title: Biophysical and morphological studies on the dual interaction of non-octarepeat prion protein peptides with copper and nucleic acids.
abstract: Conversion of prion protein (PrP) to an altered conformer, the scrapie PrP (PrP(Sc)), 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.
authors.affiliation: Faculdade de Farmácia, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho 373, Bloco B, Subsolo, Sala 17, Rio de Janeiro, RJ, 21941-902, Brazil.
authors.forename: Juliana A P
authors.initials: JA
authors.lastname: Chaves
authors.forename: Carolina
authors.initials: C
authors.lastname: Sanchez-López
authors.forename: Mariana P B
authors.initials: MP
authors.lastname: Gomes
authors.forename: Tháyna
authors.initials: T
authors.lastname: Sisnande
authors.forename: Bruno
authors.initials: B
authors.lastname: Macedo
authors.forename: Vanessa End
authors.initials: VE
authors.lastname: de Oliveira
authors.forename: Carolina A C
authors.initials: CA
authors.lastname: Braga
authors.forename: Luciana P
authors.initials: LP
authors.lastname: Rangel
authors.forename: Jerson L
authors.initials: JL
authors.lastname: Silva
authors.forename: Liliana
authors.initials: L
authors.lastname: Quintanar
authors.forename: Yraima
authors.initials: Y
authors.lastname: Cordeiro
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003300:Copper / Q000737:chemistry*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008667:Metalloproteins / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D009696:Nucleic Acids / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D011328:Prions / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D008667:Metalloproteins; D009696:Nucleic Acids; D010455:Peptides; D011328:Prions; D003300:Copper