Exploring the Structural Details of Cu(I) Binding to α-Synuclein by NMR Spectroscopy

Binolfi, Andrés; Valiente-Gabioud, Ariel A.; Durán, Rosario; Zweckstetter, Markus; Griesinger, Christian; Fernandez, Claudio O.

doi:10.1021/ja107842f

Cited by 80 publications

(111 citation statements)

References 23 publications

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“…The participation of H50 in metal binding may induce different folding of the protein through the formation of this macrochelate or may act as an intermolecular metal-anchoring point bridging different protein molecules, explaining how H50-Cu 2+ complexation might impact on aSyn aggregation (33). Added to that, the independent, noninteractive H50-Cu 2+ binding mode described in our study and those reported for Cu + binding to aSyn (47) indicate that the H50 site constitutes a unique target for in vivo Cu 2+ /Cu + redox chemistry and oxidative damage, a reaction that might lead to a cascade of structural alterations promoting oligomerization and the subsequent amyloid aggregation of aSyn (33). Thus, H50 might play an important role in the structures adopted by soluble aSyn at the beginning of the aggregation reaction and, likely, of the polymerization rates and the final conformation in the resulting aggregates, which would explain the conformational diversity of WT +Cu 2+ and H50Q +Cu 2+ aggregates.…”

Section: Discussionsupporting

confidence: 53%

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Villar‐Piqué

Fonseca

Sant’Anna

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.α-synuclein | copper | H50Q mutation | inclusions | protein aggregation

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Section: Discussionsupporting

confidence: 53%

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Villar‐Piqué

Fonseca

Sant’Anna

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…These apparent affinities of Cu I for truncated or full-length aS were in the lower-mm range. [21,23,38] Thus, affinitieslower than the estimated Cu I affinities here wereobtained.…”

Section: Discussionmentioning

confidence: 96%

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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“…In case of ␣-synuclein, reduction of Cu(II) to Cu(I) occurs in the absence of oxygen whereas reoxidation during aggregation takes place in the presence of oxygen [16]. It has been illustrated that binding of Cu(I) to ␣-synuclein involves specific Met residues [20]. In case of the human prion protein, the N-terminal tandem repeat region was found to reduce Cu(II) to Cu(I) where Trp was found to be the key amino acid residue [17].…”

Section: Introductionmentioning

confidence: 99%