Quenched hydrogen/deuterium exchange NMR characterization of amyloid-beta peptide aggregates formed in the presence of Cu2+ or Zn2+.
Alzheimer's disease, a neurodegenerative disorder causing synaptic impairment and neuronal cell death, is strongly correlated with aggregation of the amyloid-beta peptide (Abeta). Divalent metal ions such as Cu(2+) and Zn(2+) are known to significantly affect the rate of aggregation and morphology of Abeta assemblies in vitro and are also found at elevated levels within cerebral plaques in vivo. The present investigation characterized the architecture of the aggregated forms of Abeta(1-40) and Abeta(1-42) in the presence or absence of either Cu(2+) or Zn(2+) using quenched hydrogen/deuterium exchange combined with solution NMR spectroscopy. The NMR analyses provide a quantitative and residue-specific structural characterization of metal-induced Abeta aggregates, showing that both the peptide sequence and the type of metal ion exert an impact on the final architecture. Common features among the metal-complexed peptide aggregates are two solvent-protected regions with an intervening minimum centered at Asn27, and a solvent-accessible N-terminal region, Asp1-Lys16. Our results suggest that Abeta in complex with either Cu(2+) or Zn(2+) can attain an aggregation-prone beta-strand-turn-beta-strand motif, similar to the motif found in fibrils, but where the metal binding to the N-terminal region guides the peptide into an assembly distinctly different from the fibril form.
Olofsson
Anders
A
Department of Medical Biochemistry and Biophysics, Umeå University, Sweden. anders.olofsson@medchem.umu.se
Lindhagen-Persson
Malin
M
Vestling
Monika
M
Sauer-Eriksson
A Elisabeth
AE
Ohman
Anders
A
D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000187:drug effects; D003300:Copper / Q000494:pharmacology*; D003903:Deuterium; D006801:Humans; D006859:Hydrogen; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force; D009391:Nephelometry and Turbidimetry; D010446:Peptide Fragments / Q000737:chemistry*; D058225:Plaque, Amyloid / Q000473:pathology; D011994:Recombinant Proteins / Q000737:chemistry; D015032:Zinc / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); D003300:Copper; D006859:Hydrogen; D003903:Deuterium; D015032:Zinc