NR AFNY
AU Horiuchi,M.; Priola,S.A.; Chabry,J.; Caughey,B.W.
TI Interactions between heterologous forms of prion protein: binding, inhibition of conversion, and species barriers.
QU Proceedings of the National Academy of Sciences of the United States of America 2000 May 23; 97(11): 5836-41
PT journal article
AB The self-induced formation of the disease-associated, protease-resistant prion protein (PrPres) from the normal protease-sensitive isoform (PrP-sen) appears to be a key event in the pathogenesis of transmissible spongiform encephalopathies. The amino acid sequence specificity of PrPres formation correlates with, and may account for, the species specificity in transmission of transmissible spongiform encephalopathy agents in vivo. To analyze the mechanism controlling the sequence specificity of PrPres formation, we compared the binding of PrP-sen to PrPres with its subsequent acquisition of protease resistance by using cell-free systems consisting of heterologous versus homologous mouse and hamster PrP isoforms. Our studies showed that heterologous PrP-sen can bind to PrPres with little conversion to the protease-resistant state and, in doing so, can interfere with the conversion of homologous PrP-sen. The interference occurred with molar ratios of homologous to heterologous PrP-sen molecules as low as 1:1. The interference was due primarily to the inhibition of conversion, but not the binding, of the homologous PrP-sen to PrPres. The results provide evidence that the sequence specificity of PrPres formation in this model is determined more by the conversion to protease resistance than by the initial binding step. These findings also imply that after the initial binding, further intermolecular interactions between PrP-sen and PrPres are required to complete the process of conversion to the protease-resistant state.
MH Amino Acid Sequence; Animal; Biopolymers; Cell-Free System; Comparative Study; Endopeptidases/pharmacology; Glycosylphosphatidylinositols/chemistry; Hamsters; Mesocricetus/*metabolism; Mice/*metabolism; PrPc Proteins/chemistry/*metabolism; PrPsc Proteins/chemistry/*metabolism; Prion Diseases/transmission; Protein Binding; Recombinant Fusion Proteins/chemistry/metabolism; Species Specificity
AD Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
SP englisch
PO USA