Modulation of prion protein oligomerization, aggregation, and beta-sheet conversion by 4,4'-dianilino-1,1'-binaphthyl-5,5'-sulfonate (bis-ANS).
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 alpha-helical content, becoming a beta-sheet-rich protein, known as PrP(Sc). 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 beta-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 beta-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.
Cordeiro
Yraima
Y
Departamento de Bioquímica Médica, Centro Nacional de Ressonância Magnética Nuclear de Macromoléculas, Departamento de Bioquímica Médica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-590, Brazil.
Lima
Luís Maurício T R
LM
Gomes
Mariana P B
MP
Foguel
Débora
D
Silva
Jerson L
JL
D000817:Anilino Naphthalenesulfonates / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002942:Circular Dichroism; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008027:Light; D008647:Mesocricetus; D008956:Models, Chemical; D009841:Oligonucleotides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012542:Scattering, Radiation; D013050:Spectrometry, Fluorescence; D013053:Spectrophotometry; D013997:Time Factors; D014466:Ultraviolet Rays; D014508:Urea / Q000494:pharmacology
D000817:Anilino Naphthalenesulfonates; D009841:Oligonucleotides; D010455:Peptides; D011328:Prions; C035763:5,5'-bis(8-(phenylamino)-1-naphthalenesulfonate); D014508:Urea