NR AFQV
AU Huang,Z.; Gabriel,J.M.; Baldwin,M.A.; Fletterick,R.J.; Prusiner,S.B.; Cohen,F.E.
TI Proposed three-dimensional structure for the cellular prion protein
QU Proceedings of the National Academy of Sciences of the United States of America 1994 Jul 19; 91(15): 7139-43
PT journal article
AB 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.
IN Ein auf Messungen von Zirkulardichroismus und mit Infrarotspectroscopie beruhendes Computermodel normaler Prionproteine spricht für eine Struktur mit einem X-Bündel aus 4 Alphahelices. Nach diesem Modell befänden sich 5 von 11 durch fatale Mutationen bekannten Aminosäuren im hydrophoben, für die Interaktion der Alphahelices wichtigen Kernbereich dieses Bündels.
MH Amino Acid Sequence; Animal; Circular Dichroism; Crystallography, X-Ray; Human; Magnetic Resonance Spectroscopy; Molecular Sequence Data; PrPsc Proteins; Prions/*chemistry; Protein Structure, Secondary; Protein Structure, Tertiary; Spectrophotometry, Infrared; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.
AD Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
SP englisch
PO USA
OR Prion-Krankheiten H