Binding of the protease-sensitive form of PrP (prion protein) to sulfated glycosaminoglycan and congo red [corrected].
Congo red and certain sulfated glycans are potent inhibitors of protease-resistant PrP accumulation in scrapie-infected cells. One hypothesis is that these inhibitors act by blocking the association between protease-resistant PrP and sulfated glycosaminoglycans or proteoglycans (e.g., heparan sulfate proteoglycan) that is observed in amyloid plaques of scrapie-infected brain tissue. Accordingly, we have investigated whether the apparent precursor of protease-resistant PrP, protease-sensitive PrP, binds to Congo red and heparin, a highly sulfated glycosaminoglycan with an inhibitory potency like that of heparan sulfate. Protease-sensitive PrP released from the surface of mouse neuroblastoma cells bound to heparin-agarose and Congo red-glass beads. Sucrose density gradient fractionation provided evidence that at least some of the PrP capable of binding heparin-agarose was monomeric. Free Congo red blocked PrP binding to heparin and vice versa, suggesting that these ligands share a common binding site. The relative efficacies of pentosan polysulfate, Congo red, heparin, and chondroitin sulfate in blocking PrP binding to heparin-agarose corresponded with their previously demonstrated potencies in inhibiting protease-resistant PrP accumulation. These results are consistent with the idea that sulfated glycans and Congo red inhibit protease-resistant PrP accumulation by interfering with the interaction of PrP with an endogenous glycosaminoglycan or proteoglycan.
Caughey
B
B
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute for Allergy and Infectious Diseases, Hamilton, Montana 59840.
Brown
K
K
Raymond
G J
GJ
Katzenstein
G E
GE
Thresher
W
W
D000818:Animals; D003224:Congo Red / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism; D005898:Glass; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate / Q000378:metabolism*; D051379:Mice; D009417:Nerve Tissue / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology; D018620:PrPSc Proteins; D011233:Precipitin Tests; D011328:Prions / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011498:Protein Precursors / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D003224:Congo Red; D010450:Endopeptidases; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D009419:Nerve Tissue Proteins; D010426:Pentosan Sulfuric Polyester; D018620:PrPSc Proteins; D011328:Prions; D011498:Protein Precursors; D011509:Proteoglycans