NR AMSA
AU Wong,C.; Xiong,L.W.; Horiuchi,M.; Raymond,L.D.; Wehrly,K.; Chesebro,B.; Caughey,B.W.
TI Sulfated glycans and elevated temperature stimulate PrPsc-dependent cell-free formation of protease-resistant prion protein
QU EMBO Journal 2001 Feb 1; 20(3): 377-86
PT journal article
AB A conformational conversion of the normal, protease- sensitive prion protein (PrP-sen or PrPc) to a protease-resistant form (PrPres or PrPsc) is commonly thought to be required in transmissible spongiform encephalopathies (TSEs). Endogenous sulfated glycosaminoglycans are associated with PrPres deposits in vivo, suggesting that they may facilitate PrPres formation. On the other hand, certain exogenous sulfated glycans can profoundly inhibit PrPres accumulation and serve as prophylactic anti-TSE compounds in vivo. To investigate the seemingly paradoxical effects of sulfated glycans on PrPres formation, we have assayed their direct effects on PrP conversion under physiologically compatible cell-free conditions. Heparan sulfate and pentosan polysulfate stimulated PrPres formation. Conversion was stimulated further by increased temperature. Both elevated temperature and pentosan polysulfate promoted interspecies PrP conversion. Circular dichroism spectropolarimetry measurements showed that pentosan polysulfate induced a conformational change in PrP-sen that may potentiate its PrPres-induced conversion. These results show that certain sulfated glycosaminoglycans can directly affect the PrP conversion reaction. Therefore, depending upon the circumstances, sulfated glycans may be either cofactors or inhibitors of this apparently pathogenic process.
MH Animal; Cell-Free System; Circular Dichroism; Endopeptidases/metabolism; Hamsters; Heat; In Vitro; Mice; Pentosan Sulfuric Polyester/pharmacology; PrPc Proteins/*chemistry/*metabolism; PrPsc Proteins/*chemistry/*metabolism; Prion Diseases/etiology/metabolism/prevention & control; Protein Conformation/drug effects
AD Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories/NIH, 903 South 4th Street, Hamilton, MT 59840, USA
SP englisch
PO England