Aβ under stress: the effects of acidosis, Cu<sup>2+</sup>-binding, and oxidation on amyloid β-peptide dimers

Liao, Qinghua; Owen, Michael C.; Bali, Sofia; Barz, Bogdan; Strodel, Birgit

doi:10.1039/c8cc02263a

Cited by 41 publications

(32 citation statements)

References 36 publications

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“…The result is consistent with a previous MD analysis showing that D3 disrupts the formation of β-sheet structures in Aβ42 by binding adjacently to the n-terminal half of Aβ42, where the central hydrophobic core is located [49]. In fact, the content of β-sheet structures in Aβ42 and D3 complexes (~5%) is much lower than that observed for the Aβ42 dimer (~15%) in previous simulations in the same force field [50]. The rather unordered structure of Aβ42 monomers in complex with D3 makes them incapable of participating in Aβ nuclei growth and amplification processes encompassing the accumulation of a certain amount of ordered structures [51,52,53].…”

Section: Discussionsupporting

confidence: 91%

Interference with Amyloid-β Nucleation by Transient Ligand Interaction

et al. 2019

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Amyloid-β peptide (Aβ) is an intrinsically disordered protein (IDP) associated with Alzheimer’s disease. The structural flexibility and aggregation propensity of Aβ pose major challenges for elucidating the interaction between Aβ monomers and ligands. All-D-peptides consisting solely of D-enantiomeric amino acid residues are interesting drug candidates that combine high binding specificity with high metabolic stability. Here we characterized the interaction between the 12-residue all-D-peptide D3 and Aβ42 monomers, and how the interaction influences Aβ42 aggregation. We demonstrate for the first time that D3 binds to Aβ42 monomers with submicromolar affinities. These two highly unstructured molecules are able to form complexes with 1:1 and other stoichiometries. Further, D3 at substoichiometric concentrations effectively slows down the β-sheet formation and Aβ42 fibrillation by modulating the nucleation process. The study provides new insights into the molecular mechanism of how D3 affects Aβ assemblies and contributes to our knowledge on the interaction between two IDPs.

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Section: Discussionsupporting

confidence: 91%

Interference with Amyloid-β Nucleation by Transient Ligand Interaction

et al. 2019

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“…The sequence of C‐peptide (EAEDLQVGQVELGGGPGAGSLQPLALEGSLQ) contains multiple glutamic acid residues; the possible binding mode of Zn II to C‐peptide is suspected to be at some of these residues, but the structural consequence and signaling mechanism remain elusive. Essential d‐block transition metals, present in trace amounts and fluxional in serum, are receiving increased attention for their abilities to perturb structure and alter function of bioactive peptides, including amyloid‐β and α‐synuclein, as well as hormones, including insulin, oxytocin, and hepcidin …”

Section: Figurementioning

confidence: 99%

Analysis of Metal Effects on C‐Peptide Structure and Internalization

et al. 2019

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The connecting peptide (C‐peptide) has received increased attention for its potential therapeutic effects in ameliorating illnesses such as kidney disease and diabetes. Although the mechanism of C‐peptide signaling remains elusive, evidence supports its internalization and intracellular function. Emerging research is uncovering the diverse biological roles metals play in controlling and affecting the function of bioactive peptides. The work presented herein investigates interactions between C‐peptide and first‐row d‐block transition metals, as well as their effects on C‐peptide internalization into cells. Through spectroscopic techniques, it is demonstrated that CrIII, CuII, and ZnII bind to C‐peptide with differing stoichiometries and biologically relevant affinities. In addition, metal binding elicits both subtle changes in secondary structure and inhibits adoption of an α‐helical character in environments where the dielectric constants are reduced. This study shows how metal ions can modulate peptide hormone activity through subtle structural changes to disrupt cellular uptake.

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“…Their results illustrated that Cu(II) binding and mild acidic conditions can shift the conformational equilibrium towards aggregation-prone conformers for the monomeric Aβ42 (57). In an additional study, Strodel and co-workers reported the conformational changes of the Aβ42 dimer upon Cu(II) coordination using the Asp and His coordination nodes via conducting H-REMD simulations (58). They showed that Cu(II) binding, oxidation and a decrease in pH are relevant to the oligomerization of Aβ42.…”

Section: Introductionmentioning

confidence: 99%

Revisiting Cu(II) Bound Amyloid-β40 and Amyloid-β42 Peptides: Varying Coordination Chemistries

Coskuner‐Weber¹

2018

Journal of the Turkish Chemical Society Section A: Chemistry

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Metal ions and intrinsically disordered peptides amyloid-β40 and amyloid-β42 are at the center of Alzheimer´s disease pathology. Divalent copper ion binds to amyloid-β40 and amyloid-β42 peptides with varying coordination chemistries. Experiments face challenges in the measurements of divalent copper ion bound monomeric amyloid-β40 and amyloid-β42 in an aqueous solution medium because of fast conformational changes, rapid aggregation processes and solvent effects. Theoretical studies complement experiments and provide insights at the atomic and molecular levels with dynamics. However, until recently, potential functions for simulating divalent copper ion bound amyloid-β40 and amyloid-β42 peptides with varying coordination chemistries were lacking. Using new potential functions that were developed for divalent copper centers, Cu(II), including three histidine residues and an oxygen-ligated amino acid residue, the structures and thermodynamic properties of Cu(II)-bound amyloid-β40 and amyloid-β42 peptides in an aqueous solution medium were studied. For these purposes, extensive first principles calculations and replica exchange molecular dynamics simulations were conducted. In this study, the secondary and tertiary structural properties, conformational Gibbs free energy values, potential of mean force surfaces, salt bridges and aggregation propensities of aqueous Cu(II)-bound amyloid-β40 and amyloid-β42 peptides are presented. Different than previous findings in the literature, results clearly show that the coordination chemistry variations impact the structural and thermodynamic properties of divalent Cu(II) bound amyloid-β alloforms in water. Specificities about these differences are revealed in this study at the atomic level with dynamics. Results presented herein are the first to offer a comparison of the monomeric Cu(II)-bound amyloid-β40 and amyloid-β42 peptides with varying coordination chemistries using bonded model potential functions.

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Aβ under stress: the effects of acidosis, Cu²⁺-binding, and oxidation on amyloid β-peptide dimers

Cited by 41 publications

References 36 publications

Interference with Amyloid-β Nucleation by Transient Ligand Interaction

Interference with Amyloid-β Nucleation by Transient Ligand Interaction

Analysis of Metal Effects on C‐Peptide Structure and Internalization

Revisiting Cu(II) Bound Amyloid-β40 and Amyloid-β42 Peptides: Varying Coordination Chemistries

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Aβ under stress: the effects of acidosis, Cu2+-binding, and oxidation on amyloid β-peptide dimers

Cited by 41 publications

References 36 publications

Interference with Amyloid-β Nucleation by Transient Ligand Interaction

Interference with Amyloid-β Nucleation by Transient Ligand Interaction

Analysis of Metal Effects on C‐Peptide Structure and Internalization

Revisiting Cu(II) Bound Amyloid-β40 and Amyloid-β42 Peptides: Varying Coordination Chemistries

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Aβ under stress: the effects of acidosis, Cu²⁺-binding, and oxidation on amyloid β-peptide dimers