid-beta peptide. AU - Drew,Simon C, AU - Noble,Christopher J, AU - Masters,Colin L, AU - Hanson,Graeme R, AU - Barnham,Kevin J, PY - 2009/1/6/entrez PY - 2009/1/6/pubmed PY - 2009/3/11/medline SP - 1195 EP - 207 JF - Journal of the American Chemical Society JO - J Am Chem Soc VL - 131 IS - 3 N2 - Numerous conflicting models have been proposed regarding the nature of the Cu(2+) coordination environment of the amyloid beta (Abeta) peptide, the causative agent of Alzheimer's disease. This study used multifrequency CW-EPR spectroscopy to directly resolve the superhyperfine interactions between Cu(2+) and the ligand nuclei of Abeta, thereby avoiding ambiguities associated with introducing point mutations. Using a library of Abeta16 analogues with site-specific (15)N-labeling at Asp1, His6, His13, and His14, numerical simulations of the superhyperfine resonances delineated two independent 3N1O Cu(2+) coordination modes, {N(a)(D1), O, N(epsilon)(H6), N(epsilon)(H13)} (component Ia) and {N(a)(D1), O, N(epsilon)(H6), N(epsilon)(H14)} (component Ib), between pH 6-7. A third coordination mode (component II) was identified at pH 8.0, and simulation of the superhyperfine resonances indicated a 3N1O coordination sphere involving nitrogen ligation by His6, His13, and His14. No differences were observed upon (17)O-labeling of the phenolic oxygen of Tyr10, confirming it is not a key oxygen ligand in the physiological pH range. Hyperfine sublevel correlation (HYSCORE) spectroscopy, in conjunction with site-specific (15)N-labeling, provided additional support for the common role of His6 in components Ia and Ib, and for the assignment of a {O, N(epsilon)(H6), N(epsilon)(H13), N(epsilon)(H14)} coordination sphere to component II. HYSCORE studies of a peptide analogue with selective (13)C-labeling of Asp1 revealed (13)C cross-peaks characteristic of equatorial coordination by the carboxylate oxygen of Asp1 in component Ia/b coordination. The direct resolution of Cu(2+) ligand interactions, together with the key finding that component I is composed of two distinct coordination modes, provides valuable insight into a range of conflicting ligand assignments and highlights the complexity of Cu(2+)/Abeta interactions. SN - 1520-5126 UR - https://www.unboundmedicine.com/medline/citation/19119811/Pleomorphic_copper_coordination_by_Alzheimer's_disease_amyloid_beta_peptide_ L2 - https://doi.org/10.1021/ja808073b DB - PRIME DP - Unbound Medicine ER -