PROPOSED 3-DIMENSIONAL STRUCTURE FOR THE CELLULAR PRIOR PROTEIN

Prion diseases are a group of neurodegenerative disorders in humans an d animals that seem to result from a conformational change in the prio n protein (PrP). Utilizing data obtained by circular dichroism and inf rared spectroscopy, computational studies predicted the three-dimensio nal structure of the cellular form of PrP (PrPc). A heuristic approach consisting of the prediction of secondary structures and of an evalua tion of the packing of secondary elements was used to search for plaus ible tertiary structures. After a series of experimental and theoretic al constraints were applied, four structural models of four-helix bund les emerged. A group of amino acids within the four predicted helices were identified as important for tertiary interactions between helices . These amino acids could be essential for maintaining a stable tertia ry structure of PrPc. Among four plausible structural models for PrPc, the X-bundle model seemed to correlate best with 5 of 11 known point mutations that segregate with the inherited prion diseases. These 5 mu tations cluster around a central hydrophobic core in the X-bundle stru cture. Furthermore, these mutations occur at or near those amino acids which are predicted to be important for helix-helix interactions. The three dimensional structure of PrPc proposed here may not only provid e a basis for rationalizing mutations of the PrP gene in the inherited prion diseases but also guide design of genetically engineered PrP mo lecules for further experimental studies.