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.
Huang
Z
Z
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
Gabriel
J M
JM
Baldwin
M A
MA
Fletterick
R J
RJ
Prusiner
S B
SB
Cohen
F E
FE
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
D018620:PrPSc Proteins; D011328:Prions