Metal binding behavior of the prion protein and relevance to disease progression

The prion protein (PrP) can bind Cu2+ in its flexible N-terminal region. Expressed primarily at neuronal synapses in the central nervous system, the function of PrP is likely related to its occurrence in the brain. This affinity for copper has been suggested to be related to PrP's neuroprotective role through sequestration of redox active copper. Many details about copper coordination by PrP have been previously determined in order to understand its function. This work shows several new details about copper and zinc binding in the prion protein. PrP can bind zinc with high affinity and can simultaneously coordinate both metals and this binding takes place within the octarepeat region. PrP has many disease causing mutations, including the octarepeat insertions which involve residues responsible for copper coordination. Here we show that additional octarepeats added to PrP can shift the copper coordination mode. This shift strongly correlates with a change in the disease progression and thus alteration of copper binding may change disease propensities. Although the copper coordination details of PrP within the octarepeat region have been extensively studied, an additional non-octarepeat binding site has not been fully characterized. This work displays that there are two similar sites that bind with roughly equal affinity located at residues His 96 and His 111. The combination of these three studies helps further the idea that PrP can bind to metals and that these affinities play a role in the overall function of PrP.