Abstract
Conversion of prion protein (PrP) to an altered conformer, the scrapie PrP (PrPSc), is a critical step in the development of transmissible spongiform encephalopathies. Both Cu(II) and nucleic acid molecules have been implicated in this conversion. Full-length PrP can bind up to six copper ions; four Cu(II) binding sites are located in the octarepeat domain (residues 60–91), and His-96 and His-111 coordinate two additional copper ions. Experimental evidence shows that PrP binds different molecules, resulting in diverse cellular signaling events. However, there is little information about the interaction of macromolecular ligands with Cu(II)-bound PrP. Both RNA and DNA sequences can bind PrP, and this interaction results in reciprocal conformational changes. Here, we investigated the interaction of Cu(II) and nucleic acids with amyloidogenic non-octarepeat PrP peptide models (comprising human PrP residues 106–126 and hamster PrP residues 109–149) that retain His-111 as the copper-anchoring residue. The effect of Cu(II) and DNA or RNA sequences in the aggregation, conformation, and toxicity of PrP domains was investigated at low and neutral pH. Circular dichroism and EPR spectroscopy data indicate that interaction of the PrP peptides with Cu(II) and DNA occurs at pH 7. This dual interaction induces conformational changes in the peptides, modulating their aggregation, and affecting the morphology of the aggregated species, resulting in different cytotoxic effects. These results provide new insights into the role of Cu(II) and nucleic acid sequences in the structural conversion and aggregation of PrP, which are both critical events related to prion pathogenesis.
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Abbreviations
- CD:
-
Circular dichroism
- dsDNA:
-
Double-stranded DNA
- EPR:
-
Electron paramagnetic resonance
- LS:
-
Light scattering
- MES:
-
2-(N-Morpholino)ethanesulfonic acid
- PBS:
-
Phosphate-buffered saline
- PrP:
-
Prion protein
- PrPC :
-
Cellular prion protein
- PrPSc :
-
Scrapie prion protein
- rPrP:
-
Recombinant prion protein
- TEM:
-
Transmission electron microscopy
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Acknowledgments
The authors thank Icaro A. Marques for help with protein purification, Trinidad Arcos-Lopez and Jose Luis Esquivel for help with PrP109–112 synthesis and initial characterization, and Luis Mauricio T. R. Lima and Lina Rivillas-Acevedo for helpful discussions. We are very grateful to the Laboratório de Ultraestrutura Celular Hertha Meyer (Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro) and the Laboratório de Biologia Estrutural (Instituto Nacional de Metrologia, Rio de Janeiro) for use of the TEM facility. This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico, Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem, Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, and Consejo Nacional de Ciencia y Tecnología (grant 128255 to L.Q. and fellowship to C. S.-L.).
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Chaves, J.A.P., Sanchez-López, C., Gomes, M.P.B. et al. Biophysical and morphological studies on the dual interaction of non-octarepeat prion protein peptides with copper and nucleic acids. J Biol Inorg Chem 19, 839–851 (2014). https://doi.org/10.1007/s00775-014-1115-8
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DOI: https://doi.org/10.1007/s00775-014-1115-8