Using NMR spectroscopy to investigate the role played by copper in prion diseases

Abstract

Prion diseases are a group of rare neurodegenerative disorders that develop as a result of the conformational conversion of normal prion protein (PrP C) to the disease-associated isoform (PrP Sc). The mechanism that actually causes disease remains unclear. However, the mechanism underlying the conformational transformation of prion protein is partially understood-in particular, there is strong evidence that copper ions play a significant functional role in prion proteins and in their conformational conversion. Various models of the interaction of copper ions with prion proteins have been proposed for the Cu (II)-binding, cell-surface glycoprotein known as prion protein (PrP). Changes in the concentration of copper ions in the brain have been associated with prion diseases and there is strong evidence that copper plays a significant functional role in the conformational conversion of PrP. Nevertheless, because copper ions have been shown to have both a positive and negative effect on prion disease onset, the role played by Cu (II) ions in these diseases remains a topic of debate. Because of the unique properties of paramagnetic Cu (II) ions in the magnetic field, their interactions with PrP can be tracked even at single atom resolution using nuclear magnetic resonance (NMR) spectroscopy. Various NMR approaches have been utilized to study the kinetic, thermodynamic, and structural properties of Cu (II)-PrP interactions. Here, we highlight the different models of copper interactions with PrP with particular focus on studies that use NMR spectroscopy to investigate the role played by copper ions in prion diseases.

Liquid–liquid phase separation of full-length prion protein initiates conformational conversion in vitro

“…It has been shown that this aggregation process is triggered by binding between PrP and Cu 2+ ( 44 ). Because Cu 2+ binds to the N-terminal region in histidine residues, Cu 2+ affects its flexibility and initiates conformational changes ( 45 , 46 ). Therefore, our result that rPrP was unable to undergo LLPS in the presence of Cu 2+ can be explained by the loss of flexibility of the N-terminal region due to Cu 2+ and rPrP binding.…”

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

“…Binding of copper (Cu(II), Cu 2+ ) to PrP C facilitates redox balance and copper homeostasis [ 289 ] both of which are often disturbed in the TME where cancer drug resistance is associated with higher serum copper levels in patients compared to healthy controls or patients who responded to chemotherapy [ 290 , 291 ]. Copper also changes the conformation of the N-terminal domain [ 292 , 293 , 294 , 295 ], which may impede LLPS [ 121 , 296 ] or even prevent the formation of straight β-strands backbone structures in the infectious PrP Sc form when bound to the non-octarepeat peptides (residues 92–96) [ 297 , 298 ]. However, the Cu 2+ inhibition of amyloid formation is dependent upon binding capacity that becomes less effective at a lower pH [ 93 , 299 ], which is characteristic of most TMEs.…”

“What Doesn’t Kill You Makes You Stronger”: Future Applications of Amyloid Aggregates in Biomedicine

“…Metal ions may regulate the toxicity related to amyloidal oligomers by modulating the aggregation kinetics and oligomer conformation. Moreover, metals can also direct the aggregation towards more toxic species, and generate reactive oxygen species [ 15 , 80 ].…”

“…Around approximately 50 peptides and proteins are known to form amyloid fibrils in humans and are associated with diseases [ 5 , 6 , 7 ]. These include α-synuclein (α-Syn) in Parkinson’s disease (PD) [ 8 , 9 , 10 ], amyloid beta (Aβ) and Tau in Alzheimer’s disease (AD) [ 11 , 12 , 13 ], prion protein (PrP) in prion disease [ 14 ], and islet amyloid peptide (IAPP), also known as amylin, in type 2 diabetes mellitus (T2DM) [ 15 , 16 , 17 , 18 , 19 ].…”