Copper(II) Interaction with Unstructured Prion Domain Outside the Octarepeat Region:  Speciation, Stability, and Binding Details of Copper(II) Complexes with PrP106−126 Peptides

Natale, Giuseppe Di; Grasso, Giulia; Impellizzeri, Giuseppe; Mendola, Diego La; Micera, Giovanni; Mihala, Nikolett; Nagy, Zoltán; Ősz, Katalin; Pappalardo, Giuseppe; Rigó, Viktória; Rizzarelli, Enrico; Sanna, Daniele; Sóvágó, Imre

doi:10.1021/ic050754k

Cited by 97 publications

(149 citation statements)

References 64 publications

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“…The copper(II) coordination to chicken peptide induces the same conformational effects observed in human peptide. The metal ion drives a change from a random coil towards a structured bent conformation, an effect not observed on analogous scrambled peptide with a different primary sequence [135].…”

Section: Copper Binding Sites Outside the Repeat Regionmentioning

confidence: 83%

“…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%

“…The only remarkable difference is due to a slight contribution of Met sulphur atom for the species 3N1O in which copper is bound to histidine imidazole and two amides of His and Lys residues [135]. The copper(II) coordination to chicken peptide induces the same conformational effects observed in human peptide.…”

Section: Copper Binding Sites Outside the Repeat Regionmentioning

confidence: 96%

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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: Copper Binding Sites Outside the Repeat Regionmentioning

confidence: 83%

mentioning

confidence: 73%

Section: Copper Binding Sites Outside the Repeat Regionmentioning

confidence: 96%

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Prion Proteins Leading to Neurodegeneration

Mendola

Pietropaolo²,

Pappalardo³

et al. 2008

CAR

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“…Even the overall stability constants of the protonated species from [HL] + to [H 7 L] 7 + show high similarity between the values, but this is especially clear from the stepwise pK values. From the previous studies on small peptide fragments [29,34] it is evident that the high pK values (in the range from 9.26 to 10.68) can be assigned to the deprotonation of the lysyl ammonium groups. The average values for these deprotonation reactions are between 10.05 and 10.09, and this range is comparable to the error in the data.…”

Section: Resultsmentioning

confidence: 99%

“…[33] Most recent publications from our laboratories have contributed towards a better understanding of the metal-binding ability of histidyl residues outside the octarepeat domain. [29,34,35] Copper(II) complexes of tetra-, penta-and nonapeptide fragments of HuPrP including His96, His111 and His187 residues have been studied by the combined applications of potentiometric and the most common spectroscopic techniques, including UV/Vis, CD, EPR, and NMR spectroscopy. Histidyl imidazole N-donor atoms were found to be the primary Cu 2 + binding sites in all peptides, and the preference for the formation of 3N-and 4N-complexes that contain an additional two or three deprotonated amide functions was suggested around the physiological pH range.…”

Section: A C H T U N G T R E N N U N G (84-114) His96ala Huprpa C H mentioning

confidence: 99%

Copper(II) Interaction with Prion Peptide Fragments Encompassing Histidine Residues Within and Outside the Octarepeat Domain: Speciation, Stability Constants and Binding Details

Ősz

Nagy

Pappalardo

et al. 2007

Chemistry A European J

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A 31-mer polypeptide, which encompasses residues 84-114 of human prion protein HuPrP(84-114) and contains three histidyl residues, namely one from the octarepeat (His85) and two histidyl residues from outside the octarepeat region (His96 and His111), and its mutants with two histidyl residues HuPrP(84-114)His85Ala, HuPrP(84-114) His96Ala, HuPrP(84-114)His111Ala and HuPrP(91-115) have been synthesised and their Cu2+ complexes studied by potentiometric and spectroscopic (UV/Vis, CD, EPR, ESI-MS) techniques. The results revealed a high Cu2+-binding affinity of all peptides, and the spectroscopic studies made it possible to clarify the coordination mode of the peptides in the different complex species. The imidazole nitrogen donor atoms of histidyl residues are the exclusive metal-binding sites below pH 5.5, and they have a preference for macrochelate structure formation. The deprotonation and metal-ion coordination of amide functions take place by increasing the pH; all of the histidines can be considered to be independent metal-binding sites in these species. As a consequence, di- and trinuclear complexes can be present even in equimolar samples of the metal ion and peptides, but the ratios of polynuclear species do not exceed the statistically expected ones; this excludes the possibility of cooperative Cu2+ binding. The species with a (N(im),N,N)-binding mode are favoured around pH 7, and their stability is enhanced by the macrochelation from another histidyl residue in the mononuclear complexes. The independence of the histidyl sites results in the existence of coordination isomers and the preference for metal binding follows the order of: His111>His96>His85. Deprotonation and metal-ion coordination of the third amide functions were detected in slightly alkaline solutions at each of the metal-binding sites; all had a (N(im),N,N,N)-coordination mode. Spectroscopic measurements also made it clear that the four lysyl amino groups of the peptides are not metal-binding sites in any cases.

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Environmental Effects on a Prion's Helix II Domain: Copper(II) and Membrane Interactions with PrP180–193 and Its Analogues

Grasso

Guantieri

et al. 2005

Chemistry A European J

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An abnormal interaction between copper and the prion protein is believed to play a pivotal role in the pathogenesis of prion diseases. Copper binding has been mainly attributed to the N-terminal domain of the prion protein, but this hypothesis has recently been challenged in some papers which suggest that the C-terminal domain might also compete for metal anchoring. In particular, the segment corresponding to the helix II region of the prion protein, namely PrP180-193, has been shown both to bind copper and to exhibit a copper-enhanced cytotoxicity, as well as to interact with artificial membranes. The present work is aimed at extending these results by choosing the most representative model of this domain and by determining its copper affinity. With this aim, the different role played by the electrostatic properties of the C- and N-termini of PrP180-193 (VNITIKQHTVTTTT) in determining its conformational behaviour, copper coordination and ability to perturb model membranes was investigated. Owing to the low solubility of PrP180-193, its copper affinity was evaluated by using the shorter PrPAc184-188NH2 (IKQHT) analogue as a model. ESI-MS, ESR, UV/Vis, and CD measurements were carried out on the copper(II)/PrPAc184-188NH2 and copper(II)/PrP180-193NH2 systems, and showed that PrPAc184-188NH2 is a reliable model for the metal interaction with the helix II domain. The affinity of copper(II) for the helix II fragment is higher than that for the octarepeat and PrP106-126 peptides. Finally, the different ability of PrP180-193 analogues to perturb the DPPC model membrane was assessed by DSC measurements. The possible biological consequences of these findings are also discussed briefly.

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Copper(II) Interaction with Unstructured Prion Domain Outside the Octarepeat Region: Speciation, Stability, and Binding Details of Copper(II) Complexes with PrP106−126 Peptides

Cited by 97 publications

References 64 publications

Prion Proteins Leading to Neurodegeneration

Prion Proteins Leading to Neurodegeneration

Copper(II) Interaction with Prion Peptide Fragments Encompassing Histidine Residues Within and Outside the Octarepeat Domain: Speciation, Stability Constants and Binding Details

Environmental Effects on a Prion's Helix II Domain: Copper(II) and Membrane Interactions with PrP180–193 and Its Analogues

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