NR AFNX
AU Horiuchi,M.; Baron,G.S.; Xiong,L.W.; Caughey,B.W.
TI Inhibition of interactions and interconversions of prion protein isoforms by peptide fragments from the C-terminal folded domain
QU The Journal of Biological Chemistry 2001 May 4; 276(18): 15489-97
PT journal article
AB The formation of protease-resistant prion protein (PrPres or PrPsc) involves selective interactions between PrPres and its normal protease-sensitive counterpart, PrP-sen or PrPc. Previous studies have shown that synthetic peptide fragments of the PrP sequence corresponding to residues 119-136 of hamster PrP (Ha119-136) can selectively block PrPres formation in cell-free systems and scrapie-infected tissue culture cells. Here we show that two other peptides corresponding to residues 166-179 (Ha166-179) and 200-223 (Ha200-223) also potently inhibit the PrPres induced cell-free conversion of PrP-sen to the protease-resistant state. In contrast, Ha121-141, Ha180-199, and Ha218-232 were much less effective as inhibitors. Mechanistic analyses indicated that Ha166-179, Ha200-223, and peptides containing residues 119-136 inhibit primarily by binding to PrP-sen and blocking its binding to PrPres. Circular dichroism analyses indicated that Ha117-141 and Ha200-223, but not non-inhibitory peptides, readily formed high beta-sheet structures when placed under the conditions of the conversion reaction. We conclude that these inhibitory peptides may mimic contact surfaces between PrPres and PrP-sen and thereby serve as models of potential therapeutic agents for transmissible spongiform encephalopathies.
MH Amino Acid Sequence; Animal; Cell-Free System; Circular Dichroism; Hamsters; Molecular Sequence Data; Peptide Fragments/*metabolism; Prions/*antagonists & inhibitors/chemistry/metabolism; Protein Binding; Protein Isoforms/*antagonists & inhibitors/chemistry/metabolism; Protein Structure, Secondary; Support, Non-U.S. Gov't
AD Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, National Institutes of Health, Hamilton, Montana 59840, USA
SP englisch
PO USA