Proposed three-dimensional structure for the cellular prion protein.
Prion diseases are a group of neurodegenerative disorders in humans and animals that seem to result from a conformational change in the prion protein ( PrP). Utilizing data obtained by circular dichroism and infrared spectroscopy, computational studies predicted the three-dimensional structure of the cellular form of PrP (PrPc). A heuristic approach consisting of the prediction of secondary structures and of an evaluation of the packing of secondary elements was used to search for plausible tertiary structures. After a series of experimental and theoretical constraints were applied, four structural models of four-helix bundles 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 tertiary 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 mutations cluster around a central hydrophobic core in the X-bundle structure. 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 provide a basis for rationalizing mutations of the PrP gene in the inherited prion diseases but also guide design of genetically engineered PrP molecules for further experimental studies.[1]References
- Proposed three-dimensional structure for the cellular prion protein. Huang, Z., Gabriel, J.M., Baldwin, M.A., Fletterick, R.J., Prusiner, S.B., Cohen, F.E. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
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