The effect of a membrane-mimicking environment on the interactions of Cu²⁺with an amyloidogenic fragment of chicken prion protein

Abstract

Prion proteins (PrP) from different species have the ability to tightly bind Cu ions. Copper coordination sites are located in the disordered and flexible N-terminal region which contains several His anchoring sites. Among them, two His residues are found in the so called amyloidogenic PrP region which is believed to play a key role in the process leading to oligomer and fibril formation. Both chicken and human amyloidogenic regions have a hydrophobic C-terminal region rich in Ala and Val amino acids. Recent findings revealed that this domain undergoes random coil to α-helix structuring upon interaction with membrane models. This interaction might strongly impact metal binding abilities either in terms of donor sets or affinity. In this study we investigated Cu interaction with an amyloidogenic fragment, chPrP105-140, derived from chicken prion protein (chPrP), in different solution environments. The behavior of the peptide and its metal complexes was analyzed in water and in the presence of negative and positive charged membrane mimicking environments formed by sodium dodecyl sulfate (SDS) and dodecyl trimethyl ammonium chloride (DTAC) micelles. The metal coordination sphere, the metal binding affinity and stoichiometry were evaluated by combining spectroscopic and potentiometric methods. Finally we compare copper(ii) interactions with human and chicken amyloidogenic fragments. Our results indicate that the chicken amyloidogenic fragment is a stronger copper ligand than the human amyloidogenic fragment.

Impact of sphingosine and acetylsphingosines on the aggregation and toxicity of metal-free and metal-treated amyloid-β

“…These distinct behaviors of the compounds against metal-Ab at the concentrations above their CACs were also supported by the previous studies displaying that ionic micelles can induce structural changes of peptides and proteins in a manner affecting their Cu(II)-binding properties. [65][66][67] Taken together, as Please do not adjust margins Please do not adjust margins expected from the compounds' metal-binding affinities, the spectroscopic studies manifest that SP potentially sequesters the metal ion from metal-Ab.…”

Structural Consequences of Copper Binding to the Prion Protein

“…While three histidines are involved in binding for the human OR, the binding involves four histidines for the chicken OR, suggesting that the aromatic ring of tyrosine residues present in the chicken OR sequence may stabilize copper anchoring site [137]. Interestingly, both human and chicken OR regions were found to bind copper ions more efficiently than the corresponding amyloidogenic fragments, probably due to the presence of four histidines compared to the two histidines in the amyloidogenic sequence [138].…”

Thermodynamic surprises of Cu(II)–amylin analogue complexes in membrane mimicking solutions

“…The presence of biological membranes is known to affect the binding mode of copper(II) ions, both in terms of the type of donor atoms and affinity. Among amyloid proteins, such as human prion protein (hPrP) 45 or chicken prion protein (chPrP) 46 , a change in secondary structure from random coil to α-helix is observed. The conformational change affects the interaction with copper(II) ions.…”