The Octapeptide Repeat Region of Prion Protein Binds Cu(II) in the Redox-Inactive State

Shiraishi, Noriyuki; Ohta, Yuriko; Nishikimi, Morimitsu

doi:10.1006/bbrc.1999.1944

Cited by 41 publications

(33 citation statements)

References 24 publications

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“…21 It is also suggested that PrP C plays a protective role by binding Cu 2+ in a redox inactive state. 23, 24 An enzymatic role for CuPrP has also been proposed as it exhibits superoxide dismutase activity. from diseased brain is found to be metal occupied 31 and copper content at a cellular level is modulated by scrapie infection.…”

Section: 16mentioning

confidence: 99%

A survey of diamagnetic probes for copper²⁺binding to the prion protein.¹H NMR solution structure of the palladium²⁺bound single octarepeat

2006

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The prion protein (PrP C ) is a copper binding cell surface glycoprotein which when misfolded causes transmissible spongiform encephalopathies. The cooperative binding of Cu 2+ to an unstructured octarepeat sequence within PrP C causes profound folding of this region. The use of NMR to determine the solution structure of the octarepeat region of PrP with Cu 2+ bound has been hampered by the paramagnetic nature of the Cu 2+ ions. Using NMR we have investigated the binding of candidate diamagnetic replacement ions, to the octarepeat region of PrP. We show that Pd 2+ forms diamagnetic complexes with the peptides HGGG, HGGGW and QPHGGGWGQ with 1 : 1 stoichiometry. The 1 H NMR spectra indicate that these peptides are in slow-exchange between free and bound Pd 2+ on the chemical-shift time-scale. We demonstrate that the Pd-peptide complex forms slowly with a time taken to reach half-maximal signal of 3 hours. Other candidate metal ions, Ni 2+ , Pt 2+ and Au 3+ , were investigated but only the Pd 2+ complexes gave resolvable 1 H NMR spectra. We have determined the solution structure of the QPHGGGWGQ-Pd 1 : 1 complex using 71 NOE distance restraints. A backbone RMSD of 0.30 Å was observed over residues 3 to 7 in the final ensemble. The co-ordinating ligands consist of the histidine imidazole side chain Ne, the amide N of the second and third glycines with possibly H 2 O as the fourth ligand. The co-ordination geometry differs markedly from that of the HGGGW-Cu crystal structure. This survey of potential replacement metal ions to Cu 2+ provides insight into the metal specificity and co-ordination chemistry of the metal bound octarepeats.

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Section: 16mentioning

confidence: 99%

A survey of diamagnetic probes for copper²⁺binding to the prion protein.¹H NMR solution structure of the palladium²⁺bound single octarepeat

2006

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“…Functionally, Cu(II) binding to the octarepeats induces PrP C endocytosis in neuronal cells, indicating a role for PrP C in Cu(II) sensing, uptake and/or transport (26). Superoxide dismutase (SOD)-like activities have also been reported for the Cu(II)-bound PrP C , suggesting a neuronal function of PrP C as an anti-oxidant (27)(28)(29), although that is still a subject of debate (30). Treatment of scrapie-infected mice with Cu(II) chelator D-(Ϫ)-penicillamine (D-PEN) delays the onset of prion disease in mice (31).…”

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Probing the Role of PrP Repeats in Conformational Conversion and Amyloid Assembly of Chimeric Yeast Prions

Dong

Bloom

Goncharov

et al. 2007

Journal of Biological Chemistry

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“…An enzymatic role for Cu-PrP is also proposed as it exhibits superoxide dismutase activity (20 -22). It is also suggested that PrP has a protective role binding Cu 2ϩ in a redox-inactive state (23)(24)(25). Mice deficient in cellular PrP show a reduction in copper concentration in the brain relative to wild type mice and a reduction in activity of copper/zinc superoxide dismutase (4), although this observation is contested (26).…”

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confidence: 99%

Copper Binding to the Octarepeats of the Prion Protein

Garnett

Viles

2003

Journal of Biological Chemistry

194

134

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The prion protein (PrP) is a Cu 2؉ binding cell surface glycoprotein. There is increasing evidence that PrP functions as a copper transporter. In addition, strains of prion disease have been linked with copper binding. We present here CD spectroscopic studies of Cu 2؉ binding to various fragments of the octarepeat region of the prion protein. We show that glycine and L-histidine will successfully compete for all Cu 2؉ ions bound to the PrP octapeptide region, suggesting Cu 2؉ coordinates with a lower affinity for PrP than the fM dissociation constant reported previously. We show that each of the octarepeats do not form an isolated Cu 2؉ binding motif but fold up cooperatively within multiple repeats. In addition to the coordinating histidine side chain residues, we show that the glycine residues and the proline within each octarepeat are also necessary to maintain the coordination geometry. The highly conserved octarepeat region in mammals is a hexarepeat in birds that also binds copper but with different coordination geometry. Finally, in contrast to other reports, we show that Mn 2؉ does not bind to the octarepeat region of PrP.

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The Octapeptide Repeat Region of Prion Protein Binds Cu(II) in the Redox-Inactive State

Cited by 41 publications

References 24 publications

A survey of diamagnetic probes for copper²⁺binding to the prion protein.¹H NMR solution structure of the palladium²⁺bound single octarepeat

A survey of diamagnetic probes for copper²⁺binding to the prion protein.¹H NMR solution structure of the palladium²⁺bound single octarepeat

Probing the Role of PrP Repeats in Conformational Conversion and Amyloid Assembly of Chimeric Yeast Prions

Copper Binding to the Octarepeats of the Prion Protein

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The Octapeptide Repeat Region of Prion Protein Binds Cu(II) in the Redox-Inactive State

Cited by 41 publications

References 24 publications

A survey of diamagnetic probes for copper2+binding to the prion protein.1H NMR solution structure of the palladium2+bound single octarepeat

A survey of diamagnetic probes for copper2+binding to the prion protein.1H NMR solution structure of the palladium2+bound single octarepeat

Probing the Role of PrP Repeats in Conformational Conversion and Amyloid Assembly of Chimeric Yeast Prions

Copper Binding to the Octarepeats of the Prion Protein

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A survey of diamagnetic probes for copper²⁺binding to the prion protein.¹H NMR solution structure of the palladium²⁺bound single octarepeat

A survey of diamagnetic probes for copper²⁺binding to the prion protein.¹H NMR solution structure of the palladium²⁺bound single octarepeat