Copper(II) complexes with chicken prion repeats: influence of proline and tyrosine residues on the coordination features

Mendola, Diego La; Bonomo, Raffaele P.; Impellizzeri, Giuseppe; Maccarrone, Giuseppe; Pappalardo, Giuseppe; Pietropaolo, Adriana; Rizzarelli, Enrico; Zito, Valeria

doi:10.1007/s00775-005-0659-z

Cited by 43 publications

(64 citation statements)

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“…Interestingly, it has recently been proposed that dipeptides of the avian hexa-repeat form more stable copper chelates than their mammalian octameric repeat analogs. This is attributed to the structural effects of four rather than two proline residues (57). Unlike the octa-repeats, the fifth-site histidines have no adjacent prolines that may stabilize the structure, leading to a higher binding affinity.…”

Section: Discussionmentioning

confidence: 99%

High Affinity Binding between Copper and Full-length Prion Protein Identified by Two Different Techniques

Thompsett

Abdelraheim

Daniels

et al. 2005

Journal of Biological Chemistry

113

134

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The cellular prion protein is known to be a copper-binding protein. Despite the wide range of studies on the copper binding of PrP, there have been no studies to determine the affinity of the protein on both full-length prion protein and under physiological conditions. We have used two techniques, isothermal titration calorimetry and competitive metal capture analysis, to determine the affinity of copper for wild type mouse PrP and a series of mutants. The cellular prion protein PrP c is a cell surface glycoprotein with large ␣-helical content that is attached to the plasma membrane by a glycosylphosphatidylinositol anchor. This cellular form of the protein binds copper, and it is argued that this copper binding to PrP c is intimately linked to the normal cellular function of the protein either in copper transport, sequestration, or antioxidant activity (1-3). The native cellular protein may undergo a conformational transformation to a proteaseresistant species known as a prion (PrP Sc ) with high ␤-sheet content and a tendency to aggregate. This transformed species is the putative proteinaceous infectious agent of transmissible spongiform encephalopathies or prion diseases (4). Prion diseases are characterized by a metal imbalance in the brain that occurs simultaneously to conversion of PrP c to PrPSc . The metal imbalance is associated with the loss of copper binding from PrP c on conversion to PrP Sc (5, 6). This raises important questions concerning the role of copper and other metals in prion diseases. Loss of protein function as a result of impaired copper binding in diseased PrPSc could have serious implications for disease progression.As a result, knowledge of copper binding to PrP is important in considering both the normal function of PrP c and its influence in prion diseases.Although it is accepted that PrP c is a Cu(II) binding protein, there are many facets of the interaction of Cu(II) and PrP c that are disputed. These include the exact number of binding sites and their relative affinity for Cu(II). Initial studies focused on a fragment of the protein termed the octameric repeat region because it contains four repeats of an octamer. This region contains histidine and so was a likely candidate for the binding site. These early studies (7, 8) suggested Cu(II) binds to this region with a micromolar affinity that was little more specific than histidine on its own. Further studies with larger fragments also suggested that Cu(II) binds PrP c , but again the affinity seen was similarly a low micromolar association (9). A study of the effect of PrP c expression on Cu(II) uptake into cells suggested that the affinity must at least be in the nanomolar range (1). Nanomolar affinities for the octameric repeat region have rarely been suggested (10). Only one publication has suggested that the affinity of Cu(II) for PrP is in the femtomolar range (11). Although such a high affinity implies that PrP is a very specific Cu(II)-binding protein, this finding has never been reproduced. Therefore, there is currently no...

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Section: Discussionmentioning

confidence: 99%

High Affinity Binding between Copper and Full-length Prion Protein Identified by Two Different Techniques

Thompsett

Abdelraheim

Daniels

et al. 2005

Journal of Biological Chemistry

113

134

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“…Moreover, an interesting dependence of the peptide shape on the tyrosine residue deprotonation was also detected; the deprotonation causes a shortening of the distance between the phenolate oxygen of tyrosine and the amide side chain hydrogens of asparagine thus tilting the glycine residue. This appears to be the driving force for the increase of unordered structures at basic pH explaining the relative blue shift in the CD spectra found in a previous study [87].…”

Section: The Avian Prion and Its Difference From Mammal Analoguementioning

confidence: 82%

“…Comparative analysis carried out on copper(II) complex species formed by different hexapeptide sequences PHNPGY, HNPGYP and NPGYPH, reveal a different behaviour with respect to an octarepeat sequence [87]. There is no formation of an analogous CuLH -2 species in which the 16 copper ion is involved in a 3N1O coordination environment.…”

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

confidence: 96%

“…shape on the tyrosine residue deprotonation was also detected; the deprotonation causes a shortening of the distance between the phenolate oxygen of tyrosine and the amide side chain hydrogens of asparagine thus tilting the glycine residue. This appears to be the driving force for the increase of unordered structures at basic pH explaining the relative blue shift in the CD spectra found in a previous study [87].The analysis of the more extended hexarepeat domain, (PHNPGY) 4 , from CD and molecular dynamics simulations [84], reveals a conformational dependence on the protonation states of histidine and tyrosine residues (Fig. (3)).…”

mentioning

confidence: 91%

“…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.…”

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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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Circular Dichroism ( CD ) Spectroscopy

Presta¹,

Stillman²

2005

Encyclopedia of Inorganic Chemistry

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Circular dichroism (CD) spectroscopy is of fundamental importance as a tool in all areas of chemistry and biochemistry because this technique is the simplest and fastest measure of the presence of the chiral species that lead to optical activity. Chiral centers and chiral species exist from the simplest molecules to complex organic molecules, from inorganic complexes to metal‐based biological molecules, typically metalloproteins; from folded polymers, which are typically peptides and proteins; to the supramolecular organization of the quaternary structure of proteins; including all forms of helical structure typified by the the double helix; to liquid crystals and beyond, to even more massive and organized species. For all these species, CD spectroscopy provides insight into the presence and the extent of the chiral electric field induced by the atomic and molecular organization. The optical activity is detected under electronic and vibrational absorption bands as a result of the differential absorption of left‐ and right‐circularly polarized light. Measurement of mirror images of the CD spectrum is commonly used to determine the enantiomeric purity of small molecules. The measurement of the change, and sometimes loss, of optical activity measured in the spectral region of the chiral chromophores can be used to determine and understand the denaturation of a folded protein as the chirality changes with the change in gross structural features associated with the folding. We focus particularly in this chapter on the influence of metals on the chiral properties of proteins. Metal binding results in changes in molecular and supramolecular conformations readily measured under metal‐based spectral bands. In cases for which the folding of the protein is almost entirely metal‐induced, the CD spectrum becomes an extremely sensitive marker for structural change as a function of metal loading allowing both the stoichiometry of metal binding and the coordination geometry to be proposed. Measurement of the chirality of a molecule is easy in the region 190–1000 nm as several relatively inexpensive instruments provide high sensitivity. Time‐resolved CD spectral data are also readily achievable using stopped‐flow devices. Measurement in the infrared regions is also popular and provides invaluable information; instruments can now be purchased “off the shelf”. The new growth area is the use of synchrotron radiation as the light source allowing CD spectral data to be measured in all regions of the electromagnetic spectrum, but particularly, for energies higher than 50 000 cm −1 (below 200 nm).

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Copper(II) complexes with chicken prion repeats: influence of proline and tyrosine residues on the coordination features

Cited by 43 publications

References 50 publications

High Affinity Binding between Copper and Full-length Prion Protein Identified by Two Different Techniques

High Affinity Binding between Copper and Full-length Prion Protein Identified by Two Different Techniques

Prion Proteins Leading to Neurodegeneration

Circular Dichroism ( CD ) Spectroscopy

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