Metal binding to the amyloid-β peptides in the presence of biomembranes: potential mechanisms of cell toxicity

Abstract The amyloid-β (Aβ) peptides are key molecules in Alzheimer’s disease (AD) pathology. They interact with cellular membranes, and can bind metal ions outside the membrane. Certain oligomeric Aβ aggregates are known to induce membrane perturbations and the structure of these oligomers—and their membrane-perturbing effects—can be modulated by metal ion binding. If the bound metal ions are redox active, as e.g., Cu and Fe ions are, they will generate harmful reactive oxygen species (ROS) just outside the membrane surface. Thus, the membrane damage incurred by toxic Aβ oligomers is likely aggravated when redox-active metal ions are present. The combined interactions between Aβ oligomers, metal ions, and biomembranes may be responsible for at least some of the neuronal death in AD patients.

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Crystallographic and X-ray absorption spectroscopic characterization of Helicobacter pylori UreE bound to Ni2+ and Zn2+ reveals a role for the disordered C-terminal arm in metal trafficking

Biochemical Journal ◽

10.1042/bj20111659 ◽

2012 ◽

Vol 441 (3) ◽

pp. 1017-1035 ◽

Cited By ~ 39

Author(s):

Katarzyna Banaszak ◽

Vlad Martin-Diaconescu ◽

Matteo Bellucci ◽

Barbara Zambelli ◽

Wojciech Rypniewski ◽

...

Keyword(s):

Helicobacter Pylori ◽

Metal Ions ◽

Metal Binding ◽

Metal Ion ◽

Mutual Influence ◽

Accurate Information ◽

Metal Ion Binding ◽

X Ray ◽

X Ray Absorption

The survival and growth of the pathogen Helicobacter pylori in the gastric acidic environment is ensured by the activity of urease, an enzyme containing two essential Ni2+ ions in the active site. The metallo-chaperone UreE facilitates in vivo Ni2+ insertion into the apoenzyme. Crystals of apo-HpUreE (H. pylori UreE) and its Ni2+- and Zn2+-bound forms were obtained from protein solutions in the absence and presence of the metal ions. The crystal structures of the homodimeric protein, determined at 2.00 Å (apo), 1.59 Å (Ni2+) and 2.52 Å (Zn2+) resolution, show the conserved proximal and solvent-exposed His102 residues from two adjacent monomers invariably involved in metal binding. The C-terminal regions of the apoprotein are disordered in the crystal, but acquire significant ordering in the presence of the metal ions due to the binding of His152. The analysis of X-ray absorption spectral data obtained using solutions of Ni2+- and Zn2+-bound HpUreE provided accurate information of the metal-ion environment in the absence of solid-state effects. These results reveal the role of the histidine residues at the protein C-terminus in metal-ion binding, and the mutual influence of protein framework and metal-ion stereo-electronic properties in establishing co-ordination number and geometry leading to metal selectivity.

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Coordination of redox active metal ions to the amyloid precursor protein and to amyloid-β peptides involved in Alzheimer disease. Part 1: An overview

Coordination Chemistry Reviews ◽

10.1016/j.ccr.2012.03.037 ◽

2012 ◽

Vol 256 (19-20) ◽

pp. 2164-2174 ◽

Cited By ~ 115

Author(s):

Christelle Hureau

Keyword(s):

Alzheimer Disease ◽

Amyloid Precursor Protein ◽

Metal Ions ◽

Amyloid Β ◽

Precursor Protein ◽

Redox Active ◽

Active Metal ◽

Redox Active Metal

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Computational approaches for de novo design and redesign of metal-binding sites on proteins

Bioscience Reports ◽

10.1042/bsr20160179 ◽

2017 ◽

Vol 37 (2) ◽

Cited By ~ 12

Author(s):

Gunseli Bayram Akcapinar ◽

Osman Ugur Sezerman

Keyword(s):

Metal Ions ◽

Metal Binding ◽

Binding Sites ◽

Metal Ion ◽

De Novo ◽

De Novo Design ◽

Ion Binding ◽

Chemical Transformations ◽

Metal Ion Binding ◽

Metal Binding Sites

Metal ions play pivotal roles in protein structure, function and stability. The functional and structural diversity of proteins in nature expanded with the incorporation of metal ions or clusters in proteins. Approximately one-third of these proteins in the databases contain metal ions. Many biological and chemical processes in nature involve metal ion-binding proteins, aka metalloproteins. Many cellular reactions that underpin life require metalloproteins. Most of the remarkable, complex chemical transformations are catalysed by metalloenzymes. Realization of the importance of metal-binding sites in a variety of cellular events led to the advancement of various computational methods for their prediction and characterization. Furthermore, as structural and functional knowledgebase about metalloproteins is expanding with advances in computational and experimental fields, the focus of the research is now shifting towards de novo design and redesign of metalloproteins to extend nature’s own diversity beyond its limits. In this review, we will focus on the computational toolbox for prediction of metal ion-binding sites, de novo metalloprotein design and redesign. We will also give examples of tailor-made artificial metalloproteins designed with the computational toolbox.

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Coordination of redox active metal ions to the amyloid precursor protein and to amyloid-β peptides involved in Alzheimer disease. Part 2: Dependence of Cu(II) binding sites with Aβ sequences

Coordination Chemistry Reviews ◽

10.1016/j.ccr.2012.03.034 ◽

2012 ◽

Vol 256 (19-20) ◽

pp. 2175-2187 ◽

Cited By ~ 104

Author(s):

Christelle Hureau ◽

Pierre Dorlet

Keyword(s):

Alzheimer Disease ◽

Amyloid Precursor Protein ◽

Metal Ions ◽

Binding Sites ◽

Amyloid Β ◽

Precursor Protein ◽

Redox Active ◽

Active Metal ◽

Redox Active Metal

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Metal ion coordination delays amyloid-β peptide self-assembly by forming an aggregation–inert complex

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.012738 ◽

2020 ◽

Vol 295 (21) ◽

pp. 7224-7234 ◽

Cited By ~ 3

Author(s):

Cecilia Wallin ◽

Jüri Jarvet ◽

Henrik Biverstål ◽

Sebastian Wärmländer ◽

Jens Danielsson ◽

...

Keyword(s):

Metal Ions ◽

Self Assembly ◽

Metal Ion ◽

Amyloid Β ◽

Bound State ◽

Ion Binding ◽

Amyloid Β Peptide ◽

Aβ Peptide ◽

Metal Ion Binding

A detailed understanding of the molecular pathways for amyloid-β (Aβ) peptide aggregation from monomers into amyloid fibrils, a hallmark of Alzheimer's disease, is crucial for the development of diagnostic and therapeutic strategies. We investigate the molecular details of peptide fibrillization in vitro by perturbing this process through addition of differently charged metal ions. Here, we used a monovalent probe, the silver ion, that, similarly to divalent metal ions, binds to monomeric Aβ peptide and efficiently modulates Aβ fibrillization. On the basis of our findings, combined with our previous results on divalent zinc ions, we propose a model that links the microscopic metal-ion binding to Aβ monomers to its macroscopic impact on the peptide self-assembly observed in bulk experiments. We found that substoichiometric concentrations of the investigated metal ions bind specifically to the N-terminal region of Aβ, forming a dynamic, partially compact complex. The metal-ion bound state appears to be incapable of aggregation, effectively reducing the available monomeric Aβ pool for incorporation into fibrils. This is especially reflected in a decreased fibril-end elongation rate. However, because the bound state is significantly less stable than the amyloid state, Aβ peptides are only transiently redirected from fibril formation, and eventually almost all Aβ monomers are integrated into fibrils. Taken together, these findings unravel the mechanistic consequences of delaying Aβ aggregation via weak metal-ion binding, quantitatively linking the contributions of specific interactions of metal ions with monomeric Aβ to their effects on bulk aggregation.

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DNA interaction with biologically active metal ions. Cooperativity of metal ion binding at compacting of DNA.

Acta Biochimica Polonica ◽

10.18388/abp.1998_4325 ◽

1998 ◽

Vol 45 (1) ◽

pp. 107-117 ◽

Cited By ~ 16

Author(s):

S Kornilova ◽

E Hackl ◽

L Kapinos ◽

V Andrushchenko ◽

Y Blagoi

Keyword(s):

Metal Ions ◽

Metal Ion ◽

Binding Constants ◽

Dna Interaction ◽

Biologically Active ◽

Ion Binding ◽

Metal Ion Binding ◽

Binding Isotherms ◽

Active Metal ◽

Free Metal

The interaction of Cu2+, Mn2+ and Ca2+ ions with DNA in aqueous and water-ethanol solutions at different metal ion concentrations was studied by IR-spectroscopy. At sufficiently high DNA concentrations, DNA interaction with Cu2+, Ca2+ and Mn2+ ions results in compacting of DNA in the aqueous solutions. This process shows a very high cooperativity. In the presence of alcohol, DNA condensation takes place at much lower concentrations of metal ions used than in pure aqueous solution. Binding constants and cooperativity of the metal ion binding rise, and the non-monotonous dependencies of the binding degree, r, on the concentration of free metal ions, Cf, become pronounced. Binding isotherms take the S-like form similar to van der Waals isotherms for phase transitions of the liquid-vapour type. Cu2+ and Ca2+ ion binding to DNA in water-ethanol solutions also results in compacting of DNA macromolecule. The process is characterised by a high positive cooperativity and has a phase transition character.

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Anodic Stripping Voltammetry with the Hanging Mercury Drop Electrode for Trace Metal Detection in Soil Samples

Chemosensors ◽

10.3390/chemosensors9050107 ◽

2021 ◽

Vol 9 (5) ◽

pp. 107

Author(s):

Kequan Xu ◽

Clara Pérez-Ràfols ◽

Amine Marchoud ◽

María Cuartero ◽

Gastón A. Crespo

Keyword(s):

Metal Ions ◽

Limit Of Detection ◽

Anodic Stripping Voltammetry ◽

Stripping Voltammetry ◽

Hanging Mercury Drop Electrode ◽

Mercury Drop Electrode ◽

Redox Active ◽

Active Metal ◽

Metal Detection ◽

Trace Metal Detection

The widely spread use of the hanging mercury drop electrode (HMDE) for multi-ion analysis is primarily ascribed to the following reasons: (i) excellent reproducibility owing to the easy renewal of the electrode surface avoiding any hysteresis effect (i.e., a new identical drop is generated for each measurement to be accomplished); (ii) a wide cathodic potential window originating from the passive hydrogen evolution and solvent electrolysis; (iii) the ability to form amalgams with many redox-active metal ions; and (iv) the achievement of (sub)nanomolar limits of detection. On the other hand, the main controversy of the HMDE usage is the high toxicity level of mercury, which has motivated the scientific community to question whether the HMDE deserves to continue being used despite its unique capability for multi-metal detection. In this work, the simultaneous determination of Zn2+, Cd2+, Pb2+, and Cu2+ using the HMDE is investigated as a model system to evaluate the main features of the technique. The analytical benefits of the HMDE in terms of linear range of response, reproducibility, limit of detection, proximity to ideal redox behavior of metal ions and analysis time are herein demonstrated and compared to other electrodes proposed in the literature as less-toxic alternatives to the HMDE. The results have revealed that the HMDE is largely superior to other reported methods in several aspects and, moreover, it displays excellent accuracy when simultaneously analyzing Zn2+, Cd2+, Pb2+, and Cu2+ in such a complex matrix as digested soils. Yet, more efforts are required towards the definitive replacement of the HMDE in the electroanalysis field, despite the elegant approaches already reported in the literature.

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Regulation of divalent metal ions to the aggregation and membrane damage of human islet amyloid polypeptide oligomers

RSC Advances ◽

10.1039/d1ra00354b ◽

2021 ◽

Vol 11 (21) ◽

pp. 12815-12825

Author(s):

Yajie Wang ◽

Feihong Meng ◽

Tong Lu ◽

Chunyun Wang ◽

Fei Li

Keyword(s):

Metal Ions ◽

Metal Binding ◽

Membrane Damage ◽

Islet Amyloid Polypeptide ◽

Divalent Metal ◽

Human Islet ◽

Divalent Metal Ions ◽

Islet Amyloid ◽

Induced Membrane ◽

Human Islet Amyloid Polypeptide

Their is a counteraction between a decrease in the disruptive ability of metal-associated oligomer species and an increase in the quantity of oligomers promoted by the metal binding in the activity of hIAPP induced membrane damage.

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Acylated Anthocyanins from Red Cabbage and Purple Sweet Potato Can Bind Metal Ions and Produce Stable Blue Colors

International Journal of Molecular Sciences ◽

10.3390/ijms22094551 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4551

Author(s):

Julie-Anne Fenger ◽

Gregory T. Sigurdson ◽

Rebecca J. Robbins ◽

Thomas M. Collins ◽

M. Mónica Giusti ◽

...

Keyword(s):

Metal Ions ◽

Sweet Potato ◽

Metal Binding ◽

Metal Ion ◽

High Resolution Mass Spectrometry ◽

Large Set ◽

Water Addition ◽

Red Cabbage ◽

Aluminum Ions ◽

Purple Sweet Potato

Red cabbage (RC) and purple sweet potato (PSP) are naturally rich in acylated cyanidin glycosides that can bind metal ions and develop intramolecular π-stacking interactions between the cyanidin chromophore and the phenolic acyl residues. In this work, a large set of RC and PSP anthocyanins was investigated for its coloring properties in the presence of iron and aluminum ions. Although relatively modest, the structural differences between RC and PSP anthocyanins, i.e., the acylation site at the external glucose of the sophorosyl moiety (C2-OH for RC vs. C6-OH for PSP) and the presence of coordinating acyl groups (caffeoyl) in PSP anthocyanins only, made a large difference in the color expressed by their metal complexes. For instance, the Al3+-induced bathochromic shifts for RC anthocyanins reached ca. 50 nm at pH 6 and pH 7, vs. at best ca. 20 nm for PSP anthocyanins. With Fe2+ (quickly oxidized to Fe3+ in the complexes), the bathochromic shifts for RC anthocyanins were higher, i.e., up to ca. 90 nm at pH 7 and 110 nm at pH 5.7. A kinetic analysis at different metal/ligand molar ratios combined with an investigation by high-resolution mass spectrometry suggested the formation of metal–anthocyanin complexes of 1:1, 1:2, and 1:3 stoichiometries. Contrary to predictions based on steric hindrance, acylation by noncoordinating acyl residues favored metal binding and resulted in complexes having much higher molar absorption coefficients. Moreover, the competition between metal binding and water addition to the free ligands (leading to colorless forms) was less severe, although very dependent on the acylation site(s). Overall, anthocyanins from purple sweet potato, and even more from red cabbage, have a strong potential for development as food colorants expressing red to blue hues depending on pH and metal ion.

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