Copper(II) complexes with an avian prion N-terminal region and their potential SOD-like activity

Mendola, Diego La; Bonomo, Raffaele P.; Caminati, Serena; Natale, Giuseppe Di; Emmi, Salvatore S.; Hansson, Örjan; Maccarrone, Giuseppe; Pappalardo, Giuseppe; Pietropaolo, Adriana; Rizzarelli, Enrico

doi:10.1016/j.jinorgbio.2008.10.002

Cited by 27 publications

(37 citation statements)

References 71 publications

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“…The study of copper interaction with the tetrahexarepeat (PHNPGY) 4 confirms the difference with mammalian (PHGGGWGQ) 4 [140,141]. Differently from that reported for the human (PHGGGWQG) 4 , the copper(II) complex species of chicken (PHNPGY) 4 , where the copper ion is bound to four imidazole nitrogens, results predominant in a wide range of pH; this occurs when copper to ligand ratio increases and not only with sub-stoichiometric amount of metal.…”

Section: Prion and Copper(ii) Coordination Features: Mammal Vs Aviansupporting

confidence: 65%

“…Differently from that reported for the human (PHGGGWQG) 4 , the copper(II) complex species of chicken (PHNPGY) 4 , where the copper ion is bound to four imidazole nitrogens, results predominant in a wide range of pH; this occurs when copper to ligand ratio increases and not only with sub-stoichiometric amount of metal. Such a copper(II) complex species with the avian tetrahexapeptide shows the same stability constant value of the analogous complex with mammalian tetraoctarepeat [140,141]; similar hamiltonian parameters for the two metal complexes have also been found [140,128]. These magnetic parameters indicate that the four imidazole nitrogen atoms are in a planar arrangement, forming a macrochelate (Fig.…”

Section: Prion and Copper(ii) Coordination Features: Mammal Vs Avianmentioning

confidence: 59%

“…(5)). The (PHNPGY) 4 is able to bind no more than two copper ions and always with the involvement of tyrosine side chain [140]. The addition of more than two equivalents of copper ions favours precipitation phenomena as reported for the entire protein.…”

mentioning

confidence: 70%

“…Copper complex species with chPrP C peptide fragments show binding constant values [84,87,[133][134][135]140] lower than those found in SOD-1 enzymes. This appears in contrast with the biological significance of a true SOD-like enzyme in vivo, which has to bind strongly the metal ion.…”

mentioning

confidence: 73%

“…In particular the experimental approach (indirect assay based on xanthine/xanthine oxidase system) has been challenged [153]. Consequently, the use of a direct method, such as the pulse radiolysis, to determine SOD-like activity is more valuable than indirect assays [140].…”

Section: The Sod-like Activity Of Copper(ii) Bound To Prp C N-terminamentioning

confidence: 99%

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Prion Proteins Leading to Neurodegeneration

Mendola

Pietropaolo²,

Pappalardo³

et al. 2008

CAR

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Prion diseases are fatal neurodegenerative disorders related to the conformational alteration of the prion protein (PrP C ) into a pathogenic and protease-resistant isoform PrP Sc . PrP C is a cell surface glycoprotein expressed mainly in the central nervous system and despite numerous efforts to elucidate its physiological role, the exact biological function remains unknown. Many lines of evidences indicate that prion is a copper binding protein and thus involved in the copper metabolism. Prion protein is not expressed only in mammals but also in other species such as birds, reptiles and fishes. However, it is noteworthy to point out that prion diseases are only observed in mammals while they seem to be spared to other species. The chicken prion protein (chPrP C ) shares about 30% of identity in its primary sequence with mammal PrP C . Both types of proteins have an N-terminal domain endowed with tandem amino acid repeats (PHNPGY in the avian protein, PHGGGWQ in mammals), followed by a highly conserved hydrophobic core. Furthermore, NMR studies have highlighted a similar globular domain containing three α-helices, one short 3 10 -helix and a short antiparallel β-sheet. Despite this structural similarity, it should be noted that the normal isoform of mammalian PrP C is totally degraded by proteinase K, while avian PrP C is not, thereby producing N-terminal domain peptide fragments stable to further proteolysis. Notably, the hexarepeat domain is considered essential for protein endocytosis, and it is supposed to be the analogous copper-binding octarepeat region of mammalian prion proteins. The number of copper binding sites, the affinity and the coordination environment of metal ions are still matter of discussion for both mammal and avian proteins.In this review, we summarize the similarities and the differences between mammalian and avian prion proteins, as revealed by studies carried out on the entire protein and related peptide fragments, using a range of experimental and computational approaches. In addition, we report the metaldriven conformational alteration, copper binding modes and the superoxide dismutase-like (SODlike) activity of the related copper(II) complexes. necessary to obtain data on copper ions binding, complex species, affinity and coordination mode, in order to have valuable grounding to explain the so-called "metal paradox".As shown in the previous example of rat and human Aβ, a useful approach consists in making comparative studies on proteins and peptides of different organisms. This approach allows us also to obtain information on the possible biological role of the proteins. Currently another common aspect of several proteins or peptides involved in such diseases is that their biological function remains unknown.8 PrP C is a highly conserved protein in mammals, but genes encoding homologous prion proteins have been reported in different species such as avians/birds, turtles, amphibians and fish [53][54][55][56][57][58][59]. It is important to point out that prion diseases are ob...

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Section: Prion and Copper(ii) Coordination Features: Mammal Vs Aviansupporting

confidence: 65%

Section: Prion and Copper(ii) Coordination Features: Mammal Vs Avianmentioning

confidence: 59%

mentioning

confidence: 70%

mentioning

confidence: 73%

Section: The Sod-like Activity Of Copper(ii) Bound To Prp C N-terminamentioning

confidence: 99%

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Prion Proteins Leading to Neurodegeneration

Mendola

Pietropaolo²,

Pappalardo³

et al. 2008

CAR

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Copper, BDNF and Its N‐terminal Domain: Inorganic Features and Biological Perspectives

Travaglia

Mendola

Magrı̀

et al. 2012

Chemistry A European J

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Brain-derived neurotrophic factor (BDNF) is a neurotrophin that influences development, maintenance, survival, and synaptic plasticity of central and peripheral nervous systems. Altered BDNF signaling is involved in several neurodegenerative disorders including Alzheimer's disease. Metal ions may influence the BDNF activity and it is well known that the alteration of Cu(2+) homeostasis is a prominent factor in the development of neurological pathologies. The N-terminal domain of BDNF represents the recognition site of its specific receptor TrkB, and metal ions interaction with this protein domain may influence the protein/receptor interaction. In spite of this, no data inherent the interaction of BDNF with Cu(2+) ions has been reported up to now. Cu(2+) complexes of the peptide fragment BDNF(1-12) encompassing the sequence 1-12 of N-terminal domain of human BDNF protein were characterized by means of potentiometry, spectroscopic methods (UV/Vis, CD, EPR), parallel tempering simulations and DFT-geometry optimizations. Coordination features of the acetylated form, Ac-BDNF(1-12), were also characterized to understand the involvement of the terminal amino group. Whereas, an analogous peptide, BDNF(1-12)D3N, in which the aspartate residue was substituted by an asparagine, was synthesized to provide evidence on the possible role of carboxylate group in Cu(2+) coordination. The results demonstrated that the amino group is involved in metal binding and the metal coordination environment of the predominant complex species at physiological pH consisted of one amino group, two amide nitrogen atoms, and one carboxylate group. Noteworthy, a strong decrease of the proliferative activity of both BDNF(1-12) and the whole protein on a SHSY5Y neuroblastoma cell line was found after treatment in the presence of Cu(2+). The effect of metal addition is opposite to that observed for the analogous fragment of nerve growth factor (NGF) protein, highlighting the role of specific domains, and suggesting that Cu(2+) may drive different pathways for the BDNF and NGF in physiological as well as pathological conditions.

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Cross‐Talk Between the Octarepeat Domain and the Fifth Binding Site of Prion Protein Driven by the Interaction of Copper(II) with the N‐terminus

Natale

Turi

Pappalardo

et al. 2015

Chemistry A European J

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Prion diseases are a group of neurodegenerative diseases based on the conformational conversion of the normal form of the prion protein (PrP(C)) to the disease-related scrapie isoform (PrP(Sc)). Copper(II) coordination to PrP(C) has attracted considerable interest for almost 20 years, mainly due to the possibility that such an interaction would be an important event for the physiological function of PrP(C). In this work, we report the copper(II) coordination features of the peptide fragment Ac(PEG11)3PrP(60-114) [Ac = acetyl] as a model for the whole N-terminus of the PrP(C) metal-binding domain. We studied the complexation properties of the peptide by means of potentiometric, UV/Vis, circular dichroism and electrospray ionisation mass spectrometry techniques. The results revealed that the preferred histidyl binding sites largely depend on the pH and copper(II)/peptide ratio. Formation of macrochelate species occurs up to a 2:1 metal/peptide ratio in the physiological pH range and simultaneously involves the histidyl residues present both inside and outside the octarepeat domain. However, at increased copper(II)/peptide ratios amide-bound species form, especially within the octarepeat domain. On the contrary, at basic pH the amide-bound species predominate at any copper/peptide ratio and are formed preferably with the binding sites of His96 and His111, which is similar to the metal-binding-affinity order observed in our previous studies.

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Copper(II) complexes with an avian prion N-terminal region and their potential SOD-like activity

Cited by 27 publications

References 71 publications

Prion Proteins Leading to Neurodegeneration

Prion Proteins Leading to Neurodegeneration

Copper, BDNF and Its N‐terminal Domain: Inorganic Features and Biological Perspectives

Cross‐Talk Between the Octarepeat Domain and the Fifth Binding Site of Prion Protein Driven by the Interaction of Copper(II) with the N‐terminus

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