8b9r | pdb_00008b9r
Molecular structure of Cu(II)-bound amyloid-beta monomer implicated in inhibition of peptide self-assembly in Alzheimer's disease
Structural highlights
FunctionB4DM00_HUMAN Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.[RuleBase:RU367156] Publication Abstract from PubMedMetal ions, such as copper and zinc ions, have been shown to strongly modulate the self-assembly of the amyloid-beta (Abeta) 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 Abeta 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 Abeta. We found that monomeric Abeta 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 Abeta complex, exhibiting heavy backbone RMSD values of 1.9 and 2.1 A, respectively. Further, applying aggregation kinetics assays, we identified the specific effect of Cu(II) binding on the Abeta nucleation process. Our results show that Cu(II) efficiently retards Abeta 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 Abeta oligomer generation promoted by Cu(II). These results can quantitatively be understood by Cu(II) interaction with the Abeta 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 Abeta self-assembly, where the metal ion binding to monomeric Abeta is a key determinant. Molecular Structure of Cu(II)-Bound Amyloid-beta Monomer Implicated in Inhibition of Peptide Self-Assembly in Alzheimer's Disease.,Abelein A, Ciofi-Baffoni S, Morman C, Kumar R, Giachetti A, Piccioli M, Biverstal H JACS Au. 2022 Nov 11;2(11):2571-2584. doi: 10.1021/jacsau.2c00438. eCollection , 2022 Nov 28. PMID:36465548[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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