A New Paradigm for Enzymatic Control of α-Cleavage and β-Cleavage of the Prion Protein

McDonald, Alex J.; Dibble, Jessie P.; Evans, Eric G. B.; Millhauser, Glenn L.

doi:10.1074/jbc.m113.502351

Cited by 100 publications

(106 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our limited proteolysis experiments indicate that copper(II) binds to the N-terminal His residues of PrP within and outside the octarepeat domain at low metal/ligand ratios. Analogous results [115] have also been reported in a recent investigation, which shows that a member of the ADAM (a disintegrin and metallo proteinase) enzyme family, namely ADAM8, is able to cleave MoPrP C in a Cu 2+ dependent manner. Copper(II) coordination to His residues of the tetraoctarepeat domain and His110 has been found to suppress the cleavage of histidine peptide bonds.…”

Section: Resultssupporting

confidence: 79%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 79%

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

View full text Add to dashboard Cite

show abstract

“…These results provide useful clues to understand the earlier onset of D178N-associated FFI diseases. It has been reported that reactive oxygen species (ROS) might mediate β-cleavage of PrP [16,[61][62][63], but there was no notable β-cleavage observed in our study. In the β-cleavage experiments studied in these reports, PrP samples were treated with H 2 O 2 and copper or other metal ion together, the generation of ROS is promoted by the presence of copper and iron through the Fenton reaction [61,64].…”

Section: Discussioncontrasting

confidence: 80%

Methionine oxidation accelerates the aggregation and enhances the neurotoxicity of the D178N variant of the human prion protein

Feng

Wang

Liu

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

The D178N mutation of the prion protein (PrP) results in the hereditary prion disease fatal familial insomnia (FFI). Little is known regarding the effects of methionine oxidation on the pathogenesis of D178N-associated FFI. In the present study, we found that the D178N variant was more susceptible to oxidation than wild-type PrP, as indicated by reverse-phase high performance liquid chromatography (RP-HPLC) and mass spectrometry (MS) analysis. Circular dichroism (CD), differential scanning calorimetry (DSC), thioflavin T (ThT) binding assay studies demonstrated that methionine oxidation decreased the structural stability of the D178N variant, and the oxidized D178N variant exhibited a greater propensity to form β-sheet-rich oligomers and aggregates. Moreover, these aggregates of oxidized D178N PrP were more resistant to proteinase K (PK) digestion. Additionally, using fluorescence confocal microscopy, we detected a high degree of aggregation in D178N-transfected Neuro-2a (N2a) cells after treatment with hydrogen peroxide (H2O2). Furthermore, the oxidation and consequent aggregation of the D178N variant induced greater apoptosis of N2a cells, as monitored using flow cytometry. Collectively, these observations suggest that methionine oxidation accelerates the aggregation and enhances the neurotoxicity of the D178N variant, possibly providing direct evidence to link the pathogenesis of D178N-associated FFI with methionine oxidation.

show abstract

“…108 and 109) and a recent study suggests a more complex scenario than initially expected, involving different members of the ADAM family of metalloproteases. 110 In contrast, the role of ADAM10 as the major PrP C sheddase has been established by recent studies. 95,96,107,111 While knowledge on the concrete localization of the two cleavage events is limited 54,111-113 both processing steps seem to depend on PrP C membrane attachment.…”

Section: Anchorage and Localization Of Prp C May Influence Its Proteomentioning

confidence: 99%

The GPI-anchoring of PrP

Puig

Altmeppen

Glatzel

2014

Prion

View full text Add to dashboard Cite

A New Paradigm for Enzymatic Control of α-Cleavage and β-Cleavage of the Prion Protein

Cited by 100 publications

References 42 publications

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

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

Methionine oxidation accelerates the aggregation and enhances the neurotoxicity of the D178N variant of the human prion protein

The GPI-anchoring of PrP

Contact Info

Product

Resources

About