The coordination pattern in the Cu2+-PrP fragments are relatively well understood, although several questions still remain including the basic problem of a cooperative effect in metal ion binding. It is also not clear whether PrP really needs to be completely loaded with copper ions to be biologically relevant. In all cases the His residue is an anchor and a basic binding site for the Cu2+ ion and several His can be involved in the coordination of one copper ion but the relations between the specific binding site and its biological implications are still not understood.
The other basic chemical question, still open, concerns the SOD-like activity of the Cu2+-PrP system and a clear answer is needed to the question: Which binding site and species are relevant for the redox activity of prion bound copper?
The role of His residues is also critical for the binding ability of Cu2+ to other proteins like APP fragments, including the Ap peptide. The formed complexes are thermodynamically not very potent and there is the very biological question to be answered. How do Cu2+ ions and particular proteins meet in the natural milieu?
The binding of metal ions has a critical impact on protein conformation and it is likely that metal ions induce in the protein structure (e.g., p-structure) the ability to aggregate. This problem still needs more data to make clear relations between metal ion binding and neurological disorders.
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