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Amyloid-beta binds Cu2+ in a mononuclear metal ion binding site.
J Am Chem Soc. 2004 Oct 20; 126(41):13534-8.JA

Abstract

Amyloid-beta (Abeta) peptide is the principal constituent of plaques associated with Alzheimer's disease and is thought to be responsible for the neurotoxicity associated with the disease. Metal ions have been hypothesized to play a role in the formation and neurotoxicity of aggregates associated with Alzheimer's disease (Bush, A. I.; et al. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 11934). Elucidation of the chemistry through which transition-metal ions participate in the assembly and toxicity of Abeta oligomers is important to drug design efforts if inhibition of Abeta containing bound metal ions becomes a treatment for Alzheimer's disease. In this paper, we report electron paramagnetic resonance (EPR) spectroscopic characterization of Cu(2+) bound to soluble and fibrillar Abeta. Addition of stoichiometric amounts of Cu(2+) to soluble Abeta produces an EPR signal at 10 K with observable Cu(2+) hyperfine lines. A nearly identical spectrum is observed for Abetafibrils assembled in the presence of Cu(2+). The EPR parameters are consistent with a Type 2 Cu(2+) center with three nitrogen donor atoms and one oxygen donor atom in the coordination sphere of Cu(2+): g(parallel) = 2.26 and A(parallel) = 174 +/- 4 G for soluble Abeta with Cu(2+), and g(parallel) = 2.26 and A(parallel) = 175 +/- 1 G for Abeta fibrils assembled with Cu(2+). Investigation of the temperature dependence of the EPR signal for Cu(2+) bound to soluble Abetaor Cu(2+) in fibrillar Abeta shows that the Cu(2+) center displays normal Curie behavior, indicating that the site is a mononuclear Cu(2+) site. Fibrils assembled in the presence of Cu(2+) contain one Cu(2+) ion per peptide. These results show that the ligand donor atom set to Cu(2+) does not change during organization of Abetamonomers into fibrils and that neither soluble nor fibrillar forms of Abeta(1-40) with Cu(2+) contain antiferromagnetically exchange-coupled binuclear Cu(2+) sites in which two Cu(2+) ions are bridged by an intervening ligand.

Authors+Show Affiliations

Karr JW
Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, Maryland 21250, USA.
Kaupp LJ
No affiliation info available
Szalai VA
No affiliation info available

MeSH

Amyloid beta-PeptidesBinding SitesCations, DivalentCold TemperatureCopperElectron Spin Resonance SpectroscopyOrganometallic CompoundsPeptide FragmentsProtein Binding

Pub Type(s)

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

Language

eng

PubMed ID

15479110

Citation

Karr, Jesse W., et al. "Amyloid-beta Binds Cu2+ in a Mononuclear Metal Ion Binding Site." Journal of the American Chemical Society, vol. 126, no. 41, 2004, pp. 13534-8.
Karr JW, Kaupp LJ, Szalai VA. Amyloid-beta binds Cu2+ in a mononuclear metal ion binding site. J Am Chem Soc. 2004;126(41):13534-8.
Karr, J. W., Kaupp, L. J., & Szalai, V. A. (2004). Amyloid-beta binds Cu2+ in a mononuclear metal ion binding site. Journal of the American Chemical Society, 126(41), 13534-8.
Karr JW, Kaupp LJ, Szalai VA. Amyloid-beta Binds Cu2+ in a Mononuclear Metal Ion Binding Site. J Am Chem Soc. 2004 Oct 20;126(41):13534-8. PubMed PMID: 15479110.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amyloid-beta binds Cu2+ in a mononuclear metal ion binding site. AU - Karr,Jesse W, AU - Kaupp,Lauren J, AU - Szalai,Veronika A, PY - 2004/10/14/pubmed PY - 2005/4/20/medline PY - 2004/10/14/entrez SP - 13534 EP - 8 JF - Journal of the American Chemical Society JO - J Am Chem Soc VL - 126 IS - 41 N2 - Amyloid-beta (Abeta) peptide is the principal constituent of plaques associated with Alzheimer's disease and is thought to be responsible for the neurotoxicity associated with the disease. Metal ions have been hypothesized to play a role in the formation and neurotoxicity of aggregates associated with Alzheimer's disease (Bush, A. I.; et al. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 11934). Elucidation of the chemistry through which transition-metal ions participate in the assembly and toxicity of Abeta oligomers is important to drug design efforts if inhibition of Abeta containing bound metal ions becomes a treatment for Alzheimer's disease. In this paper, we report electron paramagnetic resonance (EPR) spectroscopic characterization of Cu(2+) bound to soluble and fibrillar Abeta. Addition of stoichiometric amounts of Cu(2+) to soluble Abeta produces an EPR signal at 10 K with observable Cu(2+) hyperfine lines. A nearly identical spectrum is observed for Abetafibrils assembled in the presence of Cu(2+). The EPR parameters are consistent with a Type 2 Cu(2+) center with three nitrogen donor atoms and one oxygen donor atom in the coordination sphere of Cu(2+): g(parallel) = 2.26 and A(parallel) = 174 +/- 4 G for soluble Abeta with Cu(2+), and g(parallel) = 2.26 and A(parallel) = 175 +/- 1 G for Abeta fibrils assembled with Cu(2+). Investigation of the temperature dependence of the EPR signal for Cu(2+) bound to soluble Abetaor Cu(2+) in fibrillar Abeta shows that the Cu(2+) center displays normal Curie behavior, indicating that the site is a mononuclear Cu(2+) site. Fibrils assembled in the presence of Cu(2+) contain one Cu(2+) ion per peptide. These results show that the ligand donor atom set to Cu(2+) does not change during organization of Abetamonomers into fibrils and that neither soluble nor fibrillar forms of Abeta(1-40) with Cu(2+) contain antiferromagnetically exchange-coupled binuclear Cu(2+) sites in which two Cu(2+) ions are bridged by an intervening ligand. SN - 0002-7863 UR - https://www.unboundmedicine.com/medline/citation/15479110/Amyloid_beta_binds_Cu2+_in_a_mononuclear_metal_ion_binding_site_ DB - PRIME DP - Unbound Medicine ER -