The Catalytically Active Copper‐Amyloid‐Beta State: Coordination Site Responsible for Reactive Oxygen Species Production

Cassagnes, Laure‐Estelle; Hervé, Vincent; Nepveu, Françoise; Hureau, Christelle; Faller, Peter; Collin, Fabrice

doi:10.1002/anie.201305372

Cited by 109 publications

(125 citation statements)

References 39 publications

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“…Protein-metal interactions play an important role in AS aggregation and growing evidence indicates that this process might represent the link between the pathological processes of protein aggregation, oxidative damage and neuronal cell loss [3][4][5][6][7][8]. As reported for the Aβ peptide and prion protein, AS is also highly susceptible to copper-catalyzed oxidation, a reaction that induces extensive oligomerization of these proteins [9][10][11][12][13]. This mechanism is a highly selective, site-specific process that involves interactions of the protein with both oxidation states of the copper ion.…”

mentioning

confidence: 99%

Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS–Cu(I) interactions

Miotto

Binolfi

Zweckstetter

et al. 2014

Journal of Inorganic Biochemistry

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The aggregation of alpha-synuclein (AS) is a critical step in the etiology of Parkinson's disease (PD) and other neurodegenerative synucleinopathies. This process is selectively enhanced by copper in vitro and the interaction is proposed to play a potential role in vivo. Presently, the identity of the Cu(I) binding sites in AS and their relative affinities are under debate. In this work we have addressed unresolved details related to the structural binding specificity and affinity of Cu(I) to full-length AS. We demonstrated conclusively that: (i) the binding preferences of Cu(I) for the Met-binding sites at the N-(K d = 20 μM) and C-terminus (K d = 270 μM) of AS are widely different: (ii) the imidazole ring of His-50 acts as an effective anchoring residue (K d = 50 μM) for Cu(I) binding to AS; and (iii) no major structural rearrangements occur in the protein upon Cu(I) binding. Overall, our work shows that Cu(I) binding to the N-and C-terminal regions of AS are two independent events, with substantial differences in their affinities, and suggest that protein oxidative damage derived from a misbalance in cellular copper homeostasis would target preferentially the N-terminal region of AS. This knowledge is key to understanding the structural-aggregation basis of the copper catalyzed oxidation of AS.

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confidence: 99%

Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS–Cu(I) interactions

Miotto

Binolfi

Zweckstetter

et al. 2014

Journal of Inorganic Biochemistry

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“…According to Cassagnes et al, the Asp1, His13 and His14 residues seem to participate in the redox reactive state. 74 These results suggest that the coordination of Asp1 triggers the redox activation. The intrinsically fast dynamics of the Aβ protein may also facilitate this switching.…”

Section: Catalytic Properties and Toxicity Of Cu-aβ Aggregatesmentioning

confidence: 92%

“…73 Other recent studies suggest that apart from His13 and His14, Asp1 is the other main ligand in the most redox-active site that efficiently allow the oxidation of copper by H 2 O 2 and its reduction by ascorbate. 74 As the ligand sphere is different from the main Cu(II)-Aβ and Cu(I)-Aβ coordination spheres, it has been identified as an in-between state, which is only sparsely populated (0.1%). This is probably why it has not been detected so far by spectroscopic studies, both for Cu(I)-Aβ and Cu(II)-Aβ.…”

Section: Catalytic Properties and Toxicity Of Cu-aβ Aggregatesmentioning

confidence: 99%

Copper in Alzheimer’s disease: Implications in amyloid aggregation and neurotoxicity

Gámez

Caballero

2015

AIP Advances

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The relationship of copper dyshomeostasis with neurodegenerative diseases has become evident in the last years. Because of the major role that this metal ion plays in biological processes, most of which being located in the brain, it is not surprising that changes in its distribution are closely related with the advent of neurodegenerative disorders such as Alzheimer’s disease (AD). An increasing number of works have dealt with this subject in the last years, and opened an intense debate in some points while raising new questions that still remain unanswered. This revision work puts together and discusses the latest findings and insights on how copper ions are involved in AD progression, including its interaction with Aβ and its consequently induced aggregation.

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“…34 Therefore, sequestration of Cu 2+ from the Aβ species was an important strategy to prevent redox processinduced ROS generation to suppress the metal directed Aβ toxicity. 18 First, we studied the metal 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 sequestration ability of P6 was studied by performing mass spectral analysis. The Aβ42-Cu 2+ complex treated with P6 showed mass peak at 431 (m/2 of P6-Cu 2+ ) corresponding to the P6-Cu 2+ complex which confirmed the efficient Cu 2+ sequestration by P6 (Figure 4a and supporting information).…”

Section: Inhibition Of Aβ Oligomeric Aggregatesmentioning

confidence: 99%

Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity

Rajasekhar

Madhu

Govindaraju

2016

ACS Chem. Neurosci.

115

157

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Accumulation of amyloid beta (Aβ) peptide and its aggregates in the human brain is considered as one of the hallmarks of Alzheimer's disease (AD). The polymorphic oligomers and fully grown fibrillar aggregates of Aβ exhibit different levels of neuronal toxicity. Moreover, aggregation of Aβ in the presence of redox-active metal ions like Cu(2+) is responsible for the additional trait of cellular toxicity induced by the generation of reactive oxygen species (ROS). Herein, a multifunctional peptidomimetic inhibitor (P6) has been presented, based on a naturally occurring metal chelating tripeptide (GHK) and the inhibitor of Aβ aggregation. It was shown by employing various biophysical studies that P6 interact with Aβ and prevent the formation of toxic Aβ forms like oligomeric species and fibrillar aggregates. Further, P6 successfully sequestered Cu(2+) from the Aβ-Cu(2+) complex and maintained it in a redox-dormant state to prevent the generation of ROS. P6 inhibited membrane disruption by Aβ oligomers and efficiently prevented DNA damage caused by the Aβ-Cu(2+) complex. PC12 cells were rescued from multifaceted Aβ toxicity when treated with P6, and the amount of ROS generated in cells was reduced. These attributes make P6 a potential therapeutic candidate to ameliorate the multifaceted Aβ toxicity in AD.

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The Catalytically Active Copper‐Amyloid‐Beta State: Coordination Site Responsible for Reactive Oxygen Species Production

Cited by 109 publications

References 39 publications

Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS–Cu(I) interactions

Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS–Cu(I) interactions

Copper in Alzheimer’s disease: Implications in amyloid aggregation and neurotoxicity

Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity

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