Modulation of Prion Protein Oligomerization, Aggregation, and β-sheet Conversion by 4,4′-Dianilino-1,1′-binaphthyl-5,5′sulfonate (bis-ANS)

Abstract

The prion protein (PrP) is the major agent implicated in the diseases known as transmissible spongiform encephalopathies. The onset of transmissible spongiform encephalopathy is related to a change in conformation of the PrP c, which loses most of its α-helical content, becoming a β-sheet-rich protein, known as PrPSc. Here we have used two Syrian hamster prion domains (PrP 109-141 and PrP 109-149) and the murine recombinant PrP (rPrP 23-231) to investigate the effects of anilino-naphtalene compounds on prion oligomerization and aggregation. Aggregation in the presence of bis-ANS (4,4′-dianilino-1,1′binaphthyl-5,5′-sulfonate), ANS (1-anilinonaphthalene-8-sulfonate), and AmNS (1-amino-5-naphtalenesulfonate) was monitored. Bis-ANS was the most effective inhibitor of prion peptide aggregation. Bis-ANS binds strongly to rPrP 23-231 leading to a substantial increase in β-sheet content and to limited oligomerization. More strikingly, the binding of bis-ANS to full-length rPrP is diminished by the addition of nanomolar concentrations of oligonucleotides, demonstrating that they compete for the same binding site. Thus, bis-ANS displays properties similar to those of nucleic acids, causing oligomerization and conversion to β-sheet (Cordeiro, Y., Machado, F., Juliano, L., Juliano, M. A., Brentani, R. R., Foguel, D., and Silva, J. L. (2001) J. Biol. Chem. 276, 49400-49409). This dual effect of bis-ANS on prion protein makes this compound highly important to sequester crucial conformations of the protein, which may be useful to the understanding of the disease and to serve as a lead for the development of new therapeutic strategies.