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Liquid-liquid phase separation and fibrillation of the prion protein modulated by a high-affinity DNA aptamer.
Matos, Carolina O; Passos, Yulli M; do Amaral, Mariana J; Macedo, Bruno; Tempone, Matheus H; Bezerra, Ohanna C L; Moraes, Milton O; Almeida, Marcius S; Weber, Gerald; Missailidis, Sotiris; Silva, Jerson L; Uversky, Vladimir N; Pinheiro, Anderson S; Cordeiro, Yraima.
Afiliação
  • Matos CO; Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
  • Passos YM; Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
  • do Amaral MJ; Institute of Medical Biochemistry Leopoldo de Meis, National Center for Structural Biology and Bioimaging (CENABIO), Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
  • Macedo B; Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
  • Tempone MH; Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
  • Bezerra OCL; Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.
  • Moraes MO; Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.
  • Almeida MS; Institute of Medical Biochemistry Leopoldo de Meis, National Center for Structural Biology and Bioimaging (CENABIO), Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
  • Weber G; Department of Physics, Federal University of Minas Gerais, Belo Horizonte, Brazil.
  • Missailidis S; Institute of Technology in Immunobiologics (Bio-Manguinhos), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.
  • Silva JL; Institute of Medical Biochemistry Leopoldo de Meis, National Center for Structural Biology and Bioimaging (CENABIO), Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
  • Uversky VN; Department of Molecular Medicine, USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
  • Pinheiro AS; Laboratory of New Methods in Biology, Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Russia.
  • Cordeiro Y; Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
FASEB J ; 34(1): 365-385, 2020 01.
Article em En | MEDLINE | ID: mdl-31914616
Structural conversion of cellular prion protein (PrPC) into scrapie PrP (PrPSc) and subsequent aggregation are key events associated with the onset of transmissible spongiform encephalopathies (TSEs). Experimental evidence supports the role of nucleic acids (NAs) in assisting this conversion. Here, we asked whether PrP undergoes liquid-liquid phase separation (LLPS) and if this process is modulated by NAs. To this end, two 25-mer DNA aptamers, A1 and A2, were selected against the globular domain of recombinant murine PrP (rPrP90-231) using SELEX methodology. Multiparametric structural analysis of these aptamers revealed that A1 adopts a hairpin conformation. Aptamer binding caused partial unfolding of rPrP90-231 and modulated its ability to undergo LLPS and fibrillate. In fact, although free rPrP90-231 phase separated into large droplets, aptamer binding increased the number of droplets but noticeably reduced their size. Strikingly, a modified A1 aptamer that does not adopt a hairpin structure induced formation of amyloid fibrils on the surface of the droplets. We show here that PrP undergoes LLPS, and that the PrP interaction with NAs modulates phase separation and promotes PrP fibrillation in a NA structure and concentration-dependent manner. These results shed new light on the roles of NAs in PrP misfolding and TSEs.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Priônicas / Aptâmeros de Nucleotídeos / Extração Líquido-Líquido / Proteínas Priônicas / Amiloide Limite: Animals Idioma: En Revista: FASEB J Assunto da revista: BIOLOGIA / FISIOLOGIA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Priônicas / Aptâmeros de Nucleotídeos / Extração Líquido-Líquido / Proteínas Priônicas / Amiloide Limite: Animals Idioma: En Revista: FASEB J Assunto da revista: BIOLOGIA / FISIOLOGIA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos