Inhibition of interactions and interconversions of prion protein isoforms by peptide fragments from the C-terminal folded domain.
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| Abstract |
The formation of protease-resistant prion protein (PrP-res or PrP(Sc)) involves selective interactions between PrP-res and its normal protease-sensitive counterpart, PrP-sen or PrP(C). 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 PrP-res 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 PrP-res 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 PrP-res. 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 PrP-res and PrP-sen and thereby serve as models of potential therapeutic agents for transmissible spongiform encephalopathies.
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| Authors | M Horiuchi, G S Baron, L W Xiong, B Caughey |
| Journal | The Journal of biological chemistry (J Biol Chem) Vol. 276 Issue 18 Pg. 15489-97 (May 04 2001) ISSN: 0021-9258 [Print] United States |
| PMID | 11279046 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Chemical References |
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