Molecular Structure of Cu(II)-Bound Amyloid-ß Monomer Implicated in Inhibition of Peptide Self-Assembly in Alzheimer's Disease.
JACS Au
; 2(11): 2571-2584, 2022 Nov 28.
Article
em En
| MEDLINE
| ID: mdl-36465548
ABSTRACT
Metal ions, such as copper and zinc ions, have been shown to strongly modulate the self-assembly of the amyloid-ß (Aß) peptide into insoluble fibrils, and elevated concentrations of metal ions have been found in amyloid plaques of Alzheimer's patients. Among the physiological transition metal ions, Cu(II) ions play an outstanding role since they can trigger production of neurotoxic reactive oxygen species. In contrast, structural insights into Cu(II) coordination of Aß have been challenging due to the paramagnetic nature of Cu(II). Here, we employed specifically tailored paramagnetic NMR experiments to determine NMR structures of Cu(II) bound to monomeric Aß. We found that monomeric Aß binds Cu(II) in the N-terminus and combined with molecular dynamics simulations, we could identify two prevalent coordination modes of Cu(II). For these, we report here the NMR structures of the Cu(II)-bound Aß complex, exhibiting heavy backbone RMSD values of 1.9 and 2.1 Å, respectively. Further, applying aggregation kinetics assays, we identified the specific effect of Cu(II) binding on the Aß nucleation process. Our results show that Cu(II) efficiently retards Aß fibrillization by predominately reducing the rate of fibril-end elongation at substoichiometric ratios. A detailed kinetic analysis suggests that this specific effect results in enhanced Aß oligomer generation promoted by Cu(II). These results can quantitatively be understood by Cu(II) interaction with the Aß monomer, forming an aggregation inert complex. In fact, this mechanism is strikingly similar to other transition metal ions, suggesting a common mechanism of action of retarding Aß self-assembly, where the metal ion binding to monomeric Aß is a key determinant.
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MEDLINE
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En
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JACS Au
Ano de publicação:
2022
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Article
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Suécia