Zinc modulates copper coordination mode in prion protein octa-repeat subdomains

Stellato, Francesco; Spevacek, Ann R.; Proux, Olivier; Minicozzi, Velia; Millhauser, Glenn L.; Morante, Silvia

doi:10.1007/s00249-011-0713-4

Cited by 36 publications

(41 citation statements)

References 33 publications

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“…By performing a systematic XAS study of a set of samples in which Cu(II) at increasing concentrations was added to tetra-octarepeat–Zn(II) complexes, we showed that the metal–peptide coordination mode depends not only, as expected, on the relative concentrations of the metals but, by comparison with the old XAS measurement of Stellato et al (2011), that the order in which the two metal ions are added to metal–tetra-octarepeat complexes is also important. Indeed, not only is Zn(II) unable to completely remove octarepeat-bound Cu(II) ions (as was already made clear by Stellato et al 2011) but, as we prove here, the opposite is also true, i.e. Cu(II) modifies the mode of Zn(II) coordination by partly displacing it, but fails to completely remove octarepeat-bound Zn(II) ions.…”

Section: Introductionmentioning

confidence: 55%

“…A parallel X-ray absorption spectroscopy (XAS) study (Stellato et al 2011) confirmed the ability of Zn(II) to modulate Cu(II) coordination, adding the important information that a single tetra-octarepeat domain can bind Cu(II) and Zn(II) ions simultaneously. Analysis of the XAS data also showed that Zn(II) competes with Cu(II) for His-binding by directly interacting with the tetra-octarepeat region, but it is unable to completely displace Cu(II).…”

Section: Introductionmentioning

confidence: 93%

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Copper–zinc cross-modulation in prion protein binding

et al. 2014

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In this paper we report a systematic XAS study of a set of samples in which Cu(II) was progressively added to complexes in which Zn(II) was bound to the tetra-octarepeat portion of the prion protein. This work extends previous EPR and XAS analysis in which, in contrast, the effect of adding Zn(II) to Cu(II)–tetra-octarepeat complexes was investigated. Detailed structural analysis of the XAS spectra taken at both the Cu and Zn K-edge when the two metals are present at different relative concentrations revealed that Zn(II) and Cu(II) ions compete for binding to the tetra-octarepeat peptide by cross-regulating their relative binding modes. We show that the specific metal–peptide coordination mode depends not only, as expected, on the relative metal concentrations, but also on whether Zn(II) or Cu(II) was first bound to the peptide. In particular, it seems that the Zn(II) binding mode in the absence of Cu(II) is able to promote the formation of small peptide clusters in which triplets of tetra-octarepeats are bridged by pairs of Zn ions. When Cu(II) is added, it starts competing with Zn(II) for binding, disrupting the existing peptide cluster arrangement, despite the fact that Cu(II) is unable to completely displace Zn(II). These results may have a bearing on our understanding of peptide-aggregation processes and, with the delicate cross-regulation balancing we have revealed, seem to suggest the existence of an interesting, finely tuned interplay among metal ions affecting protein binding, capable of providing a mechanism for regulation of metal concentration in cells.

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Section: Introductionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 93%

Copper–zinc cross-modulation in prion protein binding

et al. 2014

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“…A reduced Zn content in brains with prion disease has been revealed, 20,113 and a few other studies suggest that Zn binds to the octapeptide repeats in PrP C , albeit at an apparently lower affinity. [154][155][156] Evidence also exists that the interaction promotes the endocytosis of PrP c . 157,158 Although Spevacek et al showed that Zn binding changes the structure of murine PrP c , 159 the structural and functional consequences of Zn-prion interaction are still largely unknown.…”

Section: Role Of Other Metals In Prion Diseasementioning

confidence: 93%

Manganese and Prion Disease

Jin¹,

Harischandra²,

Choi³

et al. 2014

Manganese in Health and Disease

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Prion diseases are a class of fatal neurodegenerative diseases caused by misfolding of the endogenous prion protein (PrPC) induced by exposure to the pathogenic conformational isomer of PrP (PrPSc) or by heritable mutation of PrPC. Although the exact role of the protein has yet to be determined, considerable evidence reveals prion protein to be a metalloprotein harboring divalent metal-binding sites for various cations such as copper, manganese, zinc, and nickel. Despite low-affinity binding to prion protein, when manganese interacts with prion, it can alter the development and transmission of prion disease. In this chapter, the role of metals in the pathogenesis of prion disease will be discussed. Particular emphasis will be placed on the link between manganese and PrPC.

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“…The concentration of Zn in the brain is much higher compared to Cu; therefore, Zn 2+ may influence PrP C binding to Cu [34]. Bioinformatics analysis has revealed evolutionary similarities between prion genes and gene-encoding ZIP transporters [35,36].…”

Section: Zn and Normal Prion Proteinmentioning

confidence: 99%

Disruption of Metal Homeostasis and the Pathogenesis of Prion Diseases

Kawahara¹,

Tanaka²,

Mizuno³

2017

Prion - An Overview

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Prion diseases are progressive neurodegenerative diseases that are associated with the conformational conversion of normal cellular prion protein (PrP C ) into abnormal pathogenic prion protein (PrP Sc ). PrP C is a metal-binding protein that is located in the synapse and possesses the ability to bind to various metals, including Cu, Zn, Mn and Fe. Moreover, increasing evidence suggests that PrP C plays essential roles in the maintenance of metal homeostasis in the synapse. Trace elements have a crucial influence on the conformational change of PrP C . Given that other disease-related proteins such as β-amyloid protein and its precursor protein (APP) in Alzheimer's disease also exist in the synapse and possess a metal-binding ability, an interaction between PrP and metals and between PrP and APP, may occur in the synapse; the resulting metal homeostasis may lead to the pathogenesis of prion diseases. Here, we review our studies and other new findings that inform the current understanding of the link between trace elements and physiological functions of PrP C and the neurotoxicity of PrP Sc .

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Zinc modulates copper coordination mode in prion protein octa-repeat subdomains

Cited by 36 publications

References 33 publications

Copper–zinc cross-modulation in prion protein binding

Copper–zinc cross-modulation in prion protein binding

Manganese and Prion Disease

Disruption of Metal Homeostasis and the Pathogenesis of Prion Diseases

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