A Revised Picture of the Cu(II)−α-Synuclein Complex: The Role of N-Terminal Acetylation

Moriarty, Gina M.; Minetti, Conceição A.S.A.; Remeta, David P.; Baum, Jean

doi:10.1021/bi5003025

Cited by 75 publications

(120 citation statements)

References 28 publications

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“…Nevertheless, numerous studies proposed only a single high affinity coordination mode, with disagreement regarding the role of Met1 and His50 and/or overlooking the effect of pH-dependent equilibrium. [20][21][22][27][28][29][30][31][32][33][34][35][36] To characterize the Cu II -binding properties, 65 CuCl 2 was first titrated into a solution of aSyn56 at pH 7.4 and analyzed using X-band EPR spectroscopy. Between 0-1 equiv Cu II , two sets of hyperfine features could be distinguished (Figure 1 a), indicating the presence of more than one coordination mode.…”

Section: Resultsmentioning

confidence: 99%

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The N Terminus of α‐Synuclein Forms Cu^II‐Bridged Oligomers

Drew

2015

Chemistry A European J

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The oligomerization of α-synuclein (αSyn) is one of the defining features of Parkinson's disease. Binding of divalent copper to the N terminus of αSyn has been implicated in both its function and dysfunction. Herein, the molecular details of the Cu(II) /αSyn binding interface have been revealed using a library of synthetic 56-residue αSyn peptides containing site-specific isotopic labels. Using electron paramagnetic resonance spectroscopy, αSyn is shown to coordinate Cu(II) with high affinity via two pH-dependent coordination modes between pH 6.5-8.5. Most remarkably, the data demonstrate that the dominant mode is associated with binding to oligomers (antiparallel dimers and/or cyclic trimers) in which Cu(II) ions occupy intermolecular bridging sites. The findings provide a molecular link between Cu(II) -bound αSyn and its associated quaternary oligomeric structure.

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Section: Resultsmentioning

confidence: 99%

“…[19,22] The first approximately 35 residues of aSyn do not form part of the 5-strand, 4-turn b-sandwich structure of parallel, in-register aSyn140 fibrils, remaining structurally heterogeneous; [43,44] however, His50 resides within the first loop between b strands 1 and 2.…”

Section: Mode II Is a Cu Ii -Bridged Oligomermentioning

confidence: 99%

The N Terminus of α‐Synuclein Forms Cu^II‐Bridged Oligomers

Drew

2015

Chemistry A European J

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“…This form reduces the Cu II affinity,a nd hence Cu II distribution between Ab and aS would be even more pushed towardA b. [51] It is important to note that the presence of His50 and the Nterminal acetylation does not have any impact on the Cu I affinity and hence on the Cu I distribution between Ab anda /bS because neither His50 nor the N-terminal amine is involved as al igand in the highest-affinity Cu I binding site in aS. Although the affinitiesc an be modulated (see above), our data indicate that for monomeric Ab, aS and bS, Cu in either redox state can be preferentially,b ut not exclusively,b ound by one peptide.…”

Section: Biological Implicationsmentioning

confidence: 99%

Copper(I/II), α/β‐Synuclein and Amyloid‐β: Menage à Trois?

et al. 2015

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Copper binding to α-synuclein (aS) and to amyloid-β (Ab) has been connected to Parkinson's and Alzheimer's disease (AD), respectively, because Cu ions can modulate the peptide aggregation, and these Cu ⋅ peptide complexes can catalyse the production of reactive oxygen species (ROS). In a significant proportion of AD brains, aggregation of aS and Ab has been detected, and it was proposed that Ab and aS interact with each other. Thus, we investigated the potential interactions of Ab and aS through their binding of copper(I) and copper(II). Additionally, β-synuclein (bS) was investigated, due to its additional methionine residue, a potential Cu(I) ligand. We found that: 1) the peptides containing the Cu-binding domains Ab1-16, aS1-15 and bS1-15 have similar affinities towards Cu(II) and towards Cu(I), with Ab1-16 being slightly stronger, 2) in the case of Cu(I), the additional Met residue in bS1-15 increased the affinity slightly, 3) the exchange of Cu(I/II) between the two peptides is rapid (≤ ms), 4) a/bS1-15 and Ab1-16 form a heterodimeric complex with Cu(II), 5) Cu(I) probably promotes a transient ternary complex, 6) the different Cu(I/II) coordination of Ab1-16, aS1-15 and bS1-15 impacts the capacity to produce ROS and to oxidise catechol, and 7) when Ab1-16, aS1-15 and Cu are present, the ROS production more closely resembles that by Ab1-16. The work gives insights into the coordination chemistry of these related peptides, and the relevance of coordination differences, the ternary complex and ROS production are discussed.

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“…Metal ions show different binding affinities for α-syn but the binding sites are similar for the majority of metal ions. Generally, divalent cations (such as Fe 2+ , Mn 2+ , Co 2+ , Ni 2+ , Ca 2+ , and Cu 2+ ) bind to the CT of α-syn (Nielsen et al, 2001; Lowe et al, 2004; Binolfi et al, 2006) but binding sites for copper have been described also in NT and NAC segment (Camponeschi et al, 2013; Moriarty et al, 2014). Among metal ions, copper shows the highest binding affinity estimated in the μM range and it can bind to residues Met-1, Asp-2, His-50, Asp-119, Asp-121, and Glu-123 (Binolfi et al, 2006, 2012; Rodríguez et al, 2016; Figure 1).…”

Section: Role Of Metals In Synucleinopathiesmentioning

confidence: 99%

Metal Dyshomeostasis and Their Pathological Role in Prion and Prion-Like Diseases: The Basis for a Nutritional Approach

Toni¹,

Massimino

Mario

et al. 2017

Front. Neurosci.

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Metal ions are key elements in organisms' life acting like cofactors of many enzymes but they can also be potentially dangerous for the cell participating in redox reactions that lead to the formation of reactive oxygen species (ROS). Any factor inducing or limiting a metal dyshomeostasis, ROS production and cell injury may contribute to the onset of neurodegenerative diseases or play a neuroprotective action. Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of fatal neurodegenerative disorders affecting the central nervous system (CNS) of human and other mammalian species. The causative agent of TSEs is believed to be the scrapie prion protein PrPSc, the β sheet-rich pathogenic isoform produced by the conformational conversion of the α-helix-rich physiological isoform PrPC. The peculiarity of PrPSc is its ability to self-propagate in exponential fashion in cells and its tendency to precipitate in insoluble and protease-resistance amyloid aggregates leading to neuronal cell death. The expression “prion-like diseases” refers to a group of neurodegenerative diseases that share some neuropathological features with prion diseases such as the involvement of proteins (α-synuclein, amyloid β, and tau) able to precipitate producing amyloid deposits following conformational change. High social impact diseases such as Alzheimer's and Parkinson's belong to prion-like diseases. Accumulating evidence suggests that the exposure to environmental metals is a risk factor for the development of prion and prion-like diseases and that metal ions can directly bind to prion and prion-like proteins affecting the amount of amyloid aggregates. The diet, source of metal ions but also of natural antioxidant and chelating agents such as polyphenols, is an aspect to take into account in addressing the issue of neurodegeneration. Epidemiological data suggest that the Mediterranean diet, based on the abundant consumption of fresh vegetables and on low intake of meat, could play a preventive or delaying role in prion and prion-like neurodegenerative diseases. In this review, metal role in the onset of prion and prion-like diseases is dealt with from a nutritional, cellular, and molecular point of view.

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A Revised Picture of the Cu(II)−α-Synuclein Complex: The Role of N-Terminal Acetylation

Cited by 75 publications

References 28 publications

The N Terminus of α‐Synuclein Forms Cu^II‐Bridged Oligomers

The N Terminus of α‐Synuclein Forms Cu^II‐Bridged Oligomers

Copper(I/II), α/β‐Synuclein and Amyloid‐β: Menage à Trois?

Metal Dyshomeostasis and Their Pathological Role in Prion and Prion-Like Diseases: The Basis for a Nutritional Approach

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A Revised Picture of the Cu(II)−α-Synuclein Complex: The Role of N-Terminal Acetylation

Cited by 75 publications

References 28 publications

The N Terminus of α‐Synuclein Forms CuII‐Bridged Oligomers

The N Terminus of α‐Synuclein Forms CuII‐Bridged Oligomers

Copper(I/II), α/β‐Synuclein and Amyloid‐β: Menage à Trois?

Metal Dyshomeostasis and Their Pathological Role in Prion and Prion-Like Diseases: The Basis for a Nutritional Approach

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Product

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The N Terminus of α‐Synuclein Forms Cu^II‐Bridged Oligomers

The N Terminus of α‐Synuclein Forms Cu^II‐Bridged Oligomers