8B9Q

Molecular structure of Cu(II)-bound amyloid-beta monomer implicated in inhibition of peptide self-assembly in Alzheimer's disease

Summary for 8B9Q

• Entry DOI: 10.2210/pdb8b9q/pdb
• NMR Information: BMRB: 34762
• Descriptor: Amyloid-beta A4 protein, COPPER (II) ION (2 entities in total)
• Functional Keywords: amyloid-beta peptide, alzheimer's disease, copper ion, paramagnetic nmr, aggregation kinetics, metal binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 4399.40

Authors

Abelein, A.,Ciofi-Baffoni, S.,Kumar, R.,Giachetti, A.,Piccioli, M.,Biverstal, H. (deposition date: 2022-10-06, release date: 2023-02-08, Last modification date: 2024-06-05)

Primary citation

Abelein, A.,Ciofi-Baffoni, S.,Morman, C.,Kumar, R.,Giachetti, A.,Piccioli, M.,Biverstal, H.
Molecular Structure of Cu(II)-Bound Amyloid-beta Monomer Implicated in Inhibition of Peptide Self-Assembly in Alzheimer's Disease.
Jacs Au, 2:2571-2584, 2022

PubMed Abstract: Metal ions, such as copper and zinc ions, have been shown to strongly modulate the self-assembly of the amyloid-β (Aβ) 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 Aβ 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 Aβ. We found that monomeric Aβ 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 Aβ 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 Aβ nucleation process. Our results show that Cu(II) efficiently retards Aβ 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 Aβ oligomer generation promoted by Cu(II). These results can quantitatively be understood by Cu(II) interaction with the Aβ 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 Aβ self-assembly, where the metal ion binding to monomeric Aβ is a key determinant.

PubMed: 36465548
DOI: 10.1021/jacsau.2c00438

Experimental method

SOLUTION NMR