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

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dc.contributor.authorCordeiro, Y.
dc.contributor.authorMachado, F.
dc.contributor.authorJuliano, Luiz [UNIFESP]
dc.contributor.authorJuliano, Maria Aparecida [UNIFESP]
dc.contributor.authorBrentani, R. R.
dc.contributor.authorFoguel, D.
dc.contributor.authorSilva, J. L.
dc.contributor.institutionUniversidade Federal do Rio de Janeiro (UFRJ)
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionInst Ludwig Pesquisa Sobre Canc
dc.date.accessioned2016-01-24T12:33:09Z
dc.date.available2016-01-24T12:33:09Z
dc.date.issued2001-12-28
dc.description.abstractThe 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.en
dc.description.affiliationUniv Fed Rio de Janeiro, Programa Biol Estruct, Dept Bioquim Med, Inst Ciencias Biomed, BR-21941590 Rio de Janeiro, Brazil
dc.description.affiliationUniv Fed Rio de Janeiro, Ctr Nacl Ressonancia Magnet Nucl Macromol, BR-21941590 Rio de Janeiro, Brazil
dc.description.affiliationUniv Fed Estado São Paulo, Dept Biofis, BR-04023900 São Paulo, Brazil
dc.description.affiliationInst Ludwig Pesquisa Sobre Canc, BR-01509010 São Paulo, Brazil
dc.description.affiliationUnifespUniv Fed Estado São Paulo, Dept Biofis, BR-04023900 São Paulo, Brazil
dc.description.sourceWeb of Science
dc.format.extent49400-49409
dc.identifierhttp://dx.doi.org/10.1074/jbc.M106707200
dc.identifier.citationJournal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 276, n. 52, p. 49400-49409, 2001.
dc.identifier.doi10.1047/jbc.M106707200
dc.identifier.issn0021-9258
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/26678
dc.identifier.wosWOS:000173922100101
dc.language.isoeng
dc.publisherAmer Soc Biochemistry Molecular Biology Inc
dc.relation.ispartofJournal of Biological Chemistry
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleDNA converts cellular prion protein into the beta-sheet conformation and inhibits prion peptide aggregationen
dc.typeinfo:eu-repo/semantics/article
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