title: Proposed three-dimensional structure for the cellular prion protein.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
authors.forename: J M
authors.initials: JM
authors.lastname: Gabriel
authors.forename: M A
authors.initials: MA
authors.lastname: Baldwin
authors.forename: R J
authors.initials: RJ
authors.lastname: Fletterick
authors.forename: S B
authors.initials: SB
authors.lastname: Prusiner
authors.forename: F E
authors.initials: FE
authors.lastname: Cohen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D018620:PrPSc Proteins; D011328:Prions / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013055:Spectrophotometry, Infrared
chemical_list: D018620:PrPSc Proteins; D011328:Prions