This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prion diseases are fatal neurodegenerative diseases of mammals and include Creutzfeld-Jacob disease (humans), scrapie (sheep), chronic wasting disease (elk, deer), and mad cow disease (cattle). These illnesses are characterized by the accumulation of misfolded prion protein (PrP), in the central nervous system. It is well known that the normal form of PrP (alpha-PrP) binds copper(II) at several sites within the N-terminal domain. Although the details of metal coordination and relative affinities for copper at these sites are not completely understood, a consensus view is emerging that alpha-PrP is able to bind up ~5 mononuclear copper(II) ions. In contrast, little is known about the copper environments in misfolded PrP, despite the indications that copper plays a role in this and other amyloid diseases. The PI s expertise in metallo-enzymes provides a unique perspective to elucidate the details of copper binding in misfolded /infectious PrP, and its effect on the conversion of normal protein to the diseased state. This information will help unravel the mechanism of prion propagation and infectivity. Dr. McGuirl's lab is investigating metal ion binding to various isoforms of recombinant PrP using biophysical techniques, including fluorescence and electron paramagnetic resonance (EPR) spectroscopies, isothermal titration calorimetry (ITC), and inductively coupled plasma-mass spectrometry (ICP-MS). In contrast with some published reports, we see no evidence for a high affinity copper(II) binding site within the C-terminal half of alpha-PrP. Studies of the other isoforms, including infectious PrP, are ongoing.
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