Coordination features of prion protein domains

Many systemic and neurodegenerative disorders, collectively termed as “protein conformational diseases” are characterized by the accumulation of intracellular or extracellular protein aggregates. Abnormal metal-protein interactions have now been implicated in some of these degenerative disorders including Alzheimer’s disease, cataracts, Parkinson’s, Creutzfeldt-Jakob disease, etc.). Prion diseases provide a typical example in which the conversion of the normal folded α-helical PrPC isoform into a β-sheet rich conformation PrPSc, results in neurodegeneration. The physiological function of PrPC has not yet been identified, even though it is emerging that this highly conserved protein is important for a healthy brain. Increasing evidence indicates that PrPc is a copper-binding protein, and its localisation at pre and postsynaptic levels suggests an involvement in copper uptake and transmembrane signalling. Copper(II)-PrPC studies can be problematic due to the formation of PrPc insoluble species, therefore different protein fragments have been used to determine the metalprotein stoichiometry, the copper(II) affinity of different regions, the binding sites and the coordination features of the resulting metal complexes. Conflicting results have been reported, probably due to an oversimplification of metal complex speciation. A combined thermodynamic and spectroscopic approach has been recently used to characterize the coordination features of different prion domains. The results questioned the role of octarepeats present in the unstructured N-terminus region as the main binding site for copper(II), rather suggesting preferential metal coordination outside of the octarepeat region. Furthermore, comparative analysis of the human and chicken PrP copper(II) binding sites may provide new insights into the prion protein structure-function relationship and the conversion process of PrP.