title: NMR reveals anomalous copper(II) binding to the amyloid Abeta peptide of Alzheimer's disease.
abstract: The Abeta peptide is the major protein component of amyloid deposits in Alzheimer's disease (AD). Age-related microenvironmental changes in the AD brain promote amyloid formation that leads to cell injury and death. Altered levels of metals (such as Cu and Zn) exist in the AD brain, and because Cu and Zn can be bound to the Abeta in the amyloid plaques, it is thought that these binding events in vivo may trigger or prevent Abeta amyloid formation in the AD brain. Although several structural models have been proposed, all of these are undefined due to the lack of definitive structural data. The present NMR studies utilized uniformly 15N-labeled Abeta(1-40) peptide and 1H-15N HSQC experiments and demonstrate for the first time that the Abeta binds Cu and Zn in a distinct manner. The binding promotes NH signal disappearance of E3-V18, which was not due to the paramagnetic effect of Cu2+, as identical NMR studies were seen with Zn2+, which is diamagnetic. NMR titration experiments showed that the amide NH peak intensities of R5-L17 showed the most pronounced intensity reduction, and that the 1H signals for the side chain aromatic signals of the three histidines shift upfield (H6, H13, and H14). We propose that initially Cu2+ is anchored to the Abeta monomer (fast exchange rate) and is followed by deprotonation and/or severe line broadening of the backbone amide NH for E3-V18 (intermediate exchange rate). By contrast, Cu2+ binding to soluble Abeta aggregates leads to rapid aggregation and nonfibrillar amorphous structures, and without metal, the Abeta can undergo the normal time-dependent aggregation, eventually producing more ordered, late-stage parallel beta-sheet structures. These anomalous (rare) binding events may account for some of the unique properties associated with the Abeta, such as its proposed "dual role", where sequestration of metal ions by the monomer is neuroprotective, while that by beta-aggregates generates oxygen radicals and causes neuronal death.
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106-7078, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Hou
authors.forename: Michael G
authors.initials: MG
authors.lastname: Zagorski
mesh_terms: D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D003300:Copper / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding; D015032:Zinc / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D003300:Copper; D015032:Zinc