DNA converts cellular prion protein into the beta-sheet conformation and inhibits prion peptide aggregation

DNA converts cellular prion protein into the beta-sheet conformation and inhibits prion peptide aggregation

Autor Cordeiro, Y. Google Scholar
Machado, F. Google Scholar
Juliano, Luiz Autor UNIFESP Google Scholar
Juliano, Maria Aparecida Autor UNIFESP Google Scholar
Brentani, R. R. Google Scholar
Foguel, D. Google Scholar
Silva, J. L. Google Scholar
Instituição Universidade Federal do Rio de Janeiro (UFRJ)
Universidade Federal de São Paulo (UNIFESP)
Inst Ludwig Pesquisa Sobre Canc
Resumo The main hypothesis for prion diseases proposes that the cellular protein (PrPc) can be altered into a misfolded, beta-sheet-rich isoform (PrPSc), which in most cases undergoes aggregation. in an organism infected with PrPSc, PrPC is converted into the beta-sheet form, generating more PrPSc. We find that sequence-specific DNA binding to recombinant murine prion protein (mPrP(23-231)) converts it from an alpha-helical conformation (cellular isoform) into a soluble, beta-sheet isoform similar to that found in the fibrillar state. the recombinant murine prion protein and prion domains bind with high affinity to DNA sequences. Several double-stranded DNA sequences in molar excess above 2:1 (pH 4.0) or 0.5:1 (pH 5.0) completely inhibit aggregation of prion peptides, as measured by light scattering, fluorescence, and circular dichroism spectroscopy. However, at a high concentration, fibers (or peptide aggregates) can rescue the peptide bound to the DNA, converting it to the aggregating form. Our results indicate that a macromolecular complex of prion-DNA may act as an intermediate for the formation of the growing fiber. We propose that host nucleic acid may modulate the delicate balance between the cellular and the misfolded conformations by reducing the protein mobility and by making the protein-protein interactions more likely. in our model, the infectious material would act as a seed to rescue the protein bound to nucleic acid. Accordingly, DNA would act on the one hand as a guardian of the Se conformation, preventing its propagation, but on the other hand may catalyze Sc conversion and aggregation if a threshold level is exceeded.
Idioma Inglês
Data 2001-12-28
Publicado em Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 276, n. 52, p. 49400-49409, 2001.
ISSN 0021-9258 (Sherpa/Romeo, fator de impacto)
Editor Amer Soc Biochemistry Molecular Biology Inc
Extensão 49400-49409
Fonte http://dx.doi.org/10.1074/jbc.M106707200
Direito de acesso Acesso aberto Open Access
Tipo Artigo
Web of Science WOS:000173922100101
URI http://repositorio.unifesp.br/handle/11600/26678

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