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Prion Proteins
 
  Prion diseases are fatal neurodegenerative conditions. Probably the most famous at the moment is bovine spongiform encephalopathy (BSE) or "mad cow" disease, with substantial evidence that bovine prions from infected cows have been transmitted to humans, manifesting a new variant of Creutzfeldt-Jakob disease. Much data indicate that a protein commonly found in neuronal cells, the prion protein PrP, undergoes a structural change from its common cellular form (PrP-C) to an abnormal form (PrP-Sc) that may be responsible for the propagation of fatal neurodegenerative diseases. Indeed, it appears that PrP-Sc induces PrP-C molecules to convert. A few years ago, we used NMR to determine the structure of a 142-residue recombinant protein (residues 90-231 from the full-length 23-231 sequence of PrP) corresponding to the normal cellular form of the protein. This work was carried out in collaboration with Prof. Stan Prusiner's lab. Structure stability and dynamics are almost certainly essential for transformation of the normal cellular to infectious forms of the prion protein. More recent work has entailed using high-pressure as a means of unfolding the protein. Pressure directly and efficiently perturbs the conformational equilibrium of proteins in solution, increasing the population of rare conformers with respect to that of the abundant conformer under closely physiological solution conditions. NMR spectra were obtained as a function of pressure from 30 to 2500 bar. This enabled identification a partially folded conformer, estimated to be present at about 1% abundance, that may be related to PrP*, which binds to PrP-Sc in the transformation of PrP-C to PrP-Sc.