NR AUPB
AU Yin,S.; Yu,S.; Li,C.; Wong,P.; Chang,B.; Xiao,F.; Kang,S.C.; Yan,H.; Xiao,G.; Grassi,J.; Tien,P.; Sy,M.S.
TI Prion proteins with insertion mutations have altered N-terminal conformation and increased ligand binding activity and are more susceptible to oxidative attack
QU The Journal of Biological Chemistry 2006 Apr 21; 281(16): 10698-705
PT journal article
AB We compared the biochemical properties of a wild type recombinant normal human cellular prion protein, rPrPc, with a recombinant mutant human prion protein that has three additional octapeptide repeats, rPrP(8OR). Monoclonal antibodies that are specific for the N terminus of rPrPc react much better with rPrP(8OR) than rPrPc, suggesting that the N terminus of rPrP(8OR) is more exposed and hence more available for antibody binding. The N terminus of PrPc contains a glycosaminoglycan binding motif. Accordingly, rPrP(8OR) also binds more glycosaminoglycan than rPrPc. In addition, the divalent cation copper modulates the conformations of rPrPc and rPrP(8OR) differently. When compared with rPrPc, rPrP(8OR) is also more susceptible to oxidative damage. Furthermore, the abnormalities associated with rPrP(8OR) are recapitulated, but even more profoundly, in another insertion mutant, which has five extra octapeptide repeats, rPrP(10OR). Therefore, insertion mutants appear to share common features, and the degree of abnormality is proportional to the number of insertions. Any of these anomalies may contribute to the pathogenesis of inherited human prion disease.
MH Amino Acid Motifs; Antibodies, Monoclonal/chemistry; Calcium/metabolism; Carbon/chemistry; Cations; Copper/chemistry; DNA, Complementary/metabolism; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Epitopes; Glycosaminoglycans/chemistry; Humans; Ligands; Magnetic Resonance Spectroscopy; Models, Genetic; Mutagenesis, Site-Directed; *Mutation; Oxygen/*chemistry/metabolism; Peptides/chemistry; PrPc Proteins/chemistry; Prions/*chemistry/metabolism; Protein Binding; Protein Structure, Tertiary; Recombinant Proteins/chemistry; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.
AD Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44120, USA
SP englisch
PO USA