Cordeiro Yraima, Lima Luís Maurício T R, Gomes Mariana P B, Foguel Débora, Silva Jerson L
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.
J Biol Chem. 2004 Feb 13;279(7):5346-52. doi: 10.1074/jbc.M312262200. Epub 2003 Nov 21.
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.
朊病毒蛋白（PrP）是与被称为传染性海绵状脑病的疾病相关的主要病原体。传染性海绵状脑病的发病与PrP（C）构象的改变有关，PrP（C）失去了大部分α-螺旋结构，变成富含β-折叠的蛋白质，即PrP（Sc）。在这里，我们使用了两个叙利亚仓鼠朊病毒结构域（PrP 109 - 141和PrP 109 - 149）以及小鼠重组PrP（rPrP 23 - 231）来研究苯胺基萘化合物对朊病毒寡聚化和聚集的影响。监测了在双-ANS（4,4'-二苯胺基-1,1'-联萘-5,5'-磺酸盐）、ANS（1-苯胺基萘-8-磺酸盐）和AmNS（1-氨基-5-萘磺酸盐）存在下的聚集情况。双-ANS是朊病毒肽聚集最有效的抑制剂。双-ANS与rPrP 23 - 231强烈结合，导致β-折叠含量大幅增加并有限地寡聚化。更引人注目的是，加入纳摩尔浓度的寡核苷酸会减少双-ANS与全长rPrP的结合，表明它们竞争相同的结合位点。因此，双-ANS表现出与核酸相似的特性，导致寡聚化并转化为β-折叠（科代罗，Y.，马查多，F.，朱利亚诺，L.，朱利亚诺，M. A.，布伦塔尼，R. R.，福盖尔，D.，和席尔瓦，J. L.（2001年）《生物化学杂志》276，49400 - 49409）。双-ANS对朊病毒蛋白的这种双重作用使得该化合物对于隔离蛋白质的关键构象非常重要，这可能有助于理解该疾病并作为开发新治疗策略的先导。
