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Proposed Three-Dimensional Structure for the Cellular Prion Protein
Ziwei Huang, Jean-Marc Gabriel, Michael A. Baldwin, Robert J. Fletterick, Stanley B. Prusiner and Fred E. Cohen
Proceedings of the National Academy of Sciences of the United States of America
Vol. 91, No. 15 (Jul. 19, 1994), pp. 7139-7143
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/2365235
Page Count: 5
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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.
Proceedings of the National Academy of Sciences of the United States of America © 1994 National Academy of Sciences