How copper ions and membrane environment influence the structure of the human and chicken tandem repeats domain?

Prion proteins (PrPs) from different species have the enormous ability to anchor copper ions. The N-terminal domain of human prion protein (hPrP) contains four tandem repeats of the -PHGGGWGQ- octapeptide sequence. This octarepeat domain can bind up to four Cu²⁺ ions. Similarly to hPrP, chicken prion protein (chPrP) is able to interact with Cu²⁺ through the tandem hexapeptide -HNPGYP- region (residues 53-94). In this work, we focused on the human octapeptide repeat (human Octa₄, hPrP_60-91) (Ac-PHGGGWGQPHGGGWGQPHGGGWGQPHGGGWGQ-NH₂) and chicken hexapeptide repeat (chicken Hexa₄, chPrP_54-77) (Ac-HNPGYPHNPGYPHNPGYPHNPGYP-NH₂) prion protein fragments. Due to the fact that PrP is a membrane-anchored glycoprotein and its unstructured and flexible N-terminal domain may interact with the lipid bilayer, our studies were carried out in presence of the surfactant sodium dodecyl sulfate (SDS) mimicking the membrane environment in vitro. The main objective of this work was to understand the effects of copper ion on the structural rearrangements of the human and chicken N-terminal repeat domain. The obtained results provide a fundamental first step in describing the thermodynamic (potentiometric titrations) and structural properties of Cu(II) binding (UV-Vis, NMR, CD spectroscopy) to both human Octa₄ and chicken Hexa₄ repeats in both a DMSO/water and SDS micelle environment. Interestingly, in SDS environment, both ligands indicate different copper coordination modes, which results of the conformational changes in micelle environment. Our results strongly support that copper binding mode strongly depends on the protein backbone structure. Moreover, we focused on previously obtained results for amyloidogenic human and chicken fragments in membrane mimicking environment.